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Lower dose direct oral anticoagulants and improved survival: A combined analysis in patients with established atherosclerosis

Published:November 03, 2020DOI:https://doi.org/10.1016/j.ejim.2020.09.007

      Highlights

      • Selection of lower rather than higher dose DOAC better protects against the risk of all-cause mortality in patients with established atherosclerosis and with indication for antiplatelets or oral anticoagulants.
      • Benefit of lower dose DOAC selection evidenced across variable clinical manifestations (acute coronary syndrome, stable coronary or peripheral artery disease, with or without atrial fibrillation).
      • Benefit of lower dose selection manifest at antithrombotic and anticoagulant DOAC regimens.

      Abstract

      Background

      Antithrombotic/anticoagulation effects of direct oral anticoagulants (DOACs) are dose-dependent. However, recent observations suggest that administering lower dose DOACs may better protect against all-cause mortality. We investigated whether, in patients with established atherosclerosis, DOAC dose selection would affect the risk of all-cause mortality.

      Methods

      We performed a structured literature research for controlled trials allowing random assignment to a lower dose DOAC, a higher dose DOAC, or control therapy in patients with established atherosclerosis. Pooled risk ratios (RRs) of all-cause mortality in lower and higher dose DOACs versus control therapy were estimated using a random-effect model.

      Results

      Atherosclerosis manifested as acute coronary syndrome (n=17,220), stable coronary (CAD) and/or peripheral artery disease (PAD) (n=27,395) or CAD associated with atrial fibrillation (n=4,510). Antithrombotic doses of rivaroxaban (2.5 mg or 5.0 mg BID) or dabigatran (50 mg, 75 mg, 110 mg, or 150 mg, BID) were tested in three trials versus single or dual antiplatelet control therapy, whereas anticoagulation doses of edoxaban (30 mg or 60 OD) were tested versus warfarin in one trial. Compared to control, patients receiving lower dose (RR 0.80, 95% CI 0.73-0.89, p<0.0001, =0%), but not those receiving higher dose DOACs (RR 0.95, 95% CI 0.87-1.05, p=0.3074, =0%), had a significant reduction of all-cause mortality. Benefit from lower dose DOACs remained after sensitivity analysis or direct comparison with higher dose DOACs (RR 0.84, 95% CI 0.76-0.93, p=0.0009, =0%).

      Conclusions

      Within antithrombotic/anticoagulation regimens of DOAC administration, selection of lower dose appears to protect from all-cause mortality in patients with established atherosclerosis.

      Keywords

      1. Introduction

      Anti-thrombotic and anti-coagulation effects of direct oral anticoagulants (DOACs) are dose-dependent [
      • Mega J.L.
      • Braunwald E.
      • Wiviott SD
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      ,
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ,
      • Ruff CT
      • Giugliano RP
      • Braunwald E
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      ,
      • Weitz JI
      • Harenberg J.
      New developments in anticoagulants: past, present and future.
      ,
      • Mega JL
      • Braunwald E
      • Mohanavelu S
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomized, double-blind, phase II trial.
      ]. Conversely, the benefit from higher dose DOACs is counterbalanced by a dose-dependent risk of bleeding [
      • Weitz JI
      • Harenberg J.
      New developments in anticoagulants: past, present and future.
      ]. Currently recommended regimens are the result of pre-clinical [
      • Mega JL
      • Braunwald E
      • Mohanavelu S
      • et al.
      Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomized, double-blind, phase II trial.
      ,
      • Steg PG
      • Metha SR
      • Jukema JW
      • et al.
      RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexan (YM150) following acute coronary syndrome.
      ] and phase III studies [
      • Mega J.L.
      • Braunwald E.
      • Wiviott SD
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      ,
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ,
      • Weitz JI
      • Lensing AWA
      • Prins MH
      • et al.
      Rivaroxaban or aspirin for extended treatment of venous thromboembolism.
      ,
      • Agnelli G
      • Buller HR
      • Cohen A
      • et al.
      Apixaban for extended treatment of venous thromboembolism.
      ,
      • Schulman S
      • Kearon C
      • Kakkar AK
      • et al.
      Extended use of dabigatran, warfarin, or placebo in venous thromboembolism.
      ,
      • Büller HR
      • Prins MH
      • Lensin AW
      • et al.
      Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
      ,
      • Connolly SL
      • Ezekowitz MD
      • Yusuf S
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ,
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ] in which various doses of DOACs were investigated and compared to standard of care in various conditions such as acute or stable coronary artery disease (CAD), peripheral artery disease (PAD), non-valvular atrial fibrillation (AF), and venous thromboembolism (VTE).
      Observations from some of the clinical trials conducted on DOACs suggest that, while exposed to a higher risk of thrombosis and thromboembolism, patients with CAD and/or PAD receiving lower dose may have a reduced risk of death than those receiving a higher dose therapy [
      • Mega J.L.
      • Braunwald E.
      • Wiviott SD
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      ,
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ,
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ]. Due to the public health implications of these observations, we reviewed the literature in search for controlled trials allowing random assignment to a lower dose DOAC, a higher dose DOAC, or control therapy, in order to assess whether, within the same clinical condition, dose assignment would affect the risk of all-cause mortality.

      2. Methods

      The data, analytical methods, and study materials will be available to other researchers for purposes of reproducing the results or replicating the procedure from the corresponding author on reasonable request.

      2.1 Search strategy

      We identified eligible studies in PubMed, Embase, BioMedCentral, Google Scholar, and Cochrane Central Register of Controlled Trials through database inception to July 2019. We used the following search terms to search the different databases: ("dabigatran"[tiab] OR "rivaroxaban"[tiab] OR "apixaban"[tiab] OR "edoxaban"[tiab]) AND "clinical trial"[Publication Type].

      2.2 Selection criteria

      Inclusion criteria were the following: 1) patients with CAD (acute or stable) and/or PAD; 2) random assignment to a lower dose DOAC, a higher dose DOAC, or control therapy; 3) an accurate report of all-cause mortality in all randomized groups. We excluded studies if they allowed changes in administered dose or regimen during the enrollment time. We excluded also studies in which lower-dose regimens either exceeded (eg., dabigatran 110 mg BID and dabigatran 150 mg BID) or were less than half the dose (eg., apixaban 2.5 mg BID and apixaban 10.0 mg BID) of the study highest dose regimens. We also excluded studies with overlapping populations. Finally, studies in which data on mortality were not available for all arms or were aggregated between two or more arms, studies not focused on CAD and/or PAD patients and phase I studies performed on healthy volunteers were also excluded.

      2.3 Data extraction

      Three investigators (M.C, M.B., M.G.) independently reviewed the abstracts of articles returned from our initial search (n=729) and determined their eligibility for inclusion based on the aforementioned selection criteria. Discrepancies in eligibility were discussed at each stage of the process until the investigators, alone or with the contribution of a fourth reviewer (G.S.), reached a joint consensus. When discussing studies throughout this meta-analysis, we are referring to the entirety of each publication. If studies included more than two DOAC doses, split into sub-studies was allowed, if this respected a randomization ratio of 1:1:1 between lower dose DOAC, higher dose DOAC, and control therapy. After removal of 17 duplicates, we excluded 686 articles from the initial search because of incompatibility with the inclusion criteria (Fig. 1). We contacted corresponding authors for clarification on published and unpublished data as needed. The full texts of 26 articles were screened for eligibility; 22 were excluded due to insufficient data report, lack of focus on CAD and/or PAD, or conduction on healthy volunteers. Four studies were finally included. The present meta-analysis follows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and checklist (supplementary appendix) [
      • Moher D
      • Liberati A
      • Tetzlaff J
      • Altman DG
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ].
      Fig. 1
      Fig. 1Flow chart depicting article selection process.
      We extracted the following data from selected studies: 1) author names, 2) publication year, 3) population size and characteristics, 4) intervention type, 5) intervention dose, 6) study quality, 7) funding sources, 8) post-intervention values of all-cause mortality, 9) post-intervention values of fatal bleeding, 10) and, when applicable, post-intervention values of cardiovascular and non-cardiovascular mortality.
      The full text of selected articles was screened for quality as part of the data extraction strategy by 3 reviewers (M.C.M.B.,M.G.) with the revised Cochrane Risk of Bias (RoB 2.0) [
      • Sterne JAC
      • Savović J
      • Page MJ
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ]. For each selected study, the following domains of bias were assessed: 1) randomization process, 2) deviations from intended interventions, 3) missing outcome data, 4) measurement of the outcome, and 5) selection of the reported results (Supplemental Table 1). This study is registered with the PROSPERO International Prospective Register of Systematic Reviews at CRD42018092025.

      2.4 Statistical analysis

      The results were summarized qualitatively into Frequentist meta-analysis. We pooled relative risks (RRs) with inverse variance weighting using DerSimonian-Laird random effect models to account for between-trial variance (τ2 ) [
      • DerSimonian R
      • Laird N.
      Meta-analysis in clinical trials.
      ].
      Heterogeneity among the trials was quantified by I2-index and Cochran's Q test. [
      • Borenstein M
      • Hedges LV
      • Higgins JP
      Introduction to meta-analysis.
      ], considering significant heterogeneity when p-value was <0.10 or I2-index was >50% [
      • Higgins JP
      • Thompson SG
      • Deeks JJ
      • Altman DG
      Measuring inconsistency in meta-analyses.
      ]. A leave-one-out sensitivity analysis was performed by iteratively removing one study at a time to confirm that our findings were not driven by any single study. The 95% confidence intervals (CIs) were based on normal approximation and Z-score test was performed for assessment of the overall treatment effect. Two sided p-values were considered statistically significant when <0.05. All analyses and graphs were carried out using R software (version 3.2.2). Analyses were performed according to the intention-to-treat principle reflected by all selected studies.

      3. Results

      3.1 Study characteristics

      The study characteristics of the four selected studies, representing 49,125 patients, are described in Tables 1A and 1B. Sample sizes ranged from 1,878 to 27,395 participants, and mean ages ranged from 49 to 78 years. Patients in the ATLAS ACS-2 TIMI 51 [
      • Mega J.L.
      • Braunwald E.
      • Wiviott SD
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      ] and RE-DEEM trials [
      • Oldgren J
      • Budaj A
      • Granger CB
      • Khder Y
      • Roberts J
      • Siebbahn A
      • Tijssen JGP
      • Van de Werf F
      • Wallentin L
      for the RE-DEEM investigators
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, bouble-blind, phase II trial.
      ] were younger and had less co-morbidities. Patients in the COMPASS [
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ] trial had the highest incidence of prior myocardial infarction, whereas patients in the ENGAGE AF TIMI 48 CAD sub-study [
      • Zelniker TA
      • Ruff CT
      • Wiviott SD
      • et al.
      Edoxaban in atrial fibrillation patients with established coronary artery disease: insights from ENGAGE AF-TIMI 48.
      ] were the oldest and had the highest incidence of hypertension (Table 2).
      Table 1AMain characteristics of the trials included in the meta-analysis.
      Name of studyEntry criteriaStudy populationPrimary efficacyStudy result
      Lower DOAC doseHigher DOAC doseControloutcome
      (N, 16,539)(N, 16,472)(N, 16,114)
      ATLAS ACS-2 TIMI 51
      • Mega J.L.
      • Braunwald E.
      • Wiviott SD
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      (N, 15,342)
      ACS receiving PTCA plus stentRivaroxaban 2.5 mg BID (N, 5,114)Rivaroxaban 5.0 mg BID (N, 5,115)Dual or single antiplatelet therapy (N, 5,113)Composite of CV death, stroke or MILower and higher dose rivaroxaban similarly reduced the primary efficacy endpoint vs control
      COMPASS [
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ] (N, 27,395)
      Stable CAD and/or PADRivaroxaban 2.5 mg BID plus aspirin (N, 9,152)Rivaroxaban 5.0 mg BID (N, 9,117)aspirin (N, 9,126)Composite of CV death, stroke or MILower dose rivaroxaban plus aspirin reduced the primary efficacy endpoint vs control
      ENGAGE AF sub-study in patients with CAD [
      • Zelniker TA
      • Ruff CT
      • Wiviott SD
      • et al.
      Edoxaban in atrial fibrillation patients with established coronary artery disease: insights from ENGAGE AF-TIMI 48.
      ] (N, 4,510)
      Non-valvular AF with CHADS2 score ≥2 and CADEdoxaban 30 mg OD (N, 1,530)Edoxaban 60 mg OD (N, 1,478)VKA (N, 1,502)Composite of stroke and SE*Higher dose edoxaban reduced primary efficacy endpoint vs. control
      RE-DEEM sub-study 50-110 [
      • Oldgren J
      • Budaj A
      • Granger CB
      • Khder Y
      • Roberts J
      • Siebbahn A
      • Tijssen JGP
      • Van de Werf F
      • Wallentin L
      for the RE-DEEM investigators
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, bouble-blind, phase II trial.
      ] (N, 1,156)
      ACS receiving PTCA plus stentDabigatran 50 mg BID (N, 372)Dabigatran 110 mg BID (N, 411)Dual or single antiplatelet therapy (N, 373)No efficacy outcome investigated-
      RE-DEEM sub-study 75-150 [
      • Oldgren J
      • Budaj A
      • Granger CB
      • Khder Y
      • Roberts J
      • Siebbahn A
      • Tijssen JGP
      • Van de Werf F
      • Wallentin L
      for the RE-DEEM investigators
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, bouble-blind, phase II trial.
      ] (N, 1,095)
      ACS receiving PTCA plus stentDabigatran 75 mg BID (N, 371)Dabigatran 150 mg BID (N, 351)Dual or single antiplatelet therapy (N, 373)No efficacy outcome investigated-
      Table 1BMain characteristics of the trials included in the meta-analysis.
      Name of studyMajor safety outcomesStudy result‡Discontinuation rateFatal-bleeding rate
      ATLAS ACS-2 TIMI 51
      • Mega J.L.
      • Braunwald E.
      • Wiviott SD
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      (N, 15,342) (FU, 13 mos)
      TIMI major bleeding not associated with CABG, fatal bleedingLower and higher rivaroxaban doses increased the risk of major and fatal bleeding vs control, with less risk in lower dose arm27% in the lower dose rivaroxaban arm, 29%, in the higher dose rivaroxaban arm, 26% in the control arm0.1% in rivaroxaban 2.5 mg arm 0.4% in rivaroxaban 5.0 mg arm 0.2% in control arm
      COMPASS
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      (N, 27,395) (FU, 23 mos)
      Modified ISTH major bleeding, fatal bleedingLower dose rivaroxaban plus aspirin had similar fatal bleeding as higher dose rivaroxaban16% in the lower dose rivaroxaban plus aspirin arm, 17% in the higher dose rivaroxaban, 15% in the control arm0.2% in rivaroxaban 2.5 mg arm 0.2% in rivaroxaban 5.0 mg arm 0.1% in control arm
      ENGAGE AF sub-study in patients with CAD
      • Zelniker TA
      • Ruff CT
      • Wiviott SD
      • et al.
      Edoxaban in atrial fibrillation patients with established coronary artery disease: insights from ENGAGE AF-TIMI 48.
      (N, 4,510) (FU, 34 mos)
      *ISTH major bleeding, fatal bleedingSimilar fatal bleeding in lower dose and higher dose edoxaban, with*less major bleeding >2 g/dl Hb blood loss in lower than in higher dose edoxaban§33% in the lower dose edoxaban arm, 34% in the higher dose edoxaban arm, 34% in the control arm0.4% in edoxaban 30 mg arm 0.4% in edoxaban 60 mg arm 0.4% in control arm
      RE-DEEM sub-study 50-110
      • Oldgren J
      • Budaj A
      • Granger CB
      • Khder Y
      • Roberts J
      • Siebbahn A
      • Tijssen JGP
      • Van de Werf F
      • Wallentin L
      for the RE-DEEM investigators
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, bouble-blind, phase II trial.
      (N, 1,156) (FU, 6 mos)
      Composite of ISTH major or clinically relevant minor bleedingDose dependent increase in major or clinically relevant minor bleeding vs control-0.0% in dabigatran 50 mg arm 0.3% in dabigatran 110 mg arm 0.3% in control arm
      RE-DEEM sub-study 75-150
      • Oldgren J
      • Budaj A
      • Granger CB
      • Khder Y
      • Roberts J
      • Siebbahn A
      • Tijssen JGP
      • Van de Werf F
      • Wallentin L
      for the RE-DEEM investigators
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, bouble-blind, phase II trial.
      (N, 1,095) (FU, 6 mos)
      Composite of ISTH major or clinically relevant minor bleedingDose dependent increase in major or clinically relevant minor bleeding vs control-0.0% in dabigatran 75 mg arm 0.0% in dabigatran 150 mg arm 0.3% in control arm
      *Efficacy and safety outcomes are those reported in the seminal ENGAGE AF TIMI 48 study
      • Giugliano RP
      • Ruff CT
      • Braunwald E
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      In RE-DEEM, patients in the control arm of the two-sub-studies are from the same population. The population of the study totals 1,878 patients.
      ‡In aggregate, the discontinuation rates were 24.4% (5,211/21,328) in lower dose DOACs, 25.7% (5,487/21,305) in higher dose DOACs, and 24.5% (5,216/21,314) in control therapy patients’ groups.
      §Discontinuation rates are those reported in the seminal ENGAGE AF TIMI 48 study.
      • DerSimonian R
      • Laird N.
      Meta-analysis in clinical trials.
      Abbreviations: ACS, acute coronary syndrome; AF, atrial fibrillation, BID, twice daily; CABG, coronary artery by-pass graft ; CAD, coronary artery disease; CV, cardiovascular; MI, myocardial infarction; N, number of patients; DOAC, direct oral anticoagulant; OD, once daily; PAD, peripheral artery disease; PTCA, percutaneous transcatheter coronary angioplasty; SE systemic embolism, VKA, vitamin K antagonist
      Table 2Characteristics of the patients at baseline in the included trials.
      ATLAS ACSCOMPASSENGAGE AFRE-DEEM
      TIMI 51TIMI 48 sub-study in patients with CAD
      (N, 15,342)(N, 27,395)(N, 4,510)(N, 1,878)
      Age (years, mean)61.768.272.261.8
      Male sex (percent)74.778.076.877.0
      Weight
      (Kg)78.0-86.6-
      (Kg/m²)-28.4-27.3
      Creatinine clearance (ml/min)85.173.873.0-
      Creatinine clearance ≥30 and < 50 ml/min (percent)---7.5
      Hypertension (percent)67.475.394.866.6
      Dyslipidaemia (percent)48.590.074.1-
      Previous myocardial infarction (percent)26.962.353.929.0
      History of heart failure (percent)-21.563.111.7
      Diabetes mellitus (percent)31.937.744.431.3
      Stroke/transient ischaemic attack (percent)2.63.825.8-
      Aspirin at randomization (percent)98.666.645.1-
      Empty boxes indicate that data are not not available.
      Abbreviations as in Table 1.
      CAD manifested as ACS in 15,342 patients in the ATLAS ACS-2 TIMI 51 trial and 1,878 in the RE-DEEM trial, as stable CAD and/or PAD in 27,395 patients in the COMPASS trial, and as stable CAD associated with AF (nonvalvular) in 4,510 patients in the ENGAGE AF TIMI 48 sub-study [
      • Zelniker TA
      • Ruff CT
      • Wiviott SD
      • et al.
      Edoxaban in atrial fibrillation patients with established coronary artery disease: insights from ENGAGE AF-TIMI 48.
      ]. The median follow-up was 19 months. Antithrombotic doses of rivaroxaban (2.5 mg or 5.0 mg BID) (in ATLAS ACS-2 TIMI 51 and COMPASS) or dabigatran (50 mg, 75 mg, 110 mg, or 150 mg, BID) (in RE-DEEM) were tested in three trials versus single or dual antiplatelet control therapy. Anticoagulation doses of edoxaban (30 mg and 60 OD) were tested versus warfarin in one trial (ENGAGE AF TIMI 48 CAD sub-study). In the ENGAGE AF TIMI 48 trial, about one-fourth of patients received half of the nominal dose (i.e., 15 mg or 30 mg OD), if, according to study protocol, they had a creatinine clearance of 30 to 50 ml/min, a body weight of ≤60 kg, or were taking P-glycoprotein inhibitors. Patients receiving half-nominal doses of edoxaban or matching placebo at randomization had also similar rates in the three treatment groups.

      3.2 Investigated doses of DOAC and control therapies

      Overall, 16,539 patients were randomly assigned to a lower dose DOAC, 16,472 to a higher dose DOAC and 16,114 patients to single or dual antiplatelet agents (14,612 patients) [
      • Mega J.L.
      • Braunwald E.
      • Wiviott SD
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      ,
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ,
      • Oldgren J
      • Budaj A
      • Granger CB
      • Khder Y
      • Roberts J
      • Siebbahn A
      • Tijssen JGP
      • Van de Werf F
      • Wallentin L
      for the RE-DEEM investigators
      Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, bouble-blind, phase II trial.
      ], or vitamin K antagonists (1,502 patients) [
      • Zelniker TA
      • Ruff CT
      • Wiviott SD
      • et al.
      Edoxaban in atrial fibrillation patients with established coronary artery disease: insights from ENGAGE AF-TIMI 48.
      ] as control therapy. Lower investigated doses of DOACs consisted of rivaroxaban 2.5 mg BID from ATLAS ACS-2 TIMI 51 and COMPASS, dabigatran 50 mg and 75 mg BID from RE-DEEM and edoxaban 30 mg (or 15 mg) OD in the ENGAGE AF-TIMI 48 CAD sub-study. Conversely, higher investigated doses of DOACs consisted of rivaroxaban 5.0 mg BID from ATLAS ACS-2 TIMI 51 and COMPASS, dabigatran 110 mg and 150 mg BID from RE-DEEM and edoxaban 60 mg (or 30 mg) OD in ENGAGE AF-TIMI 48 CAD sub-study (Tables 1A and 1B).
      Patients in the lower rivaroxaban dose group of COMPASS received co-therapy with aspirin 100 mg OD, whereas those in the higher rivaroxaban dose group did not. In RE-DEEM, which enrolled four dabigatran dose groups, 2 sub-studies were generated, each enabling comparative assessment of one single lower (50 mg or 75 mg BID) and one single higher dabigatran dose (110 mg or 150 mg BID) versus control.
      Control therapies consisted of single or dual antiplatelet therapy (low-dose aspirine plus/minus thienopyridine) in ATLAS ACS-2 TIMI 51, and RE-DEEM, aspirin 100 mg OD in COMPASS, and dose-adjusted warfarin in ENGAGE AF-TIMI 48 CAD sub-study.

      3.3 Effects of lower and higher dose DOACs versus control therapies on all-cause mortality

      Compared to patients in the control group, patients receiving lower dose DOACs had a significantly lower risk of all-cause mortality (RR 0.80, 95% CI 0.73-0.89, p<0.0001, =0%) (Fig. 2A), whereas patients receiving higher dose DOACs failed to show such benefit (RR 0.95, 95% CI 0.87-1.05, p=0.3074, =0%) (Fig. 2B). The risk ratio for all-cause mortality in patients assigned to lower dose versus control therapy and in patients assigned to higher dose versus control therapy did not change when ATLAS ACS-2 TIMI 51, COMPASS, ENGAGE AF TIMI 48 CAD sub-study and RE-DEEM sub-studies were each subtracted, respectively, from comparison in the leave-one-out sensitivity analysis. Benefit from lower dose DOACs remained after direct comparison with higher dose DOACs (RR 0.84, 95% CI 0.76-0.93, p=0.0009, =0%) (Supplemental Fig. 1).
      Fig. 2
      Fig. 2A. Forest plot and sensitivity analysis of all-cause mortality in lower dose DOACs versus control therapy. B. Forest plot and sensitivity analysis of all-cause mortality in higher dose DOACs versus control therapy.
      Fig. 2
      Fig. 2A. Forest plot and sensitivity analysis of all-cause mortality in lower dose DOACs versus control therapy. B. Forest plot and sensitivity analysis of all-cause mortality in higher dose DOACs versus control therapy.
      Fatal bleedings never exceeded the incidence of 0.2% per year in any of the investigated studies’ arms (Table 1A and 1B). Compared to higher dose DOACs, assignment to lower dose DOACs did not provide significant protection against the risk of fatal bleeding (RR 0.77, 95% CI 0.46-1.28, p=0.3053, =1%) (Supplemental Fig. 2).

      3.4 Publication bias

      All trials, enrolling large populations of wide geographical distribution, were at low risk of bias for each of the estimates of investigated domains (Supplemental Table 1).

      4. Discussion

      4.1 Main findings

      Among patients with established atherosclerosis, assignment to a lower antithrombotic or anticoagulant dose of DOAC was associated with a 20% reduced risk of all-cause mortality compared to control therapy. This benefit disappeared when, within the same studies, patients were assigned to a higher DOAC dose. The low and superimposable risk of fatal bleeding in lower and higher dose therapy groups makes the direct role of this complication unlikely to explain the different mortality risks of the two DOAC groups versus control therapy. In spite of the variable clinical manifestations (i.e., ACS, stable CAD with or without PAD, and stable CAD with AF) all patients contributing to our analysis shared a common substrate of active atherosclerosis, thereby offering a unique opportunity to investigate the impact of DOAC dose selection in this setting. Our results suggest that chronic administration of DOACs in patients with established atherosclerosis may influence their prognosis during intermediate follow-up depending on dose selection. These findings may be useful for selecting the appropriate DOAC doses in similar conditions of daily practice.

      4.2 Results in relation to previous literature

      Recent observations indicate the possible presence, within the same population, of discordant patterns between anti-thrombotic protection and prognostic benefit depending on DOAC dose selection. ATLAS ACS-2 TIMI 51 and ENGAGE AF-TIMI 48 showed that patients receiving lower dose DOACs had similar protection from thrombo-embolic (i.e., stroke) and/or thrombotic (i.e., myocardial infarction) as patients receiving control therapies. However, patients in the lower dose DOACs had a lower risk of all-cause mortality. In the same studies, patients receiving higher dose DOACs tended to show some benefit on thrombotic/thrombo-embolic events compared to control patients, but no benefit with regard to all-cause mortality. Mega et al. [
      • Mega JL
      • Braunwald E
      • Wiviott SD
      • et al.
      Comparison of the efficacy and safety of two rivaroxaban doses in acute coronary syndrome (from ATLAS ACS 2-TIMI 51).
      ] also reported about the presence in the lower dose rivaroxaban group from ATLAS ACS-2 TIMI 51 of 30 less fatal events, inclusive of myocardial infarction, unwitnessed, congestive heart failure/cardiogenic shock and arrhythmic, but 42 more non-fatal myocardial infarctions than in the higher dose rivaroxaban group.
      RE-DEEM and APPRAISE [
      APPRAISE steering committee and investigators
      Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome. Results of the apixaban for prevention of acute ischemic and safety events (APPRAISE) trial.
      ] were phase II trials investigating safety outcomes of multiple doses dabigatran and apixaban versus control. Therefore, patient volumes in these studies did not allow for comparative assessment of thrombotic/thromboembolic events between study arms. Of four investigated doses and regimens in APPRAISE, mortality data were incompletely reported and, in particular, entirely unavailable for two groups. Therefore, this study could not be included in our analysis.

      4.3 Potential mechanisms

      The mechanisms behind the protective effect of lower dose DOACs are unknown and largely speculative at present. While low and superimposable rates in the lower and higher dose DOACs do not support a role for fatal bleeding as a direct mechanism, we cannot exclude that dose-dependent larger exposure to bleeding complications may have contributed to increased late mortality in the higher dose DOAC group. Previous studies have shown that patients experiencing major or clinically relevant non-major bleeding have a higher need for blood transfusion, longer hospitalizations and an increased risk of ischemic events following discontinuation of anti-thrombotic therapy [
      • Valgimigli M
      • Costa F
      • Lokhnygina Y
      • et al.
      Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRACER) randomized trial.
      ,
      • Kazi DS
      • Leong TK
      • Chang TI
      • et al.
      Association of spontaneous bleeding and myocardial infarction with long-term mortality after percutaneous coronary intervention.
      ,
      • Gómez-Outes A
      • Lagunar-Ruíz J
      • Terleira-Fernández AI
      • Calvo-Rojas G
      • Suárez-Gea ML
      • Vargas-Castrillón E
      Causes of death in anticoagulated patients with atrial fibrillation.
      ]. These conditions, together with an increased risk of intra-plaque hemorrhage, possibly leading to larger and even fatal infarctions or sudden death [
      • Kolodgie FD
      • Gold HK
      • Burke AP
      • Fowler DR
      • Kruth HS
      • Weber DK
      • Farb AF
      • Guerrero LJ
      • Hayase M
      • Kutys R
      • Narula J
      • Finn AV
      • Virmani R
      Intraplaque hemorrhage and progression of coronary atheroma.
      ], may adversely influence patient's prognosis. Aspirin co-administration [
      • Gurbel PA
      • Fox KAA
      • Tantry AS
      • ten Cate H
      • Weits JI
      Combination antiplatelet and oral anticoagulant therapy in patients with coronary and peripheral artery disease. Focus on the COMPASS trial.
      ] in the lower rivaroxaban dose group of COMPASS would not represent a possible confounder, as antiplatelet drugs may, if at all, adversely influence the risk of intraplaque hemorrhage intraplaque hemorrhage [
      • Cao X
      • Zhang J
      • Geng D
      Use of oral anticoagulant drugs is associated with carotid intraplaque hemorrhage in atherosclerosis patients: a meta-analysis.
      ,
      • Mujaj B
      • Bos D
      • Muka T
      • van der Lugt A
      • Ikram MA
      • Verneooij MW
      • Stiker BH
      • Franco OH
      Antithrombotic treatment is associated with intraplaque haemorrhage in the atherosclerotic carotid artery: a cross-sectional analysis of the Rotterdam study.
      ]. The unidirectional character and the similar magnitude of benefit, regardless of doses and regimens tested in the contributing trials of our analysis, further support a possible role of less bleeds of any type ultimately favoring a better outcome in patients receiving lower dose DOACs.

      4.4 Strengths and limitations

      The present analysis reflects, to our knowledge, the only assessment of the effects of DOAC dose selection on all-cause mortality in patients with atherosclerotic disease. Strengths of the present study include the use of results derived from a systematic search process conducted and reviewed by several investigators. In particular, the inclusion of studies using randomized controlled trials allowed us to draw causal conclusion with low risk of bias for each of the estimates of investigated domains. Also, the overall population included in the present meta-analysis was relatively large, and of wide geographical distribution. There was substantial homogeneity in study methods and measures, with low I2-indexes for heterogeneity for all primary outcome analyses. Use of all-cause mortality as the primary study outcome provided a stringent endpoint for accurate data assessment.
      Limitations of the present study also warrant consideration. First, we had no access to individual patient data. Therefore, we are unable to provide accurate description of the causes and timing of deaths in the study groups. Similarly, we were unable to evaluate whether an excess discontinuation rate, if present, could be a co-determinant of excess mortality in patients receiving higher dose DOACs. This hypothesis appears mitigated by the small difference (1.5%) in discontinuation rates between lower and higher dose therapy groups from all studies contributing to our analysis (Tables 1A and 1B). Second, co-therapy with aspirin in patients receiving a lower dose, but not in those receiving a higher dose of DOACs in COMPASS [
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ] introduces a confounding element in our analysis. The observation that sensitivity analysis after subtraction of COMPASS revealed a risk ratio similar to that obtained in the primary analysis of our study indicates that aspirin would unlikely add to the protective effect of lower dose DOACs on all-cause mortality. This finding is consistent with our knowledge that aspirin is not effective for primary prevention of cardiovascular mortality in patients with CAD, a condition characterizing about 40% of patients in COMPASS [
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • et al.
      Rivaroxaban with or without aspirin in stable cardiovascular disease.
      ], and that there is no conclusive evidence about the role of aspirin to reduce all-cause mortality in patients with prior myocardial infarction. [
      • Chiarito M
      • Sanz-Sanchez J
      • Cannata F
      • Sturla M
      • Panico C
      • Godino C
      • Regazzoli D
      • Reimers B
      • De Caterina R
      • Condorelli G
      • Ferrante G
      • Stefanini G
      Monotherapy with a P2Y12 inhibitor or aspirin for secondary prevention in patients with established atherosclerosis: a systematic review and meta-analysis.
      ,
      • Baigent C
      • Blackwell L
      • Collins R
      • et al.
      Antithrombotic Trialists' (ATT) Collaboration
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      ].
      Third, APPRAISE, a trial enabling comparison between control therapy and multiple DOAC apixaban doses was excluded from our analysis due to discontinuous criteria during enrollment and drug assignment. In addition, all-cause mortality data were not reported for two of the four study arms. Similarly, RE-LY could not be incorporated in our analysis as there were no data from this study specifically addressing CAD and/or PAD population (R3, GC). ARISTOTLE, a phase III trial investigating the benefit of oral apixaban versus VKA therapy in patients with non-valvular AF, could also not be incorporated in our analysis as the study protocol provided random assignment to just one DOAC dose. Finally, age, prevalence of co-morbidity and administered therapies differed quite consistently among patients in the selected trials. However, use of randomization in all trials rendered every group of our study rather similar to the others, thus making comparative inter-group analyses reliable. Similarly, age, co-morbidities and administered therapies showed no differences between patients in the lower and in the higher DOAC groups in any of the four trials included in our analysis. Altogether, these findings make the possibility of uneven patient distribution in the 3 groups of our study unlikely.

      4.5 Future directions and conclusions

      The present findings are in need of confirmation from dedicated studies. Even when confirmed, careful analyses should be performed to assess the magnitude and severity of the excess risk of thrombotic/thromboembolic events that patients receiving lower dose DOACs might experience during their extended life span. Data available at present are scarce. Future interventions should also investigate whether prognostic benefit from lower dose DOACs also applies to other drugs such as apixaban, or conditions such as AF or VTE. In ENGAGE AF-TIMI 48, patients assigned to higher dose edoxaban had a lower risk of stroke or peripheral embolism versus control warfarin, whereas no benefit was observed in patients receiving lower drug dose. Of interest, most of the benefit in the higher dose therapy group was found in the category of non-fatal non-disabling stroke, whereas no differences between each of the two edoxaban groups and control were observed with regard to fatal or disabling stroke.
      In conclusions, findings from the present study suggest that, in patients with established atherosclerosis, a better prognosis may be associated with administration of lower dose DOACs. If confirmed, this observation may have relevant clinical implications, particularly in light of the large populations of DOACs recipients in real world life.

      Acknowledgments

      We are indebted to Silvio Garattini, MD, for his review of the manuscript and precious suggestions.

      Appendix. Supplementary materials

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