Antithrombotic drugs in coronary artery disease: risk benefit ratio and bleeding
2010; Elsevier BV; Volume: 8; Issue: 4 Linguagem: Inglês
10.1111/j.1538-7836.2010.03737.x
ISSN1538-7933
AutoresSam Schulman, Frederick A. Spencer,
Tópico(s)Acute Myocardial Infarction Research
ResumoSummaryThe antithrombotic treatment of coronary artery disease is becoming increasingly complex. Aspirin is often combined with more potent antiplatelet agents such as thienopyridines and glycoprotein IIb/IIIa inhibitors. The classic anticoagulant unfractionated heparin is giving way to low‐molecular‐weight heparin, the pentasaccharide fondaparinux and the direct thrombin inhibitor bivalirudin. Warfarin (or another vitamin K antagonist) and antiplatelet agents are often required in combination for several months. Patients and physicians who have experienced major bleeding complications sometimes question the benefit of these treatment strategies. It is therefore crucial to try and weigh the impact on efficacy against safety. In this review the net benefit is discussed both numerically, comparing absolute reductions vs. increases in risks, and also by addressing the qualitative importance of each component in reaching the net benefit. Except for primary prophylaxis in patients at low‐moderate risk for coronary events, there is a net benefit of antithrombotic therapy. With increasing severity of the coronary condition the net benefit generally prevails even with an increasing number of antithrombotic drugs combined. However, as the patient slowly stabilizes after appropriate interventions, it is necessary to de‐escalate the treatment in accordance with decreasing net benefit of prolonged combination therapy. The antithrombotic treatment of coronary artery disease is becoming increasingly complex. Aspirin is often combined with more potent antiplatelet agents such as thienopyridines and glycoprotein IIb/IIIa inhibitors. The classic anticoagulant unfractionated heparin is giving way to low‐molecular‐weight heparin, the pentasaccharide fondaparinux and the direct thrombin inhibitor bivalirudin. Warfarin (or another vitamin K antagonist) and antiplatelet agents are often required in combination for several months. Patients and physicians who have experienced major bleeding complications sometimes question the benefit of these treatment strategies. It is therefore crucial to try and weigh the impact on efficacy against safety. In this review the net benefit is discussed both numerically, comparing absolute reductions vs. increases in risks, and also by addressing the qualitative importance of each component in reaching the net benefit. Except for primary prophylaxis in patients at low‐moderate risk for coronary events, there is a net benefit of antithrombotic therapy. With increasing severity of the coronary condition the net benefit generally prevails even with an increasing number of antithrombotic drugs combined. However, as the patient slowly stabilizes after appropriate interventions, it is necessary to de‐escalate the treatment in accordance with decreasing net benefit of prolonged combination therapy. Antithrombotic therapy in coronary artery disease (CAD) is becoming increasingly complex with the use of intracoronary stents, requiring highly efficient prevention of stent thrombosis. Combined antiplatelet therapy with aspirin and clopidogrel becomes a challenge when the patient also has a strong indication for anticoagulant therapy. In the aftermath of acute coronary syndromes (ACS), even without primary coronary intervention (PCI), the discussion about the optimal antithrombotic therapy (i.e. aspirin alone or in combination with clopidogrel or a vitamin K antagonist) is still open [1Becker R.C. Antithrombotic therapy after myocardial infarction.N Engl J Med. 2002; 347: 1019-22Crossref PubMed Scopus (36) Google Scholar, 2Pfeffer M.A. Jarcho J.A. The charisma of subgroups and the subgroups of CHARISMA.N Engl J Med. 2006; 354: 1744-6Crossref PubMed Scopus (55) Google Scholar, 3Serebruany V.L. Aggressive antiplatelet strategies: time to reconsider?.Eur Heart J. 2007; 28: 2183-4Crossref PubMed Scopus (12) Google Scholar]. The problems clinicians have to deal with include (i) weighing the benefits of improved protection against recurrent ACS against the risk of bleeding, (ii) assessing when an apparent short‐term net benefit of combination therapy disappears during long‐term management and (iii) identifying the subgroups of patients that benefit the most and/or have the smallest risk of harm. Moreover, the antithrombotic drugs currently emerging on the clinical stage will pose new challenges. These drugs include the P2Y12 receptor blockers prasugrel [4Montalescot G. Wiviott S.D. Braunwald E. Murphy S.A. Gibson C.M. McCabe C.H. Antman E.M. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST‐elevation myocardial infarction (TRITON‐TIMI 38): double‐blind, randomised controlled trial.Lancet. 2009; 373: 723-31Abstract Full Text Full Text PDF PubMed Scopus (957) Google Scholar] and ticagrelor [5Wallentin L. Becker R.C. Budaj A. Cannon C.P. Emanuelsson H. Held C. Horrow J. Husted S. James S. Katus H. Mahaffey K.W. Scirica B.M. Skene A. Steg P.G. Storey R.F. Harrington R.A. Freij A. Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-57Crossref PubMed Scopus (5517) Google Scholar], specific coagulation inhibitors directed against factor Xa for acute, parenteral therapy, otamixaban [6Sabatine M.S. Antman E.M. Widimsky P. Ebrahim I.O. Kiss R.G. Saaiman A. Polasek R. Contant C.F. McCabe C.H. Braunwald E. Otamixaban for the treatment of patients with non‐ST‐elevation acute coronary syndromes (SEPIA‐ACS1 TIMI 42): a randomised, double‐blind, active‐controlled, phase 2 trial.Lancet. 2009; 374: 787-95Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar], or rivaroxaban [7Mega J.L. Braunwald E. Mohanavelu S. Burton P. Poulter R. Misselwitz F. Hricak V. Barnathan E.S. Bordes P. Witkowski A. Markov V. Oppenheimer L. Gibson C.M. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS‐TIMI 46): a randomised, double‐blind, phase II trial.Lancet. 2009; 374: 29-38Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar] or apixaban [8Alexander J.H. Becker R.C. Bhatt D.L. Cools F. Crea F. Dellborg M. Fox K.A. Goodman S.G. Harrington R.A. Huber K. Husted S. Lewis B.S. Lopez‐Sendon J. Mohan P. Montalescot G. Ruda M. Ruzyllo W. Verheugt F. Wallentin L. 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.Circulation. 2009; 119: 2877-85Crossref PubMed Scopus (428) Google Scholar]for oral, secondary prophylaxis, or against thrombin [9Wallentin L. Wilcox R.G. Weaver W.D. Emanuelsson H. Goodvin A. Nystrom P. Bylock A. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.Lancet. 2003; 362: 789-97Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 10Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. Pogue J. Reilly P.A. Themeles E. Varrone J. Wang S. Alings M. Xavier D. Zhu J. Diaz R. Lewis B.S. Darius H. Diener H.C. Joyner C.D. Wallentin L. the RE‐LY Steering Committee and InvestigatorsDabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-51Crossref PubMed Scopus (8831) Google Scholar]. Data from clinical phase II or III trials have been published but little is known about the risk of these therapies in different combinations with other antithrombotic agents. Thrombolytic therapy is not part of the topic reviewed here but adds another practical dimension to the era of combination therapies. Instead this review will focus on the different platelet inhibitors and anticoagulants although, due to space limitations, without going into details regarding different bolus or maintenance doses or exact timing. Plaque rupture involves platelet activation with adhesion and aggregation as well as ensuing thrombin generation and formation of a fibrin clot [11Boersma E. Mercado N. Poldermans D. Gardien M. Vos J. Simoons M.L. Acute myocardial infarction.Lancet. 2003; 361: 847-58Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar]. It is therefore logical to suggest a therapeutic strategy reducing the activity of many components in this process. Platelets, with their large numbers of agonists and receptors, are only moderately inhibited when a single target is aimed for, such as aspirin‐mediated cyclooxygenase inhibition with reduced formation of thromboxane A2. Additional blockade of the fibrinogen receptor, gpIIb/IIIa, or the ADP receptor, P2Y12, seems crucial to minimize platelet aggregation. This review of antithrombotic therapy will start from the simplest setting of primary prevention, where only one antithrombotic drug may be indicated. Continuing with established CAD the review ends with the three conditions requiring highly effective antithrombotic treatment: ST‐segment elevation myocardial infarction (STEMI), non‐ ST‐segment elevation myocardial infarction (NSTEMI) and PCI. The effectiveness of these agents (singly and in combination) will be balanced against the harm in terms of bleeding. Bleeding is often merely reported as ‘major bleeding’, for which not only various definitions exist [12Schulman S. Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients.J Thromb Haemost. 2005; 3: 692-4Crossref PubMed Scopus (3110) Google Scholar] but the components have very different clinical importance. A gastro‐intestinal bleeding event, requiring hospitalization for a couple of days and a few blood transfusions but thereafter full recovery, and an intracerebral hemorrhage with residual hemiparesis and complete dependence will count the same in the definition. Whenever possible, the internal balance between the types of hemorrhage will also be accounted for. A major hemorrhage is associated with worse prognosis, expressed as a 5‐fold higher risk of death within 30 days in patients with ACS [13Eikelboom J.W. Mehta S.R. Anand S.S. Xie C. Fox K.A. Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes.Circulation. 2006; 114: 774-82Crossref PubMed Scopus (1126) Google Scholar]. These fatal events may or may not be included in the efficacy outcome, depending on the definition including any death or only vascular death. In a recent meta‐analysis of individual data from six studies with 95 000 individuals with or without risk factors for IHD, the benefits and risks of aspirin (at doses between 75 and 500 mg) were assessed [14Baigent C. Blackwell L. Collins R. Emberson J. Godwin J. Peto R. Buring J. Hennekens C. Kearney P. Meade T. Patrono C. Roncaglioni M.C. Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta‐analysis of individual participant data from randomised trials.Lancet. 2009; 373: 1849-60Abstract Full Text Full Text PDF PubMed Scopus (2792) Google Scholar]. The absolute reduction of serious vascular events (myocardial infarction, stroke or vascular death) was modest compared with control (0.06% per year, P= 0.0001), with a similar effect on major coronary events (0.06%) and on non‐fatal myocardial infarction (0.05%). There was no reduction of vascular death or overall mortality. At the same time there was a borderline significant absolute increase in the risk of hemorrhagic stroke (0.01% per year, P= 0.05) and a significant increase of major extracranial hemorrhage (0.03%, P< 0.0001). Fatal hemorrhagic strokes were more frequent than fatal ischemic strokes. Taking into account that some of the extracranial hemorrhages were gastrointestinal, there may be a small net‐benefit clinically by using aspirin, but this is uncertain. Interestingly, the small proportional reduction in serious vascular events did not vary significantly based on age, sex, or other co‐morbidities (e.g. hypertension, hyperlipidemia, diabetes). The authors also questioned whether any observed benefit of aspirin for the prevention of vascular events might be even less in the current era given increased use of statins and antihypertensive medications in this population Table 1.Table 1Effect and harm of antithrombotic prophylaxis in primary prevention of coronary artery diseaseAgent [reference]PopulationEffectARR*, %HarmARI*, %Aspirin [14Baigent C. Blackwell L. Collins R. Emberson J. Godwin J. Peto R. Buring J. Hennekens C. Kearney P. Meade T. Patrono C. Roncaglioni M.C. Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta‐analysis of individual participant data from randomised trials.Lancet. 2009; 373: 1849-60Abstract Full Text Full Text PDF PubMed Scopus (2792) Google Scholar]No risk factorsMI/stroke/vascular death0.06Hemorrhagic stroke Extracranial major hemorrhage0.01 0.03Warfarin, INR 1.5 [18The Medical Research Council’s General Practice Research FrameworkThrombosis prevention trial: randomised trial of low‐intensity oral anticoagulation with warfarin and low‐dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk.Lancet. 1998; 351: 233-41Abstract Full Text Full Text PDF PubMed Scopus (862) Google Scholar]Men, high riskCoronary death, fatal & non‐fatal MI0.26Hemorrhagic stroke Extracranial major hemorrhage0.03 0.04ARR, absolute risk reduction in % per year; ARI, absolute risk increase in % per year; MI, myocardial infarction; INR, International Normalized Ratio. Open table in a new tab ARR, absolute risk reduction in % per year; ARI, absolute risk increase in % per year; MI, myocardial infarction; INR, International Normalized Ratio. In the largest single trial, the Women’s Health Study, primary prevention with aspirin, 100 mg, did not reduce the incidence of fatal or non‐fatal myocardial infarction or death from cardiovascular causes, whereas there was an absolute reduction of ischemic stroke (0.02% per year, P= 0.009) [15Ridker P.M. Cook N.R. Lee I.M. Gordon D. Gaziano J.M. Manson J.E. Hennekens C.H. Buring J.E. A randomized trial of low‐dose aspirin in the primary prevention of cardiovascular disease in women.N Engl J Med. 2005; 352: 1293-304Crossref PubMed Scopus (1707) Google Scholar]. Subgroup analysis indicated that there might be more benefit in women who are at least 65 years old. There was a significant increase in gastrointestinal bleeding and a non‐significant increase in intracerebral hemorrhage with aspirin. A recent meta‐analysis including 10 117 subjects enrolled in six randomized trials has also examined the role of aspirin in the prevention of cardiovascular events in subjects with diabetes [16De Berardis G. Sacco M. Strippoli G.F. Pellegrini F. Graziano G. Tognoni G. Nicolucci A. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta‐analysis of randomised controlled trials.BMJ. 2009; 339: b4531Crossref PubMed Scopus (333) Google Scholar]. Although a trend was seen toward the reduction of major cardiovascular events [cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke, and all‐cause mortality; relative risk (RR) 0.90, 95% confidence interval (CI) 0.81–1.00; P= 0.06], there were no significant decreases in the risk of myocardial infarction (0.86, 0.61–1.21), stroke (0.83, 0.60–1.14), vascular death (0.94, 0.72–1.23), or all‐cause mortality (0.93, 0.82–1.05). The combination of clopidogrel and aspirin compared with aspirin alone was studied in the CHARISMA trial, but 78% of the patients had already manifested cardiovascular disease [17Bhatt D.L. Fox K.A. Hacke W. Berger P.B. Black H.R. Boden W.E. Cacoub P. Cohen E.A. Creager M.A. Easton J.D. Flather M.D. Haffner S.M. Hamm C.W. Hankey G.J. Johnston S.C. Mak K.H. Mas J.L. Montalescot G. Pearson T.A. Steg P.G. et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. 2006; 354: 1706-17Crossref PubMed Scopus (2441) Google Scholar]. Among the remaining asymptomatic patients with multiple risk factors, the rate of major vascular events did not differ significantly between patients on combination therapy vs. aspirin alone (6.6% vs. 5.2%, P= 0.2). In addition, the rate of cardiovascular death was higher with clopidogrel (3.9% vs. 2.2%, P= 0.01). Warfarin at a low intensity, targeted at an International Normalized Ratio (INR) of 1.5 was compared with aspirin, 75 mg per day, in a factorial design in the Thrombosis Prevention Trial with 5085 men at high risk of ischemic heart disease [18The Medical Research Council’s General Practice Research FrameworkThrombosis prevention trial: randomised trial of low‐intensity oral anticoagulation with warfarin and low‐dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk.Lancet. 1998; 351: 233-41Abstract Full Text Full Text PDF PubMed Scopus (862) Google Scholar]. Both aspirin and warfarin reduced the risk of a first episode of IHD by 20%, corresponding to an absolute risk reduction of 0.26% and 0.23%, respectively, per year. There was an absolute increase of hemorrhagic stroke and of extracranial bleeding of 0.03% and 0.04% per year, respectively, with warfarin compared with no warfarin and of 0.05% and 0.04% per year, respectively, with aspirin compared with no aspirin, thus still retaining a net benefit with either alternative. This applies to men in the top 20–25% risk score stratum. In summary, primary prevention provides a clear net benefit only in patients at high risk and may then be given with either low‐intensity warfarin or with aspirin. The combination of aspirin and clopidogrel for primary prevention is not indicated and may be associated with harm. The meta‐analysis by the Antithrombotic Therapy Trialists’ Collaboration also addressed studies on secondary prophylaxis with aspirin [14Baigent C. Blackwell L. Collins R. Emberson J. Godwin J. Peto R. Buring J. Hennekens C. Kearney P. Meade T. Patrono C. Roncaglioni M.C. Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta‐analysis of individual participant data from randomised trials.Lancet. 2009; 373: 1849-60Abstract Full Text Full Text PDF PubMed Scopus (2792) Google Scholar]. The absolute risk reduction of serious vascular events was more impressive than in primary prevention, 1.5% per year compared with placebo (P< 0.0001) and specifically for coronary events 1.0%. Hemorrhagic strokes and other major bleeding were incompletely reported in the trials on secondary prophylaxis but the authors identified an incidence of hemorrhagic stroke of 0.17% per year with aspirin vs. 0.09% per year on placebo Table 2.Table 2Effect and harm of antithrombotic prophylaxis in secondary prevention of coronary artery diseaseAgent [reference]PopulationEffectARR*, %HarmARI*, %Aspirin [14Baigent C. Blackwell L. Collins R. Emberson J. Godwin J. Peto R. Buring J. Hennekens C. Kearney P. Meade T. Patrono C. Roncaglioni M.C. Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta‐analysis of individual participant data from randomised trials.Lancet. 2009; 373: 1849-60Abstract Full Text Full Text PDF PubMed Scopus (2792) Google Scholar]Previous vascular eventMI/stroke/vascular death Major coronary events1.5 1.0Hemorrhagic stroke Extracranial major hemorrhage0.08 NEClopidogrel + aspirin (vs. aspirin alone) [21Bowry A.D. Brookhart M.A. Choudhry N.K. Meta‐analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events.Am J Cardiol. 2008; 101: 960-6Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]After ACSMajor coronary events1.2Major hemorrhage, long treatment, short treatment1.9 0.05Ticagrelor (+ASA) vs. Clopidogrel (+ASA) [5Wallentin L. Becker R.C. Budaj A. Cannon C.P. Emanuelsson H. Held C. Horrow J. Husted S. James S. Katus H. Mahaffey K.W. Scirica B.M. Skene A. Steg P.G. Storey R.F. Harrington R.A. Freij A. Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-57Crossref PubMed Scopus (5517) Google Scholar]After ACSMI/stroke/vascular death All‐cause mortality1.9 1.4Major hemorrhage (non‐CABG)0.7Warfarin + aspirin (vs. aspirin alone) [22Andreotti F. Testa L. Biondi‐Zoccai G.G. Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta‐analysis of 25,307 patients.Eur Heart J. 2006; 27: 519-26Crossref PubMed Scopus (270) Google Scholar]After ACSAll‐cause mortality, non‐fatal MI or ischemic stroke3.0Hemorrhagic stroke Major hemorrhage0.2 1.5ARR, absolute risk reduction in % per year; ARI, absolute risk increase in % per year; MI, myocardial infarction; NE, non‐evaluable; ACS, acute coronary syndrome; CABG, coronary artery bypass grafting. Open table in a new tab ARR, absolute risk reduction in % per year; ARI, absolute risk increase in % per year; MI, myocardial infarction; NE, non‐evaluable; ACS, acute coronary syndrome; CABG, coronary artery bypass grafting. The efficacy and safety of combination of clopidogrel and aspirin compared with antiplatelet monotherapy was assessed in a Cochrane review [19Keller T.T. Squizzato A. Middeldorp S. Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease.Cochrane Database Syst Rev. 2007; : CD005158PubMed Google Scholar] including two randomized clinical trials (the CHARISMA trial [17Bhatt D.L. Fox K.A. Hacke W. Berger P.B. Black H.R. Boden W.E. Cacoub P. Cohen E.A. Creager M.A. Easton J.D. Flather M.D. Haffner S.M. Hamm C.W. Hankey G.J. Johnston S.C. Mak K.H. Mas J.L. Montalescot G. Pearson T.A. Steg P.G. et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. 2006; 354: 1706-17Crossref PubMed Scopus (2441) Google Scholar] and the Clopidogrel in Unstable Angina to Prevent Recurrent Events, CURE, study [20Yusuf S. Zhao F. Mehta S.R. Chrolavicius S. Tognoni G. Fox K.K. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST‐segment elevation.N Engl J Med. 2001; 345: 494-502Crossref PubMed Scopus (6033) Google Scholar]). The use of combination therapy vs. aspirin alone was associated with a lower risk of cardiovascular events (OR 0.87, 95% CI 0.81–0.94) but a higher risk of major bleeding [odds ratio (OR) 1.34, 95% CI 1.14–1.57]. Interestingly, treatment effect differed by study. In the CURE study, which treated patients following NSTEMI for 3–12 months, 23 vascular events would be avoided and 10 major bleeds would be caused by treating 1000 patients with combination therapy for a mean period of 9 months. In CHARISMA, which enrolled subjects with existing vascular disease or at high risk for vascular disease, five vascular events would be avoided and three major bleeds caused for every 1000 subjects treated for 28 months [17Bhatt D.L. Fox K.A. Hacke W. Berger P.B. Black H.R. Boden W.E. Cacoub P. Cohen E.A. Creager M.A. Easton J.D. Flather M.D. Haffner S.M. Hamm C.W. Hankey G.J. Johnston S.C. Mak K.H. Mas J.L. Montalescot G. Pearson T.A. Steg P.G. et al.Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. 2006; 354: 1706-17Crossref PubMed Scopus (2441) Google Scholar]. Furthermore, in a meta‐analysis of eight trials with 91 744 patients [21Bowry A.D. Brookhart M.A. Choudhry N.K. Meta‐analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events.Am J Cardiol. 2008; 101: 960-6Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar] three of the studies were in 61 905 patients with unstable angina or myocardial infarction. The follow‐up in these studies ranged from 28 days to 12 months. The absolute risk reduction for major coronary events was 1.2% with dual therapy but again without any reduction in all‐cause mortality. The risk of major bleeding was not increased significantly by dual therapy in these three trials (OR 1.24, 95% CI 0.97–1.59). However, when studies in patients with various indications and with long treatment (8–28 months) were analyzed there was an absolute increase of major bleeding of 1.9% vs. a non‐significant increase of 0.05% in patients from studies with 1 month of treatment. Combined treatment specifically in ACS patients during the first 30 days is discussed below. Given the success of dual antiplatelet therapy, subsequent studies have evaluated agents that may prove even more effective than clopidogrel in combination with aspirin. Clopidogrel is a prodrug and an irreversible inhibitor of the adenosine diphosphate receptor P2Y12. It was recently compared with the direct and reversible inhibitor ticagrelor in 18 624 patients with ACS, out of whom about 60% had unstable angina or NSTEMI [5Wallentin L. Becker R.C. Budaj A. Cannon C.P. Emanuelsson H. Held C. Horrow J. Husted S. James S. Katus H. Mahaffey K.W. Scirica B.M. Skene A. Steg P.G. Storey R.F. Harrington R.A. Freij A. Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-57Crossref PubMed Scopus (5517) Google Scholar]. Aspirin was also given to 97.5% of the patients. After 12 months ticagrelor provided an absolute risk reduction for the composite outcome (vascular death, myocardial infarction or stroke) of 1.9%, driven by reductions in myocardial infarction and vascular death. There was also an absolute risk reduction of all‐cause mortality of 1.4%. Against this there was an absolute increase of non‐bypass surgery‐related major bleeding of 0.6% and life‐threatening bleeding of 0.5%. Given the importance of both platelet activity and plasma coagulation for the development of ACS and plaque development, the combination of aspirin and warfarin has been heavily studied in patients with CAD. A meta‐analysis of 14 studies with 25 307 patients treated after ACS did not reveal a significant reduction of the composite of all‐cause mortality and non‐fatal myocardial infarction or ischemic stroke with the combination compared with aspirin alone [22Andreotti F. Testa L. Biondi‐Zoccai G.G. Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta‐analysis of 25,307 patients.Eur Heart J. 2006; 27: 519-26Crossref PubMed Scopus (270) Google Scholar]. However, when four studies with the therapeutic range INR below 2.0 were excluded, the absolute risk reduction for these events was 3.0%, driven by reductions of non‐fatal myocardial infarction or ischemic stroke but not all‐cause mortality. The absolute increase in the risk of major bleeding with combination therapy was 1.5% and for intracranial hemorrhage it was 0.2%, which was not statistically significant. The largest individual study with the therapeutic range of at least INR 2.0 was the warfarin sub‐study of OASIS 2 with 3712 patients [23The Organization to Assess Strategies for Ischemic Syndromes (OASIS) InvestigatorsEffects of long‐term, moderate‐intensity oral anticoagulation in addition to aspirin in unstable angina.J Am Coll Cardiol. 2001; 37: 475-84Crossref PubMed Scopus (104) Google Scholar]. The authors further sub‐grouped the study population as belonging to good‐complier countries, where at least 70% were still on warfarin at 35 days, and poor‐complier countries, where this proportion was lower. The absolute risk reduction in these two sub‐groups for the primary outcome (cardiovascular death, myocardial infarction or stroke) was 2.8% and 1.2%, respectively, whereas the absolute increase in the risk of life‐threatening bleeding or major bleeding was 0.4% and 1.6% vs. 0.8% and 1.0%, respectively. In WARIS II, which continued for a mean of 4 years, the combination of warfarin and aspirin provided an absolute risk reduction of death, non‐fatal myocardial infarction or thrombotic stroke of 1.2% per year vs. aspirin alone and of 0.4% vs. higher intensity warfarin alone [24Hurlen M. Abdelnoor M. Smith P. Erikssen J. Arnesen H. Warfarin, aspirin, or both after myocardial infarction.N Engl J Med. 2002; 347: 969-74Crossref PubMed Scopus (783) Google Scholar]. The risk of major bleeding increased by 0.45% per year with both the combined treatment and with warfarin alone vs. aspirin alone. The vast majority of the major bleedings were gastrointestinal. There was neither any decrease in mortality nor any increase in intracerebral hemorrhage with the combination. It should be borne in mind that 77% of cross‐sectional INR results were at least 2.0 and that warfarin management is traditionally well performed in Norway. In summary, there is a substantial net benefit of aspirin alone vs. nothing after acute coronary syndromes. The additional net benefit of aspirin plus clopidogrel is convincing for up to 3–12 months following acute coronary syndrome but is of no clear benefit thereafter. Ticagrelor may prove to be a better alternative than clopidogrel, offering increased net benefit but with an increased risk of important bleeding. The net benefit identified for aspirin plus warfarin seems to be present mainly when the treatment continues for several months or perhaps years in the case of access to good management, as seen in WARIS II. It can be assumed that the vast majority of patients with STEMI (except those with aspirin allergy) receive aspirin, which therefore will not be discussed here. The net‐benefit derived from clopidogrel in addition to aspirin has been discussed above. The CURE trial was specifically in patients (n = 12 562) with NSTEMI [20Yusuf S. Zhao F. Mehta S.R. Chrolavicius S. Tognoni G. Fox K.K. Effects of clopidogrel in addition to aspirin in patients with acute corona
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