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Efficacy and Safety of the Novel Oral Anticoagulants in Atrial Fibrillation

A Systematic Review and Meta-Analysis of the Literature
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.112.115410Circulation. 2012;126:2381–2391

Abstract

Background—

Novel oral anticoagulants (NOACs) have been proposed as alternatives to vitamin K antagonists for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Individually, NOACs were at least noninferior to vitamin K antagonists, but a clear superiority in overall and vascular mortality was not consistently proven.

Methods and Results—

We performed a meta-analysis of phase II and phase III randomized, controlled trials comparing NOACs with vitamin K antagonists in patients with atrial fibrillation. The MEDLINE and EMBASE databases, supplemented with conference abstract books and www.clinicaltrials.gov, were searched up to the first week of July 2012 with no language restriction. Two reviewers performed independent article review and study quality assessment. Data on overall and cardiovascular mortality, stroke or systemic embolism, ischemic stroke, major and intracranial bleeding, and myocardial infarction were collected. NOACs were pooled to perform a comparison with vitamin K antagonists, calculating pooled relative risks (RRs) and associated 95% confidence intervals (CIs). We retrieved 12 studies (3 administering dabigatran, 4 administering rivaroxaban, 2 administering apixaban, and 3 administering edoxaban) enrolling a total of 54 875 patients. NOACs significantly reduced total mortality (5.61% versus 6.02%; RR, 0.89; 95% CI, 0.83–0.96), cardiovascular mortality (3.45% versus 3.65%; RR, 0.89; 95% CI, 0.82–0.98), and stroke/systemic embolism (2.40% versus 3.13%; RR, 0.77; 95% CI, 0.70–0.86). There was a trend toward reduced major bleeding (RR, 0.86; 95% CI, 0.72–1.02) with a significant reduction of intracranial hemorrhage (RR, 0.46; 95% CI, 0.39–0.56). No difference in myocardial infarction was observed.

Conclusions—

NOACs are associated with an overall clinical benefit compared with vitamin K antagonists. Additional research is required to confirm these findings outside the context of randomized trials.

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia, with an overall prevalence of 5.5% that increases up to 17.8% in individuals ≥85 years of age.1 AF is a major risk factor for stroke,2 with a 30-day mortality rate of 24% in the absence of treatment.3

Clinical Perspective on p 2391

Vitamin K antagonists (VKAs) are highly effective for the prevention of stroke, mainly of ischemic origin, in patients with AF, resulting in a 64% risk reduction compared with placebo and a 37% risk reduction compared with antiplatelet therapy.4 For this reason, VKAs are currently recommended in all AF patients at moderate to high risk for stroke or systemic embolism (SE).5 However, VKAs have significant limitations, particularly their unpredictable anticoagulant response and numerous food and drug interactions, mandating regular laboratory monitoring.6 These limitations make treatment with VKAs problematic for many patients; as a result, only about half of all potentially eligible AF patients are treated with VKAs.6

Over the last several years, novel oral anticoagulant drugs (NOACs), including direct thrombin inhibitors and factor Xa inhibitors, have been developed. These drugs have the potential to address some of the limitations of VKAs.7 These agents have fewer food and drug interactions and a more predictable anticoagulant effect, thus allowing fixed dosing without the need for laboratory monitoring. Furthermore, their shorter half-life may produce additional advantages, eg, if temporary interruption is required for a surgical procedure or in the case of an hemorrhagic complication.

The NOACs have been compared with warfarin for the prevention of stroke and SE in patients with AF.810 These trials have been favorable for the NOACs but have not consistently demonstrated superiority over warfarin, particularly in terms of overall and vascular mortality. To better assess the clinical benefit, we carried out a systematic review of the literature and a meta-analysis of phase II and phase III randomized, clinical trials (RCTs) of these agents compared with VKAs for the prevention of stroke or SE in patients with AF.

Methods

A protocol for this review was prospectively developed that detailed the specific objectives, criteria for study selection, approach to assess study quality, outcomes, and statistical methods. This protocol is available for review through the investigators.

Data Sources and Searches

We identified all published studies that compared the risk of thromboembolic and/or major bleeding (MB) events in AF patients randomized to VKAs (warfarin, phenprocoumon, acenocumarol, fluindione, and tecarfarin) or NOACs (dabigatran, AZD0837, sofigatran, rivaroxaban, apixaban, edoxaban, betrixaban, eribaxaban, LY517717, YM150, TAK442, and TTP889) using the MEDLINE (1966 to week 1 of July 2012) and the EMBASE (1980 to week 1 of July 2012) electronic databases. The term ximelagatran was excluded from the search because this drug has been withdrawn from the market. The search strategy was developed without any language restriction and used the medical subject headings and text words presented in Table 1 in the online-only Data Supplement. We supplemented our search by reviewing abstracts books from the congresses of the International Society on Thrombosis and Haemostasis (2003–2011), European Society of Cardiology (2005–2011), American Society of Hematology (2004–2011), and American College of Cardiology (2008–2011) and by manually reviewing the reference lists of all retrieved articles. We also searched on the www.clinicaltrials.gov Web site to identify unpublished trials.

Study Selection

Two reviewers (N.R. and F.D.) performed study selection independently, with disagreements solved through discussion and by the opinion of a third reviewer (W.A.) if necessary. Studies were considered potentially eligible for this systematic review if they met the following criteria: They were phase III RCTs or phase II RCTs including at least one of the evaluated dosages subsequently used in phase III trials; NOACs were compared with therapeutic doses of VKAs in patients with AF; and thromboembolic and bleeding events were objectively assessed in both groups.

For trials that were reported in >1 publication, we extracted data from the most complete publication and used other publications to clarify data.

To assess the agreement between reviewers for study selection, we used the κ statistic, which measures agreement beyond chance.11

Data Extraction and Quality Assessment

We extracted and presented data according to the Providing Innovative Service Models and Assessment (PRISMA) criteria.12 Two reviewers (N.R. and F.D.) independently extracted data on study (year of publication, design), population characteristics (number of patients, mean age, sex), and treatment (therapeutic indication, type of drug, dose, and duration).

Information on the following outcomes was collected in the 2 groups: number of total and ischemic strokes (ISs), SE, total and cardiovascular mortality, MB and intracranial bleeding, and myocardial infarctions (MIs). No attempt was made to reclassify bleeding events. However, in the included studies, MBs were classified mostly according to International Society on Thrombosis and Haemostasis criteria13 as bleeding causing a fall in hemoglobin levels of ≥2 g/dL, bleeding leading to transfusion of ≥2 U whole blood or red cells, symptomatic bleeding in a critical area (intracranial, intraspinal, intraocular, retroperitoneal, intrarticular, pericardial, or intramuscular with compartment syndrome), or bleeding events leading to death.

If outcome data for extraction could not be identified, we contacted the study authors by e-mail, with a reminder after 15 days. For unpublished trials, we also contacted the pharmaceutical companies.

Two reviewers (N.R. and F.D.) independently assessed study quality using a validated scale14 based on the following criteria: methods used to generate the randomization sequence, method of double blinding, and description of patient withdrawals and dropouts. A score of 1 point was given for each criterion satisfied, and 1 additional point was given for high quality of randomization and double blinding, for a maximum of 5 points. Studies with a score >2 were considered high quality, and studies with a score ≤2 were considered low quality. Although concealed treatment allocation is not part of this rating scale, it was included in our study quality assessment.

We resolved disagreements about study data extraction by consensus or by discussion with a third reviewer (W.A.).

Statistical Analyses

Primary Analyses

We determined pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) for all-cause and cardiovascular mortality in AF patients who received VKAs or treatment with a NOAC. Furthermore, the pooled RR of any cardioembolic event (which included stroke or SE), IS, MB and intracranial bleeding, and MI in the 2 arms of treatment was calculated. Because transient ischemic attacks are frequently subjective, seldom consistently reported, and not usually considered a primary outcome in AF trials, we decided not to include them in our analysis.

Although we acknowledge that direct thrombin inhibitors and factor Xa inhibitors have different pharmacodynamic and pharmacokinetic properties, they all act on the final phase of the coagulation cascade, the common pathway, and represent as a whole the current alternative to VKAs. For this reason, we considered it appropriate to pool the NOACs together to perform a comparison with VKAs.

From phase II dose-ranging RCTs, we summed all groups whose total daily dose was equal to the regimens used in phase III RCTs. For all the treatment effects that were statistically significant, we determined the absolute risk reduction (ARR) or the absolute risk increase and the corresponding number needed to treat (NNT) or number needed to harm. Data were pooled by use of a fixed-effects model (Mantel-Haenszel method),15 and results were compared with the results obtained with a random-effects (RE) model (DerSimonian-Laird method).16 A value of P<0.05 was considered statistically significant. All analyses were performed with Review-Manager software (RevMan, version 5.1.6 for Windows; The Cochrane Collaboration, Oxford, UK; 2008). Because combining trials with extremely low or zero event rates can yield biased results, we repeated the analyses using Comprehensive Meta-Analysis software, version 2 (Biostat Software Corp, Englewood, NJ), which provides exact fixed-effect point and interval estimates for the odds ratio.17 The appropriateness of pooling data across studies was assessed with the use of the Cochran Q and the I2 test for heterogeneity, which measures the inconsistency across study results and describes the proportion of total variation in study estimates that is due to heterogeneity rather than sampling error.18 For the preparation of the forest plots, we also used the Meta Data Viewer software version 1.02 (National Toxicology Program, Research Triangle Park, NC).19 The presence of publication bias was investigated by the use of funnel plots of effect size versus standard error.20

Sensitivity Analyses

We repeated sensitivity analyses by using only studies that satisfied each item of our prespecified quality evaluation.21 Furthermore, separate analyses of studies published in peer-reviewed journals were provided.

Subgroup Analyses

We planned to perform separate analyses of studies assessing short-term outcomes (1–3 months) and long-term outcomes (>1 year).

We also performed separate analyses including, from phase II trials, only the exact same dose regimen of the NOAC that was subsequently used in phase III trials and, in a separate analysis, excluding the lower dosage of dabigatran (110 mg twice daily), which is not licensed by the US Food and Drug Administration.

Results

Study Identification and Selection

We identified 1454 potentially relevant studies: 364 from MEDLINE and 1090 from EMBASE. A total of 317 studies were duplicated, and 1106 studies were excluded after title and abstract screening. The remaining 31 studies were retrieved in full for detailed evaluation. A list of the 24 excluded studies and reasons for exclusion is available on request. Two additional studies were identified from a personal library.22,23 We identified 3 more studies by searching unpublished trials on www.clinicaltrials.gov.2426 A review of the reference lists of included studies did not provide any additional references. Twelve studies were therefore included in this systematic review.810,2230 Interobserver agreement for study selection was almost perfect (κ=0.89). The study identification and selection progression are summarized in Figure I in the online-only Data Supplement.

Data from 2 studies were supplemented with information extracted from more recent publications.31,32 Supplementary data for 7 trials were provided by the investigators involved in the trial or the pharmaceutical companies.2227,29 Data on dabigatran and rivaroxaban were also supplemented with information from their Food and Drug Administration reviews.33,34

Study Characteristics and Study Quality

Baseline characteristics of patients included in the studies are summarized in the Table. For 4 NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban), a phase III RCT was published or was ongoing. The comparator VKA was warfarin in all studies. All studies were published in English. Study size ranged from 100 patients26 to 18 201 patients,10 for a total of 54 875 included patients. Eight studies were phase II RCTs22,2430 and 4 studies were phase III RCTs.810,23 Three studies involved dabigatran,8,24,30 4 involved rivaroxaban,9,23,25,26 2 involved apixaban,10,27 and 3 involved edoxaban.22,28,29

Table. Characteristics of Included Studies

Study (Year)Study DesignPopulationPatients Randomized, nPatients Characteristics*
Age, ySex, M/F, %CHADS2 ScoreVKA at Inclusion, %Concomitant ASA, %Intervention DrugComparator DrugDuration of TreatmentMajor Bleeding (Definition)
NCT01136408(24) (2007)RCT phase II, U dabigatran and warfarinNVAF, ≥1 risk factor (HTN, DM, HF, previous stroke or TIA, age >75 y, CAD), Japanese patients174 (53 and 59 each dabigatran group, 62 warfarin)68.4±8.6 (mean±SD)88.0/12.0NANANADabigatran 110 mg bid, 150 mg bidWarfarin (INR range, 2.0–3.0 or 1.6–2.6 if age ≥70 y); TTR, NA12 wkISTH criteria
PETRO(30) (2007)RCT phase II, B dabigatran, U warfarin and aspirinNVAF, ≥1 risk factor (HTN, DM, HF, previous stroke or TIA, age >75 y)502 (105, 166, 161 each dabigatran group, 70 warfarin)70±8.3 (mean±SD)81.9/18.13 (median)10036.1Dabigatran 50 mg bid, 150 mg bid, 300 mg bid alone or combined with ASA 81 or 325 mgWarfarin (INR range, 2.0–3.0); TTR, 57.2%12 wkISTH criteria+bleeding events requiring surgery
RE-LY(8) (2009)RCT phase III, B dabigatran, U warfarinNVAF, ≥1 risk factor (previous stroke or TIA, HF, age ≥75 y, age 65–74 y+DM or HTN or CAD)18 113 (6015 and 6076 each dabigatran group, 6022 warfarin)71 (mean)63.6/36.42.1 (mean)61.820.5Dabigatran 110 mg bid, 150 mg bidWarfarin (INR range, 2.0–3.0 or 2.0–2.6 if Japanese age ≥70 y); TTR (mean), 64%2.0 y (median)ISTH criteria+bleeding events requiring inotropic agents or surgery
Weitz et al(29) (2010)RCT phase II, B edoxaban, U warfarinNVAF, CHADS2score ≥21146 (235, 245, 235, 180 each edoxaban group, 251 warfarin)65±8.7 (mean±SD)62.1/37.92 (63.3% patients)35.6NAEdoxaban 30 mg od, 30 mg bid, 60 mg od, 60 mg bidWarfarin (INR range, 2.0–3.0); TTR, 49.7%12 wkISTH criteria
Chung et al(28) (2011)RCT phase II, B edoxaban, U warfarinNVAF, CHADS2score ≥1, Asian patients235 (79 and 80 each edoxaban group, 76 warfarin)64.9±9.1, 65.9±7.7, 64.5±9.5 (mean±SD in each group)65.4/34.62.0±1.10, 1.9±1.03, 1.8±1.10 (mean±SD in each group)51.739.7Edoxaban 30 mg od, 60 mg odWarfarin (INR range, 2.0–3.0); TTR, 45.1%3 moModified ISTH criteria (transfusion ≥800 mL packed red blood cells or whole blood)
Yamashita et al(22) (2012)RCT phase II, B edoxaban, U warfarinNVAF, CHADS2score ≥1, Japanese patients536 (135, 135, 132 each edoxaban group, 134 warfarin)69.4, 69.5, 68.4, 68.8 (mean in each group)82.5/17.51.9, 2.1, 2.1, 2.2 (mean in each group)84.825.1Edoxaban 30 mg od, 45 mg od, 60 mg odWarfarin (INR range, 2.0–3.0 if age <70 y or 1.6–2.6 if age ≥70 y); TTR, 73% for <70 y and 83% for age ≥70 y12 wkModified ISTH criteria (blood transfusion ≥4 U)
ARISTOTLE-J(27) (2011)RCT phase II, B apixaban, U warfarinNVAF, ≥1 risk factor (age ≥75 y, HF, HTN, DM, previous stroke or TIA), Japanese patients222 (74 and 74 each apixaban group, 74 warfarin)69.3, 70.7, 71.7 (mean in each group)82.9/17.11.8, 2.1, 1.9 (mean in each group)85.324.8Apixaban 2.5 mg bid, 5 mg bidWarfarin (INR range, 2.0–3.0 if age ≤70 y or 2.0–2.6 if age >70 y); TTR, overall ≥60% of patients had INR within the 2.0–3.0 range for 60% of the treatment period regardless of age12 wkISTH criteria
ARISTOTLE(10) (2011)RCT phase III, B apixaban and warfarinNVAF or flutter, ≥1 risk factor (age ≥75 y, previous stroke or TIA or SE, HF, DM, HTN)18 201 (9120 apixaban, 9081 warfarin)70 (median)64.7/35.32.1 (mean)57.1NAApixaban 5 mg bid or 2.5 mg bid (if ≥2 criteria: age ≥80 y, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL)Warfarin (INR range, 2.0–3.0); TTR (mean), 62.2%1.8 y (median)ISTH criteria (hemoglobin drop was censored over a 24-h period)
NCT00973245(25) (2008)RCT phase II, U rivaroxaban and warfarinNVAF age ≥60 y or ≥1 risk factor (HTN, DM, CAD, HF) Japanese patients102 (26, 25, 24 each rivaroxaban group, 27 warfarin)65.9±8.8, 65.7±8.2, 67.4±7.2, 68.7±8.4 (mean±SD in each group)78.4/21.6NANANARivaroxaban 10 mg od, 15 mg od, 20 mg odWarfarin (INR range, 2.0–3.0 or 1.6–2.6 if age ≥70 y); TTR, NA28 dISTH criteria
NCT00973323(26) (2008)RCT phase II, U rivaroxaban and warfarinNVAF, age ≥60 y or ≥1 risk factor (HTN, DM, CAD, HF), Japanese patients100 (24, 26, 24 each rivaroxaban group, 26 warfarin)67.7±9.3, 70.5±9.5, 66.3±11.2, 67.6±10.4 (mean±SD in each group)80.0/20.0NANANARivaroxaban 2.5 mg bid, 5 mg bid, 10 mg bidWarfarin (INR range, 2.0–3.0 or 1.6–2.6 if age ≥70 y); TTR, NA28 dISTH criteria
ROCKET-AF(9) (2011)RCT phase III, B rivaroxaban and warfarinNVAF, CHADS2 score ≥214 264 (7131 rivaroxaban, 7133 warfarin)73 (median)60.3/39.73.5 (mean)62.435.6Rivaroxaban 20 mg od or 15 mg od (if creatinine clearance 30–49 mL/min)Warfarin (INR range, 2.0–3.0); TTR (mean), 55%590 d (median)ISTH criteria+bleeding events associated with permanent disability
J-ROCKET-AF(23) (2012)RCT phase III, B rivaroxaban and warfarinNVAF; prior stroke, TIA, or SE or ≥2 risk factors (HF, HTN, age ≥75 y, DM), Japanese patients1280 (640 rivaroxaban, 640 warfarin)71.1±8.1 (mean±SD)80.6/19.43.2590.0NARivaroxaban 15 mg od or 10 mg od (if creatinine clearance 30–49 mL/min)Warfarin (INR range, 2.0–3.0 if age <70 y or 1.6–2.6 if age ≥70 y); TTR, 65%71 and 69 wk (median for rivaroxaban and warfarin, respectively)ISTH criteria

ARISTOTLE indicates Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; ASA, acetylsalicylic acid (aspirin); B, blinded; bid, twice daily; CAD, coronary artery disease; DM, diabetes mellitus; HF, heart failure; HTN, hypertension; INR, international normalized ratio; ISTH, International Society on Thrombosis and Haemostasis; J-ARISTOTLE, Japanese Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; J-ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation in Japan; NVAF, nonvalvular atrial fibrillation; od, once daily; RCT, randomized, controlled trial; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy; ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation; SE, systemic embolism; TIA, transient ischemic attack; TTR, time within therapeutic-range INR; U, unblinded; and VKA, vitamin K antagonist. For the CHADS2 score, 1 point is given for cardiac heart failure, hypertension, age ≥75 years, and diabetes mellitus; 2 points are given for previous stroke, transient ischemic attack, and systemic embolism.

*When the characteristics of randomized patients were not available, we reported the characteristics of patients actually treated (studies in References 22–24, 28–29).

TTR was calculated in all studies according to the Rosendaal method but using different time frames.

See the text for the ISTH definition of major bleeding.

Quality assessment items are summarized in Table II in the online-only Data Supplement. With the use of the Jadad score, 6 studies were classified as low quality22,2427,30 and 6 as high quality.810,23,28,29 All the trials were randomized, but the method to generate the randomization sequence was adequately reported in 4 studies. Three studies were double-blind and double-dummy. All studies provided a description of patient withdrawals, and 6 reported concealed treatment allocation.

Outcomes

Table III in the online-only Data Supplement summarizes the outcomes assessed during oral anticoagulant treatment. When possible, we performed analyses using intention-to-treat populations. The intention-to-treat populations were not available for all outcomes for 2 studies9,23; therefore, we used the safety-on-treatment populations.

Primary Analyses

Total Mortality

Death occurred in 1715 of 30 584 patients (5.61%) treated with NOACs and in 1416 of 23 531 patients (6.02%) treated with VKAs (Figure 1A). Use of NOACs was associated with a significant reduction in total death (RR, 0.89; 95% CI, 0.83–0.96; I2=0%; ARR, 0.41%; NNT, 244). Reanalysis with an RE model did not change these results.

Figure 1.

Figure 1. Total (A) and cardiovascular (B) mortality during oral anticoagulant treatment. NOAC indicates novel oral anticoagulant; VKA, vitamin K antagonists; M-H, Mantel-Haenszel; CI, confidence interval; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy; ARISTOTLE, Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; J-ARISTOTLE, Japanese Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation; and J-ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation in Japan.

Cardiovascular Mortality

Cardiovascular death occurred in 1054 of 30 584 patients (3.45%) treated with NOACs and in 858 of 23 531 patients (3.65%) treated with VKAs (Figure 1B). Use of NOACs was associated with a significant reduction in cardiovascular death (RR, 0.89; 95% CI, 0.82–0.98; I2=0%; ARR, 0.20%; NNT, 500). Reanalysis with an RE model did not change these results.

Stroke or SE and IS

Stroke or SE occurred in 733 of 30 604 patients (2.40%) treated with NOACs and in 736 of 23 539 patients (3.13%) treated with VKAs (Figure 2A). Use of NOACs was associated with a significant reduction in the composite outcome of stroke or SE (RR, 0.77; 95% CI, 0.70–0.86; I2=0%; ARR, 0.73%; NNT, 137). Reanalysis with an RE model did not change these results.

Figure 2.

Figure 2. Stroke or systemic embolism (A) and ischemic stroke (B) during oral anticoagulant treatment. NOAC indicates novel oral anticoagulant; VKA, vitamin K antagonists; M-H, Mantel-Haenszel; CI, confidence interval; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy; ARISTOTLE, Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; J-ARISTOTLE, Japanese Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation; and J-ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation in Japan.

Separate data for IS were available from 11 studies.810,2228,30 IS occurred in 560 of 29 871 patients (1.87%) treated with NOACs and in 470 of 23 281 patients (2.02%) treated with VKAs (Figure 2B). Use of NOACs was associated with a nonsignificant reduction in the number of ISs (RR, 0.92; 95% CI, 0.81–1.04; I2=22%). Reanalysis with an RE model did not change these results.

MB and Intracranial Bleeding

The definition of MB and the proportion of patients taking VKAs before inclusion and/or taking concomitant aspirin during the trial were not declared in many studies and were variable in the others (the Table).

MB, as defined by the study, occurred in 1498 of 30 599 patients (4.90%) treated with NOACs and in 1304 of 23 548 patients (5.54%) treated with VKAs (Figure 3A). Use of NOACs was associated with a significant reduction in the rate of MB events (RR, 0.86; 95% CI, 0.80–0.93; ARR, 0.64%; I2=57%; NNT, 157). Reanalysis using an RE model demonstrated a trend toward a reduction in MB (RR, 0.86; 95% CI, 0.72–1.02). Given the significant heterogeneity (P<0.05), we performed a subgroup analysis examining each NOAC (Figure II in the online-only Data Supplement). In this analysis, apixaban and dabigatran reduced MB events, whereas neither rivaroxaban nor edoxaban reduced bleeding.

Figure 3.

Figure 3. Major (A) and intracranial (B) bleeding during oral anticoagulant treatment. NOAC indicates novel oral anticoagulant; VKA, vitamin K antagonists; M-H, Mantel-Haenszel; CI, confidence interval; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy; ARISTOTLE, Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; J-ARISTOTLE, Japanese Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation; and J-ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation in Japan.

Intracranial bleeding occurred in 180 of 30 599 patients (0.59%) treated with NOACs and in 307 of 23 548 patients (1.30%) treated with VKAs (Figure 3B). Use of NOACs was associated with a significant reduction in the risk of intracranial bleeding events (RR, 0.46; 95% CI, 0.39–0.56; I2=34%; ARR, 0.71%; NNT, 141). Reanalysis with an RE model did not change these results.

Myocardial Infarction

MI occurred in 394 of 30 584 patients (1.29%) treated with NOACs and in 304 of 23 531 patients (1.29%) treated with VKAs (Figure 4). There was no difference in the risk of developing MI between NOACs and VKAs (RR, 0.99; 95% CI, 0.85–1.15; I2=55%). Reanalysis using an RE model did not show significant changes in the results (RR, 1.00; 95% CI, 0.75–1.33). Given the high level of heterogeneity, we performed a subgroup analysis separately to assess each novel drug, but we did not find any statistically significant difference between the NOACs and VKAs (Figure III in the online-only Data Supplement).

Figure 4.

Figure 4. Myocardial infarction during oral anticoagulant treatment. NOAC indicates novel oral anticoagulant; VKA, vitamin K antagonists; M-H, Mantel-Haenszel; CI, confidence interval; RE-LY, Randomized Evaluation of Long-Term Anticoagulant Therapy; ARISTOTLE, Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; J-ARISTOTLE, Japanese Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation; and J-ROCKET-AF, An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation in Japan.

Sensitivity Analyses

Sensitivity analyses including only high-quality810,23,28.29 and published810,22.23,2730 studies confirmed the results of the primary analyses (Figures IV–VII in the online-only Data Supplement).

Similarly, repeating our analyses with Comprehensive Meta Analysis software including trials with extremely low or zero event rates did not change the results of the primary analyses (results available on request).

Subgroup Analyses

In the subgroup analysis that included only studies with short-term follow-up,22,2430 only the rate of stroke and SE appears to be significantly reduced in patients randomized to NOACs, whereas the rates of cardiovascular and total death, IS, MB, intracranial bleeding, and MI were similar in the 2 groups. In contrast, the subgroup analyses that included only studies with long-term follow-up810,23 and only the dose regimens used in phase III studies provided the same results as the primary analyses.

The analysis excluding the lower dosage of dabigatran showed a reduction of IS with NOACs compared with VKAs (RR, 0.86; 95% CI, 0.76–0.99; I2=30%) using a fixed-effects model. This result was not statistically significant with an RE model (RR, 0.85; 95% CI, 0.70–1.02; Figures IV–VII in the online-only Data Supplement).

Publication Bias

Funnel plots of effect size versus standard error are summarized in Figures VIII–XI in the online-only Data Supplement. The funnel plot for stroke or SE was asymmetrical with the absence of studies on the right side of the plot, whereas the funnel plot for MI was lacking studies on the left side of the plot. The funnel plots for total mortality and MB appeared symmetrical.

Discussion

This is, to the best of our knowledge, the first systematic review and meta-analysis of phase II and phase III RCTs that compared the NOACs with warfarin for the prevention of stroke and SE in patients with AF. Our analysis, incorporating >50 000 patients, found a statistically significant 11% RR reduction in the incidence of both total mortality and cardiovascular mortality, which corresponds to an NNT of 244 patients to prevent 1 death and to an NNT of 500 patients to prevent 1 cardiovascular death. The observed advantage of the NOACs is consistent for all outcomes, including stroke and SE reduction (RR reduction, 23%; NNT, 137) and MB reduction (RR reduction, 14%; NNT, 157).

Following the favorable results of the individual clinical trials, dabigatran and rivaroxaban have received approval from the regulatory agencies and apixaban is expected to be licensed in the near future. However, the cost-effectiveness of these compounds remains unclear. This lack of clarity exists, in part, as a result of the observation that single studies have reported small and often nonstatistically significant differences between the NOACs and warfarin for hard end points such as overall mortality and vascular mortality.

We believe that our study could provide more accurate estimates of the expected clinical benefits of the NOACs. Taken together, our results suggest that the use of the NOACs not only provides practical advantages over the VKAs but also is associated with an overall clinical benefit, suggesting their cost-effectiveness.

More important, the NOACs both reduce clinical events and offer the possibility of increasing the use of adequate prophylactic strategies in patients with AF. It is well known that AF remains a major cause of stroke2 and that the severity of stroke is greater in patients with AF than in other subgroups.35 Despite this evidence, the use of VKAs in the real world of patients with AF remains unacceptably low, with an overall prevalence of treated high-risk patients not exceeding 70%.36 The availability of NOACs has the potential to reduce the incidence of AF-related strokes and SE because of both their superior efficacy and their potential to be more widely used compared with the VKAs.

In this meta-analysis, we have combined the results of clinical trials carried out with 4 NOACs. These drugs present some important differences in terms of mechanisms of action; 1 drug (dabigatran etexilate) is a direct thrombin inhibitor and 3 drugs (rivaroxaban, apixaban, and edoxaban) are direct factor Xa inhibitors. Moreover, there are some differences in the mechanisms of excretion, in their mean half-lives, and in the drug-drug interactions, among others.37 These differences may suggest that combining the results of these drugs may not be appropriate. However, there were no signs of heterogeneity when the outcomes of total and cardiovascular mortality, stroke, or SE were analyzed, thus suggesting that the advantages in terms of efficacy are consistent among all the new agents included in our study. On the other hand, significant heterogeneity was documented when the outcome of MB was analyzed.

This finding may be due in part to some drug-specific or regimen-specific differences in terms of safety, although none of the NOACs were less safe than warfarin, and to patient-specific characteristics. Indeed, some studies enrolled an intermediate-risk population with a mean CHADS2 score of ≈2,8,10,22,2729 whereas other studies enrolled a population at higher risk not only for thromboembolic but also for bleeding complications, with a mean CHADS2 score >3.9,23

When the analysis was repeated with the exclusion of the lower dose of dabigatran, which is not approved in the United States and is recommended for more fragile patients in other countries, the results were fully comparable to those of the main analysis in terms of total mortality and safety, whereas a tendency toward a greater benefit in the reduction of IS was observed.

There is great interest in the potential increased risk of MI with the use of the NOACs, particularly dabigatran. The results of a recent meta-analysis of trials involving dabigatran for the primary and secondary prevention of cardiovascular diseases found a 33% RR increase in acute coronary events with the novel direct thrombin inhibitors compared with traditional anticoagulant drugs.38 Another recent analysis comparing warfarin with other antithrombotic drugs (ximelagatran, dabigatran, idraparinux, and clopidogrel) in AF clinical trials found a 23% RR reduction in the rate of MI with warfarin, suggesting the protective effect of the VKA.39 In this meta-analysis, we failed to detect any difference in the overall risk of MI, with a 1.29% rate in both NOAC- and VKA-treated patients. Of interest, no statistically significant difference was detected after subgroup analysis.

The strengths of this study include the rigorous methodological approach, the selection of all the studies performed with the 4 NOACs considered, and the consistency of the results of sensitivity analyses. Furthermore, to the greatest extent possible, we confined our analysis to clinically relevant events, and because all the studies were performed as a component of product registration, it is likely that all reported outcome events were objectively confirmed.

The study has a number of limitations. First, because this was a study-level meta-analysis, we were unable to confirm the overall results in specific subgroups of patients according to their baseline stroke or bleeding risk. Population characteristics were quite different among the single studies; however, several subgroup analyses have already been published suggesting the consistency of the principal findings across different subgroups such as patients with previous stroke31,40.41 or more advanced age.42 Second, we could not compare the patients receiving NOACs with different subgroups of warfarin-treated patients according to the time in therapeutic range, and it has been shown that the magnitude of the benefit of the NOACs compared with standard treatment is dependent on the quality of control of warfarin.43 Third, the results of our meta-analysis are driven mainly by 3 large RCTs involving dabigatran,8 rivaroxaban,9 and apixaban,10 whereas fewer data are available on edoxaban because the phase III RCT is currently ongoing. Fourth, the funnel plot for stroke or SE was asymmetrical with a lack of studies on the right part of the plot, suggesting that unpublished studies likely to demonstrate an increased risk of stroke or SE with NOACs were not included in our meta-analysis. Instead, the funnel plot for MI was lacking studies on the left side of the plot, suggesting that studies demonstrating a reduction in the risk of MI with NOACs were not included. However, because we performed an extensive research of the literature, including abstracts presented at congresses of several international societies, and because we contacted pharmaceutical companies asking for unpublished trials, the existence of other trials not included in our systematic review is extremely unlikely.

Conclusions

NOACs reduced overall and cardiovascular mortality, stroke and SE, and MB and intracranial bleeding compared with warfarin. These favorable efficacy and safety profiles now need to be confirmed in postmarketing studies.

Acknowledgments

We are grateful to Drs Jeffrey Weitz, Masatsugu Hori, Andreas Clemens, Mariko Kajikawa, and Kazuhiro Kanmuri for kindly providing additional data.

Disclosures

Dr Crowther discloses having served on advisor boards for Leo Pharma, Pfizer, Bayer, Boehringer Ingelheim, Alexion, CSL Behring, and Artisan Pharma. Dr Crowther has prepared educational materials for Pfizer, Octapharm, and CSL Behring; has provided expert testimony for Bayer; and holds a Career Investigator Award from the Heart and Stroke Foundation of Ontario and the Leo Pharma Chair in Thromboembolism Research at McMaster University. Dr Crowther's institution has received funding for research projects from Boehringer Ingelheim, Octapharm, Pfizer, and Leo Pharma. Dr Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, Biotronik, Portola, and Boehringer Ingelheim and has been on the speakers' bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi-Aventis. Dr Ageno has served on the advisory boards for Bayer, BMS/Pfizer, and Daiichi Sankyo; has received honoraria for speaking activities from Boehringer Ingelheim, Bayer, BMS, Pfizer, Sanofi, GlaxoSmithKline; and has received funding for research projects from Bayer, GlaxoSmithKline, and Alexion. Dr Turpie has served on advisory boards for Bayer, Astellas, and Takeda and has received honoraria for speaking activities from Boehringer Ingelheim, Bayer, BMS, Pfizer, Sanofi, and GlaxoSmithKline. Drs Dentali and Riva report no conflicts.

Footnotes

Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.112.115410/-/DC1.

Correspondence to Francesco Dentali,
UO Medicina Interna, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy
. E-mail

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Clinical Perspective

Novel oral anticoagulants, including direct thrombin inhibitors and factor Xa inhibitors, have been proposed as alternatives to vitamin K antagonists for the prevention of stroke and systemic embolism in patients with atrial fibrillation. We conducted a systematic review and a meta-analysis of published and unpublished phase II and III randomized, controlled trials comparing the novel oral anticoagulants with the vitamin K antagonists in patients with atrial fibrillation. We retrieved 12 studies (3 administering dabigatran, 4 administering rivaroxaban, 2 administering apixaban, and 3 administering edoxaban) enrolling >50 000 patients. We found that the novel oral anticoagulants significantly reduced overall mortality, cardiovascular mortality, and stroke or systemic embolism. Furthermore, these drugs showed a trend toward reduced major bleeding, with a significant reduction of intracranial hemorrhage. The novel oral anticoagulants may potentially address some of the limitations of vitamin K antagonists because they have fewer food and drug interactions and a more predictable anticoagulant effect, thus allowing fixed-dose regimens without the need for routine laboratory monitoring. Our meta-analysis also provided robust evidence on the overall clinical benefit of the novel oral anticoagulants, suggesting their cost-effectiveness in the real-life healthcare systems.

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