European Heart Journal Advance Access published May 28, 2014
EDITORIAL
European Heart Journal doi:10.1093/eurheartj/ehu227
Improving outcomes with bivalirudin in primary percutaneous coronary intervention Gregg W. Stone* Columbia University Medical Center, New York-Presbyterian Hospital, and the Cardiovascular Research Foundation, New York, NY, USA
Optimal pharmacotherapy is essential to realize the best outcomes in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). In this regard, effectively restoring reperfusion and maintaining the patency of the infarct artery after stenting requires a balance between the haemorrhagic risks and the ischaemic benefits of anticoagulant and antiplatelet agents. Over the last three decades, as the principal device used for primary PCI has evolved from balloon angioplasty to bare metal stents to drug-eluting stents, parallel advances have occurred in antithrombotic and antiplatelet regimens, from unfractionated heparin (UFH) alone, to UFH plus a glycoprotein IIb/IIIa inhibitor (GPI), to bivalirudin with provisional (bailout) GPI use, and from ticlopidine and clopidogrel to prasugrel and ticagrelor (on a background of aspirin). Given the time, complexity, and costs of performing appropriately powered randomized trials, clinical practice has progressed faster than the evidence base required to inform optimal drug and device usage for all possible drug and device permutations. Unfractionated heparin, a heterogeneous mixture of polysaccharides of varying chain lengths, while familiar and inexpensive, has numerous shortcomings,1 which become most clinically apparent in acute coronary syndromes (ACS). Unfractionated heparin has an indirect mechanism of action (binding to and activation of antithrombin III, the amount of which varies in disease states) and has limited activity against clot-bound thrombin. Non-specific protein and cellular binding of UFH results in variable biological activity and can result in heparin-induced thrombocytopenia and thrombosis. Moreover, UFH binds to the glycoprotein IIb/IIIa receptor, thereby paradoxically activating platelets.1 Kastrati and colleagues elegantly demonstrated that, despite pre-treatment with aspirin and clopidogrel, myocardial infarction rates in non-STEMI are substantially reduced after PCI with abciximab.2 Meta-analysis of eight randomized trials in 3949 patients with STEMI undergoing PCI demonstrated that the addiion of abciximab to UFH reduced the 30 day odds of re-infarction by 37%
(P , 0.001) and the 6 –12 month odds of mortality by 28% (P ¼ 0.01).3 In the largest such study, CADILLAC, 30 day stent thrombosis was also reduced with abciximab plus UFH vs. UFH alone (P ¼ 0.01).4 These benefits more than offset the increased rates of bleeding and thrombocytopenia that may occur with GPI.5 As such, aspirin, clopidogrel, and UFH plus GPI became the preferred regimen to support primary PCI in STEMI, used in .90% of patients in the USA and in the majority of patients in Europe.6,7 This regimen remained the standard for more than a decade until challenged by the direct thrombin inhibitor bivalirudin, a rapidly reversible agent (half-life 25 min), which overcomes many of the limitations of UFH. Specifically, bivalirudin does not require antithrombin III for activation, is able to inhibit fibrin-found thrombin, has predictable biological activity and dosing, does not cause thrombocytopenia or activate platelets, and indeed, blocks both collagen- and thrombin-induced platelet activation.1 A series of multicentre randomized PCI trials across the spectrum of coronary artery disease has demonstrated that in comparison to UFH plus GPI, bivalirudin with provisional GPI use results in similar rates of composite ischaemic events, with 40–50% reductions in major bleeding and thrombocytopenia.8 – 12 The EuroMax trial confirmed that the bleeding benefits of bivalirudin are present in patients treated with radial as well as femoral access,12 which is not surprising given that the majority of major bleeding events after PCI in ACS are not access site related.13 Morevoer, in the largest randomized primary PCI trial to date, anticoagulation with bivalirudin in comparison to UFH plus GPI resulted in reduced cardiac and all-cause mortality at 30 days,11 benefits which were sustained to 3 years,14 reflecting both haematological and nonhematological benefits of bivalirudin.15 As a result, in many countries bivalirudin has supplanted UFH plus GPI as the preferred regimen to support primary PCI in STEMI. How can the results with bivalirudin be improved further? One glaring deficiency of bivalirudin monotherapy in primary PCI during STEMI (which has not been observed in other settings) was first noted in the HORIZONS-AMI trial, and subsequently confirmed in EuroMax; stent thrombosis, occurring within the first 4 h after the end of the procedure, occurs in 1% more patients treated with bivalirudin alone than with UFH plus GPI.12,16 Thereafter, the rate of stent thrombosis in bivalirudin-treated patients is similar to or
* Corresponding author. Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, NY 10022, USA. Tel: +1 646 434 4134, Fax: +1 646 434 4715, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from http://eurheartj.oxfordjournals.org/ at Fachbereichsbibliothek on September 12, 2014
This editorial refers to ‘Prasugrel plus bivalirudin versus clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction’, by S. Schulz et al., doi:10.1093/ eurheartj/ehu182
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lower after STEMI than in other clinical settings,19 which necessitates a trial size of thousands of randomized patients to examine composite ischaemia (even more for stent thrombosis). We can thus draw little inference from the composite ischaemic event rates in BRAVE-4 [4.8% with bivalirudin plus prasugrel vs. 5.5% with UFH plus clopidogrel; relative risk (95% confidence interval), 0.89 (0.40–1.96)], consistent with bivalirudin plus prasugrel ranging from 60% better to 96% worse. Second, the control arm in BRAVE-4 did not include the routine use of a GPI, which while on the surface may appear to be a step backward, is less costly and not uncommon practice outside the USA. Indeed, other than ISAR-REACT-3, which did show reduced major bleeding with bivalirudin in comparison to UFH alone in troponinnegative PCI patients,9 there is a paucity of randomized trial data comparing bivalirudin with UFH monotherapy, although large-scale registries and meta-analyses also suggest that bivalirudin reduces bleeding and mortality in comparison to UFH alone.20 – 22 However, in the large-scale, multicentre EuroMax trial, bailout GPI were required in 25.4% of UFH-treated PCI patients, suggesting an unacceptable incidence of refractory thrombotic complications when primary PCI in STEMI is performed with UFH alone.12 In BRAVE-4, bailout GPI were required in 6.1% of UFH plus clopidogrel patients vs. 3.0% with bivalirudin plus prasugrel (P ¼ 0.07). Most importantly, omitting GPI from the UFH control arm would be expected to lower bleeding rates in comparison to UFH alone, further complicating interpretation of a NACE endpoint. The similar bleeding rates with bivalirudin plus prasugrel compared with UFH plus clopidogrel in BRAVE-4 does suggest that adding prasugrel to bivalirudin has diminished some of the safety benefit of bivalirudin plus clopidogrel in comparison to UFH plus clopidogrel, although caution in interpretation is again required given the wide confidence intervals. Lastly, isolated haematomas (used in the HORIZONS-AMI and BRAVE-4 principal bleeding endpoints) should no longer be considered an important yardstick of safety because they have no long-term consequences.23
Figure 1 Incidence and timing of stent thrombosis with the potent oral ADP antagonists prasugrel and ticagrelor in comparison to clopidogrel. Left panel: among 12 844 patients with acute coronary syndromes undergoing stent implantation who were randomized to prasugrel vs. clopidogrel (with treatment in most patients at the time of the procedure), prasugrel resulted in a significant reduction in stent thrombosis. No differences between the groups, however, were present within the first 24 h (oval).18 Right panel: among 11 284 patients with STEMI undergoing stent implantation who were randomized to prasugrel vs. clopidogrel (with treatment prior to the emergent procedure), ticagrelor resulted in a significant reduction in stent thrombosis.No differences between the groups, however, were present within the first 24 h (circle).26
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even decreased compared with UFH plus GPI.12,14 The presumed mechanism of this event, given its time frame, is inadequate ADPinduced platelet receptor inhibition and/or residual thrombin activity after discontinuation of bivalirudin. Although not outweighing the benefits of bivalirudin in terms of reduced major bleeding, thrombocytopenia, and mortality, and while rarely fatal when occurring in this closely observed setting, any increase in stent thrombosis is clearly an undesirable event that warrants preventative efforts. Reported in this issue of the European Heart Journal, BRAVE-4 is the first randomized trial to examine whether the potent oral ADP antagonist prasugrel is capable of improving outcomes with bivalirudin anticoagulation during primary PCI for STEMI.17 The trial was powered to demonstrate a 40% reduction in net adverse clinical events (NACE; a composite of adverse ischaemic and bleeding events) with bivalirudin plus prasugrel in comparison to UFH plus clopidogrel in 1240 primary PCI patients. Unfortunately, the trial was terminated prematurely for slow enrolment after only 548 patients were recruited, resulted in 51% post hoc power. Only 93% of patients had a confirmed myocardial infarction, further reducing power. Not surprisingly, no significant differences in NACE were observed between the two groups [15.6 vs. 14.5%; relative risk (95% confidence interval), 1.07 (0.70–1.64)], consistent with bivalirudin plus prasugrel ranging from 30% better to 64% worse for this endpoint, with 95% confidence. BRAVE-4 raises several important trial design issues. First, in comparison to clopidogrel, prasugrel would be expected to increase noncoronary artery bypass graft-related bleeding; a primary NACE endpoint would therefore mask its expected benefits in reducing stent thrombosis and re-infarction.18 Ideally, pharmacotherapy trials should be powered for separate efficacy (ischaemic events) and safety endpoints (bleeding) to be able to discriminate the relative merits of this expected trade-off. However, because of difficulty in accurately detecting and adjudicating re-infarction in the peri-PCI period, 48 h composite ischaemic event rates are paradoxically
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Conflict of interest: within the last 36 months G. W. Stone has served as a consultant to Abbott Vascular, Boston Scientific, Medtronic, The Medicines Company, Daiichi Sankyo, Eli Lilly, Bristol-Meyers-Squibb, and Astra Zeneca.
References 1. Stone GW, Ohman EM. Antithrombin alternatives in STEMI. Lancet 2011;378: 643 –645. 2. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schu¨hlen H, Dirschinger J, Berger PB, Scho¨mig A. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006;295:1531 –1538. 3. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE, Neumann FJ, Van de Werf F, Antman EM, Topol EJ. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005;293:1759 –1765. 4. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, Guagliumi G, Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957 –966. 5. Kandzari DE, Hasselblad V, Tcheng JE, Stone GW, Califf RM, Kastrati A, Neumann FJ, Brener SJ, Montalescot G, Kong DF, Harrington RA. Improved clinical outcomes with abciximab therapy in acute myocardial infarction: a systematic overview of randomized clinical trials. Am Heart J 2004;147:457 –462. 6. Dauerman HL, Frederick PD, Miller D, French WJ. Current incidence and clinical outcomes of bivalirudin administration among patients undergoing primary
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coronary intervention for ST-segment elevation acute myocardial infarction. Coron Artery Dis 2007;18:141 –148. Fox KA, Steg PG, Eagle KA, Goodman SG, Anderson FA Jr, Granger CB, Flather MD, Budaj A, Quill A, Gore JM. Decline in rates of death and heart failure in acute coronary syndromes, 1999 –2006. JAMA 2007;297:1892 – 1900. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863. Kastrati A, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Bu¨ttner HJ, Khattab AA, Schulz S, Blankenship JC, Pache J, Minners J, Seyfarth M, Graf I, Skelding KA, Dirschinger J, Richardt G, Berger PB, Scho¨mig A. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359:688 –696. Ndrepepa G, Neumann FJ, Deliargyris EN, Mehran R, Mehilli J, Ferenc M, Schulz S, Scho¨mig A, Kastrati A, Stone GW. Bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention after clopidogrel pretreatment: pooled analysis from the ACUITY and ISAR-REACT 4 trials. Circ Cardiovasc Interv 2012;5:705 –712. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218 –2230. Steg PG, van’t Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, Ten Berg J, Van Grunsven P, Eggink GJ, Nibbe L, Zeymer U, Campo dell’ Orto M, Nef H, Steinmetz J, Soulat L, Huber K, Deliargyris EN, Bernstein D, Schuette D, Prats J, Clayton T, Pocock S, Hamon M, Goldstein P. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207 –2217. Verheugt FW, Steinhubl SR, Hamon M, Darius H, Steg PG, Valgimigli M, Marso SP, Rao SV, Gershlick AH, Lincoff AM, Mehran R, Stone GW. Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention. JACC Cardiovasc Interv 2011;4:191 –197. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Fahy M, Parise H, Mehran R. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011;377:2193 –2204. Stone GW, Clayton T, Deliargyris EN, Prats J, Mehran R, Pocock SJ. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: the HORIZONS-AMI Trial. J Am Coll Cardiol 2014;63:15– 20. Dangas GD, Caixeta A, Mehran R, Parise H, Lansky AJ, Cristea E, Brodie BR, Witzenbichler B, Guagliumi G, Peruga JZ, Dudek D, Mo¨eckel M, Stone GW. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation 2011;123:1745 –1756. Schulz S, Richardt G, Laugwitz K-L, Morath T, Neudecker J, Hoppmann P, Mehran R, Gershlick AH, To¨lg R, Fiedler KA, Abdel-Wahab M, Kufner S, Schneider S, Schunkert H, Ibrahim T, Mehilli J, Kastrati A. Prasugrel plus bivalirudin versus clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J 2014; doi:10.1093/eurheartj/ehu182. Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial. Lancet 2008;371:1353 – 1363. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimsky´ P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Ge´ne´reux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368:1303 –1313. Bertrand OF, Jolly SS, Rao SV, Patel T, Belle L, Bernat I, Parodi G, Costerousse O, Mann T. Meta-analysis comparing bivalirudin versus heparin monotherapy on ischemic and bleeding outcomes after percutaneous coronary intervention. Am J Cardiol 2012;110:599 –606. Kinnaird T, Medic G, Casella G, Schiele F, Kaul U, Radke PW, Eijgelshoven I, Bergman G, Chew DP. Relative efficacy of bivalirudin versus heparin monotherapy in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: a network meta-analysis. J Blood Med 2013;4: 129 –140. Bangalore S, Pencina MJ, Kleiman NS, Cohen DJ. Heparin monotherapy or bivalirudin during percutaneous coronary intervention in patients with non-ST-segmentelevation acute coronary syndromes or stable ischemic heart disease: results from
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Third, and perhaps most importantly, both prasugrel and ticagrelor have delayed absorption in STEMI, not reaching peak pharmacodynamic efficacy for 4–6 h.24,25 Both agents have been shown to reduce stent thrombosis in comparison to clopidogrel in ACS and STEMI, but not within the first 24 h (Figure 1).18,26 In BRAVE-4, no insights can be drawn from the three vs. four stent thrombosis events in the bivalirudin plus prasugrel and UFH plus clopidogrel arms, respectively. In contrast, the investigational potent intravenous ADP-antagonist cangrelor, which achieves peak pharmacodynamic effect within minutes, has been demonstrated to reduce intraprocedural and acute stent thrombosis post-PCI, without increasing major bleeding.19 Cangrelor would thus likely be the preferred synergistic partner for bivalirudin, subsequently transitioning to a potent oral agent. In addition to cangrelor, an alternative approach to reduce acute stent thrombosis might be a several hour bivalirudin infusion to offset residual thrombin activity. In EuroMax, a low-dose (0.25 mg/kg/h) post-PCI infusion was given to the majority of bivalirudin-treated patients and did not mitigate acute stent thrombosis.12 Conversely, acute stent thrombosis occurred in only one of 274 (0.4%) EuroMax patients treated with a high-dose (1.75 mg/kg/h) bivalirudin infusion without increasing bleeding, which warrants further study.27 Along with system improvements and advances in interventional devices and technique, bivalirudin anticoagulation during primary PCI has substantially improved clinical outcomes in STEMI, resulting in high event-free survival rates, which are difficult to enhance further. BRAVE-4 is noteworthy not only as the first clinical trial to attempt to fine-tune the benefits of bivalirudin during primary PCI, but also in demonstrating the challenges that all such studies will face regarding adequate sample size and feasibility. Nonetheless, given the substantial morbidity and mortality that STEMI entails, these efforts are not only justified but are essential to improve outcomes further for highrisk patients with ACS.
Page 4 of 4 the evaluation of drug-eluting stents and ischemic events registry. Circ Cardiovasc Interv 2014 Apr 15.[Epub ahead of print].PMID: 24736878. 23. Mehran R, Pocock SJ, Nikolsky E, Clayton T, Dangas GD, Kirtane AJ, Parise H, Fahy M, Manoukian SV, Feit F, Ohman ME, Witzenbichler B, Guagliumi G, Lansky AJ, Stone GW. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010;55:2556 –2566. 24. Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2012;5:797 –804. 25. Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, Carrabba N, Santini A, Gensini GF, Abbate R, Antoniucci D. Comparison of prasugrel and
Editorial
ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013;61:1601 –1606. 26. Steg PG, Harrington RA, Emanuelsson H, Katus HA, Mahaffey KW, Meier B, Storey RF, Wojdyla DM, Lewis BS, Maurer G, Wallentin L, James SK. Stent thrombosis with ticagrelor versus clopidogrel in patients with acute coronary syndromes: an analysis from the prospective, randomized PLATO trial. Circulation 2013;128: 1055 –1065. 27. Clemmensen P, van’t Hof A, Deliargyris EN, Coste P, ten Berg J, Wiberg S, Cavallini C, Hamon M, Dudek D, Zeymer U, Tabone X, Kristensen SD, Clayton T, Bernstein D, Prats J, Steg PG. Predictors associated with acute stent thrombosis after primary PCI: The EUROMAX Trial. J Am Coll Cardiol 2014;63(12S):A27.
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EDITORIAL
European Heart Journal doi:10.1093/eurheartj/ehu227
Improving outcomes with bivalirudin in primary percutaneous coronary intervention Gregg W. Stone* Columbia University Medical Center, New York-Presbyterian Hospital, and the Cardiovascular Research Foundation, New York, NY, USA
Optimal pharmacotherapy is essential to realize the best outcomes in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). In this regard, effectively restoring reperfusion and maintaining the patency of the infarct artery after stenting requires a balance between the haemorrhagic risks and the ischaemic benefits of anticoagulant and antiplatelet agents. Over the last three decades, as the principal device used for primary PCI has evolved from balloon angioplasty to bare metal stents to drug-eluting stents, parallel advances have occurred in antithrombotic and antiplatelet regimens, from unfractionated heparin (UFH) alone, to UFH plus a glycoprotein IIb/IIIa inhibitor (GPI), to bivalirudin with provisional (bailout) GPI use, and from ticlopidine and clopidogrel to prasugrel and ticagrelor (on a background of aspirin). Given the time, complexity, and costs of performing appropriately powered randomized trials, clinical practice has progressed faster than the evidence base required to inform optimal drug and device usage for all possible drug and device permutations. Unfractionated heparin, a heterogeneous mixture of polysaccharides of varying chain lengths, while familiar and inexpensive, has numerous shortcomings,1 which become most clinically apparent in acute coronary syndromes (ACS). Unfractionated heparin has an indirect mechanism of action (binding to and activation of antithrombin III, the amount of which varies in disease states) and has limited activity against clot-bound thrombin. Non-specific protein and cellular binding of UFH results in variable biological activity and can result in heparin-induced thrombocytopenia and thrombosis. Moreover, UFH binds to the glycoprotein IIb/IIIa receptor, thereby paradoxically activating platelets.1 Kastrati and colleagues elegantly demonstrated that, despite pre-treatment with aspirin and clopidogrel, myocardial infarction rates in non-STEMI are substantially reduced after PCI with abciximab.2 Meta-analysis of eight randomized trials in 3949 patients with STEMI undergoing PCI demonstrated that the addiion of abciximab to UFH reduced the 30 day odds of re-infarction by 37%
(P , 0.001) and the 6 –12 month odds of mortality by 28% (P ¼ 0.01).3 In the largest such study, CADILLAC, 30 day stent thrombosis was also reduced with abciximab plus UFH vs. UFH alone (P ¼ 0.01).4 These benefits more than offset the increased rates of bleeding and thrombocytopenia that may occur with GPI.5 As such, aspirin, clopidogrel, and UFH plus GPI became the preferred regimen to support primary PCI in STEMI, used in .90% of patients in the USA and in the majority of patients in Europe.6,7 This regimen remained the standard for more than a decade until challenged by the direct thrombin inhibitor bivalirudin, a rapidly reversible agent (half-life 25 min), which overcomes many of the limitations of UFH. Specifically, bivalirudin does not require antithrombin III for activation, is able to inhibit fibrin-found thrombin, has predictable biological activity and dosing, does not cause thrombocytopenia or activate platelets, and indeed, blocks both collagen- and thrombin-induced platelet activation.1 A series of multicentre randomized PCI trials across the spectrum of coronary artery disease has demonstrated that in comparison to UFH plus GPI, bivalirudin with provisional GPI use results in similar rates of composite ischaemic events, with 40–50% reductions in major bleeding and thrombocytopenia.8 – 12 The EuroMax trial confirmed that the bleeding benefits of bivalirudin are present in patients treated with radial as well as femoral access,12 which is not surprising given that the majority of major bleeding events after PCI in ACS are not access site related.13 Morevoer, in the largest randomized primary PCI trial to date, anticoagulation with bivalirudin in comparison to UFH plus GPI resulted in reduced cardiac and all-cause mortality at 30 days,11 benefits which were sustained to 3 years,14 reflecting both haematological and nonhematological benefits of bivalirudin.15 As a result, in many countries bivalirudin has supplanted UFH plus GPI as the preferred regimen to support primary PCI in STEMI. How can the results with bivalirudin be improved further? One glaring deficiency of bivalirudin monotherapy in primary PCI during STEMI (which has not been observed in other settings) was first noted in the HORIZONS-AMI trial, and subsequently confirmed in EuroMax; stent thrombosis, occurring within the first 4 h after the end of the procedure, occurs in 1% more patients treated with bivalirudin alone than with UFH plus GPI.12,16 Thereafter, the rate of stent thrombosis in bivalirudin-treated patients is similar to or
* Corresponding author. Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, NY 10022, USA. Tel: +1 646 434 4134, Fax: +1 646 434 4715, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from http://eurheartj.oxfordjournals.org/ at Fachbereichsbibliothek on September 12, 2014
This editorial refers to ‘Prasugrel plus bivalirudin versus clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction’, by S. Schulz et al., doi:10.1093/ eurheartj/ehu182
Page 2 of 4
lower after STEMI than in other clinical settings,19 which necessitates a trial size of thousands of randomized patients to examine composite ischaemia (even more for stent thrombosis). We can thus draw little inference from the composite ischaemic event rates in BRAVE-4 [4.8% with bivalirudin plus prasugrel vs. 5.5% with UFH plus clopidogrel; relative risk (95% confidence interval), 0.89 (0.40–1.96)], consistent with bivalirudin plus prasugrel ranging from 60% better to 96% worse. Second, the control arm in BRAVE-4 did not include the routine use of a GPI, which while on the surface may appear to be a step backward, is less costly and not uncommon practice outside the USA. Indeed, other than ISAR-REACT-3, which did show reduced major bleeding with bivalirudin in comparison to UFH alone in troponinnegative PCI patients,9 there is a paucity of randomized trial data comparing bivalirudin with UFH monotherapy, although large-scale registries and meta-analyses also suggest that bivalirudin reduces bleeding and mortality in comparison to UFH alone.20 – 22 However, in the large-scale, multicentre EuroMax trial, bailout GPI were required in 25.4% of UFH-treated PCI patients, suggesting an unacceptable incidence of refractory thrombotic complications when primary PCI in STEMI is performed with UFH alone.12 In BRAVE-4, bailout GPI were required in 6.1% of UFH plus clopidogrel patients vs. 3.0% with bivalirudin plus prasugrel (P ¼ 0.07). Most importantly, omitting GPI from the UFH control arm would be expected to lower bleeding rates in comparison to UFH alone, further complicating interpretation of a NACE endpoint. The similar bleeding rates with bivalirudin plus prasugrel compared with UFH plus clopidogrel in BRAVE-4 does suggest that adding prasugrel to bivalirudin has diminished some of the safety benefit of bivalirudin plus clopidogrel in comparison to UFH plus clopidogrel, although caution in interpretation is again required given the wide confidence intervals. Lastly, isolated haematomas (used in the HORIZONS-AMI and BRAVE-4 principal bleeding endpoints) should no longer be considered an important yardstick of safety because they have no long-term consequences.23
Figure 1 Incidence and timing of stent thrombosis with the potent oral ADP antagonists prasugrel and ticagrelor in comparison to clopidogrel. Left panel: among 12 844 patients with acute coronary syndromes undergoing stent implantation who were randomized to prasugrel vs. clopidogrel (with treatment in most patients at the time of the procedure), prasugrel resulted in a significant reduction in stent thrombosis. No differences between the groups, however, were present within the first 24 h (oval).18 Right panel: among 11 284 patients with STEMI undergoing stent implantation who were randomized to prasugrel vs. clopidogrel (with treatment prior to the emergent procedure), ticagrelor resulted in a significant reduction in stent thrombosis.No differences between the groups, however, were present within the first 24 h (circle).26
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even decreased compared with UFH plus GPI.12,14 The presumed mechanism of this event, given its time frame, is inadequate ADPinduced platelet receptor inhibition and/or residual thrombin activity after discontinuation of bivalirudin. Although not outweighing the benefits of bivalirudin in terms of reduced major bleeding, thrombocytopenia, and mortality, and while rarely fatal when occurring in this closely observed setting, any increase in stent thrombosis is clearly an undesirable event that warrants preventative efforts. Reported in this issue of the European Heart Journal, BRAVE-4 is the first randomized trial to examine whether the potent oral ADP antagonist prasugrel is capable of improving outcomes with bivalirudin anticoagulation during primary PCI for STEMI.17 The trial was powered to demonstrate a 40% reduction in net adverse clinical events (NACE; a composite of adverse ischaemic and bleeding events) with bivalirudin plus prasugrel in comparison to UFH plus clopidogrel in 1240 primary PCI patients. Unfortunately, the trial was terminated prematurely for slow enrolment after only 548 patients were recruited, resulted in 51% post hoc power. Only 93% of patients had a confirmed myocardial infarction, further reducing power. Not surprisingly, no significant differences in NACE were observed between the two groups [15.6 vs. 14.5%; relative risk (95% confidence interval), 1.07 (0.70–1.64)], consistent with bivalirudin plus prasugrel ranging from 30% better to 64% worse for this endpoint, with 95% confidence. BRAVE-4 raises several important trial design issues. First, in comparison to clopidogrel, prasugrel would be expected to increase noncoronary artery bypass graft-related bleeding; a primary NACE endpoint would therefore mask its expected benefits in reducing stent thrombosis and re-infarction.18 Ideally, pharmacotherapy trials should be powered for separate efficacy (ischaemic events) and safety endpoints (bleeding) to be able to discriminate the relative merits of this expected trade-off. However, because of difficulty in accurately detecting and adjudicating re-infarction in the peri-PCI period, 48 h composite ischaemic event rates are paradoxically
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Conflict of interest: within the last 36 months G. W. Stone has served as a consultant to Abbott Vascular, Boston Scientific, Medtronic, The Medicines Company, Daiichi Sankyo, Eli Lilly, Bristol-Meyers-Squibb, and Astra Zeneca.
References 1. Stone GW, Ohman EM. Antithrombin alternatives in STEMI. Lancet 2011;378: 643 –645. 2. Kastrati A, Mehilli J, Neumann FJ, Dotzer F, ten Berg J, Bollwein H, Graf I, Ibrahim M, Pache J, Seyfarth M, Schu¨hlen H, Dirschinger J, Berger PB, Scho¨mig A. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006;295:1531 –1538. 3. De Luca G, Suryapranata H, Stone GW, Antoniucci D, Tcheng JE, Neumann FJ, Van de Werf F, Antman EM, Topol EJ. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005;293:1759 –1765. 4. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, Guagliumi G, Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957 –966. 5. Kandzari DE, Hasselblad V, Tcheng JE, Stone GW, Califf RM, Kastrati A, Neumann FJ, Brener SJ, Montalescot G, Kong DF, Harrington RA. Improved clinical outcomes with abciximab therapy in acute myocardial infarction: a systematic overview of randomized clinical trials. Am Heart J 2004;147:457 –462. 6. Dauerman HL, Frederick PD, Miller D, French WJ. Current incidence and clinical outcomes of bivalirudin administration among patients undergoing primary
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coronary intervention for ST-segment elevation acute myocardial infarction. Coron Artery Dis 2007;18:141 –148. Fox KA, Steg PG, Eagle KA, Goodman SG, Anderson FA Jr, Granger CB, Flather MD, Budaj A, Quill A, Gore JM. Decline in rates of death and heart failure in acute coronary syndromes, 1999 –2006. JAMA 2007;297:1892 – 1900. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863. Kastrati A, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Bu¨ttner HJ, Khattab AA, Schulz S, Blankenship JC, Pache J, Minners J, Seyfarth M, Graf I, Skelding KA, Dirschinger J, Richardt G, Berger PB, Scho¨mig A. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359:688 –696. Ndrepepa G, Neumann FJ, Deliargyris EN, Mehran R, Mehilli J, Ferenc M, Schulz S, Scho¨mig A, Kastrati A, Stone GW. Bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention after clopidogrel pretreatment: pooled analysis from the ACUITY and ISAR-REACT 4 trials. Circ Cardiovasc Interv 2012;5:705 –712. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218 –2230. Steg PG, van’t Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, Ten Berg J, Van Grunsven P, Eggink GJ, Nibbe L, Zeymer U, Campo dell’ Orto M, Nef H, Steinmetz J, Soulat L, Huber K, Deliargyris EN, Bernstein D, Schuette D, Prats J, Clayton T, Pocock S, Hamon M, Goldstein P. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207 –2217. Verheugt FW, Steinhubl SR, Hamon M, Darius H, Steg PG, Valgimigli M, Marso SP, Rao SV, Gershlick AH, Lincoff AM, Mehran R, Stone GW. Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention. JACC Cardiovasc Interv 2011;4:191 –197. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Fahy M, Parise H, Mehran R. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011;377:2193 –2204. Stone GW, Clayton T, Deliargyris EN, Prats J, Mehran R, Pocock SJ. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: the HORIZONS-AMI Trial. J Am Coll Cardiol 2014;63:15– 20. Dangas GD, Caixeta A, Mehran R, Parise H, Lansky AJ, Cristea E, Brodie BR, Witzenbichler B, Guagliumi G, Peruga JZ, Dudek D, Mo¨eckel M, Stone GW. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation 2011;123:1745 –1756. Schulz S, Richardt G, Laugwitz K-L, Morath T, Neudecker J, Hoppmann P, Mehran R, Gershlick AH, To¨lg R, Fiedler KA, Abdel-Wahab M, Kufner S, Schneider S, Schunkert H, Ibrahim T, Mehilli J, Kastrati A. Prasugrel plus bivalirudin versus clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J 2014; doi:10.1093/eurheartj/ehu182. Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, Van de Werf F, Downey WE, Scirica BM, Murphy SA, Antman EM. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial. Lancet 2008;371:1353 – 1363. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimsky´ P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Ge´ne´reux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368:1303 –1313. Bertrand OF, Jolly SS, Rao SV, Patel T, Belle L, Bernat I, Parodi G, Costerousse O, Mann T. Meta-analysis comparing bivalirudin versus heparin monotherapy on ischemic and bleeding outcomes after percutaneous coronary intervention. Am J Cardiol 2012;110:599 –606. Kinnaird T, Medic G, Casella G, Schiele F, Kaul U, Radke PW, Eijgelshoven I, Bergman G, Chew DP. Relative efficacy of bivalirudin versus heparin monotherapy in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: a network meta-analysis. J Blood Med 2013;4: 129 –140. Bangalore S, Pencina MJ, Kleiman NS, Cohen DJ. Heparin monotherapy or bivalirudin during percutaneous coronary intervention in patients with non-ST-segmentelevation acute coronary syndromes or stable ischemic heart disease: results from
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Third, and perhaps most importantly, both prasugrel and ticagrelor have delayed absorption in STEMI, not reaching peak pharmacodynamic efficacy for 4–6 h.24,25 Both agents have been shown to reduce stent thrombosis in comparison to clopidogrel in ACS and STEMI, but not within the first 24 h (Figure 1).18,26 In BRAVE-4, no insights can be drawn from the three vs. four stent thrombosis events in the bivalirudin plus prasugrel and UFH plus clopidogrel arms, respectively. In contrast, the investigational potent intravenous ADP-antagonist cangrelor, which achieves peak pharmacodynamic effect within minutes, has been demonstrated to reduce intraprocedural and acute stent thrombosis post-PCI, without increasing major bleeding.19 Cangrelor would thus likely be the preferred synergistic partner for bivalirudin, subsequently transitioning to a potent oral agent. In addition to cangrelor, an alternative approach to reduce acute stent thrombosis might be a several hour bivalirudin infusion to offset residual thrombin activity. In EuroMax, a low-dose (0.25 mg/kg/h) post-PCI infusion was given to the majority of bivalirudin-treated patients and did not mitigate acute stent thrombosis.12 Conversely, acute stent thrombosis occurred in only one of 274 (0.4%) EuroMax patients treated with a high-dose (1.75 mg/kg/h) bivalirudin infusion without increasing bleeding, which warrants further study.27 Along with system improvements and advances in interventional devices and technique, bivalirudin anticoagulation during primary PCI has substantially improved clinical outcomes in STEMI, resulting in high event-free survival rates, which are difficult to enhance further. BRAVE-4 is noteworthy not only as the first clinical trial to attempt to fine-tune the benefits of bivalirudin during primary PCI, but also in demonstrating the challenges that all such studies will face regarding adequate sample size and feasibility. Nonetheless, given the substantial morbidity and mortality that STEMI entails, these efforts are not only justified but are essential to improve outcomes further for highrisk patients with ACS.
Page 4 of 4 the evaluation of drug-eluting stents and ischemic events registry. Circ Cardiovasc Interv 2014 Apr 15.[Epub ahead of print].PMID: 24736878. 23. Mehran R, Pocock SJ, Nikolsky E, Clayton T, Dangas GD, Kirtane AJ, Parise H, Fahy M, Manoukian SV, Feit F, Ohman ME, Witzenbichler B, Guagliumi G, Lansky AJ, Stone GW. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010;55:2556 –2566. 24. Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2012;5:797 –804. 25. Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, Carrabba N, Santini A, Gensini GF, Abbate R, Antoniucci D. Comparison of prasugrel and
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ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013;61:1601 –1606. 26. Steg PG, Harrington RA, Emanuelsson H, Katus HA, Mahaffey KW, Meier B, Storey RF, Wojdyla DM, Lewis BS, Maurer G, Wallentin L, James SK. Stent thrombosis with ticagrelor versus clopidogrel in patients with acute coronary syndromes: an analysis from the prospective, randomized PLATO trial. Circulation 2013;128: 1055 –1065. 27. Clemmensen P, van’t Hof A, Deliargyris EN, Coste P, ten Berg J, Wiberg S, Cavallini C, Hamon M, Dudek D, Zeymer U, Tabone X, Kristensen SD, Clayton T, Bernstein D, Prats J, Steg PG. Predictors associated with acute stent thrombosis after primary PCI: The EUROMAX Trial. J Am Coll Cardiol 2014;63(12S):A27.
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