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Sanders GD, Lowenstern A, Borre E, et al. Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Oct. (Comparative Effectiveness Reviews, No. 214.)

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Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update [Internet].

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Introduction

Background

Atrial fibrillation (AF) is an irregular supraventricular tachyarrhythmia (any tachycardic rhythm originating above the ventricular tissue). It is characterized by uncoordinated atrial activation with consequent deterioration of mechanical function.1 Atrial flutter is a common abnormal heart rhythm, similar to AF. Both conditions are types of supraventricular tachycardia in which the upper chambers of the heart beat too fast, which results in loss of effective atrial muscle contractions. Within this systematic review, we will use AF to include patients with either atrial fibrillation and atrial flutter.

AF is the most common cardiac arrhythmia seen in clinical practice, accounting for approximately one-third of hospitalizations for cardiac rhythm disturbances. The estimated prevalence of AF is 0.4 percent to 1 percent in the general population,2,3 occurring in about 2.2 million people in the United States. The prevalence increases to about 6 percent in people 65 years of age or older, and to 10 percent in people 80 years of age or older.4 It is estimated that by the year 2050 there will be 12.1 million Americans with AF, representing more than a two-fold increase since 2000. However, this estimate assumes no further increase in the age-adjusted incidence of AF beyond 2000. If the incidence of AF increases at the same pace, then the projected number of adults with AF would be 15.9 million, a three-fold increase from 2000.5

Management of AF involves three distinct areas, namely, rate control, rhythm control, and prevention of thromboembolic events. This review will focus on prevention of thromboembolic events.

Atrial Fibrillation and Stroke

Although generally not as immediately life-threatening as ventricular arrhythmias, AF is associated with significant morbidity and mortality. Patients with AF have increased risk of embolic stroke, heart failure, and cognitive impairment; reduced quality of life; and higher overall mortality.6–8 Patients with AF have a five-fold increased risk of stroke, and it is estimated that up to 25 percent of all strokes in the elderly are a consequence of AF.4 Further, AF-related strokes are more severe than other types of stroke, with AF patients being twice as likely to become bedridden than patients with stroke from other etiologies and more likely to die from the stroke.9–11 Consistent with the nature of these events, AF-related stroke constitutes a significant economic burden, costing Medicare approximately $8 billion annually.12

The rate of ischemic stroke among patients with nonvalvular AF averages 5 percent per year, which is 2 to 7 times that of the general adult population.9 The risk of stroke increases from 1.5 percent for patients with AF who are 50 to 59 years of age to 23 percent for those who are aged 80 to 89.10 Congestive heart failure, hypertension, age greater than 75 years, diabetes mellitus, and prior stroke or transient ischemic attack (TIA) are considered independent risk factors for stroke as well as for AF. Aggressive primary prevention and intervention after these risk factors are present is essential to optimally manage the increased risk of developing AF or stroke independently or together.

Stroke Prevention Strategies in Atrial Fibrillation

A 2013 AHRQ Comparative Effectiveness Review (CER) evaluated questions related to stroke prevention in patients with AF and atrial flutter.13 The original review found that CHADS2 (congestive heart failure, hypertension, age >75, diabetes, stroke/transient ischemic attack) and CHA2DS2-VASc (congestive heart failure/left ventricular ejection fraction ≤40%, hypertension, age ≥75, diabetes, stroke/TIA/thromboembolism, vascular disease, age 65-74, sex) scores have the best prediction ability for stroke events in patients with AF, whereas HAS-BLED provides the best prediction ability of bleeding risk. The review found insufficient evidence on imaging tools such as transthoracic echo (TTE), transesophageal echo (TEE), computed tomography (CT) scans, or cardiac magnetic resonance imaging (MRI) in relation to risk stratification for thromboembolic events. Newer anticoagulants (direct oral anticoagulants [DOACs]) resulted in reduced stroke and bleeding events when compared with warfarin, and apixaban showed better efficacy and similar safety to aspirin in patients who are not candidates for warfarin. Given the uncertainties which remained within the limitations of the available evidence, and the new data which have emerged since that report, an update of the systematic review was commissioned.

Risk Stratification

Stroke prevention in AF is complex. Strategies for preventing thromboembolic events can be categorized into (1) optimal risk stratification of patients and (2) prophylactic treatment of patients identified as being at risk. Appropriate allocation of treatment to patients at the highest risk is critical to reduce morbidity after stroke in AF patients. However, as will be discussed, the prevention of stroke in AF comes at a cost, namely bleeding. As a result, risk stratification is paramount in patients with AF. For example, treatment with high-risk medications that can cause bleeding may unnecessarily expose patients with a low probability of thromboembolic events to the complications of monitoring and increased risk of bleeding. Likewise, not treating patients at high risk for thromboembolic events increases the likelihood of such an event. Risk stratification allows the appropriate matching of patients at risk with appropriate therapy, recognizing that there is a clinical balance that needs to be struck when treating a patient at high risk of stroke with a medication that increases the risk of major or life-threatening bleeds. The ultimate goal of risk stratification is achieving maximum treatment benefit with the lowest risk of complications for each patient based on his/her individual risk for each outcome. How best to balance the various outcomes of interest with their differing safety and effectiveness—and patient preferences for these outcomes—is challenging.

As mentioned previously, independent risk factors for stroke include congestive heart failure, hypertension, older age (≥75 years), diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, and female sex, and several of these factors are associated with AF. These risk factors are the elements that form the CHADS2 and CHA2DS2-VASc scores.14,15 The CHADS2 score ranges from 0 to 6, with increasing scores corresponding to increasing stroke risk, and is easy to calculate and apply in clinical practice. The adjusted annual rates of stroke vary from 1.9 percent in patients with a CHADS2 score of 0 to 18.2 percent in patients with a CHADS2 score of 6.14 Similarly, the CHA2DS2-VASc score ranges from 0 to 9, with increasing scores corresponding to increasing stroke risk, and is easy to calculate and apply in clinical practice.1 The adjusted annual rates of stroke vary from 1.3 percent in patients with a CHA2DS2-VASc score of 1 to 15.2 percent in patients with a CHA2DS2-VASc score of 9.16 A number of studies have examined the appropriate populations and therapies for adequate stroke prophylaxis in AF. The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) Guideline for the Management of Patients with Atrial Fibrillation recommends the use the CHA2DS2-VASc score to estimate the stroke risk, and states oral anticoagulation is indicated for patients with a score ≥2 and should be considered for patients with a score of 1 (i.e., with one risk factor).17

Use of Anticoagulation Therapy

While anticoagulation for prevention of stroke can be beneficial, it is not without risks. Assessing the risk of bleeding in patients with AF who are being considered for anticoagulation is as important as assessing the risk of stroke. Unfortunately, in clinical practice it is challenging to estimate the tradeoff between stroke risk and risk of bleeding complications from long-term anticoagulation therapy because many risk factors for stroke are also associated with increased risk of bleeding. Prothrombin time is a blood test that measures the time (in seconds) that it takes for a clot to form in the blood. It indirectly measures the activity of five coagulant factors (I, II, V, VII and X) involved in the coagulation cascade. Some diseases and the use of some oral anticoagulation therapy (e.g., vitamin K antagonists [VKAs]) can prolong the prothrombin time. In order to standardize the results, the prothrombin time test can be converted to an international normalized ratio (INR) value, which provides the result of the actual prothrombin time over a normalized value. It has been demonstrated that an INR value of 2 to 3 provides the best tradeoff between preventing ischemic events and causing bleeding. Clinicians use the prothrombin time and INR as clinical tools to guide anticoagulation therapy.

Many factors are potentially related to bleeding risk in general (older age, known cerebrovascular disease, uncontrolled hypertension, history of myocardial infarction or ischemic heart disease, anemia, and concomitant use of antiplatelet therapy in anticoagulated patients). The HAS-BLED score was developed for estimating bleeding risk in patients with chronic AF treated with warfarin and is one of the most widely examined scores for bleeding risk in AF. Scores range from 0 to 9. A score ≥3 indicates a high risk of bleeding with oral anticoagulation and/or aspirin.18 The HAS-BLED score may aid decisionmaking in clinical practice and is recommended by the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation.17

Based on the original systematic review, however, the strength of evidence was low for the CHA2DS2-VASc score and moderate for the HAS-BLED score. After the initial review, several evidence gaps remain, including how best to predict the overall clinical risk of patients (combining both their risk of stroke and their risk of bleeding), how best to use imaging studies to assess thromboembolic risk, and how to increase the dissemination of point-of-care tools to improve risk assessment and guide treatment choices for clinicians.

Therapeutic Options for Stroke Prevention in Atrial Fibrillation

Much of the focus of AF management has been on treatment strategies for stroke prevention. Antithrombotic therapies are the mainstays used to prevent thromboembolic events in patients with AF. VKAs are highly effective for the prevention of stroke in patients with nonvalvular AF. VKAs such as warfarin have been in use for more than 50 years. These compounds create an anticoagulant effect by inhibiting the у-carboxylation of vitamin K-dependent factors (II, VII, IX, and X).19 In a meta-analysis of 29 randomized controlled trials (RCTs) including 28,000 patients with nonvalvular AF, warfarin therapy led to a 64 percent reduction in stroke (95% CI 49% to 74%) compared with placebo. Even more importantly, warfarin therapy was associated with a 26 percent reduction in all-cause mortality (95% CI 3% to 34%).20

Unfortunately, two critical issues regarding stroke prevention in AF remain: (1) despite existing evidence, only a minority of patients who have AF and are at risk for stroke receive optimal treatment for thromboembolic prevention,21,22 and (2) patients with AF on stroke prophylaxis with warfarin still have higher rates of stroke than non-AF patients,17 suggesting that gaps still exist in our understanding of risk stratification and treatment. With the introduction of DOACs for stroke prevention, providers, and patients have wider choices available for treatment. Accordingly, identifying high-risk patients and choosing the optimal treatment have become even more complex.

In recent years (since 2009), four large trials comparing direct oral anticoagulants with VKAs have been completed, with a combined sample size of over 71,000 subjects:

  • RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), with approximately 18,000 subjects and evaluating the direct Factor IIa (thrombin) inhibitor dabigatran (2009)23
  • ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), with approximately 14,000 subjects and evaluating the direct factor Xa inhibitor rivaroxaban (2011)24
  • ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), with approximately 18,000 subjects and evaluating the direct factor Xa inhibitor apixaban (2011)25
  • ENGAGE-AF TIMI-48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), with approximately 21,000 subjects and evaluating the direct Xa inhibitor edoxaban (2013)26

At the time of release of this report, all four of these agents (dabigatran, rivaroxaban, apixaban, and edoxaban) have been approved by the U.S. Food and Drug Administration (FDA). Additional anticoagulant therapies in the investigational stage (without FDA approval) include idraparinux. Only the 150mg dose of dabigatran has been approved for atrial fibrillation. Dabigatran 110mg is not approved for stroke prevention in atrial fibrillation in the US. In addition, studies evaluating procedural interventions of stroke prevention are also entering the evidence base.

Table 1 provides an overview of the therapeutic options currently considered for stroke prevention for patients with AF. Following recent recommendations from the European Society of Cardiology on the management of AF,27 antiplatelet agents are no longer recommended for stroke prevention in AF. Because the ACC/AHA/HRS Guidelines have not yet been updated with a similar recommendation,17 we include antiplatelet agents as a comparator of interest but do not include it in the table.

Table Icon

Table 1

Major therapeutic options for stroke prevention in atrial fibrillation.

Scope and Key Questions

Scope of the Review

There are several areas of insufficient evidence and uncertainty within the field of stroke prevention in patients with AF:

  • The comparative diagnostic accuracy and impact on clinical decisionmaking of available clinical and imaging tools for predicting thromboembolic and bleeding risk in patients with AF are uncertain.
  • There is a lack of information to guide decisions regarding the best specific anticoagulant (versus warfarin) for a given patient.
  • The safety and effectiveness of DOACs are unclear in patients not included or not well-represented in randomized controlled trials (e.g., patients with moderate to severe chronic kidney disease (CKD) with estimated glomerular filtration rate [GFR]<60, valvular heart disease, extremes of body mass index [BMI], older age, women, multiple comorbidities, and a history of bleeding or frequent falls).
  • The relative safety and effectiveness of DOACs as compared to left atrial appendage (LAA) occlusion devices are uncertain.

This systematic review was commissioned by the Patient-Centered Outcomes Research Institute (PCORI) to update the report published in 2013 that evaluated questions related to stroke prevention in patients with AF and atrial flutter.13 Given the evidence that has emerged since the publication of the 2013 report, this review focuses on updating and expanding on that report in three key areas: evaluating the accuracy and utility of imaging tools used to prevent stroke and clot risk, evaluating the accuracy and utility of clinical tools used to predict bleeding risk, and exploring the comparative safety and effectiveness of various pharmacologic interventions used to prevent blood clots in patients with nonvalvular atrial fibrillation. In addition, this review explores the strengths and weaknesses of shared decisionmaking tools available to aid patients and clinicians in selecting an intervention to prevent stroke.

To increase applicability to the U.S. setting, we restricted our review to interventions available in the United States. For each Key Question (KQ), we further considered whether the comparative safety and effectiveness of the interventions evaluated differ among specific patient subgroups of interest, including patients with comorbid conditions, such as dementia, or renal or hepatic failure; patients with multiple coexisting conditions (e.g., combinations of hypertension, diabetes, congestive heart failure, coronary artery disease, and high cholesterol); patients with prior stroke (by type of event); patients with prior bleed (by type of bleed); patients in the therapeutic range (versus those not in range); type of AF (paroxysmal, persistent, and permanent); patients stratified by age; pregnant patients; patients stratified by race/ethnicity; and patients who are noncompliant with treatment.

Key Questions

The KQs for this systematic review update derive from the original review and have been updated based on stakeholder feedback obtained by PCORI. These questions were constructed using the general approach of specifying the Populations, Interventions, Comparators, Outcomes, Timings, and Settings of interest (PICOTS; see the section on “Inclusion and Exclusion Criteria” in the Methods chapter for details).

The KQs considered in this CER are:

  • KQ 1. In patients with nonvalvular atrial fibrillation, what are the comparative diagnostic accuracy and impact on clinical decisionmaking (diagnostic thinking, therapeutic efficacy, and patient outcome efficacy) of available clinical and imaging tools and associated risk factors for predicting thromboembolic risk?
  • KQ 2. In patients with nonvalvular atrial fibrillation, what are the comparative diagnostic accuracy and impact on clinical decisionmaking (diagnostic thinking, therapeutic efficacy, and patient outcome efficacy) of clinical tools and associated risk factors for predicting bleeding events?
  • KQ 3. What are the comparative safety and effectiveness of specific anticoagulation therapies, antiplatelet therapies, and procedural interventions for preventing thromboembolic events:
    (a)

    In patients with nonvalvular atrial fibrillation?

    (b)

    In specific subpopulations of patients with nonvalvular atrial fibrillation?

Contextual Question (CQ)

Contextual Questions are not systematically reviewed but instead use a “best evidence” approach prioritizing evidence based on study design, reporting, and relevance. Information about the contextual question may be included as part of the introduction or discussion section and related as appropriate to the systematic review.

  • CQ: What are currently available shared decisionmaking tools for patient and provider use for stroke prophylaxis in atrial fibrillation, and what are their relative strengths and weaknesses?

Analytic Framework

Figure 1 depicts the analytic framework for this project.

Figure 1. Analytic framework.

Figure 1

Analytic framework. Abbreviations: AF=atrial fibrillation; DVT=deep vein thrombosis; KQ=Key Question; ICH=intracranial hemorrhage; PE=pulmonary embolism

This figure depicts the KQs within the context of the PICOTS described elsewhere in this document. The patient population of interest is adults with nonvalvular AF. Interventions of interest are clinical and imaging tools for predicting thromboembolic risk (KQ 1); clinical tools and individual risk factors for predicting intracranial hemorrhage bleeding risk (KQ 2); and anticoagulation therapies, procedural interventions, and antiplatelet therapies in patients with nonvalvular AF (KQ 3a) and in specific subpopulations of patients with nonvalvular AF (e.g., age, presence of heart disease, type of AF, previous thromboembolic event, previous bleed, comorbid conditions, patients in therapeutic range, pregnant patients, and noncompliant patients) (KQ 3b). Outcomes of interest are thromboembolic events (cerebrovascular infarction; TIA; and systemic embolism, excluding pulmonary embolism and deep vein thrombosis); bleeding outcomes (hemorrhagic stroke, intracranial hemorrhage [intracerebral hemorrhage, subdural hematoma], major bleed, and minor bleed); other clinical outcomes (mortality, myocardial infarction, infection, heart block, esophageal fistula, tamponade, dyspepsia [upset stomach], health-related quality of life, healthcare utilization, and adherence to therapy); and efficacy of the risk assessment tools (diagnostic accuracy, diagnostic thinking, therapeutic, and patient outcome efficacy).

Organization of This Report

The remainder of the report details our methodology and presents the results of our literature synthesis, with summary tables and strength of evidence grading for major comparisons and outcomes. In the discussion section, we offer our conclusions, summaries of findings, and other information that may be relevant to translating this work for clinical practice and future research.

Appendixes provide further details on our methods and the studies we assessed, as follows:

Footnotes

Note: The reference list follows the appendixes.

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