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Lopes RD, Crowley MJ, Shah BR, et al. Stroke Prevention in Atrial Fibrillation [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Aug. (Comparative Effectiveness Reviews, No. 123.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Introduction

Background

Atrial Fibrillation and Stroke

Atrial fibrillation (AF) is a common type of supraventricular tachyarrhythmia. While a supraventricular tachyarrhythmia is any tachycardic rhythm originating above the ventricular tissue, AF is characterized by uncoordinated atrial activation with consequent deterioration of mechanical function.1 AF is the most common cardiac arrhythmia 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 adult population,2,3 occurring in about 2.2 million people in the United States. The prevalence increases to about 6 percent in people age 65 or older and to 10 percent in people age 80 or older.4 The burden of AF in the United States is increasing. It is estimated that by the year 2050 there will be an estimated 12.1 million Americans with AF (95% confidence interval [CI] 11.4 to 12.9), representing more than a two-fold (240%) 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 3-fold increase from 2000.5

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.68 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 Furthermore, AF-related strokes are more severe, with patients twice as likely to be bedridden as patients with stroke from other etiologies, and are also more likely to result in death.911 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 50–59 years old to 23 percent for those who are 80–89 years old.10 Congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack (TIA) are considered independent risk factors for stroke as well as risk factors for AF. These risk factors are the elements that form the classic CHADS2 risk score for stroke prevention (Congestive heart failure, Hypertension, Age ≥75, Diabetes mellitus, prior Stroke/transient ischemic attack [2 points]).13,14 This score ranges from 0–6, 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 1.9 percent in patients with a CHADS2 score of 0, to 18.2 percent in patients with a CHADS2 score of 6. Aggressive primary prevention and intervention once these risk factors are present are essential to optimally manage the increased risk of developing AF and stroke independently or as a result of AF.

Stroke Prevention Strategies in AF

Management of AF involves three distinct areas: rate control, rhythm control, and prevention of thromboembolic events. This Comparative Effectiveness Review (CER) focuses on the last area. CER 119, focusing on the treatment of AF through rate or rhythm control, was conducted in parallel with this CER and is available on the Effective Health Care Web site (www.effectivehealthcare.ahrq.hhs.gov/reports/final.cfm).

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.

Risk Stratification

Stroke prevention in AF is complex. 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 below, 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.

A number of studies have examined the appropriate populations and therapies for stroke prevention in AF. Despite existing risk stratification tools with overlapping characteristics, the major risk factors for ischemic stroke and systemic embolism in patients with nonvalvular AF are congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and prior stroke or TIA. As stated previously, these risk factors are the elements that form the CHADS2 score, one of the most widely studies and applied clinical risk scores from stroke in AF.13 However, because of the overlap with factors also associated with increased risk of bleeding, the CHADS2 score currently appears to be underused to guide decisions about antithrombotic therapy.

Lip and colleagues built upon the CHADS2 score and other risk stratification schema to develop the CHA2DS2-VASc score (Congestive heart failure/left ventricular ejection fraction ≤40%, Hypertension, Age ≥75 [2 points], Diabetes mellitus, prior Stroke/transient ischemic attack/thromboembolism [2 points], Vascular disease, Age 65–74, Sex category female), which ranges from 0–9 and aims to be more sensitive than the CHADS2 score, specifically seeking to identify patients at low risk for stroke based on earlier risk scores but for whom antithrombotic therapy may be beneficial, for example, women and younger patients.15 Additionally, the Framingham risk score for predicting future cardiovascular events has been also used to predict stroke in AF. Other scores have been examined, as well as other clinical risk factors but these have not been shown to provide incremental improvement or better discrimination of risk than the CHADS2, CHA2DS2-VASc, and Framingham scores.

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 with 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 INR (international normalized ratio) value, which provides the result of the actual prothrombin time over a normalized value. It has been demonstrated that an INR value of 2–3 provides the best trade-off 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 scale (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [> 65 years], Drugs/alcohol concomitantly) 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 on this scale range from 0–9. A score ≥3 indicates a high risk of bleeding with oral anticoagulation and/or aspirin.16 The HAS-BLED score may aid decisionmaking in clinical practice and is recommended by the current European Society of Cardiology (ESC) AF guidelines.17 However, uncertainty remains, both about whether other clinical or imaging tools might improve prediction of stroke or bleeding risk, and about how the available tools can best be disseminated into routine management of AF patients.

The current underutilization of risk assessment tools could be due to a number of reasons, including perceived lack of evidence to support routine use, limited comparative studies on the different tools, difficulty in using the tools at the bedside, clinical inertia, and inadequate provider knowledge and awareness of the existing tools. Independent assessments of the currently available risk assessment tools for thromboembolic events and major bleeding episodes are needed to highlight the relative strengths of the various tools for predicting events. A comparative and thorough assessment of current tools could assist providers in understanding the clinical value of appropriately judging risk and treating accordingly. Also, an assessment of how application of these tools may improve outcomes could help improve their utility in clinical practice.

Finally, the use of imaging tools for assessing thromboembolic risk has not been formally reviewed to date. Understanding the role and accuracy of these tools with a comparative assessment would provide clinicians with improved decisionmaking in the use of these technologies in patients with AF and the outcomes associated with specific imaging results.

Therapeutic Options for Stroke Prevention in AF

Vitamin K antagonists (VKAs) are highly effective for the prevention of stroke in patients with nonvalvular AF. VKAs such as warfarin have been in use for over 50 years. These compounds create an anticoagulant effect by inhibiting the y-carboxylation of vitamin K-dependent factors (II, VII, IX, and X).18 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%).19 Aspirin has commonly been recognized as an alternative strategy for prevention of stroke, despite limited evidence, for those intolerant of warfarin or at high-risk for bleeding on warfarin, such as the elderly. The best estimate of stroke reduction by antiplatelet drugs is reported to be approximately 20 percent. No major benefit of adding clopidogrel to aspirin in patients with nonvalvular AF has been found.20

Over the last decades, oral anticoagulation with VKAs has been the gold standard therapy for stroke prevention in nonvalvular AF. Thromboprophylaxis with VKAs for patients with nonvalvular AF at risk for stroke is, however, suboptimal, due primarily to the many limitations and disadvantages in use of VKAs. VKAs have a narrow therapeutic window and require frequent monitoring and lifestyle adjustments, which make their use less than ideal and adherence sometimes problematic.

The narrow therapeutic window for warfarin has clinical implications in the undertreatment and overtreatment of patients, which increase the risk of thromboembolic events and bleeding, respectively. Warfarin-naïve patients experience a three-fold increased risk of bleeding in the first 90 days of treatment compared with patients already on warfarin.21,22 This increased risk of bleeding in warfarin-naïve patients also contributes to the underuse of warfarin in the elderly population with AF. Failure to prescribe warfarin in eligible patients is a pervasive problem, despite the adoption of performance measures and guidelines advocating its use in patients with nonvalvular AF who have moderate to severe risk of stroke.23,24 One out of three Medicare AF patients eligible for anticoagulation therapy is not prescribed warfarin. In the Get With The Guidelines (GWTG) registry, only 65 percent of eligible patients with heart failure and AF were prescribed warfarin at discharge.25,26 Unfortunately, use of warfarin in the GWTG quality improvement program did not increase over time, and when warfarin was not prescribed at discharge after a stroke related to AF, initiation in eligible patients was low in the ambulatory setting. Thus, a large number of patients with AF who might benefit from warfarin are either not being offered treatment, are refusing to take it, or are stopping it.

New devices and systemic therapies have been developed for stroke prophylaxis and are in testing or have been approved for use. Mechanical interventions for stroke prophylaxis have emerged and are growing in use. For example, left atrial appendage (LAA) occlusive devices are an alternative treatment strategy used to prevent blood clot formation in patients with AF. These devices currently remain investigational pending approval by the FDA. For patients with AF who are elderly (at high risk for falls), have a prior bleeding history, are pregnant, and/or are noncompliant (which can be a significant issue for those on warfarin), LAA occlusion may be a better stroke prevention strategy than oral anticoagulation. Therefore, both anticoagulation and LAA occlusion need to be considered when evaluating stroke prevention strategies for patients with AF.

New anticoagulants are challenging the predominance of VKAs for stroke prophylaxis in AF. Since 2007, three large trials comparing novel anticoagulants with VKAs have been completed, with a combined sample size of ~50,000 subjects:

  • RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), with approximately 18,000 subjects and evaluating the new direct Factor IIa (thrombin) inhibitor dabigatran27
  • 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 new direct factor Xa inhibitor rivaroxaban28
  • ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation), with approximately 18,000 subjects and evaluating the new direct factor Xa inhibitor apixaban29

At the time of release of this report, all three of these agents (dabigatran, rivaroxaban, and apixaban) have been approved by the FDA. Additional anticoagulant therapies in the investigational stage (without FDA approval) include edoxaban and idraparinux.

The evolution of newer anticoagulation agents, like those studied in the large trials above, as well as the risks and benefits when compared with LAA occlusion devices and older antiplatelet and anticoagulation strategies, make stroke prevention in AF an area of further clinical uncertainty that supports both the importance and appropriateness of further evidence development and a new systematic review of existing evidence. Furthermore, these new therapies highlight the need to reconsider their comparative effectiveness and safety when compared with standard antithrombotic and antiplatelet therapies and with each other. Even though the ESC 2012 guidelines for AF recommend that the critical assessment necessary in the new era of newer oral anticoagulation is the identification of ‘truly low risk’, e.g. those who do not need oral anticoagulation, from those who have at least 1 or more risk factors for stroke and should be recommended oral anticoagulation, appropriate and accurate risk assessment is required as these new anticoagulants are still not without bleeding risk.

Even with treatment for stroke prophylaxis in patients with nonvalvular AF, numerous unanswered questions persist around managing patients undergoing invasive or surgical procedures. Patients receiving long-term anticoagulation therapy may need to stop this therapy temporarily before undergoing certain procedures where the risk of bleeding is high. Because VKAs have a long half-life, patients need to stop these medications approximately 5 days before an invasive procedure. However, 5 days without an oral anticoagulant can increase the risk of ischemic events. Thus, one option often used in clinical practice is a “bridging” therapy, in which a different, parenteral anticoagulant with a shorter half-life (e.g., low-molecular-weight heparin or unfractionated heparin) is given preprocedure and after the oral anticoagulant is stopped. Usually, this parenteral anticoagulant is restarted and maintained after the procedure, together with the VKA, until the INR is in the 2–3 range. Although bridging is done in clinical practice, there are data demonstrating that it is associated with increased risk of bleeding.3034 In summary, the real risk-benefit of bridging from VKAs to a parenteral anticoagulant in patients with AF undergoing an invasive procedure is unknown, and is currently under study in an National Institutes of Health (NIH) sponsored trial called BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery).

In addition, there is uncertainty regarding strategies for switching patients from warfarin to the new generation of direct thrombin inhibitors and considerations when restarting anticoagulation in patients after a hemorrhagic event. For example, in patients with AF undergoing surgery or percutaneous procedures, the duration of withholding anticoagulant therapy is not well defined. Also, synthesis of the evidence on the safety and timing of restarting patients on VKAs or antithrombin inhibitors after a hemorrhagic stroke remains lacking. These are complex and common scenarios, and a systematic review of the currently available data can provide clinicians with evidence to incorporate into their clinical practice, while at the same time shedding light on areas that require further research.

Scope and Key Questions

Scope of the Review

This CER was funded by the Agency for Healthcare Research and Quality (AHRQ) and is designed to evaluate the comparative safety and effectiveness of stroke prevention strategies in patients with nonvalvular AF. Further details are provided under “Key Questions” and “Analytic Framework,” below, and in the section on “Inclusion and Exclusion Criteria” in the Methods chapter. To increase applicability to the U.S. setting, we restrict our review to interventions available in the United States. For each Key Question (KQ), we further consider whether the comparative safety and effectiveness of the interventions evaluated differs 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.

Over the last decades, oral anticoagulation with VKAs has been the gold standard therapy for stroke prevention in nonvalvular AF. Limitations with monitoring and compliance of VKAs have fueled the development of new antithrombotic strategies, devices, and oral anticoagulants, including oral direct thrombin inhibitors and oral factor Xa inhibitors. After 60 years with essentially one class of drug for stroke prevention in nonvalvular AF, today there are several agents that are available to treat these AF populations of varying CHADS2 risk. So, there is a real challenge in how to select the treatment option most suitable for a given patient, as well as how to best utilize the available risk stratification tools to assist physicians in making important decisions. In the light of this new clinical scenario around patients with AF, comparative safety and effectiveness analyses of these novel agents and new strategies for patients with AF are needed. Existing systematic reviews of the evidence either do not include the most recent clinical evidence, or have not yet been performed exploring a broader spectrum of important clinical and policy questions of interest. Thus, a review of the available data will not only address these uncertainties, but it will define gaps in knowledge and identify important future research needs.

By summarizing data that support improved stroke prevention strategies in patients with AF, we hope to enhance patient-centered outcomes and reduce health care utilization and costs. Thus, our findings will have direct implications for improved patient care and for the allocation of Medicare and other health care resources. This project will benefit patients, providers, payers, and policymakers. Patients will benefit from more robust data on the comparative safety and effectiveness of different stroke prevention strategies for AF. Providers will benefit by gaining a better understanding of which patients benefit the most from available strategies. Policymakers will be able to design and implement programs to make better use of scarce health care resources while improving the health status of adult patients with AF.

Key Questions

With input from our Key Informants, we constructed KQs 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, and patient outcome efficacy) of available clinical and imaging tools 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, 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:
    1. In patients with nonvalvular atrial fibrillation?
    2. In specific subpopulations of patients with nonvalvular atrial fibrillation?
  • KQ 4: What are the comparative safety and effectiveness of available strategies for anticoagulation in patients with nonvalvular atrial fibrillation who are undergoing invasive procedures?
  • KQ 5: What are the comparative safety and effectiveness of available strategies for switching between warfarin and other novel oral anticoagulants, in patients with nonvalvular atrial fibrillation?
  • KQ 6: What are the comparative safety and effectiveness of available strategies for resuming anticoagulation therapy or performing a procedural intervention as a stroke prevention strategy following a hemorrhagic event (stroke, major bleed, or minor bleed) in patients with nonvalvular atrial fibrillation?

Analytic Framework

Figure 1 depicts the analytic framework for this project.

Figure 1. Analytic framework. 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 intracerebral hemorrhage bleeding risk (KQ 2); 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); strategies for patients who are undergoing invasive procedures (KQ 4); strategies for patients who switch between warfarin and direct thrombin inhibitors (KQ 5); and strategies for patients with hemorrhagic events (KQ 6). The outcomes of interest are thromboembolic events (cerebrovascular infarction; TIA; and systemic embolism, excluding pulmonary embolism and deep vein thrombosis); bleeding outcomes (hemorrhagic stroke, 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).

Figure 1

Analytic framework. Abbreviations: AF=atrial fibrillation; DVT=deep vein thrombosis; ICH=intracranial hemorrhage; KQ=Key Question; 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); 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); strategies for patients who are undergoing invasive procedures (KQ 4); strategies for patients who switch between warfarin and direct thrombin inhibitors (KQ 5); and strategies for patients with hemorrhagic events (KQ 6). The 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).

Cover of Stroke Prevention in Atrial Fibrillation
Stroke Prevention in Atrial Fibrillation [Internet].
Comparative Effectiveness Reviews, No. 123.
Lopes RD, Crowley MJ, Shah BR, et al.

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