Spotlight on Perimenopause and Menopause: What Pharmacy Teams Should Know

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

Awareness about menopause is growing. It is now common to see menopause information on social media platforms and national news outlets. Menopause, sometimes referred to as “the change of life,” is a natural part of biological aging in women. Every woman who lives long enough will experience menopause, but its arrival affects some women physically, mentally, and emotionally. Menopausal hormone replacement therapy (HRT) is an option for treatment of certain symptoms, but it comes with risks. The U.S. Food and Drug Administration (FDA) has specific approved indications for HRT and various organizations such as the United States Preventive Task Force and the Menopause Society have issued their positions and recommendations for its use. Non-hormonal therapies are available, and lifestyle modifications may also help offset some health risks that are associated with this stage in a woman’s life.

INTRODUCTION

Menopause is a natural part of biological aging in women. This phenomenon marks the end of reproductive years, and every woman who lives long enough will experience it.¹ Often beginning in perimenopause—the period of time leading up to menopause—women experience many symptoms and health risks.^1,2

Approximately 1.3 million women in the United States (U.S.) enter menopause every year.³ Despite being a natural result of aging, menopause has historically been shrouded in secrecy and seldom openly discussed, but the New York Times reports that high profile women and female celebrities alike are now openly discussing their experience with menopause. It also reports that the market is being flooded with menopause-related beauty products and telemedicine start-ups.⁴

With increased interest, a growing movement to increase awareness, and information flooding the Internet, it is important now more than ever for women to receive accurate information from healthcare providers and reputable sources. However, a recent survey revealed that nationally, most obstetrics and gynecology residency programs lack a dedicated menopause curriculum. Most program directors also agreed that their programs needed more menopause education resources.⁵

Many symptoms and health risks of menopause, if left unmanaged, have an impact on a woman’s quality of life, productivity, and emotional state. Women are living longer, and a woman may live many years after menopause. Globally, a woman aged 60 years in 2019 could expect to live on average another 21 years.¹

Years after the National Institutes of Health's (NIHs) Women's Health Initiative, HRT as an option for certain symptoms in postmenopausal women is back in the spotlight. Now, physicians take a nuanced approach to HRT, considering certain individual patient factors.^6,7

It is important for women to recognize symptoms, understand the risk of chronic conditions, and generally educate themselves about the menopause transition. Being well-informed about the menopause transition means women can be proactive and lead healthier lifestyles to counter the issues that may arise with menopause such as bone loss and cardiovascular disease. Proper management during this period results in healthy aging and better quality of life. Menopause is a universal female experience, and it is vital that both physicians and women alike be appropriately informed about it.

PAUSE AND PONDER: What do you wish you knew about menopause before you or a loved one began the menopause transition?

DEFINING MENOPAUSE AND ITS EFFECTS

Perimenopause is the period leading up to menopause and signals the final years of a woman’s reproductive life. This period can last several years, the average being four years.² It begins with irregular menstrual cycles marked by a gradual loss of ovarian follicular function (i.e., ovaries begin to stop releasing eggs for fertilization) and a decline in circulating estrogen and progesterone levels.^1,2 This period may usher in a slew of symptoms, and the hormonal changes and fluctuations are often responsible for them.²A woman can still get pregnant during perimenopause because although menstruation is irregular, the ovaries can still release eggs for fertilization. It is impossible to accurately predict ovulation, and women must use adequate birth control until one full year after the last period to avoid unwanted pregnancy.²

Menopause marks the end of the reproductive years for women.^1,2 Menopause occurs or is diagnosed after 12 consecutive months without menstruation in the absence of clinical intervention or other physiologic or pathologic cause.¹ This means that a woman could go 11 months with no menstruation and then have a period in the 12^th month. The clock would then begin all over again. A woman cannot become naturally pregnant after menopause because the ovaries have stopped releasing eggs for fertilization. Importantly, they can still contract sexually transmitted diseases, so experts advise women to use adequate protective measures.²

The average age of menopause in the U.S. is 52.² Genetics, lifestyle, and environmental factors influence the age at menopause and the timing of symptoms throughout the menopausal transition. According to the World Health Organization, for women worldwide, natural menopause generally occurs between age 45 and 55.¹ The SIDEBAR lists factors that trigger early menopause.

SIDEBAR: Factors That Trigger an Early Onset of Menopause^1,2

Surgical procedures that involve removing both ovaries
Medical interventions that cause termination of ovarian function, such as radiation therapy and chemotherapy
Premature menopause, or menopause before age 40 due to chromosomal abnormalities, autoimmune disorders, or other unknown causes

Menopausal Hormone Changes

Years before menopause occurs, ovarian function begins to fluctuate.² This is a progressive process often responsible for many of the symptoms women experience during this period.

How this Happens

Ovaries are the primary estrogen source in a woman’s body, with follicles synthesizing and releasing the hormone. An ovary has the greatest number of oocytes (about 1 to 2 million) at birth. Oocytes are the immature cells within a follicle that potentially mature into fully developed eggs. A fully developed egg is released from the ovary during ovulation and travels down the fallopian tube to be potentially fertilized.^8,9

As women age, the number of follicles in their ovaries decrease. During a physiological process known as atresia, ovarian follicles that contain oocytes degenerate and die. This is a normal process that happens in all women. The process ensures that only healthy follicles with oocytes mature and ovulate. During atresia, follicle cells die, eggs break down, and macrophages and other follicular cells resorb the follicle contents. Although ovulation will also decrease the number of follicles, the vast number of follicles are decreased through atresia. At some point the number of follicles and oocytes reach critically low levels in the ovaries. Since these are responsible for producing estrogen, this is when women begin to experience symptoms associated with estrogen depletion.^8,9

At various stages during the menopause transition, women may only have a few hundred to a few thousand oocytes left. Estrogen levels decrease and menstrual periods become irregular. As various tissues in the body have estrogen receptors, when estrogen levels decrease or fluctuate, several systems can develop and women experience many of the symptoms of perimenopause and menopause.^8,9

Progesterone levels also decrease during the menopausal transition. After ovulation releases the egg from the follicle, the leftover contents of the empty follicle form the corpus luteum, a temporary gland that produces progesterone.¹⁰ Progesterone thickens the endometrium (lining of the uterus) for a fertilized egg to implant and grow. If pregnancy occurs, the placenta takes over the production of progesterone. In the absence of pregnancy, progesterone levels drop, causing the endometrium to shed (causing menstruation). During the menopause transition, the ovaries no longer produce high levels of estrogen and progesterone in the absence of regular ovulation.¹⁰

Symptoms of Menopause

Hormonal changes and fluctuations lead to the many symptoms associated with perimenopause and menopause, some more common than others and affecting each woman differently, with varying degrees of severity. Vasomotor symptoms (VMS) like hot flashes are the most recognized and reported symptom of menopause.¹¹Table 1 describes the symptoms a woman may experience during and after the menopause transition listed in the order in which they typically occur. For less common symptoms of menopause, see the SIDEBAR. Some women may be able to tolerate menopausal symptoms with lifestyle changes alone, while others may require hormonal remedies, non-hormonal remedies, or a combination of both.¹¹

Table 1. Signs and Symptoms of Perimenopause and Menopause^2,12-15

Symptom	Description
Irregular periods	Starts the menopause transition Unpredictable ovulation causes changes in menstrual cycle patterns Could be months of missed periods, varying lengths of time between cycles (longer or shorter), and menstrual flow changes
Vasomotor Symptoms ( hot flashes, night sweats)	This is a sudden feeling of heat in the face, neck, and chest that is often accompanied by flushing, perspiration, and acute feelings of physical discomfort. May be followed by cold shivering. This may last up to several minutes. Night sweats are hot flashes that cause sweating during sleep. Vasomotor symptoms can occur before, during, and after menopause.
Genitourinary symptoms	Symptoms include dysuria, urinary incontinence, increased urinary frequency, vaginal and cervical atrophy (thinning, drying, and inflammation of the vaginal walls), sexual dysfunction, and decreased libido. Vaginal dryness presents an increased risk for sexually transmitted diseases.
Weight gain	While weight gain occurs in both men and women with aging, a particular increased deposition of visceral and subcutaneous adipose tissue to the abdomen in women during the menopause transition occurs. For weight gain before menopause, estrogen makes it possible for subcutaneous adipose tissue to deposit in the gluteal and femoral regions. After menopause this deposition moves to the abdominal region due to the decrease in estrogen levels. Abdominal fat distribution carries the risk of cardiovascular and metabolic diseases.
Sleep disruption	Sleep duration changes with advancing age, however during the menopause transition, concurrent changes in women’s reproductive hormone levels influence sleep duration and quality. It may be harder to fall asleep and stay asleep. Night sweats may also disrupt sleep.
Mood changes depression, anxiety	Estrogen receptors are in the brain including areas involved in mood regulation. Stress, work, and family responsibilities affect mood during this period. Although the exact mechanism is unknown, mood symptoms may additionally be related to fluctuating estrogen levels. Some women may feel irritable or have crying spells. Depression and anxiety may be caused by fluctuating hormones, menopausal symptoms, or both.

SIDEBAR: Less Common Symptoms of Menopause¹⁶

Experts are continually learning about menopause’s symptoms. Gradual estrogen loss may be responsible for these less common symptoms of menopause:

Dry eye syndrome and vision changes
Easier bruising due collagen changes in the skin
Return of acne
Joint pain and stiffness
Growing rogue hairs on chin or cheeks

The menopause transition can cause a wide variety of symptoms, but other serious conditions can cause these too. It is always important to consult a provider to rule these out.

PAUSE AND PONDER: How many symptoms of perimenopause and menopause can you name aside from hot flashes?

Chronic Conditions and Long-Term Consequences

Long term complications of menopause are related to low estrogen levels. Two major complications of concern are cardiovascular disease and osteoporosis.

Declining estrogen in menopause increases the risk of cardiovascular disease.² Coronary heart disease rates are two to three times higher in those who have reached menopause than those at the same age who have not. Women generally have a lower risk of heart disease than men before the age of 55, but after menopause, women reach the same level of risk for heart disease as men of the same age.²

Estrogen deficiency during menopause also causes the typical bone loss or decreased bone density seen in osteoporosis.²Up to 20% of bone loss can happen during this period.¹⁷ The consequences of osteoporosis are an increased risk of fractures, pain, mobility issues, and loss of height. Osteoporosis, a progressive condition, can worsen over time.

Menopause symptoms also adversely affect women in the workplace. Middle aged women contribute greatly to the global workforce and could potentially face increased health care costs and lost opportunities for career advancement. Mayo Clinic conducted a study to determine the estimated economic impact of menopause symptoms based on missed days from work; hours cut back at work; and quitting, retiring, or changing jobs. Based on missed workdays alone, these researchers estimated an annual loss of $1.8 billion in the U.S. due to menopause-related symptoms.¹⁸

MENOPAUSAL HORMONE REPLACEMENT THERAPY

The Ongoing Debate of HRT

Experts have debated menopausal HRT use for decades. Studies in the mid-1970s showed that women who used estrogen alone had an increased risk of endometrial cancer.^19,20 Researchers found that adding progesterone to estrogen provided protection against uterine cancer. Since then, progesterone is added to hormone treatment for women who have an intact uterus.^7,19,20

Between 1993 and 1998, the NIH began The Women’s Health Initiative, to study strategies to prevent and control some of the most common causes of morbidity and mortality in postmenopausal women (e.g., cardiovascular disease, osteoporosis, cancer).²¹ Researchers randomized more than 27,000 postmenopausal women aged 50 to 79 in the HRT portion of the trial. Those with a uterus (n = 16,608) received either combined conjugated equine estrogen (CEE 0.625 mg/day) plus medroxyprogesterone acetate (MPA 2.5 mg/day) or placebo. Women without a uterus (i.e., prior hysterectomies) were assigned to CEE alone or placebo.^22,23 The primary outcome was coronary heart disease incidence, and the primary safety outcome was invasive breast cancer incidence. To summarize overall effects, researchers also looked at other risks and benefits of HRT in addition to the primary outcomes. These included colorectal cancer, hip fracture, and cardiovascular risks.^22,23

After about five years, results began to show that the risks of HRT outweighed the benefits. HRT was associated with an increased risk of stroke, heart disease, and breast cancer. However, the results also indicated a reduction in osteoporotic fractures and colorectal cancers but no significant cardiovascular benefits. Ultimately, the research team stopped the trial early. Many physicians stopped prescribing HRT, and many women abandoned it altogether.^6,7

Despite stopping the trial, researchers continued to follow up with trial participants until 2010.^24,25 They reanalyzed the data based on results from the intervention, post-intervention, and follow-up phases with consideration for the trial participants’ ages. Researchers concluded that the trial findings do not support HRT for chronic disease prevention. They have since noted that HRT may be beneficial for bothersome symptoms among women in early menopause (i.e., women 50 to 59 years of age) or within 10 years of menopause onset. Data do not support HRT for chronic disease prevention in this subset either. These women must have no contraindications and must be interested in taking HRT.^24,25

Extensive debate continues, but several groups such as the U.S. Preventive Service Task Force (USPSTF) and the Menopause Society, have published position statements and recommendations for HRT use. The USPSTF is an independent panel of experts in disease prevention and evidence-based medicine that makes recommendations about clinical preventive services. The Menopause Society, formerly known as the North American Menopause Society, is a non-profit organization dedicated to improving women’s health during menopause and beyond, by providing resources for both healthcare professionals and the public.

Several organizations have issued recommendations on HRT use in postmenopausal individuals, particularly regarding its benefits, risks, and approved indications. While the general consensus is that HRT is the most effective treatment for VMS and genitourinary syndrome of menopause, its role in preventing chronic conditions such as osteoporosis remains controversial. The U.S. Food and Drug Administration (FDA) and the Menopause Society support HRT for VMS, genitourinary symptom management, and osteoporosis prevention in appropriate candidates, especially women younger than age 60 or within 10 years of menopause onset. In contrast, USPSTF recommends against using HRT solely for the primary prevention of chronic conditions in asymptomatic individuals. Recommendations emphasize shared decision-making and individual risk assessment.^26-28

Forms of Hormone Therapy

Menopausal HRT involves the administration of synthetic estrogen and progesterone to replace a woman’s hormone levels to help alleviate symptoms. Women should be educated on the risks and benefits of HRT, consider their personal risk, and be willing to take HRT, before starting treatment.^26-28

The current recommendations are for postmenopausal women younger than 60 years or who are within 10 years of menopause onset and have no contraindications. These women must also be willing to take HRT.^26-28 HRT use is not recommended in women after the age of 60, or in those who are 10 years post menopause. The FDA has approved HRT for postmenopausal VMS, urogenital symptoms, and osteoporosis prevention.

HRT may be given as estrogen alone, progestin alone, or a combination estrogen and progestin. The FDA has approved several formulations, including oral, topical, transdermal, and injectable dosage forms.²⁹ Table 2 lists FDA-approved HRT products.

Women with an intact uterus with no other contraindications or risks who are willing to take HRT for menopause may receive estrogen in combination with progesterone. Estrogen therapy alone causes the endometrial lining to grow unopposed. Adding progesterone to the regimen prevents this abnormal growth and thus reduces risk of malignancy.^19,20

Women with no other contraindications or risks who have had a hysterectomy and are willing to take HRT may receive estrogen therapy alone. In such cases, progesterone is unnecessary.^19,20

Table 2. FDA-Approved Hormone Replacement Therapies²⁹

Generic Name	How Supplied	Brand Name(s)
Estrogen-Only
Conjugated estrogens	Oral	Premarin
	Vaginal cream	Premarin
	Injection	Premarin
Estradiol	Gel	Divigel, Elestrin, Estrogel
	Transdermal patch	Alora, Climara, Menostar*, Minivelle, Vivelle, Vivelle-Dot
	Transdermal skin spray	Evamist
	Vaginal cream	Estrace
	Vaginal ring	Estring
	Vaginal tablet	Vagifem
Estradiol acetate	Vaginal ring	Femring
Estradiol acetate	Vaginal ring	Femring
Estradiol valerate	Injection	Delestrogen
Estropipate	Oral	Ogen
Progestin-Only
Medroxyprogesterone acetate	Oral	Provera
Micronized progesterone	Oral	Prometrium
Combination Therapies
Conjugated estrogen/ bazedoxifene**	Oral	Duavee
Conjugated estrogen/ medroxyprogesterone	Oral	Prempro
Estradiol/drospirenone	Oral	Angeliq
Estradiol/levonorgestrel	Transdermal patch	Climara Pro
Estradiol/norethindrone acetate	Oral	Activella
Estradiol/norethindrone acetate	Transdermal patch	Combipatch
Norethindrone acetate/ethinyl estradiol	Oral	Femhrt

*Menostar is for osteoporosis prevention only. **Bazedoxifene is not a hormonal therapy.

Due to the known risks of menopausal HRT use, all patients need a thorough evaluation—including a detailed medical history and physical examination—for a proper diagnosis and to identify potential contraindications. Providers and patients must also assess whether the benefits outweigh the risks on an individualized basis. Women should use HRT at the lowest possible dose and for the shortest possible duration to achieve symptomatic relief while avoiding adverse effects.³⁰

Women should not take HRT if they have²⁹

problems with vaginal bleeding
current or past cancers, such as breast cancer or uterine cancer
current or past blood clot, stroke, or heart attack
bleeding disorders
liver disease
allergy to hormone medicine

NON-HORMONAL THERAPIES FOR MENOPAUSE

Risks of menopausal HRT outweigh its benefits for many patients, so additional options are needed. The FDA has approved a few non-hormonal options for women who are ineligible for or uninterested in HRT, and others many opt to use off-label or complementary and alternative medicines.²⁶

FDA-Approved Therapies

Fezolinetant

The FDA recently approved an oral medication fezolinetant (Veozah) for the treatment of moderate to severe VMS caused by menopause. Fezolinetant is a neurokinin-3 (NK3) receptor antagonist that binds to and blocks the activities of the neurokinin-3 receptor, which plays a role in the brain’s regulation of body temperature.³¹

Fezolinetant is supplied as a 45 mg tablet, taken once daily with or without food. It has been associated with a risk of elevated hepatic transaminases, leading the FDA to add a Boxed Warning about the risk of liver injury more than a year after initial approval.³² Blood work to check for liver damage is required before fezolinetant use and every three months for the first nine months after initiation of therapy.³¹

Adverse effects of fezolinetant include abdominal pain, diarrhea, insomnia, back pain, hot flush, and elevated hepatic transaminases. Symptoms relating to liver damage to watch for include nausea, vomiting, and yellowing of the skin and eyes. Patients experiencing these must consult their prescriber immediately. Fezolinetant is contraindicated in patients with cirrhosis, severe renal damage, or end-stage renal disease.³¹

Paroxetine

Paroxetine (Brisdelle) is a selective serotonin reuptake inhibitor (SSRI) FDA-approved for the treatment of moderate to severe VMS. It is not an estrogen and its mechanism of action for the treatment of VMS is unknown.³³ The recommended dose is one 7.5 mg capsule daily at bedtime with or without food. This medication contains a lower dose of paroxetine than those used for other indications (e.g., depression, obsessive compulsive disorder) and is not approved for any psychiatric conditions.

Paroxetine’s common adverse effects include headache, fatigue, and nausea and vomiting. Paroxetine has a Boxed Warning for the potential of increased risk of suicidal thoughts and behaviors, and serotonin syndrome. The FDA warns prescribers to monitor for worsening and emergence of these severe symptoms. Contraindications include concomitant use or within 14 days of monoamine oxidase inhibitors, use with thioridazine or pimozide, hypersensitivity to any ingredient, and pregnancy. VMS do not occur during pregnancy and paroxetine may cause fetal harm.³³

Selective Estrogen Receptor Modulators

Raloxifene and ospemifene are selective estrogen receptor modulators (SERMs) FDA-approved for varying uses during menopause. Bazedoxifene is another FDA-approved SERM, which is found only in a combination tablet with conjugated estrogens.

Raloxifene (Evista) is SERM indicated for treatment and prevention of osteoporosis in post-menopausal women.³⁴ Patients take one 60 mg tablet once daily. Common adverse effects include hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, and sweating.³⁴Raloxifene is contraindicated in women with active or history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. It is also contraindicated for use in pregnancy, as it may cause fetal harm.³⁴ The FDA’s Boxed Warning cautions of an increased risk of venous thromboembolism and death from stroke. Providers must consider the risk-benefit balance in women at risk for stroke. Concomitant use is not recommended or caution should be used when raloxifene is taken with cholestyramine, warfarin, and other highly protein-bound drugs (e.g., diazepam, diazoxide, lidocaine).³⁴

Ospemifene (Osphena) is a SERM indicated for the treatment of moderate to severe vaginal dryness and dyspareunia due to menopause.³⁵ Patients take one 60 mg oral tablet once daily with food. Ospemifene acts just like estrogen in some parts of the body but not in others.³⁵ It has estrogen agonistic effects on the endometrium, which has led the FDA to add a Boxed Warning of a risk of endometrial cancer. With its estrogen agonist/antagonist profile, the FDA has another Boxed Warning of an increased risk of cardiovascular disorders (stroke, coronary heart disease, venous thromboembolism).³⁵ Ospemifene should be used for the shortest duration consistent with treatment goals and risks for the individual woman.³⁵ Common adverse effects include hot flush, vaginal discharge, muscle spasms, headache, hyperhidrosis, vaginal hemorrhage, and night sweats. Contraindications to ospemifene use include³⁵

undiagnosed abnormal genital bleeding
estrogen-dependent neoplasia
hypersensitivity to ospemifene
active or history of deep vein thrombosis or pulmonary embolism
active or history of arterial thromboembolic disease (e.g., stroke, myocardial infarction)

Women taking ospemifene should not take estrogen or estrogen agonist/antagonists, fluconazole, or rifampin concomitantly.³⁵

Bazedoxifene is a SERM available in combination with conjugated estrogens (Dauvee) indicated for the treatment of moderate to severe VMS and postmenopausal osteoporosis prevention in women with a uterus. Bazedoxefine acts as an estrogen agonist in some estrogen-sensitive tissues and as an antagonist in others (e.g., the uterus). The pairing of conjugated estrogens with bazedoxifene produces a composite effect that is specific to each target tissue. The bazedoxifene component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component. Patients take one tablet (conjugated estrogens/bazedoxifene 0.45 mg/20 mg)daily with or without food for both indications.³⁶

Women taking conjugated estrogens/bazedoxifene should add supplemental calcium and/or vitamin D to their diets if intake is inadequate.

Contraindications to conjugated estrogens/bazedoxifene include³⁶

Undiagnosed abnormal uterine bleeding
Known, suspected, or a history of breast cancer
Known or suspected estrogen-dependent neoplasia
Active or history of deep vein thrombosis and pulmonary embolism
Active or history of arterial thromboembolic disease (stroke, myocardial infarction)
Known hepatic impairment or disease
Hypersensitivity to estrogens, bazedoxifene or any ingredients
Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders
Pregnancy

Women taking conjugated estrogens/bazedoxifene should not take progestins, additional estrogens, or additional estrogen agonists/antagonists.

Adverse reactions include a risk for malignant neoplasms (endometrial cancer, breast cancer, ovarian cancer), cardiovascular disorders (stroke, coronary heart disease, venous thromboembolism), gallbladder disease and hypertriglyceridemia.³⁶

Off-Label Therapies

In 2023, The Menopause Society conducted an evidence-based review of the most current and available literature to determine whether to recommend some management options for menopause associated VMS. They recommended some SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentin.³⁷

Researchers have found in large randomized, double-blind, placebo-controlled trials that paroxetine, citalopram, escitalopram, venlafaxine, desvenlafaxine, and duloxetine reduce hot flashes by 24% to 69%. These medications are also first-line therapies for mood disorders such as depression and anxiety. For women with new onset or worsening mood disorders, which are common in menopause, these medications may be beneficial.^38,37 Common adverse effects associated with use of SSRIs and SNRIs include nausea, weight gain, gastrointestinal disorders, headache, and sexual dysfunction. Lower doses are generally used for VMS rather than the higher doses used for mood disorders.³⁸

In very small randomized double-blind, placebo-controlled trials, gabapentin was effective at reducing hot flash frequency by 45% to 51% compared to placebo.^39,40 It was also shown to be a well-tolerated treatment for hot flashes.⁴⁰ Gabapentin is also used as treatment for neuropathic pain and epilepsy and may help with sleep when taken at bedtime. Adverse effects include dizziness and coordination difficulties, weight gain, edema, and lethargy. Patients should use the lowest effective dose to minimize these negative adverse effects.³⁸

Complementary and Alternative Medicine

Some complementary and alternative medicines (CAMs) make claims about easing menopausal symptoms. Complementary health approaches to menopause may include any or all of the following⁴¹:

nutritional (e.g., dietary supplements, special diets)
psychological (e.g., meditation, hypnosis, relaxation therapies)
physical (e.g., massage therapy, acupuncture)
combination approaches (e.g., yoga, tai chi [physical and psychological])

CAMs are not regulated the same way as FDA-approved medications. Although some dietary supplements have been studied for menopause symptoms, none have been shown to be clearly helpful. Little information is available on long term safety of dietary supplements for menopause and some supplements may have harmful adverse effects or drug interactions.

In 2023, the Menopause Society released its position statement on non-hormonal approaches for menopause-related VMS based on an evidence-based review of current literature.³⁷ For CAM, it recommended cognitive behavioral therapy and clinical hypnosis as options for the treatment of VMS. The Menopause Society did not recommend yoga, acupuncture, or any natural products for VMS.³⁷

According to the NIH’s National Center for Complementary and Integrative Health, the evidence has not clearly shown that phytoestrogens, herbs, and other dietary supplements; acupuncture; or yoga relieve menopause symptoms.⁴¹

Phytoestrogens are substances from plants that have chemical structures similar to those of estrogen. Flaxseed is a phytoestrogen source and the isoflavones found in soy and red clover are also phytoestrogens. Studies on their ability to relieve menopause symptoms have been inconsistent, or no more effective than placebo. Phytoestrogens may be safe for short term use, but their long-term safety has not been established and may not be safe for women who should not take estrogen.⁴¹

Regarding custom-mixed (compounded) bioidentical hormones, the group reports that the evidence does not support claims that they are more effective than conventional HRT. They also warn that compounded bioidentical hormones have not been shown to be safer than other forms of HRT, and that their content may vary from batch to batch.⁴¹

PAUSE AND PONDER: In what ways have you made or supported a loved one in making lifestyle changes to adequately prepare for “the change of life?”

Lifestyle Modification During and After Menopause^,

To stay healthy during and after menopause, lifestyle changes and modifications (illustrated in Figure 1) are beneficial. Lifestyle changes and modifications may make menopausal symptoms bearable even if symptoms are not completely eliminated. Lifestyle changes may also help prevent the chronic conditions of menopause such as cardiovascular disease, osteoporosis, and insulin resistance. It may also help with mood and sleep and help prepare a woman for healthy aging.⁴²

Figure 1. Lifestyle Modifications for During and After Menopause⁴³

At least 30 minutes of physical activity on most days of the week helps women maintain a healthy weight and is good for the bones, heart, and mood. Women should aim for a mix of moderate and vigorous aerobic activities and exercises that build muscle strength, such as weight-bearing exercises.^42,44 Women should obtain advice from their healthcare provider before beginning any physical activity.

Eating a healthy diet can help counter some of the symptoms women experience in the menopause transition and prevent chronic illnesses and certain cancers. Essential nutrients to focus on in menopause include vitamins B, C, D, calcium, and protein for energy. A healthy diet also helps with the maintenance of a healthy weight, which improves cholesterol levels, reduces the risk for diabetes, improves blood pressure, and improves daily function.^42,44

Good sleep is essential for health and emotional well-being. Insufficient sleep duration and quality may be a problem during this period in a woman’s life. Hot flashes and night sweats are also disruptive to sleep. Getting enough sleep lowers the risks for chronic conditions such as high blood pressure, diabetes, and heart disease. It also improves attention and memory. Regular exercise, a healthy diet, avoiding caffeine and alcohol before bedtime, and going to bed and getting up at the same time each day can improve sleep.⁴⁴

Cognitive function at midlife appears to be influenced by the stage of menopause and menopausal symptoms such as sleep difficulties and mood changes. Many life stressors cannot be altered, but coping skills and strategies are beneficial to maintain a balance between self-nurturing and the obligations of work and caring for others. To improve and maintain cognition and mood, women should consider maintaining a social network, remaining physically and mentally active, and following a healthy diet.⁴⁴ Maintaining quality social contacts is beneficial during this period. Actively engaging with friends, family, and the community in positive ways helps improve health and emotional wellbeing.

Smoking is damaging to health in many ways. It causes heart disease, reduces bone density, and causes many forms of cancer. Experts advise women to stop smoking and limit alcohol consumption.^42,44

CONCLUSION

Discussions about menopause are no longer taboo. While HRT is beneficial and remains an option for women with no risk factors and contraindications, it is not a one-size fits all solution. HRT comes with risks and providers must assess patients carefully before treatment initiation and consider patient preferences. Non-hormonal therapies are available for women who may be unable or unwilling to take HRT. Women are living longer, and a woman may live for several years post-menopause. Lifestyle changes and modifications help counter the chronic conditions that often arise post-menopause and are important and necessary for healthy aging in women.

Spotlight on Perimenopause and Menopause: What Pharmacy Teams Should Know
Pharmacist Post-test 25-051

After completing this continuing education activity, pharmacists will be able to
• DIFFERENTIATE between perimenopause and menopause
• DISCUSS the age-related loss of estrogen and its relation to symptoms of perimenopause and menopause
• IDENTIFY remedies and lifestyle adjustments for perimenopause and menopause

1. Which of the following is caused by the fluctuating hormone levels of perimenopause?
A. Immediate, permanent cessation of ovulation
B. Early onset menopause
C. Symptoms that signal the transition to menopause

2. AB is a 45-year-old woman who has been on the same birth control for 5 years. She is experiencing occasional night sweats, and she has noticed weight gain particularly in her abdominal region. She has not had a menstrual period in 6 months. What is AB most likely experiencing?
A. Menopause
B. Perimenopause
C. Adverse effects of birth control

3. Women naturally undergo a process where follicles containing oocytes degenerate and die ensuring that only healthy follicles with oocytes mature and ovulate. What is this process known as?
A. Perimenopause
B. Atresia
C. Pregnancy

4. BC is a 48-year-old woman with an intact uterus seeking a remedy for her bothersome vasomotor symptoms. Based on her medical history, labs, and risk assessment, her OBGYN determines she is a candidate for hormone replacement therapy and BC agrees. Which of these regimens is appropriate?
A. Estradiol/norethindrone acetate
B. Conjugated estrogen/bazedoxifene
C. Medroxyprogesterone acetate

5. MD is 48 years old with an intact uterus experiencing bothersome vasomotor symptoms. Her provider determines that she is a candidate for hormone therapy based on her medical history, labs, and a risk assessment. MD is very concerned about the risks associated with hormone therapy. Which of the following is the BEST response?
A. “As long as you use both estrogen and progesterone, the risks are minimal.”
B. “The gabapentin you already take for neuropathic pain should be enough.”
C. “Fezolinetant may be a better option for you, I can contact your doctor.”

6. Experts advise women to make lifestyle modifications for healthy aging after menopause. Which one of these is the BEST recommendation?
A. Isolating from others for peace of mind
B. Drinking one glass of wine nightly for relaxation
C. Improving the diet and incorporating exercise

7. KG is in perimenopause, and although she is still asymptomatic, she expresses concern about the health conditions some women face post-menopause. She requests menopausal hormone replacement therapy to prevent possible cardiovascular disease and Type 2 diabetes. Which of these is the MOST appropriate response?
A. Hormone therapy is not recommended to prevent these chronic conditions
B. It’s a good idea to start hormone therapy early before symptoms arise
C. Her provider should prescribe paroxetine as preventive therapy instead

8. Which of the following is the progressive loss of estrogen during the menopause transition responsible for?
A. Ensuring that only healthy follicles with oocytes mature and ovulate
B. Thickening the endometrial lining to prepare for cessation of menstruation
C. Unpredictable ovulation and changes in menstrual cycle patterns

9. When do women experience vasomotor symptoms?
A. Only during menopause
B. During perimenopause and menopause
C. Only during post-menopause

10. What strategies can women implement to lower the risk for chronic conditions associated with menopause, including heart disease and osteoporosis?
A. Request hormone therapy before they begin the menopause transition
B. Make lifestyle modifications that may help counter some future health risks
C. Do nothing, the risk of menopause complications is not that significant

Spotlight on Perimenopause and Menopause: What Pharmacy Teams Should Know
Pharmacy Technician Post-test 25-051

4. BC is a 48-year-old woman seeking a remedy for her bothersome vasomotor symptoms. She presents a prescription to the pharmacy for fezolinetant 60 mg tablet to be taken once daily. Why should you bring this to the pharmacist’s attention?
A. Fezolinetant is a 45 mg tablet
B. Fezolinetant is a suspension
C. Fezolinetant is not FDA-approved

5. MD is 48 years old and experiencing bothersome vasomotor symptoms. Her provider determines that she is a candidate for hormone therapy based on her medical history, labs, and a risk assessment. MD is very concerned about the risks associated with hormone therapy. Which of the following is a non-hormonal option to consider for MD?
A. Bazedoxifene
B. Estradiol vaginal ring
C. Fezolinetant

7. KG presents a prescription to the pharmacy for paroxetine 20 mg tablets. She mentions that it has been prescribed for her hot flashes. Why should you bring this to the pharmacist’s attention?
A. Paroxetine cannot be prescribed for hot flashes
B. Paroxetine dosing for hot flashes is 7.5 mg daily
C. Paroxetine 20 mg has been discontinued

9. When do women experience vasomotor symptoms?
A. Only during menopause
B. During perimenopause and menopause
C. Only during post-menopause

1. World Health Organization. Menopause. October 16, 2024. Accessed April 10, 2025. https://www.who.int/news-room/fact-sheets/detail/menopause
2. U.S. Department of Health and Human Services. Office on Women’s Health. Menopause Basics. March 17, 2025. Accessed April 10, 2025. https://womenshealth.gov/menopause/menopause-basics
3. Society for women’s health research. Menopause. Accessed July 9, 2025. https://swhr.org/health_focus_area/menopause/
4. Larocca A. Welcome to the menopause gold rush. The New York Times. December 20, 2022. Accessed April 10, 2025. https://www.nytimes.com/2022/12/20/style/menopause-womens-health-goop.html
5. Allen JT, Laks S, Zahler-Miller C, et al. Needs assessment of menopause education in United States obstetrics and gynecology residency training programs. Menopause. 2023;30(10):1002-1005. doi:10.1097/GME.0000000000002234
6. Lobo RA. Hormone-replacement therapy: current thinking. Nat Rev Endocrinol. 2017;13(4):220-231. doi: 10.1038/nrendo.2016.164\
7. Cagnacci A, Venier M. The controversial history of hormone replacement therapy. Medicina (Kaunas). 2019;55(9):602. doi: 10.3390/medicina55090602.
8. Vollenhoven B, Hunt S. Ovarian ageing and the impact on female fertility. F1000Res. 2018;7:F1000 Faculty Rev-1835. doi: 10.12688/f1000research.16509.1
9. Zhou J, Peng X, Mei, S. Autophagy in Ovarian follicular development and Atresia. Int J Biol Sci. 2019;15(4):726-737. doi: 10.7150/ijbs.30369
10. Cleveland Clinic. Progesterone. December 29, 2022. Accessed April 10, 2025. https://my.clevelandclinic.org/health/body/24562-progesterone
11. The Menopause Society. Menopause Topics: Symptoms. Accessed April 10, 2025. https://menopause.org/patient-education/menopause-topics/symptoms
12. National Institute on Aging. What is menopause? October 16, 2024. Accessed April 10, 2025. https://www.nia.nih.gov/health/menopause/what-menopause
13. Knight MG, Anekwe C, Washington K, Akam EY, Wang E, Stanford FC. Weight regulation in menopause. Menopause. 2021;28(8):960-965. doi: 10.1097/GME.0000000000001792
14. Vahratian A. Sleep duration and quality among women aged 40–59, by menopausal status. NCHS data brief, no 286. Hyattsville, MD: National Center for Health Statistics. 2017. Accessed April 10, 2025. https://www.cdc.gov/nchs/data/databriefs/db286.pdf
15. The Menopause Society. Menopause Topics: Mental Health. Accessed April 10, 2025. https://menopause.org/patient-education/menopause-topics/mental-health
16. Mayo Clinic Press. Could this be menopause? Exploring lesser-known symptoms and what to do about them. April 23, 2024. Accessed April 10, 2025. https://mcpress.mayoclinic.org/menopause/could-this-be-menopause-exploring-lesser-known-symptoms-and-what-to-do-about-them/
17. Endocrine Society. Menopause and Bone Loss. January 24, 2022. Accessed July 14, 2025. endocrine.org/patient-engagement/endocrine-library/menopause-and-bone-loss
18. Faubion SS, Enders F, Hedges MS, et al. Impact of Menopause Symptoms on Women in the Workplace. Mayo Clin Proc. 2023;98(6):833-845. doi:10.1016/j.mayocp.2023.02.025
19. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol. 1994;170(5 Pt 1):1213-23. doi: 10.1016/s0002-9378(94)70129-6
20. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med. 1975;293(23):1167-1170. doi:10.1056/NEJM197512042932303
21. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials. 1998;19(1):61-109. doi:10.1016/s0197-2456(97)00078-0
22.Rossouw JE, Anderson GL, Prentice RL, et al; Writing group for the Women's Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. doi: 10.1001/jama.288.3.321
23. Anderson GL, Limacher M, Assaf AR, et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-1712. doi: 10.1001/jama.291.14.1701
24. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368. doi:10.1001/jama.2013.278040
25. Manson JE, Crandall CJ, Rossouw JE, et al. The Women’s Health Initiative randomized trials and clinical practice: A review. JAMA. 2024;331(20):1748–1760. doi:10.1001/jama.2024.6542
26. U.S. Food and Drug Administration. Menopause. December 14, 2023. Accessed April 10, 2025. https://www.fda.gov/consumers/womens-health-topics/menopause
27. The 2022 Hormone Therapy Position Statement of The North American Menopause Society Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi: 10.1097/GME.0000000000002028
28. US Preventive Services Task Force. Hormone therapy for the primary prevention of chronic conditions in postmenopausal persons: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;328(17):1740–1746. doi:10.1001/jama.2022.18625
29. U.S. Food and Drug Administration. Menopause: Medicines to help you. August 22, 2019. Accessed April 10, 2025. https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you
30. U.S. Department of Health and Human Services. Office on Women’s Health. Menopause Treatment. March 11, 2025. Accessed April 10, 2025. https://womenshealth.gov/menopause/menopause-treatment
31. U.S. Food and Drug Administration. FDA approves novel drug to treat moderate to severe hot flashes caused by menopause. May 12, 2023. Accessed April 10, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause
32. U.S. Food and Drug Administration. FDA adds warning about rare occurrence of serious liver injury with the use of Veozah (fezolinetant) for hot flashes due to menopause. September 12, 2024. Accessed April 10, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-warning-about-rare-occurrence-serious-liver-injury-use-veozah-fezolinetant-hot-flashes-due
33. National Institute of Health. National Library of Medicine. DAILYMED. Paroxetine capsule. September 1, 2023. Accessed April 10, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1383d713-79b9-45bd-bd06-65707f28bc99
34. National Institute of Health. National library of medicine DAILYMED. Raloxifene hydrochloride tablet. September 24, 2014. Accessed April 10, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8f4fe353-c5de-44ba-9c68-b75a185f7dc5
35. National Institute of Health. National library of medicine DAILYMED. Osphena. March 16, 2023. Accessed April 10, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8462d6ab-e3cd-4efa-a360-75bf8f917287
36. National Institute of Health. National library of medicine DAILYMED. DUAVEE- conjugated estrogens/bazedoxifene tablet, film coated. January 13, 2025. Accessed July 15, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e16705d8-4472-4f83-96ac-69fa2be066cb
37. “The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society” Advisory Panel. The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause. 2023;30(6):573-590. doi:10.1097/GME.0000000000002200
38. Iyer TK, Fiffick AN, Batur P. Nonhormone therapies for vasomotor symptom management. Cleve Clin J Med. 2024;91(4):237-244. doi:10.3949/ccjm.91a.23067
39. Guttuso T Jr, Kurlan R, McDermott MP, Kieburtz K. Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101(2):337-45. doi: 10.1016/s0029-7844(02)02712-6
40. Butt DA, Lock M, Lewis JE, Ross S, Moineddin R. Gabapentin for the treatment of menopausal hot flashes: a randomized controlled trial. Menopause. 2008;15(2):310-8. doi: 10.1097/gme.0b013e3180dca175
41. National Institutes of Health. National Center for Complementary and Integrative Health. Menopausal symptoms: in-depth. May 2017. Accessed April 25, 2025. https://www.nccih.nih.gov/health/menopausal-symptoms-in-depth
42. U.S. Department of Health and Human Services. Office on women’s Health. Menopause and your health. March 12, 2025. Accessed April 10, 2025. https://womenshealth.gov/menopause/menopause-and-your-health
43. National Institutes of Health. National Institute on Aging. Infographic: Staying healthy during and after menopause. January 27, 2025. Accessed April 10, 2025. https://www.nia.nih.gov/health/menopause/staying-healthy-during-and-after-menopause
44. Centers for Disease Control and Prevention. Women’s Health. Age is just a number: health tips for women over 50. September 23, 2024. Accessed April 10, 2025. https://www.cdc.gov/womens-health/features/age-just-a-number.html

Sjogren’s Disease: How Dry Am I?

At the completion of this activity, pharmacists will be able to:
1. Discuss current theories postulating how Sjogren's disease develops
2. Identify biomarkers used in diagnosis and patient classification
3. Interpret guidelines and evidence-based medicine to use best practices to manage Sjogren's disease
4. Use elements of an integrated approach to care among specialists and other pharmacists

At the completion of this activity, the pharmacy technicians will be able to:
1. Describe Sjogren's disease's basic pathology and symptoms
2. Outline prescription and non-prescription treatments used in Sjogren's disease
3. Identify when to refer patients to the pharmacists for recommendations or referrals

If you took that CE, you will not be able to receive credit for this one. The only change is in terminology.
This disease recently underwent a name change from “Sjogren’s syndrome (SjS).” The name change from Sjögren’s syndrome to Sjögren’s disease was proposed and endorsed by the 2023 International Rome Consensus Task Force, a multidisciplinary panel of international experts and patient representatives. The name was changed to better reflect its nature as a distinct systemic autoimmune disease, rather than a vague collection of symptoms implied by the term “syndrome.” The change also aimed to eliminate the confusing and potentially misleading distinction between “primary” and “secondary” forms, which does not align with how other autoimmune diseases are classified and was viewed by patients as diminishing the seriousness of their condition.

For further information, see Ramos-Casals M, Baer AN, Brito-Zerón MDP, et al. 2023 International Rome consensus for the nomenclature of Sjögren disease. Nat Rev Rheumatol. 2025;21(7):426-437. doi:10.1038/s41584-025-01268-z

Once considered a “dry eye-dry mouth-arthritis” illness, Sjogren’s syndrome (SjS) is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Systemic SjS is linked to autoimmune dysfunction that may eventually be irreversible. This disease affects about 2 to 4 million Americans, but every patient presents differently and symptoms mimic those of various other conditions, posing a challenge for diagnosis and treatment. SjS’s classic symptoms include sicca (ocular and oral dryness), arthralgia (joint pain), and fatigue. The pathogenesis of the disease is complex and multifactorial, but researchers are looking for a well-defined cause and modern understanding of SjS is improving. The search for biomarkers, therapeutic targets, and disease-modifying treatments for SjS is underway. Health care providers—including pharmacists and pharmacy technicians—who are up to date on current understanding and recently-updated guidelines will be better prepared to make evidence-based recommendations and appropriate referrals to improve care and outcomes for patients with SjS.

Sjogren’s Disease: How Dry Am I?

Author: Kelsey Giara, PharmD

Program Goal: To educate pharmacists and pharmacy technicians about emerging theories related to Sjogren’s disease, including use of biomarkers to diagnose and classify patients. This continuing education activity will cover guidelines, evidence-based medicine, and supportive material that the integrated healthcare team can employ to improve quality of life for patients who have Sjogren’s disease.

Learning Objectives:

Upon completion of this activity, pharmacists will be able to

Discuss current theories postulating how Sjogren’s disease develops
Identify biomarkers used in diagnosis and patient classification
Interpret guidelines and evidence-based medicine to use best practices to manage Sjogren’s disease
Use elements of an integrated approach to care among specialists and other pharmacists

Upon completion of this activity, pharmacy technicians will be able to

Describe Sjogren’s disease’s basic pathology and symptoms
Outline prescription and non-prescription treatments used in Sjogren’s disease
Identify when to refer patients to the pharmacists for recommendations or referrals

ABSTRACT

Once considered a “dry eye-dry mouth-arthritis” illness, Sjogren’s disease (SjD) is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Systemic SjD is linked to autoimmune dysfunction that may eventually be irreversible. This disease affects about 2 to 4 million Americans, but every patient presents differently and symptoms mimic those of various other conditions, posing a challenge for diagnosis and treatment. SjD’s classic symptoms include sicca (ocular and oral dryness), arthralgia (joint pain), and fatigue. The pathogenesis of the disease is complex and multifactorial, but researchers are looking for a well-defined cause and modern understanding of SjD is improving. The search for biomarkers, therapeutic targets, and disease-modifying treatments for SjD is underway. Health care providers—including pharmacists and pharmacy technicians—who are up to date on current understanding and recently-updated guidelines will be better prepared to make evidence-based recommendations and appropriate referrals to improve care and outcomes for patients with SjD.

INTRODUCTION

The medical community’s understanding of Sjogren’s disease (SjD) has evolved a great deal since it was first recognized in the late 1800s. A surgeon reported the first clinical case of what is now called SjD in 1888, describing a male patient with painless bilateral swelling of the lacrimal, parotid, and submandibular glands (i.e., the glands that produce tears and saliva).¹ Following a series of case reports over about a century detailing a “dry eye-dry mouth-arthritis” illness, physicians pieced together and named the disease known today as SjD.^1,2

Importantly, this disease recently underwent a name change from “Sjogren’s syndrome (SjD).” The name change from Sjögren’s syndrome to Sjögren’s disease was proposed and endorsed by the 2023 International Rome Consensus Task Force, a multidisciplinary panel of international experts and patient representatives.² The name was changed to better reflect its nature as a distinct systemic autoimmune disease, rather than a vague collection of symptoms implied by the term “syndrome.” The change also aimed to eliminate the confusing and potentially misleading distinction between “primary” and “secondary” forms, which does not align with how other autoimmune diseases are classified and was viewed by patients as diminishing the seriousness of their condition.²

Epidemiologic data about SjD in the United States (U.S.) is limited. It is estimated to affect about 2 to 4 million Americans, but only about 1 million are definitively diagnosed.^3,4 Women are nine times more likely to have the condition, and it typically emerges around menopause (i.e., after age 50). SjD is the second most common rheumatologic disorder in the U.S. behind systemic lupus erythematous (SLE).⁵ Autoimmune conditions don’t discriminate; many famous people have historically battled them publicly. Selena Gomez postponed a concert tour to undergo treatment for SLE. Kim Kardashian suffers from psoriasis. SjD, as a rarer condition, doesn’t make the news quite as often as other autoimmune conditions, but here are a few people you may recognize who are battling the disease today^6-8:

Carrie Ann Inaba: In 2021, the 30-season judge of Dancing with the Stars and co-host of The Talk took a leave of absence from television to focus on her health and wellbeing. The chronic pain associated with her SjD, SLE, fibromyalgia, and rheumatoid arthritis forced her to stay in bed three days a week.
Shannon Boxx: This World Cup soccer player and Olympic gold medalist was diagnosed with SjD in 2002 and suffered from severe fatigue and joint pain. Ahead of the 2007 World Cup, she was put on corticosteroids to alleviate her symptoms and needed specific approval from the U.S. Anti-Doping Agency to take them while competing.
Venus Williams: While dominating the sport of tennis as the most decorated female tennis player to compete in the Olympic Games, she has also been in a battle against her own body. SjD-related fatigue caused her to pull out of the 2011 U.S. Open, and she was temporarily booted from the top 100 tennis players for the first time in 15 years.

As an autoimmune condition, SjD’s cause is unclear. Genetic, environmental, and hormonal factors likely work collaboratively to produce the cardinal symptoms of dry eyes and/or mouth, fatigue, and limb pain. Some patients experience additional manifestations in the lymph nodes, lungs, kidneys, muscles, nervous system, skin, teeth, and brain. Glandular and joint involvement is also possible, and constitutional symptoms (e.g., fever, involuntary weight loss, night sweats) can affect quality of life. Patients with SjD have an elevated risk of lymphoma, about 15 to 20 times higher than the general population.^9,10

Clinical Presentation

SjD is a systemic condition strongly associated with organ-specific and systemic autoimmunity. Since it impacts multiple systems in the body, SjD can manifest various ways. Affected patients may have symptoms that cycle between mild and severe. Symptoms also tend to worsen as patients age and the function of the exocrine glands subsides.

SjD’s main symptoms are dry mouth and dry eyes (collectively, sicca). More than 95% of patients with SjD present with sicca symptoms, which are irritating and poorly tolerated.¹¹ About half of patients also have dermatologic involvement (i.e., dry skin or rashes).^3,12 Xerostomia (oral dryness) can substantially impact daily life, interfering with eating, speaking, or sleeping.⁴ When patients’ salivary volume decreases, they also lose saliva’s antibacterial properties. This can accelerate tooth decay, infection, and periodontal disease. Patients with dry mouth also report swallowing difficulties, halitosis (bad breath), and burning sensations in the mouth. Using artificial saliva products to manage dry mouth is time-consuming and ineffective for many patients with SjD.¹³

Patients with ocular dryness complain of itchy, gritty, sore, or dry sensations in the eyes despite appearing physically normal.⁴ Decreased tear production over time can cause chronic irritation and destruction of conjunctival epithelium that lines the inside of the eyelids and covers the sclera (whites of the eyes).

Patients may also experience symptoms elsewhere in the body, including

Dry cough
Fatigue
Joint and muscle pain
Numbness or tingling of the hands and feet
Vaginal dryness

Patients who develop musculoskeletal symptoms may have difficulty remaining active. About 53% of patients experience arthralgias (joint stiffness) and 22% experience myalgias (muscle pain).⁴ SjD-associated arthralgia occurs primarily in small joints, sometimes asymmetrically. Providers may confuse these symptoms with SLE or rheumatoid arthritis.

Disease Classification and Severity

Experts classify SjD as primary or secondary (see Table 1). Primary SjD (pSjD) is an autoimmune disease that causes immune cells to mistakenly attack and destroy healthy cells in the glands that produce tears and saliva. SjD can also be secondary to other autoimmune diseases (e.g., SLE, rheumatoid arthritis, scleroderma), as is the case for about 60% of patients.⁴

Table 1. American-European Consensus Group Criteria for the Classification of SjD¹⁴

Primary SjD Criteria

Secondary SjD Criteria

SjD Exclusion Criteria

At least 4 of the following, including at least criterion 5 or 6:

1. Ocular symptoms (dry eyes for ≥ 3 months, foreign-body sensation, use of tear substitutes > 3 times daily)

2. Oral symptoms (dry mouth, recurrently swollen salivary glands, frequent use of liquids to aid swallowing)

3. Ocular signs (Schirmer test* performed without anesthesia [< 5 mm in 5 minutes], positive vital dye staining results)

4. Oral signs (abnormal imaging of salivary glands, unstimulated salivary flow < 1.5 mL in 15 minutes)

5. Positive minor salivary gland biopsy findings

6. Positive anti-SDA or anti-SDB antibody results

In the presence of a connective-tissue disease, symptoms of oral or ocular dryness exist in addition to criterion 3, 4, or 5 for primary SjD.

Any of the following:

· AIDS

· Graft versus host disease

· Hepatitis C virus infection

· Past head-and-neck radiation

· Prior lymphoma

· Sarcoidosis

· Use of anticholinergic drugs

*Schirmer test is used to determine whether the eye produces enough tears to keep it moist; AIDS = acquired immunodeficiency syndrome; SjD = Sjogren’s disease; SDA = Sjogren's disease A; SDB = Sjogren’s disease B

There is a broad range of disease severity in SjD. Some patients experience mild glandular dryness and constitutional symptoms while others have severe glandular involvement and various manifestations throughout the rest of the body, including systemic autoimmune features. Mild SjD has a good prognosis, but patients often have difficulty managing their symptoms and moderate-to-severe disease can severely impact quality of life.¹⁵ SjD symptoms cause considerable psychological distress. About one third of patients with the condition have clinically significant anxiety and half have diagnosable depression.¹⁶

Measuring Systemic Disease Activity

The European League Against Rheumatism (EULAR) created a disease activity index for primary SjD (ESSDAI) to measure systemic disease activity.^17,18 The ESSDAI includes 12 domains: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematological, glandular, constitutional, lymphadenopathic, and biological. Each domain is divided into three or four levels of activity, and patients are scored based on that domain’s severity (i.e., 0 indicates no activity and 3 or 4 indicates high activity).¹⁸

Each domain’s weight reflects its relative importance to disease activity, and the score for each domain is equal to the level of activity multiplied by the domain’s weight. A final ESSDAI score (i.e., the sum of all the domain scores) could theoretically be between 0 and 123. Patients’ disease activity based on ESSDAI score is as follows^17,18:

0 = no activity
1 to 4 = low activity
5 to 13 = moderate activity
14 or greater, or high activity in any domain with a definition of high activity = severe activity

Measuring Patient-Reported Outcomes

EULAR also created the SjD patient reported index (ESSPRI) to assess patient-reported outcomes in pSjD.¹⁸ This scale focuses solely on the three major manifestations of SjD: dryness, fatigue, and musculoskeletal pain. Patients rank each of these domains on a scale of 0 to 10, and the total ESSPRI score is the mean (average) of those scores. A “patient acceptable symptom state” is defined as an ESSPRI score of less than 5, and clinicians and researchers define “minimally clinically important improvement” as an increase in ESSPRI score 1 point or more or 15%.¹⁸

Recognition and Treatment are Inadequate

SjD’s variable symptoms are not always present at the same time, leading providers—including physicians, dentists, and ophthalmologists—to treat each symptom individually, unaware of the systemic disease’s presence. Patients suffer from SjD symptoms an average of 10 years before obtaining a diagnosis.^4,19 The condition has historically been misdiagnosed because providers consider symptoms minor or vague and they often mimic other diseases. Up to 30% of people 65 years or older, with SjD or not, report dryness of the eyes and mouth.¹⁹ Sicca and/or parotid gland enlargement can result from various other conditions, including¹⁹

Alzheimer’s disease
anxiety and depression
Bell’s palsy
bulimia
chronic conjunctivitis or blepharitis (inflammation of the membrane on the eye or the eyelid, respectively)
chronic pancreatitis
complications from contact lenses
dehydration
diabetes mellitus
hepatitis C
Parkinson’s disease
rosacea
viral infections (e.g., cytomegalovirus, influenza, mumps)

About half of patients with SjD lack a definitive diagnosis, so undertreatment is considerable.⁴ For those who are diagnosed, treatment guidelines have historically been unclear and available treatments are limited and often unsuccessful. Recently, evidence-based treatment guidelines have emerged (discussed below) to help providers make decisions regarding SjD care. SjD is incurable; targeted, disease-modifying therapies are needed.

DISEASE MECHANISMS AND BIOMARKERS

pSjD’s pathogenesis is complex and multifactorial. Underlying genetic predisposition, epigenetic mechanisms (i.e., things that cause changes that affect the way your genes work), and environmental factors contribute to disease development.²⁰ There is no identified causal agent for SjD and it presents with multiple organ involvement. This makes the pursuit for defining an etiology and identifying biomarkers all the more important.

Researchers historically considered SjD a specific, self-perpetuating immune-mediated loss of exocrine tissue as the main cause of glandular dysfunction.²⁰ Today, with more sophisticated research methods, experts believe this fails to fully explain several SjD-related phenomena and experimental findings.

Genetics and Epigenetics

Genetic studies are a powerful tool for discovering new pathogenic pathways. Scientists have made great strides in studying genetic susceptibility to pSjD, but the evidence still does not match that of other autoimmune conditions.²⁰ Several genome-wide association studies in pSjD have shown that the strongest association lies within human leukocyte antigen (HLA) genes.

The non-HLA genes IRF5 and STAT4 (relevant to the innate and adaptive immune systems) also show consistent associations but on a smaller scale.²⁰ These genes activate interferon (IFN) pathways as part of the innate immune system. Epigenetic mechanisms (e.g., DNA methylation) also play a role in pSjD pathogenesis by modulating gene expression without altering DNA sequences. This may serve as a dynamic link between the genome and SjD manifestation.

Chronic Immune System Activation

Chronic immune system activation is central to SjD pathophysiology. Innate (“nonspecific”) immunity is the defense system people are born with to protect them from all antigens (foreign substances) that enter the body. Unlike the innate immune system, which attacks based on identification of general threats, the adaptive immune system is activated by pathogen exposure. Adaptive immunity uses its “memory” to learn about the threat and enhance the immune system accordingly over time. The adaptive immune system relies on B cells and T cells—otherwise known as lymphocytes—to function.

IFNs exert antiviral, antimicrobial, antitumor, and immunomodulatory effects as part of the innate immune system. Literature widely recognizes the SjD-associated “IFN signature,” as increased IFN levels activate multiple IFN-responsive genes involved in immune activities.²¹ Research indicates that type 1 IFN dysregulation is a major pathogenic mechanism in many autoimmune conditions, including SjD.^21,22 It is also suggested that “crosstalk” between the type 1 IFN pathway and B-cell activation causes a vicious cycle of immune activation where type 1 IFNs drive production of autoantibodies (made against substances formed by a person's own body) which further promotes IFN production.²¹ Toll-like receptors (TLRs) also play key roles in the innate immune system.²¹ Research suggests that TLR-dependent IFN expression may contribute to immune system activation and autoimmunity development in pSjD.²¹

In patients with SjD, lymphocytes infiltrate the salivary and lacrimal glands and other glands of the respiratory and gastrointestinal tracts and vagina.⁴ T cells in this infiltrate produce interleukin (IL)-2, IL-4, IL-6, IL-1β, and tumor necrosis factor while the B cells cause hypergammaglobulinemia (overproduction of immunoglobulins/antibodies) and produce autoantibodies.⁴ Some of these autoantibodies target cellular antigens of salivary ducts, the thyroid gland, the gastric mucosa, erythrocytes, the pancreas, the prostate, and nerve cells. About 60% of patients with SjD also express non-organ-specific autoantibodies, including rheumatoid factors, antinuclear antibodies, and antibodies to the small RNA-protein complexes Ro/SS-A and La/SS-B.⁴ These processes eventually lead to glandular dysfunction that manifests as dry eyes and mouth and enlargement of major salivary glands.

B-cell activating factor (BAFF) may also contribute to pSjD development. BAFF is usually an active part of the innate immune system, but B cells, T cells, and epithelial cells in the salivary glands also release BAFF in response to IFNs.²¹ This suggests that epithelial cells are not only passive victims of pSjD autoimmunity but also contributors to immune system overactivation. This also shows that BAFF serves as a link between the innate and adaptive immune systems in pSjD and could also represent an important therapeutic target in pSjD.²¹

Other Theories

Research into a well-defined cause of SjD is ongoing. Additional theories include a potential viral trigger, neuroendocrine abnormalities, and autoimmune epithelitis. Evidence for a viral trigger in pSjD development is conflicting, but studies have been unable to replicate an association between SjD and Epstein-Barr virus, hepatitis C virus, retroviruses, or Coxsackie A virus.²¹ Researchers think that the microbial stimuli driving pSjD development could be diverse or that the initiating viral stimulus is no longer detectable once the disease manifests.

The classic triad of symptoms in pSjD is sicca, arthralgia, and fatigue. Pathogenic mechanisms producing fatigue remain unknown, but neuroendocrine dysfunction may play a key role in the process.²¹ Studies show that patients with pSjD have decreased hormone levels (e.g., cortisol) compared with healthy individuals, indicating dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is suggested to promote fatigue and depression in patients with pSjD.

The Search for Biomarkers

Disclosing a disease’s etiology allows researchers to identify biomarkers (i.e., a biological molecule in the body that is a sign of an abnormal process) for diagnosis and assessment of disease process and treatment response. It also stimulates discovery of treatment targets. Researchers have been hard at work searching for biomarkers for SjD. Biomarkers can drive more precise diagnosis and may be used to measure disease severity or see how well the body responds to treatment. Scientists have discovered potential biomarkers, but studies have yet to validate their utility in SjD diagnosis and treatment.

Novel tissue-specific autoantibodies (TSAs) have been described in the early stages of pSjD, including salivary protein-1, parotid secretory protein, and carbonic anhydrase 6.²³ These are detectable even before the classic autoantibodies Ro/SS-A and La/SS-B. Further studies are needed to determine the utility of TSAs in screening patients with dry eye for SjD.

Some researchers hope to look beyond blood for reliable biomarkers for pSjD, more specifically in tears or saliva. They have studied y=tear proteins LACTO and LIPOC-1 as potential biomarkers for pSjD and one study shows they are more accurate indicators than traditional clinical tests for disease detection.²³ Other studies have examined salivary levels of S100A8/A9 as a potential biomarker for lymphoma development in patients with pSjD. Imaging biomarkers are also gaining attention. Salivary gland ultrasounds, for example, are non-invasive and valuable for studying the morphology (structure) of major salivary glands.²³

EVIDENCE-BASED TREATMENT STRATEGIES

SjD has no cure, and treatment varies from person to person based on their symptoms. Until recently, guidelines were unavailable to help clinicians manage Sjogren’s disease rationally.

In 2019, EULAR released evidence-based guidelines on which to rely, but clinicians may be unaware of its availability.¹¹ Medication is the cornerstone of these recommendations, so pharmacists and pharmacy technicians should be prepared to make evidence-based recommendations and appropriate referrals to improve care for patients with SjD. It is important to remember that no therapy is explicitly approved for SjD disease modification. Rather, providers use therapies indicated for each symptom separately—and some off label (i.e., for a non-FDA-approved indication)—on a trial-and-error basis based on available evidence from small trials that sometimes include a subset of patients with SjD.

Sicca

Glandular dysfunction—the cause of sicca symptoms—appears to be stable for long periods of time (up to 12 years) and has a chronic course in patients with pSjD.¹¹ No therapeutic intervention can reverse or slow the progression of glandular dysfunction, so sicca symptoms cannot be cured. EULAR guidelines state that the first therapeutic approach to sicca symptoms should be symptomatic relief using topical therapies (e.g., saliva substitutes, artificial tears).¹¹ This minimizes the risk of adverse effects (AEs) seen with systemic therapies.

Finding the optimal lubrication is a matter of trial and error, so pharmacy staff should be prepared to set realistic expectations for patients seeking relief of sicca symptoms. They should also help patients recognize when it may be time to talk to their prescriber about stepping up to pharmacologic treatment.

Oral Dryness

Treatment of oral dryness depends on the severity of salivary gland dysfunction (Figure 1).¹¹ No evidence indicates any non-pharmacologic stimulant is better than another, so patients with mild glandular dysfunction should use a trial-and-error approach to find one that works for them. If these therapies don’t help or patients do not wish to use non-pharmacologic stimulants, providers should move on to pharmacologic stimulation. Muscarinic agonists’ main AE is excessive sweating.¹¹ To avert this, EULAR recommends increasing the dose progressively up to 15 to 20 mg/day when possible.

Figure 1. Treating Oral Dryness Based on Degree of Glandular Dysfunction¹¹

Cevimeline and pilocarpine are cholinergic agents, meaning they activate muscarinic receptors in the parasympathetic nervous system (which controls bodily functions when a person is at rest) to stimulate saliva production. Patients with SjD take cevimeline 30 mg by mouth three times daily or pilocarpine 5 mg by mouth four times daily to treat dry mouth.^24,25 The most common AEs of cevimeline and pilocarpine are excessive sweating, nausea, rhinitis (stuffy nose), and diarrhea.

The ideal saliva substitute will have a neutral pH mimicking natural saliva composition and contain fluoride and other electrolytes.¹¹ Gel formulations are ideal for patients with acceptable salivary flow output, especially those with oral dryness at night. However, patients often dislike these formulations due to their sticky mouth-feel. Pharmacists can recommend that patients dilute oral gel formulations to reduce this phenomenon for better adherence. Thinner preparations are preferred for patients with better-preserved glandular function.¹¹

Some experts feel that all patients with oral dryness should use salivary substitutes regardless of the degree of glandular dysfunction.¹¹ Whether patients use these formulations or not, all patients with salivary dysfunction should use a neutral pH sodium fluoride gel to prevent extensive caries (i.e., cavities).

Ocular Dryness

Reflex tears are the tears we produce when we cry, while we produce basal tears continuously to lubricate the ocular surface (the surface layers of the eye, namely the cornea and conjunctiva).²⁶ While tears may taste like salt water, their composition is more complex. Both types of tears contain water but they also contain mucin, lipids, proteins (lysozyme, lactoferrin, lipocalin, immunoglobulins, and peroxidase), electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, and calcium), growth factors (epidermal growth factor), cytokines, and glucose.

Artificial tears and ocular gels/ointments are first line therapies for volume replacement and lubrication for ocular dryness.¹¹ While many people refer to over-the-counter (OTC) drops, gels, ointments, and lubricants as artificial tears, these products lack the biologically active components found in natural tears.²⁷ Their primary role is to supplement the patient’s natural tear production and provide sufficient lubrication to avoid eye complications.

Many artificial tear formulations are available, so patients may need assistance navigating the options. Table 2 lists common ingredients in artificial tears and their functions. A major difference between OTC products is the presence of chemical formulations that increase viscosity (thickness/stickiness) and adhesion and facilitate even distribution across the ocular surface.²⁷ As a general rule, drops are the lowest viscosity products, ointments have the highest viscosity, and suspensions fall in between. Lubricants with a polymeric base or viscosity agent are preferred for patients with SjD to¹¹

Add volume to the tear lake
Increase the time the lubricant remains on the ocular surface
Cushion the ocular surface to reduce friction between the eye and the eyelid

Table 2. Artificial Tear Ingredients and Their Functions^27-30

Ingredient Class	Function	Examples
Astringent	Precipitate protein to clear mucus from outer eye surface	zinc sulfate
Buffering agent	Maintain normal tear film pH	bicarbonate, phosphate
Demulcent	Protect and lubricate mucous membrane surfaces	carboxymethylcellulose sodium, dextran, gelatin, glycerin, hydroxyethyl cellulose, hypromellose, methylcellulose, polyethylene glycol, polysorbate, polyvinyl alcohol, povidone, propylene glycol
Lipid formulations	Improve gland function and increase tear film stability	castor oil, phospholipids, triglycerides
Preservatives	Prevent bacterial contamination	benzalkonium chloride (BAK), ethylenediaminetetraacetic acid (EDTA), polyquaternium-1, sodium chlorite, sodium perborate

Not all artificial tear products are equal, and different products work better for different patients. The optimal artificial tear offers long-lasting, effective symptom relief. It should also have low blur and be comfortable to administer.³¹ Surface tension, pH, viscosity, duration of action, and preservative presence or absence affect these factors.

OTC eye drops commonly include preservatives to prevent bacterial contamination. Repeated use of preservative-containing eye drops is associated with ocular allergies and toxicities, which can lead to product nonadherence and worsening symptoms.²⁷ Benzalkonium chloride (BAK)—the most common preservative used in eye formulations—is an epitheliotoxin and a toxic detergent.^28,29 It attracts monocytes and lymphocytes to the conjunctiva, worsening inflammation and thickening the tissue. This effect is cumulative; the more the eye is exposed to BAK, the greater the negative effects.²⁹ As a rule-of-thumb, pharmacists should always recommend products without BAK as a preservative.²⁸

EULAR recommends that all patients with SjD who present with ocular dryness use artificial tears containing methylcellulose or hyaluronate at least twice daily.¹¹ They should increase frequency as symptoms reappear as often as hourly. Individuals who use artificial tears four or more times daily should always use preservative-free products. Patients who experience overnight dryness should consider ophthalmic ointments before bedtime, as they remain in the eye longer. These are not recommended for daytime use because they blur vision.

Patients who are refractory to artificial tears and ointments—those who do not improve after maximum use—should see an ophthalmologist for prescription treatment. Short-term non-steroidal anti-inflammatory drug (NSAID) or corticosteroid eye drops are indicated for a maximum of two to four weeks.¹¹ This is due to the potential for AEs with long-term use, including

NSAIDs: corneal-scleral melts, perforation, ulceration, severe keratopathy
corticosteroids: infections, increased intraocular pressure, cataract worsening or development

Cyclosporine 0.05% is another therapeutic option for patients who are refractory to or do not tolerate artificial tears and ointments and those with severe ocular dryness requiring multiple courses of a glucocorticoid eye drop.¹¹ Cyclosporine is a calcineurin inhibitor that prevents T cell maturation.³² This counteracts SjD’s vicious cycle of inflammation. Patients administer the drug in the eyes twice daily, and the most common AEs are eye burning, stinging, and irritation. Of note, a small trial investigating topical tacrolimus showed promising results, but larger trials are needed to confirm the role of this drug for SjD-associated ocular dryness. Some providers also use lifitegrast ophthalmic solution or varenicline nasal spray off-label to treat SjD-associated dry eye, but EULAR makes no recommendation for their use.

Serum eye drops are blood-derived eye drops that may be autologous (uses the patient’s own blood) or allogenic (the blood comes from a donor).²⁶ These are compounded; a specialized pharmacy collects the patient’s blood, then clots, centrifuges, and dilutes it with sterile saline. The serum drops also contain increased concentrations of proteins, growth factors, vitamins A and C, antioxidants, and electrolytes found in natural tears.²⁶ This is meant to mimic natural basal tears’ biochemical properties to heal the cells of the ocular surface.

Small uncontrolled studies have examined serum eye drops for SjD patients, and results are inconsistent.¹¹ Nevertheless, ophthalmologists may use this option for patients with severe symptoms who are refractory to topical cyclosporine drops. When considering serum eye drops, individuals should consider storage needs, as they should be frozen until use (up to six months) and then refrigerated once opened for up to one week. Contamination during and after the compounding process is also possible.¹¹

Studies have investigated the utility of other therapies—hydroxychloroquine, immunosuppressive agents, and rituximab—for SjD-related ocular dryness, but EULAR does not recommend any of them for ocular dryness alone based on available clinical data.

Fatigue and Pain

Patients with pSjD often present with general non-inflammatory joint/muscle pain and fatigue/weakness. After ruling out potential concomitant conditions (e.g., osteoarthritis, hypothyroidism, vitamin deficiencies, depression), providers should evaluate whether the patient is experiencing joint pain (arthralgia) or joint inflammation (arthritis, tenosynovitis).¹¹ The ESSDAI score defines low articular activity level as arthralgia in the hands, wrists, ankles, and feet accompanied by morning stiffness longer than 30 minutes, always ruling out concomitant osteoarthritis.¹⁷ Objective inflammation (i.e., redness, heat, and swelling) in one or more joints is considered arthritis, and the ESSDAI score classifies arthritis severity based on the number of joints involved. Management of arthritis is covered under systemic disease treatment, and Table 3 outlines EULAR recommendations for non-arthritis musculoskeletal pain.

Table 3. EULAR-Recommended Management of SjD-Associated Musculoskeletal Pain*¹¹

Acute Pain

Frequent Acute Pain

Chronic, Daily Pain

· Acetaminophen or NSAIDs for symptomatic relief for up to 7 to 10 consecutive days

· Topical diclofenac may be effective for local pain with fewer adverse effects

· Consider hydroxychloroquine in patients with articular pain based on its evidence for use in other SAD

· Off-label use of biologics (even as rescue therapy) is not recommended

· Emphasize non-pharmacologic management (e.g., physical activity) before medications

· Goal is to avoid repeated use of NSAIDs or glucocorticoids

· Musculoskeletal: antidepressants and anticonvulsants

· Neuropathic: gabapentin, pregabalin, or amitriptyline

· Opioids are not recommended

*Providers must first rule out concomitant osteoarthritis (i.e., objective inflammation in 1 or more joints); NSAID = non-steroidal anti-inflammatory drug; SAD = systemic autoimmune diseases

Systemic Disease

EULAR defines systemic SjD as disease involvement that affects or has affected any of the organs/systems included in the ESSDAI score (i.e., all domains except biological).¹¹ Systemic disease is linked to autoimmune dysfunction that may eventually become irreversible. Providers should limit systemic therapies to patients with active systemic disease following careful evaluation of symptom severity and organ damage. Clinicians should consider systemic therapy on an individual basis, as not all patients with active systemic disease will require it.¹¹

EULAR makes a few general recommendations regarding systemic therapy¹¹:

Consider systemic therapies for most patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score (i.e., greater than 5).
Therapeutic response is considered a reduction of 3 or more points in the global ESSDAI score.
Providers should follow a sequential (or combined) use of glucocorticoids, immunosuppressive agents, and biologics to treat organ-specific systemic manifestations.
Use glucocorticoids at the minimum dose and duration necessary to control active systemic disease.
Use synthetic immunosuppressive agents (e.g., azathioprine, cyclophosphamide, leflunomide, methotrexate, mycophenolate) mainly as glucocorticoid-sparing agents in patients requiring long-term glucocorticoid therapy (i.e., those with severe organ impairments).
Consider B-cell targeted therapies (e.g., belimumab, rituximab) in patients with severe, refractory systemic disease.

Evidence regarding the use of glucocorticoids for SjD is weak and studies report high rates of AEs.¹¹ Guidelines recommend administering pulses of methylprednisolone followed by doses of 0.5 mg/kg daily or less as induction therapy in patients with severe disease and lower doses in patients with less severe disease. The goal is to withdraw glucocorticoids in patients whose SjD becomes inactive as soon as possible or at least target a maintenance dose of 5 mg daily or less with the aid of steroid-sparing immunosuppressive agents.¹¹ Studies of immunosuppressive agents are lacking, so EULAR does not recommend one agent over another, except in the case of patient characteristics or comorbidities. Dose, route of administration, and duration of treatment are not established given the lack of clinical data, so physicians should follow similar dosing schedules to other systemic autoimmune diseases.¹¹

EULAR guidelines also include algorithms for each ESSDAI domain based on available trial data and the clinical experience of the individuals on the EULAR task force.¹¹ Figure 2 summarizes these recommendations, including standard of care, second line, and third line recommendations.

Figure 2. EULAR Algorithms for Systemic Therapy Based on ESSDAI Domain¹¹

ABA = abatacept 0, 2, 4 weeks and every 4 weeks; BLM = belimumab 10 mg/kg (0, 2 and 4 weeks and then every 4 weeks); CyC = cyclophosphamide pulses 0.5g/15 day (maximum six pulses); ESSDAI = EULAR Sjogren's syndrome disease activity index; GC = glucocorticoid (recommended dose in mg/kg/day), short-term course whenever possible, consider methylprednisolone pulses in severe cases; G-CSF = granulocyte-colony stimulating factor; Hb = hemoglobin; HCQ = hydroxychloroquine 200 mg/day; ID = immunosuppressive agents, no head-to-

head comparisons available; ivIG = intravenous immunoglobulins 0.4-2 g/kg 5 days; MP = methylprednisolone; NSAID = non-steroidal anti-inflammatory drug; Pex = plasma exchanges; RTX = rituximab 1 g/15 days (x2)

Considering Comorbidities

More than 20% of people with SjD are older than 65 years, making them more likely to have pulmonary, liver, kidney, or heart-related comorbidities.¹⁹ It is especially important to consider alternative causes of sicca in older patients since many conditions and drugs produce oral and ocular dryness. Older people are nearly twice as likely to suffer from dry eyes than younger individuals.¹⁹ Older age is also associated with decreased salivary flow rate. Dry mouth is more than a bothersome symptom. Addressing dry mouth in older adults is vital because worsening oral health increases risks of malnutrition, social isolation, care dependency, and frailty that tend to affect this population.¹⁹

An estimated 45% to 80% of the older adult population reports some pain, most commonly musculoskeletal.¹⁹ Treatment plans for these patients should emphasize non-pharmacologic relief rather than medications as first-line therapy. Also, despite the lack of available evidence, experts suggest that topical NSAID formulations may be effective for local SjD-related pain in older adults with fewer AEs than oral NSAIDs.¹⁹

Treating systemic symptoms in this population also requires special considerations. Older adults are more likely to experience AEs from glucocorticoids—including blood clots, osteoporosis, and bone fractures—than younger individuals.¹⁹ Pharmacists should also consider the greater frequency of hepatic and renal impairment in older patients. For example, renal function decline and decreased folate stores may increase methotrexate-related toxicity.¹⁹ Studies suggest that disease-modifying antirheumatic drugs (including some biologics) have similar effects on younger and older patients while maintaining favorable AE profiles.¹⁹ Older people, therefore, should not be excluded from the use of these agents for systemic disease where appropriate.

Autoimmune conditions increase the risk of lymphoma, cancer stemming from the lymph nodes.³³ More specifically, pSjD is the autoimmune disease associated with the highest risk of B-cell lymphoma, occurring in 5% to 10% of patients.³³ This risk increases by 2.2% per year of age in this population.³³ In patients with pSjD, chronic stimulation of autoimmune B cells leads to development of B-cell lymphoma. Screening for lymphoma is an important part of a comprehensive treatment plan given the increased risk. Similar to other autoimmune conditions, SjD also increases patients’ risk for atherosclerosis and coronary artery disease.²²

Research Continues

Researchers continue to define new therapeutic targets and investigate new treatments for SjD. Targeting B cells appears to be the most promising therapeutic approach for this condition.¹⁸ Studies are evaluating anti-CD20 antibodies and antibodies targeting the BAFF signaling pathway to target B cells and anti-CD40 antibodies to block the crosstalk between T cells and B cells.¹⁸ So far, two agents have met their primary outcome—improvement in systemic disease activity—in pSjD clinical trials: anti-BAFF receptor antibodies and anti-CD40 antibodies.

BAFF receptors are exclusively expressed on B cells, so targeting these receptors effectively depletes B cells to blunt the autoimmune response in pSjD. Clinical trials have assessed an anti-BAFF receptor antibody, ianalumab (VAY736) in patients with pSjD with positive results.^34,35 In the phase 2b study, patients experienced improved ESSDAI scores from baseline to week 24 and improvement in stimulated saliva flow rate.³⁵ This is a promising option for a future disease-modifying pSjD treatment, and phase 3 trials are ongoing.

The interaction between CD40 and the CD40 ligand (CD40L) is important for B cell development, antibody production, and optimal T cell-dependent antibody responses. Patients with pSjD have increased expression of CD40L compared to healthy individuals, which suggests that CD40-CD40L interactions could be a practical target for pSjD treatment.¹⁸ Phase 2 studies have shown promising results for iscalimab, an anti-CD40 antibody, to treat pSjD. However, the drug’s manufacturer discontinued development of iscalimab, citing a non-competitive risk/benefit profile to other agents.³⁶ A phase 2 trial of another anti-CD40L antibody frexalimab (SAR441344) also shows promise for SjD, but the manufacturer is not currently pursuing this indication.³⁷

Additional therapeutic targets under investigation include¹⁸

Bruton’s tyrosine kinase, an important molecule in B cell receptor signaling
plasmacytoid dendritic cells, which secrete type 1 IFNs
downstream type 1 and 2 IFN signaling (using Janus kinase inhibitors)
IL-12 signaling pathway and induction of T helper 1 cell, which secrete type 2 IFNs (using ustekinumab)

MULTIDISCIPLINARY TEAM CARE IS IDEAL

EULAR guidelines recommend a multidisciplinary approach to SjD treatment.¹¹ This is the second strongest recommendation included in the 2020 guidelines, with only a recommendation for patients who develop B-cell lymphoma to receive individualized treatment receiving a stronger grade. SjD’s overall prevalence in the general population is low and the condition presents differently in every patient, making it difficult for any one provider to ensure in-depth expertise in managing it. At minimum, the SjD care team should include a primary care provider (PCP), a rheumatologist, a dentist, and an ophthalmologist. Pharmacy staff should understand the roles and responsibilities of each provider to better recognize their own place on the care team.

Rheumatologist

Rheumatologists are usually the “lead” of the medical team for SjD and have the primary responsibility for managing it.³⁸ The rheumatologist should verify the diagnosis, including looking for disease mimics and screening and monitoring for coexisting rheumatologic or autoimmune conditions. They should also screen for lymphoma risk factors and common comorbidities. They may collaborate with the patient’s PCP for comorbidity monitoring and management. Rheumatologists also provide treatment for systemic features of SjD.³⁸

Primary Care Provider

The PCP should provider routine, comprehensive health care addressing a wide range of issues, including patients’ mental health.³⁸ They should collaborate with the patient’s rheumatologist to establish who is responsible for overlapping areas of practice (e.g., comorbidities, immunizations, nutrition concerns). Screening for comorbidities—including cardiovascular disease, osteoporosis, sinusitis, and others—is an important task for PCPs, but they may be unaware of the increased risk of these conditions in patients with SjD. Pharmacy teams should encourage patients to advocate for themselves, and direct patients to www.sjogrensadvocate.com for advice on how to do so effectively.³⁸

Ophthalmologist

Ophthalmologists are responsible for managing severe dry eye.³⁸ Occasionally, the ophthalmologist is the first provider to suspect SjD and refers patients to rheumatology for general management. They perform diagnostic tests (e.g., Schirmer’s test, ocular staining score, tear breakup time) to determine the severity of SjD ocular symptoms and blood tests to screen for biologic signs of SjD. These clinicians also provide routine dry eye management, including prescription medications/drops and recommendations for OTC therapies.

Dentist

Many patients with SjD require extensive dental care exceeding the recommended checkups every 6 months for otherwise healthy individuals.³⁸ Preventative dental visit frequency depends on patients’ level of dryness and decay. At every checkup, dentists should examine the entire oral region, including palpating (i.e., feeling with the fingers) salivary glands, face, and neck for swelling and masses.³⁸ They should also provide dental caries prevention, screening, and treatment.

Where Pharmacy Fits In

Most often, pharmacy technicians will encounter patients with SjD at the pickup counter, so they should be prepared to refer patients to the pharmacist when appropriate. Sometimes, patients request assistance finding the eye care aisle for OTC drops. Before pointing them in the right direction, pharmacy technicians should refer patients to the pharmacist for counseling if they indicate they are new to using artificial tears (e.g., asking your opinion about product selection).

Technicians can also help patients locate products based on pharmacist recommendations and provide informational handouts about proper administration technique (see Sidebar). While cost in an important factor in therapy adherence, consider recommending name brand products rather than store brand generics whenever feasible. While the active ingredients may be consistent across proprietary and store brand products, the concentration of these components is often less than 5% of each drop.³⁹ The amount of inactive ingredients (i.e., “filler”) differs from brand to brand.

Sidebar: Don’t Leave Patients High and Dry^40,41

To provide maximum relief, patients must administer eye formulations correctly. Many patients struggle with this, especially older patients, and joint pain in SjD can make it even more difficult. Counseling patients on proper eye drop and ointment instillation is crucial to improving outcomes.

Eye Drop Administration

Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses, unless the product is specifically designed for use with contact lenses. If using a suspension, shake well.
Tilt head back, gently grasp the lower eyelid below lashes and pull away from the eye to create a pouch.
Look up, and administer a single drop into the pouch without touching the tip of the container to the eye.
As soon as the drop is instilled, release the eyelid slowly. Close eyes gently for 3 minutes and position the head downward (gravity pulls the drop onto the ocular surface). Minimize blinking or squeezing the eyelid.
Use a finger to gently apply pressure to the opening of the tear duct (inner corner of the eye) to prevent medication from draining through the tear duct and increase medication contact time in the eye.
If additional ophthalmic therapy is indicated, wait 5 to 10 minutes in between. Also, wait 5 to 10 minutes before reinserting contact lenses, if applicable.

Pro-Tip: tell patients, “If you have a hard time deciphering whether you’ve successfully installed eye drops, refrigerate the solution before administration to more easily detect the drops on your eye’s surface. Do NOT use this trick with a suspension.”

Eye Ointment Administration

Thoroughly wash hands and areas of the face around the eyes. Remove contact lenses, unless the product is designed for use with contact lenses specifically.
Tilt head back, gently grasp the lower eyelid below lashes, and pull away from the eye to create a pouch.
Look up, and with a sweeping motion, place a strip of ointment ¼ to ½ inch wide inside the lower eyelid by gently squeezing the tube (avoid touching the tube tip to any tissue surface).
Release the eyelid slowly and close eyes gently for 1 to 2 minutes.
Vision may blur temporarily, so avoid activities that require good visual acuity until vision improves. Also, wait 15 minutes before reinserting contact lenses, if applicable.

Clearly, a medication expert needs to contribute to patient and provider education and oversee prescribed and OTC medications. Pharmacists can offer various clinical pearls to help patients with SjD avoid dry eyes, mouth, and skin.

Lifestyle modifications⁴²:

Avoid windy or drafty environments and wear sunglasses outdoors
Use a humidifier indoors to keep the air moist
Practice good oral hygiene (e.g., chew sugarless gum, stay well hydrated, see a dentist three times a year)
Consciously remember to blink when working at a computer or reading extensively
Avoid wearing eye makeup
Consider smoking cessation and avoid smoky environments
After showering, pat dry gently and apply an emollient to damp skin within three minutes

Separation and timing^40,41:

Separate administration of multiple eye drops by at least 5 minutes to ensure the first drop is not flushed away by the second and the second drop is not diluted by the first
If using multiple products, use them in order of least viscous to most viscous to ensure efficacy of all treatments
If using drops and ointment, administer drops at least 10 minutes before ointment so the ointment does not create a barrier to the drops’ absorption
If using a suspension with another dosage form, use the suspension last because its retention time in the tear film is longer

Pharmacists and pharmacy technicians should also be aware of medications that could worsen symptoms of dryness (Table 4). Technicians should refer patients with SjD to the pharmacist when they see these at the pick-up counter. They should also stay up to date on available eye care formulations and discuss new products with the pharmacist. Pharmacists should counsel patients with SjD about which OTC products to avoid and offer to contact prescribers to recommend prescription therapy changes.

Table 4. Medications That Cause or Worsen Ocular Dryness^19,25,28

Medication/Class	Examples	Rx/OTC	Mechanism for Ocular Dryness
Anticholinergics	benztropine trihexyphenidyl	Rx	Blocking acetylcholine blurs vision and stops the signals that normally tell the eyes to produce tears
Antihistamines (especially first-generation)	cetirizine chlorpheniramine diphenhydramine loratadine	OTC	Dry secretions (including tears) and produce anticholinergic adverse effects
Beta-blockers	atenolol metoprolol propranolol	Rx	Cause the body to make less of a protein present in tears, and can lower pressure in the eyes, affecting the amount of water in the tears
Decongestants	phenylephrine pseudoephedrine	OTC	Decrease nasal/mucosal mucus production (including the eyes), which decreases tear production
Diuretics	furosemide hydrochlorothiazide	Rx	Help the body eliminate water and salt, which can alter tear composition
Hormones	estrogen/progesterone and other hormones used for contraception, infertility, or hormone replacement	Rx	Unknown
Isotretinoin	N/A	Rx	Lessens oil production by certain glands to treat acne, but some of those glands are in eyelids, decreasing oil in tears
Tricyclic antidepressants	amitriptyline amoxapine clomipramine imipramine maprotiline	Rx	Anticholinergic adverse effect stops the signals that normally tell the eyes to produce tears

OTC = over-the-counter; Rx = prescription only

CONCLUSION

SjD is a complex, multifactorial condition that impacts patients’ quality of life substantially. Providing optimal care for this disease requires a multidisciplinary team, on which pharmacists and pharmacy technicians provide a link between all providers to ensure continuity of care. Recognizing patients with SjD in the pharmacy is crucial to prevent polypharmacy, ensure patients know how to use eye care formulations, assist patients in finding OTC products to address symptoms, and refer to other providers when necessary. This will improve care and outcomes for patients with SjD.

PAUSE AND PONDER:

Why are patients with SjD so difficult to identify and diagnose?
How would your daily life change if you had SjD? What hardships might you face?
How often do you encounter patients asking for help choosing artificial tear products? What could you improve about your ability to assist them?

Sjogren’s Disease: How Dry Am I?

Pharmacist Post-test 25-050 H01 P

Upon completion of this activity, pharmacists will be able to
1. DISCUSS current theories postulating how Sjogren’s disease develops
2. IDENTIFY biomarkers used in diagnosis and patient classification
3. INTERPRET guidelines and evidence-based medicine to use best practices to manage Sjogren’s disease
4. USE elements of an integrated approach to care among specialists and other pharmacists

1. Which gene(s) shows the strongest association with primary SjD?
A. STAT4
B. IRF5
C. HLA

2. Which of the following is associated with SjD pathogenesis?
A. Interferon signature
B. T-cell activating factor
C. Epstein-Barr virus

3. Which sentence describes the potential role of BAFF in primary SjD development?
A. It is an unexplored and unreliable therapeutic target for SjD treatment
B. It proves that epithelial cells are passive victims of SjD autoimmunity
C. It serves as a link between the innate and adaptive immune systems

4. Which of the following biomarkers may be more accurate than traditional clinical tests for SjD detection?
A. TSAs
B. LACTO and LIPOC-1
C. S100A8/A9

5. Which is TRUE about the ESSDAI score?
A. A 14 is the highest score possible
B. It measures disease activity in 12 domains
C. It assesses patient-reported outcomes

6. A patient consults with you about her SjD-induced dry mouth symptoms. She has been using a gel saliva substitute for a week. It works well, but she finds it annoyingly sticky and is hoping to find an alternative. She tells you her rheumatologist says she has mild gland dysfunction and acceptable saliva output. What is the best recommendation for this patient?
A. Dilute the saliva substitute with water
B. Switch to xylitol-free chewing gum
C. Talk to your rheumatologist about trying cevimeline

7. A patient is using artificial tear drops for SjD-related ocular dryness, but he complains that he must use them every 2 hours because they wear off. Which of the following is the best recommendation for this patient?
A. Switch to an artificial tear suspension containing hyaluronate
B. Switch to an artificial tear ointment containing BAK
C. Talk to your ophthalmologist about prescription therapies

8. A patient with SjD complains of visible redness, considerable heat, and ample swelling in three of his joints. He brings acetaminophen and ibuprofen to your pharmacy counter and asks which one will work better. Which of the following is the best recommendation for this patient?
A. Ibuprofen is the better choice because it is anti-inflammatory
B. A topical NSAID like diclofenac is a better choice because it is locally-acting
C. Talk to your rheumatologist about systemic hydroxychloroquine with NSAIDs

9. A patient presents to your pharmacy to buy artificial tears. She mentions that her ophthalmologist recommended that she see a rheumatologist because she thinks the patient has SjD. She doesn’t understand why that’s necessary when she can just use OTC drops to lubricate her dry eyes, and she doesn’t plan to see another provider. Which of the following is the best response?
A. You can use OTC drops as long as you choose a product with methylcellulose and no benzalkonium chloride
B. SjD affects your whole body, not just your eyes, so you may need additional treatment from a rheumatologist
C. Your ophthalmologist can prescribe prescription therapies for your dry eye symptoms, so you don’t need to see a rheumatologist

10. A patient’s neurologist prescribed propranolol for migraine prevention. He presents to your pharmacy to pick up the prescription along with a facewash for acne and artificial tear drops for SjD. What should you do?
A. Offer to contact the patient’s neurologist for an alternative migraine prevention therapy
B. Recommend a suspension, not drops, to prevent blurred vision that could worsen his migraines
C. Advise him to avoid the acne facewash as it could worsen his SjD-related dry eye symptoms

Sjogren’s Disease: How Dry Am I?

Pharmacy Technician Post-test 25-050 H01 T

Upon completion of this activity, pharmacy technicians will be able to
1. DESCRIBE Sjogren’s disease’s basic pathology and symptoms
2. OUTLINE prescription and non-prescription treatments used in Sjogren’s disease
3. IDENTIFY when to refer patients to the pharmacists for recommendations or referrals

1. Which is the most common symptom of SjD?
A. Arthralgia
B. Fatigue
C. Sicca

2. Which of the following sentences accurately describes SjD symptoms?
A. Symptoms are the same in every patient
B. Symptoms may cycle between mild and severe
C. Younger patients have worse symptoms than older patients

3. Which gene(s) shows the strongest association with primary SjD?
A. STAT4
B. IRF5
C. HLA

4. Which of the following should ALL patients with SjD-related dry mouth use?
A. Gel formulation saliva substitute
B. Prescription muscarinic agonists
C. Neutral pH sodium fluoride gel

5. Which of the following has the lowest viscosity?
A. Eye drops
B. Eye suspensions
C. Eye ointments

6. Which prescription therapy does EULAR recommend for SjD-related ocular dryness?
A. Hydroxychloroquine oral tablets
B. Cyclosporine ophthalmic solution
C. Lifitegrast ophthalmic solution

7. Which of the following is used to treat frequent acute SjD-associated articular pain?
A. Hydroxychloroquine
B. Biologics
C. Amitriptyline

8. Which of the following does EULAR recommend for patients with SjD who present with ocular dryness?
A. Use artificial tears containing methylcellulose of hyaluronate at least twice daily
B. Use artificial tears containing benzalkonium chloride at least four times daily
C. Use artificial tear ointments during the day because they last the longest in the eyes

9. A patient is picking up a pilocarpine prescription for SjD-induced dry eyes. She mentions that she has daily, throbbing pain in her back. She is also purchasing naproxen (an NSAID) that she hopes will help with the pain and OTC artificial tears for her dry eyes. Why should you refer this patient to the pharmacist?
A. Acetaminophen is a better choice for this patient’s pain
B. The patient should not use artificial tears with pilocarpine
C. This patient may require prescription treatment for her pain

10. Which of the following patients with SjD should you refer to the pharmacist?
A. A 74-year-old male purchasing topical diclofenac for local, acute pain
B. A 52-year-old female purchasing artificial tears, cevimeline, and phenylephrine
C. A 33-year-old female purchasing artificial tears and insulin for diabetes

1. Talal N. Sjögren's syndrome: historical overview and clinical spectrum of disease. Rheum Dis Clin North Am. 1992;18(3):507-515.
2. Ramos-Casals M, Baer AN, Brito-Zerón MDP, et al. 2023 International Rome consensus for the nomenclature of Sjögren disease. Nat Rev Rheumatol. 2025;21(7):426-437. doi:10.1038/s41584-025-01268-z
3. Sjogren’s syndrome. National Institute of Dental and Craniofacial Research. Updated July 2018. Accessed June 1, 2022. https://www.nidcr.nih.gov/health-info/sjogrens-syndrome
4. Kassan SS, Moutsopoulos HM. Clinical manifestations and early diagnosis of Sjögren syndrome. Arch Intern Med. 2004;164(12):1275-1284. doi:10.1001/archinte.164.12.1275
5. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25. doi:10.1002/art.23177
6. Venus Williams stands up for Sjogren’s awareness. Sjogren’s Foundation. April 30, 2022. Accessed June 1, 2022. https://www.sjogrens.org/blog/2022/venus-williams-stands-up-for-sjogrens-awareness
7. Taylor T. Perseverance in pursuit: U.S.'s Boxx eyes World Cup title despite illness. June 5, 2015. Accessed June 1, 2022. https://www.si.com/soccer/2015/06/05/shannon-boxx-womens-world-cup-us-national-team
8. Ramirez CD. Carrie Ann Inaba announces leave of absence from The Talk to focus on her health. April 26, 2021. Accessed June 1, 2022. https://people.com/tv/carrie-ann-inaba-taking-leave-of-absence-from-the-talk-to-focus-on-health/
9. Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a metaanalysis. Arch Intern Med. 2005;165:2337-2344.
10. Lazarus, M.N.; Robinson, D.; Mak, V.; Møller, H.; Isenberg, D.A. Incidence of cancer in a cohort of patients with primary sjogren’s syndrome. Rheumatology. 2006;45:1012-1015.
11. Ramos-Casals M, Brito-Zerón P, Bombardieri S, et al. EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies. Ann Rheum Dis. 2020;79(1):3-18. doi:10.1136/annrheumdis-2019-216114
12. Kittridge A, Routhouska SB, Korman NJ. Dermatologic manifestations of Sjögren syndrome. J Cutan Med Surg. 2011;15(1):8-14. doi:10.2310/7750.2010.09033
13. Engel GL. The clinical application of the biopsychosocial model. J Med Philos. 1981;6(2):101-123. doi:10.1093/jmp/6.2.101
14. Tzioufas AG, Voulgarelis M. Update on Sjögren's syndrome autoimmune epithelitis: from classification to increased neoplasias. Best Pract Res Clin Rheumatol. 2007;21(6):989-1010. doi:10.1016/j.berh.2007.09.001
15. Carsons SE, Patel BC. Sjogren Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; November 2, 2021. https://www.ncbi.nlm.nih.gov/books/NBK431049/
16. Valtýsdóttir ST, Gudbjörnsson B, Lindqvist U, Hällgren R, Hetta J. Anxiety and depression in patients with primary Sjögren's syndrome. J Rheumatol. 2000;27(1):165-169.
17. Seror R, Bowman SJ, Brito-Zeron P, et al. EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide. RMD Open. 2015;1(1):e000022. Published 2015 Feb 20. doi:10.1136/rmdopen-2014-000022
18. Seror R, Nocturne G, Mariette X. Current and future therapies for primary Sjögren syndrome. Nat Rev Rheumatol. 2021;17(8):475-486. doi:10.1038/s41584-021-00634-x
19. Retamozo S, Baldini C, Bootsma H, et al. Therapeutic recommendations for the management of older adult patients with Sjögren's syndrome. Drugs Aging. 2021;38(4):265-284. doi:10.1007/s40266-021-00838-6
20. Jonsson R. Disease mechanisms in Sjögren's syndrome: What do we know? Scand J Immunol. 2022;95(3):e13145. doi:10.1111/sji.13145
21. Nocturne G, Mariette X. Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nat Rev Rheumatol. 2013;9(9):544-556. doi:10.1038/nrrheum.2013.110
22. Skarlis C, Raftopoulou S, Mavragani CP. Sjogren's syndrome: recent updates. J Clin Med. 2022;11(2):399. doi:10.3390/jcm11020399
23. Cafaro G, Croia C, Argyropoulou OD, et al. One year in review 2019: Sjögren's syndrome. Clin Exp Rheumatol. 2019;37 Suppl 118(3):3-15.
24. Evoxac [prescribing information]. Daiichi Pharmaceutical Co.; 2006. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/020989s008lbl.pdf
25. Paulsen AJ, Cruickshanks KJ, Fischer ME, et al. Dry eye in the beaver dam offspring study: prevalence, risk factors, and health-related quality of life. Am J Ophthalmol. 2014;157(4):799-806. doi:10.1016/j.ajo.2013.12.023
26. Dang VT, Hoyle B. Autologous serum tears: an overlooked treatment for dry eye. Modern Optometry. July 2020. Accessed June 1, 2022. https://modernod.com/articles/2020-july-aug/autologous-serum-tears-an-overlooked-treatment-for-dry-eye?
27. Pucker AD, Ng SM, Nichols JJ. Over the counter (OTC) artificial tear drops for dry eye syndrome. Cochrane Database Syst Rev. 2016;2:CD009729. doi:10.1002/14651858.CD009729.pub2
28. Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 2015;112(5):71-82. doi:10.3238/arztebl.2015.0071
29. Benzalkonium chloride (BAK). Not a Dry Eye. Accessed June 13, 2022. https://www.notadryeye.org/all-about-dry-eye-syndrome/treatments-for-dry-eye-syndrome-and-related-conditions/lubricating-eye-drops/glaucoma-eyedrops-a-fresh-look-at-preservatives/
30. CFR—Code of Federal Regulations Title 21. U.S. Food and Drug Administration. Updated March 28, 2022. Accessed June 13, 2022. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=349
31. Horton M, Horton M, Reinhard E. Master the maze of artificial tears. Review of Optometry. November 20, 2018. Accessed June 13, 2022. https://www.reviewofoptometry.com/article/master-the-maze-of-artificial-tears
32. Gupta PK, Asbell P, Sheppard J. Current and future pharmacological therapies for the management of dry eye. Eye Contact Lens. 2020;46 Suppl 2:S64-S69. doi:10.1097/ICL.0000000000000666
33. Nocturne G, Pontarini E, Bombardieri M, Mariette X. Lymphomas complicating primary Sjögren's syndrome: from autoimmunity to lymphoma. Rheumatology (Oxford). 2019;60(8):3513-3521. doi:10.1093/rheumatology/kez052
34. Dörner T, Posch MG, Li Y, et al. Treatment of primary Sjögren's syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis. 2019;78(5):641-647. doi:10.1136/annrheumdis-2018-214720
35. Dörner T, Bowman SJ, Fox R, et al. Ianalumab (VAY736), a dual mode of action biologic combining BAFF receptor inhibition with B cell depletion, reaches primary endpoint for treatment of primary Sjogren’s syndrome [abstract OP0302]. Ann Rheum Dis. 79(Suppl 1);187-188 (2020).
36. Waldron J. Novartis gives up on anti-CD40 antibody to treat Sjögren's due to 'benefit/risk profile.' Fierce Biotech. January 31, 2025. Accessed July 14, 2025. https://www.fiercebiotech.com/biotech/novartis-gives-anti-cd40-antibody-treat-sjogrens-due-benefitrisk-profile
37. Fatima T, Mirza A, Fatima F, et al. Frexalimab (SAR441344) as a potential multiautoimmune disorder tackling mAB targeting the CD40-CD40L pathway undergoing clinical trials: a review. Ann Med Surg (Lond). 2024;86(12):7305-7313. Published 2024 Nov 12. doi:10.1097/MS9.0000000000002745
38. For the newly diagnosed. Sjogren’s Advocate. Updated June 10, 2022. Accessed June 13, 2022. https://www.sjogrensadvocate.com/newly-diagnosed
39. So many choices…what drops are best for my dry eyes? Summit Eye Center. March 5, 2019. Accessed June 13, 2022. https://www.summiteyekc.com/blog/eye-drop-overload-at-the-pharmacy
40. Evans K, Madden L. Recommended dry eye treatments in community pharmacy. The Pharmaceutical Journal. August 2, 2016. Accessed June 13, 2022. https://pharmaceutical-journal.com/article/ld/recommending-dry-eye-treatments-in-community-pharmacy
41. Fiscella RG, Jensen MK. Ophthalmic disorders. In: Krinsky DL, Ferreri SP, Hemstreet BA, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs. 19th ed. Washington, DC: APhA Publications;2018:545-566.
42. Wick JY. Sjogren’s syndrome: dry as a desert. Pharmacy Times. February 18, 2014. Accessed June 13, 2022. https://www.pharmacytimes.com/view/sjogrens-syndrome-dry-as-a-desert

Laboratory Monitoring of Anticoagulation 2025 Revision

UConn has developed web-based continuing pharmacy education activities to enhance the practice of pharmacists and assist pharmacists in making sound clinical decisions to affect the outcome of anticoagulation therapy for the patients they serve. There are a total of 17.25 hours of CPE credit available. Successful completion of these 17.25 hours (13 activities) or equivalent training will prepare the pharmacist for the Anticoagulation Traineeship, which described below in the Additional Information Box.

The activities below are available separately for $17/hr or as a bundle price of $199 for all 13 activities (17.25 hours). These are the pre-requisites for the anticoagulation traineeship. Any pharmacist who wishes to increase their knowledge of anticoagulation may take any of the programs below.

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

At the completion of this activity, the participant will be able to:

Explain the role of common laboratory tests used in monitoring of anticoagulation therapy.
Identify an alternative to INR monitoring for warfarin therapy.
Identify the clinical situations requiring Activated whole blood Clotting Time (ACT) and anti-factor Xa activity monitoring for unfractionated heparin.
Discuss the technical differences between point of care testing and laboratory testing and the influence on patient care.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

The University of Connecticut School of Pharmacy and The UConn Health Center Outpatient Anticoagulation Clinic have developed 2-day practice-based ACPE certificate continuing education activity for registered pharmacists and nurses who are interested in the clinical management of patients on anticoagulant therapy and/or who are looking to expand their practice to involve patient management of outpatient anticoagulation therapy. This traineeship will provide you with both the clinical and administrative aspects of a pharmacist-managed outpatient anticoagulation clinic. The activity features ample time to individualize your learning experience. A “Certificate of Completion” will be awarded upon successful completion of the traineeship.

More Information About Traineeship

INTRODUCTION

This module of the UConn Anticoagulation Certificate Program discusses laboratory monitoring of various anticoagulants. It builds on previous modules and repeats some information. Repetition will help consolidate learning and perhaps stimulate thought.

Coagulation Cascade

To monitor anticoagulation therapy effectively, it’s essential to first understand the coagulation cascade. This process begins with two distinct pathways—the intrinsic and extrinsic pathways—which ultimately converge at a critical step.¹ At that step, Factor X is activated to Factor Xa. Factor Xa, along with Factor Va and calcium (Ca²⁺), then catalyzes the conversion of prothrombin (Factor II) into thrombin (Factor IIa). Thrombin plays a pivotal role by converting fibrinogen into fibrin, the key structural protein that crosslinks with platelets to form a stable clot.¹

Two of the most widely used laboratory tests for assessing coagulation function are²

activated partial thromboplastin time (aPTT) – primarily monitors the intrinsic pathway.
prothrombin time (PT) – primarily monitors the extrinsic pathway.

By evaluating these tests, clinicians can assess both pathways’ functionality, making them valuable tools for screening coagulation disorders. These tests are particularly useful when investigating unexplained bleeding, as they help determine whether one or both pathways are impaired.

Prothrombin Time

PT measures the time it takes for plasma to clot after exposure to a tissue factor reagent. This test assesses both the extrinsic and common coagulation pathways. Laboratory and point-of-care machines detect clots using various methods, such as visual, optical, or electromechanical techniques, depending on the device. A normal PT range typically falls between nine and 13 seconds³; however, this range can vary significantly based on the laboratory equipment and reagents employed. Therefore, it is crucial to verify the normal range for a specific laboratory’s setup regularly to ensure accurate interpretation of results.^4,5

PT and INR Standardization

The therapeutic level of vitamin K antagonists (VKA) is measured by PT and international normalized ratio (INR). The INR is a standardized ratio the World Health Organization (WHO) developed in the 1980s specifically for VKA monitoring, as PT varies greatly between laboratories.⁶ WHO’s goal was to allay the discrepancy in tissue factor (TF) activity between PT reagents to create a common scale that would display PT results consistently. The INR uses data and processes from the International Sensitivity Index (ISI), a WHO project that quantifies analyzers and individual PT reagents’ reactivity. In addition, each laboratory has its own geometric mean PT (MNPT), which laboratory staff calculate using is the average PT calculated from at least 20 normal donors of both sexes, tested on the same local analyzer and under the same test conditions as the patient’s PT. The formula for INR is INR = (patient’s PT/MNPT). A normal INR is usually in the range of 0.8 to 1.2.^7,8

Clinical Uses of PT/INR

When patients present with unexplained bleeding, measuring the PT/INR can provide valuable insights. An elevated PT/INR suggests a potential issue within the patient’s coagulation system, indicating that something may be wrong.^4,5 Conversely, if the PT is normal, healthcare providers may need to investigate alternative causes for the bleeding, as the coagulation factors may not be the source of the problem. Table 1 describes several important clinical applications for the PT and INR.^4,5

Table 1. Clinical Uses for the Prothrombin Time and International Normalized Ratio^4,5
Warfarin monitoring	PT and INR are crucial for managing patients on warfarin therapy, as warfarin interferes with the synthesis of certain clotting factors, including factor II (prothrombin).
General assessment of anticoagulation state	These tests provide a general overview of a patient's anticoagulation status, helping clinicians determine if the anticoagulation therapy is effective.
Assessment of liver disease and synthetic function	The PT can also reflect the synthetic function of the liver, as the liver produces several clotting factors. Prolonged PT may indicate liver dysfunction.
Diagnosing disseminated intravascular coagulation (DIC)	An elevated PT/INR can serve as a diagnostic indicator for DIC, a serious condition characterized by widespread clotting and subsequent bleeding.
ABBREVIATIONS: INR = International Normalized Ratio; PT = prothrombin time

Factors That Prolong the PT/INR

Several factors can influence PT/INR, complicating the monitoring of patients on warfarin therapy^4,5,9:

Warfarin: The primary medication affecting PT/INR, warfarin requires careful monitoring to ensure that patients remain within the therapeutic range.
Other anticoagulant drugs: Direct oral anticoagulants (DOACs) and argatroban can impact PT/INR readings. For instance, transitioning a patient from argatroban to warfarin requires caution, as argatroban significantly increases INR measurements, potentially leading to misleading results.
Heparin and low molecular weight heparins (LMWH): Although traditional references indicate that these medications affect PT measurements, modern reagents, and laboratory techniques typically correct for this interference, making it less of a clinical concern.
Liver disease: The PT is a reliable indicator of both anticoagulation status and liver function. Patients with severe liver disease often present with elevated PT values due to impaired clotting factor synthesis.
Vitamin K deficiency: Poor dietary intake or nutritional issues can lead to vitamin K deficiency, resulting in elevated PT levels.
Coagulation factor deficiencies: Genetic disorders that reduce the production of specific coagulation factors can also manifest as elevated PT, even if they are not related to liver disease.
Antiphospholipid antibodies: The presence of these antibodies can influence PT measurements, adding another layer of complexity in monitoring anticoagulation.

It is crucial to consider these factors when monitoring patients on warfarin therapy, as they can significantly affect PT/INR results beyond the effects of the medication itself.

Understanding Warfarin Monitoring and Its Mechanism

Warfarin inhibits the production of vitamin K-dependent coagulation factors, specifically Factors II, VII, IX, and X, along with proteins C and S. The INR is particularly effective for monitoring warfarin therapy because it directly measures Factors II, VII, and X.¹⁰

Anticoagulation does not occur immediately upon achieving adequate warfarin serum levels. Instead, anticoagulation begins when the serum levels of affected coagulation factors decrease. Warfarin reduces the production of these factors rather than directly affecting them. The half-lives of these factors vary significantly^11,12:

Factor VII has a short half-life of approximately three to six hours, causing it to decrease quickly.
Factor II (prothrombin) has a long half-life of about 24 to 48 hours (and up to 60 hours), making it the most significant factor in determining the time it takes for warfarin to become effective.

This long half-life is why it takes a couple of days for warfarin to exert its full anticoagulant effect; the therapy is essentially waiting for Factor II levels to decrease adequately.

Monitoring Warfarin Therapy: When and How Often?

The frequency of monitoring may vary depending on whether the patient is treated in an inpatient or outpatient setting. In 2018, The Joint Commission published National Patient Safety Goals for anticoagulant therapy, highlighted below.¹³

Baseline PT/INR Testing

Before initiating warfarin therapy, obtaining a baseline PT/INR level is crucial. The Joint Commission mandates this step to ensure no underlying deficiencies in coagulation factors could affect future monitoring.¹³ Clinicians can order baseline testing on the day therapy starts or use a previous test, if the results are relevant. For stable patients, a result from a month or two ago may suffice. However, if the patient has fluctuating liver function or other issues, the baseline should be determined from a more recent test.¹³

Monitoring Schedule After Initiating Warfarin

After establishing the baseline, the timing for subsequent INR testing is essential. Testing the INR the day after the first dose of warfarin may not provide significant insights since coagulation factors usually take at least two days to decrease.^11,13 In rare cases, if a higher-than-expected dose is administered, especially in elderly patients with comorbidities and drug interactions, a noticeable increase in INR might occur within the first day or two. However, routine daily testing is typically unnecessary.

Generally, clinicians don't see significant changes until day three after starting therapy.¹² Warfarin’s full effects are usually evident within five to seven days.¹²

For stable patients, there’s some debate regarding the frequency of testing. Typically, unstable patients may need testing every few days to once a week.¹² Clinicians can monitor stable patients less frequently, often every four weeks or, in some cases, even every 12 weeks. Other modules will discuss lengthening the testing interval.¹²

PAUSE AND PONDER: What alternative methods can we use to monitor warfarin therapy without relying on PT/INR?

The alternative method for monitoring warfarin therapy in patients with antiphospholipid antibody syndrome is to measure Factor II or Factor X activity levels.¹⁴ (In other patients, measuring these indices may confirm pharmcodynamic issues.) While the PT/INR tests provide a broad assessment of coagulation factors affected by warfarin, monitoring just one of these factors can be sufficient.¹⁴ Ordering a factor level test is typically straightforward, similar to any other blood test. However, it’s important for clinicians to ensure that the lab understands that a Factor X activity level, not an anti-Factor Xa level, is needed. These are different tests altogether.

Factor activity levels are reported as a percentage of normal, indicating how much the factor has decreased compared to a healthy individual. For instance, a Factor X level between 24% and 45% of normal correlates with an INR of 2-3.^15-17 This approach allows continuous monitoring of these patients without relying on INR, which may be unreliable due to the interference caused by their condition. The module on challenging topics covers this subject in more depth.¹⁸

Activated Partial Thromboplastin Time

The aPTT, or simply PTT, is a test that measures the time it takes for plasma to clot after exposure to a reagent, but importantly, it does not use tissue factor. The aPTT specifically assesses the intrinsic pathway down to the common pathway.^4,5

Normal Ranges and Variability

The normal range for aPTT is highly dependent on the laboratory equipment and reagents used, similar to PT testing. However, unlike PT, there is no standardization mechanism like the INR to correct aPTT results. Each laboratory, along with its reagents and testing equipment, will have its own normal values, generally falling between 25 to 35 seconds.¹⁹

Additionally, the behavior of aPTT results can vary significantly; for example, as heparin is administered, the aPTT will increase over time.¹⁹ This response can differ between labs and within the same lab if they change reagent companies or reagent lot numbers. Therefore, continuous testing and calibration are essential to ensure accuracy in aPTT results.

Establishing aPTT Therapeutic Range for Heparin Monitoring

Given the variability in aPTT testing, it is crucial to ensure that the therapeutic range for heparin is accurately established based on the specific reagents and tests being used. Each laboratory must perform a correlation whenever it introduces new equipment or switches reagent lot numbers.

Guidelines for Establishing PTT Range

Laboratories must adapt the PTT range based on the responsiveness of the reagent and the coagulometer in use.^20,21 The recommended approach is as follows:

Select a therapeutic PTT range: This range should correlate with a heparin level of 0.3 to 0.7 units.
Sample collection: Collect blood samples from patients receiving heparin therapy.
Testing with anti-Factor Xa: Measure the heparin levels in the blood using an anti-Factor Xa test.
Regression analysis: Conduct a regression analysis to determine the appropriate PTT range that corresponds to the established therapeutic range for your heparin protocol.

This process ensures that the PTT monitoring accurately reflects heparin’s therapeutic effect, thereby enhancing patient safety and treatment efficacy.

Interpreting Regression Analysis for Heparin Monitoring

Figure 1. Regression Analysis for Heparin Monitoring²²

Figure 1 illustrates a regression analysis used to establish the therapeutic range for heparin monitoring. In this analysis, researchers evaluated a cohort of patients to determine their PTT values in relation to their anti-Factor Xa heparin levels. By plotting this data on a graph and drawing reference lines, the laboratory defined the appropriate PTT therapeutic range for its heparin protocols. In this cohort, the therapeutic PTT range appeared to be approximately 60 to 120 seconds, represented by the horizontal lines that correspond to heparin levels of 0.3 to 0.7 units.²²

However, as highlighted in the circled areas, clusters of patients experienced significant variability²²:

Supra-therapeutic patients: The group in the upper right corner appeared to have PTT values within the therapeutic range but were actually supra-therapeutic with respect to their heparin levels.
Sub-therapeutic patients: Conversely, the circled group in the middle had PTT values indicating they were slightly sub-therapeutic, even though their actual heparin levels were adequate.

This variability can lead to unnecessary dose adjustments, as some patients may be treated for perceived under-dosing although their anticoagulation therapy is effective.

The take-home message is clear: interpatient variability and the differences in testing methods necessitate continuous adjustments to the therapeutic range for heparin protocols. Each time a laboratory receives a new reagent lot or changes equipment it must re-evaluate and adjust the therapeutic range accordingly to ensure optimal patient care.²²

Clinical Uses of aPTT

Table 3 demonstrates how the aPTT test serves several important clinical functions.

Table 3. Clinical Uses of the aPTT^4,5
Indication	Clinical Pearls
Monitoring heparin therapy	Therapeutic ranges are typically established at 1.5 to 2.5 times the control value of the PTT. However, the most accurate method for determining this range is through regression analysis, as recommended by the CHEST guidelines and other major medical organizations.
Monitoring direct thrombin inhibitors (DTIs)	aPTT can also be used to monitor patients receiving injectable DTIs (i.e., argatroban)
General assessment of anticoagulation status	aPTT serves as a general screening tool to assess the overall state of the coagulation system.
Diagnosing DIC
ABBREVIATIONS: aPTT = activated partial thromboplastin time; DIC = disseminated intravascular coagulation; DTI = direct thrombin inhibitors

Factors That Prolong aPTT

Several factors can lead to an elevated aPTT²³:

Heparin and DTIs are well-known for prolonging the aPTT due to their mechanisms of action within the coagulation cascade.
DOACs can prolong the aPTT, but this test is not reliable for monitoring these agents.
Liver disease can serve as a general marker for coagulation status and may prolong the aPTT.
Specific factor deficiencies, such as hemophilia A or B, where specific coagulation factors are deficient, will result in prolonged aPTT.
Antiphospholipid antibodies can interfere with coagulation testing, leading to aPTT prolongation. Although the impact on aPTT is not as significant as on INR, patients with antiphospholipid syndrome may still experience coagulation issues.

Understanding these factors is crucial for interpreting aPTT results accurately and making informed decisions regarding patient management.

THROMBIN TIME OVERVIEW

Thrombin time (TT) is a laboratory test that measures the time it takes for fibrinogen to convert to fibrin,²⁴ marking the final step in the coagulation cascade. Unlike other coagulation tests, TT specifically focuses on this critical transition, which results in clot formation. The normal range for TT typically falls between 14 to 19 seconds. However, this can vary depending on the specific laboratory equipment and reagents used. As with the other tests, the TT is highly dependent on the specific methods and instruments employed in the laboratory.²⁴

Clinical Uses of TT

TT is not commonly used as a broad screening tool due to its specificity to the final step of coagulation. However, Table 4 lists the clinical situations in which it is invaluable.

Table 4. Situations in which TT is Invaluable²⁴
Situation	Notes
Evaluation of fibrinogen disorders	Abnormalities in the conversion of fibrinogen to fibrin this process can indicate issues with fibrinogen production or functionality. Abnormal TT results may indicate disorders that affect fibrinogen levels or structure.
Detection of heparin	If there is uncertainty about whether a plasma sample has been contaminated with heparin, TT can definitively confirm its presence. This is especially useful in situations where other tests may be inconclusive.
Diagnosis of DIC	In cases of DIC involving excessive clotting and subsequent bleeding, abnormalities in fibrinogen levels and conversion can be detected through prolonged TT.
ABBREVIATIONS: DIC = disseminated intravascular coagulation; TT = thrombin time

Although TT is a valuable test for specific conditions, it is not typically used as a general screening test for coagulation disorders.²⁴ Since it measures only the final step of the coagulation process, it does not provide comprehensive insight into earlier steps in the cascade. Therefore, its use is generally reserved for diagnosing issues directly related to fibrinogen conversion, such as inherited fibrinogen disorders, heparin contamination, or DIC.²⁴

ACTIVATED WHOLE BLOOD CLOTTING TIME

The activated whole blood clotting time (ACT) is a laboratory test used to assess the time it takes for whole blood to clot when exposed to a reagent that activates the intrinsic pathway of coagulation.²⁵ Unlike other coagulation tests that use plasma samples, ACT measures the clotting time of whole blood, making it unique in this regard. The normal range for ACT typically falls between 70 and 120 seconds, although the time can vary depending on the specific laboratory equipment, reagents, and protocols used. As with other coagulation tests, the normal range is highly dependent on the testing environment.²⁵

Clinical Uses of ACT

ACT is primarily used in clinical settings where large doses of heparin are administered, such as during procedures in a cardiac catheterization lab (Cath Lab) or during cardiopulmonary bypass. Table 5 explains these uses in more detail. It is a quicker, more reliable alternative to other coagulation tests, particularly when measuring the effects of high doses of heparin.

Table 5. Clinical Uses for the Activated Whole Blood Clotting Time²⁵
Monitoring heparin during large doses	Heparin is commonly used to prevent clotting during invasive procedures, and in the Cath Lab. Regular heparin infusions usually involve a bolus dose of around 80 units/kg. However, in the Cath Lab, the heparin dose can range from 300 to 400 units/kg. Under these conditions, other coagulation tests, such as the PTT, would become excessively prolonged and would be unreliable.
Bedside use in cardiac procedures	One advantage of ACT is quick bedside results for cardiac procedures that require real-time monitoring of anticoagulation. Healthcare providers can adjust heparin administration if needed during critical procedures.
Cardiopulmonary bypass (i.e., open-heart surgery)	Heparin is used to prevent clotting in the bypass machine. In these cases, the therapeutic range for ACT is generally above 480 seconds to ensure proper anticoagulation. For less invasive procedures like cardiac catheterization, the target range is typically 300 to 350 seconds.
ABBREVIATIONS: ACT = activated whole blood clotting time

While ACT is an essential test in certain high-risk procedures, it is not routinely used for general anticoagulation monitoring.²⁵ It is most valuable in settings where high doses of heparin are required, and where quick, real-time results are crucial. Additionally, the normal therapeutic ranges for ACT vary based on the specific procedure being conducted, and so results must be interpreted within the context of the clinical setting.²⁵

PRACTICE PATIENT CASE

A 41-year-old pregnant woman carrying twins is admitted for a DVT. She begins treatment with a heparin drip at 80 units/kg bolus, followed by an 18 units/kg/hour infusion. Over time, her infusion rate is adjusted to approximately 2000 units/hour, which equates to 25.7 units/kg/hour, a relatively high heparin dose. Despite seeming to be in a therapeutic range, she develops gross hematuria, and her hemoglobin drops from 10.4 to 7.9 over four days. Given these complications, the medical team is concerned about why she requires such a large heparin infusion and whether the rate should be reduced.

Key Questions to Ask

Is the patient's weight correct? The first thing to check is whether the patient’s weight was accurately recorded on the scale and entered into the infusion pump. This ensures the proper amount of heparin is being delivered based on her body mass. If the weight was incorrect, it could explain why she is receiving an excessive amount of heparin.
Was the infusion rate correctly calculated? It's crucial to verify that the infusion rate calculation was accurate. Errors in dosage calculations can lead to the patient receiving more heparin than intended, potentially contributing to bleeding complications like the one seen in this case.
Is the patient’s lab work accurate and correctly matched? Mislabeling or mixing up lab work can lead to incorrect patient data being used, which could explain why the infusion rate appears to be appropriate when it is actually too high. Checking that the lab results are from the correct patient is essential.

Testing for Heparin Levels

If the above factors are ruled out and the patient's weight, infusion calculations, and lab results all appear correct, testing the anti-factor Xa level is the next logical step. This test measures the level of heparin activity in the blood and provides a more reliable measure of anticoagulation than other tests like the PTT, which can be influenced by various patient-specific factors.

Anti-factor Xa level: This test would reveal the true extent of heparin activity in the bloodstream. The patient's remarkably elevated anti-Xa levels indicate that she has a high amount of heparin in her system, far beyond what would be expected based on the current infusion rate. This suggests heparin resistance.

Management and Resolution

Upon discovering the elevated anti-Xa levels, the infusion rate was adjusted down to 1500 units/hour, which is closer to typical dosing for patients of this clinical presentation. Following this adjustment, the patient's symptoms resolved, and she was no longer experiencing the bleeding complications associated with excessive heparin.

This case illustrates the importance of monitoring heparin therapy and being aware of heparin resistance. Even though the patient was receiving what seemed to be a therapeutic dose of heparin, the excessive infusion led to bleeding complications. By testing anti-factor Xa levels, the underlying issue was identified and treated. This highlights the need for accurate dosing calculations, laboratory testing to monitor heparin levels, and consideration of heparin resistance in patients who require unusually high doses of the drug to achieve anticoagulation.

HEPARIN RESISTANCE AND APPARENT HEPARIN RESISTANCE

Heparin resistance can be categorized into two types: true resistance and apparent resistance.²⁰ Understanding the differences between these is crucial for diagnosing and managing patients who require unusually high doses of heparin, as was the case with the 41-year-old pregnant patient.

True Heparin Resistance

In true heparin resistance, the patient does not respond to heparin despite receiving therapeutic or even higher-than-expected doses.²⁶ This can happen due to several pharmacokinetic or pharmacodynamic factors, including²⁶

Increased heparin clearance: The patient's body may metabolize heparin faster than expected, requiring higher doses to maintain therapeutic anticoagulation.
Increased heparin-binding proteins: Some patients have elevated levels of plasma proteins that bind to heparin, effectively reducing the amount of free, active heparin available to exert its anticoagulant effect.
Altered volume of distribution: Changes in the patient's body composition, such as a higher volume of distribution, can affect how heparin is distributed throughout the body, requiring higher doses to achieve the desired effect.

These factors contribute to the need for much higher doses of heparin to achieve the expected anticoagulant effect, making it a true form of resistance to the drug.

Apparent Heparin Resistance

In contrast, apparent heparin resistance refers to a situation where the patient appears to require more heparin than expected, but the issue is not due to pharmacokinetic resistance.²⁶ In the case of apparent heparin resistance, the PTT does not accurately reflect the patient's anticoagulant status. For example, elevated levels of coagulation factors like Factor VIII can lead to a falsely short PTT, suggesting that the patient is adequately anticoagulated when, in reality, they may require higher doses of heparin to achieve the correct therapeutic effect. This condition can make it difficult to assess the patient's true anticoagulation status, which can lead to the overuse of heparin and the risk of bleeding complications.²⁶

ANTI-FACTOR Xa TEST

The anti-factor Xa test is an important when using drugs like heparin, enoxaparin, and dalteparin. Unlike clotting tests like the PTT, the anti-factor Xa test does not measure clotting time. It is a functional test that quantifies the enzymatic activity involved in coagulation. The test is often referred to as chromogenic anti-factor Xa because it involves a color change as a result of the chemical reaction between the reagent and the substance being tested.^4,5

The chromogenic test measures the activity level of Factor Xa, which is essential for blood clotting. In the presence of a specific anticoagulant (such as heparin), the test measures the inhibition of Factor Xa activity.^4,5 The results are reported in units/mL (e.g., units of heparin per mL), which indicates the concentration of the anticoagulant drug in the patient’s blood. The normal range for this test is 0, meaning if there's no drug present, there’s no activity detected, and the test result is zero.^4,5

Clinical Uses of Anti-Factor Xa Testing

A primary uses of anti-factor Xa is to monitor heparin therapy, especially in institutions where heparin infusions are used for anticoagulation.²⁰ This test has become more commonly used than PTT for monitoring heparin therapy due to its simplicity and lack of interference from factors like factor XIII levels or warfarin. Anti-factor Xa can also be used to monitor LMWHs (e.g., enoxaparin and dalteparin) and fondaparinux, although the calibration curves for these drugs are different. Each drug may have its own specific calibration and the lab will need to adjust accordingly. Some oral anticoagulants, such as direct factor Xa inhibitors (e.g., apixaban, rivaroxaban), can affect coagulation assays. To quantify their activity rapidly and accurately, anti-factor Xa testing must be calibrated specifically to the DOAC being assessed.²⁷

Advantages of anti-factor Xa for monitoring heparininclude²⁸

Less interference: Unlike the PTT test, which can be influenced by many factors (e.g., factor XIII levels, warfarin therapy), the anti-factor Xa test is more specific and free from interference, providing a more reliable result.
No calibration issues: Since anti-factor Xa directly measures drug concentration, there’s no need for recalibration each time new reagent lots are used, unlike with PTT testing. The therapeutic range for heparin is consistently set at 0.3 to 0.7 units per mL, which simplifies monitoring.
Improved accuracy: The anti-factor Xa test provides a more accurate assessment of heparin levels, reducing the chance of over- or under-dosing, which can lead to complications like bleeding or thrombosis. This accuracy reduces the frequency of dosage adjustments and the associated risk of error.
Less frequent retesting: Because there’s less need for frequent adjustments in dosing, patients may require fewer tests, which reduces laboratory workload and improves overall patient care.

Anti-factor Xa Testing for LMWHs and Fondaparinux

The use of anti-factor Xa testing for LMWHs like enoxaparin and dalteparin, and fondaparinux, has been an area of ongoing discussion. While it is not universally required for all patients on these medications, testing can provide valuable information and improve patient safety in specific situations.²⁹

In patients who are extremely obese or very small (i.e., children), the pharmacokinetics of LMWHs can be unpredictable.³⁰ These patients may have altered drug clearance or distribution, meaning they may handle the drug differently than expected based on weight alone. In these cases, testing can ensure that the drug is working effectively and that the patient is within a therapeutic range.²⁹

Renal dysfunction is another consideration.²⁹ Patients with impaired renal function may not clear LMWH or fondaparinux as efficiently, leading to drug accumulation and potentially dangerous levels in the bloodstream. Testing anti-factor Xa levels in these patients helps assess if their drug concentrations are within a safe therapeutic window.²⁹

Pregnancy introduces significant pharmacokinetic changes that can affect how LMWH are metabolized.²⁹ These changes are especially pronounced in the third trimester, as women experience substantial physiological shifts, including weight gain, blood volume changes, and increased renal clearance. Regular anti-factor Xa testing during pregnancy, especially in the third trimester, ensures that dosing adjustments are appropriate to maintain effective venous thrombosis prevention without putting the patient at risk of bleeding.²⁹

Prior to surgery, particularly when patients have been on LMWH or fondaparinux, there is a concern about the drug's clearance from the system.³² While guidelines generally recommend holding the dose for about 24 hours before surgery, anti-factor Xa testing can be particularly useful in emergent situations or when there is uncertainty about the drug's clearance. In these cases, testing can provide additional reassurance that the anticoagulant effect has sufficiently diminished before surgical intervention.

Anti-factor Xa Testing for Direct Factor Xa Inhibitors

Routine monitoring of DOAC concentrations is not necessary in standard clinical practice due to their predictable pharmacokinetics and wide therapeutic windows. However, in emergent situations, such as active bleeding, urgent surgical intervention, suspected overdose, or impaired renal function, assessment of anticoagulant activity may be warranted to guide clinical decision-making and ensure patient safety.

In these cases, chromogenic anti-factor Xa assays can be used to measure the anticoagulant effect of factor Xa inhibitors (e.g., apixaban, rivaroxaban, edoxaban). These assays are available in many hospital and reference laboratory settings and can provide relatively rapid and quantitative estimations of drug levels, provided they are calibrated specifically to the DOAC in question. While not universally available, when accessible and properly calibrated, they serve as a valuable tool for managing complex or high-risk situations involving DOAC therapy.³²

COAGULATION FACTOR ACTIVITY TESTING

Coagulation factor activity testing is a straightforward, valuable method for evaluating various factors involved in the coagulation cascade.^4,5 This test is especially useful in diagnosing factor deficiencies or other coagulation abnormalities. The most common reason for performing coagulation factor activity testing is to diagnose hereditary bleeding disorders caused by deficiencies in one or more coagulation factors. These include hemophilia A (a Factor VIII deficiency) and hemophilia B (a Factor IX deficiency). This testing may identify other rarer factor deficiencies that could result in bleeding problems.^4,5

While INR is most commonly used for warfarin monitoring, coagulation factor activity testing can be employed as an alternative method. This might be necessary in cases where INR results are unreliable or not available, or when more specific information about the patient’s coagulation status is needed.

D-DIMER TEST

D-dimer is a protein fragment produced when plasmin breaks down fibrin, a major component of blood clots.³³ This process occurs during fibrinolysis. In simple terms, when a blood clot forms and then begins to dissolve, D-dimer is released into the bloodstream. The normal range for D-dimer levels can vary depending on the method of testing (whole-blood agglutination assays, ELISA [enzyme-linked immunosorbent assay], or latex immunoagglutination method) and each test manufacturer establishes the normal range and different assay manufacturers use different units (e.g., ng/mL, mcg/mL). Laboratories frequently report the results in units other than those recommended by the assay manufacturer.^24,34

D-dimer testing is most commonly used as a screening tool to help rule out the presence of active thrombotic activity, such as a DVT or a pulmonary embolism (PE).³³ For example, clinicians may order a D-dimer test for a patient presenting with calf pain in the emergency department. If the test comes back with normal D-dimer levels, it essentially rules out an active DVT or PE without needing further, more invasive testing like ultrasound.³³

In patients who have experienced a previous thrombotic event (e.g., DVT or PE), D-dimer testing can help determine whether ongoing anticoagulation therapy is needed. Elevated D-dimer levels approximately one month after the acute event might suggest an increased risk of recurrence, and the patient may need to continue anticoagulation therapy for a longer period.^33-36 Conversely, normal D-dimer levels can suggest the risk of recurrence is low, and the patient may be safely transitioned off anticoagulation therapy, depending on other clinical factors.^35,36

PRACTICE PATIENT CASE

Joyce has been on warfarin and has maintained a therapeutic INR range for the past six weeks. She comes into your outpatient anticoagulation clinic, and reports no changes to her diet, exercise, or overall health. Her POC test result on your clinic’s machine shows an INR of 4.7. Following clinic policy, you send Joyce to the lab for venipuncture to confirm this critical value. After a couple of hours, the lab result comes back with an INR of 3.2. Now, you're in a bit of a dilemma. You inform Joyce of the new lab result, and she asks why there's a discrepancy, what test she should trust, and why the POC result isn’t aligning.

What to Communicate with the Patient

Despite advances, we have been unable to fully standardize INR testing across different methods. The fact that two testing methods yield different results does not automatically mean that one is correct and the other is incorrect; both could be slightly inaccurate. In medical testing, there are distinctions between accuracy, reliability, and repeatability, all of which contribute to overall test validity. Repeatability—how consistently a test produces the same result—is an important factor in assessing reliability.

The medical community and laboratory testing guidelines generally accept that a difference of 0.5 INR units between two different testing methods is reasonable. However, in clinical practice, a 0.5 INR difference can be significant.³⁷ When managing warfarin therapy, such a discrepancy might mean the difference between adjusting a patient’s dose or keeping it the same, which adds to the complexity of interpreting INR results.

Ultimately, when discussing test discrepancies with patients, it's essential to reassure them that variability is expected and that INR management is based on trends rather than single data points. Clinical judgment, alongside repeat testing when necessary, helps ensure that anticoagulation therapy remains both safe and effective.

POINT OF CARE TESTING

Point of care testing (POCT) refers to the use of small, often handheld devices to perform diagnostic tests outside of a traditional laboratory. One of its earliest applications was INR testing, allowing INR measurements to be performed at the bedside or in outpatient settings.

POCT’s advantages include³⁸

Rapid turnaround time: INR results, for example, can be obtained in about a minute, whereas lab testing takes significantly longer.
Home testing capability: Patients can monitor their INR levels at home, improving convenience and adherence.
Ease of use: POCT devices are designed for simple operation, making them accessible for both healthcare providers and patients.

POCT also has some disadvantages.³⁹ POCT devices tend to be expensive, both in terms of initial purchase and per-test cost compared to traditional lab testing. In addition, each device has specific testing guidelines. These may include temperature sensitivity, hematocrit limitations, and other operational constraints. However, for the majority of patients, these devices function effectively without issues.³⁹

Understanding INR Result Discrepancies

Result variability issue has long been recognized, which is why the WHO introduced the INR system to standardize results across different testing methods. However, even with standardization, variation still exists because different thromboplastin reagents are used in different testing systems.

One key limitation is that thromboplastins are only standardized for their International Sensitivity Index (ISI) up to an INR of approximately 4.0—4.5. Beyond this range, variability between testing methods increases significantly. This means that INR values above 4.5—whether measured by a POC device or a lab test—become less precise.⁴⁰ For example, all healthcare clinicians should interpret an INR of 5.0, 6.0, or 7.0 with caution, as these values are more of an estimation than an exact measurement.

Device Correlation Testing

When comparing INR results from different testing methods, we essentially perform correlation testing. This process assesses how well two testing methods align by analyzing multiple samples side by side and plotting the results on a correlation graph. Studies commonly use this approach, where investigators compare two or more devices by testing the same samples simultaneously and then measuring how closely the results match. A strong correlation, often above 90%, suggests that the methods are generally in agreement. However, these studies rarely explain the inconsistencies visible in the data.

Correlation testing does not determine whether one method is "right" or "wrong"; it simply tells us how similar or different the results are between two methods. There is no true gold standard for INR measurement. No single test can definitively provide the "correct" INR. Many assume that the laboratory venipuncture method is the gold standard simply because it has been used the longest and is more complex. Recent studies have generally found that both methods tend to be accurate provided the testing devices are well-maintained and calibrated.^41-43

Pre-analytical errors in INR testing occur before the test is even run, affecting both POC and venipuncture testing methods. Pre-analytical errors can introduce variability into the results, making it harder to interpret the patient’s true anticoagulation status. Table 6 explains these errors in more detail.

Table 6. Pre-Analytical Errors in INR Testing⁴⁴

POC Error

Squeezing finger too hard

Too much time between lancing and applying blood to the test strip

Improper storage of test strip

Venipuncture Error

Under/over-filling the collecting tube

Low HGB/HCT

Device not calibrated appropriately

ABBREVIATIONS: HCG/HCT = hemoglobin/hematocrit; INR = International Normalized Ratio; POC = point of care

Understanding pre-analytical errors highlights how both POC and venipuncture tests are susceptible to variability—even before testing begins. Recognizing these potential issues reinforces the need to interpret INR results cautiously, especially when discrepancies arise between testing methods. Proper sample collection techniques, equipment calibration, and awareness of external factors all play vital roles in producing accurate and reliable test results.

Evidence Supporting the Accuracy of POC INR Testing

How do we know that POC INR devices are reliable? The answer lies in extensive clinical evidence. Numerous large-scale clinical trials have demonstrated that these devices provide accurate and effective INR monitoring, leading to positive patient outcomes. In fact, some of the most significant trials in anticoagulation therapy—such as ARISTOTLE (for apixaban)⁴⁵ and ROCKET AF (for rivaroxaban)^30,31—used POC devices to monitor patients taking warfarin. These studies achieved excellent results, showing effective stroke prevention with low bleeding risks, reinforcing confidence in the reliability of POC INR testing.

Key Takeaways

POC devices are clinically validated. They have been used in major anticoagulation trials and have consistently produced reliable results. When clinicians receive an unexpected out-of-range INR, they must consider all possible factors:

Could a pre-analytical error be affecting the test?
Did the patient take an over-the-counter medication that interacted with warfarin?
Is there an adherence issue that the patient forgot to mention?

Single abnormal results are no reason to panic. If the result seems inconsistent with the patient’s history and condition, a simple retest may be the best approach rather than immediately adjusting therapy.

ORAL ANTICOAGULATION

DOACs do not require routine monitoring due to their predictable pharmacokinetics and pharmacodynamics. However, laboratory testing can be useful in urgent situations to determine if the drug is still in the system. Table 7 lists the standard laboratory tests that can be used to monitor these anticoagulation agents.

Table 7. Laboratory Testing for DOACs⁴⁶
	Coagulometric Method(s)	Chromogenic Method(s)
Dabigatran	DTT, ECT	ECA, Anti-FIIa
Apixaban	–	Anti-FXa calibrated with apixaban
Rivaroxaban	–	Anti-FXa calibrated with rivaroxaban
Edoxaban	–	Anti-FXa calibrated with edoxaban
ABBREVIATIONS: DOACs = direct oral anticoagulants; DTT: dilute thrombin time; ECT: ecarin clotting time; ECA: ecarin chromogenic assay

Liquid Chromatography-Mass Spectrometry

Liquid chromatography-mass spectrometry (LC-MS) is considered the gold standard for measuring direct oral anticoagulants (DOACs) due to its high specificity, sensitivity, selectivity, and reproducibility.²⁷ However, its use is limited in routine practice because of the complexity and labor-intensive nature of the method. LC-MS requires expensive equipment and highly trained personnel to perform the test correctly. As a result, while not routinely used in clinical practice, LC-MS serves as the reference method against which other testing methods are compared to assess their accuracy.²⁷

Laboratory Testing for Dabigatran

Dilute Thrombin Time

Dilute thrombin time (DTT) is a coagulometric method specifically designed to measure the concentration of dabigatran.⁴⁷ It is a modification of the standard TT, which is extremely sensitive to dabigatran and often becomes excessively prolonged. By using a diluted thrombin reagent, DTT establishes a linear relationship between dabigatran concentration and clotting time, allowing for more accurate and quantitative assessment of the drug's anticoagulant activity. LC-MS is extensively used for research and clinical trials, but it cannot be used in routine conditions for rapid testing in laboratories.

Ecarin Clotting Time

The Ecarin Clotting Time (ECT) is a highly sensitive qualitative test where clotting time is directly related to dabigatran concentrations.⁴⁸ In this assay, ecarin, a metalloprotease enzyme derived from the venom of Echis carinatus (the saw-scaled viper), is added to the plasma sample. Ecarin converts prothrombin to meizothrombin, an intermediate that promotes clotting. In the presence of dabigatran, however, the conversion of prothrombin is inhibited, resulting in a prolonged clotting time.⁴⁸

The ECT has a linear dose-response relationship and can be used to measure dabigatran levels within the therapeutic range. Due to its simplicity, the ECT can be automated for use with modern coagulation analyzers, although performance verification is required for accuracy.⁴⁸

While the ECT is primarily a research tool with limited clinical availability in the United States, the development of commercial kits could potentially improve its practicality. However, these kits have not been fully standardized or validated for dabigatran, and thus their use may be problematic.⁴⁸

It is important to note that low prothrombin levels or hypofibrinogenemia can lead to falsely elevated clotting times that are disproportionate to dabigatran or other DTI concentrations. For these reasons, the ECT is not recommended for emergency monitoring of anticoagulant effects, despite its inclusion in some prescribing information.

Ecarin Chromogenic Assay

The Ecarin Chromogenic Assay (ECA) is a quantitative coagulometric test specifically designed to assess the concentration of dabigatran, a DTI.⁴⁸ Unlike some other coagulation tests, the ECA is not influenced by levels of prothrombin or fibrinogen, which can cause inaccurate results in other assays. This makes the ECA particularly useful in clinical situations where these factors may be variable, such as in patients with coagulopathies or low fibrinogen levels. The linear dose-response relationship between dabigatran concentration and clotting time allows the ECA to provide precise, quantitative measurement across the therapeutic range.⁴⁸

Although the ECA is a reliable method for assessing dabigatran activity, it is not widely available due to its complexity and the need for specialized equipment.⁴⁸ The assay requires appropriate calibration and performance verification to ensure accuracy. While it has shown promise for emergency settings, such as in cases of bleeding or urgent surgery, its clinical use is still somewhat limited, primarily due to availability issues and the high cost of the reagents.⁴⁸

Despite these limitations, the ECA remains a valuable tool for assessing the anticoagulant effect of dabigatran in specialized clinical scenarios where precise quantification of drug levels is necessary.

Anti-Factor IIa Testing for DTIs

The anti-factor IIa assay is a valuable tool for the precise quantification of the anticoagulant effect of DTIs, such as dabigatran.⁴⁷This assay works by measuring the cleavage of a thrombin substrate in the plasma. Plasma is mixed with the substrate, which is typically cleaved by thrombin to produce a measurable signal. If dabigatran is present, it inhibits thrombin activity, leading to a decrease in substrate cleavage. As a result, the extent of inhibition correlates with the dabigatran concentration. This assay is particularly useful in situations where accurate quantification of dabigatran levels is critical, such as in emergency scenarios or for monitoring patients with renal impairment.⁴⁸

CONCLUSION

When it comes to clotting and anticoagulation, pharmacists need expertise. They must consider the reason for the testing, be it screening, diagnosis, or monitoring. Patient factors complicate the decision, and unexpected results need to be researched and mitigated. Laboratory results are the clues that inform the detective work of anticoagultion.

1. Which of the following laboratory test measures both the extrinsic and common coagulation pathways?
A. Activated Partial Thromboplastin Time
B. activated whole blood clotting time
C. Prothombin time

2. Which of the following is a situation in which the INR would be the preferred test?
A. Diagnosing disseminated intravascular coagulation
B. Establishing a therapeutic range for heparin
C. Bedside use in cardiac procedures

3. In which situation would the anticoagulation team need to employ anti-factor Xa testing for patients using LMWH?
A. In patients with hepatic impairment
B. In post-surgical patients
C. In patients who are extremely obese or very small

4. Alejandro is a gentleman who has received acute treatment for a pulmonary embolism. He has antiphospholipid syndrome. He also has a heart block. Which of the following tests should your anticoagulation team use to monitor warfarin going forward?
A. Factor X activity level
B. Anti-Factor Xa level
C. INR/PTT

5. What do factor activity levels measure?
A. Factor activity levels are reported the laboratory’s geometric mean level, indicating how the factor compares to more than 20 normal individuals.
B. Factor activity levels are reported as a percentage of normal, indicating how much the factor has increased compared to a healthy individual.
C. Factor activity levels are reported as a percentage of normal, indicating how much the factor has decreased compared to a healthy individual.

6. A patient’s INR seems “off.” It remains elevated despite adjustments in warfarin doses. The pharmacist thinks it’s a pharmacodynamic issue. What should the anticoagulation team check?
A. INR, but use a different lab
B. Factor II and factor X activity
C. Anti-Factor Xa level

7. In which of the following situations would the Activated Whole Blood Clotting Time (ACT) be used?
A. Monthly monitoring of patients with APS
B. Bedside Use in Cardiac Procedures
C. Routine monitoring in pregnant women

8. A 34-year-old pregnant woman is admitted for a DVT. The attending orders a heparin drip at 80 units/kg bolus, followed by an 18 units/kg/hour infusion. Over time, her infusion rate is adjusted to approximately 2000 units/hour, which equates to 25.7 units/kg/hour, a relatively high heparin dose. She report to the nurse that she is “peeing blood.” A STAT hemoglobin indicates it has dropped 11.2 to 6.8 since admission. Given these complications, which of the following steps should the medical team do FIRST?
A. Ascertain that the patient is indeed pregnant and it is not twins
B. Draw the anti-factor Xa level
C. Confirm that the data was entered into the infusion pump correctly

9. Which of the following can be monitored using the anti-factor Xa test?
A. heparin, enoxaparin, and dalteparin
B. heparin, apixiban, and rivaroxiban
C. enoxaparin, dalteparin, and warfarin

10. This is a description of a device: reports test results rapidly, convenient for patients, is easy to use. What is it?
A. Laboratory-based testing
B. Point-of-care testing device
C. Correlation testing

11. What does correlations testing measure?
A. Which method is right and which method is wrong
B. The quantity of blood in the patient’s sample
C. Differences between the results from two methods

12. Jack is a patient on warfarin who works as a laborer. He uses POC testing. He has had three unexpected out-of-range INRs in the last five days. What is the MOST LIKELY reason?
A. Nonadherence
B. Pregnancy
C. OTC medication use

References

Chaturvedi S, Brodsky RA, McCrae KR. Complement in the Pathophysiology of the Antiphospholipid Syndrome. Front Immunol. 2019;10:449. doi:10.3389/fimmu.2019.00449
Blennerhassett R, Favaloro E, Pasalic L. Coagulation studies: achieving the right mix in a large laboratory network. Pathology. 2019;51(7):718-722.
Dorgalaleh A, Favaloro EJ, Bahraini M, Rad F. Standardization of Prothrombin Time/International Normalized Ratio (PT/INR). Int J Lab Hematol. 2021;43(1):21-28.
Dela Pena LE. 2013. Hematology: blood coagulation tests. In: M. Lee, editor. Basic skills in interpreting lab reports. 5^th ed. Bethesda (MD): ASHP. P 373‐399.
DeMott WR. 1994. Coagulation. In: Jacobs et al, editor. Laboratory test handbook. 3rd ed. Hudson (OH): Lexi‐Comp. P398‐480
Riley RS, Rowe D, Fisher LM. Clinical utilization of the international normalized ratio (INR). J Clin Lab Anal. 2000;14(3):101-114. doi:10.1002/(sici)1098-2825(2000)14:3<101::aid-jcla4>3.0.co;2-a
McRae HL, Militello L, Refaai MA. Updates in Anticoagulation Therapy Monitoring. Biomedicines. 2021;9(3):262. doi:10.3390/biomedicines9030262
Gardiner C, Coleman R, de Maat MPM, et al. International Council for Standardization in Haematology (ICSH) laboratory guidance for the evaluation of haemostasis analyser-reagent test systems. Part 1: Instrument-specific issues and commonly used coagulation screening tests. Int J Lab Hematol. 2021;43(2):169-183. doi:10.1111/ijlh.13411
Lau M, Huh J. Retrospective Analysis of the Effect of Argatroban and Coumadin on INR Values in Heparin Induced Thrombocytopenia. Blood. 2006;108(11):4118. https://doi.org/10.1182/blood.V108.11.4118.4118
Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S-198S. doi:10.1378/chest.08-0670
7 Procoagulators. Transfus Med Hemother. 2009;36(6):419-436.
COUMADIN (warfarin) prescribing information. Bristol-Myers Squibb Company. Accessed April 11, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009218s108lbl.pdf
The Joint Commission. R³Report—Requorement, Rationale, Reference. National Patient Safety Goals for Anticoagulant Therapy. Accessed April 10, 2025. https://www.jointcommission.org/-/media/tjc/documents/standards/r3-reports/r3_19_anticoagulant_therapy_rev_final1.pdf?db=web&hash=7C6FA69A5DF9294B7BADF2B52C653FCA
Masucci M, Li Kam Wa A, Shingleton E, Martin J, Mahir Z, Breen K. Point of care testing to monitor INR control in patients with antiphospholipid syndrome. EJHaem. 2022;3(3):899-902. doi:10.1002/jha2.522
Rosborough TK, Jacobsen JM, Shepherd MF. Relationship between chromogenic factor X and international normalized ratio differs during early warfarin initiation compared with chronic warfarin administration. Blood Coagul Fibrinolysis. 2009;20(6):433-435. doi:10.1097/MBC.0b013e32832ca31f
Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med. 1997; 127:177–185.
McGlasson DL, Romick BG, Rubal BJ. Comparison of a chromogenic factor X assay with international normalized ratio for monitoring oral anticoagulation therapy. Blood Coagul Fibrinolysis. 2008; 19:513–517.
Moll, S AntiphospholipidAntibody Syndrome and Thrombosis. Accessed April 30, 2025. Webinar archived at http://www.standingstoneinc.com/Webinars/WebinarArchive.aspx
What Is The Normal Range For PTT? | Essential Insights. Accessed April 11, 2025. https://wellwisp.com/what-is-the-normal-range-for-ptt/
Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) [published correction appears in Chest. 2008 Aug;134(2):473]. Chest. 2008;133(6 Suppl):141S-159S. doi:10.1378/chest.08-0689
May JE, Siniard RC, Taylor LJ, Marques MB, Gangaraju R. From Activated Partial Thromboplastin Time to Antifactor Xa and Back Again. Am J Clin Pathol. 2022;157(3):321-327. doi:10.1093/ajcp/aqab135
Bates SM, Weitz JI, Johnston M, Hirsh J, Ginsberg JS. Use of a fixed activated partial thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med. 2001;161(3):385-391. doi:10.1001/archinte.161.3.385
Barbosa ACN, Montalvão SAL, Barbosa KGN, et al. Prolonged APTT of unknown etiology: A systematic evaluation of causes and laboratory resource use in an outpatient hemostasis academic unit. Res Pract Thromb Haemost. 2019;3(4):749-757. Published 2019 Sep 8. doi:10.1002/rth2.12252
Campbell S. Hemostasis. IN: Contemporary Practice in Clinical Chemistry. Academic Press, 2020. 445-467.
Evidence-based Medicine Consult. Lab Test: Activated Clotting Time (ACT; Activated Coagulation Time). Accessed April 11, 2025. https://www.ebmconsult.com/articles/lab-test-act-activated-clotting-time
Maier CL, Connors JM, Levy JH. Troubleshooting heparin resistance. Hematology Am Soc Hematol Educ Program. 2024;(1):186–191.
Qiao J, Tran MH. Challenges to Laboratory Monitoring of Direct Oral Anticoagulants. Clin Appl Thromb Hemost. 2024;30:10760296241241524. doi:10.1177/10760296241241524
Francis JL, Groce JB 3rd; Heparin Consensus Group. Challenges in variation and responsiveness of unfractionated heparin. Pharmacotherapy. 2004;24(8 Pt 2):108S-119S. doi:10.1592/phco.24.12.108s.36114
Babin JL, Traylor KL, Witt DM. Laboratory Monitoring of Low-Molecular-Weight Heparin and Fondaparinux. Semin Thromb Hemost. 2017;43(3):261-269. doi:10.1055/s-0036-1581129
ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159(3):340-347.e1. doi:10.1016/j.ahj.2009.11.025
Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and dosing of unfractionated heparin in comparative studies with low-molecular-weight heparin. Ann Intern Med. 2003;138(9):720-723. doi:10.7326/0003-4819-138-9-200305060-00008
Sukumar S, Cabero M, Tiu S, Fang MC, Kogan SC, Schwartz JB. Anti-factor Xa activity assays of direct-acting oral anticoagulants during clinical care: An observational study. Res Pract Thromb Haemost. 2021;5(4):e12528. doi:10.1002/rth2.12528
Weitz, J, Fredenburgh, J, Eikelboom, J. A Test in Context: D-Dimer. JACC. 2017;70(19):2411-2420. https://doi.org/10.1016/j.jacc.2017.09.024
Johnson ED, Schell JC, Rodgers GM. The D-dimer assay. Am J Hematol. 2019;94(7):833-839. doi:10.1002/ajh.25482
Kearon C, Parpia S, Spencer FA, et al. D-dimer levels and recurrence in patients with unprovoked VTE and a negative qualitative D-dimer test after treatment. Thromb Res. 2016;146:119-125. doi:10.1016/j.thromres.2016.06.023
Kearon C, Stevens SM, Julian JA. D-Dimer Testing in Patients With a First Unprovoked Venous Thromboembolism. Ann Intern Med. 2015;162(9):671. doi:10.7326/L15-5089-2
Isert M, Miesbach W, Schüttfort G, et al. Monitoring anticoagulant therapy with vitamin K antagonists in patients with antiphospholipid syndrome. Ann Hematol. 2015;94(8):1291-1299. doi:10.1007/s00277-015-2374-3
Raimann FJ, Lindner ML, Martin C, et al. Role of POC INR in the early stage of diagnosis of coagulopathy. Pract Lab Med. 2021;26:e00238. doi:10.1016/j.plabm.2021.e00238
Medical Advisory Secretariat. Point-of-Care International Normalized Ratio (INR) Monitoring Devices for Patients on Long-term Oral Anticoagulation Therapy: An Evidence-Based Analysis. Ont Health Technol Assess Ser. 2009;9(12):1-114.
Fitzmaurice DA, Geersing GJ, Armoiry X, Machin S, Kitchen S, Mackie I. ICSH guidance for INR and D-dimer testing using point of care testing in primary care. Int J Lab Hematol. 2023;45(3):276-281. doi:10.1111/ijlh.14051
Ganapati A, Mathew J, Yadav B, et al. Comparison of Point-of-Care PT-INR by Hand-Held Device with Conventional PT-INR Testing in Anti-phospholipid Antibody Syndrome Patients on Oral Anticoagulation. Indian J Hematol Blood Transfus. 2023;39(3):450-455. doi:10.1007/s12288-022-01611-4
Bitan J, Bajolle F, Harroche A, et al. A retrospective analysis of discordances between international normalized ratio (INR) self-testing and INR laboratory testing in a pediatric patient population. Int J Lab Hematol. 2021;43(6):1575-1584. doi:10.1111/ijlh.13652
Munir R, Schapkaitz E, Noble L, et al. A Comprehensive Clinical Assessment of the LumiraDx International Normalized Ratio (INR) Assay for Point-of-Care Monitoring in Anticoagulation Therapy. Diagnostics (Basel). 2024;14(23):2683. Published 2024 Nov 28. doi:10.3390/diagnostics14232683
Arine K, Rodriquez C, Sanchez K, Reliability of Point-of-Care International Normalized Ratio Measurements in Various Patient Populations. POC: J of Near-Patient Test & Tech. 2020;19(1):12-18, DOI: 10.1097/POC.0000000000000197
Ogawa S, Shinohara Y, Kanmuri K. Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. -The ARISTOTLE-J study-. Circ J. 2011;75(8):1852-1859. doi:10.1253/circj.cj-10-1183
Margetić S, Goreta SŠ, Ćelap I, Razum M. Direct oral anticoagulants (DOACs): From the laboratory point of view. Acta Pharm. 2022;72(4):459-482. doi:10.2478/acph-2022-0034
Dunois C. Laboratory Monitoring of Direct Oral Anticoagulants (DOACs). Biomedicines. 2021;9(5):445. doi:10.3390/biomedicines9050445
Gosselin RC, Dwyre DM, Dager WE. Measuring Dabigatran Concentrations Using a Chromogenic Ecarin Clotting Time Assay. Annals of Pharmacotherapy. 2013;47(12):1635-1640. doi:10.1177/1060028013509074

Vitamin K Antagonist Pharmacology, Pharmacotherapy and Pharmacogenomics 2025 Revision

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

More Information About Traineeship

1. What is the primary mechanism by which warfarin exerts its anticoagulant effect?
A. Inhibits thrombin directly
B. Inhibits vitamin K epoxide reductase (VKOR)
C. Inhibits platelet aggregation

2. Which clotting factor is most rapidly affected by warfarin therapy due to its short half-life?
A. Factor II (Prothrombin)
B. Factor X
C. Factor VII

3. A patient on warfarin starts amiodarone. What is the most appropriate clinical action?
A. Stop warfarin for 3 days
B. Increase warfarin dose
C. Monitor INR more frequently and adjust dose as needed

4. What is the INR goal range for a patient with a mechanical mitral valve?
A. 2.0–3.0
B. 2.5–3.5
C. 1.5–2.0

5. Which of the following best explains why warfarin requires an overlap with heparin during initiation?
A. Warfarin causes rapid bleeding initially
B. Protein C is depleted before procoagulant factors
C. Warfarin acts immediately on all clotting factors

6. A consistent intake of which nutrient is essential for patients taking warfarin?
A. Vitamin K
B. Vitamin B
C. Calcium

7. What is the most appropriate INR goal for a patient being treated for a DVT with warfarin?
A. 1.5–2.0
B. 2.0–3.0
C. 3.5–4.0

8. Which patient would most appropriately be started on a lower initial warfarin dose (≤5 mg)?
A. 25-year-old male with no comorbidities
B. 70-year-old female with heart failure and liver disease
C. 35-year-old woman with DVT and no medication interactions

9. What is the main reason INR needs to be monitored frequently during the first few weeks of warfarin therapy?
A. To detect liver toxicity
B. Because INR can fluctuate as factor levels change
C. To determine bone density

10. What is a major advantage of the On-X mechanical aortic valve compared to other mechanical valves?
A. It allows a lower INR goal
B. It requires no anticoagulation
C. It eliminates risk of thromboembolism

Clinical Overview of Direct Oral Anticoagulants 2025 Revision

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

More Information About Traineeship

If a patient is undergoing a percutaneous coronary intervention and already taking rivaroxaban daily for atrial fibrillation, what are the recommendations for dual antiplatelet therapy (DAPT) and oral anticoagulant therapy?
There is no need for any antiplatelet therapy in this situation because rivaroxaban is sufficient to cover the risks with less bleeding risk
DAPT therapy + rivaroxaban for one month and then the P2Y12 inhibitor + rivaroxaban for 5 months and then just rivaroxaban thereafter
DAPT therapy + rivaroxaban is needed for 6 months and then rivaroxaban can be stopped with just DAPT therapy continued thereafter

Which of the following agents would be unable to satisfactorily reverse the effects of the anticoagulant to which is was linked when used with in cases of life threatening bleeds such as intercranial hemorrhage?
Idarucizumab reverses dabigatran
Andexanet alfa reverses apixaban
Vitamin K reverses edoxaban

A 47-year-old patient with recurrent venous thromboembolism has a creatinine clearance of 99 mL/min. Which of the following oral anticoagulants should be avoided?
All anticoagulants can be used
Edoxaban should not be used
Rivaroxaban should not be used

A 67-year-old patient is currently taking itraconazole, a potent CYP3A4 inhibitor, for a toenail infection and has four months of therapy left. You want to start an oral anticoagulant that is not a substrate for CYP3A4 to avoid an interaction. Which of the following anticoagulants could you use?
Rivaroxaban
Apixaban
Dabigatran

A 49-year-old patient has chronic GERD and takes a proton pump inhibitor daily and occasional antacids for acute heartburn. Which of the following oral anticoagulants is most likely to exacerbate the acid reflux and to have mild drug interactions with the patient’s current medicatio?
Rivaroxaban
Apixaban
Dabigitran

A 77-year-old patient needs to be switched from warfarin to apixaban. When would you counsel the patient to start the apixaban?
When the INR falls below 2
At the time the next dose of warfarin was scheduled
48 hours after the last dose of warfarin

A Practical Approach to Perioperative Oral Anticoagulation Management 2025 Revision

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

More Information About Traineeship

ABSTRACT

Many different guidelines and clinical studies address how to manage anticoagulation around the time of surgeries or procedures. This module’s goal is to help learners pull dry information together and apply it to real-world anticoagulation situations. It discusses terminology, renal function assessment, recent guideline changes, and how to stratify a patient’s periprocedural risk of thrombosis and bleeding. In addition, the module covers anticoagulation during the periprocedural period, potential interactions with over-the-counter products, and how to communicate the plan with patients and caregivers. It includes practice pearls from an experienced certified anticoagulation provider. Finally, it concludes with a sample case to show learners how to use this information in typical situations in direct patient care.

INTRODUCTION

Appropriate perioperative anticoagulation management is essential for patient safety. Guidelines can be valuable tools for identifying a potential course of action when tailoring perioperative plans for individual patients who take anticoagulants. However, significant gray areas remain. Clinicians must consider individual patient characteristics before finalizing any plan. This module familiarizes learners with the most recent guidelines and demonstrates how to optimize perioperative anticoagulation care for patients.

Many guidelines about anticoagulation are available. Good clinical practice requires occasional surveillance for changes in the current landscape. Select organizations that periodically release guidelines include the American Society of Hematology (ASH), the American College of Cardiology/American Heart Association (ACC/AHA), and the American College of Chest Physicians (CHEST). This module primarily uses the 2022 Perioperative CHEST Guideline. Please note, guidelines sometimes refer to medications that are used internationally, but this module only discusses medications available in the United States. Additionally, each institution’s protocol or clinician’s opinion may vary from the views presented here.

TERMINOLOGY

"Bridging" refers to using a shorter half-life anticoagulant to act as a "bridge" between pre-procedure and post-procedure maintenance anticoagulation. This action minimizes patients' exposure to subtherapeutic anticoagulation while their maintenance anticoagulation is held for a procedure. Most commonly, this refers to using low molecular weight heparin (LMWH) while warfarin is held.
- Practice Pearl: Patients or providers sometimes incorrectly refer to simply holding an anticoagulant as "bridging."
“DOAC” refers to the direct oral anticoagulants (the Factor Xa inhibitors rivaroxaban [Xarelto], apixaban [Eliquis], edoxaban [Savaysa], and the Factor IIa inhibitor dabigatran [Pradaxa]). The old term "NOAC" has fallen out of favor as it implies a negative connotation.
“Glycoprotein IIb-IIIa inhibitor” refers to the antiplatelet agents eptifibatide (Integrilin) and tirofiban (Aggrastat).
“Low-molecular weight heparin” refers to enoxaparin (Lovenox) and dalteparin (Fragmin).
“P2Y₁₂ inhibitor” refers to the antiplatelet drugs clopidogrel (Plavix), prasugrel (Effient), ticagrelor (Brilinta), and cangrelor (Kengreal).
The terms “surgery” and “procedure” are sometimes used interchangeably.

ESTIMATING RENAL FUNCTION

Some anticoagulants are renally cleared, so clinicians must be prepared to make dose adjustments for renal impairment. Directly measuring glomerular filtration rate (GFR) is not practical, so formulas that estimate renal function guide treatment decisions. Commonly used formulas use serum creatinine (SCr), height, age, and some form of body weight (in kg) to estimate renal function (discussed in more detail later). Calculators for these equations are available online.

Renal function formulas assume stable renal function and the results are just estimates, so the anticoagulation team must consider the whole patient when making dosing adjustments. Note that neither the CKD-EPI Creatinine Equation (2021) nor the Cockcroft-Gault formula have been validated for use in children, pregnancy, or patients with low creatinine values.

The most recent Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines recommend using the CKD-EPI Creatinine Equation (2021) to estimate renal function. This formula takes body habitus (common variations in the shape of the human body, which in turn determines the position of internal viscera) and gender into account and is now widely used.¹

CKD-EPI Creatinine Equation (2021)

eGFR_Cr= 142 x min (S_Cr/k,1)^α x max (S_Cr/k,1)^-1.200 x 0.9938^Age x 1.012 [if female]

Female: k = 0.7, α = -0.241; Male: k=0.9, α= -0.302

“min” =minimum of SCr/k or 1; “max” = the maximum of SCr/k or 1

Then convert the result to a non-indexed eGFR using BSA as follows:

BSA (m²) = 0.007184 x (weight in kg) ^0.425 x (height in cm) ^0.725

Non-indexed eGFR = indexed eGFR x BSA /1.73 (result expressed as mL/min/1.73 m²)

This formula estimates kidney function more accurately than others, is widely regarded as the current standard of care, and reference laboratories use it. However, the pharmacokinetic studies that lead to United States (U.S.) Food and Drug Administration (FDA) approval often use the historical Cockcroft-Gault (CG) formula instead. Therefore, FDA-approved prescribing information often bases renal dosing adjustments on CG creatinine clearance (CrCl).²

Cockcroft-Gault Formula (1976)

CrCl = [((140–age) x (weight in kg))/ (72 x SCr)] x 0.85 (for females)

The Cockcroft-Gault formula was developed from data collected from white adult males and often yields inaccurate results when applied to the general population. The formula’s developers suggestion for an 85% correction for female gender was not derived from clinical data. They acknowledged its limitations. Its flaws have been extensively discussed.^1,3,4 Common patient characteristics that may yield inaccurate results include:

Actual body weight (ABW) either below or more than 30% above, ideal body weight (IBW)
Edema
Frailty
Height under 60"
Hydration status
Low muscle mass

Special Populations

Unfortunately, choosing an appropriate measure of body weight to use in CG is not always as simple as having the patient step on the scale. Table 1 describes how clinicians use different representations of body weights in different circumstances.

Table 1. Choosing a Measure of Body Weight for Use in Cockcroft-Gault
Representation of Body Weight	Patient Population
Actual body weight (ABW)	Underweight, and all patients using rivaroxaban
Ideal body weight (IBW)	Between IBW and 30% overweight
Adjusted body weight (AdjBW0.4)	More than 30% overweight

Adjusting Weight for Obesity

The literature suggests adjusting body weight for obesity (body weight greater than 30% over IBW). The adjusted body weight (AdjBW) is calculated using the following formula, and the result is used in the CG formula.⁵

IBW (male) = 50 + (2.3 x (height minus 60 inches))

IBW (female) = 45.5 + (2.3 x (height minus 60 inches))

AdjBW0.4 = IBW + 0.4 (ABW - IBW)

Practice Pearl: Note that the rivaroxaban prescribing information specifically calls for using Actual Body Weight when calculating CrCl.⁶

Adjusting Weight for Amputations

Currently, no validated method is available to estimate renal function in patients who are amputees. One possible method is to estimate the IBW before the amputation, subtracting an approximation of what that limb might have weighed (see Table 2), then using the AdjBW in the formula. Alternatively, clinicians can use an online calculator such as https://clincalc.com/kinetics/ebwl.aspx.⁷

Table 2. Estimating Body Weight Lost from Amputations⁸
Body Section	Specific Location	Percent of Total Weight
Lower body	Foot	1.5%
	Calf and foot	5.9%
	Entire lower extremity	16%
Upper body	Hand	0.7%
	Forearm and hand	2.3%
	Entire upper extremity	5%

Transgender Patients

Hormonal therapy influences lean body mass and should be considered when estimating renal function in transgender patients. For transgender patients who have completed at least six months of hormone therapy, the team should calculate CrCl using their gender identity, not their sex assigned at birth.⁹

PAUSE AND PONDER: In what situations should heparin be used to protect the patient from thrombosis while oral anticoagulants are held for surgery?

CHEST GUIDELINE

CHEST released an updated Clinical Practice Guideline for the Perioperative Management of Antithrombotic Therapy in 2022.¹⁰ The new more user-friendly guideline replaces the 2012 version.¹¹ It only provides guidance for elective procedures that are not urgent. The 2022 version provides more comprehensive and detailed guidance on the perioperative use of DOACs, antiplatelet medications, and heparin bridging. It also includes more specific guidance on perioperative risk of thrombosis and bleeding.

Many CHEST Guideline recommendations are presented as being supported by either "Low" or "Very Low" Certainty of Evidence. For these, individual patient characteristics and clinical judgment become more important when determining a plan of action. The main body of the text sometimes describes specific considerations for different patient populations.

The CHEST Guideline only makes two strong recommendations, both regarding warfarin¹⁰:

Prescribers should not bridge patients using warfarin with LMWH when atrial fibrillation (AF) is the sole indication.
Warfarin should be continued, not held, for ICD or pacemaker placement if the international normalized ratio (INR) is less than 3.0.

It makes several other important recommendations¹⁰:

Warfarin patients at high risk of venous thromboembolism (VTE) should be bridged with heparin.
Avoid heparin bridging for patients who take DOACs.
Avoid heparin bridging for warfarin patients with minimal to moderate risk of VTE with the following:
1. Mechanical heart valves
2. VTE as the only risk factor (post-procedure low-dose heparin may be used)
3. A colonoscopy with polypectomy
Avoid adjusting
1. LMWH or DOAC dosing to anti-Xa levels
2. Antiplatelet medications based on antiplatelet testing
Discontinue apixaban, dabigatran, edoxaban, and rivaroxaban before procedures.
Continue aspirin (ASA) for patients having non-cardiac surgery.
Patients who take ASA and have coronary artery bypass graft (CABG) scheduled should continue ASA.
Patients who take dual antiplatelet therapy (DAPT) who had a coronary artery stent placed six to 12 weeks ago should either continue both antiplatelet agents or should hold one of them seven to 10 days pre-procedure.
DAPT patients who had a coronary artery stent placed three to 12 months ago, and patients who are having CABG surgery, should hold their P2Y₁₂ inhibitor (clopidogrel, prasugrel, ticagrelor, or cangrelor).
Do not use glycoprotein IIb-IIIa inhibitors (eptifibatide, tirofiban) or cangrelor to bridge antiplatelet patients.
When holding a DOAC, continue holding until at least 24 hours post-procedure, as restarting sooner can increase bleeding risk.
Patients with an INR above 1.5 up to two days before the procedure should not receive vitamin K as this can delay return to full therapeutic INR post-procedure.
Continue warfarin for dental procedures.
1. Exceptions: Hold warfarin if the patient has poor gingival condition or is expected to bleed profusely. Consider patient history.
2. Tranexamic acid and additional sutures can be used to limit bleeding.
Continue warfarin for minor dermatologic procedures.
1. Exceptions: Hold warfarin if the patient is having a skin graft or expected to bleed profusely.
Continue warfarin for minor ophthalmologic procedures.
1. Exceptions: Retinal surgery or any time retrobulbar anesthesia is used

Practice Pearl: It can be challenging to find information that applies to a highly specific patient population in a dry document like a CHEST Guideline. This is an optional exercise: under what heading in the CHEST Guideline does it describe specific patient characteristics that may make you inclined to hold an anticoagulant or antiplatelet drug for a dental extraction?

Assessing Perioperative Risk for Surgery/Procedure Related Bleeding
Summary of Key Recommendations
Patients Having a Minor Dental, Dermatologic, or Ophthalmologic Procedure

Table 3 summarizes CHEST Guideline recommendations for how long to hold an anticoagulant before a procedure and when to resume it after a procedure.¹⁰

Table 3. Recommended Perioperative Anticoagulant Holding Times¹⁰
Anticoagulant	Procedure Bleed Risk	How Long to Hold Before Procedure	When to Resume Post-Procedure	Post-Procedure Notes
Warfarin	-	5-6 days	Within 24 hours	-
IV UFH (therapeutic dose)	-	At least 4 hours	At least 24 hours	No bolus. Target a lower aPTT.
LMWH	Low-moderate	Half the total daily dose in AM, 24 hours prior	At least 24 hours	-
LMWH	High	24 hours	At least 48-72 hours	If needed, low-dose LMWH may be used for the first 2-3 days.
Apixaban	Low-moderate	1 day	All DOACs: At least 24 hours post procedure after low-moderate risk At least 48-72 hours after high risk
Apixaban	High	2 days
Dabigatran	Low-moderate, CrCl at least 50 mL/min	1 day
	Low-moderate, CrCl less than 50 mL/min	2 days
	High risk, CrCl at least 50 mL/min	2 days
	High risk, CrCl less than 50 mL/min	4 days
Edoxaban	Low-moderate	1 day
Edoxaban	High risk	2 days
Rivaroxaban	Low-moderate	1 day
Rivaroxaban	High risk	2 days
ASA	-	At least 7 days*	*Evaluate whether antiplatelet agents need to be held at all on a case-by-case basis.
Clopidogrel	-	At least 5 days*
Ticagrelor	-	3-5 days*
Prasugrel	-	7 days*

PAUSE AND PONDER; How do clinicians decide who is at high enough risk of thromboembolism to interrupt anticoagulation for a surgery or procedure or to warrant the additional bleeding risk of LMWH during a warfarin bridge?

PATIENT-SPECIFIC PERIOPERATIVE ANTICOAGULATION PLAN

Overview

Step 1: Begin by collecting basic information:

What procedure or surgery is happening, and when?
Which anticoagulant is the patient using?
What herbal and vitamin supplements are the patient currently taking?
What is the patient's medical history and allergies? Are there any recent updates from either inside or outside your healthcare system?
Does the patient have a history of heparin-induced thrombocytopenia (HIT), severe bleeding such as SDH, thrombosis, or other complications during a historical perioperative period?
Do you need to update the patient's weight or lab work?

Step 2: Communicate with other healthcare team members involved in this patient's care.

Step 3: Assess risks and prepare the perioperative plan.

Assess the risk of thrombosis. Is holding the anticoagulant really necessary? How long? Is bridging required?
Assess the risk of procedure-related bleeding.
Calculate renal function and Child-Pugh score if applicable.
Obtain or place orders as necessary following the institution's protocol.
Review plan for feasibility and accuracy. Examples of potential errors include
1. Bridging warfarin patients in end stage renal disease (ESRD) with therapeutic-dose LMWH
2. Bridging DOAC patients with LMWH
3. Holding warfarin for 5 days without LMWH bridging in mechanical mitral valve replacement (MVR) patient with antiphospholipid syndrome (APS), a history of VTE, with low bleeding risk
4. Holding warfarin 7 days before a single dental extraction in patients with paroxysmal AF
5. Holding warfarin 1 day before spinal surgery

Step 4: Educate the patient and/or caregiver.

A written plan can facilitate adherence and communication between team members and the patient, especially if the plan is complicated. Clinicians who review the plan verbally with patients can evaluate feedback and clarify questions instantly. If applicable, patient education should cover subcutaneous injection technique and sharps disposal. Confirm that patients and caregivers understand the plan using the teach-back technique and spot-checks. A critical element is how to recognize the signs of bleeding or thrombosis with patients, so the patient knows when to call 911.

Practice Pearl: The electronic health record (EHR) often contains errors or omissions. Reviewing medication and problem lists with patients may identify medication that was discontinued (sometimes years ago!). Sometimes, patients do too much yard work and injure a knee; they start ibuprofen without notifying their healthcare provider. Perhaps they visited London and didn’t tell their provider about the pulmonary embolism they developed on the flight, or the fact that they are now using rivaroxaban. They may have been hiking in the Grand Canyon when they had a myocardial infarction and didn’t think to mention they are now using clopidogrel and aspirin. Clinicians will not know unless they ask.

OVER-THE-COUNTER PRODUCTS

Many foods and over-the-counter (OTC) products can increase bleeding risk and should be held in the perioperative period. Table 4 shows a sample of interactions between foods/supplements and selected anticoagulants. For example, using cannabidiol (CBD) with apixaban can increase the patient's bleeding risk; if patients who have a high bleeding risk procedure restart apixaban and CBD after the procedure, bleeding risk will be high during that time.

Some supplements and foods have intrinsic anticoagulant or antiplatelet properties and can increase the bleeding risk even wihout a CYP450 or P-glycoprotein interaction. St. John’s Wort can increase risk of thrombosis when used with apixaban, dabigatran, rivaroxaban, and warfarin; it induces CYP3A4 and P-glycoprotein. When in doubt, it is generally best to err on the side of caution and hold all patient-initiated supplements in the perioperative period.

Practice Pearl: Surgeons often require tobacco cessation before scheduling surgery. This can increase warfarin sensitivity through a CYP1A2 interaction.

Cannabis is widely used. It is primarily metabolized by the liver, but about a fifth is renally eliminated. It inhibits CYP450 enzymes, including 3A4, 2D6, 2C9, and 2C19. In addition to its potential interactions with anticoagulants, it can also prolong sedation and increase the risk of myocardial ischemia. Patients with cannabis use disorder can experience increased perioperative morbidity and mortality.^12-14

Table 4. Interactions Between OTCs and Common Anticoagulants^15-19
OTC Product	Possible Intrinsic Antiplatelet Activity	Possible Intrinsic Anticoagulant Activity	Apixaban	ASA	Clopidogrel	Enoxaparin	Dabigatran	Rivaroxaban	Warfarin
Aspirin	x		x	x	x	x	x	x	x
Alpha-lipoic acid	x		x	x	x	x	x	x	x
Berberine	x		x	x	x	x	x	x	x
Black seed	x	x	x	x	x	x	x	x	x
Cannabidiol			x		x			x	x
Chamomile			x		x			x	x
Cocoa	x		x	x	x	x	x	x	x
Danshen	x	x	x	x	x	x	x	x	x
Dong quai	x		x	x	x	x	x	x	x
Echinacea			x		x			x	x
Eucalyptus			x		x			x	x
Feverfew	x		x	x	x	x	x	x	x
Garcinia cambogia	x		x	x	x	x	x	x	x
Garlic	x		x	x	x	x	x	x	x
Ginger	x		x	x	x	x	x	x	x
Gingko biloba	x		x	x	x	x	x	x	x
Ginseng (American)									x
Ginseng (Panax)			x	x	x	x	x	x	x
Grapefruit			x		x			x	x
Ibuprofen*			x	x	x	x	x	x	x
Jackfruit		x	x	x	x	x	x	x	x
Lime			x		x			x	x
Melatonin		x	x	x	x	x	x	x	x
Naproxen*			x	x	x	x	x	x	x
Turmeric	x		x	x	x	x	x	x	x
Vitamin E	x	x	x	x	x	x	x	x	x
Yerba mate	x		x	x	x	x	x	x	x

*Ibuprofen and naproxen may block antiplatelet effect of ASA.

PERIOPERATIVE RISK ASSESSMENT

The following risk stratification methods are general guides, not absolute rules. Pharmacists must consider the whole patient and use good clinical judgement. Caution and prioritizing patient safety are always prudent.

Risk of Thrombosis

Certain patient characteristics increase a patient’s risk of thrombosis during a procedure. The CHEST Guideline presents three main risk categories: AF, VTE, and mechanical heart valves. When a patient has an elevated risk score in multiple categories, the team should use the highest value for stratification purposes. For example, if a patient has a CHA₂DS₂VASc score of 2 and antiphospholipid antibodies, classify the patient as high risk of thrombosis.

Atrial Fibrillation

The CHADS₂ and CHA₂DS₂VASc scoring formulas classify patients with AF as having a high, medium, or low risk of stroke as described in Table 5. the CHEST Guideline references both:

CHADS₂: Add one point for each of the following conditions: congestive heart failure (CHF), hypertension, age at least 75 years, and diabetes; add two points for a history of stroke/TIA.
CHA₂DS₂VASc: Add one point for each of the following conditions: CHF, hypertension, diabetes, vascular disease (myocardial infarction, peripheral artery disease, aortic plaque), age 65-74 years, and sex category of female; add two points each for age at least 75 years and history of cerebrovascular accident (CVA)/TIA/thromboembolism.

CHA₂DS₂VASc identifies low-risk patients more accurately and classifies fewer patients as moderate risk.²⁰

Table 5. Risk of Thrombosis Secondary to Atrial Fibrillation¹⁰

High

Moderate

Low

CHADS₂: 5-6

CHA₂DS₂VASc: at least 7

CVA/TIA in the past 3 months

Rheumatic valvular heart disease

CHADS₂: 3-4

CHA₂DS₂VASc: 5-6

CHADS₂: 0-2 (no CVA/TIA)

CHA₂DS₂VASc: 1-4

Source: Adapted from reference 10 p.e212.

Venous Thromboembolism

Table 6. Risk of Thrombosis Secondary to Hypercoagulable States.

High Risk

Moderate Risk

Low Risk

VTE within the past 3 months

Protein C or S deficiency

Antithrombin deficiency

Homozygous Factor V Leiden

Homozygous gene G20210A mutation

Antiphospholipid antibodies

Active brain, gastric, pancreatic, or esophageal cancer

Myeloproliferative disorders

VTE 3-12 months prior

Recurrent VTE

Heterozygous Factor V Leiden

Heterozygous gene G20210A mutation

Active or recent malignancy other than those specifically listed in high risk category

VTE more than 12 months prior

Mechanical Heart Valves

Table 7. Risk of Thrombosis Secondary to Mechanical Heart Valves¹⁰

High Risk

Moderate Risk

Low Risk

MVR + major risk factor(s)*

Caged-ball, tilting-disc AVR/MVR

CVA/TIA within the past 3 months

MVR without major risk factors*

AVR (bileaflet) with major risk factors

AVR (bileaflet) without major risk factors*

*Major risk factors for CVA: History of AF, CVA/TIA during previous anticoagulation hold, rheumatic heart disease, valve thrombosis, HTN, diabetes, CHF, age 75 or greater.

Bleeding Risk

Some patients develop serious bleeding during or after a procedure, so risk assessment is critical. The literature describes several different bleeding-risk scoring systems, including HAS‐BLED, HEMORR₂HAGES, ORBIT‐AF, ATRIA, and GARFIELD‐AF. In short, while these tools can help identify potentially high-bleeding-risk patients, their accuracy varies depending on the patient population studied.^21,22 The CHEST Guideline includes empiric classification guidance.¹⁰

High

Generally, surgeries and procedures performed on highly vascularized organs, that cause extensive tissue damage, or are spinal-invasive are considered high risk. Anticoagulants should be held long enough to reverse their effects. Examples include

Cancer
Cardiac
Colonic polyp or bowel resection
Epidural injections
Gastrointestinal (GI)
Kidney
Major orthopedic
Major thoracic
Neuraxial interventions
Reconstructive plastic
TURP
Urologic

Low to Moderate

These surgeries are considered low to moderate bleeding risk surgeries and procedures, regardless of whether biopsies are performed. Anticoagulants can be held for less time during the perioperative period.

Arthroscopy
Bronchoscopy
Colonoscopy
Coronary angiography, femoral approach
Foot, hand
GI endoscopy
Hemorrhoidal surgery
Hysterectomy
Laparoscopic cholecystectomy
Lymph node biopsies

Minimal

Many patients can remain fully anticoagulated for minimal bleeding risk procedures, although it would be reasonable to consider holding a DOAC on the day of the procedure. In certain circumstances, such as a dental extraction in a patient who has poor gingival health, it may be reasonable to hold anticoagulation before a minimal bleed risk procedure.

Cataract procedures
Coronary angiography, radial approach
Minor dental procedures, including extraction(s)
Minor dermatologic procedures, including excision of skin cancers
Pacemaker or ICD placement

DIRECT ORAL ANTICOAGULANTS

Since heparin bridging is not used for patients who use DOACs, these instructions are simple. Clinicians should provide patients with instructions to hold their DOAC on specific dates. However, they need to know the audience! For some patients, verbal communication suffices. In this case, the best practice would be to ask the patient to repeat the instructions to confirm understanding. Other patients find it more helpful to have written instructions, especially those who have caregivers. For patients who live in assisted living facilities that manage their medications, pharmacists can do two things: (1) review the instructions with the patient for their own knowledge and (2) provide instructions directly to the facility.

DOACs only take a few hours to become fully effective. Ask the patient to check with the surgeon after the procedure is complete to make sure it’s safe to restart the DOAC.²³

WARFARIN

The inter-patient variability in responses to warfarin cannot be understated. Warfarin’s half-life is 20 to 60 hours and varies significantly from patient to patient. Warfarin ultimately inhibits activation of clotting factors II, VII, IX, and X, and it also affects the natural anticoagulants protein C and S. Table 8 compares these factors’ half-lives and reveals that they are not necessarily pivoting in concert while warfarin doses are being adjusted.

Table 8. Half-lives of Clotting Factors Relevant to Warfarin Use
Factor	Half-life (hours)
II	42-72
VII	4-6
IX	21-30
X	27-48
Protein C	8
Protein S	60

Source: Adapted from 24 p. 20.

Many factors affect a patient's response to a warfarin dose. These include interactions with diet, pharmacokinetic medication interactions, pharmacodynamic interactions, liver function, edema status, and many more. Surgery and hospitalization commonly cause physical stress and decrease appetite; both increase warfarin sensitivity. The patient's history can be invaluable when determining post-procedure doses but caution is warranted. Even if the patient had a similar warfarin holding situation in the past available for comparison, they may respond differently this time.

It can take three to seven days (or more) to see the effect of warfarin dosing changes on the INR. Therefore, patients usually resume warfarin in the evening after a procedure is completed. It can take weeks for INR to stabilize after major surgery. This is when shorter-acting LMWH and unfractionated heparin (UFH) become useful.

Heparin Bridging During Warfarin Interruption

Unless otherwise specified, when the CHEST Guideline mentions "heparin bridging," it specifically refers to using a therapeutic-dose LMWH. Examples include enoxaparin 1 mg/kg twice daily or 1.5 mg/kg daily, dalteparin 100 international units/kg BID or 200 international units/kg daily, or full-dose UFH to achieve target aPTT of 1.5-2x the control, or a target anti-Xa level of 0.35 to 0.70 international units/mL. Lower prophylactic or intermediate doses may be used in certain circumstances.¹⁰Clinicians need to calculate renal function before finalizing a dose. If a patient with ESRD needs to bridge for a procedure, it is best to use IV UFH for inpatient bridging rather than LMWH.

Practice Pearl: It may be difficult for patients who are underweight (with little subcutaneous fat) or who have had major surgery (scarring or local trauma) to find suitable sites for subcutaneous injections.

Practice Pearl: It can be challenging to determine an appropriate therapeutic dose of LMWH for patients with BMI exceeding 40 kg/m², especially in the outpatient setting, where monitoring anti-Xa levels would be more challenging. Whether or not to cap the dose at some amount lower than 1 mg/kg twice daily is a controversial topic.^14,25

Practice Pearl: Procedures that require LMWH bridging and are scheduled without much notice can cause logistical challenges for patients. Questions to consider include

When does the patient need to start using LMWH?
Does the pharmacy have it in stock?
If not, how long will it take them to order it?
Will the patient be able to afford the copay?

Practice Pearl: Significant drops in hemoglobin, hematocrit, or platelets after a surgery or procedure can be the first warning sign of severe post-operative bleeding.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition that is a possible reaction to heparin. The ASH Guideline suggests monitoring for drops in platelet count for patients who are considered to have moderate or high risk of HIT, including patients using UFH and patients using LMWH after major surgery or trauma. In these cases, the guideline recommends monitoring platelet count every two to three days until heparin is discontinued.²⁶

Example Warfarin Bridge Plan

Oliver is a 52-year-old male patient with a MVR, antiphospholipid antibodies, and a history of CVA. He has a colonoscopy scheduled next month. Lab work done 9 months ago was largely unremarkable, except his platelets were 30 points below the minimum EHR reference range (unknown etiology). His medication list includes warfarin 5 mg daily, lisinopril 20 mg daily, and aspirin 81 mg daily. He said he does not use supplements. His INR has been stable and therapeutic for the past two months. He has had no other procedures in the past year. Repeat bloodwork indicates his platelets are now within normal limits. He will return home the same day as the procedure.

Vitals: Weight 174 lb, BP 135/82 mmHg. CrCl 65 mL/min.

Your institution's protocol indicates he should bridge with therapeutic dose enoxaparin for this procedure, and you have whatever approvals you need to proceed. You send a prescription for 80 mg enoxaparin syringes #20 to his local pharmacy, to be used twice daily as instructed in Table 9. Since his procedure is still a month away, his pharmacy has time to order the enoxaparin if necessary.

Table 9. Example Patient Instructions for Perioperative Anticoagulation
Month	Day	Day of Week	Warfarin Dose	Injectable Anticoagulant: 80 mg Enoxaparin
Apr	17	Thursday	Last dose: 5 mg	None
Apr	18	Friday	None	None
Apr	19	Saturday	None	None
Apr	20	Sunday	None	Begin enoxaparin injections under the skin every 12 hours, starting this morning
Apr	21	Monday	None	Continue enoxaparin injections every 12 hours
Apr	22	Tuesday	None	Continue enoxaparin injections, just once today, with the last dose at least 24 hours before the procedure
Apr	23	Procedure Wednesday	If the surgeon approves, restart after procedure is complete with 7.5 mg	None
Apr	24	Thursday	7.5 mg	If the surgeon approves, restart enoxaparin injections, just once today, starting 24 hours after procedure is complete
Apr	25	Friday	5 mg	Continue enoxaparin injections every 12 hours
Apr	26	Saturday	5 mg	Continue enoxaparin injections every 12 hours
Apr	27	Sunday	5 mg	Continue enoxaparin injections every 12 hours
Apr	28	Monday	Further instructions are to be provided at today's appointment	Continue enoxaparin injections, but please wait until after this morning's visit before using enoxaparin today to allow for fingerstick INR
Please continue injections until the Anticoagulation Clinic asks you to stop. Your next appointment is 4/28/25. On days when you are scheduled for a post-procedure INR check, please hold your morning injection until after your morning appointment. If you will be doing errands after your visit, please bring a syringe with you to stay on schedule with your injections.

PAUSE AND PONDER: How would you provide instructions to the patient in a way that they both understand and are willing and able to follow?

COMMUNICATION TECHNIQUES

Practice Pearl: Use active listening, reflective statements, and motivational interviewing techniques to ensure patients know you hear their concerns and are comfortable asking questions.

In the ambulatory setting, the patient must fully understand and accept the perioperative plan to minimize the risk of harm. Patients may not follow through if they think the team doesn’t care about their concerns.

Consider Emma, who has been your patient for several years. She arrives at the clinic irritated and you do not know why. You try to make small talk with her, but she snaps, “Just get on with the visit.” She crosses her arms across her chest and looks away. You do not know this yet, but her mother was just diagnosed with metastatic colon cancer and is considering foregoing treatment and entering hospice care.

Emma is here today to review perioperative instructions for her upcoming colonoscopy. She has had precancerous polyps removed in the past and has recently developed a small amount of hematochezia (presence of fresh [bright red] blood in stools). Emma was not expecting to have to bridge for her colonoscopy because she didn’t bridge for the last one. She recently established care with a new provider who is more concerned about her risk of thrombosis than her last one was.

She is expecting to hold her warfarin five days prior to her procedure and restart it the same evening, but then you show her a detailed calendar of LMWH bridging instructions and begin reviewing them. She becomes increasingly disengaged and even a little tearful and refuses to follow the plan. She says, “Forget it. I am cancelling the colonoscopy.”

The sooner you identify a bad situation developing, the easier it is to avert it. The patient's body language is a signal to address concerns immediately. The moment Emma crossed her arms across her chest and looked away was your cue to stop and attempt to determine the problem. If she shares her concern about her mother’s recent diagnosis and her concerns about her own health, use a reflective statement (summarize and repeat the problem back to her). Don’t judge, contradict, or redirect her. Demonstrate you are really listening to her and trying to understand her concerns. She will probably uncross her arms and make eye contact with you again.

At an appropriate time, gently guide the discussion back to the reason she is here. You might say something like, "Thank you for sharing your concerns. I hear that you are feeling very stressed right now. You only want the best for your mother, and this news is devastating. You’re worried about what the doctor will find in your own colonoscopy. I went right into all these details about a complicated, unexpected bridge plan. I would feel anxious myself if I were you. I want you to know that you are always in control of your own healthcare. You get to decide for yourself if you want to proceed, if and when you are ready. If it turned out that you have another polyp, would you want to have the opportunity to have it removed?"

While you are having this discussion, it is important to remain attentive and welcome her to interrupt you with new information or questions or concerns as they come up. Emma agrees to proceed, and you review the instructions with her. After presenting the plan, ask her to explain to you what she will be doing at each step of the process to confirm understanding. This is called a “teach-back technique.”

Practice Pearl: Use teach-back techniques and spot-checking to ensure understanding.

Language Barriers and Hearing Impairment

Practice Pearl: Use only qualified interpreters when communicating complicated instructions to patients who do not share your native language. Use alternate communication methods as needed for deaf or hard-of-hearing patients.

Patients may find it more difficult to understand instructions that contain slang or medical jargon. Sometimes, patients nod to indicate they understand what you are saying, even when they do not, to be polite or to avoid social discomfort. When using interpreters, make eye contact with and speak directly to the patient, not the interpreter. Speaking louder will not improve understanding when the obstacle is a language barrier. Patients with hearing impairment may benefit from careful enunciation, especially of consonants. They may also lip-read, even if they do not realize they are doing it. This can be challenging in situations when masking is required.

Practice Pearl: In the United States, the format frequently used to describe dates is month-day-year; however, other countries use day-month-year. To minimize confusion, provide written dates with the month shown as a word instead of a number, e.g., “August 3” instead of “8-3.”

Cognitive Impairment

Practice Pearl: Be prepared to repeat your instructions as often as needed to ensure understanding.

Cognitive impairment occurs across a broad spectrum that can make it challenging for patients to understand and/or follow detailed instructions.²⁷ Some patients may need to review the material with you several times. Other patients may bring a caregiver or friend to help them think of questions to ask and to remember their instructions. Some patients cannot take their medication on their own; in this case, it is essential to provide education to a caregiver who can help them navigate the process. If caregivers accompanies a patient to an appointment, acknowledge their presence and include them in the discussion. They may have relevant questions, concerns, or valuable feedback.²⁷

The following resources provide more tips on patient communication:

https://www.cds.udel.edu/wp-content/uploads/2017/02/effective-communication.pdf
https://store.jointcommissioninternational.org/assets/3/7/jci-wp-communicating-clearly-final_(1).pdf

Vision Impairment and Tremor or Arthritis

Practice Pearl: Round a dose to the nearest commercially available dose instead of strict weight-based dosing.

The more complicated or physically challenging the perioperative instructions are, the greater the risk of dosing errors. For example, enoxaparin syringes are graduated but the small markings may be hard for patients with vision impairment to see. Additionally, tasks requiring fine motor skills, such as removing a tiny amount of liquid from a syringe, or even administering an injection, may be difficult or impossible for patients with tremors or arthritis. Dose rounding to the nearest commercially available strength can help with this.

Enoxaparin comes in the following prefilled syringe doses: 30, 40, 60, 80, 100, 120, and 150 mg.²⁸

Common Patient Misconceptions

Practice Pearl: To prevent patient misunderstandings, explain the independent roles of warfarin and LMWH in the bridge and why both are used simultaneously.

Sometimes, patients misunderstand the role of warfarin and LMWH in the bridging process, even when they have detailed written instructions. They may not resume LMWH post-procedure because they think their INR will return to their therapeutic range immediately after restarting warfarin. They may not resume warfarin post-procedure because they believe the LMWH increases their INR. You can prevent these kinds of misunderstandings by providing a basic explanation of the independent roles of warfarin and LMWH in the bridge, and why they will be using both at the same time post-procedure.

Practice Pearl: Ask patients to "hold" the anticoagulant on specific dates (and resume it on specific dates). Do not use the term "stop." If you tell patients to stop their warfarin on Tuesday, they might take that to mean you want them to take their last dose of warfarin on Tuesday, not to take the last dose of warfarin on Monday and start holding it on Tuesday. This misunderstanding can result in a patient holding warfarin for only four days before their procedure, instead of five

Revisions Due to Unexpected Developments

Clinicians involved in anticoagulation must remain flexible and prepared to adapt to an evolving situation after a patient’s surgery or procedure. Some common examples of periprocedural situations that may warrant closer monitoring post-procedure include

Bleeding may delay the resumption of anticoagulation post-procedure.
NSAIDs prescribed for pain control on discharge can increase bleeding risk.
Vitamin K reversal increases warfarin dosing requirements post-procedure.
Reduced appetite or food intake post-procedure may reduce rivaroxaban absorption or increased warfarin sensitivity.
Bariatric surgery can have unpredictable effects on warfarin dosing requirements. Although patients are eating less, they may have initiated supplements that contain more vitamin K than they consumed pre-procedure.
Dental procedures can temporarily decrease food intake; however, some dentists ask patients to use protein shakes (many of which contain vitamin K) post-procedure.
Tobacco cessation increases warfarin sensitivity
Changes in kidney or liver function may affect medication clearance.

CONCLUSION

Assembling an appropriate perioperative plan for a patient's anticoagulation can be complicated. The material and pearls provided in this activity can help clinicians devise and implement a plan that is appropriate for each patient.

1. Which of the following patients should be bridged for a hip replacement surgery?
a. A 46-year-old male who uses a DOAC for atrial fibrillation
b. A 38-year-old female who uses warfarin for heterozygous Factor V Leiden mutation
c. A 42-year-old male who uses warfarin for Protein S deficiency

2. Which of the following surgeries carries the highest risk of perioperative bleeding?
a. Colonic polyp resection
b. Hemorrhoidal surgery
c. Hysterectomy

3. Which of the following patients has the highest risk of perioperative thromboembolism, assuming all medical conditions are listed?
a. A 34-year-old female with antiphospholipid antibodies
b. A 75-year-old female with atrial fibrillation and aortic plaque
c. A 65-year-old male with atrial fibrillation, history of stroke, and hypertension

4. A 26-year-old Ukrainian patient who does not speak English comes to your clinic to review perioperative instructions for a laparoscopic cholecystectomy next week. His only other medical condition is asthma. You have arranged for a professional interpreter to attend today’s visit. While using the interpreter, which of the following will help the patient understand your instructions?
a. Increasing your voice’s volume so he can hear what you are saying
b. Making eye contact and speaking directly to the patient
c. Using medical jargon and using highly technical terms

For the next two questions, consider the following patient case:
Evelyn is a 50-year-old female patient with an MVR, diabetes, protein C deficiency, Crohn’s disease, and hypertension. She has a bowel resection scheduled. Her current medications include warfarin, metformin, losartan, aspirin 81 mg, and prednisone. She also uses a daily multivitamin and alpha lipoic acid.

5. Which of the following perioperative plans would be most appropriate?
a. Hold both warfarin and ASA for seven days before the surgery, bridge with therapeutic dose LMWH, with the last pre-surgery LMWH dose, at half the total daily dose, 48 hours before the surgery and restarting LMWH 24 hours after the procedure if hemostasis is achieved. Continue ASA and alpha lipoic acid for the surgery.
b. Hold warfarin for five days before the resection and restart warfarin the evening of the surgery with no LMWH bridging if hemostasis is achieved. Hold the aspirin and alpha lipoic acid starting the week before until at least a week after the surgery.
c. Hold warfarin for five days before the surgery, bridge with therapeutic dose LMWH, at half the total daily dose, with the last pre-surgery LMWH dose 24 hours before the surgery and restarting LMWH 48 hours after the surgery if hemostasis is achieved. Continue ASA but hold alpha lipoic acid starting the week before until at least a week after the surgery.

6. If Evelyn was having a pacemaker placement instead of a bowel resection, which of the following perioperative plans would be most appropriate?
a. Hold warfarin for five days before the surgery, bridge with therapeutic dose LMWH, with the last pre-procedure LMWH dose, at half the total daily dose, 24 hours before the procedure and restarting LMWH 48 hours after the surgery if hemostasis is achieved. Continue ASA but hold alpha lipoic acid starting the week before until at least a week after the surgery.
b. Continue warfarin and ASA for the procedure but hold alpha lipoic acid starting the week before until at least a week after the surgery.
c. Hold both warfarin and ASA for seven days before the surgery, bridge with therapeutic dose LMWH, with the last pre-surgery LMWH dose, at half the total daily dose, 48 hours before the surgery and restarting LMWH 24 hours after the procedure if hemostasis is achieved. Continue ASA and alpha lipoic acid for the surgery.

7. Lily is a 78-year-old female with atrial fibrillation, CHF, and hypertension. She has a Watchman left atrial appendage closure device and a history of hemorrhagic stroke. Her current medications include sacubitril/valsartan and ASA. If she were to have an epidural injection, which of the following supplements would you be most concerned about her using during the perioperative period?
a. Echinacea
b. Gingko biloba
c. Grapefruit

8. John is a 67-year-old male who is scheduling a TURP. His medications include apixaban 5 mg BID, tamsulosin 0.4 mg daily, and metoprolol tartrate 50 mg BID. What is the minimum number of hours John would need to hold apixaban before the surgery?
a. Hold apixaban starting 12 hours before the surgery and restart no sooner than 24 hours after the surgery
b. Apixaban does not need to be held for this surgery
c. Hold apixaban starting 48 hours before the surgery and restart no sooner than 48 hours after the surgery

The following two questions are about the following patient case: Samantha is a 72-year-old female who lives alone and is 5’ 8” and weighs 210 lb. She uses topical diclofenac gel for arthritis. She also uses a daily multivitamin. She had a lab draw last month that was within normal limits. Her serum creatinine was 1.64 mg/dL. She is having hip replacement surgery in two weeks.
9. If she uses warfarin for antithrombin deficiency, what would be the most appropriate enoxaparin dose for her to use as an outpatient?
a. 95 mg
b. 40 mg
c. 100 mg

10. If she used a DOAC, which of the following would need to be held four days before the procedure?
a. Apixaban
b. Rivaroxaban
c. Dabigatran

Pharmacist Reimbursement for Anticoagulation Services 2025 Revision

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

More Information About Traineeship

Post-Test Questions:
1. Which of the following challenges is most likely to affect a pharmacist’s ability to get reimbursed for anticoagulation visits?
a. Lack of provider status
b. Location proximity to the hospital
c. Small Medicare population

2. Your clinic is taking over a population of nursing home patients. Why may this negatively affect reimbursement?
a. Most patients in nursing homes do not have Medicare
b. Pharmacists may only care for patients in their organization
c. Telephone encounters are often not billable

3. Your clinic will begin seeing patients in person and administering a POCT to check INR and provide subsequent dosing instructions. Which of the following CPT code combinations would be appropriate for these visits?
a. 99211 and 93792
b. 99211 and 85610
c. 93793 and 85610

4. Which of the following is true regarding a pharmacist’s ability to bill?
a. ‘Incident to bill’ can only be done under direct supervision by a provider (MD or PA/APRN)
b. ‘Incident to bill’ can only be done under a medical doctor’s supervision (MD)
c. ‘Incident to bill’ can only be done under a PA or APRN specialized in anticoagulation

5. Which of the following strategies would be ideal for optimizing reimbursement?
a. Shift to a telephone only care to improve efficiency
b. Consider utilizing pharmacy students to offset costs
c. Develop a standardized note template for all clinicians

6. Which of the following stakeholders is crucial in ensuring ongoing billing and reimbursement is accurate?
a. The cosigning provider
b. The financial department
c. The receptionist

Heparin/Low Molecular Weight Heparin and Fondaparinux Pharmacology and Pharmacotherapy 2025 Revision

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

More Information About Traineeship

1. Ty is admitted to your hospital for community-acquired pneumonia. You notice that he is a candidate for VTE prophylaxis. He is a 70-year-old male, 5’5”, and 75 kg (165 lbs). Labs include INR 1.1, BUN 30, and SCr 2.5. What is the most appropriate recommendation?
a. Enoxaparin 40 mg SC daily
b. Heparin IV per thromboembolic protocol
c. Enoxaparin 30 mg SC daily

2. Which of the following is an approved indication for low molecular weight heparin?
a. Treatment of venous thromboembolism
b. Anticoagulation in patients with a history of HIT
c. Prevention in patients with renal insufficiency

3. You are at a lecture on LMWH and fondaparinux and the speaker says that these two medications have three things in common. He says, “First, with both medications, you would not dose adjust or avoid using them in patients with impaired renal function. Second, you must order anti-Xa testing on Days 2 and 4 of therapy. Third, with both, active major bleeding is a contraindication for use.” What should you do?
a. Raise your hand and challenge his statement on patients with impaired renal function
b. Raise your hand and challenge his statement on ordering anti-Xa testing
c. Do nothing; these great clinical pearls will make it easier for you to screen patients.

4. A nurse calls, concerned about a patient on heparin for a new blood clot. The patient is going for hemodialysis today. They are unsure of how dialysis will affect the patient's heparin therapy. What would you recommend?
a. Recommend an additional bolus heparin dose immediately following dialysis
b. Ask the prescriber to change to LMWH because heparin is contraindicated in dialysis
c. Say hemodialysis will not affect heparin levels so continue therapy as prescribed
5. A patient who is on LMWH is experiencing a major bleed and needs surgery. The surgeon wants to give protamine. What should you tell her?
a. Protamine will completely reverse LMWH’s anti-factor IIa and Xa effects
b. Give 1 mg protamine per mg of LMWH and repeat every 8 hours for 4 additional doses
c. Anti-factor IIa and Xa activities may return up to three hours after you give the dose

6. Why should prescribers never use enoxaparin sodium injection from multiple dose vials in neonates, infants or pregnant women?
a. No studies have established the appropriate dose
b. It contains benzyl alcohol preservative
c. It causes gastrointestinal colic-like symptoms

7. Which of the following is a contraindication for fondaparinux?
a. Body weight greater than 150 kg (330 lbs)
b. Bacterial endocarditis
c. Sever hepatic impairment

8. A patient accidentally injects her dalteparin twice and the prescriber is frantic and wants to handle the overdose quickly. What is the appropriate dose of protamine?
a. 1 mg protamine for every 1 mg dalteparin administered
b. 1 mg protamine for every 100 anti-Xa units of dalteparin given
c. 1 mg protamine for every 1 mg dalteparin in excess of the normal dose

9. What are the most serious symptoms of protamine overdose?
a. Severe hypotensive fatal reactions, often resembling anaphylaxis
b. Excessive bleeding unresponsive to further protamine doses
c. Epidural or spinal hematomas causing long-term/permanent paralysis

10. Which of the following is a boxed warning on the LMWHs and fondaparinux?
a. Severe hypotensive fatal reactions, often resembling anaphylaxis
b. Excessive bleeding unresponsive to intervention with protamine
c. Epidural or spinal hematomas with neuraxial anesthesia or spinal puncture

Management of Hypercoagulable States 2025 Revision

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

More Information About Traineeship

Post-Test Questions:
1. Which of the following factors would more likely indicate an inherited thrombophilia?
a. A relative with a known clotting disorder
b. Active combination oral contraception use
c. Recent travel overseas on a long flight

2. Which of the following conditions is more likely to be an acquired form of thrombophilia?
a. Antiphospholipid antibody
b. Factor V Leiden
c. Prothrombin gene mutation

3. Which of the following are the most appropriate next steps following a ‘normal’ functional assay for AT III deficiency?
a. Administer vitamin K PO 5mg once and discontinue anticoagulation
b. Confirm functional assay results with an antigenic assay
c. Continue anticoagulation and consider alternative diagnosis

4. Which of the following pharmacotherapy is associated with acquired protein s deficiency?
a. Oral contraceptives
b. Unfractionated heparin
c. Vitamin K

5. A patient develops microthrombi in extremities two days after starting warfarin 10mg for 2 doses. His INR is 1.8. Which of the following is the most appropriate initial management?
a. Bridge warfarin with apixaban 5mg
b. Vitamin K administration
c. Warfarin 10mg again to hit goal INR

6. A patient screens positive for prothrombin gene mutation, but has no signs of active thrombosis. What is the best treatment plan?
a. Begin chronic oral anticoagulation with a DOAC to prevent future thrombotic events
b. Consider prophylactic doses of anticoagulation should the patient ever have surgery
c. Start warfarin therapy with a goal INR of 2.5-3.5 given increased risk of VTE

7. Which of the following could result in a false negative result for a factor V leiden functional assay?
a. Current use of apixaban therapy
b. Multivitamins containing vitamin K
c. O negative blood types

8. Which of the following therapies is associated with lowering homocysteine levels in the blood?
a. Apixaban
b. Folic acid
c. Warfarin

9. Following a PE a patient is started on apixaban therapy. She is ultimately found to have positive lupus anticoagulant in the plasma. Why can we not definitively give an antiphospholipid antibody syndrome diagnosis?
a. Her laboratory values need to be confirmed by an additional test in 3 months
b. Her positive lupus anticoagulant is likely secondary to her apixaban use
c. She needs to meet at least 2 clinical criteria to qualify for diagnosis

10. Which of the following options is the most appropriate management strategy for a patient diagnosed with Antiphospholipid Syndrome?
a. Apixaban
b. Dabigatran
c. Warfarin

Developing an Anticoagulation Clinic 2025 Revision

When you are ready to submit quiz answers, go to the Blue "Take Test/Evaluation" Button.

If desired, “bundle” pricing can be obtained by registering for the activities in groups. It consists of thirteen anticoagulation activities in our online selection.

You may register for individual topics at $17/CE Credit Hour, or for the Entire Anticoagulation Pre-requisite Series.

Pharmacist General Registration for 13 Anticoagulation Pre-requisite activities-(17.25 hours of CE) $199.00

In order to attend the 2-day Anticoagulation Traineeship, you must complete all of the Pre-requisite Series or the equivalent.

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

More Information About Traineeship

Post-Test Questions:
1. Which of the following reasons best denotes the benefits of initiating a pharmacist-run anticoagulation clinic?
a. Improved outcomes for patients
b. Less need for space and resources
c. Patient willingness to come to clinic

2. As you run reports for the first year of service of your anticoagulation clinic, what results do you expect to see based on previous literature?
a. Decreased patient satisfaction scores
b. Increased frequency of bleeding
c. Improved time in therapeutic range

3. Which of the following establishes the greatest need for a pharmacist-run anticoagulation clinic from a regulatory standpoint?
a. Ensuring compliance with National Patient Safety Goals
b. Legally pharmacists are required to manage warfarin
c. National guidelines recommend pharmacist management

4. Identify which of the following is a crucial step in establishing an anticoagulation clinic
a. Finding rental space in the region to create clinic space
b. Identifying stakeholders to provide institutional backing
c. Obtaining an NPI certificate to allow for reimbursement

5. In a low budget, low resource pharmacist-run clinic, which staff member would be most important other than the pharmacist?
a. Medical director
b. Registered nurse
c. Receptionist

6. Identify the most important resource to acquire ahead of starting patient visits:
a. A fax machine
b. A private space
c. A white coat

7. What poses the biggest financial challenge for establishing a pharmacist-run anticoagulation clinic?
a. Cost of supplies is significant
b. Lack of pharmacist reimbursement
c. Services are free for patients

8. Which of the following strategies could be utilized to minimize overall clinic costs?
a. Reduce clinic hours
b. Streamline staff
c. Utilize an iSTAT meter

9. Which of the following processes will ensure standardized, legal autonomous care by a pharmacist?
a. Development and approval of a collaborative practice agreement with 1 or more providers
b. Purchase and attainment of an NPI and DEA number by each employed pharmacist
c. Requiring a PGY2 residency completed in ambulatory care by all employed pharmacists

10. Which of the following strategies will allow for sustained function and improvement of the clinic once established?
a. Reducing hours once less time is needed for appointments
b. Routine evaluation and reporting of clinical outcomes
c. Transitioning majority of patients to a DOAC

Learning Objectives

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

Learning Objectives

An Educational Grant has been provided by:

Accreditation Statements

Disclosure of Discussions of Off-label and Investigational Drug Use

Faculty

Faculty Disclosure

THIS IS A RE-ACCREDITATION OF A PREVIOUS CE CALLED SJOGREN’S SYNDROME: HOW DRY AM I?

ABSTRACT

CONTENT

Content

Pharmacist Post Test (for viewing only)

Pharmacy Technician Post Test (for viewing only)

References

Full List of References

About this Course

Target Audience

Pharmacist Learning Objectives

Bundle Options

Additional Information

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

Accreditation Statement

Grant Funding

Requirements for Successful Completion

Faculty

Faculty Disclosure

Disclaimer

Program Content

Download PDF

Post Test

View Questions for Laboratory Monitoring of Anticoagulation

References

Additional Courses Available for Anticoagulation

About this Course

Target Audience

Pharmacist Learning Objectives

Bundle Options

Additional Information

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

Accreditation Statement

Grant Funding

Requirements for Successful Completion

Faculty

Faculty Disclosure

Disclaimer

Program Content

Program Handouts

Post Test

View Questions for Vitamin K Antagonist Questions

Additional Courses Available for Anticoagulation

About this Course

Target Audience

Pharmacist Learning Objectives

Bundle Options

Additional Information

Anticoagulation Traineeship at the University of Connecticut Health Center, Farmington, CT

Accreditation Statement

Grant Funding

Requirements for Successful Completion

Faculty

Faculty Disclosure

Disclaimer

Program Content

Program Handouts

Post Test

View Questions for Clinical Overview of Direct Oral Anticoagulants 2025

Additional Courses Available for Anticoagulation

About this Course

Target Audience