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Causes of Death in AnticoagulatedPatients With Atrial Fibrillation

Antonio Gómez-Outes, MD, PHD,a Julián Lagunar-Ruíz, MD,b Ana-Isabel Terleira-Fernández, MD, PHD,b,c

Gonzalo Calvo-Rojas, MD, PHD,d Maria Luisa Suárez-Gea, PHARMD, PHD,a Emilio Vargas-Castrillón, MD, PHDb,c

ABSTRACT

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BACKGROUND Oral anticoagulation reduces the risk of mortality in atrial fibrillation (AF), but examination

of the causes of death is essential to design new strategies to further reduce the high mortality rates observed in

this population.

OBJECTIVES The authors sought to analyze and compare causes of death in patients receiving direct oral

anticoagulants (DOAC) or warfarin for prevention of stroke and systemic embolism (SE) in AF.

METHODS The authors systematically searched for randomized trials of DOAC versus warfarin for prevention of stroke/

SE in AF. The main outcome was mortality and independently adjudicated specific causes of death. The authors used

the random effects model of meta-analysis to combine the studies.

RESULTS 71,683 patients from 4 trials were included (134,046 patient-years of follow-up). A total of 6,206

patients (9%) died during follow-up. Adjusted mortality rate was 4.72%/year (95% confidence interval [CI]: 4.19

to 5.28). Cardiac deaths accounted for 46% of all deaths, whereas nonhemorrhagic stroke/SE and hemorrhage-

related deaths represented 5.7% and 5.6% of the total mortality, respectively. Compared with patients who were

alive, those who died had more frequent history of heart failure (odds ratio [OR]: 1.75; 95% CI: 1.25 to 2.44),

permanent/persistent AF (OR: 1.38; 95% CI: 1.25 to 1.52) and diabetes (OR: 1.37; 95% CI: 1.11 to 1.68); were more

frequently male (OR: 1.24; 95% CI: 1.13 to 1.37) and older (mean difference 3.2 years; 95% CI: 1.6 to 4.8); and had

a lower creatinine clearance (�9.9 ml/min; 95% CI: �11.3 to �8.4). There was a small, but significant, reduction in

all-cause mortality with the DOAC versus warfarin (difference �0.42%/year; 95% CI: �0.66 to �0.18), mainly

driven by a reduction in fatal bleedings.

CONCLUSIONS In contemporary AF trials, most deaths were cardiac-related, whereas stroke and bleeding

represented only a small subset of deaths. Interventions beyond anticoagulation are needed to further reduce mortality

in AF. (J Am Coll Cardiol 2016;68:2508–21) © 2016 by the American College of Cardiology Foundation.

A trial fibrillation (AF) is the most commonarrhythmia in the developed world, beingassociated with a 5-fold increased risk of

stroke and higher mortality (1). Oral anticoagulationwith warfarin and other vitamin K antagonists (VKA)are highly effective treatments in reducing therisk of stroke and mortality in AF (2), but their man-agement remains problematic due to their narrowtherapeutic index and variability in drug ex-posure necessitating routine coagulation monitoring

m the aDivision of Pharmacology and Clinical Drug Evaluation, Spanish A

drid, Spain; bDepartment of Clinical Pharmacology, Hospital Clínico San C

iversidad Complutense, Madrid, Spain; and the dDepartment of Clinical P

thors have reported that they have no relationships relevant to the conte

nuscript received June 29, 2016; revised manuscript received August 25,

(international normalized ratio), clinical surveillance,and continuous patient education (3).

In recent years, several direct oral anticoagulants(DOACs) (dabigatran, rivaroxaban, apixaban, andedoxaban) (3), also referred in the published reports as“novel anticoagulants” or “non–vitamin K antagonistoral anticoagulants” and “target-specific oralanticoagulants,” have been developed to overcomesome of these limitations. Contemporary studies ofanticoagulation in AF have shown a significant

gency for Medicines and Medical Devices (AEMPS),

arlos, Madrid, Spain; cDepartment of Pharmacology,

harmacology, Hospital Clinic, Barcelona, Spain. The

nts of this paper to disclose.

2016, accepted September 13, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

AF = atrial fibrillation

CI = confidence interval

CV = cardiovascular

DOAC = direct oral

J A C C V O L . 6 8 , N O . 2 3 , 2 0 1 6 Gómez-Outes et al.D E C E M B E R 1 3 , 2 0 1 6 : 2 5 0 8 – 2 1 DOAC Meta-Analysis of Causes of Death

2509

mortality rate (z8%) (4). Examination of the causes ofdeath during these studies is essential to understandthe specific impact of the new antithrombotic agentscompared with warfarin in the risk of death, and todesign new strategies, beyond anticoagulation, tofurther reduce the high mortality rates observed inthis indication.

SEE PAGE 2522

anticoagulant

HD = high-dose

LD = low-dose

OR = odds ratio

RR = relative risk

SE = systemic embolism

TTR = time within therapeutic

range

VKA = vitamin K antagonist

We systematically reviewed and meta-analyzeddata from randomized controlled trials of theDOACs for prophylaxis against stroke and systemicembolism (SE) in patients with AF with the aim ofdescribing the specific causes of death reported dur-ing these studies and exploring potential differencesin cause-specific mortality between the DOACs andwarfarin.

METHODS

ELIGIBILITY CRITERIA. We considered randomizedcontrolled trials comparing any of the approved neworal anticoagulants (dabigatran, rivaroxaban, apix-aban, and edoxaban) with warfarin in patients withAF at risk of stroke and $1-year follow-up. Weincluded all doses tested in the experimental arms ofpivotal trials of the DOACs in this indication in thebase-case (primary) analysis (3).

TRIAL IDENTIFICATION AND DATA COLLECTION.

We searched Medline and CENTRAL (up to May 2016),websites of regulatory agencies, clinical trial regis-tries, and relevant conference proceedings (OnlineAppendix 1). No language restrictions were applied.Two investigators (A.G.-O. and J.L.-R.) separatelyassessed trials for eligibility and extracted data. If atrial was covered in >1 report, we used the followinghierarchy of data sources: peer-reviewed articles,public reports from regulatory authorities, reportsfrom the web-based repository for results of clinicalstudies, and other sources. Finally, we contacted themain investigators by e-mail to retrieve unpublisheddata from clinical trials (differential demographiccharacteristics in patients who died and those aliveafter follow-up, as well as disaggregated classificationof causes of death when they were reported as acomposite, e.g., death due to stroke, death due tohemorrhage). In case of no response, we sent areminder to the main investigator after 1 week, withcopy to a sponsor’s representative (e.g., coauthor/sbeing employee/s of the sponsor).

STUDY CHARACTERISTICS AND QUALITY ASSESSMENT.

We collected data on patient characteristics, numbersof patients evaluable for efficacy and safety,dosage used in the experimental and control groups,

duration of treatment and follow-up, as wellas inclusion and exclusion criteria andmethodology for the adjudication of deaths.We assessed study quality using the CochraneCollaboration’s tool for assessing risk of biasin randomized studies (5).

OUTCOME MEASURES. The pre-specifiedoutcome was all-cause death and adjudi-cated specific causes of death. They had tocorrespond to the principal cause of death asassessed by the adjudication committees ofthe studies. Therefore, each death wasattributed to one cause exclusively. Fatalhemorrhagic stroke was counted among fatalbleedings, but not among fatal strokes, inorder to avoid double counting.

QUANTITATIVE DATA SYNTHESIS. We conductedthis meta-analysis in accordance with the PreferredReporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (6). We usedthe intention-to-treat population whenever available.Firstly, we conducted an incidence rate meta-analysisto describe the average rate of deaths (total and spe-cific causes) in each treatment group and overallpopulation, for each study and pooled studies. Wecalculated exposure-adjusted incidence rate as thenumber of patients who died (numerator) by theperson-time at risk, expressed as patient-years(denominator), in order to standardize differentfollow-up durations across studies. We calculatedpatient-years by multiplying the number of patientsin each treatment group by the mean years thatpatients in each group were in the study. Secondly,we conducted a proportion meta-analysis of therelative risk (RR) of death with the DOACs (all dosescombined) and warfarin. Thirdly, we conducted anincidence-rate difference meta-analysis of the abso-lute risk of death with the DOACs (all dosescombined) and warfarin, expressed as difference inevents per 10,000 patients/year. We also comparedbaseline characteristics of patients who died versusthose alive during follow-up using the odds ratio (OR)as measure of association. Heterogeneity betweenstudies was assessed using the Cochran Q test and theHiggins I2 index (percentage of variation acrossstudies that is due to heterogeneity rather thanchance). A Cochran’s Q p < 0.05 and I2 >50% indicatesignificant heterogeneity. We used the randomeffects model described by Der-Simonian and Laird(7) for the main analysis.

ANCILLARY ANALYSES. We also conducted ancillaryanalyses for high-dose (HD) and low-dose (LD) DOACregimens, in order to explore potential differences in

FIGURE 1 Study Identification, Selection, and Exclusions

4712 citations identified fromelectronic literature search

and screened

8 potentially relevantreports retrieved fromother sources (public

assessment reports fromregulatory authorities)

4665 citations excluded: No mortality data (4167) Mortality data but no RCT (464) Mortality data and RCT but not in AF (34)

37 reports excluded: Secondary analyses (29)* Phase II studies (5) Long-term extension study (1) Inappropriate comparison (1) Specific causes of death not reported (1)

47 potentially relevantreports retrieved for scrutiny

(full text)

55 potentially relevantreports

18 reports included in thereview describing deathsfrom 4 unique RCTs in AF

*Subgroups, biomarkers, and so on. AF ¼ atrial fibrillation; RCT ¼ randomized clinical trial.

Gómez-Outes et al. J A C C V O L . 6 8 , N O . 2 3 , 2 0 1 6

DOAC Meta-Analysis of Causes of Death D E C E M B E R 1 3 , 2 0 1 6 : 2 5 0 8 – 2 1

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rates and specific causes of death depending on theDOAC dose tested. The HD DOAC regimen wasdefined as the use of dabigatran 150 mg twice daily,edoxaban 60 mg once daily, or standard doses ofrivaroxaban 20 mg once daily and apixaban 5 mgtwice daily. The LD DOAC regimen was defined as theuse of dabigatran 110 mg twice daily and edoxaban30 mg once daily.

SENSITIVITY ANALYSES. We conducted sensitivityanalyses taking into account different methodologicalissues that could influence the results of themeta-analysis: 1) statistical model (fixed effectsinstead of the random effects model); 2) type ofmeasure (OR instead of RR); 3) type of analysis(incidence rate meta-analysis instead of proportionmeta-analysis); and 4) study quality (including onlystudies at low risk of bias).

STATISTICAL SOFTWARE. Analyses of incidencerates were done using StatsDirect software, version2.8.0 (StatsDirect, Cheshire, United Kingdom),whereas analyses of proportions were done usingRevMan statistical software, version 5.1 (NordicCochrane Center, Copenhagen, Denmark).

RESULTS

STUDY SELECTION, DESIGN, AND METHODOLOGY.

The literature search identified 4,712 articles. Of

these, 47 reports were related to clinical trialsincluding mortality data in AF, and were selected forchecking as full text. An additional hand searchidentified 8 reports from regulatory authoritiesrelated to assessment of the DOACs in AF (Figure 1).Of these, 37 reports were excluded due to severalcauses detailed in Figure 1. Finally, 18 reports (8–25)including mortality data from 4 unique randomizedclinical trials with dabigatran (RE-LY [RandomizedEvaluation of Long-Term Anticoagulation Therapy])(8–13), rivaroxaban (ROCKET AF [An Efficacy andSafety Study of Rivaroxaban With Warfarin for thePrevention of Stroke and Non-Central NervousSystem Systemic Embolism in Patients WithNon-Valvular Atrial Fibrillation]) (14–18), apixaban(ARISTOTLE [Apixaban for the Prevention of Stroke inSubjects With Atrial Fibrillation]) (19–21), and edox-aban (ENGAGE AF–TIMI 48 [Effective AnticoagulationWith Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48]) (22–25), inpatients with AF were included in the quantitativemeta-analysis.

The 4 studies comprised 71,683 AF patients(134,046 patient-years of exposure) (Table 1), whowere randomized to receive a DOAC or warfarin. Therisk of bias was low in 3 studies (14,19,22) and unclearin the RE-LY trial due to lack of double-blinding (8)(Table 1, Online Appendix 2, Online Table 1).

TABLE 1 Characteristics of Trials and Patients Included in the Systematic Review

RE-LY ROCKET AF ARISTOTLE ENGAGE AF-TIMI 48

Trial characteristics

Randomized 18,113 14,264 18,201 21,105

ITT patients 18,113 14,171 18,201 21,026

Safety patients 18,113 14,236 18,201 21,026

Patient-yrs* 31,274 22,390 33,318 47,064

Experimental drug Dabigatran 150 mg and110 mg twice daily

Rivaroxaban 20 mgonce daily†

Apixaban 5 mgtwice daily†

Edoxaban 60 mg and30 mg once daily†

Exposure, mean, yrs 1.69–1.71 1.57 1.84 2.21–2.26

Control drug Warfarin Warfarin Warfarin Warfarin

Exposure, mean, yrs 1.78 1.59 1.83 2.22

TTR (%), mean 64.4 55.2 62.2 65

Median follow-up, yrs 2 1.9 1.8 2.8

Trial phase III III III III

Design Open-labelPROBE

Double-blind Double-blind Double-blind

Adjudication of deaths IAC, blind IAC, blind IAC, blind IAC, blind

Population and time-point foradjudication of deaths

ITT, end of study ITT, end of study ITT, end of intendedtreatment period

Randomized patients, endof study

Unknown vital status at endof study

Dabigatran: 13 (0.1%)Warfarin: 11 (0.2%)

Rivaroxaban: 6 (0.1%)Warfarin: 8 (0.1%)

Apixaban: 180 (2%)Warfarin: 179 (2%)

Edoxaban: 29 (0.2%)Warfarin: 12 (0.2%)

Risk of bias (Cochrane) unclear low low low

Patient characteristics

Age, yrs 72 (mean) 73 (median) 70 (median) 72 (median)

>75 yrs 39 43 31 40

Male (%) 64 60 65 62

CHADS2 score, mean 2.1 3.5 2.1 2.8

Congestive heart failure 32 63 36 58

Hypertension 79 90 88 94

Diabetes 23 40 25 36

Prior stroke/TIA (%) 20 55 19 28

Atrial fibrillation type

Permanent/persistent (%) 67 81 83 75

Paroxysmal (%) 33 18 17 25

History of VKA use (%) 50 63 57 59

*Referred to the ITT population for the RE-LY, ROCKET AF and ARISTOTLE trials, and for randomized patients in the ENGAGE AF trials. †Dose-reduction was applied in patientswith CrCl 15 to 50 ml/min (rivaroxaban from 20 mg to 15 mg in the ROCKET AF trials), in patients with$2 of the following characteristics: age$80 years, body weight#60 kg,or serum creatinine $1.5 mg/dl (apixaban from 5 mg to 2.5 mg twice daily) and in patients with a CrCl 30 to 50 ml/min, a body weight #60 kg, or concomitant potentP-glycoprotein inhibitors (edoxaban from 60 mg to 30 mg once daily in the high-dose group; from 30 mg to 15 mg once daily in the low-dose group).

ARISTOTLE ¼ Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation trial; CHADS2 score ¼ congestive heart failure, hypertension, age >75, diabetesmellitus, prior stroke or transient ischemic attack doubled; CrCl ¼ creatinine clearance; ENGAGE AF–TIMI 48 ¼ Effective Anticoagulation With Factor Xa Next Generation inAtrial Fibrillation-Thrombolysis In Myocardial Infarction 48 trial; IAC ¼ independent adjudication committee; NA ¼ not available; ITT ¼ intention to treat; PROBE ¼ prospective,randomized, open-label, blinded endpoint; RE-LY ¼ Randomized Evaluation of Long-Term Anticoagulation Therapy trial; ROCKET AF ¼ An Efficacy and Safety Study ofRivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation; SE ¼ systemicembolism; TIA ¼ transient ischemic attack; TTR ¼ time within therapeutic range; VKA ¼ vitamin K antagonist.

J A C C V O L . 6 8 , N O . 2 3 , 2 0 1 6 Gómez-Outes et al.D E C E M B E R 1 3 , 2 0 1 6 : 2 5 0 8 – 2 1 DOAC Meta-Analysis of Causes of Death

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An independent adjudicating committee blindlyadjudicated deaths in all 4 studies. Adjudication ofdeaths was made in the intention-to-treat populationin 3 studies (9,15,20) and in randomized patients inthe remaining study (23). The time-point for adjudi-cation of deaths was up to end of study in 3 studies(8,14,22) and at the end of the intended treatmentperiod (expected date of attainment of the study’sevent target) in the remaining study (19). The rate ofpatients lost to follow-up for vital status at end ofstudy ranged from 0.1% to 2% across studies, withoutsignificant differences between treatment groups

(Table 1). Each death was attributed to 1 causeexclusively in all studies (principal cause of death).For more detailed information on the adjudicationprocess of causes of deaths by trial and assumptionsmade in the meta-analysis for pooling cause-specificdeaths, see Online Appendix 3 and Online Table 2.

PATIENT CHARACTERISTICS. Mean or median ageranged between 70 and 73 years (Table 1). There was apredominance of men (range 60% to 65%) andpermanent/persistent AF (range 67% to 83%). Meanthromboembolic risk (CHADS2) was the highest in the

TABLE 2 Descriptive Analysis of Causes of Death as Total Numbers and as

Percentage of Total Deaths

Cause of Death All Patients DOAC Warfarin

All-cause death 6,206 (100) 3,579 (100) 2,627 (100)

Vascular death 3,970 (64) 2,297 (64) 1,673 (64)

Cardiac death 2,855 (46) 1,699 (47) 1,156 (44)

Sudden death/dysrhythmia 1,759 (28) 1,044 (29) 715 (27)

Heart failure 922 (15) 547 (15) 375 (14)

Myocardial infarction 174 (3) 108 (3) 66 (3)

Ischemic stroke/SE* 356 (6) 206 (6) 150 (6)

Hemorrhage (all) 350 (6) 148 (4) 202 (8)

Hemorrhagic stroke 202 (3) 77 (2) 125 (5)

Other intracranial hemorrhage 63 (1) 28 (1) 35 (1)

Extracranial hemorrhage 85 (1) 43 (1) 42 (2)

Other vascular death† 409 (7) 244 (7) 165 (6)

Nonvascular death 1,849 (30) 1,103 (31) 746 (28)

Malignancies 706 (11) 441 (12) 265 (10)

Infections 533 (9) 318 (9) 215 (8)

Respiratory 177 (3) 89 (2) 88 (3)

Trauma/accidental 72 (1) 34 (1) 38 (1)

Hepatobiliary/liver failure 17 (0.3) 9 (0.3) 8 (0.3)

All other 344 (6) 212 (6) 132 (5)

Undetermined death 387 (6) 179 (5) 208 (8)

Values are n (%). *Only 14 of 356 fatal ischemic stroke/SE events correspond to fatal SE (z0.2%of total deaths). †Includes CABG, non-coronary atherosclerotic disease, pulmonary embolism andother unspecified vascular deaths.

CI ¼ confidence interval; DOAC ¼ direct oral anticoagulant; SE¼ systemic embolism (other thanembolic stroke).

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ROCKET AF and ENGAGE AF trials (3.5 and2.8, respectively) and the lowest in the RE-LY andARISTOTLE trials (2.1 each). Consistently, the rate ofpatients aged >75 years and history of heart failure,hypertension, diabetes, and prior stroke was higher inthe ROCKET-AF and ENGAGE AF trials than in theRE-LY and ARISTOTLE trials. Demographic character-istics by vital status were available from 2 studies(Online Table 3). Patients who died during thestudies were significantly older (difference 3.2 years;95% confidence interval [CI]: 1.6 to 4.8), had a lowercreatinine clearance (difference �9.9 ml/min;95% CI: �11.3 to �8.4), were more frequently male(OR: 1.24; 95% CI: 1.13 to 1.37), and had morefrequent history of congestive heart failure (OR: 1.75;95% CI: 1.25 to 2.44), diabetes (OR: 1.37; 95% CI: 1.11to 1.68), permanent/persistent AF (OR: 1.38; 95% CI:1.25 to 1.52), and less history of VKA use (OR: 0.88;95% CI: 0.78 to 0.98) than patients alive at the endof follow-up.

DESCRIPTIVE ANALYSIS OF CAUSES OF DEATH. Atotal of 6,206 deaths were adjudicated in the 4studies. Vascular deaths accounted for 64% of alldeaths, whereas 30% of deaths were of nonvascularcause, and 6% of deaths were due to unknown causes

(Table 2). The more frequent causes of death werecardiac death, in 46% of cases (28% sudden cardiacdeaths/dysrhythmia, 15% heart failure, and 3%myocardial infarction), followed by malignancies(11%), infections (9%), ischemic stroke/SE (6%), andbleeding (6%).

The average annual mortality rate in the studypopulations was 4.63%/year (95% CI: 3.99 to 5.32)(Table 3), but there was significant heterogeneityacross studies (p < 0.0001; I2 ¼ 95.5%). Heterogeneitywas due to a higher death rate in the ROCKET AF andENGAGE AF trials than in the other studies, which isconsistent with a higher rate of elderly patientsand significant comorbidities in the ROCKET AFand ENGAGE AF trials than in the other 2 studies(Table 1). Average annual incidences for the morefrequent specific categories were cardiac death2.07%/year (95% CI: 1.55% to 2.68%/year), nonvas-cular death 1.37%/year (1.18% to 1.57%/year), heartfailure 0.67%/year (0.53% to 0.82%/year), malig-nancies 0.52%/year (0.42% to 0.63%/year), infec-tions 0.37%/year (0.23% to 0.55%/year), bleeding0.27%/year (0.19% to 0.35%/year), and ischemicstroke/SE 0.26%/year (0.20% to 0.32%/year) (Table 3).

The average annual mortality rate by anticoagulanttype was 4.46%/year (95% CI: 3.85% to 5.12%/year)with the DOACs and 4.87%/year (4.15% to 5.64%/year)with warfarin (Online Tables 4 and 5, respectively).The main difference in annual rates of specific causesof death between the DOACs and warfarin was inthe fatal bleeding subcategory (DOACs 0.19%/year[0.13% to 0.26%/year] and warfarin 0.38%/year[0.28% to 0.49%/year]) (Online Tables 4 and 5).DIFFERENCES IN SPECIFIC CAUSES OF DEATH

BETWEEN DOACs AND WARFARIN. There were sig-nificant relative risk differences in favor of the DOACsin comparison with warfarin with respect to all-causemortality (RR: 0.90; 95% CI: 0.86 to 0.95) (Figure 2A),as well as for cardiovascular (CV) deaths (RR: 0.89;95% CI: 0.84 to 0.95) and unknown/undetermineddeaths (RR: 0.80; 95% CI: 0.66 to 0.98) (Figure 2B),with homogeneity between trials. The differences inCV mortality were mainly driven by a reduction infatal bleedings (hemorrhagic stroke, other fatalintracranial and extracranial bleedings) (Figure 3).There was a significant difference in the effect onbleeding and nonbleeding CV mortality (heterogene-ity p < 0.00001; I2 ¼ 97%) (Figure 4). Finally, no dif-ferences in specific causes of non-CV mortality wereapparent between treatments, although the DOACswere also associated to a nonsignificant trend towarda lower risk of some specific types of deaths thanwarfarin, such as those due to trauma/accident(RR: 0.62; 95% CI: 0.39 to 1.01) (Figure 5).

TABLE 3 Descriptive Analysis of Causes of Death and Adjusted Event Rates per 100 Patients per Year (All Study Patients, Regardless of

Treatment Group)

RE-LY ROCKET AF ARISTOTLE ENGAGE AF–TIMI 48Total*

%/yr (95% CI) Heterogeneity p Value; I2

Patient/years 31,274 22,390 33,318 47,064

All-cause death 1,371 (4.38) 1,214 (5.42) 1,272 (3.82) 2,349 (4.99) 4.63 (3.99–5.32) <0.0001; 97%

Vascular death 842 (2.69) 776 (3.47) 684 (2.05) 1668 (3.54) 2.91 (2.23–3.68) <0.0001; 98.4%

Cardiac death 553 (1.77) 554 (2.47) 501 (1.50) 1247 (2.65) 2.07 (1.55–2.68) <0.0001; 98.1%

Sudden death/dysrhythmia 305 (0.98) 359 (1.60) 295 (0.89) 800 (1.70) 1.27 (0.88–1.73) <0.0001; 98%

Heart failure 207 (0.66) 157 (0.70) 168 (0.50) 390 (0.83) 0.67 (0.53–0.82) <0.0001; 90.5%

Myocardial infarction 41 (0.13) 38 (0.17) 38 (0.11) 57 (0.12) 0.13 (0.11–0.15) 0.3292; 12.7%

Ischemic stroke/SE 61 (0.20) 63 (0.28) 78 (0.23) 154 (0.33) 0.26 (0.20–0.32) 0.0026; 78.9%

Hemorrhage (all) 74 (0.24) 92 (0.41) 60 (0.18) 124 (0.26) 0.27 (0.19–0.35) <0.0001; 88.4%

Hemorrhagic stroke 35 (0.11) 62 (0.28) 28 (0.08) 77 (0.16) 0.15 (0.09–0.23) <0.0001; 91.1%

Other intracranial hemorrhage 21 (0.07) 8 (0.04) 13 (0.04) 21 (0.04) 0.05 (0.04–0.06) 0.3432; 10%

Extracranial hemorrhage 18 (0.06) 22 (0.10) 19 (0.06) 26 (0.06) 0.07 (0.05–0.08) 0.2196; 32.1%

Other vascular death† 154 (0.49) 67 (0.30) 45 (0.14) 142 (0.30) 0.29 (0.17–0.46) <0.0001; 95.9%

Nonvascular death 491 (1.57) 305 (1.36) 372 (1.12) 681 (1.45) 1.37 (1.18–1.57) <0.0001; 89.3%

Malignancies 191 (0.61) 118 (0.53) 126 (0.41) 271 (0.58) 0.52 (0.42–0.63) <0.0001; 86.5%

Infections 61 (0.20) 97 (0.43) 119 (0.36) 256 (0.54) 0.37 (0.23–0.55) <0.0001; 95.6%

Respiratory 79 (0.25) 44 (0.20) 54 (0.16) ‡ 0.20 (0.15–0.26) 0.0395; 69.1%

Trauma/accidental 12 (0.04) 15 (0.07) 20 (0.06) 25 (0.05) 0.05 (0.04–0.07) 0.479; 0%

Hepatobiliary/liver failure 10 (0.03) 1 (0.00) 0 (0.00) 6 (0.01) 0.01 (0.00–0.03) 0.0009; 81.8%

All other 138 (0.44) 30 (0.13) 53 (0.16) 123 (0.26) 0.24 (0.13–0.37) <0.0001; 95.2%

Undetermined death 38 (0.12) 133 (0.59) 216 (0.65) § 0.41 (0.12–0.88) <0.0001; 98.7%

Values are n (%/yr) unless otherwise indicated. *Proportion meta-analysis, random effects model, StatsDirect software. †Includes coronary artery bypass grafting, noncoronary atheroscleroticdisease, pulmonary embolism and other unspecified vascular deaths. ‡Noncardiovascular deaths were not broken down into respiratory cause; they were included in all other nonvasculardeath. §No deaths were unable to be classified. Those that were unexpected and without other cause were categorized as cardiac death.

Abbreviations as in Tables 1 and 2.

J A C C V O L . 6 8 , N O . 2 3 , 2 0 1 6 Gómez-Outes et al.D E C E M B E R 1 3 , 2 0 1 6 : 2 5 0 8 – 2 1 DOAC Meta-Analysis of Causes of Death

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Absolute risk differences between DOACs andwarfarin for specific causes of deaths per 10,000patients treated per year were homogeneous acrosstrials and were generally in favor of the DOACs(Table 4). For all-cause death, the DOACs avoided42 additional deaths per 10,000 patients treated peryear (95% CI: �66 to �18) in the pool of the 4 studiesanalyzed, with approximately 238 patients needed tobe treated with the DOAC instead of warfarin toprevent 1 additional death per year (95% CI: 152to 548).

ANCILLARY ANALYSES BY DOAC DOSE. Comparedwith warfarin, all-cause mortality was significantlyreduced with both the HD DOAC regimens (RR: 0.91;95% CI: 0.86 to 0.96) and LD DOAC regimens (RR:0.89; 95% CI: 0.83 to 0.96) (Online Figure 1). Thesame applied for vascular death (Online Figure 2A)and fatal bleedings, including hemorrhagic stroke(Online Figures 3 and 4). However, the HD DOAC re-gimes tended to decrease the risk of fatal ischemicstroke/SE compared with warfarin (RR: 0.83; 95% CI:0.65 to 1.05), whereas the LD DOAC regimens tendedto increase the risk of fatal ischemic stroke/SE(RR: 1.12; 95% CI: 0.82 to 1.54) (p value for subgroup

differences ¼ 0.13; I2 ¼ 57.5%) (Online Figure 5). Nodifferences were found between HD and LD DOACregimens versus warfarin for overall nonvasculardeaths (Online Figure 2B) and subtypes (OnlineFigures 6 and 7).

SENSITIVITY ANALYSES. The sensitivity analyses(Online Table 6) were consistent with the base-caseanalysis. There were significant differences betweenthe DOACs and warfarin in all-cause mortality andvascular mortality in all cases, which were mainlydriven by a halved risk of fatal bleedings. The resultswere robust regardless of statistical model, effectmeasure, use of incidence rates instead of pro-portions, and exclusion of studies at uncertain risk ofbias (the RE-LY trial) (Online Table 6).

SELECTIVE OUTCOME REPORTING, DISSEMINATION

BIAS, AND MISSING DATA. Adjudication of causes ofdeath were pre-specified in the protocols and re-ported in the publications or regulatory reviews of thelarge multicenter studies included in this meta-analysis. No statistical methods were applied toassess publication bias due to the low number ofincluded studies.

FIGURE 2 All-Cause Death and Types of Death

Study or SubgroupALL-CAUSE DEATH1. 884 12091 487 6022 21.0% 0.90 [0.81, 1.01]2. 582 7081 632 7090 20.4% 0.92 [0.83, 1.03]3. 603 9120 669 9081 21.0% 0.90 [0.81, 1.00]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 1510 14069 839 7036 37.6% 0.90 [0.83, 0.97]

Total events 3579 2627Heterogeneity: Tau2 = 0.00; Chi2 = 0.16, df = 3 (P = 0.98); I2 = 0%Test for overall effect: Z = 4.03 (P < 0.0001)

Subtotal (95% CI) 42361 29229 100.0% 0.90 [0.86, 0.95]

VASCULAR DEATH1. 542 12091 300 6022 20.1% 0.90 [0.78, 1.03]2. 375 7081 401 7090 20.4% 0.94 [0.82, 1.07]3. 323 9120 361 9081 17.6% 0.89 [0.77, 1.03]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 1057 14069 611 7036 41.9% 0.87 [0.79, 0.95]

Total events 2297 1673Heterogeneity: Tau2 = 0.00; Chi2 = 0.89, df = 3 (P = 0.83); I2 = 0%Test for overall effect: Z = 3.67 (P = 0.0002)

Subtotal (95% CI) 42361 29229 100.0% 0.89 [0.84, 0.95]

NON-VASCULAR DEATH1. 321 12091 170 6022 25.8% 0.94 [0.78, 1.13]2. 148 7081 157 7090 17.5% 0.94 [0.76, 1.18]3. 181 9120 191 9081 21.4% 0.94 [0.77, 1.15]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 453 14069 228 7036 35.3% 0.99 [0.85, 1.16]

Total events 1103 746Heterogeneity: Tau2 = 0.00; Chi2 = 0.28, df = 3 (P = 0.96); I2 = 0%Test for overall effect: Z = 0.86 (P = 0.39)

Subtotal (95% CI) 42361 29229 100.0% 0.96 [0.87, 1.05]

UNKNOWN/UNDETERMINED DEATH1. 21 12091 17 6022 9.7% 0.62 [0.32, 1.17]2. 59 7081 74 7090 34.2% 0.80 [0.57, 1.12]3. 99 9120 117 9081 56.0% 0.84 [0.65, 1.10]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 0 14069 0 7036 Not estimable

0.5 0.7 1 1.5 2

Total events 179 208Heterogeneity: Tau2 = 0.00; Chi2 = 0.79, df = 2 (P = 0.67); I2 = 0%Test for overall effect: Z = 2.17 (P = 0.03)

Subtotal (95% CI) 28292 22193 100.0% 0.80 [0.66, 0.98]

DOAC WARFARINEvents Total Events Total Weight

Risk RatioM-H, Random, 95% CI

Risk RatioM-H, Random, 95% CI

Favors DOAC Favors WARFARIN

ARISTOTLE ¼ Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation trial; CI ¼ confidence interval; DOAC ¼ direct oral anticoagulant; ENGAGE AF–TIMI

48 ¼ Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction 48 trial; M-H ¼ Mantel–Haenszel;

RE-LY ¼ Randomized Evaluation of Long-Term Anticoagulation Therapy trial; ROCKET AF¼ 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.

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DISCUSSION

The use of oral anticoagulation reduces all-causemortality in AF patients (2), but a better under-standing of causes of death among anticoagulated AFpatients is necessary to identify additional in-terventions to improve care for these patients (15).This systematic review and meta-analysis indicatesthat the main cause of death in anticoagulated

patients with AF, about 46%, is heart-related mor-tality, including sudden cardiac death, heart failure,and myocardial infarction, whereas ischemic strokeand fatal bleedings only account for approximately6% of all deaths each (Central Illustration).

We found heart failure, decreased creatinineclearance, diabetes, advanced age, and male sex tobe significantly associated with a higher risk ofdeath. These findings are consistent with published

FIGURE 3 Subtypes of Vascular Death

Favors DOAC Favors WARFARIN

Study or SubgroupSUDDEN DEATH/DYSRHYTHMIA1. 202 12091 103 6022 16.2% 0.98 [0.77, 1.24]RE-LY2. 178 7081 181 7090 21.5% 0.98 [0.80, 1.21]ROCKET AF3. 149 9120 146 9081 17.5% 1.02 [0.81, 1.27]ARISTOTLE4. ENGAGE AF-TIMI 48 515 14069 285 7036 44.7% 0.90 [0.78, 1.04]

Total events 1044 715Heterogeneity: Tau2 = 0.00; Chi2 = 0.99, df = 3 (P = 0.80); I2 = 0%Test for overall effect: Z = 1.02 (P = 0.31)

Subtotal (95% CI) 42361 29229 100.0% 0.95 [0.87, 1.05]

HEART FAILURE1. 136 12091 71 6022 23.6% 0.95 [0.72, 1.27]RE-LY2. 88 7081 69 7090 20.9% 1.28 [0.93, 1.75]ROCKET AF3. 76 9120 92 9081 21.9% 0.82 [0.61, 1.11]ARISTOTLE4. ENGAGE AF-TIMI 48 247 14069 143 7036 33.7% 0.86 [0.70, 1.06]

Total events 547 375Heterogeneity: Tau2 = 0.01; Chi2 = 5.09, df = 3 (P = 0.17); I2 = 41%Test for overall effect: Z = 0.58 (P = 0.56)

Subtotal (95% CI) 42361 29229 100.0% 0.95 [0.80, 1.13]

MYOCARDIAL INFARCTION1. 29 12091 12 6022 21.6% 1.20 [0.61, 2.36]RE-LY2. 18 7081 20 7090 24.1% 0.90 [0.48, 1.70]ROCKET AF3. 21 9120 17 9081 23.9% 1.23 [0.65, 2.33]ARISTOTLE4. ENGAGE AF-TIMI 48 40 14069 17 7036 30.4% 1.18 [0.67, 2.07]

Total events 108 66Heterogeneity: Tau2 = 0.00; Chi2 = 0.61, df = 3 (P = 0.90); I2 = 0%Test for overall effect: Z = 0.71 (P = 0.47)

Subtotal (95% CI) 42361 29229 100.0% 1.12 [0.82, 1.53]

ISCHEMIC STROKE AND NON-CNS SYSTEMIC EMBOLISM1. 38 12091 23 6022 17.2% 0.82 [0.49, 1.38]RE-LY2. 27 7081 36 7090 18.6% 0.75 [0.46, 1.24]ROCKET AF3. 37 9120 41 9081 23.4% 0.90 [0.58, 1.40]ARISTOTLE4. ENGAGE AF-TIMI 48 104 14069 50 7036 40.8% 1.04 [0.74, 1.46]

Total events 206 150Heterogeneity: Tau2 = 0.00; Chi2 = 1.33, df = 3 (P = 0.72); I2 = 0%Test for overall effect: Z = 0.87 (P = 0.38)

Subtotal (95% CI) 42361 29229 100.0% 0.91 [0.73, 1.13]

HEMORRHAGIC STROKE (INTRACEREBRAL BLEEDING)1. 16 12091 19 6022 25.4% 0.42 [0.22, 0.81]RE-LY2. 22 7081 40 7090 31.1% 0.55 [0.33, 0.93]ROCKET AF3. 2 9120 26 9081 9.3% 0.08 [0.02, 0.32]ARISTOTLE4. ENGAGE AF-TIMI 48 37 14069 40 7036 34.3% 0.46 [0.30, 0.72]

Total events 77 125Heterogeneity: Tau2 = 0.13; Chi2 = 6.76, df = 3 (P = 0.08); I2 = 56%Test for overall effect: Z = 3.65 (P = 0.0003)

Subtotal (95% CI) 42361 29229 100.0% 0.40 [0.25, 0.66]

OTHER INTRACRANIAL BLEEDINGS (EXCLUDING HEMORRHAGIC STROKE)1. 8 12091 13 6022 28.6% 0.31 [0.13, 0.74]RE-LY2. 5 7081 3 7090 18.5% 1.67 [0.40, 6.98]ROCKET AF3. 7 9120 6 9081 24.3% 1.16 [0.39, 3.46]ARISTOTLE4. ENGAGE AF-TIMI 48 8 14069 13 7036 28.6% 0.31 [0.13, 0.74]

Total events 28 35Heterogeneity: Tau2 = 0.41; Chi2 = 7.39, df = 3 (P = 0.06); I2 = 59%Test for overall effect: Z = 1.31 (P = 0.19)

Subtotal (95% CI) 42361 29229 100.0% 0.58 [0.26, 1.31]

EXTRACRANIAL BLEEDINGS1. 14 12091 4 6022 17.6% 1.74 [0.57, 5.29]RE-LY2. 7 7081 15 7090 25.4% 0.47 [0.19, 1.15]ROCKET AF3. 8 9120 11 9081 24.7% 0.72 [0.29, 1.80]ARISTOTLE4. ENGAGE AF-TIMI 48 14 14069 12 7036 32.4% 0.58 [0.27, 1.26]

Total events 43 42Heterogeneity: Tau2 = 0.04; Chi2 = 3.60, df = 3 (P = 0.31); I2 = 17%Test for overall effect: Z = 1.38 (P = 0.17)

Subtotal (95% CI) 42361 29229 100.0% 0.71 [0.43, 1.16]

OTHER (INCLUDING PE, CABG, NON-CORONARY ATHEROSCLEROTIC DISEASE, OTHER)1. 99 12091 55 6022 36.9% 0.90 [0.65, 1.24]RE-LY2. 30 7081 37 7090 17.2% 0.81 [0.50, 1.31]ROCKET AF3. 23 9120 22 9081 11.7% 1.04 [0.58, 1.87]ARISTOTLE4. ENGAGE AF-TIMI 48 92 14069 51 7036 34.2% 0.90 [0.64, 1.27]

Total events 244 165Heterogeneity: Tau2 = 0.00; Chi2 = 0.42, df = 3 (P = 0.94); I2 = 0%Test for overall effect: Z = 1.05 (P = 0.29)

Subtotal (95% CI) 42361 29229 100.0% 0.90 [0.74, 1.10]

DOAC WARFARINEvents Total Events Total Weight

Risk RatioM-H, Random, 95% CI

Risk RatioM-H, Random, 95% CI

0.05 0.2 1 5 20

CABG ¼ coronary artery bypass graft; non-CNS ¼ non-central nervous system; PE ¼ pulmonary embolism; other abbreviations as in Figure 2.

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FIGURE 4 Bleeding and Non-Bleeding Vascular Deaths

Study or Subgroup

BLEEDING VASCULAR DEATHS1. 38 12091 36 6022 22.2% 0.53 [0.33, 0.83]2. 34 7081 58 7090 25.8% 0.59 [0.38, 0.90]3. 17 9120 43 9081 14.6% 0.39 [0.22, 0.69]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 59 14069 65 7036 37.3% 0.45 [0.32, 0.64]

Total events 148 202Heterogeneity: Tau2 = 0.00; Chi2 = 1.56, df = 3 (P = 0.67); I2 = 0%Test for overall effect: Z = 6.50 (P < 0.00001)

Test for subgroup differences: Chi2 = 32.79, df = 1 (P < 0.00001); I2 = 97.0%

Subtotal (95% CI) 42361 29229 100.0% 0.49 [0.40, 0.61]

NON-BLEEDING VASCULAR DEATHS1. 504 12091 264 6022 20.0% 0.95 [0.82, 1.10]2. 341 7081 343 7090 19.9% 1.00 [0.86, 1.15]3. 306 9120 318 9081 17.9%

42.2%0.96 [0.82, 1.12]

4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 998 14069 546 7036 0.91 [0.83, 1.01]

0.5Favors DOAC Favors WARFARIN

Total events 2149 1471Heterogeneity: Tau2 = 0.00; Chi2 = 0.95, df = 3 (P = 0.81); I2 = 0%Test for overall effect: Z = 1.70 (P = 0.09)

Subtotal (95% CI) 42361 29229 100.0% 0.95 [0.89, 1.01]

DOAC WARFARINEvents Total Events Total Weight

Risk RatioM-H, Random, 95% CI

Risk RatioM-H, Random, 95% CI

0.7 1 1.5 2

Bleeding vascular deaths: includes deaths due to hemorrhagic stroke, other intracranial bleedings and extracranial bleedings. Non-bleeding vascular deaths: includes

all deaths not primarily attributed to bleeding (i.e., sudden deaths and deaths due to dysrhythmia, heart failure, myocardial infarction, ischemic stroke, systemic

embolism [other than embolic stroke], CABG, non-coronary atherosclerotic disease, pulmonary embolism, and other nonspecified cardiovascular causes).

Abbreviations as in Figure 3.

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multivariate analyses of risk factors of death in theRE-LY (9) and ROCKET AF (15) trials, which showedthat history of heart failure, previous myocardialinfarction, low creatinine clearance, and diabetesmellitus were among the strongest independent pre-dictors of cardiac death in this population, whereasthe presence of nonfatal major bleeding duringfollow-up and the history of stroke, heart failure, andolder age were strong predictors of stroke-relateddeath. In addition, statin use and optimal treatmentof heart failure and coronary artery disease wereindependently associated with a lower mortality (9).Therefore, from a global health care perspective,further measures to reduce mortality in this popula-tion, beyond an appropriate anticoagulation notincurring in excessive increase in major bleeding,have to include an improvement in the managementof relevant comorbidities, mainly heart failure, coro-nary artery disease, and diabetes, together withproven global CV risk-reduction measures andhealthy lifestyle changes (26,27).

We also found that, in comparison with warfarin,the DOAC reduced all-cause mortality and CV mor-tality, which was mainly driven by a halved risk offatal bleeding (Central Illustration). Of all fatal

bleedings, the main component accounting for thedifferences was fatal intracerebral bleeding (hemor-rhagic stroke). This trend for causes of death (halvedrisk of fatal bleeding and similar risk of fatal ischemicstroke/SE) is consistent with previous meta-analyses(4,28), in which the DOACs were associated to alower bleeding tendency, including a lower risk ofintracranial bleeding, but they were not more effec-tive than warfarin in reducing the risk of ischemicstroke/SE. The DOACs also appeared to reduce deathsdue to unknown/undetermined causes to a significantextent, but the results are difficult to interpret due tolack of data. It might suggest that these unknowncauses could be directly or indirectly related tobleeding, either due to a higher rate of sudden fatalbleedings with warfarin or due to a higher withdrawalrate due to bleeding in the warfarin group andsubsequent fatal thromboembolism. However, infor-mation bias cannot be ruled out (e.g., sufficientfollow-up information for adjudication of deathspotentially obtained more frequently when patientshad been treated with the investigational drug thanwith warfarin). Finally, the DOACs were associatedwith a trend toward a lower risk of death due totrauma or accident than warfarin. Because

FIGURE 5 Subtypes of Nonvascular Deaths

Study or Subgroup

MALIGNANCIES1. 131 12091 60 6022 25.7% 1.09 [0.80, 1.47]2. 63 7081 55 7090 18.3% 1.15 [0.80, 1.64]3. 60 9120 66 9081 19.6% 0.91 [0.64, 1.28]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 187 14069 84 7036 36.3% 1.11 [0.86, 1.44]

Total events 441 265Heterogeneity: Tau2 = 0.00; Chi2 = 1.13, df = 3 (P = 0.77); I2 = 0%Test for overall effect: Z = 0.84 (P = 0.40)

Subtotal (95% CI) 42361 29229 100.0% 1.07 [0.92, 1.25]

INFECTIONS1. 42 12091 19 6022 11.1% 1.10 [0.64, 1.89]2. 45 7081 52 7090 19.9% 0.87 [0.58, 1.29]3. 67 9120 52 9081 23.9% 1.28 [0.89, 1.84]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 164 14069 92 7036 45.2% 0.89 [0.69, 1.15]

Total events 318 215Heterogeneity: Tau2 = 0.00; Chi2 = 3.21, df = 3 (P = 0.36); I2 = 7%Test for overall effect: Z = 0.11 (P = 0.91)

Subtotal (95% CI) 42361 29229 100.0% 0.99 [0.82, 1.19]

RESPIRATORY1. 51 12091 28 6022 43.9% 0.91 [0.57, 1.44]2. 19 7081 25 7090 26.2% 0.76 [0.42, 1.38]3. 19 9120 35 9081 29.9% 0.54 [0.31, 0.94]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 0 14069 0 7036 Not estimable

Total events 89 88Heterogeneity: Tau2 = 0.00; Chi2 = 1.98, df = 2 (P = 0.37); I2 = 0%Test for overall effect: Z = 1.92 (P = 0.06)

Subtotal (95% CI) 28292 22193 100.0% 0.74 [0.55, 1.01]

TRAUMA/ACCIDENTAL1. 7 12091 5 6022 17.4% 0.70 [0.22, 2.20]2. 5 7081 10 7090 19.8% 0.50 [0.17, 1.46]3. 7 9120 13 9081 27.1%

35.7%0.54 [0.21, 1.34]

4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 15 14069 10 7036 0.75 [0.34, 1.67]

Total events 34 38Heterogeneity: Tau2 = 0.00; Chi2 = 0.51, df = 3 (P = 0.92); I2 = 0%Test for overall effect: Z = 1.93 (P = 0.05)

Subtotal (95% CI) 42361 29229 100.0% 0.62 [0.39, 1.01]

HEPATOBILIARY/LIVER FAILURE1. 5 12091 5 6022 57.2% 0.50 [0.14, 1.72]2. 1 7081 0 7090 8.6% 3.00 [0.12, 73.72]3. 0 9120 0 9081

34.3%Not estimable

4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 3 14069 3 7036 0.50 [0.10, 2.48]

Total events 9 8Heterogeneity: Tau2 = 0.00; Chi2 = 1.12, df = 2 (P = 0.57); I2 = 0%Test for overall effect: Z = 1.13 (P = 0.26)

Subtotal (95% CI) 42361 29229 100.0% 0.58 [0.23, 1.48]

ALL OTHER NON-VASCULAR DEATH1. 85 12091 53 6022 40.9% 0.80 [0.57, 1.12]2. 15 7081 15 7090 9.3%

16.5%1.00 [0.49, 2.05]

3. 28 9120 25 908133.3%

1.12 [0.65, 1.91]4.

RE-LYROCKET AFARISTOTLEENGAGE AF-TIMI 48 84 14069 39 7036 1.08 [0.74, 1.57]

0.02 0.1 1 10 50

Total events 212 132Heterogeneity: Tau2 = 0.00; Chi2 = 1.77, df = 3 (P = 0.62); I2 = 0%Test for overall effect: Z = 0.44 (P = 0.66)

Subtotal (95% CI) 42361 29229 100.0% 0.95 [0.77, 1.18]

DOAC WARFARINEvents Total Events Total Weight

Risk RatioM-H, Random, 95% CI

Risk RatioM-H, Random, 95% CI

Favors DOAC Favors WARFARIN

Abbreviations as in Figure 3.

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TABLE 4 Absolute Difference in Events per 10,000 Patients Treated per Year for the Different Cause-Specific Deaths*

Cause of Death

Risk Difference (95% CI)

Heterogeneity p Value; I2DAB vs. WRF RIV vs. WRF API vs. WRF EDO vs. WRF All DOACS vs. WRF

All-cause death �24 (�73 to 25) �37 (�98 to 24) �43 (�85 to �1) �57 (�100 to �14) �42 (�66 to �18) 0.81; 0%

Vascular death �16 (�55 to 22) �18 (�67 to 30) �25 (�56 to 6) �55 (�91 to �19) �30 (�48 to �11) 0.46; 0%

Cardiac death 5 (�26 to 36) 16 (�25 to 57) �7 (�33 to 19) �30 (�61 to 1) �6 (�24 to 12) 0.29; 20%

Sudden death/dysrhythmia 2 (�21 to 25) 0 (�34 to 33) 1 (�19 to 21) �19 (�44 to 6) �3 (�15 to 9) 0.61; 0%

Heart failure 0 (�19 to 19) 18 (�4 to 40) �10 (�25 to 5) �13 (�30 to 4) �3 (�15 to 10) 0.13; 46%

Myocardial infarction 3 (�6 to 11) �2 (�12 to 9) 2 (�5 to 10) 2 (�5 to 9) 2 (�2 to 6) 0.93; 0%

Ischemic stroke/SE �3 (�13 to 8) �8 (�22 to 6) �3 (�13 to 8) 1 (�10 to 12) �3 (�8 to 3) 0.81; 0%

Hemorrhage (all) �15 (�26 to �4) �21 (�38 to �4) �16 (�25 to �7) �23 (�33 to �13) �18 (�24 to �12) 0.74; 0%

Hemorrhagic stroke �10 (�18 to �2) �16 (�29 to �2) �14 (�21 to �8) �14 (�22 to �6) �13 (�18 to �9) 0.84; 0%

Other intracranial hemorrhage �8 (�14 to �2) 2 (�3 to 7) 1 (�4 to 5) �6 (�10 to �2) �2 (�7 to 2) 0.03; 67%

Extracranial hemorrhage 3 (�3 to 9) �7 (�15 to 1) �2 (�7 to 3) �3 (�8 to 1) �2 (�5 to 2) 0.15; 44%

Other vascular death† �3 (�20 to 13) �6 (�20 to 8) 0 (�7 to 8) �3 (�14 to 7) �2 (�7 to 4) 0.87; 0%

Nonvascular death �2 (�32 to 27) �6 (�37 to 24) �7 (�30 to 16) �2 (�25 to 21) �4 (�17 to 8) 0.99; 0%

Malignancies 8 (�10 to 26) 8 (�11 to 27) �4 (�17 to 9) 6 (�9 to 20) 3 (�5 to 11) 0.63; 0%

Infections 3 (�8 to 13) �6 (�23 to 12) 9 (�4 to 21) �7 (�21 to 7) 1 (�6 to 8) 0.37; 5%

Respiratory �1 (�13 to 10) �5 (�17 to 7) �10 (�18 to �1) ‡ �6 (�12 to 0) 0.51; 0%

Trauma/accidental �1 (�6 to 3) �4 (�11 to 2) �4 (�9 to 2) �2 (�6 to 3) �2 (�5 to 0) 0.83; 0%

Hepatobiliary/liver failure �2 (�6 to 2) 1 (�1 to 3) 0 (�1 to 1) �1 (�3 to 1) 0 (�2 to 2) 0.29; 0%

All other �8 (�24 to 7) 0 (�9 to 10) 2 (�7 to 10) 2 (�8 to 12) 0 (�5 to 5) 0.74; 0%

Undetermined death �6 (�14 to 3) �13 (�33 to 8) �11 (�29 to 6) § �8 (�15 to 0) 0.73; 0%

*Incidence-rate difference meta-analysis, random effects, StatsDirect Software. †Includes deaths due to coronary artery bypass grafting, non-coronary atherosclerotic disease, pulmonary embolism, andother unspecified vascular deaths. ‡Nonvascular deaths were not broken down into respiratory cause; they were included in all other nonvascular death. §No deaths were unable to be classified. Those thatwere unexpected and without other cause were categorized as cardiac death.

API ¼ apixaban; CI ¼ confidence interval; DAB ¼ dabigatran; DOAC ¼ direct-acting oral anticoagulant; EDO ¼ edoxaban; SE ¼ systemic embolism (other than embolic stroke); RIV ¼ rivaroxaban;WRF ¼ warfarin.

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uncontrolled post-traumatic bleeding is the leadingcause of potentially preventable death among traumapatients (29), our findings might reflect a lower risk oftrauma-associated severe bleeding in patients anti-coagulated with the DOAC than in those anti-coagulated with VKA, which may be particularlyrelevant in patients at risk of falling (30).

We also explored potential differences in rates andcauses of death depending on the DOAC dose tested.Similar to the HD regimens, the LD regimes signifi-cantly reduced all-cause death and CV death in com-parison with warfarin, mainly at the expense of areduced risk of fatal bleedings, including hemorrhagicstroke. However, compared with warfarin, the HDDOAC regimens tended to decrease the risk of fatalischemic stroke, whereas LD DOAC regimens tendedto increase the risk of fatal ischemic stroke/SE.Balancing the effects on death due to ischemic andhemorrhagic stroke, it seems reasonable to give pref-erence to the use of the HD DOAC regimens unlessthere are clinical factors for increased plasma con-centrations of the novel anticoagulant that wouldwarrant dose reduction, in accordance with approvedlabel information (package inserts).

Our review has several strengths that include thelarge sample size and analysis of studies in which

deaths were adjudicated using specific definitions by ablinded committee of expert physicians. To ourknowledge, this is the first systematic review that ex-plores the specific causes of death in the pivotal trialsconducted with the DOACs for the prevention ofstroke/SE in patients with AF. A previous relevantmeta-analysis reviewed a pool of trials that comparedthe DOAC versus warfarin in different indications (31).The authors found a reduced risk of fatal bleeding, CVmortality, and all-cause mortality with the DOACscompared with warfarin, but did not analyze specificcauses of CV mortality (beyond aggregated fatalbleedings) or non-CV mortality, and did not provide acalculation of absolute risks. We have shown that theeffect in the reduction of different types of mortality(total, CV) reflects a reduction in fatal (mainly intra-cerebral) bleedings. We have to bear in mind that thisbenefit may be highly dependent on the quality ofanticoagulation that could be achieved with warfarin,as measured by the time within therapeutic range(TTR) (32,33). The quality of anticoagulation withVKA during pivotal studies with the DOAC greatlydiffered across trials and regions, with the highest TTRreported in Western Europe, and the lowest TTR incenters from Asia and Latin America (34,35). There-fore, the expected absolute benefit in fatal bleedings

CENTRAL ILLUSTRATION Causes of Death in AF

Gómez-Outes, A. et al. J Am Coll Cardiol. 2016;68(23):2508–21.

Causes of death in 6,206 of 71,683 total patients who died during z1.87 years follow-up (z134,046 patient-years) treated with DOACs or warfarin in 4 contemporary

anticoagulation trials in AF. AF ¼ atrial fibrillation; CI ¼ confidence interval; DOACs ¼ direct oral anticoagulants; M-H ¼ Mantel–Haenszel; SE ¼ systemic embolism.

J A C C V O L . 6 8 , N O . 2 3 , 2 0 1 6 Gómez-Outes et al.D E C E M B E R 1 3 , 2 0 1 6 : 2 5 0 8 – 2 1 DOAC Meta-Analysis of Causes of Death

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and all-cause mortality versus warfarin may differacross centers and regions (36).

STUDY LIMITATIONS. First, there was heterogeneityacross trials in absolute death rates, which are likelydue to differences in baseline characteristics. Both theROCKET AF and ENGAGE AF trials included patients athigh to very high risk of stroke (CHADS2 score $2), andtherefore included a higher number of patients with ahistory of heart failure, advanced age, hypertension,diabetes, and prior stroke/SE than those patientsenrolled in the RE-LY and ARISTOTLE trials, whichrecruited a broader population with a lower thrombo-embolic risk (approximately corresponding to aCHADS2 score $1). However, because baseline charac-teristics were balanced between treatment groups, theRR of death was homogeneous across trials.

Second, there were methodological differencesacross trials in the determination of cause-specificmortality by the adjudicating committees (e.g.,particularly in the subclassification of cardiac deaths ordeaths due to stroke or hemorrhage). These differ-ences may have led to under- or overestimation ofspecific causes of death. Anyway, as the subclassifi-cation of deaths made by the adjudicating committeesof the studies was blinded, any potential differencesare likely to be randomly distributed between treat-ment groups. In addition, there were some differences

in the quality of follow-up for vital status acrossstudies, thus potentially leading to underestimation ofthe numbers of deaths to some extent. However, therate of patients lost to follow-up for vital status at endof studywas atmost 2% (the ARISTOTLE trial), withoutsignificant imbalances between treatment groups,thus making detection bias unlikely.

Third, our meta-analysis is based on data fromselected populations from clinical trials, and there-fore, the extrapolation to general practice should bedone cautiously. The populations included incontemporary AF trials with the DOAC included ahigh proportion of VKA-experienced patients withdemonstrated tolerance to warfarin (37), whereaspatients with anticipated poor adherence to treat-ment or conditions associated with a high risk ofbleeding and mortality were excluded, such as thosewith severe renal impairment (38). In fact, <50% ofAF patients in real-life cohorts would have met thestrict inclusion/exclusion criteria applied in thesestudies (39). The main gap seems to be an under-representation of women and elderly patients incontemporary AF trials compared with those fromregistries (40). Some reports have shown that despitethese baseline differences, mortality rates in real-lifecohorts of patients with AF are consistent with thosereported in clinical trials (41,42), but caution in theinterpretation of the data is still necessary.

PERSPECTIVES

COMPETENCY IN PATIENT CARE AND

PROCEDURAL SKILLS: In contemporary trials of

anticoagulation, most deaths among patients with

nonvalvular AF were related to underlying cardiovas-

cular disease, whereas stroke and bleeding accounted

for a relatively small proportion of deaths.

TRANSLATIONAL OUTLOOK: Further studies are

necessary to investigate new interventions, beyond

anticoagulation, to reduce mortality in patients

with AF.

Gómez-Outes et al. J A C C V O L . 6 8 , N O . 2 3 , 2 0 1 6

DOAC Meta-Analysis of Causes of Death D E C E M B E R 1 3 , 2 0 1 6 : 2 5 0 8 – 2 1

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CONCLUSIONS

Almost one-half of deaths in contemporary AF anti-coagulation trials are cardiac deaths (sudden cardiacdeath, heart failure, and myocardial infarction),whereas stroke and bleeding only account forapproximately 6% of all deaths each as the principalcause. The introduction of the DOAC may confer somebenefit in the reduction of fatal bleedings comparedwith VKA, but there is still a need to improve currentmanagement of comorbidities and associated riskfactors in order to reduce mortality rates in AFbeyond anticoagulation.

ACKNOWLEDGMENTS The authors thank Prof. Dr.Martina Brückmann (Boehringer Ingelheim PharmaGmbH & Co. KG) and Prof. Dr. Robert P. Giugliano(Division of Cardiovascular Medicine, Brigham andWomen’s Hospital, Boston, Massachusetts) foranswering the authors’ request for supplementaryinformation related to the RE-LY and ENGAGE AFstudies, respectively.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Antonio Gómez-Outes, Division of Pharmacology andClinical Drug Evaluation, Agencia Española de Medi-camentos y Productos Sanitarios (AEMPS), Campezo1, 28022 Madrid, Spain. E-mail: agomezo@aemps.es.

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KEY WORDS apixaban, atrial fibrillation,dabigatran, rivaroxaban, stroke, warfarin

APPENDIX For an expanded Methods sectionas well as supplemental tables and figures,please see the online version of this paper.