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European Journal of Clinical Pharmacology

, Volume 74, Issue 7, pp 853–862 | Cite as

Recent major advances in cardiovascular pharmacotherapy

  • James Milner
  • Andreia Cunha
  • Carlota Gamboa-Cruz
  • Julie Reis
  • Márcia Campos
  • Natália António
Review

Abstract

The field of cardiovascular pharmacotherapy remains extremely active. The aim of this review is to summarize the recent major advances in cardiovascular pharmacotherapy, with a focus on (1) the new approved drug for treatment of heart failure with reduced ejection fraction—sacubitril/valsartan; (2) proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors; (3) the novel reversal agents for non-vitamin K oral anticoagulants (NOACs); and finally, (4) new evidence on pharmacological treatment of coronary artery disease.

Keywords

Cardiovascular drugs Systolic heart failure Coronary artery disease Hypercholesterolemia Anticoagulation agents Antidotes 

Notes

Author contributions

All authors listed meet the International Committee of Medical Journal Editors criteria for authorship. The first draft was written by Milner J, Cunha A, Gamboa-Cruz C, and Reis J, and Campos M designed the work. António N critically revised the manuscript. All authors take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Havakuk O, Elkayam U (2017) Angiotensin receptor-neprilysin inhibition. J Cardiovasc Pharmacol Ther 22(4):356–364CrossRefPubMedGoogle Scholar
  2. 2.
    McCormack PL (2016) Sacubitril/valsartan: a review in chronic heart failure with reduced ejection fraction. Drugs 76(3):387–396CrossRefPubMedGoogle Scholar
  3. 3.
    Howell E, Cameron S (2016) Neprilysin inhibition: a brief review of past pharmacological strategies for heart failure treatment and future directions. Cardiol J 23(6):591–598CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Kaplinsky E (2016) Sacubitril/valsartan in heart failure: latest evidence and place in therapy. Ther Adv Chronic Dis 7(6):278–290CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sible AM, Nawarskas JJ, Alajajian D, Anderson JR (2016) Sacubitril/valsartan: a novel cardiovascular combination agent. Cardiol Rev 24(1):41–47CrossRefPubMedGoogle Scholar
  6. 6.
    Singh JSS, Burrell LM, Cherif M, Squire IB, Clark AL, Lang CC (2017) Sacubitril/valsartan: beyond natriuretic peptides. Heart 103(20):1569–1577CrossRefPubMedGoogle Scholar
  7. 7.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, ESC Scientific Document Group (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 37(27):2129–2200CrossRefPubMedGoogle Scholar
  8. 8.
    Farmakis D, Bistola V, Karavidas A, Parissis J (2016) Practical considerations on the introduction of sacubitril/valsartan in clinical practice: current evidence and early experience. Int J Cardiol 223:781–784CrossRefPubMedGoogle Scholar
  9. 9.
    McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, PARADIGM-HF Investigators and Committees (2014) Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371(11):993–1004CrossRefPubMedGoogle Scholar
  10. 10.
    Vodovar N, Paquet C, Mebazaa A, Launay JM, Hugon J, Cohen-Solal A (2015) Neprilysin, cardiovascular, and Alzheimer’s diseases: the therapeutic split? Eur Heart J 36(15):902–905CrossRefPubMedGoogle Scholar
  11. 11.
    Russo R, Borghi R, Markesbery W, Tabaton M, Piccini A (2005) Neprylisin decreases uniformly in Alzheimer’s disease and in normal aging. FEBS Lett 579(27):6027–6030CrossRefPubMedGoogle Scholar
  12. 12.
    Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, W Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH (2004) Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364(9435):685–696CrossRefPubMedGoogle Scholar
  13. 13.
    Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J, Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K, Goormastic M, Tuzcu EM, ASTEROID Investigators (2006) Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 295(13):1556–1565CrossRefPubMedGoogle Scholar
  14. 14.
    Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgozo lu L, Nordestgaard BG, Bruckert E, de Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, Marz W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN, European Atherosclerosis Society Consensus, European Atherosclerosis Society Consensus, Stroes E, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgozo lu L, Nordestgaard BG, Bruckert E, Krauss RM, Laufs U, Santos RD, Marz W, Newman CB, John Chapman M, Ginsberg HN, John Chapman M, Ginsberg HN, de Backer G, Catapano AL, Hegele RA, Kees Hovingh G, Jacobson TA, Leiter L, Mach F, Wiklund O (2015) Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society consensus panel statement on assessment, aetiology and management. Eur Heart J 36(17):1012–1022CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Svatikova A, Kopecky SL (2017) Cholesterol management in the era of PCSK9 inhibitors. Curr Cardiol Rep 19(9):1–5CrossRefGoogle Scholar
  16. 16.
    Gencer B, Montecucco F, Nanchen D, Carbone F, Klingenberg R, Vuilleumier N, Aghlmandi S, Heg D, Räber L, Auer R, Jüni P, Windecker S, Lüscher TF, Matter CM, Rodondi N, Mach F (2016) Prognostic value of PCSK9 levels in patients with acute coronary syndromes. Eur Heart J 37(6):546–553CrossRefPubMedGoogle Scholar
  17. 17.
    Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34(2):154–156CrossRefPubMedGoogle Scholar
  18. 18.
    Scherer DJ, Nelson A, Psaltis PJ (2017) Targeting LDL cholesterol with PCSK9 inhibitors. Intern Med J 47(8):856–865CrossRefPubMedGoogle Scholar
  19. 19.
    Lagace TA (2014) PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol 25(5):387–393CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJP, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE (2016) Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 316(22):2373–2384CrossRefPubMedGoogle Scholar
  21. 21.
    Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators (2017) Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 376(18):1713–1722CrossRefPubMedGoogle Scholar
  22. 22.
    Chaudhary R, Garg J, Shah N, Sumner A (2017) PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol 9(2):76–91CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, Flather M, Glynn RJ, Gregoire J, Jukema JW, Karpov Y, Kastelein JJP, Koenig W, Lorenzatti A, Manga P, Masiukiewicz U, Miller M, Mosterd A, Murin J, Nicolau JC, Nissen S, Ponikowski P, Santos RD, Schwartz PF, Soran H, White H, Wright RS, Vrablik M, Yunis C, Shear CL, Tardif JC, SPIRE Cardiovascular Outcome Investigators (2017) Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 376(16):1527–1539CrossRefPubMedGoogle Scholar
  24. 24.
    Toth PP, Worthy G, Gandra SR et al (2017) Systematic review and network meta-analysis on the efficacy of evolocumab and other therapies for the management of lipid levels in hyperlipidemia. J Am Heart Assoc 6(10):e005367CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Stadler SL, Cook TJ (2017) PCSK9 inhibitors and managing cost in the managed care setting. Am J Manag Care 23(9 Suppl):S149–S155PubMedGoogle Scholar
  26. 26.
    Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, el Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, ODYSSEY LONG TERM Investigators (2015) Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 372(16):1489–1499CrossRefPubMedGoogle Scholar
  27. 27.
    Pucci G, Cicero AF, Borghi C, Schillaci G (2017) Emerging biologic therapies for hypercholesterolaemia. Expert Opin Biol Ther 17(9):1077–1087CrossRefPubMedGoogle Scholar
  28. 28.
    Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, Hall T, Troquay RPT, Turner T, Visseren FLJ, Wijngaard P, Wright RS, Kastelein JJP (2017) Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 376(15):1430–1440CrossRefPubMedGoogle Scholar
  29. 29.
    Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, de Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GYH, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37(38):2893–2962CrossRefPubMedGoogle Scholar
  30. 30.
    Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146(12):857–867CrossRefPubMedGoogle Scholar
  31. 31.
    Mekaj YH, Mekaj AY, Duci SB, Miftari EI (2015) New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 11:967–977CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W (2002) Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 45(9):1757–1766CrossRefPubMedGoogle Scholar
  33. 33.
    Wienen W, Stassen J, Priepke H, Ries UJ, Hauel N (2007) In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. Thromb Haemost 98(1):155–162PubMedGoogle Scholar
  34. 34.
    Garcia D, Libby E, Crowther MA (2010) The new oral anticoagulants. Blood 115(1):15–20CrossRefPubMedGoogle Scholar
  35. 35.
    Crowther M, Crowther MA (2015) Antidotes for novel oral anticoagulants: current status and future potential. Arterioscler Thromb Vasc Biol 35(88):1736–1745CrossRefPubMedGoogle Scholar
  36. 36.
    Hu TY, Vaidya VR, Asirvatham SJ (2016) Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag 12:35–44PubMedPubMedCentralGoogle Scholar
  37. 37.
    Singer AJ, Wilson S (2017) Reversal strategies for newer oral anticoagulants. AACN Adv Crit Care 28(4):322–331CrossRefPubMedGoogle Scholar
  38. 38.
    Monagle S, Eikelboom JW, Ng KH, Bhagirath VC (2017) Clinical implications of reversal agents for direct oral anticoagulants. Futur Cardiol 13(2):153–159CrossRefGoogle Scholar
  39. 39.
    Pollack CV Jr, Reilly PA, van Ryn J et al (2017) Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med 377(5):431–441CrossRefPubMedGoogle Scholar
  40. 40.
    Ghadimi K, Dombrowski KE, Levy JH, Welsby IJ (2016) Andexanet alfa for the reversal of factor Xa inhibitor related anticoagulation. Expert Rev Hematol 9(2):115–122CrossRefPubMedGoogle Scholar
  41. 41.
    Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso MA, Brown K, Dishy V, Lanz HJ, Mercuri MF, Noveck RJ, Costin JC (2017) Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost 117(2):238–245CrossRefPubMedGoogle Scholar
  42. 42.
    Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, Sacco RL, Connolly SJ, Cryptogenic Stroke/ESUS International Working Group (2014) Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 13(4):429–438CrossRefPubMedGoogle Scholar
  43. 43.
    Diener HC, Bernstein R, Hart R (2017) Secondary stroke prevention in cryptogenic stroke and embolic stroke of undetermined source (ESUS). Curr Neurol Neurosci Rep 17(9):64CrossRefPubMedGoogle Scholar
  44. 44.
    Perera KS, Vanassche T, Bosch J, Giruparajah M, Swaminathan B, Mattina KR, Berkowitz SD, Arauz A, O’Donnell MJ, Ameriso SF, Hankey GJ, Yoon BW, Lavallee P, Cunha L, Shamalov N, Brouns R, Gagliardi RJ, Kasner SE, Pieroni A, Vermehren P, Kitagawa K, Wang Y, Muir K, Coutinho J, Vastagh I, Connolly SJ, Hart RG, ESUS Global Registry Investigators (2016) Embolic strokes of undetermined source: prevalence and patient features in the ESUS Global Registry. Int J Stroke 11(5):526–533CrossRefPubMedGoogle Scholar
  45. 45.
    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, ATLAS ACS 2–TIMI 51 Investigators (2012) Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 366(1):9–19CrossRefPubMedGoogle Scholar
  46. 46.
    Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, Pare G, Kirsch B, Pogue J, Pater C, Peters G, Davalos A, Lang W, Wang Y, Wang Y, Cunha L, Eckstein J, Tatlisumak T, Shamalov N, Mikulik R, Lavados P, Hankey GJ, Czlonkowska A, Toni D, Ameriso SF, Gagliardi RJ, Amarenco P, Bereczki D, Uchiyama S, Lindgren A, Endres M, Brouns R, Yoon BW, Ntaios G, Veltkamp R, Muir KW, Ozturk S, Arauz A, Bornstein N, Bryer A, O’Donnell MJ, Weitz J, Peacock F, Themeles E, Connolly SJ (2016) Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: design of the NAVIGATE ESUS randomized trial. Eur Stroke J 1(3):146–154CrossRefGoogle Scholar
  47. 47.
    Loomba RS, Nijhawan K, Aggarwal S, Arora RR (2016) Oxygen in the setting of acute myocardial infarction. J Cardiovasc Pharmacol Ther 21(2):143–149CrossRefPubMedGoogle Scholar
  48. 48.
    Stub D, Smith K, Bernard S, Nehme Z, Stephenson M, Bray JE, Cameron P, Barger B, Ellims AH, Taylor AJ, Meredith IT, Kaye DM, on behalf of the AVOID Investigators* (2015) Air versus oxygen in ST-segment-elevation myocardial infarction. Circulation 131(24):2143–2150CrossRefPubMedGoogle Scholar
  49. 49.
    Hofmann R, James SK, Jernberg T, Lindahl B, Erlinge D, Witt N, Arefalk G, Frick M, Alfredsson J, Nilsson L, Ravn-Fischer A, Omerovic E, Kellerth T, Sparv D, Ekelund U, Linder R, Ekström M, Lauermann J, Haaga U, Pernow J, Östlund O, Herlitz J, Svensson L, DETO2X–SWEDEHEART Investigators (2017) Oxygen therapy in suspected acute myocardial infarction. N Engl J Med 377(13):1240–1249CrossRefPubMedGoogle Scholar
  50. 50.
    McNulty PH, Robertson BJ, Tulli MA et al (2007) Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease. J Appl Physiol (1985) 102(5):2040–2045CrossRefGoogle Scholar
  51. 51.
    Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P, ESC Scientific Document Group (2018) 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 39(2):119–177CrossRefPubMedGoogle Scholar
  52. 52.
    Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O’Shaughnessy C, Ganz P, Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators (2005) Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 352(1):29–38CrossRefPubMedGoogle Scholar
  53. 53.
    Capodanno D, Angiolillo DJ (2017) Canakinumab for secondary prevention of atherosclerotic disease. Expert Opin Biol Ther 18(2):215–220CrossRefPubMedGoogle Scholar
  54. 54.
    Ridker PM, Everett BM, Thuren T, MacFadyen J, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131CrossRefPubMedGoogle Scholar
  55. 55.
    Libby P (2017) Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. J Am Coll Cardiol 70(18):2278–2289CrossRefPubMedGoogle Scholar
  56. 56.
    Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, de Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L, APPRAISE-2 Investigators (2011) Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 365(8):699–708CrossRefPubMedGoogle Scholar
  57. 57.
    Andreotti F, Testa L, Biondi-Zoccai GGL, Crea F (2006) Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25 307 patients. Eur Heart J 27(5):519–526CrossRefPubMedGoogle Scholar
  58. 58.
    Anand SS, Yusuf S (2003) Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 41(4 Suppl S):62S–69SCrossRefPubMedGoogle Scholar
  59. 59.
    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, Störk 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, COMPASS Investigators (2017) Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 377(14):1319–1330CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cardiology DepartmentCoimbra Hospital and Universitary CentreCoimbraPortugal
  2. 2.Institute of Pharmacology and Therapeutics, Faculty of MedicineUniversity of CoimbraCoimbraPortugal

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