- Email: [email protected]
IIIa Inhibitors
Canadian Journal of Cardiology 27 (2011) 534 –535
Editorial
Upstream Treatment of ST-Segment Elevation Myocardial Infarction: The Role of Glycoprotein IIb/IIIa Inhibitors Dominique Joyal, MD,a and Mark J. Eisenberg, MD, MPHa,b a b
Division of Cardiology, Jewish General Hospital, Montreal, Québec, Canada
Division of Clinical Epidemiology, Jewish General Hospital/McGill University, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
(See article by Sethi et al. on pages 548-554 in this issue.) Glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa-Is) can be used for the upstream treatment of ST-segment elevation myocardial infarction in several contexts. “Facilitated” percutaneous coronary intervention (PCI) refers to GPIIb/IIIa-I use just prior to planned primary PCI. This term is generally used when primary PCI is expected to be performed soon after GPIIb/ IIIa-I administration. “Routine” use of GPIIb/IIIa-Is typically refers to use at the time of PCI. “Selective” use refers to administration in patients at high risk, such as those with high clot burden or patients with inadequate loading of oral antiplatelet agents. “Bailout” use refers to GPIIb/IIIa-I administration in the context of suboptimal results, such as poor distal flow. With all these potential strategies, how does one choose the appropriate use of GPIIb/IIIa-Is in primary PCI? In the 2009 American College of Cardiology/American Heart Association ST-segment elevation myocardial infarction guidelines,1 the strongest recommendation for the use of GPIIb/IIIa-Is is in selected patients at the time of primary PCI. This “selected” use is given a class-IIa indication. The use of GPIIb/IIIa-Is prior to the patient’s arrival in the catheterization laboratory is now deemed uncertain and is given a class-IIb indication. This is a downgrading from a class-IIa indication in the 2007 guidelines. The reasons for this less-robust recommendation are that much of the evidence favouring the use of GPIIb/IIIa-Is came from the era before the routine use of upstream optimal dual antiplatelet loading. Several studies in which patients received dual antiplatelet therapy before catheterization have recently questioned the benefit of GPIIb/IIIa-Is in primary PCI. They refer to all 3 GPIIb/IIIa-Is, namely abciximab, ebtifibatide, and tirofiban.2-4 A recent meta-analysis examining abciximab studies showed that routine use in priReceived for publication June 15, 2011. Accepted June 16, 2011. Corresponding author: Dr Mark J. Eisenberg, Professor of Medicine, Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital/ McGill University, 3755 Cote Ste Catherine Road/Suite H-421.1, Montreal, Québec H3T 1E2, Canada. E-mail: [email protected] See page 535 for disclosure information.
mary PCI is not beneficial in terms of short-term rates of death or reinfarction in patients who receive preprocedure thienopyridine loading. In terms of facilitated PCI, the Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events (FINESSE) trial evaluated prehospital abciximab to peri-PCI abciximab and found no benefit but did find a tendency toward excess bleeding with the prehospital regimen. On the basis of these data, it is fair to say that the benefit of routine use of GPIIb/IIIa-Is or facilitated use prePCI is unproven in patients receiving dual antiplatelet loading prior to catheterization. Abciximab remains the most studied GPIIb/IIIa-I agent in primary PCI. Although in the same drug class, abciximab differs from eptifibatide and tirofiban. Abciximab is a monoclonal antibody directed against the receptor, whereas eptifibatide and tirofiban are high-affinity nonantibody receptor inhibitors. Eptifibatide and tirofiban are generally referred to as “small molecule” GPIIb/IIIa-Is. Their clinical efficacy compared with abciximab has long been questioned. However, 2 recent meta-analyses showed no significant difference in death, reinfarction, or major bleeding when ebtifibatide or tirofiban was compared to abciximab.5,6 Hence, the current evidence suggests similar effectiveness and risk profiles in the context of primary PCI. In this issue of the Canadian Journal of Cardiology, Sethi et al. report an analysis of the tirofiban-only data.7 From a meta-analysis of 6 randomized controlled trials, encompassing 1429 patients and pertaining to pre-PCI tirofiban administration, the authors found a decrease in major adverse cardiac events (MACEs) without a significant increase in major bleeding. This benefit was seen despite pre-PCI dual-antiplatelet loading in each of the trials. As the trials studied used tirofiban before primary PCI, the terms “routine early” or “upstream” treatment are used in the paper. Because the trial designs differed from ambulance or referring centre to in-catheterizationlaboratory tirofiban administration, this upstream treatment then refers to a mixture of facilitated and routine in-lab tirofiban administration. The bulk of the data in this analysis comes from a single trial, Ongoing Tirofiban in Myocardial Infarction Evaluation (ON-TIME) 2, which defined its facili-
0828-282X/$ – see front matter © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.cjca.2011.06.007
Joyal and Eisenberg Upstream Treatment of STEMI
tated tirofiban protocol as “pre-hospital first medical contact.”3 The investigators in this large trial did not find significant differences in terms of mortality, MACEs, or major bleeding. However, when this study was pooled with other, smaller trials of different designs, the authors found a significant decrease in MACEs but insignificant findings in terms of mortality and bleeding. Thrombolysis in myocardial infarction flow and blush grade were unaffected by GPIIb/IIIa-I administration. It is thus unexplained how MACEs can be reduced. As the sample size is relatively small for a meta-analysis, it is not possible to draw firm conclusions. A larger sample may confirm increased bleeding, because the current analysis shows a trend toward increased major bleeding. Because only MACEs are significantly affected in the analysis, and not mortality, it is not advisable to change practice based on these results. If a benefit were to exist with upstream tirofiban administration, it remains unclear why this would be so in the context of the disappointing data using abciximab. Although these 2 agents differ pharmacologically, there has not been solid proof of an increased risk profile with one vs the other. Tirofiban is cheaper than abciximab, however, and would be more cost-effective, if effectiveness is proven. This issue can be settled only with a large randomized controlled trial. This is an unlikely scenario in the near future, however, given the results of the ON-TIME 2 trial. Until further randomized data are available, we must conform to the current guidelines. Facilitated PCI is not advocated. Routine GPIIb/IIIa-I use is not advocated. Selective GPIIb/IIIa-I use is currently the strategy of choice and is the most supported from the literature. In case of lengthy expected delays, such as long-distance transportation, a fibrinolytic agent should be administered instead. GPIIb/IIIa-I use has dramatically decreased in the past few years, mainly because of the benefit observed with early dual antiplatelet therapy loading. GPIIb/IIIa-I use may even be less in the future, with the introduction of more potent antiplatelet agents with faster bioavailability. Unless a large trial demonstrates otherwise, selective GPIIb/IIIa-I use is still advocated. This strategy simplifies primary PCI management and leaves the pharmacologic decisions to the operator, based on anatomic and procedural considerations.
535
Funding Sources Dr Eisenberg is a Chercheur-National of the Fond de la Recherche en Santé du Québec (FRSQ).
Disclosures The authors have no conflicts of interest to disclose.
References 1. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/ AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205-41. 2. Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading: a randomized double-blind trial. Circulation 2009;119:1933-40. 3. Van’t Hof AW, Ten Berg J, Heestermans T, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (ON-TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet 2008;372:537-46. 4. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358: 2218-30. 5. Gurm HS, Tamhane U, Meier P, et al. A comparison of abciximab and small-molecule glycoprotein IIb/IIIa inhibitors in patients undergoing primary percutaneous coronary intervention: a meta-analysis of contemporary randomized controlled trials. Circ Cardiovasc Interv 2009;2:230-6. 6. De Luca G, Ucci G, Cassetti E, et al. Benefits from small molecule administration as compared with abciximab among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a metaanalysis. J Am Coll Cardiol 2009;53:1668-73. 7. Sethi A, Bahekar A, Doshi H, et al. Tirofiban use on top of clopidogrel and aspirin decreases adverse cardiovascular events after percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis of randomized trials. Can J Cardiol 2011;27:548-54.
Editorial
Upstream Treatment of ST-Segment Elevation Myocardial Infarction: The Role of Glycoprotein IIb/IIIa Inhibitors Dominique Joyal, MD,a and Mark J. Eisenberg, MD, MPHa,b a b
Division of Cardiology, Jewish General Hospital, Montreal, Québec, Canada
Division of Clinical Epidemiology, Jewish General Hospital/McGill University, Lady Davis Institute for Medical Research, Montreal, Québec, Canada
(See article by Sethi et al. on pages 548-554 in this issue.) Glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa-Is) can be used for the upstream treatment of ST-segment elevation myocardial infarction in several contexts. “Facilitated” percutaneous coronary intervention (PCI) refers to GPIIb/IIIa-I use just prior to planned primary PCI. This term is generally used when primary PCI is expected to be performed soon after GPIIb/ IIIa-I administration. “Routine” use of GPIIb/IIIa-Is typically refers to use at the time of PCI. “Selective” use refers to administration in patients at high risk, such as those with high clot burden or patients with inadequate loading of oral antiplatelet agents. “Bailout” use refers to GPIIb/IIIa-I administration in the context of suboptimal results, such as poor distal flow. With all these potential strategies, how does one choose the appropriate use of GPIIb/IIIa-Is in primary PCI? In the 2009 American College of Cardiology/American Heart Association ST-segment elevation myocardial infarction guidelines,1 the strongest recommendation for the use of GPIIb/IIIa-Is is in selected patients at the time of primary PCI. This “selected” use is given a class-IIa indication. The use of GPIIb/IIIa-Is prior to the patient’s arrival in the catheterization laboratory is now deemed uncertain and is given a class-IIb indication. This is a downgrading from a class-IIa indication in the 2007 guidelines. The reasons for this less-robust recommendation are that much of the evidence favouring the use of GPIIb/IIIa-Is came from the era before the routine use of upstream optimal dual antiplatelet loading. Several studies in which patients received dual antiplatelet therapy before catheterization have recently questioned the benefit of GPIIb/IIIa-Is in primary PCI. They refer to all 3 GPIIb/IIIa-Is, namely abciximab, ebtifibatide, and tirofiban.2-4 A recent meta-analysis examining abciximab studies showed that routine use in priReceived for publication June 15, 2011. Accepted June 16, 2011. Corresponding author: Dr Mark J. Eisenberg, Professor of Medicine, Divisions of Cardiology and Clinical Epidemiology, Jewish General Hospital/ McGill University, 3755 Cote Ste Catherine Road/Suite H-421.1, Montreal, Québec H3T 1E2, Canada. E-mail: [email protected] See page 535 for disclosure information.
mary PCI is not beneficial in terms of short-term rates of death or reinfarction in patients who receive preprocedure thienopyridine loading. In terms of facilitated PCI, the Facilitated Intervention With Enhanced Reperfusion Speed to Stop Events (FINESSE) trial evaluated prehospital abciximab to peri-PCI abciximab and found no benefit but did find a tendency toward excess bleeding with the prehospital regimen. On the basis of these data, it is fair to say that the benefit of routine use of GPIIb/IIIa-Is or facilitated use prePCI is unproven in patients receiving dual antiplatelet loading prior to catheterization. Abciximab remains the most studied GPIIb/IIIa-I agent in primary PCI. Although in the same drug class, abciximab differs from eptifibatide and tirofiban. Abciximab is a monoclonal antibody directed against the receptor, whereas eptifibatide and tirofiban are high-affinity nonantibody receptor inhibitors. Eptifibatide and tirofiban are generally referred to as “small molecule” GPIIb/IIIa-Is. Their clinical efficacy compared with abciximab has long been questioned. However, 2 recent meta-analyses showed no significant difference in death, reinfarction, or major bleeding when ebtifibatide or tirofiban was compared to abciximab.5,6 Hence, the current evidence suggests similar effectiveness and risk profiles in the context of primary PCI. In this issue of the Canadian Journal of Cardiology, Sethi et al. report an analysis of the tirofiban-only data.7 From a meta-analysis of 6 randomized controlled trials, encompassing 1429 patients and pertaining to pre-PCI tirofiban administration, the authors found a decrease in major adverse cardiac events (MACEs) without a significant increase in major bleeding. This benefit was seen despite pre-PCI dual-antiplatelet loading in each of the trials. As the trials studied used tirofiban before primary PCI, the terms “routine early” or “upstream” treatment are used in the paper. Because the trial designs differed from ambulance or referring centre to in-catheterizationlaboratory tirofiban administration, this upstream treatment then refers to a mixture of facilitated and routine in-lab tirofiban administration. The bulk of the data in this analysis comes from a single trial, Ongoing Tirofiban in Myocardial Infarction Evaluation (ON-TIME) 2, which defined its facili-
0828-282X/$ – see front matter © 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.cjca.2011.06.007
Joyal and Eisenberg Upstream Treatment of STEMI
tated tirofiban protocol as “pre-hospital first medical contact.”3 The investigators in this large trial did not find significant differences in terms of mortality, MACEs, or major bleeding. However, when this study was pooled with other, smaller trials of different designs, the authors found a significant decrease in MACEs but insignificant findings in terms of mortality and bleeding. Thrombolysis in myocardial infarction flow and blush grade were unaffected by GPIIb/IIIa-I administration. It is thus unexplained how MACEs can be reduced. As the sample size is relatively small for a meta-analysis, it is not possible to draw firm conclusions. A larger sample may confirm increased bleeding, because the current analysis shows a trend toward increased major bleeding. Because only MACEs are significantly affected in the analysis, and not mortality, it is not advisable to change practice based on these results. If a benefit were to exist with upstream tirofiban administration, it remains unclear why this would be so in the context of the disappointing data using abciximab. Although these 2 agents differ pharmacologically, there has not been solid proof of an increased risk profile with one vs the other. Tirofiban is cheaper than abciximab, however, and would be more cost-effective, if effectiveness is proven. This issue can be settled only with a large randomized controlled trial. This is an unlikely scenario in the near future, however, given the results of the ON-TIME 2 trial. Until further randomized data are available, we must conform to the current guidelines. Facilitated PCI is not advocated. Routine GPIIb/IIIa-I use is not advocated. Selective GPIIb/IIIa-I use is currently the strategy of choice and is the most supported from the literature. In case of lengthy expected delays, such as long-distance transportation, a fibrinolytic agent should be administered instead. GPIIb/IIIa-I use has dramatically decreased in the past few years, mainly because of the benefit observed with early dual antiplatelet therapy loading. GPIIb/IIIa-I use may even be less in the future, with the introduction of more potent antiplatelet agents with faster bioavailability. Unless a large trial demonstrates otherwise, selective GPIIb/IIIa-I use is still advocated. This strategy simplifies primary PCI management and leaves the pharmacologic decisions to the operator, based on anatomic and procedural considerations.
535
Funding Sources Dr Eisenberg is a Chercheur-National of the Fond de la Recherche en Santé du Québec (FRSQ).
Disclosures The authors have no conflicts of interest to disclose.
References 1. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/ AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205-41. 2. Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading: a randomized double-blind trial. Circulation 2009;119:1933-40. 3. Van’t Hof AW, Ten Berg J, Heestermans T, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (ON-TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet 2008;372:537-46. 4. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358: 2218-30. 5. Gurm HS, Tamhane U, Meier P, et al. A comparison of abciximab and small-molecule glycoprotein IIb/IIIa inhibitors in patients undergoing primary percutaneous coronary intervention: a meta-analysis of contemporary randomized controlled trials. Circ Cardiovasc Interv 2009;2:230-6. 6. De Luca G, Ucci G, Cassetti E, et al. Benefits from small molecule administration as compared with abciximab among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a metaanalysis. J Am Coll Cardiol 2009;53:1668-73. 7. Sethi A, Bahekar A, Doshi H, et al. Tirofiban use on top of clopidogrel and aspirin decreases adverse cardiovascular events after percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis of randomized trials. Can J Cardiol 2011;27:548-54.