Abstract
The mortality effects and risk–benefit profile of low dose rivaroxaban (2.5 mg twice daily) in patients with coronary heart disease are not completely understood. Five randomized controlled trials (26,110 patients) were selected using PubMed and Cochrane library till April 2019. The background antiplatelet therapy was aspirin in 3 trials, P2Y12 inhibitor in 1 trial, and in 1 trial 65% patients received aspirin and 35% were on dual antiplatelet therapy (DAPT). The outcomes of interest were cardiovascular mortality, all-cause mortality, myocardial infarction (MI), stroke and major bleeding events. Random effects hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Low dose rivaroxaban did not reduce the risk of cardiovascular mortality (HR 0.90, 95% CI 0.73–1.11, P = 0.34) or all-cause mortality (HR 0.91, 95% CI 0.74–1.12, P = 0.38) compared with control. However, low dose rivaroxaban was associated with reduction in MI (HR 0.85, 95% CI 0.73–0.99, P = 0.04), and stroke (HR 0.59, 95%CI 0.48–0.73, P < 0.001) at the expense of major bleeding (HR 1.64, 95% CI 1.39–1.94, P < 0.001) compared with control. These effects did not vary according to acute coronary syndrome or stable coronary heart disease (P-interaction > 0.05). The use of low dose rivaroxaban in patients with coronary heart disease predominantly receiving antiplatelet monotherapy did not reduce cardiovascular or all-cause mortality. The benefits of preventing MI and stroke were balanced by increased risk of major bleeding.
Similar content being viewed by others
References
Bhatt DL, Eagle KA, Ohman EM, Hirsch AT, Goto S, Mahoney EM, Wilson PW, Alberts MJ, D'Agostino R, Liau CS, Mas JL, Rother J, Smith SC Jr, Salette G, Contant CF, Massaro JM, Steg PG, Investigators RR (2010) Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 304(12):1350–1357
Merlini PA, Bauer KA, Oltrona L, Ardissino D, Cattaneo M, Belli C, Mannucci PM, Rosenberg RD (1994) Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90(1):61–68
Ueda Y, Ogasawara N, Matsuo K, Hirotani S, Kashiwase K, Hirata A, Nishio M, Nemoto T, Wada M, Masumura Y, Kashiyama T, Konishi S, Nakanishi H, Kobayashi Y, Akazawa Y, Kodama K (2010) Acute coronary syndrome: insight from angioscopy. Circ J 74(3):411–417
Borissoff JI, Spronk HM, Heeneman S, ten Cate H (2009) Is thrombin a key player in the 'coagulation-atherogenesis' maze? Cardiovasc Res 82(3):392–403
van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE, Antithrombotics in the Secondary Preventionof Events in Coronary Thrombosis-2 Research G (2002) Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 360(9327):109–113
Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H (2002) Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 347(13):969–974
Anand SS, Yusuf S (1999) Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA 282(21):2058–2067
Khan SU, Arshad A, Riaz IB, Talluri S, Nasir F, Kaluski E (2018) Meta-analysis of the safety and efficacy of the oral anticoagulant agents (apixaban, rivaroxaban, dabigatran) in patients with acute coronary syndrome. Am J Cardiol 121(3):301–307
Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, Bax JJ, Borger MA, Brotons C, Chew DP, Gencer B, Hasenfuss G, Kjeldsen K, Lancellotti P, Landmesser U, Mehilli J, Mukherjee D, Storey RF, Windecker S (2016) 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 37(3):267–315
News V. Rivaroxaban gets FDA approval for treatment in CAD or PAD. https://vascularnews.com/rivaroxaban-fda-approval-cad-pad/
Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O'Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Stork S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S (2017) Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 377(14):1319–1330
Connolly SJ, Eikelboom JW, Bosch J, Dagenais G, Dyal L, Lanas F, Metsarinne K, O'Donnell M, Dans AL, Ha JW, Parkhomenko AN, Avezum AA, Lonn E, Lisheng L, Torp-Pedersen C, Widimsky P, Maggioni AP, Felix C, Keltai K, Hori M, Yusoff K, Guzik TJ, Bhatt DL, Branch KRH, Cook Bruns N, Berkowitz SD, Anand SS, Varigos JD, Fox KAA, Yusuf S, COMPASS investigators (2018) Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 391(10117):205–218
van Tulder M, Furlan A, Bombardier C, Bouter L (2003) Updated method guidelines for systematic reviews in the cochrane collaboration back review group. Spine 28(12):1290–1299
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement. BMJ 339:b2535
Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L, Sterne JAC (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:5928
Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560
Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, Birmingham M, Ianus J, Burton P, van Eickels M, Korjian S, Daaboul Y, Lip GY, Cohen M, Husted S, Peterson ED, Fox KA (2016) Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 375(25):2423–2434
Ohman EM, Roe MT, Steg PG, James SK, Povsic TJ, White J, Rockhold F, Plotnikov A, Mundl H, Strony J, Sun X, Husted S, Tendera M, Montalescot G, Bahit MC, Ardissino D, Bueno H, Claeys MJ, Nicolau JC, Cornel JH, Goto S, Kiss RG, Guray U, Park DW, Bode C, Welsh RC, Gibson CM (2017) Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 389(10081):1799–1808
Zannad F, Anker SD, Byra WM, Cleland JGF, Fu M, Gheorghiade M, Lam CSP, Mehra MR, Neaton JD, Nessel CC, Spiro TE, van Veldhuisen DJ, Greenberg B (2018) Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. N Engl J Med 379(14):1332–1342
Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366(1):9–19
Gibson William J, Gibson CM, Yee Megan K, Korjian S, Daaboul Y, Plotnikov Alexei N, Burton P, Braunwald E (2019) Safety and efficacy of rivaroxaban when added to aspirin monotherapy among stabilized post-acute coronary syndrome patients: a pooled analysis study of ATLAS ACS-TIMI 46 and ATLAS ACS 2-TIMI 51. J Am Heart Assoc 8(5):e009451
Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM (2009) Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 374(9683):29–38
Betensky RA (2015) Measures of follow-up in time-to-event studies: Why provide them and what should they be? Clin Trials 12(4):403–408
Khan SU, Rahman H, Talluri S, Kaluski E (2018) The clinical benefits and mortality reduction associated with catheter ablation in subjects with atrial fibrillation: a systematic review and meta-analysis. JACC Clin Electrophysiol 4(5):626–635
Gibson CM (2019) Rivaroxaban 2.5 mg BID combined with dual antiplatelet therapy for the prevention of death/MI/stroke: a patient level data meta-analysis of ATLAS-ACS-2 TIMI-51 and COMMANDER-HF. CRT, Washington, DC
Khan SU, Riaz IB, Rahman H, Lone AN, Raza M, Khan MS, Riaz A, Kaluski E (2019) Meta-analysis of duration of dual antiplatelet therapy in patients with acute coronary syndrome after percutaneous coronary intervention. Eur J Prev Cardiol 26(4):429–432
Lettino M, Leonardi S, De Maria E, Halvorsen S (2017) Antiplatelet and antithrombotic treatment for secondary prevention in ischaemic heart disease. Eur J Prev Cardiol 24:61–70
Funding
The authors have not received any funding for this project.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
No conflict of interest for authors Muhammad Zia Khan; Safi U. Khan; Zain Ul Abideen Asad; Shahul Valavoor; Muhammad Usman Khan, Muhammad Shahzeb Khan; Troy Krupica; and Mohamad Alkhouli. Dr. Kaluski is a speaker and consultant for Bristol-Myers Squibb, Pfizer, Janssen, and Daiichi-Saknyo.
Ethical approval
This article does not contain any studies with human participants performed by any of the authors. This article does not contain any studies with animals performed by any of the authors.
Informed consent
None needed.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Khan, S.U., Khan, M.Z., Asad, Z.U.A. et al. Efficacy and safety of low dose rivaroxaban in patients with coronary heart disease: a systematic review and meta-analysis. J Thromb Thrombolysis 50, 913–920 (2020). https://doi.org/10.1007/s11239-020-02114-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-020-02114-7