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Anticoagulation dosing in atherosclerotic cardiovascular disease: Is less more?

Published:December 16, 2020DOI:https://doi.org/10.1016/j.ejim.2020.12.004
      Pivotal randomized clinical trials (RCTs) conducted in the 1970s and 1980s comparing aspirin with placebo in patients with prior myocardial infarction established antithrombotic agents as mainstays for the prevention of cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). Since then, other oral antithrombotic agents of different classes – including P2Y12 inhibitors, protease-activated receptor-1 inhibitors, and direct oral anticoagulants (DOACs) – have been developed and tested, alone or in various combinations, in this patient population. Most of these RCTs have separately measured the effect of treatment strategies on a primary ischemic outcome, usually a composite of myocardial infarction, stroke, and cardiovascular death, and a primary bleeding outcome. Taken as a whole, these RCTs have shown that increasing potency of antithrombotic therapy leads to a reduction in ischemic events at the cost of an increase in bleeding events [
      • Fanaroff AC
      • Hasselblad V
      • Roe MT
      • Bhatt DL
      • James SK
      • Steg PG
      • et al.
      Antithrombotic agents for secondary prevention after acute coronary syndromes: A systematic review and network meta-analysis.
      ].
      Clinical management of patients with ASCVD requires balancing the risks of recurrent ischemic events and bleeding events, with a goal of minimizing bleeding but preserving efficacy for protection from ischemic events. In patients with ASCVD, both bleeding and ischemic events are prognostically important [
      • Mueller HS
      • Forman SA
      • Menegus MA
      • Cohen LS
      • Knatterud GL
      • Braunwald E.
      Prognostic significance of nonfatal reinfarction during 3-year follow-up: results of the Thrombolysis in Myocardial Infarction (TIMI) phase II clinical trial.
      ,
      • Rao SV
      • O'Grady K
      • Pieper KS
      • Granger CB
      • Newby LK
      • Van de Werf F
      • et al.
      Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes.
      ,
      • Marquis-Gravel G
      • Dalgaard F
      • Jones AD
      • Lokhnygina Y
      • James SK
      • Harrington RA
      • et al.
      Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI.
      ]. Bleeding, in particular, is associated with discontinuation of antithrombotic therapy and worse quality of life, even among patients with minor or nuisance bleeding [
      • Amin AP
      • Bachuwar A
      • Reid KJ
      • Chhatriwalla AK
      • Salisbury AC
      • Yeh RW
      • et al.
      Nuisance bleeding with prolonged dual antiplatelet therapy after acute myocardial infarction and its impact on health status.
      ,
      • Wang TY
      • McCoy L
      • Henry TD
      • Effron MB
      • Messenger JC
      • Cohen DJ
      • et al.
      Early post-discharge bleeding and antiplatelet therapy discontinuation among acute myocardial infarction patients treated with percutaneous coronary intervention.
      ]. Ultimately, though ischemic and bleeding events are real outcomes patients wish to avoid, both are surrogates for quality and quantity of life, and finding the sweet spot requires integration of both event types into a common analytical framework. A number of these frameworks have been proposed, but all have challenges related to interpretation and rest on assumptions about the relative importance of events that may not be shared by all patients [
      • Fanaroff AC
      • Cyr D
      • Neely ML
      • Bakal J
      • White HD
      • Fox KAA
      • et al.
      Days alive and out of hospital: exploring a patient-centered, pragmatic outcome in a clinical trial of patients with acute coronary syndromes.
      ].
      By contrast, all-cause mortality is an easily understandable outcome that is universally important to patients and successfully integrates the downstream consequences of bleeding and ischemic events. However, it occurs rarely enough in patients with ASCVD that RCTs powered to detect a difference in all-cause mortality would need to be much larger than trials designed to detect a difference in a composite of ischemic events. Issues related to power can sometimes be overcome by meta-analytic techniques, when studies are suitable for combining.
      In this issue of the Journal, Cappato et al. report the results of a systematic review and meta-analysis of RCTs comparing high- versus low-dose DOACs in patients with ASCVD [
      • Cappato R
      • Chiarito M
      • Giustozzi M
      • Briani M
      • Ali H
      • Riva L
      • Bonitta G
      • Lodigiani C
      • Furlanello F
      • Balla C
      • Lupo P
      • Stefanini G.
      Lower dose direct oral anticoagulants and improved survival: A combined analysis in patients with established atherosclerosis.
      ]. The authors combine the results from four studies: 1) COMPASS, which randomized patients with stable ASCVD to aspirin alone, aspirin plus 2.5 mg rivaroxaban twice daily, or rivaroxaban 5 mg twice daily; [
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • Dagenais GR
      • Hart RG
      • Shestakovska O
      • et al.
      Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.
      ] 2) ATLAS ACS-2, which randomized patients with acute coronary syndrome to dual antiplatelet therapy (DAPT) alone, DAPT plus 2.5 mg rivaroxaban twice daily, or DAPT plus rivaroxaban 5 mg twice daily;[
      • Mega JL
      • Braunwald E
      • Wiviott SD
      • Bassand JP
      • Bhatt DL
      • Bode C
      • et al.
      Rivaroxaban in patients with a recent acute coronary syndrome.
      ] 3) RE-DEEM, which randomized patients with acute coronary syndrome to DAPT alone, or DAPT plus 50, 75, 110, or 150 mg dabigatran twice daily; and 4) a subgroup analysis of ENGAGE-AF, which randomized patients with atrial fibrillation (AF) and ASCVD to warfarin, edoxaban 30 mg daily, or edoxaban 60 mg daily [

      Giugliano TAZ Christian T Ruff, Stephen D Wiviott, Jean-Jacques Blanc, Riccardo Cappato, Francesco Nordio, Michele F Mercuri, Hans Lanz, Elliott M Antman, Eugene Braunwald, Robert P. Edoxaban in atrial fibrillation patients with established coronary artery disease: Insights from ENGAGE AF–TIMI 48 - Thomas A Zelniker, Christian T Ruff, Stephen D Wiviott, Jean-Jacques Blanc, Riccardo Cappato, Francesco Nordio, Michele F Mercuri, Hans Lanz, Elliott M Antman, Eugene Braunwald, Robert P Giugliano, 2019. Eur Heart J Acute Cardiovasc Care [Internet]. 2018 Jul 24 [cited 2020 Sep 22]; Available from: http://journals.sagepub.com/doi/10.1177/2048872618790561?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed.

      ]. They found that arms using low-dose DOAC (2.5 mg rivaroxaban, 50 or 75 mg dabigatran, and 30 mg edoxaban) were associated with 20% lower all-cause mortality than non-DOAC-containing arms, whereas arms using high-dose DOAC (5 mg rivaroxaban, 110 or 150 mg dabigatran, and 60 mg edoxaban) were not associated with lower mortality than non-DOAC arms. When high- and low-dose DOAC arms were compared directly, mortality was 16% lower in the low-dose DOAC arms.
      One of the threats to the validity of a meta-analysis is heterogeneity of included studies, in terms of design, patient population, and treatments. In this case of this meta-analysis, there is extreme heterogeneity between the studies in patient population: COMPASS enrolled patients with stable ASCVD involving at least two beds or risk factors for severe ASCVD; the ENGAGE-AF ASCVD sub-study enrolled patients with AF and coronary artery disease; ATLAS ACS-2 and RE-DEEM enrolled patients with ACS undergoing percutaneous coronary intervention. The role of DOAC and rationale for the specific doses are very different in these clinical scenarios. In particular, ENGAGE-AF was the only trial that enrolled patients with AF, an established indication for oral anticoagulation. Further, there is extreme heterogeneity in terms of treatment in each study's control (non-DOAC) arm – aspirin in COMPASS, warfarin in ENGAGE-AF, and DAPT in ATLAS ACS-2 and RE-DEEM – and in the doses of DOAC considered high and low. In COMPASS and ATLAS ACS-2, the high-dose rivaroxaban regimen was half of the daily dose used for stroke prophylaxis in AF and the low-dose regimen was one-quarter; in ENGAGE-AF and RE-DEEM the high-dose regimen was the dose used for stroke prophylaxis in AF, and the low-dose regimen was approximately half-dose.
      Besides heterogeneity, the present meta-analysis defines “low-dose” arbitrarily and without regard to the clinical scenario, and some “low-dose” DOAC regimens provide different levels of anticoagulation than others. The doses of DOACs approved for use in patients with AF – selected based on pharmacokinetic data and the results of phase I and II clinical trials – provide full anticoagulation, and the use of DOACs at these doses in combination with antiplatelet agents increases the risk of major bleeding, including intracranial hemorrhage [
      • Alexander JH
      • Lopes RD
      • James S
      • Kilaru R
      • He Y
      • Mohan P
      • et al.
      Apixaban with antiplatelet therapy after acute coronary syndrome.
      ]. By contrast, the dose of rivaroxaban approved for use in patients with ASCVD is considerably lower than the dose used in AF, and is intended to be used with antiplatelet agents, providing “dual-pathway inhibition,” a treatment strategy shown in COMPASS to improve mortality [
      • Eikelboom JW
      • Connolly SJ
      • Bosch J
      • Dagenais GR
      • Hart RG
      • Shestakovska O
      • et al.
      Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.
      ,
      • Coppens M
      • Weitz JI
      • Eikelboom JWA.
      Synergy of dual pathway inhibition in chronic cardiovascular disease.
      ]. There is evidence – particularly in patients with AF – that using DOAC doses lower than those tested in RCTs increases the risk of stroke [
      • Paciaroni M
      • Agnelli G
      • Caso V
      • Silvestrelli G
      • Seiffge DJ
      • Engelter S
      • et al.
      Causes and risk factors of cerebral ischemic events in patients with atrial fibrillation treated with Non-Vitamin K antagonist oral anticoagulants for stroke prevention.
      ].
      Despite these differences in patient population and treatment, the authors report an I2 statistic of 0%, reflecting minimal inconsistency in results across studies. The leave-one-out sensitivity analysis further suggests consistency across studies. However, the mechanism by which lower dose DOAC would reduce all-cause mortality but higher dose DOAC would not is unclear. Rates of fatal bleeding were too low to account for the observed differences, and treatment discontinuation rates were too similar between arms. Broadly, the mechanisms underlying the association between bleeding and mortality in patients with ASCVD are not fully explained, and are likely multifactorial, with direct contributions to morbidity and mortality from bleeding, indirect contributions from decreased use of evidence-based antithrombotic therapy and increased incidence of blood transfusions, and some contribution of unmeasured confounding since all studies evaluating the association between bleeding and mortality are necessarily observational [
      • Cavender MA
      • Rao SV.
      Bleeding associated with current therapies for acute coronary syndrome: What are the mechanisms?.
      ].
      In light of the heterogeneity in study population and treatment regimens, the arbitrary nature of how “low-dose” DOAC was defined, and the uncertain mechanism by which lower-dose DOAC would reduce mortality compared with higher-dose DOAC, the results of this meta-analysis are hard to interpret and should not change clinical practice. Physicians should continue to use the doses of DOACs tested in RCTs and approved by regulatory authorities; in patients with AF, full-dose anticoagulation should be used, and in patients with ASCVD without AF, rivaroxaban 2.5 mg twice daily is the only approved regimen. However, this meta-analysis suggests that patients with ASCVD may benefit from lower doses of anticoagulation, a hypothesis worth testing in future RCTs, particularly those enrolling patients with AF with ACS or undergoing percutaneous coronary intervention where dual antiplatelet therapy is also indicated.

      Declaration of Competing Interest

      Renato Lopes reported grants and personal fees from Bristol-Myers Squibb and Pfizer, personal fees from Boehringer Ingelheim and Bayer AG and grants from Amgen Inc, GlaxoSmithKline, Medtronic PLC, and Sanofi Aventis
      Alexander Fanaroff receives grant funding and honoraria from the American Heart Association, and grant funding from Boston Scientific.

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