NEWS & VIEWS DECADE IN REVIEW—ACUTE CORONARY SYNDROMES

Successes and future objectives in acute coronary syndrome Frans Van de Werf

The past decade has seen considerable advances in the treatment of acute coronary syndromes (ACS), particularly in the search for improved antithrombotic therapies. Despite these successes, however, renewed efforts are needed to improve long-term outcomes after ACS by reducing recurrent ischaemic events and lowering the risk of bleeding complications. Van de Werf, F. Nat. Rev. Cardiol. advance online publication 2 September 2014; doi:10.1038/nrcardio.2014.129

By 10 years ago, aspirin and clopidogrel therapy for 1 year was already the standard treatment for all patients with acute coronary syndrome (ACS), despite the benefit of this dual antiplatelet therapy never having been formally studied in patients with ST-segment elevation myocardial infarction (STEMI). Without a doubt, the majority of clinical studies in ACS performed in the past decade have focused on attempts to find more efficacious and safer antithrombotic treatments than aspirin and clopidogrel dual antiplatelet therapy. The most successful trial in this regard was PLATO,1 which showed significantly improved outcomes (including recurrent myocardial infarction, stent thrombosis, death from vascular causes, and even all-cause mortality) with ticagrelor, a new oral, reversible, directacting­P2Y purinoreceptor 12 (P2Y12) antagonist, when compared with clopidogrel; the study included patients with either STEMI or non-STEMI (NSTEMI). Pleiotropic actions, such as increased adenosine plasma concentrations, were suggested to have contributed to the beneficial effect of ticagrelor. The overall excess spontaneous bleeding rate with this new, more powerful agent was small, but the trend towards an increased risk of intracranial haemorrhage observed in this study was a concern. One of the possible reasons why newer P2Y12 antagonists, such as cangrelor, pra­ sugrel, and ticagrelor, are superior to clopi­ dogrel in large clinical trials is the existence of genetic variants of hepatic cytochrome P450 (CYP) enzymes responsible for converting clopidogrel to its active metabolite. Several

studies have shown that carriers of an allele that resulted in reduced CYP function had lower levels of the active metabolite and higher rates of major cardiovascular events. As such, carriers of CYP loss-of-function variants who are receiving clopidogrel are likely to be especially at risk of stent thrombosis. The concerns about interindividual variability in the antiplatelet effect of clopidogrel have led to a number of studies aimed at monitoring platelet function and adjusting treatment accordingly. Surprisingly, in one of the largest randomized studies, which included 2,440 patients scheduled for coronary stenting (of whom 657 had NSTEMI), no improvement in clinical outcomes at 1 year was observed with platelet-function monitoring and treatment adjustments as compared with standard treatment without monitoring.2 Genetic testing and plateletfunction monitoring have not become routine tests in patients taking clopidogrel. Bivalirudin has replaced heparin in many hospitals, especially for patients undergoing primary percutaneous coronary intervention (PCI), owing mainly to the results of the HORIZONS‑AMI study. 3 This trial showed significantly reduced bleeding rates and decreased 30‑day mortality with bivalirudin alone when compared with heparin plus a glycoprotein (GP) IIb/ IIIa (integrin αIIbβ3) antagonist.3 However, the benefit of bivalirudin for primary PCI was challenged by the results of a singlecentre trial (HEAT‑PPCI4),in which GP IIb/ IIIa antagonists were used only for bailout (bivalirudin versus heparin): fewer ischaemic events occurred with heparin than with

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bivalirudin and, surprisingly (in contrast to all previous trials), no reduction in bleeding complications was found with bivalirudin. Whether these data should change practice and whether a new, large multicentre trial is needed is currently a matter of hot debate. Despite the progress made with anti­ thrombotic therapy and revascularization in the early phase of an ACS, recurrent ischaemic events and long-term mortality remain high. One explanation could be that dual antiplatelet therapy consisting of aspirin and clopidogrel does not provide sufficient longterm protection against recurrent thrombotic events. In two large studies,5,6 an additional antithrombotic agent was tested in combination with aspirin and c­ lopidogrel: vorapaxar, an antagonist of the thrombin receptor PAR‑1 (protease-activate­d receptor 1), was used in the TRA 2P trial,5 and rivaroxaban, a direct oral inhibitor of fac­tor Xa, was used in ATLAS‑2.6 Although increased bleeding rates were observed in both studies (and the TRA 2P study even had to be stopped prematurely in the subgroup of patients with a history of stroke, owing to an excess rate of intra­cranial haemorrhage), selected populations did benefit from adding a third antithrombotic drug. In the group of >17,000 patients with a previous myocardial infarction, addition of vorapaxar reduced the risk of cardiovascular death, myo­cardial infarction, or stroke—at the cost of an increased risk of moderate or severe bleeding, but without a significant increase in intra­cranial haemorrhage. 5 In ATLAS‑2, 6 low-dose rivaroxaban (2.5 mg twice daily) also significantly reduced the risk of the composite end point of cardiovascular death, myocardial infarction, and stroke and, surprisingly, also reduced rates of stent thrombosis and death from any cause. Whether these agents are also beneficial and safe when, for instance, ticagrelor or pra­sugrel is used in combination with aspirin, is unknown. Similarly, whether aspirin can be dropped if a new P2Y12 antagonist is given in combination with vorapaxar or low-dose rivaroxaban remains to be determined. New studies of simplified antithrombotic regimens that are underway or in the planning phase should take into account the possible benefits and risks of new a­ntithrombotic combinations (Figure 1). ADVANCE ONLINE PUBLICATION  |  1

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NEWS & VIEWS

Haemorrhagic risk

PLATO1 and subgroups of TRA 2P5 or ATLAS-26

No option

Standard antithrombotic treatment

Range of possible results of a simplified antithrombotic regimen Risk of thrombosis

Figure 1 | The balance of risks in treatment of acute coronary syndrome. Patients with acute coronary syndrome receive therapies aimed at reducing the risk of thrombosis, but antithrombotic treatments carry an increased risk of bleeding complications. New therapeutic approaches should minimize the possibility of thrombotic events while keeping haemorrhagic risk at acceptable levels, or even reduce the risk when compared with current treatment.

A number of trials to study the optimal timing of angiography and revascularization in patients with NSTEMI yielded discordant results. In the TIMACS trial,7 >3,000 patients with ACS were randomly assigned to either routine early intervention or delayed intervention (either 36 h after treatment assignment, respectively). In the total population, a nonsignificant 15% reduction in the composite end point of death, myocardial infarction, or stroke was observed when comparing early versus delayed treatment. However, in line with other studies, early intervention in highrisk patients led to a significant 35% reduction in the risk of death, new myocardial infarction, or stroke when compared with delayed intervention.7 The use of increasingly powerful anti­ thrombotic agents has raised concern about bleeding. Major bleeding complications are indeed common, and most occur at the vascular access site. In the RIVAL trial,8 >7,000 patients with ACS, including almost 2,000 patients with STEMI,

were randomly allocated to either radial or femoral access. Overall, a lower rate of local vascular complications was observed with the radial approach than with femoral access. Remarkably, patients with STEMI had better clinical outcomes (including reduced mortality) when treated via radial access, suggesting that this approach might be particularly preferable in patients with STEMI.8 Data from all registries show that, in patients with STEMI, door-to-balloon times have declined significantly over the past 10 years. The implementation of emergency medical systems based on a network of hospitals with various levels of technology connected by an efficient ambulance system has reduced pre-PCI delays in many places.9 How­e ver, in a large US study of almost 100,000 patients with STEMI, in-hospital mortality remained unchanged despite significant improvement in door-to-balloon times, indicating that other components of the total ischaemic time need to be targeted.9 Administration of a fibrinolytic agent to patients who cannot undergo timely PCI is a strategy that might be incorporated into prehospital care. In the STREAM trial10 of ~2,000 patients presenting with early STEMI, prehospital administration of tenecteplase (half the normal dose in elderly individuals) to patients who could not undergo PCI within 1 h resulted in rates of the composite end point of death, shock, congestive heart failure, or recurrent infarction at 30 days that were similar to those in patients receiving standard primary PCI. Emergency coronary angiography on arrival in the PCI hospital could be avoided in almost two-thirds of patients treated with tenecteplase.10 This strategy needs to be further explored in patients with long transport times, especially elderly patients. In summary, 30‑day mortality after ACS has decreased remarkably in all age cate­ gories in the past decade, thanks to improved antithrombotic treatment and early revascularization. As a consequence, profound changes in the epidemiology of ACS have also taken place: more patients with ACS survive the initial event and go on to develop

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recurrent ischaemic events, heart failure, atrial fibrillation, or noncardiac diseases (such as cancer), and are dying at an older age. In the future, more attention will have to be paid to the long-term care of patients after ACS, of which antithrombotic agents will remain an important component. Department of Cardiovascular Sciences, University of Leuven, Herestraat 49, B‑3000 Leuven, Belgium. [email protected] Acknowledgements I thank all my colleagues on both sides of the Atlantic with whom I was able to collaborate in performing important clinical trials that have improved the treatment of patients with acute coronary syndrome. Competing interests F.V.d.W. declares that he has received research grants and fees for participating in advisory boards, data and safety monitoring boards, and speaking activities from AstraZeneca, Boehringer Ingelheim, Merck, and The Medicines Company. 1.

Wallentin, L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361, 1045–1057 (2009). 2. Collet, J. P. et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N. Engl. J. Med. 367, 2100–2109 (2012). 3. Stone, G. W. et al. Bivalirudin during primary PCI in acute myocardial infarction. N. Engl. J. Med. 358, 2218–2230 (2008). 4. Shahzad, A. et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an openlabel, single centre, randomised controlled trial. Lancet http://dx.doi.org/10.1016/S01406736(14)60924-7. 5. Morrow, D. A. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 366, 1404–1413 (2012). 6. Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 366, 9–19 (2012). 7. Mehta, S. R. et al. Early versus delayed invasive intervention in acute coronary syndromes. N. Engl. J. Med. 360, 2165–2175 (2009). 8. Jolly, S. S. et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial. Lancet 377, 1409–1420 (2011). 9. Menees, D. S. et al. Door‑to‑balloon time and mortality among patients undergoing primary PCI. N. Engl. J. Med. 369, 901–909 (2013). 10. Armstrong, P. W. et al. Fibrinolysis or primary PCI in ST‑segment elevation myocardial infarction. N. Engl. J. Med. 368, 1379–1387 (2013).

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Decade in review--acute coronary syndromes: Successes and future objectives in acute coronary syndrome.

The past decade has seen considerable advances in the treatment of acute coronary syndromes (ACS), particularly in the search for improved antithrombo...
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