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Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. PDF

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JournalofThrombosisandHaemostasis,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. References Addendum 1 Bauer KA. Recent progress in anticoagulant therapy: oral direct C. Chai-Adisaksopha and M. Crowther designed the inhibitorsofthrombinandfactorXa.JThrombHaemost2011;9 methods. C. Chai-Adisaksopha and T. Isayama per- (Suppl.1):12–9. formed the study selection. C. 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