Antithrombotics for stroke prevention in non-valvular atrial fibrillation: an update

Abstract

Nurses and nurse practitioners play an integral role in initiating and managing antithrombotic prophylaxis in patients with atrial fibrillation (AF). Since the advent of warfarin in the 1950s, there have been few changes in this field until recently. Warfarin has been used for decades and has well-demonstrated efficacy. However, it also has well-known drawbacks, including an unpredictable dose response, need for anticoagulation monitoring, frequent dose adjustments, and many drug and food interactions. A new generation of anticoagulants, which includes direct thrombin inhibitors and selective Factor Xa inhibitors, shows the potential to significantly improve options for antithrombotic prophylaxis and to positively affect patient outcomes. The objective of this review is to update nurses on the new oral anticoagulants, other recent developments, such as improved risk-assessment techniques, and the role of over-the-counter products, including aspirin.

Keywords

Atrial fibrillation anticoagulation stroke

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting approximately 1% of the general population; the incidence is strongly linked to age, gender, and the presence of cardiovascular disease.^1,2 The prevalence of AF increases sharply with age, from 0.1% among adults <55 years of age to 9.0% in adults ≥80 years of age.¹ This is of particular concern considering the growing elderly population, which, in the United States, as in most Western countries, is expected to nearly double by the year 2030.³ A diagnosis of AF increases the risk of thromboembolic stroke up to five-fold.⁴ In patients with AF, strokes are also more severe, more disabling, and more frequently fatal than strokes in patients with a normal sinus rhythm.⁵

Evidence-based guidelines recommend anticoagulation prophylaxis to reduce the risk of stroke in patients with all types of AF (e.g. persistent, paroxysmal, and permanent) except those at very low stroke risk, usually “lone AF” patients.^6–8 Because warfarin remains the agent of choice for stroke prevention in AF patients, this is not a simple task. Warfarin has inherent limitations that present challenges to both patients and clinicians and may impede effective stroke prophylaxis. Successful anticoagulation involves decreasing stroke risk and simultaneously minimizing bleeding risk. Evolving risk-assessment models, such as CHA₂DS₂VASc and HAS-BLED, take these two factors into consideration and can help guide clinicians’ decision-making processes upon initiating therapy.

A new generation of oral anticoagulants not only offers novel therapeutic options but also may provide significant benefits compared with the current standard of care. The first of these agents to be approved for this indication was dabigatran etexilate, a direct thrombin inhibitor (DTI). Rivaroxaban, a Factor Xa inhibitor, has also been approved for the reduction of the risk of stroke and systemic embolism in patients with non-valvular AF, as well as for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. Another Factor Xa inhibitor, apixaban, was approved by the US Food and Drug Administration (FDA) in December 2012 to reduce the risk of stroke and systemic embolism in non-valvular AF.

Assessing risk of stroke and bleeding through risk-assessment models

For the last decade, the CHADS₂ index has served as an easy-to-use risk assessment model to estimate stroke risk. The CHADS₂ index assigns values to major risk factors; the total is used as an estimate for gauging the risk of stroke, which in turn guides pharmacologic prophylaxis (Table 1).^7,8 The utility of the CHADS₂ index was validated in a trial that included patients from the US National Registry of Atrial Fibrillation.⁹ The lowest-risk patients (score=0) had a stroke rate of 1.9%, and this rate increased proportionally up to the highest-risk patients (score=6), who had a stroke rate of 18.2% (Table 2).^7–9

Table 1.

CHADS₂ vs CHA₂DS₂VASc scoring.

CHADS₂⁸		CHA₂DS₂VASc⁷
Risk factor	Score	Risk factor	Score
Congestive heart failure	1	Congestive heart failure/LV dysfunction	1
Hypertension	1	Hypertension	1
Age ≥75 years	1	Age ≥75 years	2
Diabetes mellitus	1	Diabetes mellitus	1
Stroke/TIA	2	Stroke/TIA/thromboembolism	2
		Vascular disease	1
		Age 65–74 years	1
		Sex category (female gender)	1

LV: left ventricular; TIA: transient ischemic attack.

Table 2.

CHADS₂ vs CHA₂DS₂VASc scoring and adjusted stroke rate.

CHADS₂^7,8		CHA₂DS₂VASc⁷
Score	Adjusted stroke rate (%/year) (95% CI)	Score	Adjusted stroke rate (%/year)
0	1.9 (1.2–3.0)	0	0
1	2.8 (2.0–3.8)	1	1.3
2	4.0 (3.1–5.1)	2	2.2
3	5.9 (4.6–7.3)	3	3.2
4	8.5 (6.3–11.1)	4	4.0
5	12.5 (8.2–17.5)	5	6.7
6	18.2 (10.5–27.4)	6	9.8
		7	9.6
		8	6.7
		9	15.5

CI: confidence interval.

Despite the usefulness of the CHADS₂ index, controversy exists concerning patients classified as “low risk” with a score of 0 or 1. Moreover, the CHADS₂ index omits certain risk factors such as female gender and the presence of vascular diseases.¹⁰ In addition, stroke risk increases yearly after the age of 65. Thus, grouping all patients ≥75 years into the same category does not account for varying degrees of risk associated with age.¹⁰ A new risk assessment model, CHA₂DS₂VASc, addresses these shortcomings. Similar to CHADS₂, in the CHA₂DS₂VASc index, points are assigned to a variety of risk factors. These include female gender, vascular disease (myocardial infarction (MI), peripheral artery disease (PAD), and complex aortic plaque), and varying degrees of stroke risk beyond the age of 65 years (Table 1).¹⁰ This newer risk assessment model has replaced the CHADS₂ index in the 2010 European Society of Cardiology (ESC) guidelines but has not yet been used in US guidelines.^7,8

A variety of risk assessment models that evaluate stroke risk in AF, including CHADS₂ and CHA₂DS₂VASc, were evaluated in a retrospective analysis of the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V trials.¹⁰ The CHA₂DS₂VASc index classified 94.2% of patients as high risk, significantly more patients than CHADS₂, which classified only 66.9% of patients as high risk.¹⁰ After considering the incidence of thromboembolic events, the CHA₂DS₂VASc index correctly identified 98.4% of patients who had a thromboembolic event as high risk.¹⁰ Based on these data the CHA₂DS₂VASc may provide a more accurate method for estimating stroke risk and ensuring that patients classified as low risk truly are at low risk for stroke. A review of the literature on both CHADS₂ and CHA₂DS₂ VASc was recently published and provides a useful comparison of their utility in a variety of patient populations.¹¹

Another new risk assessment model, HAS-BLED, has been developed to estimate the risk of bleeding in patients with AF. In HAS-BLED, 1 or 2 points are assigned to a variety of risk factors for bleeding (Table 3).⁷ Like previous risk assessment models that estimate stroke risk, HAS-BLED has been validated and demonstrates good predictability of bleeding risk.^7,12 The 2010 ESC guidelines include this scoring system and recommend that both bleeding risk and stroke risk be evaluated before initiating anticoagulation in patients with AF.⁷ A recent article provides examples of the use of both CHA₂DS₂ VASc and HAS-BLED in guiding clinical decision making.¹³

Table 3.

HAS-BLED scoring.⁷

Risk factor	Score
Hypertension	1
Abnormal renal and liver function (1 point each)	1 or 2
Stroke	1
Bleeding	1
Labile INRs	1
Elderly (age >65 years)	1
Drugs or alcohol (1 point each)	1 or 2
	Maximum 9 points

INR: international normalized ratio.

A score of 0–2 indicates low risk of bleeding; a score of ≥3 indicates high risk of bleeding, for which caution and a regular review of the antithrombotic regimen are recommended.

Challenges and limitations associated with warfarin

In the US, warfarin is well accepted as the agent of choice for stroke prevention in AF.^6,8 A meta-analysis that included a wide variety of clinical trials demonstrated that dose-adjusted warfarin reduces the risk of stroke by 68% when compared with no antithrombotic therapy and by 52% when compared with aspirin.⁶ Despite its proven efficacy, however, studies show that warfarin remains underused in many patients who are eligible for anticoagulation therapy. In a prospective study by Hylek et al. only about half of all US patients with AF and major risk factors for stroke were prescribed warfarin.¹⁴ Advanced age and a perceived risk of bleeding and falls were commonly cited reasons for not prescribing it.

Adherence is a major issue for patients receiving warfarin despite its once-daily oral administration. There are several likely reasons for this. Because individual dose-response may vary, maintaining an international normalized ratio (INR) within a specified therapeutic range may require complicated regimens. For example, to maintain an in-range INR, one patient may need to take 4 mg of warfarin every Monday, Wednesday, and Friday and 3 mg every Tuesday, Thursday, and Saturday, whereas another patient may require 5 mg daily to maintain an INR within the same range. Dietary variations pose another challenge. Foods containing vitamin K, such as leafy green vegetables, can reduce the effect of warfarin, which is a vitamin K antagonist, so it is necessary to maintain a consistent diet once a stable INR has been achieved in order to avoid dramatic INR fluctuations.¹⁵ Alcohol intake may also affect INR.¹⁶ Furthermore, many patients often do not report the use of over-the-counter (OTC) medications—including aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and natural supplements such as ginseng and St. John’s wort—all of which have the potential to interact with warfarin.¹⁶ Patients must also be educated on the importance of informing other clinicians involved in their care that they are taking warfarin and following up regularly with the clinician responsible for their warfarin management.

For clinicians, the biggest challenge related to warfarin use is maintaining patients’ INRs within a target range. A time-in-therapeutic range (TTR) of <45% is associated with increased rates of thromboembolic events and major bleeding events.¹⁷ Maintaining patients in therapeutic range is challenging even under ideal circumstances, such as in a randomized clinical trial. In a post hoc analysis of the ACTIVE W trial, which enrolled more than 3000 patients worldwide, the mean TTR varied from 46% to 78%, depending on the country.¹⁸ In addition to consistency in diet, factors that influence TTR include patient pharmacogenomics, medication adherence, and drug interactions.¹⁹ Warfarin interacts with many drugs, notably commonly prescribed antibiotics such as sulfamethoxazole/trimethoprim and antiarrhythmics used in AF, such as amiodarone and verapamil. Clinicians must be able to interpret the clinical significance of drug interactions to manage them appropriately. Recommended strategies include choosing an alternative agent in the same class with less potential for interactions (e.g. rabeprazole instead of omeprazole) and monitoring INR more frequently during the first 2 weeks of beginning or discontinuing a new agent.²⁰

Beyond factors that affect INR, the frequent monitoring required with warfarin use may be not only inconvenient but also a significant barrier to attaining effective anticoagulation. Once a stable INR is achieved, follow-up visits to clinicians’ offices or anticoagulation clinics should occur at least monthly.¹⁶ More frequent INR monitoring is required at the initiation of therapy, anytime there is an unstable INR, or when a patient needs to take a medication that could potentially interact with warfarin. A variety of point-of-care INR measuring devices have been approved by the FDA. These devices allow patients to play a more active role in their care and permit more frequent INR testing. A large-scale trial by Matchar et al. found that patients using point-of-care devices weekly had an improved TTR compared with patients who went to a clinic monthly for INR testing.²¹ Despite this, no benefit was seen regarding time to first stroke or first major bleeding event, and similar overall clinical outcomes were observed in both groups.

The role of over-the-counter products in anticoagulation

Aspirin

Guidelines differ as to the relative benefits and risks of antiplatelet therapy with aspirin in preventing stroke in patients with AF. The American College of Cardiology (ACC)/American Heart Association (AHA)/ESC guidelines state that the choice of antithrombotic therapy should be determined based on the CHADS₂ score.²² According to the 2006 guidelines, 81–325 mg of aspirin daily may be used in low-risk patients and certain medium-risk patients or in those with contraindications to oral anticoagulation. The use of aspirin should be determined by patient preference, estimated bleeding risk, and access to high-quality anticoagulation monitoring. On the other hand, the 2012 guidelines from the American College of Chest Physicians state that regardless of the CHADS₂ score, aspirin is never recommended as the initial therapy for patients with AF.²³ For those at low risk for stroke (i.e. CHADS₂ score of 0) these guidelines state that no antithrombotic therapy is preferable, as aspirin may pose a risk of bleeding that may exceed its benefit. For patients with a CHADS₂ score of 1, who are considered to be at intermediate risk for stroke, oral anticoagulant therapy is recommended, rather than aspirin or dual anti-platelet therapy with aspirin and clopidogrel. Oral anticoagulant therapy is also preferred over aspirin or aspirin and clopidogrel for high-risk patients (i.e. CHADS₂ score of ≥2). In patients who are not candidates for oral anticoagulant therapy for reasons other than bleeding, dual antiplatelet therapy with aspirin and clopidogrel is recommended over aspirin monotherapy.

Natural products

The use of omega-3 fatty acids (i.e. fish oil) has been well accepted in modern, evidence-based medicine. Not only does a prescription formulation exist, but the AHA and the ACC recommend its use to reduce the risk of coronary artery disease and, in higher doses, of hypertriglyceridemia.^24,25 Furthermore, in vitro studies have demonstrated fish oil’s aspirin-like antiplatelet activity, which is a result of the competitive inhibition of cyclooxygenase.²⁶ But despite its mechanism of action, there is no significant evidence to support the use of fish oil as an antithrombotic agent. Nonetheless, in observational studies the regular, weekly consumption of fish has been associated with modestly lower incidence rates of ischemic stroke.^27,28 Although fish oil has the ability to prolong bleeding time, studies have not shown that it can cause significant bleeding events or clinically relevant drug interactions with anticoagulants.²⁵ Nevertheless, periodic monitoring is recommended with co-administration of fish oil and anticoagulants or antiplatelet agents.²⁵

Warfarin also has the potential to interact with many other commonly used natural products, including ginseng, dong quai, and ginkgo biloba. The body of evidence for these drug interactions is highly variable and is largely based on case reports and theoretical mechanisms. Many of the mechanisms may not be obvious. A study that compared ginkgo biloba combined with aspirin versus aspirin alone found that the addition of ginkgo biloba had negligible effects on coagulation parameters,²⁹ but an animal study revealed that a component of ginkgo biloba, bilobalide, is a cytochrome P450 (CYP) inducer and may actually attenuate warfarin activity.³⁰ Unlike with prescription and OTC medications, manufacturing is not standardized for natural supplements. Therefore, amounts of the active ingredient may vary; this adds a degree of uncertainty to drug interactions with warfarin. It is essential that patients report all medications (prescription, OTC, and herbal), and this should be emphasized in patient education.

The new generation of oral anticoagulants

In an effort to address the limitations and challenges associated with warfarin, new oral anticoagulants have been developed for stroke prophylaxis in AF, among other indications. These new agents include the Factor Xa inhibitors rivaroxaban and apixaban and DTIs such as dabigatran etexilate. Factor Xa inhibitors exert their effect by binding to Factor Xa and preventing the conversion of prothrombin to thrombin (Figure 1).³¹ DTIs work on the next step in the coagulation cascade by binding to thrombin, preventing the conversion of fibrinogen to fibrin.³²

One of the major advantages of these new agents is that they do not require routine monitoring, dose titration, or adjustments. The new agents have demonstrated a predictable dose response and do not share the pharmacogenomic variability or variety of drug–drug interactions that contribute to warfarin’s unpredictability.³³ Large scale clinical trials evaluating these agents have used warfarin adjusted to an INR of 2.0–3.0 as a comparator.^34–36 These new agents have demonstrated, at a minimum, non-inferior efficacy and safety compared with warfarin, along with lower rates of intracranial hemorrhage.³⁷ Table 4 presents the key clinical trials for the DTI dabigatran and the Factor Xa inhibitors rivaroxaban and apixaban.^34–36

Table 4.

Comparison of RE-LY, ROCKET AF, and ARISTOTLE studies.

Study	Inclusion	Mean CHADS2 score	Time-in-therapeutic range	Treatment	Rates of intracranial hemorrhage^a
RE-LY³⁴	CHADS₂ score ≥1	2.1	64%	Warfarin^b	0.74%
				Dabigatran 110 mg twice daily	0.23% (RR=0.31; 95% CI: 0.20–0.47; p<0.001)
				Dabigatran 150 mg twice daily	0.30% (RR=0.40; 95%CI: 0.27–0.60; p<0.001)
ROCKET AF³⁵	CHADS₂ score ≥3^c or stroke/TIA	3.5	55%	Warfarin^b	0.7%
				Rivaroxaban 10 mg once daily	0.5% (HR=0.67; 95% CI: 0.47–0.93; p=0.02)
ARISTOTLE³⁶	CHADS₂ ≥1	2.1	62%	Warfarin^b	0.80%
				Apixaban 5 mg twice daily	0.33% (HR=0.42; 95% CI: 0.30–0.58; p<0.001)

CI: confidence interval; HR: hazard ratio; RR: relative risk; TIA: transient ischemic attack.

Direct comparisons among trial results cannot be made in the absence of a head-to-head randomized clinical trial.

Warfarin adjusted to an international normalized ratio (INR) of 2.0–3.0.

Patients with only two risk factors were capped at 10% of the overall trial population, with the remaining enrollees having at least three risk factors.

Dabigatran etexilate

Dabigatran etexilate, a DTI, has been approved in the US and Europe for reducing the risk of stroke and systemic embolism in non-valvular AF. Approval was largely based on the Randomized Evaluation of Long-Term Anticoagulation TherapY (RE-LY) study (Table 4).³⁴ The ACC Foundation/AHA Task Force update on practice guidelines now recommends dabigatran etexilate as an alternative to warfarin in patients with AF (Class I, Level B), but it also says that switching patients already receiving warfarin who have excellent INR control is of little value.³⁸

In RE-LY, patients with chronic AF were enrolled if they had at least one of the following risk factors for stroke: a history of stroke or transient ischemic attack (TIA), a left ventricular (LV) ejection fraction of <40%, heart failure symptoms of New York Heart Association Class II or higher within 6 months of screening, and an age of ≥75 years or 65–74 years plus diabetes mellitus, hypertension, or coronary artery disease.³⁴ Of the patients enrolled, 18,113 were randomized to receive either dabigatran etexilate at a dose of 110 mg or 150 mg twice daily or warfarin adjusted to an INR of 2.0–3.0. Predefined primary endpoints included the incidence of stroke and non–central nervous system (CNS) embolism to evaluate efficacy and the incidence of major bleeding events to evaluate safety.

The primary efficacy endpoint occurred at a rate of 1.53% per year in patients receiving the 110-mg dose of dabigatran etexilate, 1.11% per year in patients receiving the 150-mg dose of dabigatran etexilate, and 1.69% per year in patients receiving warfarin.³⁴ Both dabigatran etexilate doses demonstrated non-inferiority when compared with warfarin, but the 150-mg dose demonstrated superior efficacy (relative risk (RR) 0.66; 95% confidence interval (CI): 0.53–0.82; p<0.001). In regard to safety, the rates of major bleeding events were similar between the warfarin and the 150-mg dabigatran etexilate groups; however, the 110-mg dabigatran etexilate group demonstrated a significantly reduced incidence of major bleeding events (3.36% vs 2.71%; RR with dabigatran etexilate 0.80; 95% CI: 0.69–0.93; p=0.003). A subgroup analysis revealed that patients receiving dabigatran etexilate had rates of intracranial hemorrhage that were less than half that of warfarin. Higher rates of MI were observed in patients receiving dabigatran etexilate, with an incidence rate of 0.72% in the 110-mg group (RR 1.35; 95% CI: 0.98–1.97; p=0.07) and 0.74% in the 150-mg group (RR 1.38; 95% CI: 1.00–1.91; p=0.048), compared with 0.53% per year in the warfarin group.

In RE-LY, patients receiving dabigatran etexilate experienced significantly more dyspepsia than patients receiving warfarin.³⁴ Furthermore, the rate of treatment discontinuation due to an adverse event (AE) was higher for patients receiving dabigatran etexilate (21% vs 16% for warfarin). Gastrointestinal (GI) events, including dyspepsia, were cited as a major reason for discontinuation.³² Another important counseling point for patients pertains to storage issues. Once a bottle of dabigatran etexilate is opened the contents must be used within 30 days (bottles contain 60 capsules, a 30-day supply), because moisture can lead to degradation. To address this issue, the manufacturer has made unit-dose blister packs that are also commercially available. Drug interactions with dabigatran etexilate are minimal, though co-administration of strong P-glycoprotein (P-gp) inducers (e.g. rifampin) should be avoided. Dabigatran etexilate is approved for stroke prevention in AF at a dose of 150 mg twice daily or 75 mg twice daily in patients with a creatinine clearance (CrCl) of 15–30 mL/min.³² Dabigatran etexilate is not recommended for patients who have a CrCl<15 mL/min or who are on dialysis.

Following the approval of dabigatran in the US, and in response to reports of serious bleeding events associated with its use, the FDA conducted an investigation. They found that, consistent with results from RE-LY, bleeding rates with dabigatran were not higher than those associated with warfarin.³⁹ They are continuing to conduct a safety review of this issue.

Rivaroxaban

Rivaroxaban is a Factor Xa inhibitor that was recently approved both in the US and in Europe for the reduction of the risk of stroke and systemic embolism in patients with non-valvular AF. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study evaluated the use of rivaroxaban as an anticoagulant in patients with AF (Table 4).³⁵ Compared with RE-LY, ROCKET AF included patients at a significantly higher risk for stroke. Patients with chronic AF were enrolled if they had a history of stroke, TIA, or systemic embolism or if they had at least two of the following risk factors: congestive heart failure or LV ejection fraction ≤35%, hypertension, age ≥75 years, and diabetes mellitus. Of enrolled patients, 14,269 were randomized to receive 20 mg of rivaroxaban daily or warfarin adjusted to an INR of 2.0–3.0 daily. Predefined endpoints included the incidence of stroke and non-CNS embolism to evaluate efficacy and the incidence of major and clinically relevant non-major bleeding events to evaluate safety.

The intention-to-treat (ITT) analysis revealed that the primary efficacy endpoint occurred at a rate of 2.1% per year in patients receiving rivaroxaban and 2.4% per year in patients receiving warfarin (hazard ratio (HR)=0.88; 95% CI: 0.74–1.03; p=0.12), successfully establishing non-inferiority.³⁵ In addition, the rates of major and clinically relevant non-major bleeding events were not significantly different. Similar to dabigatran, the rates of intracranial hemorrhage were significantly lower in patients receiving rivaroxaban compared with warfarin. Rates of MI were not significantly different between treatment groups. The only AEs that occurred more frequently in patients receiving rivaroxaban were epistaxis and hematuria.³⁵

Rivaroxaban has few drug interactions; however, because it is a substrate for both P-gp and CYP3A4, clinically relevant drug interactions may occur with combined P-gp and strong CYP3A4 inducers or inhibitors.³¹ In addition, pharmacokinetic (PK) studies have demonstrated that patients with renal impairment may have a heightened response, so caution is advised when co-administering combined P-gp and weak or moderate CYP3A4 inhibitors, such as diltiazem and amiodarone. Patients in ROCKET AF were allowed use of combined P-gp and weak or moderate CYP3A4 inhibitors; however, no increase in bleeding was observed in patients who had a CrCl of 30–50 mL/min.^31,35

Rivaroxaban is approved in the US for stroke prevention in AF at a dose of 20 mg once daily with the evening meal, and in patients with a CrCl of 15–50mL/min at a dose of 15 mg once daily with the evening meal.³¹ Rivaroxaban is not recommended for use in patients with a CrCl of <15 mL/min or moderate or severe hepatic impairment.

Apixaban

Apixaban is another Factor Xa inhibitor. It was approved by the FDA in late December 2012 to reduce the risk of stroke and systemic embolism in patients with non-valvular AF.⁴⁰ Apixaban has been evaluated for efficacy and safety for stroke prophylaxis in AF in two landmark Phase III trials: Apixaban VErsus Acetylsalicylic Acid to Reduce the Risk Of StrokE (AVERROES)⁴¹ and Apixaban for Reduction in STroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) (Table 4).³⁶ AVERROES evaluated patients with AF who had at least one risk factor for stroke and were previously deemed clinically unsuitable candidates to receive warfarin.⁴¹ Patients were randomized to receive either 5 mg of apixaban twice daily or 81–324 mg of aspirin once daily. The trial was stopped early because of the significantly better efficacy of apixaban.

In ARISTOTLE, 18,201 patients with AF and at least one risk factor for stroke were randomized to receive either 5 mg of apixaban twice daily or warfarin adjusted to an INR of 2.0–3.0, in a double-blind fashion.³⁶ Predefined primary endpoints included occurrence of stroke or non-CNS embolism to evaluate efficacy and major bleeding events to evaluate safety.

The primary endpoint occurred at a rate of 1.27% per year in the apixaban group and 1.60% per year in the warfarin group (HR=0.79; 95% CI: 0.66–0.95; p=0.01). In addition to showing superior efficacy to warfarin, apixaban demonstrated a significant reduction in all-cause mortality. With regard to safety, major bleeding events occurred at a rate of 2.13% per year in the apixaban group and 3.09% in the warfarin group (HR=0.69; 95% CI: 0.60–0.80; p<0.001).³⁶ Rates of intracranial bleeding were significantly lower in the apixaban group. Rates of MI were not statistically different between groups.

In both AVERROES and ARISTOTLE, there were no distinct side effects associated with apixaban, and patients receiving apixaban had lower rates of discontinuation than those assigned to aspirin or warfarin.^36,41 As with the other new anticoagulants, apixaban has minimal drug interactions.⁴⁰ Combined inhibitors of CYP3A4 and P-gp should be avoided, because they significantly increase the risk of bleeding events. In addition, combined inducers of CYP3A4 and P-gp (e.g. rifampin, phenytoin, and St. John’s wort) can significantly reduce antithrombotic efficacy.

Other agents

Novel anticoagulants that are in earlier stages of clinical development include edoxaban, a Factor Xa inhibitor, and AZD0837, a DTI. Edoxaban is being evaluated in the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48).⁴² In this trial, approximately 20,000 patients have been randomized to receive 60 mg of edoxaban once daily, 30 mg of edoxaban once daily, or warfarin adjusted to an INR of 2.0–3.0.⁴¹ Higher-risk patients are being evaluated in this trial: a CHADS₂ score of ≥2 is part of the enrollment criteria. ENGAGE AF-TIMI 48 is ongoing. AZD0837 is in earlier stages of clinical development and has shown promising results in a Phase II study comparing two doses of AZD0837 to aspirin or clopidogrel in patients who are unsuitable candidates for warfarin.⁴³

The nurse’s role in caring for the patient with AF

The role of the nurse is critical in improving outcomes and ensuring safety in patients with AF who are receiving anticoagulants for stroke prevention.

What the nurse should know

Nurses should familiarize themselves with evidence-based guidelines for the treatment of patients with AF and for stroke prophylaxis in these patients. The newer oral anticoagulants are metabolized differently and have different pharmaceutical properties.^15,31,32,40 Nurses should be aware of these differences. They also need to understand the indications for these agents and for the potential AEs associated with them. For example, the patient’s level of renal function is an important consideration, since with the new oral anticoagulants, hemorrhaging appears to be associated with prolonged use in patients with impaired renal function. Because bleeding is a risk with all anticoagulants, nurses should be aware of their patients’ individual risk for bleeding, including history of bleeding as well as all current medications, including OTCs and food supplements. Patients with musculoskeletal or neurological problems should be evaluated for fall risk, and fall prevention measures should be discussed with these individuals and/or their caregivers. Anticipated surgeries should be noted and planned for in regard to use of oral antithrombotics. Finally, patients’ histories of non-adherence to medication regimens should be taken into consideration when deciding on antithrombotic use.

Educating your patients

AF is a chronic disease and medications are taken long-term. Patients should be educated about the importance of their medications and informed of potential AEs. They should be made aware of the signs of bleeding and the need to report them. Patients also should be taught that it is necessary to report any new medications they are taking, including OTCs, such as aspirin, or NSAIDs. Adherence may be a problem, particularly among patients receiving warfarin, who have the additional burden of regularly reporting to anticoagulation clinics for monitoring. Patients should be warned against discontinuing their medications, and the critical importance of stroke prevention should be reinforced.

Recently, AF clinics staffed by nurse specialists have been explored and have been shown to improve patient outcomes. Compared with routine care by cardiologists, specialized nurse-led clinical care has been shown to be superior in improving patient self-management and reducing cardiovascular hospitalizations and cardiovascular mortality.^44,45

Conclusion

Stroke prophylaxis in AF is becoming increasingly important as the population ages. Accurate and well-validated scoring systems, such as CHA₂DS₂VASc and HAS-BLED, may improve precision in evaluating a patient’s anticoagulation-related benefits and risks. Although warfarin has been the standard of care for decades, its management presents challenges to both patients and clinicians. A new generation of anticoagulants, which includes dabigatran etexilate, rivaroxaban, and apixaban, addresses many of the practical management issues associated with warfarin and has promise in preventing stroke in patients with AF.

Nurses and nurse practitioners should be aware of the benefits and any potential problems associated with the newer oral anticoagulants, so that they can counsel their patients appropriately. The role of patient education will be critical with the increasing use of these agents. Finally, there is increasing interest in specialized anticoagulation clinics for patients with AF, in which nurses can play important roles as caregivers and educators and in monitoring and fostering adherence to stroke prophylaxis.

Footnotes

Acknowledgements

The author would like to acknowledge Chameleon, which provided editorial assistance with funding from Janssen Scientific Affairs, LLC.

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Implications for practice

It is important to be familiar with the pharmaceutical properties of each of the new oral anticoagulants, as well as with their potential adverse effects, as they are not identical.

Be familiar with your patients’ characteristics and histories, including concomitant medications and risk for bleeding.

Educate patients about the importance of persisting on their medication as well as about any signs of potential adverse effects, including bleeding.

References

Hylek

Phillips

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