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Reviews |4 December 2018

Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review Free

Angela Lowenstern, MD; Sana M. Al-Khatib, MD, MHS; Lauren Sharan, MD; Ranee Chatterjee, MD, MPH; Nancy M. Allen LaPointe, PharmD, MHS; Bimal Shah, MD, MBA; Ethan D. Borre, BA; Giselle Raitz, MD; Adam Goode, DPT, PhD; Roshini Yapa, MBBS; J. Kelly Davis, BA; Kathryn Lallinger, MSLS; Robyn Schmidt, BA; Andrzej S. Kosinski, PhD; Gillian D. Sanders, PhD

Angela Lowenstern, MD

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Sana M. Al-Khatib, MD, MHS

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Lauren Sharan, MD

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Ranee Chatterjee, MD, MPH

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Nancy M. Allen LaPointe, PharmD, MHS

Duke University School of Medicine, Durham, and Premier, Charlotte, North Carolina (N.M.A.)

Bimal Shah, MD, MBA

Duke University School of Medicine, Durham, North Carolina, and Livongo, Mountain View, California (B.S.)

Ethan D. Borre, BA

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Giselle Raitz, MD

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Adam Goode, DPT, PhD

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Roshini Yapa, MBBS

University of Colorado, Aurora, Colorado (R.Y.)

J. Kelly Davis, BA

Duke University, Durham, North Carolina (J.K.D.)

Kathryn Lallinger, MSLS

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Robyn Schmidt, BA

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Andrzej S. Kosinski, PhD

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)

Gillian D. Sanders, PhD

Duke University School of Medicine and Duke University, Durham, North Carolina (G.D.S.)

Article, Author, and Disclosure Information

This article was published at Annals.org on 30 October 2018.

Duke University School of Medicine, Durham, North Carolina (A.L., S.M.A., L.S., R.C., E.D.B., G.R., A.G., K.L., R.S., A.S.K.)
Duke University School of Medicine, Durham, and Premier, Charlotte, North Carolina (N.M.A.)
Duke University School of Medicine, Durham, North Carolina, and Livongo, Mountain View, California (B.S.)
University of Colorado, Aurora, Colorado (R.Y.)
Duke University, Durham, North Carolina (J.K.D.)
Duke University School of Medicine and Duke University, Durham, North Carolina (G.D.S.)
Disclaimer: The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by PCORI, AHRQ, or the U.S. Department of Health and Human Services. AHRQ retains a license to display, reproduce, and distribute the data and the report from which this manuscript was derived under the terms of the agency's contract with the author.
Acknowledgment: The authors thank Jamie Conklin, MSLIS, for help with the literature search and retrieval; Samantha E. Bowen, PhD, and Amanda J. McBroom, PhD, for assistance with project leadership; and Liz Wing, MA, for editorial assistance.
Grant Support: This project was funded under contract HHSA-290-2015-00004-I from AHRQ, U.S. Department of Health and Human Services.
Disclosures: Dr. Lowenstern, Al-Khatib, Sharan, Chatterjee, Allen LaPointe, Shah, Raitz, Goode, Yapa, Kosinski, Sanders, Mr. Borre, Mr. Davis, Ms. Lallinger, and Ms. Schmidt report support from AHRQ and PCORI through a contract with Duke University during the conduct of the study. Dr. Allen LaPointe is an employee of Premier. Mr. Shah reports personal fees from Medtronic, Premier, and Janssen and nonfinancial support from Boehringer Ingelheim, outside the submitted work. Disclosures can also be viewed at www.acponline.org/authors/icjme/ConflictOfInterestForms.do?msNum=M18-1523.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available at www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017069999. Statistical code: Available from Dr. Sanders (e-mail, gillian.sanders@duke.edu). Data set: See Supplement and full AHRQ report (available at www.effectivehealthcare.ahrq.gov).
Corresponding Author: Gillian D. Sanders, PhD, Duke Clinical Research Institute, 2400 Pratt Street, Durham, NC 27705; e-mail, gillian.sanders@duke.edu.
Current Author Addresses: Drs. Lowenstern, Sharan, and Raitz: 2400 Pratt Street, Duke Box 3850, Durham, NC 27710.
Dr. Al-Khatib: 7521 North Pavilion Building, Durham, NC 27715.
Dr. Chatterjee: 411 West Chapel Hill Street, Suite 500, Durham, NC 27701.
Dr. Allen LaPointe: 13034 Ballantyne Corporate Place, Charlotte, NC 28277.
Dr. Shah: 150 West Evelyn Avenue, Suite 150, Mountain View, CA 94041.
Mr. Borre, Ms. Lallinger, Ms. Schmidt, and Dr. Sanders: 2400 Pratt Street, Durham, NC 27705.
Dr. Goode: 2200 West Main Street, Durham, NC 27703.
Dr. Yapa: 12700 East 19th Avenue, Campus Box C281, Aurora, CO 80045.
Mr. Davis: 100 Fuqua Drive, A05G-1, Durham, NC 27708.
Dr. Kosinski: DCRI, Room 7058, P.O. Box 17969, Durham, NC 27715.
Author Contributions: Conception and design: S.M. Al-Khatib, N.M. Allen LaPointe, A. Goode, K. Lallinger, R. Schmidt, G.D. Sanders.
Analysis and interpretation of the data: A. Lowenstern, S.M. Al-Khatib, L. Sharan, R. Chatterjee, N.M. Allen LaPointe, B. Shah, E.D. Borre, G. Raitz, A. Goode, R. Yapa, J.K. Davis, A.S. Kosinski, G.D. Sanders.
Drafting of the article: A. Lowenstern, L. Sharan, R. Chatterjee, B. Shah, G. Raitz, A. Goode, K. Lallinger, G.D. Sanders.
Critical revision for important intellectual content: A. Lowenstern, S.M. Al-Khatib, R. Chatterjee, N.M. Allen LaPointe, B. Shah, A. Goode, K. Lallinger, R. Schmidt, A.S. Kosinski, G.D. Sanders.
Final approval of the article: A. Lowenstern, S.M. Al-Khatib, L. Sharan, R. Chatterjee, N.M. Allen LaPointe, B. Shah, E.D. Borre, G. Raitz, A. Goode, R. Yapa, J.K. Davis, K. Lallinger, R. Schmidt, A.S. Kosinski, G.D. Sanders.
Statistical expertise: A.S. Kosinski, G.D. Sanders.
Obtaining of funding: G.D. Sanders.
Administrative, technical, or logistic support: J.K. Davis, K. Lallinger, R. Schmidt.
Collection and assembly of data: A. Lowenstern, S.M. Al-Khatib, L. Sharan, R. Chatterjee, N.M. Allen LaPointe, E.D. Borre, G. Raitz, A. Goode, J.K. Davis, K. Lallinger, R. Schmidt, G.D. Sanders.

Abstract

Background:

The comparative safety and effectiveness of treatments to prevent thromboembolic complications in atrial fibrillation (AF) remain uncertain.

Purpose:

To compare the effectiveness of medical and procedural therapies in preventing thromboembolic events and bleeding complications in adults with nonvalvular AF.

Data Sources:

English-language studies in several databases from 1 January 2000 to 14 February 2018.

Study Selection:

Two reviewers independently screened citations to identify comparative studies of treatments to prevent stroke in adults with nonvalvular AF who reported thromboembolic or bleeding complications.

Data Extraction:

Two reviewers independently abstracted data, assessed study quality and applicability, and rated strength of evidence.

Data Synthesis:

Data from 220 articles were included. Dabigatran and apixaban were superior and rivaroxaban and edoxaban were similar to warfarin in preventing stroke or systemic embolism. Apixaban and edoxaban were superior and rivaroxaban and dabigatran were similar to warfarin in reducing the risk for major bleeding. Treatment effects with dabigatran were similar in patients with renal dysfunction (interaction P > 0.05), and patients younger than 75 years had lower bleeding rates with dabigatran (interaction P < 0.001). The benefit of treatment with apixaban was consistent in many subgroups, including those with renal impairment, diabetes, and prior stroke (interaction P > 0.05 for all). The greatest bleeding risk reduction was observed in patients with a glomerular filtration rate less than 50 mL/min/1.73 m² (P = 0.003). Similar treatment effects were observed for rivaroxaban and edoxaban in patients with prior stroke, diabetes, or heart failure (interaction P > 0.05 for all).

Limitation:

Heterogeneous study populations, interventions, and outcomes.

Conclusion:

The available direct-acting oral anticoagulants (DOACs) are at least as effective and safe as warfarin for patients with nonvalvular AF. The DOACs had similar benefits across several patient subgroups and seemed safe and efficacious for a wide range of patients with nonvalvular AF.

Primary Funding Source:

Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42017069999)

Atrial fibrillation (AF) is characterized by uncoordinated atrial activation with consequent deterioration of mechanical function (1). It is the most common sustained cardiac arrhythmia, and according to estimates, 12.1 million Americans will have AF by 2050 (2). Patients with AF have increased risk for embolic stroke, heart failure, and cognitive impairment; reduced quality of life; and higher overall mortality (3–5). Strokes related to AF have been characterized as more severe (6, 7) and translate to a substantial economic burden, costing Medicare approximately $8 billion annually (8).

Antithrombotic therapies are the mainstays for preventing thromboembolic events in patients with AF. Oral anticoagulation with vitamin K antagonists (VKAs) has long been the gold standard therapy for stroke prevention in these patients. However, the challenges of monitoring VKA therapy and the many associated food and drug interactions have fueled the development of novel therapeutic options. Currently, 4 direct-acting oral anticoagulants (DOACs) are approved for stroke prevention in patients with nonvalvular AF: the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, rivaroxaban, and edoxaban. In addition, procedural interventions, such as left atrial appendage (LAA) occlusion devices, are an alternative treatment for patients who are at high risk for bleeding while receiving anticoagulation therapy.

Since 2009, 4 large trials comparing DOACs with warfarin (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], ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], RE-LY [Randomized Evaluation of Long Term Anticoagulant Therapy], and ENGAGE AF-TIMI 48 [Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48]) have been completed, creating a combined sample size of more than 71 000 participants (9–12). This systematic review updates previous reviews (13) and aims to compare the effectiveness of the available medical and procedural therapies in preventing thromboembolic events and bleeding complications in patients with AF.

Methods

The full report (available at www.effectivehealthcare.ahrq.gov; PROSPERO protocol available at www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017069999) provides detailed information on the methods used in this systematic review. This review was commissioned by the Patient-Centered Outcomes Research Institute (PCORI) in partnership with the Evidence-based Practice Center Program of the Agency for Healthcare Research and Quality (AHRQ) to explore the data and ongoing uncertainties regarding AF treatment. To inform the review, PCORI held 2 multi stakeholder workshops to discuss scoping and prioritizing key questions. On the basis of stakeholder feedback, an analytic framework was constructed (Appendix Figure) to further explore new evidence related to the key questions from the original report.

Appendix Figure.

Analytic framework.

AF = atrial fibrillation; DVT = deep venous thrombosis; KQ = key question; ICH = intracranial hemorrhage; PE = pulmonary embolism; TIA = transient ischemic attack.

Data Sources and Searches

Literature was identified by searching PubMed, EMBASE, and the Cochrane Database of Systematic Reviews for English-language studies published between 1 January 2000 and 14 February 2018. All searches were guided by an experienced research librarian (Supplement Table 1).

Study Selection

All studies were screened on the basis of inclusion and exclusion criteria (Supplement Table 2). We included studies that enrolled at least 20 patients aged 18 years or older with nonvalvular AF who received anticoagulation, antiplatelet, or procedural therapy. All studies were required to have had an active comparator and to have assessed an outcome of interest. Two independent investigators reviewed each title and abstract for potential relevance. Any abstract selected by 1 investigator was included in the full-text review. During the full-text review, 2 investigators independently reviewed the manuscript text and determined whether to include or exclude the study. Conflicts were resolved by further review and discussion or by a third-party arbitrator.

Data Extraction and Quality Assessment

Investigator pairs were formed on the basis of methodological and clinical experience to abstract data from the selected studies. One investigator abstracted the data into previously created data abstraction forms and table templates. The other investigator reviewed the abstracted data together with the original article to ensure accuracy and completeness.

We evaluated each study for methodological quality using the Cochrane Risk of Bias Tool (for randomized controlled trials [RCTs]) and the Risk of Bias in Nonrandomized Studies of Interventions tool (for observational studies). Studies were assigned a rating of good, fair, or poor quality. Quality assessment was outcome specific, such that a given study that analyzed its primary outcome well but did an incomplete analysis of a secondary outcome could be assigned a different quality grade for each of the 2 outcomes.

Data Synthesis and Analysis

Key features of each study were reviewed and summarized on the basis of a hierarchy of evidence, with the best available evidence as the focus of the synthesis. Treatments were grouped according to drug class to determine whether a quantitative synthesis was feasible. If at least 3 studies with similar interventions and populations were available to compare a specified outcome, we used the R statistical package, version 3.1.2 (The R Foundation), with the metafor meta-analysis library, version 1.9-7, to synthesize the available evidence. We used the random-effects DerSimonian–Laird estimator (14) to generate summary values. In addition, we used the Knapp–Hartung approach (15) to adjust the SEs of the estimated coefficients. We explored heterogeneity using graphical displays and test statistics (Q and I² statistics). For observational studies, we used adjusted results from the individual studies for pooled analyses. If an individual study included findings from more than 1 dosage of a specific drug, we chose the dosage most typically used in the United States. We considered the use of a network meta-analysis to synthesize findings from the observational studies, although because of the heterogeneity of populations, treatment dosages, treatment protocols, outcome definitions, and study quality, we did not include such analyses in our review.

We rated strength of evidence (SOE) using the approach described in the AHRQ methods guide (16, 17). We graded the SOE for each outcome individually; thus, the SOE for 2 separate outcomes in a given study may have been scored differently. In brief, the approach requires assessment of 5 domains: study limitations; consistency; directness; precision; and reporting bias, including publication bias, outcome reporting, and analysis reporting bias. These domains were considered qualitatively, and a summary rating of “high,” “moderate,” “low,” or “insufficient” SOE was assigned after discussion by 2 reviewers. For outcomes assessed by both RCTs and observational studies, we focused our SOE rating on the RCT findings and then increased or decreased it depending on whether findings from the observational studies were consistent or inconsistent with those from the RCTs. We assigned the greatest weight to findings from large RCTs.

Role of the Funding Source

This topic was nominated and funded by PCORI for systematic reviews by an Evidence-based Practice Center in partnership with AHRQ. An AHRQ representative served as the Contracting Officer's Representative and provided technical assistance during the conduct of the full evidence report. The AHRQ Contracting Officer's Representative and PCORI program officers provided comments on draft versions of the protocol and full evidence report. Neither PCORI nor AHRQ directly participated in the literature search; determination of study eligibility criteria; data analysis or interpretation; or preparation, review, or approval of the manuscript for publication.

Results

For this specific key question, our 2018 update and articles from our original review resulted in 220 included articles, representing 117 unique studies involving 3 934 374 patients (Figure 1). Supplement Table 3 provides specific details about each study, including patient population and outcomes analyzed.

Figure 1.

Evidence search and selection.

AHRQ = Agency for Healthcare Research and Quality; KQ = key question; SR = systematic review.

* Articles/studies may be relevant to more than 1 KQ.

† 18 articles representing 9 studies provided additional outcome data that had not been included in our previous SR.

Because of the large number of studies and comparisons, this article focuses on the most applicable clinical effectiveness comparisons. Figure 2 displays the number of studies for each direct comparison available and the specific study designs. Additional studies that evaluated several different treatment comparisons, including VKAs versus aspirin, clopidogrel versus warfarin, dabigatran with or without aspirin versus warfarin, and factor Xa inhibitors versus aspirin, are detailed in the full report available online.

Figure 2.

Treatment comparisons.

LAA = left atrial appendage; Obs = observational studies; RCT = randomized controlled trial; VKA = vitamin K antagonist.

Warfarin Versus Thrombin Inhibitor (Dabigatran)

The RE-LY trial (9, 18) showed that treatment with dabigatran, 150 mg, is superior to warfarin in reducing the incidence of the composite outcome of stroke or systemic embolism. No statistically significant difference was observed between the 2 therapies with regard to major bleeding, myocardial infarction, or all-cause mortality. A prespecified secondary analysis examined outcomes related to renal function. The rates of stroke or systemic embolism were lower with twice-daily dabigatran at 150 mg and similar at 110 mg compared with warfarin, without significant heterogeneity in subgroups defined by renal function (interaction P > 0.1 for all) (19). Likewise, no interaction was seen between treatment with dabigatran, 150 mg, and the presence of left ventricular hypertrophy on the outcomes of stroke or systemic embolism (P = 0.24) or major bleeding (P = 0.89) (20). Conversely, a statistically significant treatment-by-age interaction was observed in that dabigatran, 150 mg twice a day, compared with warfarin was associated with a lower risk for major bleeding in patients younger than 75 years, with a trend toward a higher risk for major bleeding in those aged 75 years or older (P < 0.001) (9).

As an extension of the RCT, the RELY-ABLE (Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation) observational study (21) extended the follow-up of patients receiving dabigatran to provide additional long-term information on dabigatran, 150 mg versus 110 mg. The RELY-ABLE study showed no difference in the rate of stroke or systemic embolism (hazard ratio [HR], 0.91 [95% CI, 0.69 to 1.20]) or all-cause mortality (HR, 0.97 [CI, 0.80 to 1.19]) between the groups. However, patients receiving the 150-mg dosage had higher rates of major hemorrhage (HR, 1.26 [CI, 1.04 to 1.53]). Of note, the dabigatran dosages currently approved in the United States for stroke prevention in AF are 150 mg and 75 mg (for patients with creatinine clearance of 15 to 30 mL/min/1.73 m²) (22).

In addition, 35 observational studies compared warfarin with dabigatran. A meta-analysis of these studies demonstrated a reduction in the risk for stroke, stroke or systemic embolism, hemorrhagic stroke, intracranial bleeding, minor bleeding, gastrointestinal bleeding, and all-cause mortality in patients receiving dabigatran compared with those receiving warfarin. No statistically significant difference was observed between treatments in rates of ischemic stroke or myocardial infarction. Forest plots for each outcome are available in Supplement Figure 1. The observational studies demonstrated a benefit in all-cause mortality for patients receiving dabigatran compared with those receiving warfarin. Evidence from RCTs, however, did not demonstrate a difference.

Warfarin Versus Factor Xa Inhibitors (Apixaban, Rivaroxaban, and Edoxaban)

The 3 RCTs detailed in this section compared warfarin with factor Xa inhibitors. Table 1 summarizes the results of these trials. Results from a meta-analysis of these studies are presented as forest plots in Figure 3. Overall, no differences were observed between treatment with Xa inhibitor and warfarin in the outcomes of stroke or systemic embolism, ischemic or uncertain stroke, major bleeding, or myocardial infarction. However, Xa inhibitor therapy showed an overall benefit with regard to hemorrhagic stroke, intracranial bleeding, all-cause mortality, and death from cardiovascular causes.

Figure 3.

Forest plots for comparison of Xa inhibitors versus warfarin (randomized controlled trials).

Outcomes examined. HR = hazard ratio.

Figure 3.

Continued

Table 1. Outcomes of Interest in RCTs Evaluating Factor Xa Inhibitors (Apixaban, Rivaroxaban, or Edoxaban) Versus Warfarin

Table 1. Outcomes of Interest in RCTs Evaluating Factor Xa Inhibitors (Apixaban, Rivaroxaban, or Edoxaban) Versus Warfarin

In addition, 38 observational studies compared warfarin with factor Xa inhibitors. Similar analyses were completed for the observational trial data, and the results are available in Supplement Figure 2. The observational studies did not show a reduction in all-cause mortality across Xa inhibitors, whereas the RCTs did. Also inconsistent with the RCT findings, observational studies comparing rivaroxaban with warfarin supported a reduction in stroke or systemic embolism and a trend toward a decrease in ischemic or uncertain stroke while providing evidence of a small increase in the risk for major bleeding. Other RCT findings were supported by existing observational studies.

Warfarin Versus Apixaban

The ARISTOTLE trial (12) showed that, compared with warfarin, treatment with apixaban, 5 mg twice daily (or a reduced dosage of 2.5 mg twice daily), in patients meeting at least 2 of the following criteria: age ≥80 years, weight ≤60 kg, or serum creatinine concentration ≥132.6 µmol/L (1.5 mg/dL), reduced the risk for stroke, systemic embolism, major bleeding, and all-cause mortality. Several substudies of ARISTOTLE have been completed. Those evaluating bleeding outcomes showed that patients who received apixaban were less likely than those who received warfarin to die within 30 days of a major hemorrhagic event (HR, 0.50 [CI, 0.33 to 0.74]) (30) or to have nonmajor bleeding (HR, 0.69 [CI, 0.63 to 0.75]) (31). They also had lower rates of intracranial hemorrhage (intracranial HR, 0.42 [CI, 0.30 to 0.58]; intracerebral HR, 0.45 [CI, 0.30 to 0.68]; subdural HR, 0.33 [CI, 0.17 to 0.65]) (32). However, the number of hospital admissions did not differ significantly between the apixaban and warfarin treatment groups (26.6% vs. 28.1%; P = 0.31) (33).

Additional ARISTOTLE substudies evaluated outcomes in specific patient groups of interest. Overall, with regard to the primary ischemic outcome of stroke or systemic embolism, no statistically significant interaction was observed between treatment and level of renal impairment (P = 0.71) (34), paroxysmal versus persistent AF (P = 0.71) (35), timing of AF diagnosis (P = 0.94) (36), history of stroke (P = 0.71) (24), age (P = 0.11) (37), history of peripheral artery disease (P = 0.52) (38), underlying anemia (P = 0.17) (39), history of chronic obstructive pulmonary disease (P = 0.62) (40), sex (P = 0.45) (41), diabetes (P = 0.71) (42), concomitant aspirin therapy (P = 0.10) (27), or history of falls (P = 0.69) (43). With regard to major bleeding, no statistically significant interaction was seen between treatment and paroxysmal versus persistent AF (P = 0.75) (35), timing of AF diagnosis (P = 0.78) (36), history of stroke (P = 0.69) (24), age (P = 0.63) (37), history of peripheral artery disease (P = 0.58) (38), underlying anemia (P = 0.57) (39), history of chronic obstructive pulmonary disease (P = 0.42) (40), sex (P = 0.06) (41), concomitant aspirin therapy (P = 0.29) (27), or history of falls (P = 0.57) (43). Although apixaban was associated with fewer bleeding events regardless of renal function, patients with a glomerular filtration rate less than 50 mL/min/1.73 m² had the greatest reduction in relative risk (P = 0.003) (34). In addition, patients without diabetes who received apixaban had lower rates of major bleeding as defined by the International Society on Thrombosis and Haemostasis, a treatment effect that was not seen in patients with diabetes (P = 0.003) (42).

Warfarin Versus Rivaroxaban

The ROCKET-AF trial (11) showed that rivaroxaban, 20 mg daily, was noninferior to warfarin in preventing stroke or systemic embolism. The rates of major bleeding and all-cause mortality also were similar between treatment groups.

Several secondary analyses of ROCKET-AF compared rivaroxaban with warfarin. One such study (44) showed higher rates of gastrointestinal bleeding (HR, 1.42 [CI, 1.22 to 1.66]) in patients who received rivaroxaban than in those who received warfarin. Conversely, a trend toward lower rates of ischemic cardiovascular outcomes (HR, 0.86 [CI, 0.73 to 1.00]) and all-cause mortality (HR, 0.85 [CI, 0.70 to 1.02]) was seen in the rivaroxaban group (45). No statistically significant difference was observed between treatment groups with regard to hospitalization rates (P = 0.45) (46).

Subsequent ROCKET-AF substudies evaluated treatment in specific patient groups of interest. Among patients with renal impairment (creatinine clearance, 30 to 49 mL/min/1.73 m²), no difference in stroke or systemic embolism (HR, 0.86 [CI, 0.63 to 1.17]) or major and nonmajor clinically relevant bleeding (P = 0.76) was observed between the rivaroxaban and warfarin groups (47). Overall, with regard to the primary outcome of stroke or systemic embolism, no statistically significant interaction was seen between treatment and history of stroke or transient ischemic attack (P = 0.23) (25), age (P = 0.31) (48), diabetes (P = 0.53) (49), concomitant aspirin therapy (P = 0.95) (28), hypertension (P = 0.06) (50), or history of heart failure (P = 0.51) (51). With regard to major and nonmajor clinically relevant bleeding events, no statistically significant interaction was observed between treatment and history of stroke or transient ischemic attack (P = 0.08) (25), age (P = 0.34) (48), diabetes (P = 0.17) (49), concomitant aspirin therapy (P = 0.76) (28), hypertension (P = 0.30) (50), or history of heart failure (P = 0.99) (51).

Warfarin Versus Edoxaban

The ENGAGE-AF trial (10) showed that edoxaban at both 30 mg/d and 60 mg/d was noninferior to warfarin in preventing stroke or systemic embolism. In addition, both edoxaban dosages reduced the risk for hemorrhagic stroke and rates of major bleeding compared with warfarin. The risk for stroke, myocardial infarction, or all-cause mortality did not differ between treatment groups. In a prespecified additional analysis (23), no statistically significant difference was seen in nonfatal systemic embolic or fatal events between high- or low-dose edoxaban and warfarin. Overall, with regard to stroke or systemic embolism, no statistically significant interaction was observed between treatment and renal function (P = 0.94) (10), history of stroke (26), concomitant aspirin use (P = 0.42) (29), history of heart failure (P = 0.97) (52), or history of coronary artery disease (P = 0.06 and P = 0.53 for high- and low-dose edoxaban, respectively) (53). With regard to major bleeding, no statistically significant interaction was noted between treatment and renal function (P = 0.62) (10), concomitant aspirin use (P = 0.59) (29), history of heart failure (P = 0.96) (52), or history of coronary artery disease (P = 0.97 and P = 0.67 for high- and low-dose edoxaban, respectively) (53).

Factor Xa Inhibitors Versus Dabigatran

No RCTs directly compared Xa inhibitors with dabigatran, although several observational studies attempted to do so. Compared with patients receiving dabigatran, those who received rivaroxaban or apixaban had a similar risk for stroke or systemic embolism (HR, 1.00 [CI, 0.75 to 1.32 for rivaroxaban vs. dabigatran; HR, 0.82 [CI, 0.51 to 1.31] for apixaban vs. dabigatran) (54), thromboembolic stroke (adjusted HR, 0.81 [CI, 0.65 to 1.01]) (55), ischemic stroke (HR, 0.91 [CI, 0.66 to 1.27] for rivaroxaban vs. dabigatran; HR, 0.93 [CI, 0.55 to 1.57] for apixaban vs. dabigatran) (54), or hemorrhagic stroke (HR, 1.70 [CI, 0.84 to 3.43] for rivaroxaban vs. dabigatran; HR, 0.72 [CI, 0.18 to 2.86] for apixaban vs. dabigatran).

Intracranial hemorrhage was evaluated in 3 observational studies, which showed an increased risk for intracranial hemorrhage with Xa inhibitors compared with dabigatran (HR, 1.63 [CI, 1.14 to 2.34]). This increase in risk also was found in the 3 studies targeting rivaroxaban versus dabigatran (HR, 1.75 [CI, 1.34 to 2.28]) (SOE, low). Seven observational studies comparing Xa inhibitors with dabigatran in terms of major bleeding did not demonstrate a difference (HR, 0.91 [CI, 0.66 to 1.24]) between any Xa inhibitor and dabigatran. They did, however, show a reduction in major bleeding for apixaban (HR, 0.67 [CI, 0.47 to 0.94]) compared with dabigatran while demonstrating an increase in major bleeding risk with rivaroxaban compared with dabigatran (HR, 1.32 [CI, 1.02 to 1.70]) (SOE, low for all comparisons). With regard to gastrointestinal bleeding with Xa inhibitors versus dabigatran, the 7 studies found no difference (HR, 0.84 [CI, 0.47 to 1.49]) between any Xa inhibitor and dabigatran, neither did the 3 studies that focused on rivaroxaban versus dabigatran (HR, 1.09 [CI, 0.63 to 1.88]) (SOE, low).

Factor Xa Inhibitor Versus Factor Xa Inhibitor

No RCTs compared the available factor Xa inhibitors. Several observational studies compared apixaban with rivaroxaban and found no statistically significant difference between them in rates of stroke or systemic embolism (HR, 1.05 [CI, 0.64 to 1.72]), ischemic stroke (HR, 1.27 [CI, 0.73 to 2.23]), or hemorrhagic stroke (HR, 0.66 [CI, 0.16 to 2.78]) (54). However, given the wide range in available CIs, a difference between the 2 treatments cannot be definitively excluded. With regard to bleeding outcomes, several studies demonstrated a reduction in major bleeding with apixaban compared with rivaroxaban (HR, 0.51 [CI, 0.38 to 0.68]) (54, 56–59).

LAA Closure Devices

Two RCTs, PROTECT AF (Watchman LAA System for Embolic Protection in Patients With Atrial Fibrillation) (60) and PREVAIL (Evaluation of the Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) (61), compared LAA closure with warfarin therapy. Overall, LAA closure showed a decrease in the rate of major bleeding compared with warfarin treatment (3.5% vs. 4.1%) and was noninferior to warfarin in terms of stroke (rate ratio, 0.71 [CI, 0.35 to 1.64]) and all-cause mortality (rate ratio, 0.62 [CI, 0.34 to 1.24]). The PREVAIL trial found no difference in the composite end point of stroke, systemic embolism, or cardiovascular or unexplained death (rate ratio, 1.07 [95% credible interval, 0.57 to 1.89]) with LAA closure compared with warfarin therapy. Although LAA closure was associated with higher rates of adverse safety events (such as serious pericardial effusion, major bleeding, and device embolization) overall, fewer safety events occurred in PREVAIL than in the earlier PROTECT AF study (4.2% vs. 8.7%; P = 0.004).

The SOE grades for all comparisons and the outcomes for which the SOE was rated as low, moderate, or high are summarized graphically in Table 2; a detailed table of findings is provided in Supplement Table 4.

Table 2. Summary of SOE Ratings for Interventions Compared With Warfarin

Table 2. Summary of SOE Ratings for Interventions Compared With Warfarin

Discussion

Atrial fibrillation is a widely prevalent arrhythmia with substantial morbidity and mortality (1, 62). Overall, our review had 4 key findings. First, evidence was found that compared with warfarin, dabigatran and apixaban are superior and rivaroxaban and edoxaban are similar in preventing stroke or systemic embolism. Second, apixaban and edoxaban are superior to warfarin in reducing the risk for major bleeding, whereas rivaroxaban and dabigatran are similar to warfarin in terms of major bleeding rates. Third, consistent treatment effects for the factor Xa inhibitors versus warfarin were observed across many subgroups of interest, including patients with a history of stroke, concomitant aspirin treatment, or heart failure, and in those with paroxysmal versus persistent AF. Fourth, LAA closure devices decrease the risk for major bleeding and show a trend toward a lower risk for stroke but with higher rates of procedural adverse events, such as serious pericardial effusion, major bleeding, and device embolization.

Substantial efforts have been made to explore the comparative effectiveness of the DOAC medications versus VKA therapy. Large RCTs have provided a foundation of evidence for each DOAC, and substudies of these trials examining specific patient groups of interest have largely corroborated the results from the main trials. In addition, enough of these substudies have been completed that the efficacy and safety of the DOAC medications can be evaluated in patient subgroups. The results of the main trials have remained consistent in these subgroups of interest. Of note, the relative risk for bleeding was reduced further by apixaban therapy in patients with a glomerular filtration rate less than 50 mL/min/1.73 m². Overall, this large body of evidence provides guidance toward the safety and efficacy of DOAC treatment for patients with a wide range of comorbid conditions. The data for use of LAA closure devices are less robust but do give some direction in using this approach in patients at high risk for bleeding with anticoagulation.

Other reviews also examined the comparative effectiveness of the available treatments for preventing thromboembolic disease in patients with AF. The most recent systematic review examined all RCTs of DOACs, warfarin, or antiplatelet therapies for AF (63). This network meta-analysis showed results similar to those of our study in that DOACs were generally superior to warfarin with regard to stroke prevention and reduced risk for major bleeding. Another network meta-analysis from 2016 also included evaluation of the Watchman device (Boston Scientific). Results showed that DOACs and the Watchman device were most efficacious in preventing stroke or systemic embolism when compared with aspirin, VKAs, or placebo (64). Our review similarly summarizes the data from these RCTs but also provides data on DOAC use in unique patient populations as well as more recent observational data comparing DOACs with one another.

Several limitations of this review should be acknowledged. First, the search was limited to English-language publications. Cost analyses comparing treatment methods were not specifically included; however, costs related to health service use may be found in the full report. The studies examined, particularly the observational analyses, were heterogeneous in patient populations, methodology, setting, and outcomes of interest; thus, some direct comparisons could not be examined, limiting our ability to perform a network meta-analysis. Additional information on the individual observational studies in terms of their characteristics and quality is included in Supplement Table 3 and in the full systematic review. Moreover, observational studies are prone to selection bias and confounding, for which even the most robust statistical methods cannot fully adjust. In addition, for many of the RCT substudies, the outcomes and patient populations were not prespecified as analyses at the start of the RCT; thus, their results do not provide the same SOEs associated with those from prespecified end points and analyses. Finally, most of the available RCT data compare new treatment options with warfarin; further high-quality evidence is needed to compare these treatments. However, given the unlikelihood that RCTs comparing DOACs will be completed, observational data comparing these medications may represent the most thorough analysis available.

Although the available evidence provides ongoing data regarding treatment for patients with AF, there are still large gaps that should be addressed by future research. Currently, all data comparing DOACs with one another are from observational studies; RCTs would provide a stronger base of evidence to guide patient care in selecting which DOAC to use for treatment. In addition, the shorter half-life of DOACs compared with the anticoagulation effects of warfarin may lead to differential treatment effects if medication adherence is a concern. Likewise, data regarding persistence of therapy and transitions between anticoagulation strategies remain inadequate.

The development of DOACs and procedural treatments has led to a wide range of options for preventing thromboembolic complications in patients with AF. Evidence suggests that DOACs are noninferior to warfarin in preventing thromboembolic complications and are generally superior to warfarin in reducing major bleeding events. In addition, the current evidence shows promise that the treatment effects observed in the overall populations of the large RCTs may hold true in many subsets of patients. The LAA closure devices also offer hope for patients at high risk for bleeding complications. Ongoing analyses are needed to understand how these newer treatment options compare in terms of therapeutic advantage as well as which patient populations might benefit most from each approach.

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Appendix Figure.

Analytic framework.

AF = atrial fibrillation; DVT = deep venous thrombosis; KQ = key question; ICH = intracranial hemorrhage; PE = pulmonary embolism; TIA = transient ischemic attack.

Figure 1.

Evidence search and selection.

AHRQ = Agency for Healthcare Research and Quality; KQ = key question; SR = systematic review.

* Articles/studies may be relevant to more than 1 KQ.

† 18 articles representing 9 studies provided additional outcome data that had not been included in our previous SR.

Figure 2.

Treatment comparisons.

LAA = left atrial appendage; Obs = observational studies; RCT = randomized controlled trial; VKA = vitamin K antagonist.

Figure 3.

Forest plots for comparison of Xa inhibitors versus warfarin (randomized controlled trials).

Outcomes examined. HR = hazard ratio.

Figure 3.

Continued

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1 Comment

Burton Abrams

no institutional affiliation

November 9, 2018

Overcoming afib by resolving sleep apnea

Afib, which can lead to stroke, is often a consequence of sleep apnea. Patients with afib should be sent for sleep apnea diagnosis and treatment. It may take up to six months for the afib to reverse following successful treatment of sleep apnea, along with the hypercoagulability that results from sleep apnea. During that time pharmaceutical products may be useful for stroke prevention, but probably will be unnecessary after the afib and hypercoagulability have resolved.

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2018 American College of Physicians

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