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INTRODUCTION

Atrial fibrillation is a condition of abnormal heart rhythm characterized by disorganized electrical signals. The lack of organized heart rhythm in atrial fibrillation can lead to pooling of blood in the atria, which promotes clot formation that can precipitate a stroke.¹ A large proportion of persons with atrial fibrillation do not exhibit symptoms, which complicates diagnosis and treatment. Understanding the various types of atrial fibrillation, available screening methods, and currently approved pharmacotherapy options can improve health outcomes in patients with atrial fibrillation.

Types of Atrial Fibrillation

Clinicians classify atrial fibrillation into 1 of 3 types based on the persistence and duration of arrhythmia episodes: paroxysmal, persistent, and permanent (see Table 1). Paroxysmal atrial fibrillation accounts for approximately two-thirds of atrial fibrillation patients. Persistent atrial fibrillation usually does not terminate until corrected by an intervention. If persistent atrial fibrillation lasts more than 12 months, it is considered long-standing persistent. In permanent atrial fibrillation, episodes continue without intervention as accepted by patient and physician.²

In addition, atrial fibrillation can be classified as valvular or nonvalvular, terms that have caused some confusion among clinicians. The distinction between the 2 focuses on the severity of mitral stenosis and/or the presence of a mechanical heart valve. Atrial fibrillation is classified as “valvular” if mitral stenosis is moderate to severe or if the person has an artificial heart valve. A person with “nonvalvular” atrial fibrillation (NVAF) will not have a mechanical or prosthetic heart valve or evidence of mild or severe mitral stenosis. Notably (and possibly a source of confusion), NVAF “does not imply the absence of valvular heart disease.”³

Burden and Consequences of Undiagnosed/Untreated Atrial Fibrillation

As the most common arrhythmia, estimates on the prevalence and incidence of atrial fibrillation highlight the condition’s scope. Recent estimates of prevalence in the United States (U.S.) suggest that 3 to 6 million people have atrial fibrillation.^4,5 With an aging population, experts expect this prevalence to climb with estimates of more than 12 million by 2030 and up to 16 million by the year 2050.^5,6 The estimated worldwide prevalence of atrial fibrillation for 2016 was approximately 46.3 million people, which experts predict will double by 2030.^5,7

Complicating epidemiology estimates is the fact that approximately one-third of atrial fibrillation cases are asymptomatic, leading to underdiagnosis.⁵ One estimate of the population in the U.S. suggests that 13.1% of atrial fibrillation cases may be undiagnosed with many of those undiagnosed patients being at considerable risk of stroke.^4,8 As Lip and colleagues point out, source data can have an outsized impact on epidemiology estimates such that using inpatient/outpatient claims data alone may underestimate the scope of atrial fibrillation by more than 100%.⁹ In that study, the combined analysis of medical and pharmacy claims suggests that current estimates for people 65 years and older may be under-estimated while those for people younger than 65 years may be over-estimated.⁹

A major consequence of atrial fibrillation, particularly if undiagnosed and untreated, is an increased stroke risk; atrial fibrillation accounts for an estimated 15% of strokes per year in the U.S.¹⁰ The hallmark of atrial fibrillation, irregular cardiac rhythm, leads to blood pooling in the left atrium. Pooled blood tends to form clots that can then travel through the cardiovascular system until they block an artery and cause a stroke. Increasing age is a major, non-modifiable risk factor for atrial fibrillation and stroke. In addition, comorbidities of atrial fibrillation (e.g., diabetes, heart failure, hypertension) also increase stroke risk.⁸

Analyses of costs associated with atrial fibrillation show the condition’s impact and burden. Two longitudinal studies (Framingham Heart Study and the Cardiovascular Health Study) analyzed data from Medicare beneficiaries. Researchers estimated that the incremental annual cost of atrial fibrillation between newly diagnosed persons and matched referents aged 65 years and older was $18,601 (95% CI: $15,981-$21,234), in 2009 US dollars.¹¹ A broader study of patients 18 years and older analyzed data from a commercial claims database and a Medicare data set. The incremental costs were higher for those ultimately diagnosed with atrial fibrillation by $10,355 for the 18- to 64-year-old cohort (p < 0.001) and by $3,616 for the 65 years and older cohort (p < 0.001).¹⁰ Extrapolating to the estimated prevalence of undiagnosed atrial fibrillation, the authors estimated that total incremental cost burden in the U.S. was $3.1 billion (95% CI: $2.7 to $3.7 billion) in 2014 U.S. dollars.¹⁰

SCREENING FOR ATRIAL FIBRILLATION

Given the scope of asymptomatic NVAF, interest in screening efforts naturally follows. In addition, up to 20% of strokes that are attributed to atrial fibrillation occur in patients not previously diagnosed with atrial fibrillation.⁸ A major challenge is determining which patients to screen and when for a condition that presents asymptomatically and where increasing age is the most prominent risk factor. Joint guidelines of the American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Rhythm Society (HRS) do not specify screening recommendations for asymptomatic atrial fibrillation, but they anticipate a role for “smart” devices in such screening.³ Further, the U.S. Preventive Services Task Force draft evidence review concluded that there is “scant direct evidence” to assess the pros and cons of wide-spread screening for asymptomatic patients.¹²

Although there is a dearth of current evidence to support extended screening, data from a number of ongoing clinical trials focusing on long duration wearable devices may influence future recommendations. For example, Diederichsen and colleagues compared various screening methods to an implantable loop recorder in patients with elevated stroke risk but without atrial fibrillation.¹³ Their results suggest that while increased screening duration and frequency can improve diagnostic sensitivity, those results could not match the sensitivity of an implantable loop recorder.¹³ Given the lack of supporting data for wide-spread screening of asymptomatic patients, ACC/AHA/HRS guidelines suggest that atrial fibrillation found using implantable cardiac devices warrants further clinical investigation. These guidelines also state that providers should use an implantable loop recorder in stroke patients when ambulatory monitoring results are inconclusive.³

Studies have investigated a range of alternative methods for atrial fibrillation screening (see Table 2) and some of these studies are ongoing. These can be classified into 4 categories: implanted devices, wearable technology, mobile device apps, and electrocardiogram (ECG) monitoring patches. Implanted devices include permanent pacemakers and implantable cardiovert-defibrillators.¹⁴ Wearable technology focuses on “smart watches” that may employ methods such as photoplethysmography (light pulses similar to those used in pulse oximetry) or external devices with leads on which patients place their fingers.¹⁵ Patients may wear ECG monitoring patches for diagnosing arrhythmias for up to 14 days and cardiac electrical data is stored throughout the time worn.¹⁶

GUIDELINE RECOMMENDATIONS FOR ANTICOAGULATION IN NVAF

Direct-Acting Oral Anticoagulants

With the introduction of dabigatran in 2010, a new era of anticoagulation pharmacotherapy for atrial fibrillation began. Dabigatran is the first in class of the direct oral anticoagulants or direct-acting oral anticoagulants (DOACs), which are also commonly known as non-vitamin K oral anticoagulants or novel oral anticoagulants (NOACs).¹⁷ In addition to dabigatran, drugs in this class that are indicated for atrial fibrillation include rivaroxaban, apixaban, and edoxaban.^18-20 Several pivotal clinical trials established the efficacy and safety of DOACs compared to vitamin K antagonists (summarized for each DOAC below). The DOACs, as a class, have several advantageous biochemical properties related to their mechanisms of action (MOAs) as summarized by Hoffman and Monroe²¹:

(1) Inhibiting a single protease in the coagulation pathway rather than multiple steps like vitamin K antagonists

(2) May more efficiently reach their target proteases as small molecules

(3) Inhibit their respective proteases reversibly at the active site, so discontinuing therapy should restore coagulation activity

(4) Safety is attributable in part by the ability of coagulation factor concentrates to reverse activity

Current ACC/AHA/HRS guidelines recommend a patient-focused approach with shared decision-making when deciding on a particular course of anticoagulation therapy for NVAF. They recommend DOACs over warfarin in patients who match DOAC eligibility and who do not have either moderate-to-several mitral stenosis or a mechanical valve replacement. When considering other factors (e.g., when the CHA₂DS₂-VASc score [discussed below] is 2 or greater for men or 3 or greater for women) warfarin or DOACs are recommended.³

DOACs and vitamin K antagonists both have established places in therapy. While DOACs may have some advantages in certain applications, clinicians should be aware that DOACs have Boxed Warnings regarding increased risk of ischemic events upon therapy discontinuation and increased risk of spinal/epidural hematoma during therapy in patients undergoing neuraxial anesthesia or spinal puncture.^17-20

Dabigatran

Dabigatran, the only DOAC that targets thrombin, exerts its anticoagulation activity by directly and competitively inhibiting the serine protease, thrombin (factor IIa).¹⁷ The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study established the safety and efficacy of dabigatran in a noninferiority trial.²² The RE-LY study compared dabigatran at 110 mg or 150 mg twice daily to warfarin (unblinded) dose-adjusted to an international normalized ratio (INR) of 2.0 to 3.0 using a primary outcome of stroke or systemic embolism in 18,113 patients. Patients in the warfarin group had a rate of stroke or systemic embolism of 1.69% per year, compared to 1.53% per year in the dabigatran 110 mg group (relative risk [RR] 0.91; 95% confidence interval [CI]: 0.74 to 1.11, P < 0.001 noninferiority) and 1.11% per year in the 150 mg group (RR 0.66; 95% CI: 0.53 to 0.82, P < 0.001 superiority). The authors concluded that patients receiving dabigatran at 150 mg twice daily had lower rates of stroke and systemic embolism than those receiving dose-adjusted warfarin, while the treatment groups had similar rates of major bleeding.²² Standard dabigatran dosing for NVAF is 150 mg twice daily for adults with creatinine clearance (CrCl) greater than 30 mL/min.¹⁷

Rivaroxaban

The U.S. Food and Drug Administration (FDA) approved rivaroxaban in 2011, which inhibits factor Xa in the coagulation cascade.¹⁸ The Rivaroxaban Once Daily Oral Di-rect Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) established the drug’s safety and efficacy.²³ The ROCKET AF study, a double-blind, noninferiority trial, assigned 14,264 patients to either rivaroxaban 20 mg once daily or dose-adjusted warfarin with a primary end point of stroke or systemic embolism. The rates of stroke or systemic embolism were 2.2% per year for the warfarin treatment group and 1.7% per year for the rivaroxaban group (hazard ratio [HR] 0.79, 95% CI: 0.66 to 0.96, P < 0.001 noninferiority). The authors concluded the noninferiority of rivaroxaban compared to warfarin with respect to stroke or systemic embolism with no significant differences between the groups for major bleeding risk.²³ Standard rivaroxaban dosing for NVAF is 20 mg once daily and it is recommended to take the drug with food.¹⁸

Apixaban

Apixaban—FDA-approved in 2012—is another factor Xa inhibitor.¹⁹ The pivotal clinical trial establishing safety and efficacy of apixaban was the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study.²⁴ The ARISTOTLE trial studied 18,201 patients who received either apixaban 5 mg twice daily or INR dose-adjusted warfarin with the primary outcome of systemic embolism or ischemic or hemorrhagic stroke. When compared on the primary outcome, apixaban demonstrated both noninferiority and superiority compared to warfarin. The primary outcome rate was 1.60% per year for the warfarin cohort and 1.27% per year in the apixaban group (HR: 0.79; 95% CI: 0.66 to 0.95; P < 0.001 for noninferiority, P = 0.01 for superiority). The authors concluded based on data from primary and secondary outcomes that apixaban was superior to warfarin in the prevention of ischemic/hemorrhagic stroke and systemic embolism while also exhibiting lower risk of major bleeding and all-cause mortality.²⁴ Standard apixaban dosing in NVAF is 5 mg twice daily.¹⁹

Edoxaban

FDA approved edoxaban, a factor Xa inhibitor, in 2014.²⁰ The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial established edoxaban’s efficacy and safety.²⁵ The ENGAGE AF-TIMI 48 trial of 21,105 patients with moderate-to-high risk atrial fibrillation studied edoxaban at 2 doses, 30 mg or 60 mg once daily, compared to dose-adjusted warfarin. This trial used a primary efficacy endpoint of stroke or systemic embolism and a primary safety endpoint of major bleeding. Results for the primary efficacy endpoint were rates of 1.50% for warfarin, 1.61% for 30 mg edoxaban (HR: 1.07; 97.5% CI: 0.87 to 1.31; P = 0.005 noninferiority), and 1.18% for 60 mg edoxaban (HR: 0.79; 97.5% CI: 0.63 to 0.99; P < 0.001 noninferiority). For the primary safety endpoint, the warfarin group exhibited an annualized rate of major bleeding of 3.43% while the rates in the 30 mg and 60 mg edoxaban groups were 1.61% (HR: 0.47; 95% CI: 0.41 to 0.55; P < 0.001) and 2.75% (HR: 0.80; 95% CI: 0.71 to 0.91; P < 0.001), respectively.

Based on those and other study results, the researchers concluded that edoxaban at 30 mg or 60 mg once daily, was noninferior to warfarin in preventing stroke or embolism, exhibited significantly less risk of major bleeding, and resulted in lower risk of cardiovascular death.²⁵ Standard edoxaban dosing for NVAF is 60 mg once daily.²⁰ Clinicians should also note that in addition to the standard Boxed Warning for other DOACs, edoxaban’s warning has an additional component about reduced efficacy in NVAF patients with CrCl greater than 95 mL/min.²⁰

Comparisons Between DOACs

Due to a lack of direct, head-to-head comparisons, the most recent AHA/ACC/HRS guidelines do not distinguish between the specific DOAC medications for greater efficacy or safety in NVAF. While comparisons from systematic reviews and retrospective chart/registry reviews provide some perspective, the results suggest limited differentiation between DOACs. A recent retrospective review of Medicare patients aged 65 years and older taking either rivaroxaban or apixaban determined that apixaban was associated with lower thromboembolic and lower bleeding rates compared to rivaroxaban.²⁶ Likewise, conclusions from 2 systematic reviews suggest that apixaban may have slight advantages over other DOACs regarding stroke prevention and bleeding risk in NVAF.^27,28 Another study using data from the Swedish anticoaguation registry determined that there were no differences between apixaban, dabigatran, and rivaroxaban with respect to efficacy of stroke prevention, but dabigatran (standard dose) and apixaban (standard and reduced doses) exhibited less bleeding risk.²⁹ While such studies do not carry the weight of randomized controlled clinical trials, the information points to limited differentiation between DOACs for safety and efficacy.

DOAC Dose Adjustments

Dose adjustments may be necessary for DOACs based on renal status (see Table 3). All of the DOACs may be used at recommended dosing for patients with normal renal function, however, as noted above, edoxaban should be avoided if CrCl is greater than 95 mL/min.²⁰ For dabigatran, when a patient’s CrCl is less than 15 mL/min or the patient is on dialysis, dabigatran is not recommended.¹⁷ Dabigatran’s renal dosing recommendations are also affected by concomitant administration of p-glycoprotein (P-gp) inhibitors. Dose reduction to 75 mg twice daily is recommended when CrCl is between 30 to 50 mL/min if the patient is also taking dronedarone or systemic ketoconazole.¹⁷

Drug-drug interactions may occur between some DOACs and inducers and inhibitors of P-gp and cytochrome P450 (CYP) 3A4. These interactions may warrant dose adjustment or avoidance of a particular DOAC. To investigate the scope and risk of drug-drug interactions with DOACs in patients with NVAF, Sandhu and colleagues studied 642,255 occurrences of DOAC prescription dispensations and found that 71,643 dispensations also had a concurrently prescribed drug with potential for interaction via P-gp or CYP3A4. Of those 71,643 dispensations, the authors determined that inappropriate dispensing occurred in 63% of the cases and that the risk of death increased significantly (HR: 1.58; 95% CI: 1.47-1.70; P < 0.001).³⁰

Dabigatran prescribing information recommends against coadministration with P-gp inducers, to reduce dose or avoid dabigatran with concomitant P-gp inhibitors if CrCl is between 30 to 50 mL/min, and to avoid dabigatran with concomitant P-gp inhibitors if CrCl is less than 30 mL/min.¹⁷ Rivaroxaban prescribing information recommends avoiding the DOAC if there is concomitant use of combined P-gp and strong CYP3A4 inhibitors and inducers.¹⁸ The potential for drug-drug interactions with apixaban results in recommendations for reducing dose or avoiding concomitant use with combined P-gp inhibitors and CYP3A4 inhibitors and avoiding use with combined inducers of P-gp and CYP3A4.¹⁹ Edoxaban prescribing information recommends against combined use of edoxaban with rifampin.²⁰

Warfarin

FDA approved warfarin in 1954, and it has been a mainstay of anticoagulation therapy for over 6 decades.³¹ The drug inhibits several vitamin K-dependent steps in the intrinsic and extrinsic coagulation pathways, specifically factors II, VII, IX, and X, and also inhibits the synthesis of anticoagulant proteins C and S.^31,32 While recent ACC/AHA/HRS guidelines recommend DOACs as “first-line therapy for eligible patients,” warfarin may be recommended in particular cases of atrial fibrillation including^3,33:

• persistent or paroxysmal NVAF with intermediate or high risk of stroke
• atrial fibrillation with mitral valve stenosis
• atrial fibrillation with prosthetic heart valve (with or without additional aspirin)

Warfarin dosing in NVAF is variable and based on a target INR ratio between 2.0 to 3.0.^3,33 While dose adjustments are inherent to warfarin use to maintain optimum INR, several scenarios require additional dose adjustments. These scenarios include patients with certain genetic factors (e.g., specific CYP2C9 and VKORC1 genotypes); concomitant administration with inhibitors or inducers of CYP2C9, CYP1A2, and CYP3A4; and concomitant administration with foods, herbal products, or drugs that can increase bleeding risk.³³ Providers should consult warfarin’s prescribing information regarding the full range of dosing adjustment situations. Warfarin also has a Boxed Warning regarding the risk of major or fatal bleeding, the need for regular INR monitoring, and the possibility of changes in bleeding status with changes in drug therapy or diet.³³

Nonpharmacologic Strategies

In addition to pharmacologic approaches, certain populations may benefit from a surgical procedure, left atrial appendage occlusion (LAAO). During this procedure, a surgeon implants a medical device called a Watchman to mechanically occlude the left atrial appendage and prevent thrombus from entering the systemic circulation.³⁴ ACC/AHA/HRS guidelines suggest that, while oral anticoagulation is the favored approach for NVAF, some patients may benefit from the LAAO procedure. The guidelines also highlight differences between the FDA indication and criteria for Centers for Medicare & Medicaid Services (CMS) approval. The FDA indication focuses on patients eligible for long-term warfarin therapy who also have an appropriate reason(s) for nonpharmacologic substitutes. CMS eligibility criteria focus on patients who are unable to tolerate long-term oral anticoagulation with warfarin and have a CHADS₂ score of 2 or greater or a CHA₂DS₂-VASc score of 3 or greater.³

SHARED DECISION-MAKING

With several options for anticoagulant therapy, providers should factor patient preferences into therapeutic decisions. ACC/AHA/HRS guidelines highlight this point with an emphasis on patient preference and shared decision-making when considering the myriad of anticoagulation therapy options.³ The impact of shared decision-making on health outcomes in atrial fibrillation is not entirely clear.^35,36 A recent study suggests that lack of shared decision-making along with conflicting information provided to patients can negatively impact adherence to anticoagulation therapy.³⁷

Ongoing efforts seek to answer numerous questions about efficacy. Options to improve patient education and the shared decision-making process include patient decision aids and understanding factors that drive patient preferences.^38,39 Online resources for shared decision-making include the stroke and bleeding risk calculator, CardioSmart, from ACC and the Mayo Clinic’s Anticoagulation Choice Decision Aid.^40,41

Assessing Stroke Risk and Interpreting CHA₂DS₂-VASc

Stroke risk is the main driver for treating atrial fibrillation patients with anticoagulants. Each patient has a different level of stroke risk and assessing that risk is important for the shared decision-making process. Of the tools available for assessing stroke risk in atrial fibrillation, the CHA₂DS₂-VASc score, outlined in Table 4, is the most commonly used.⁴² The acronym is based on the factors used to determine the score: Congestive heart failure, Hypertension, Age (2 points for over 75), Diabetes, Stroke (2 points), Vascular disease, Age (1 point for 65-74), Sex category (1 point for female).^42,43 Of note, age is counted only once in the CHA₂DS₂-VASc score. As specified in ACC/AHA/HRS guidelines, providers use the CHA₂DS₂-VASc score to differentiate between pharmacotherapy recommendations based on the propensity of stroke risk.³

Assessing Bleeding Risk

On the other end of the spectrum of stroke risk is bleeding risk, which providers should equally consider when navigating anticoagulation options. They commonly use HAS-BLED (Hypertension, Abnormal renal or hepatic function, Stroke, Bleeding tendency, Labile INRs, Elderly, Drugs or alcohol) to assess bleeding risk (see Table 5).⁴⁴ For the purposes of the HAS-BLED tool^42,44

• end-stage renal disease or serum creatinine greater than 2.26 mg/dL is considered abnormal renal function
• chronic hepatic disease or elevated liver function markers (bilirubin 2- to 3-times normal and aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase 3-times normal) is considered abnormal hepatic function
• a history of bleed or anemia counts for bleeding tendency
• time in therapeutic range less than 60% is considered labile INRs
• older than 65 years is considered elderly
• “drugs” refers to the use of non-steroidal anti-inflammatory drugs (NSAIDs) or antiplatelet drugs
• 8 units or more weekly is considered excess alcohol

HAS-BLED scores between 0 to 2 are considered low risk and scores from 3 to 9 (maximum) are considered high risk. Although HAS-BLED scores in the high-risk range do not disqualify a patient from anticoagulant use, they do indicate the need for closer monitoring and/or focus on improving modifiable risk factors. Of the HAS-BLED scoring criteria, several risk factors are potentially modifiable to reduce risk, including controlling hypertension, eliminating unnecessary or redundant antiplatelet or NSAID drugs, correcting labile INRs, and reducing excessive alcohol intake.⁴²

Other Considerations

Besides balancing the risks of stroke and bleeding, clinicians should evaluate a range of other factors when choosing appropriate therapy for atrial fibrillation. Comorbidities, dosing frequency, need for monitoring, and cost are some of the important factors to consider.

Comorbidities

Common comorbidities that can impact decision-making regarding anticoagulant therapy include heart valve disorders, renal disease, and obesity. For patients with heart valve disorders (i.e., mechanical heart valve in place or moderate-to-severe mitral stenosis), guidelines and FDA indications recommend warfarin use.^3,33 In patients with end stage renal disease or are on dialysis, warfarin or apixaban are considered reasonable options when CHA₂DS₂-VASc score is 2 or greater for men or 3 or greater for women.³ The impact of obesity on drug selection and dosing is not entirely clear mostly due to the lack of atrial fibrillation clinical trial data for patients with BMI greater than 40 kg/m².⁴⁵

Dosing and Required Monitoring

Dose frequency and monitoring needs may also affect patient adherence and preference. While warfarin is often dosed once daily, the need for monitoring INR for dose adjustments may lead to decreased adherence and increased thromboembolism risk.⁴⁶ Regarding DOACs, dabigatran and apixaban are dosed twice daily while rivaroxaban and edoxaban are dosed once daily. The difference between twice daily and once daily dosing may be sufficient to affect adherence and persistence to anticoagulation therapy.⁴⁷

Anticoagulation Reversal Options

A variety of scenarios may necessitate the use of anticoagulation reversal agents for patients on anticoagulant therapy, including major bleeding episodes or emergent surgery.⁴⁸ Reversal agents for warfarin include fresh frozen plasma and prothrombin complex concentrates.⁴⁹ When first marketed, the lack of anticoagulation reversal options for DOACs was a concern, but reversal agents are now available for DOACs. Idarucizumab was the first reversal agent approved for a DOAC, the thrombin inhibitor dabigatran.⁵⁰ Andexanet alfa is approved for the reversal of factor Xa inhibitors, rivaroxaban and apixaban.⁵¹ Another reversal agent, ciraparantag, is currently under investigation as a reversal agent for DOACs and low molecular weight heparin.^52,53

Diet and Medication Interactions

The issue of polypharmacy is common, especially among elderly patients who also happen to be at increased risk of NVAF. Patients with NVAF who are stabilized on long-term pharmacotherapy for other conditions may need to balance their current drug regimen with the need for an anticoagulant. As outlined above for each DOAC and warfarin, drug interactions can be an issue.

Availability and Cost

Medication cost remains a major concern among patients. Drug costs drive lack of adherence in pharmacotherapy, particularly in the U.S. Morgan and Lee compared the effect of cost on non-adherence across 11 developed countries and found that the cost-related nonadherence rate in the U.S. was 16.8%, which was more than double the next highest rate (Canada 8.3%).⁵⁴ With limited studies on the effects of cost on DOAC persistence, a recent conference proceeding of interest suggests that lower out-of-pocket costs for apixaban and rivaroxaban translated to increased therapy persistence.⁵⁵ Brízido and colleagues also concluded that higher out-of-pocket costs, therapy duration, and twice daily dosing were major drivers of nonadherence to DOAC therapy.⁵⁶

FOLLOW-UP AFTER ANTICOAGULANT SELECTION

Patient Counseling and Education

Patient education and counseling about anticoagulants are prime areas for pharmacist involvement in NVAF treatment. Pharmacist-led patient counseling and education can help improve patients’ health literacy regarding NVAF. By better understanding stroke risk, bleeding risk, and pharmacotherapy options, patients can be better equipped to participate in guideline-directed shared decision-making processes.³ Pharmacists are also well-positioned to educate patients on specific aspects of DOAC and warfarin dosing. Warfarin anticoagulation management services are common avenues for pharmacist participation. Many of these have evolved into total anticoagulation services that include DOAC management.⁵⁷

Facilitating Patient Adherence

Patient adherence to anticoagulant therapy is a challenge. Yao and colleagues provided a detailed analysis of adherence to 3 DOACs (apixaban, dabigatran, rivaroxaban) compared to warfarin.⁵⁸ Adjusted adherence rates (based on 80% or greater days covered by dosing) were below 65% for each DOAC (ranging from 41.4% to 64.4%) and below 53% for warfarin (ranging from 37.8% to 52.8%). In their pooled analysis, adherence to all 3 DOACs was significantly greater than adherence to warfarin for all CHA₂DS₂-VASc scores and for stratified scores (0 or 1; 2 or 3; 4 or greater).⁵⁸ Improved patient education and shared decision-making may help improve patient satisfaction and consequently patient adherence to therapy.⁵⁹

Socioeconomic Challenges

Patients may face a range of socioeconomic barriers while undergoing anticoagulant therapy. Medication cost is a recurring theme for patients in the U.S. Transportation challenges may hinder access to follow-up appointments (e.g., for INR monitoring). Lack of access to local pharmacies may also be a challenge. While pharmacy deserts may be more predominant in Black and Hispanic/Latino neighborhoods of urban areas, rural areas may also suffer from lack of pharmacy services.^60,61

Facilitating Treatment During Transitions of Care

During transitions of care (e.g., into or out of a hospital or long-term care facility), patients are more susceptible to pharmacotherapy changes that can negatively impact health outcomes. Lack of communication channels between responsible parties, formulary differences between care sites, and variations in health status that warrant pharmacotherapy changes can occur. A panel of anticoagulation experts convened by the New York State Anticoagulation Coalition recently proposed a set of 15 recommended core elements to consider during transitions of care, which they named the ACDC (Anticoagulation Communication at DisCharge) List.⁶² Table 6 summarizes the ACDC list. The purpose of the ACDC list is to clearly state the needed information to establish management expectations and limit the chance that unaddressed barriers prevent the treatment for the patient. The recurring theme of the ACDC List is proper documentation, which often leads to improved communication between the inpatient anticoagulation manager, outpatient anticoagulation manager, and patient/family.

Assessing and Addressing Risk Factors for Bleeding

Fear of bleeding is an issue for both patients and prescribers. For providers, the fear of increased bleeding from anticoagulant use is a major factor that negatively impacts prescribing behaviors.⁶³ The fear may also be tied to a perceived increased fall risk as patients age. A history of falls or high fall risk can increase bleeding risk, but methods to decrease fall risk are preferred over under-utilization of anticoagulants.^64,65 Patient’s fear of bleeding is a main theme in lack of adherence to DOAC therapy.⁶⁶ Effective and proper use of the HAS-BLED score may be useful for addressing patients’ and prescribers’ bleeding concerns.

SUMMARY

Atrial fibrillation, particularly undiagnosed NVAF, is a substantial public health concern, as 16 million people may have atrial fibrillation by the year 2050.⁵ Lack of overt symptoms in a majority of NVAF cases is a driving factor in the low diagnosis rate, which leads to increased stroke risk. While current screening options are limited, new technologies may improve screening in the future. With the availability of several DOAC medications and warfarin, patients and clinicians have a range of pharmacotherapy options for treating atrial fibrillation, including NVAF. Providers can use guidelines and risk assessment tools for stroke and bleeding effectively in shared decision-making processes to improve patient satisfaction and adherence. Central to shared decision-making is patient education wherein pharmacists can and do play a vital role.

References

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