Table Of ContentJournalofThrombosisandHaemostasis,13:2012–2020 DOI:10.1111/jth.13139
ORIGINAL ARTICLE
Mortality outcomes in patients receiving direct oral
anticoagulants: a systematic review and meta-analysis of
randomized controlled trials
C. CHAI-ADISAKSOPHA,*†‡ C. HILLIS,†§ T. ISAYAMA,‡¶ W. LIM,† A. IORIO†‡ and
M. CROWTHER†‡**
*DepartmentofMedicine,ChiangMaiUniversity,ChiangMai,Thailand;†DepartmentofMedicine,McMasterUniversity;‡Departmentof
ClinicalEpidemiology,Biostatistics,McMasterUniversity;§DepartmentofOncology,McMasterUniversity,Hamilton;¶SunnybrookHealth
SciencesCenter,UniversityofToronto,Toronto;and**DepartmentofPathologyandMolecularMedicine,McMasterUniversity,Hamilton,
ON,Canada
Tocitethisarticle:Chai-AdisaksophaC,HillisC,IsayamaT,LimW,IorioA,CrowtherM.Mortalityoutcomesinpatientsreceivingdirectoral
anticoagulants:asystematicreviewandmeta-analysisofrandomizedcontrolledtrials.JThrombHaemost2015;13:2012–20.
all-cause mortality (RR, 0.91; 95% CI, 0.87–0.96; I2 =
Summary.Background:Directoralanticoagulants(DOACs) 0%). Conclusions:The use of DOACs compared with
are widely used as an alternative for warfarin. However, warfarin is associated with a lower rate of fatal bleeding,
the impact of DOACs on mortality outcomes compared case-fatality rate of major bleeding, cardiovascular mor-
with warfarin remains unclear. Objective:To estimate the tality and all-cause mortality.
mortality outcomes in patients treated with DOACs vs.
warfarin (or another vitamin K antagonist). Methods: Keywords: anticoagulants; hemorrhage; mortality;
MEDLINE, EMBASE and CENTRAL databases (incep- thromboembolism; warfarin.
tion to September 2014), conference abstracts and www.-
clinicaltrials.gov, were searched, without language
restriction. Studies were selected if there were phase III, Background
randomized trials comparing DOACs with warfarin in
Direct oral anticoagulants (DOACs) are used increasingly
patients with non-valvular atrial fibrillation or venous
as an alternative to warfarin for the treatment of venous
thromboembolism. Results:Thirteen randomized con-
thromboembolism and prevention of stroke or systemic
trolled trials involving 102 707 adult patients were
embolism in patients with non-valvular atrial fibrillation.
included in the analysis. The case-fatality rate of major
The advantages of DOACs over warfarin are a faster
bleeding was 7.57% (95% CI, 6.53–8.68; I2 = 0%) in
onset of action, fewer drug interactions, shorter half-life,
patients taking DOACs and 11.04% (95% CI, 9.16–
13.07; I2 = 33.3%) in patients taking warfarin. The rate wide therapeutic range and lack of need for routine labo-
ratory monitoring [1].
of fatal bleeding in adult patients receiving DOACs was
0.16 per 100 patient-years (95% CI, 0.12–0.20; I2 = The efficacy and safety of DOACs have been evaluated
in numerous randomized controlled trials (RCTs). In
36.5%). When compared with warfarin, DOACs were
patients with venous thromboembolism, DOACs are com-
associated with significant reductions in fatal bleeding
parable to warfarin in terms of recurrent venous throm-
(RR, 0.53; 95% CI, 0.43–0.64; I2 = 0%), cardiovascular
boembolism (risk ratio [RR], 0.88; 95% confidence
mortality (RR, 0.88; 95% CI, 0.82–0.94; I2 = 0%) and
interval [CI], 0.74–1.05), fatal pulmonary embolism (RR,
1.02; 95% CI, 0.74–1.05) and all-cause mortality (RR,
Correspondence: Mark Crowther, Rm L-208 – 50 Charlton Ave 0.97; 95% CI, 0.83–1.14) [2]. In patients with non-valvu-
East,StJoseph’sHospital,Hamilton,ON,CanadaL8N4A6. lar atrial fibrillation, a meta-analysis demonstrated that
Tel.:+19055219140ext76332;fax:+19055215099. DOACs were associated with lower rates of stroke or sys-
E-mail:[email protected] temic embolism compared with warfarin (RR, 0.81; 95%
CI, 0.73–0.91) [3]. In addition, DOACs show a significant
This systematic reviewwas registeredwithPROSPERO(registration
reduction in major bleeding, fatal bleeding and intracra-
numberCRD42014013806).
nial bleeding and do not increase the risk of gastrointesti-
nal (GI) bleeding [4].
Received29May2015
Fatal bleeding is the most concerning complication for
Manuscripthandledby:F.R.Rosendaal
Finaldecision:F.R.Rosendaal,30August2015 all oral anticoagulants. In patients who receive warfarin
©2015InternationalSocietyonThrombosisandHaemostasis
MortalityoutcomesinpatientsreceivingDOACs 2013
(for at least 3 months; target international normalized valves because DOACs were not approved for this indi-
ratio [INR], 2–3) for the treatment of venous thromboem- cation outside of clinical trials.
bolism, the case-fatality rate of major bleeding was The primary outcome of this review was the case-fa-
13.4% for the entire period of anticoagulant therapy [5]. tality rate of major bleeding (as defined by the Interna-
Intracranial bleeding accounted for 30–85% of the fatal tional Society on Thrombosis and Haemostasis [8] or as
bleeding events [5–7]. defined by the studies) and the incidence rate of fatal
Although previous systematic reviews and meta-analy- bleeding. The secondary outcomes were all-cause
ses on the efficacy and safety profiles of DOACs have mortality and mortality from cardiovascular diseases,
been published, there are no studies specifically evaluat- which included death from stroke, systemic embolism,
ing the case-fatality rate of major bleeding and mortal- myocardial infarction (MI), deep vein thrombosis and
ity outcomes when comparing DOACs and warfarin. pulmonary embolism. This systematic review was
Moreover, as fatal events during anticoagulant treatment registered with PROSPERO (registration number
are infrequent (3–4% per year), a single study analysis CRD42014013806).
may be unable to provide the precise estimates of bleed-
ing risk and consequences of oral anticoagulant therapy.
Datasources
Concern about the case-fatality rate has been raised due
to lack of an antidote for DOACs compared with war- We searched MEDLINE, EMBASE and the Central
farin (which has two antidotes, vitamin K and pro- Register of Controlled Trials databases from inception to
thrombin complex concentrate). Therefore, we August 2015 without language restrictions. Conference
conducted a meta-analysis that aimed to assess the fatal abstracts from hematology and cardiology meetings
outcomes of patients receiving DOACs as long-term between January 2006 and August 2015 were searched.
treatment for venous thromboembolism and prevention We also searched for relevant ongoing or recently com-
of secondary stroke or systemic embolism due to atrial pleted studies up to August 2015 using www.clinicaltri-
fibrillation. The objectives of this study were to estimate als.gov. Reference lists of the included studies were
rate of fatal bleeding and case-fatality rate of major manually searched for other potentially relevant articles.
bleeding, and to compare the mortality outcomes The search used key terms including venous thrombosis,
between patients treated with DOACs and those treated thromboembolism, thrombosis, deep vein thrombosis,
with warfarin. pulmonary embolism, atrial fibrillation, atrial flutter,
rivaroxaban, dabigatran, apixaban, edoxaban, betrixaban
and darexaban.
Methods
Studyselection Studyselection anddataextraction
We performed a systematic literature search according to Two investigators (CC and TI) independently identified
the following criteria: (i) phase III RCTs of patients at studies for potential inclusion based on the defined inclu-
least 18 years old who received a DOAC (dabigatran, sion and exclusion criteria. Disagreements were resolved
rivaroxaban, apixaban, edoxaban, darexaban or betrix- by consensus or through a third reviewer (WL). Two
aban) for the treatment of venous thromboembolism or investigators (CC and CH) independently extracted data
preventionofstroke/systemicembolismduetonon-valvular using a standardized data extraction spreadsheet, with
atrial fibrillation compared with warfarin or other vita- discrepancies resolved by consensus or through a third
min K antagonists administered to a target INR between reviewer (WL).
2.0 and 3.0 (or heparin/low-molecular-weight heparin Extracted data included year of publication, study
transitioned to warfarin), (ii) the study reported fatal design, therapeutic indication (venous thromboembolism
bleeding, major bleeding, mortality related to cardiovas- or atrial fibrillation), type of DOAC, length of follow-up,
cular disease and all-cause mortality, and (iii) patients number of participants, major bleeding, death from any
received treatment for at least 3 months. Aspirin or clopi- causes and death from cardiovascular disease. A kappa
dogrel co-administration was allowed. Studies were score was calculated to assess concordance between the
excluded if the indication for anticoagulation was two investigators for study selection and data abstraction.
mechanical heart valves, acute coronary syndrome, pri- For studies reported in more than one publication, we
mary prophylaxis for venous thromboembolism in ortho- extracted data from the most complete publication, inte-
pedic or surgical patients, or treatment of left-atrial grating the information with data from the other publica-
appendage thrombus. We excluded ximelagatran as this tions when needed. All publications were referenced. We
drug was withdrawn from the market. Studies that did followed The Preferred Reporting Items for Systematic
not use warfarin as the comparator (e.g. aspirin or pla- Reviews and Meta-analyses statement for reporting of
cebo) were excluded. We excluded the study investigating systematic reviews and meta-analysis of randomized clini-
DOACs vs. warfarin in patients with prosthetic heart cal trials [9].
©2015InternationalSocietyonThrombosisandHaemostasis
2014 C.Chai-Adisaksophaetal
cases. Moreover, we prespecified a random-effects model
Quality assessment
for the primary analysis and we therefore used a fixed-
The methodological quality of the included studies was effects model for the sensitivity analysis comparing all
evaluated independently by two investigators (CC and TI) outcomes.
using the Cochrane Collaboration’s Risk of Bias tool,
scoring each study for: random sequence generation, allo-
Results
cation concealment, method of blinding, completeness of
data, selective outcome reporting and other risks of bias.
Studycharacteristics
Each parameter was judged as a high, low or unclear risk
of bias [10]. Disagreements were resolved by consensus or The literature search yielded 8989 studies. We added 204
through a third reviewer (WL). Studies were categorized articles from the updated search. After removal of dupli-
as high quality if all parameters were judged to be at low cates, we screened 6411 studies for eligibility and identi-
risk of bias. fied 78 potential articles for full-text review (Fig. 1).
Thirteen phase III RCTs were included in qualitative and
quantitative synthesis. The trials investigated dabigatran
Statisticalanalysis
(n = 4 [15–18]), rivaroxaban (n = 5 [19–23]), apixaban
The case-fatality rate of major bleeding was calculated (n = 2 [24,25]) and edoxaban (n = 2 [26,27]). Across the
using the number of fatal bleeding events divided by the 13 trials, 58 021 patients were randomly assigned to
number of major bleeds and expressed as a percentage. receive DOAC and 44 822 to receive warfarin (or hep-
The incidence rate of fatal bleeding was expressed as arin/low-molecular-weight heparin, followed by warfarin).
event rates per 100 patient-years of anticoagulant therapy. The duration of follow-up ranged from 6 to 30 months
Pooled estimates of proportion with corresponding 95% (Table 1). A kappa agreement of 0.96 was obtained for
CI of the case-fatality rate of major bleeding and rate of study selection, which indicated excellent agreement
fatal bleeding were calculated using the single-proportion between two investigators.
random-effects model [11,12]. This analysis was calculated
using MedCalc for Windows, version 12.5 (Medcalc Soft-
Studyquality
ware, Ostend, Belgium).
To compare the differences between DOACs and war- Of these 13 trials, eight were classified as high quality
farin in the case-fatality of major bleeding, death from based on rigorous randomization, allocation conceal-
cardiovascular cause and all-cause mortality, we measured ment, blinding and outcome reporting without potential
pooled risk ratios (RRs) with corresponding 95% CI bias. There were four studies at high risk of bias due to
using the Mantel-Haenszel random-effects model. A their open-label design (EINSTEIN-DVT [19], EIN-
P-value less than 0.05 was considered statistically signifi- STEIN-PE [20], J-EINSTEIN-DVT/PE [23] and RE-LY
cant for all tests. The heterogeneity between the studies [15]). One study [22] did not report the method used to
was evaluated using the I2 statistic, which measures the generate the randomization sequence and allocation con-
extent of inconsistency among the trials rather than sam- cealment, and the risk of bias was judged as unclear.
pling error. Heterogeneity was classified based on a scale The ARISTOTLE trial [24] was judged to have another
of I2: contributory (I2 = 0–40%), moderate (I2 = 30– risk of bias because research misconduct was reported at
60%), substantial (I2 = 50–90%) and considerable one site [28]. The summary of the risk of bias assess-
(I2 > 75%) [13]. We also generated funnel plots of effect ment is provided in Figure S1. Visual inspection of the
size vs. standard error of effect estimates in order to funnel plots indicated a low risk of publication bias for
assess for potential publication bias. Publication bias was all analyses.
considered if the funnel plots were asymmetrical [14]. We
performed the analyses based on an intention-to-treat
Case-fatalityrate ofmajorbleeding and rateof fatal
basis. These analyses were performed using Review Man-
bleeding
ager (RevMan, version 5.2, Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2012). There were 12 studies that reported death from major
We performed two prespecified a priori subgroup analy- bleeding. The case-fatality rate of major bleeding was
ses according to DOAC type (dabigatran, rivaroxaban, 7.57%(95%CI,6.53–8.68;I2 = 0)forDOACs(FigureS2)
apixaban and edoxaban) and indication (venous throm- and 11.05% (95% CI, 9.17–13.07; I2 = 33.3%) for war-
boembolism and atrial fibrillation). We also carried out a farin (Figure S3). During anticoagulant therapy, the rate
sensitivity analysis in order to examine the robustness of of fatal bleeding was 0.16 per 100 patient-years (95% CI,
the results. We excluded studies not achieving high qual- 0.12–0.20; I2 = 36.5%) in patients receiving DOACs (Fig-
ity based on the aforementioned criteria. Another sensi- ureS4)and0.32per100patient-years(95%CI,0.27–0.37;
tivity analysis was based on worst case scenario, when we I2 = 15.0%) in patients receiving warfarin (Figure S5).
counted the patients who were lost to follow-up as dead DOACs were associated with a significant reduction in
©2015InternationalSocietyonThrombosisandHaemostasis
MortalityoutcomesinpatientsreceivingDOACs 2015
8961 Records identified through
28 Records identified through
the databases: MEDLINE, EMBASE
meeting abstract
and CENTRAL
8989 Potential studies identified
204 articles from the
2782 Excluded (duplicates)
updated search
6411 Records screened
6333 Excluded
(cid:129) 125 Duplicates
(cid:129) 6208 Inclusion criteria not met
78 Full-text articles assessed for
eligibility
65 Excluded
(cid:129) 50 Duplicates or multiple publications
(cid:129) 13 Not a phase III RCT
(cid:129) 1 Did not include warfarin as a comparator
13 Randomized controlled trials (cid:129) 1 Unpublished and data not available
included in qualitative synthesis
and quantitative synthesis (meta-
analysis)
Fig.1. Studyflowdiagram.
Table1 Characteristicsofthetrialsincludedinthemeta-analysis
Numberof Lossto
patients follow-up
Durationoffol-
Reference DOAC Indication DOAC Control low-up(months) DOAC Control
RE-COVER[16] UFHorLMWHfor5days,followedby DVTofPE 1274 1265 6.0 9 6
dabigatran150mgbid
RE-LY[15] Dabigatran100mgbidor150mgbid AF 12091 6022 24.0 48 41
EINSTEIN- Rivaroxaban15mgbidfor3weeks, DVTwithout 1731 1718 7.2 15 18
DVT[19] followedby20mgOD symptomaticPE
ARISTOTLE Apixaban5mgbid AF 9120 9081 21.6 51 39
[25]
ROCKETAF Rivaroxaban20mgOD AF 7131 7133 23.2 18 14
[21]
EINSTEIN-PE Rivaroxaban15mgbidfor3weeks, AcutePE 2419 2413 8.7 8 10
[20] followedby20mgOD
J-ROCKETAF Rivaroxaban15mgOD AF 639 639 17.5 4 1
[22]
AMPLIFY[24] Apixaban10mgbidfor7days,followed DVTorPE 2691 2704 6.0 14 14
by5mgbid
ENGAGE-AF- Edoxaban30mgODoredoxaban60mg AF 14069 7036 33.6 1 0
TIMI-48[26] OD
RE-MEDY[17] Dabigatran150mgbid DVTorPE 1430 1426 15.8 2 6
HOKUSAI-VTE UFHorLMWHforatleast5days, DVTorPE 4143 4149 8.3 7 4
[27] followedbyedoxaban60mgOD
RECOVERII UFHorLMWHfor5days,followedby DVTorPE 1294 1295 6.0 6 3
[18] dabigatran150mgbid
J-EINSTEIN Rivaroxaban10or15mgbidfor3weeks DVTorPE 81 19 12.0 0 0
DVT/PE[23] followedby15mgOD
DOAC,directoralanticoagulant;UFH,unfractionatedheparin;LMWH,low-molecular-weightheparin;DVT,deepveinthrombosis;PE,pul-
monaryembolism;OD,oncedaily;bid,twicedaily.
©2015InternationalSocietyonThrombosisandHaemostasis
2016 C.Chai-Adisaksophaetal
fatal bleeding when compared with warfarin (RR, 0.53 tion = 0.96 for type of DOAC and P for interac-
[95%CI,0.43–0.64];P < 0.001;I2 = 0%). tion = 0.32 for indication). However, the apixaban studies
showed a significant risk reduction of all-cause mortality
in patients treated with DOACs compared with those
Cardiovascularmortality
treated with warfarin (RR, 0.89 [95% CI, 0.80–0.99];
Twelve studies reported cardiovascular mortality and all- P = 0.03; I2 = 0%), Figure S8. Only trials investigating
cause mortality. Among 57 940 patients treated with non-valvular atrial fibrillation patients showed that
DOACs, there were 1975 deaths from cardiovascular dis- DOACs were associated with significant reduction in all-
eases compared with 1318 of 44 803 patients treated with cause mortality (RR, 0.91 [95% CI, 0.86–0.96];
warfarin (RR, 0.88 [95% CI, 0.82–0.94]; P = 0.0002; P = 0.0001; I2 = 0%; Figure S9).
I2 = 0%; Fig. 2). In a subgroup analysis according to
type of DOAC, the studies investigating edoxaban
Sensitivityanalysis
showed a significant risk reduction in cardiovascular
death in patients treated with DOACs compared with In the sensitivity analyses, we included only high quality
those treated with warfarin (RR, 0.87 [95% CI, 0.80– studies in the meta-analysis. Results were similar for all
0.96]; P = 0.005; I2 = 0%), but this was not shown for outcomes. In addition, we analyzed the data using a
the other drugs (P for interaction = 0.88, Figure S6). In fixed-effects model and found similar results when com-
addition, when separated by indication for anticoagulant pared with the random-effects model for all outcomes.
therapy, DOACs showed significant reduction in cardio- The sensitivity analysis of cardiovascular mortality (RR,
vascular death in trials investigating non-valvular atrial 0.89 [95% CI, 0.83–0.95]; Figure S10) and all-cause mor-
fibrillation (RR, 0.87 [95% CI, 0.80–0.95]; P = 0.001; tality (RR, 0.92 [95% CI, 0.88–0.96]; Figure S11) based
I2 = 0%) but not in those investigating venous throm- on the worst case scenario for the loss to follow-up
boembolism (RR, 0.90 [95% CI, 0.79–1.02]; P = 0.10; patients was not different from the primary analysis.
I2 = 0%) (P for interaction = 0.70, Figure S7). When we removed the ARISTOTLE trial from the analy-
sis, cardiovascular mortality and all-cause mortality for
DOACs compared with warfarin did not change from the
All-causemortality
primary analysis (RR, 0.89 [95% CI, 0.83–0.95] and RR,
All studies provided information for this outcome. In 0.92 [95% CI, 0.87–0.97], respectively). After removing
these studies, 3921 of 58 021 patients treated with the studies with risk of bias, the results did not change
DOACs died compared with 2967 of 44 822 patients trea- (Figure S12 and S13).
ted with warfarin (Fig. 3). DOACs were associated with a
significant reduction in all-cause mortality (RR, 0.91
Discussion
[95% CI, 0.87–0.96]; P < 0.001; I2 = 0%). The subgroup
analyses based on type of DOAC and indication for anti- Our meta-analysis revealed that among patients treated
coagulation did not show a significant interaction between with DOACs for more than 3 months, the case-fatality
the intervention and all-cause mortality (P for interac- rate of major bleeding was 7.57% and the risk of fatal
DOACs Warfarin Risk Ratio Risk Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
RE-COVER II, 2014 3 1279 0 1289 0.1% 7.05 [0.36, 136.44]
RE-MEDY, 2013 1 1430 1 1426 0.1% 1.00 [0.06, 15.93]
RE-COVER, 2009 1 1274 3 1265 0.1% 0.33 [0.03, 3.18]
J-ROCKET AF, 2012 6 637 2 637 0.2% 3.00 [0.61, 14.81]
EINSTEIN-DVT, 2010 6 1731 10 1718 0.5% 0.60 [0.22, 1.63]
EINSTEIN-PE, 2012 15 2419 9 2413 0.7% 1.66 [0.73, 3.79]
AMPLIFY, 2013 15 2691 23 2704 1.1% 0.66 [0.34, 1.25]
HOKUSAI-VTE, 2013 41 4118 38 4122 2.4% 1.08 [0.70, 1.68]
ARISTOTLE, 2011 97 9120 111 9081 6.4% 0.87 [0.66, 1.14]
ROCKET AF, 2011 170 7081 193 7090 11.3% 0.88 [0.72, 1.08]
RE-LY, 2009 563 12091 317 6022 26.0% 0.88 [0.77, 1.01]
ENGAGE-AF-TIMI-48, 2013 1057 14069 611 7036 51.3% 0.87 [0.79, 0.95]
Total (95% CI) 57940 44803 100.0% 0.88 [0.82, 0.94]
Total events 1975 1318
Heterogeneity: Tau2 = 0.00; χ2 = 9.52, d.f. = 11 (P = 0.57); I2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 3.70 (P = 0.0002)
Favours [DOACs] Favours [Warfarin]
Fig.2. Cardiovascularmortalitycomparingdirectoralanticoagulantvs.warfarin.
©2015InternationalSocietyonThrombosisandHaemostasis
MortalityoutcomesinpatientsreceivingDOACs 2017
DOACs Warfarin Risk Ratio Risk Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
J-EINSTEIN DVT/PE, 2015 3 81 0 19 0.0% 1.71 [0.09, 31.74]
J-ROCKET AF, 2012 7 637 5 637 0.2% 1.40 [0.45, 4.39]
RE-MEDY, 2013 17 1430 19 1426 0.5% 0.89 [0.47, 1.71]
RE-COVER, 2009 21 1274 21 1265 0.6% 0.99 [0.55, 1.81]
RE-COVER II, 2014 25 1279 25 1289 0.7% 1.01 [0.58, 1.74]
EINSTEIN-DVT, 2010 38 1731 42 1718 1.1% 0.90 [0.58, 1.39]
AMPLIFY, 2013 41 2691 52 2704 1.3% 0.79 [0.53, 1.19]
EINSTEIN-PE, 2012 58 2419 50 2413 1.5% 1.16 [0.80, 1.68]
HOKUSAI-VTE, 2013 132 4118 126 4122 3.7% 1.05 [0.82, 1.33]
ROCKET AF, 2011 582 7081 632 7090 18.4% 0.92 [0.83, 1.03]
RE-LY, 2009 884 12091 487 6022 19.0% 0.90 [0.81, 1.01]
ARISTOTLE, 2011 603 9120 669 9081 19.0% 0.90 [0.81, 1.00]
ENGAGE-AF-TIMI-48, 2013 1510 14069 839 7036 33.9% 0.90 [0.83, 0.97]
Total (95% CI) 58021 44822 100.0% 0.91 [0.87, 0.96]
Total events 3921 2967
Heterogeneity: Tau2 = 0.00; χ2 = 4.50, d.f. = 12 (P = 0.97); I2 = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 3.83 (P = 0.0001)
Favours [DOACs] Favours [Warfarin]
Fig.3. All-causemortalitycomparingdirectoralanticoagulantvs.warfarin.
bleeding was 0.1% per 100 patient-years. Compared with Unlike warfarin, the DOACs lack reversal agents for
warfarin, DOACs were associated with a significant their anticoagulant effects. Reversal agents (prothrombin
reduction in fatal bleeding, cardiovascular mortality and complex concentrates, vitamin K and recombinant factor
all-cause mortality. To our knowledge, this is the first VIIa) have been studied in animal models [30,31], healthy
study that focused on the mortality related to anticoagu- volunteers [32] and case reports [33]. Specific antidotes for
lant treatment, comparing DOACs and warfarin for two DOACs are undergoing investigation [34,35]. The reduced
major indications (non-valvular atrial fibrillation and risk of death occurred despite the lack of available rever-
venous thromboembolism). sal agents.
A previous meta-analysis of mortality in patients with Concern over increased cardiovascular events among
venous thromboembolism who received warfarin for more patients treated with DOACs stemmed mainly from the
than 3 months demonstrated that the case-fatality rate of RE-LYstudy,whichshowedtheRRofMIwas1.38(95%
major bleeding was 13.4% [5]. We had similar findings, CI, 1.00–1.91) in patients with non-valvular atrial fibrilla-
reporting an 11.0% case-fatality rate of major bleeding tion receiving dabigatran 110 mg twice daily compared
from warfarin. When compared with warfarin, DOACs with those receiving warfarin [15]. In a meta-analysis of
were associated with a significant reduction in fatal bleed- patients receiving anticoagulants, dabigatran was associ-
ing (RR, 0.53; P < 0.001; I2 = 0%) despite a lack of an ated with a higher risk of MI or acute coronary syndrome
effective antidote. This finding is consistent across all sub- (odd ratios, 1.33; 95%CI, 1.03–1.71; P = 0.03)[36].How-
groups with minimal study heterogeneity. Consequently, ever, updated data from RE-LY reported that MI events
we consider the benefit of DOACs for fatal bleeding may werenon-significantlyincreasedwithbothdosesofdabiga-
potentially be considered a class effect. trancomparedwithwarfarin(hazardratio,1.28;P = 0.07)
The lower case-fatality rate of DOACs might be [37]. In our analysis, DOACs have a favorable effect on
explained by a decrease in anticoagulant-related intracra- death from overall vascular causes (RR, 0.88; P = 0.0002;
nial bleeding. In the warfarin era, 30–85% of fatal bleed- I2 = 0%). Subgroupanalyses showed that the reduction in
ing was from intracranial bleeding [5,7]. Intracranial cardiovascular death is more prominent among patients
bleeding is a devastating complication and associated with withnon-valvularatrialfibrillation.Thismayreflectdiffer-
a high mortality rate. Our group performed a meta-analy- ences in the patient populations of the trials investigating
sis of the bleeding outcomes among patients who received different indications for DOAC. Patients in non-valvular
DOACs compared with those who received warfarin and atrial fibrillation trials are older and more likely to have
found that DOACs were associated with a significantly cardiovascular events when compared with patients with
lower risk of intracranial bleeding (RR, 0.43; P < 0.01; venous thromboembolism. The lower event rate in trials
I2 = 2%) [4]. Although the incidence of GI bleeding was investigating venous thromboembolism results in an
slightly higher in patients who received DOACs [4], the underpowered statistical analysis for evaluating the effect
incidence of life-threatening GI bleeding was similar with ofDOACsoncardiovascularmortality.
warfarin and rivaroxaban [29]. Therefore, the benefit of Time in therapeutic range (TTR) is the parameter indi-
DOACs for case-fatality rates was mainly driven by the cating the quality of dose adjustment in patients who
substantial reduction in intracranial bleeding. receive warfarin. The factors that influenced TTR
©2015InternationalSocietyonThrombosisandHaemostasis
2018 C.Chai-Adisaksophaetal
included clinical setting (clinical trials or community prac- holds a Career Investigator award from the Heart and
tice), regions (Asia, Europe and North America) and type Stroke Foundation of Ontario, and the Leo Pharma
of vitamin K antagonist (warfarin or acenocoumarol, Chair in Thromboembolism Research at McMaster
phenprocoumon) [38–40]. Mean TTRs in patients receiv- University. M. Crowther’s institution has received fund-
ing warfarin in the RCTs ranged from 55% to 65% [4] ing for research projects from Leo Pharma and in addi-
and were expected to be higher than those in general tion has received funding for presentations from Leo
practice. Pooled analysis from the ARISTOTLE, Pharma, Bayer, Celgene, Shire and CSL Behring. The
ROCKET-AF and RE-LY trials demonstrated that an other authors state that they have no conflict of interest.
increase in warfarin’s TTR correlated with a decrease in
the rate of stroke and systemic embolism [41]. Therefore,
Supporting Information
warfarin’s low TTR might be one of the explanations for
higher mortality among warfarin users. Additional Supporting Information may be found in the
Our study has limitations. First, the duration of follow- online version of this article:
up varied between studies. Thus, we performed the analy-
Fig. S1. Risk of bias summary table for the included
sis of the rate of fatal bleeding as events per 100 patient-
studies.
years to estimate the pooled event rate more precisely.
Fig. S2. Case-fatality rate of major bleeding in patients
Second, we could not identify the proportion of patients
who received direct oral anticoagulant.
who died from intracranial bleeding. Third, the cardiovas-
Fig. S3. Case-fatality rate of major bleeding in patients
cular mortality was a composite outcome of death from
who received warfarin.
MI, stroke, systemic embolic events, deep vein thrombosis
Fig. S4. Rate of fatal bleeding in patients who received
and pulmonary embolism. We could not separate the
direct oral anticoagulant.
analysis for one particular outcome (e.g. death from MI).
Fig. S5. Rate of fatal bleeding in patients who received
Fourth, we included only studies that investigated the
warfarin.
two major indications for anticoagulation (atrial fibrilla-
Fig. S6. Subgroup analysis: cardiovascular mortality
tion and venous thromboembolism) and restricted the
according to types of direct oral anticoagulant.
duration of treatment to studies administering anticoagu-
Fig. S7. Subgroup analysis: cardiovascular mortality
lants for more than 3 months. Therefore, the findings
according to indication for anticoagulant.
from this meta-analysis may not be generalizable to other
Fig. S8. Subgroup analysis: all-cause mortality according
indications for anticoagulant therapy. Fifth, we were
to types of direct oral anticoagulant.
unable to perform the analysis based on warfarin’s TTR.
Fig. S9. Subgroup analysis: all-cause mortality according
Finally, because all of the included studies were phase III
to indication for anticoagulant.
RCTs the participants in these trials were likely to be
Fig. S10. Sensitivity analysis: cardiovascular mortality
healthier, younger and more closely monitored than
based on worst case scenario.
patients in the community. This potentially limits the gen-
Fig. S11. Sensitivity analysis: all-cause mortality based on
eralizability of our findings.
worst case scenario.
In summary, this study analyzed mortality outcomes
Fig. S12. Sensitivity analysis: cardiovascular mortality
for DOACs compared with warfarin. Our findings
(after removing studies with risk of bias).
demonstrate that the use of DOACs was associated with
Fig. S13. Sensitivity analysis: all-cause mortality (after
a lower case-fatality rate of major bleeding, fatal bleed-
removing studies with risk of bias).
ing, cardiovascular mortality and all-cause mortality.
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