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non-ST–segment elevation myocardial infarction: Appropriate interpretation of the guidelines
Glycoprotein IIb/IIIa inhibitors in patients with unstable angina/non-ST–segment elevation myocardial infarction: Appropriate interpretation of the guidelines Elliott M. Antman, MD Boston, Mass
In 2002, the American College of Cardiology and the American Heart Association published an update to their guidelines for the management of patients with unstable angina and non-ST–segment elevation myocardial infarction. These revised guidelines make specific recommendations regarding the use of glycoprotein IIb/IIIa inhibitors. This article briefly reviews the evidence supporting the use of glycoprotein IIb/IIIa inhibitors in unstable angina and non-ST–segment elevation myocardial infarction, before moving on to discuss interpretation of these new guidelines. (Am Heart J 2003;146: S18 –22.)
The American College of Cardiology (ACC) and the American Heart Association (AHA) jointly produce guidelines, based on current clinical evidence, for the management of various cardiological conditions. The ACC/AHA guidelines are updated when significant new evidence is brought to light by clinical trials. The most recent update regarding the use of intravenous glycoprotein (GP) IIb/IIIa inhibitors in patients with acute coronary syndromes (ACS) is the ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST–Segment Elevation Myocardial Infarction.1 Before looking at the updated guidelines, it is important to understand the rationale behind their modification. For this reason, the advantages and disadvantages of using GP IIb/IIIa inhibitors in patients with unstable angina/non-ST–segment elevation myocardial infarction (NSTEMI) will be discussed, the ACC/AHA recommendation system explained, and then the latest guideline updates regarding GP IIb/IIIa inhibitors outlined.
ACS clinical trials Intravenous GP IIb/IIIa inhibitors block the final common pathway of platelet activation and aggregation, and have been the subject of extensive clinical trials. A meta-analysis of ⬎30,000 patients2 found that there was an overall risk reduction of 21% for death/MI at 30 days in patients who received GP IIb/
From the Harvard Medical School, and the Coronary Care Unit, Samuel A Levine Cardiac Unit, Brigham and Women’s Hospital, Boston, Mass. Reprint requests: Reprints not available from the author. © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/j.ahj.2003.09.001
IIIa inhibitors and aspirin as support for percutaneous coronary intervention (PCI) or medical management of ACS compared with those who received placebo and aspirin. This study strongly supports the argument that the introduction of GP IIb/IIIa inhibitors was an important advance over aspirin monotherapy for platelet inhibition. However, there is considerable variation between the point estimates of the treatment effect of the GP IIb/IIIa inhibitors among the 10 trials studied in the meta-analysis (Figure 1).2 This is partly related to differences in whether all patients received PCI and medical therapy, or whether a proportion received medical therapy alone. The effects of 3 different specific GP IIb/IIIa agents are represented in the trials shown in Figure 1. Four trials—Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC), Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG), c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE), and Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT)— focused exclusively on PCI using abciximab treatment. The Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial treated patients with tirofiban, and the Platelet Glycoprotein IIb/ IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial involved treatment with eptifibatide. In these 6 trials, patients treated with GP IIb/IIIa inhibitors had a lower rate of death and MI than patients on placebo, and in those patients undergoing PCI (⬎11,000), GP IIb/IIIa inhibitors prevented death and MI largely via reduction of periprocedural MI (38% reduction in the relative risk of death and MI).2 When the composite end point of these 6
American Heart Journal Volume 146, Number 4
Figure 1
Odds ratio plot showing the effectiveness in percutaneous coronary intervention and acute coronary syndromes of GP IIb/IIIa inhibitors on death or MI at 30 days. CAPTURE, c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina; EPIC, Evaluation of c7E3 for Prevention of Ischemic Complications; EPILOG, Evaluation in PTCA to Improve Long-term Outcome with Abciximab GPIIb/IIIa blockade; EPISTENT, Evaluation of Platelet IIb/IIIa Inhibitor for Stenting; IMPACT-II, Integrilin (Eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II; PARAGON, Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PRISM, Platelet Receptor Inhibition for Ischemic Syndrome Management; PRISM-PLUS, Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RESTORE, Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis. Reprinted with permission from Elsevier (Lancet 1999;353:227–31).
trials is changed to death/MI and urgent revascularization over 30 days, there is once again a substantial reduction in relative risk and absolute risk favoring all 3 GP IIb/IIIa inhibitors. An important limitation to the interpretation of trials of GP IIb/IIIa inhibitors in ACS is the fact that the decision to refer a patient for cardiac catheterization and PCI was at the discretion of the treating physician. Thus, the postrandomization nature of the decision to pursue an invasive strategy confounds the interpretation of the relative benefit of this class of drugs in patients managed exclusively medically versus those who were managed medically initially and then treated with PCI. One method that may partially adjust for this confounding is to perform a propensity score for the likelihood of referral for PCI and then apply that propensity score when evaluating treatment effects of the drugs.
GP IIb/IIIa inhibitors and PCI Two meta-analyses of 6 ACS trials—PARAGON A, PARAGON B, PURSUIT, PRISM-PLUS, Platelet Receptor
Antman S19
Figure 2
A, Graph showing the difference in effectiveness between GP IIb/ IIIa inhibitors and placebo/control found by the Boersma et al meta-analysis of GP IIb/IIIa in ACS. B, Results from 2 strata of the Boersma et al meta-analysis of GP IIb/IIIa in ACS. D, Death; OR, odds ratio. Reprinted with permission from Elsevier (Lancet 2002;359:189 –98).
Inhibition for Ischemic Syndrome Management (PRISM), and Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries Trial IV in Acute Coronary Syndromes (GUSTO IV-ACS)— have recently been published. Boersma et al reviewed data from all 31,402 patients enrolled in the 6 trials.3 However, the meta-analysis by Roffi et al excluded 345 patients from the arm not containing heparin in the PRISM-PLUS trial, as well as 1487 patients from the low-dose eptifibatide arm in the PURSUIT trial.4 Only 21% of the patients in the Roffi et al meta-analysis underwent PCI; the rest were treated medically. The Boersma et al meta-analysis revealed a 9% reduction in the odds ratio of death or MI in those patients receiving GP IIb/IIIa inhibitors (Figure 2, A).3 When the analysis was stratified according to whether patients underwent PCI within 5 days or did not undergo PCI, the magnitude of the treatment effect was found to be greater in those who underwent PCI within 5 days (Figure 2, B). The Roffi et al meta-analysis was stratified 3 ways according to whether patients were managed exclusively medically, underwent PCI after the drug had been discontinued, or underwent PCI while GP IIb/IIIa was being administered. The odds ratio plot (Figure 3) shows a gradient of the treatment effect of GP IIb/IIIa, which ranges from small and not statistically significant in exclusively medically managed patients, to a very strong effect when PCI was performed with concomitant GP IIb/IIIa inhibitor administration. The Roffi et al meta-analysis also calculated that for every 1000 patients treated, 30 events (death or MI)
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Figure 3
Treatment effect observed across 3 strata of the Roffi et al metaanalysis of GP IIb/IIIa in ACS trials.
Figure 4
Site for GP IIb/IIIa inhibitor administration An analysis of the CAPTURE, PURSUIT, and PRISMPLUS trials showed a 1.4% absolute risk reduction in adverse events in patients receiving GP IIb/IIIa inhibitors upstream of the thrombus.6 Around 22% of those patients went on to receive PCI. While these results are encouraging, there are few other data to support the use of upstream GP IIb/IIIa inhibitors. In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18) trial, all patients received upstream GP IIb/IIIa inhibitor therapy and were randomized to either early invasive or early conservative treatment,7 so the design did not permit a definitive statement to be made as to whether upstream GP IIb/IIIa inhibition is helpful in patients who progress to an early invasive strategy. It is difficult to draw any conclusions from previous trials because there is no uniformity in the trial design or the study drugs used. Also, there has been no randomized trial in which patients were actually randomized to an early invasive strategy or were selected for an early invasive strategy and randomized to receive upstream GP IIb/IIIa inhibitors or GP IIb/IIIa inhibitors in the laboratory. There are also only limited data from randomized trials involving clopidogrel combined with GP IIb/IIIa inhibitors.
GP IIb/IIIa inhibitors: A double-edged sword A, Number of adverse events prevented per 1000 patients treated across three strata of the Roffi et al meta-analysis of GP IIb/IIIa in ACS. B, Number needed to treat (NNT) to prevent 1 adverse event across 3 strata of the Roffi et al meta-analysis of GP IIb/IIIa in ACS.
are prevented if PCI is performed concurrent to administration of GP IIb/IIIa inhibitors (Figure 4, A).4,5 If PCI is performed after GP IIb/IIIa inhibitor administration has been discontinued, only 14 events are prevented per 1000 patients treated. This figure drops to 4 events per 1000 patients treated if a GP IIb/IIIa inhibitor is used exclusively to amplify another medical treatment (usually aspirin and an antithrombin). From an alternative viewpoint, the number needed to treat to prevent 1 event in patients undergoing PCI while receiving GP IIb/IIIa therapy is 32, which increases to 71 if PCI is performed after the drug has been discontinued, and reaches 250 if the patients receive only medical treatment (Figure 4, B).4,5
Despite the recent positive findings that GP IIb/IIIa inhibitor therapy in combination with PCI reduces the absolute risk of death or MI, an apparently harmful thrombotic effect has been seen with suboptimal doses of GP IIb/IIIa inhibitors in some trials (eg, GUSTO IV-ACS) (Figure 5). It is known that atheroma-associated cells such as activated platelets express a variety of receptors, including CD40 ligand (CD40L), an important prothrombotic and proinflammatory protein with GP IIb/IIIa binding activity.8,9 When a patient undergoes PCI after receiving a dose of intravenous GP IIb/IIIa inhibitor that is sufficient to occupy at least 80% of the GP IIb/ IIIa receptors, CD40L release is inhibited, blood flow improves, shear forces diminish, and platelet activation decreases, thus decreasing the risk of adverse events.10,11 If, during the course of a prolonged infusion of GP IIb/IIIa inhibitors in patients who are treated nonsurgically, there is ⬍80% occupancy of the GP IIb/IIIa receptors for a period of time and no PCI is performed, the GP IIb/IIIa inhibitors can, paradoxically, increase the risk of thrombosis via an increase in serum CD40L and a variety of other mechanisms that
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Figure 5
Under certain conditions, suboptimal doses of platelet GP IIb/IIIa inhibitors can, in the absence of PCI, increase the risk of thrombosis. Reprinted with permission from: Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation 2002;106:379 – 85.
are still poorly understood.11 Therefore, it is important that a sufficient dose of GP IIb/IIIa inhibitor is administered.
ACC/AHA guidelines The results from these recent ACS clinical trials have been used to formulate updated ACC/AHA guidelines for the management of patients with ACS.1 These guidelines and recommendations relate to the usefulness and applicability of certain treatments in particular situations. All recommendations are given ‘Class’ and ‘Level of Evidence’ classifications, which are defined as follows: ● Class I recommendations are given in situations where an intervention is useful and effective. ● Class IIa recommendations are made when the weight of evidence/opinion is in favor of the usefulness/ efficacy of an intervention in a given situation. ● Class IIb recommendations are made when the usefulness/efficacy of an intervention in a given situation is less well established by evidence/opinion. ● Class III recommendations are made when an intervention is not useful/effective in a given situation and may be harmful.
● Level of Evidence A is based on data from many large randomized, controlled trials. ● Level of Evidence B is based on data from a few smaller, randomized, controlled trials or careful analysis of nonrandomized studies or observational registries. ● Level of Evidence C, the most frequently used level, is based on expert consensus opinion.
Interpreting the updated ACC/AHA 2002 guidelines The main difference between the new ACC/AHA recommendations and the older ones is that the updated guidelines favor an early invasive strategy in the management of patients with suspected ACS and those without ST-segment elevation after the acute ischemic insult.1 The early invasive strategy is preferred for patients with high-risk indicators, and has a Class I, Level A recommendation. The high-risk indicators in this case include the following: ● recurrent ischemia on treatment ● elevated troponin levels ● new ST-segment depression
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● hemodynamic compromise with ischemia ● high-risk noninvasive test results ● depressed left ventricular function (ejection fraction ⬍40%) ● hemodynamic instability ● sustained ventricular tachycardia ● PCI within 6 months, before coronary artery bypass grafting The new ACC/AHA guidelines have also been updated to recommend that GP IIb/IIIa inhibitors, unfractionated heparin, aspirin, and clopidogrel should be administered to patients without ST-segment elevation when PCI is planned.1 This is a Class IIa, Level B recommendation because there is uncertainty about whether GP IIb/IIIa inhibitors should be given just before PCI. In patients with continued ischemia and elevated troponin levels— or other features of high risk—in whom PCI is not planned, eptifibatide or tirofiban, together with aspirin and either low-molecular–weight heparin or unfractionated heparin, can be used (Class IIa, Level A).1 Under the same conditions, abciximab carries a Class III, Level A recommendation.1 Although it is tempting to use the comparisons of placebo and GP IIb/IIIa inhibitors from recently published clinical trials to draw conclusions about the relative efficacy of various agents, the ACC/AHA guidelines on the management of unstable angina and NSTEMI suggest that this is an inappropriate exercise.1 Each trial varies in its definition of the enrolled populations, the elements of the composite end point, and the duration of treatment with the agents, and the trials do not necessarily compare equally potent doses of GP IIb/IIIa inhibitors with respect to their ability to inhibit platelet aggregation.
Conclusions Clinical trials are the best source of data on which to base therapeutic decisions. Although it is logical to use published trial results to continually update one’s knowledge about the use of GP IIb/IIIa inhibitors in patients with unstable angina/NSTEMI, it is also important to read and understand the ACC/AHA guidelines because they have been created from careful analysis of trial data and expert opinion, and have a very useful
weighting system to indicate the importance of each recommendation.
References 1. ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366 –74. 2. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999;353:227–31. 3. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189 – 98. 4. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes: gradient of benefit related to the revascularization strategy. Eur Heart J 2002;23:1441– 8. 5. Antman EM. ’I can see clearly now’: a new view on the use of IV GP IIb/IIIa inhibitors in acute coronary syndromes. Eur Heart J 2002;23:1408 –11. 6. Boersma E, Akkerhuis KM, Theroux P, et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation 1999;100:2045– 8. 7. Cannon CP, Weintraub WS, Demopoulos LA, et al. Invasive versus conservative strategies in unstable angina and non-Q-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 Trial. Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy. Thrombolysis In Myocardial Infarction. Am J Cardiol 1998;82:731– 6. 8. Mach F, Schonbeck U, Libby P. CD40 signaling in vascular cells: a key role in atherosclerosis? Atherosclerosis 1998;137(Suppl):S89 – 95. 9. Andre P, Prasad KS, Denis CV, et al. CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat Med 2002;8:247–52. 10. Nannizzi-Alaimo L, Alves VL, Phillips DR. Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation. Circulation 2003;107: 1123– 8. 11. Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation 2002;106: 379 – 85.
In 2002, the American College of Cardiology and the American Heart Association published an update to their guidelines for the management of patients with unstable angina and non-ST–segment elevation myocardial infarction. These revised guidelines make specific recommendations regarding the use of glycoprotein IIb/IIIa inhibitors. This article briefly reviews the evidence supporting the use of glycoprotein IIb/IIIa inhibitors in unstable angina and non-ST–segment elevation myocardial infarction, before moving on to discuss interpretation of these new guidelines. (Am Heart J 2003;146: S18 –22.)
The American College of Cardiology (ACC) and the American Heart Association (AHA) jointly produce guidelines, based on current clinical evidence, for the management of various cardiological conditions. The ACC/AHA guidelines are updated when significant new evidence is brought to light by clinical trials. The most recent update regarding the use of intravenous glycoprotein (GP) IIb/IIIa inhibitors in patients with acute coronary syndromes (ACS) is the ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST–Segment Elevation Myocardial Infarction.1 Before looking at the updated guidelines, it is important to understand the rationale behind their modification. For this reason, the advantages and disadvantages of using GP IIb/IIIa inhibitors in patients with unstable angina/non-ST–segment elevation myocardial infarction (NSTEMI) will be discussed, the ACC/AHA recommendation system explained, and then the latest guideline updates regarding GP IIb/IIIa inhibitors outlined.
ACS clinical trials Intravenous GP IIb/IIIa inhibitors block the final common pathway of platelet activation and aggregation, and have been the subject of extensive clinical trials. A meta-analysis of ⬎30,000 patients2 found that there was an overall risk reduction of 21% for death/MI at 30 days in patients who received GP IIb/
From the Harvard Medical School, and the Coronary Care Unit, Samuel A Levine Cardiac Unit, Brigham and Women’s Hospital, Boston, Mass. Reprint requests: Reprints not available from the author. © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/j.ahj.2003.09.001
IIIa inhibitors and aspirin as support for percutaneous coronary intervention (PCI) or medical management of ACS compared with those who received placebo and aspirin. This study strongly supports the argument that the introduction of GP IIb/IIIa inhibitors was an important advance over aspirin monotherapy for platelet inhibition. However, there is considerable variation between the point estimates of the treatment effect of the GP IIb/IIIa inhibitors among the 10 trials studied in the meta-analysis (Figure 1).2 This is partly related to differences in whether all patients received PCI and medical therapy, or whether a proportion received medical therapy alone. The effects of 3 different specific GP IIb/IIIa agents are represented in the trials shown in Figure 1. Four trials—Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC), Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG), c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE), and Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT)— focused exclusively on PCI using abciximab treatment. The Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial treated patients with tirofiban, and the Platelet Glycoprotein IIb/ IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial involved treatment with eptifibatide. In these 6 trials, patients treated with GP IIb/IIIa inhibitors had a lower rate of death and MI than patients on placebo, and in those patients undergoing PCI (⬎11,000), GP IIb/IIIa inhibitors prevented death and MI largely via reduction of periprocedural MI (38% reduction in the relative risk of death and MI).2 When the composite end point of these 6
American Heart Journal Volume 146, Number 4
Figure 1
Odds ratio plot showing the effectiveness in percutaneous coronary intervention and acute coronary syndromes of GP IIb/IIIa inhibitors on death or MI at 30 days. CAPTURE, c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina; EPIC, Evaluation of c7E3 for Prevention of Ischemic Complications; EPILOG, Evaluation in PTCA to Improve Long-term Outcome with Abciximab GPIIb/IIIa blockade; EPISTENT, Evaluation of Platelet IIb/IIIa Inhibitor for Stenting; IMPACT-II, Integrilin (Eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II; PARAGON, Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network; PRISM, Platelet Receptor Inhibition for Ischemic Syndrome Management; PRISM-PLUS, Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PURSUIT, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RESTORE, Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis. Reprinted with permission from Elsevier (Lancet 1999;353:227–31).
trials is changed to death/MI and urgent revascularization over 30 days, there is once again a substantial reduction in relative risk and absolute risk favoring all 3 GP IIb/IIIa inhibitors. An important limitation to the interpretation of trials of GP IIb/IIIa inhibitors in ACS is the fact that the decision to refer a patient for cardiac catheterization and PCI was at the discretion of the treating physician. Thus, the postrandomization nature of the decision to pursue an invasive strategy confounds the interpretation of the relative benefit of this class of drugs in patients managed exclusively medically versus those who were managed medically initially and then treated with PCI. One method that may partially adjust for this confounding is to perform a propensity score for the likelihood of referral for PCI and then apply that propensity score when evaluating treatment effects of the drugs.
GP IIb/IIIa inhibitors and PCI Two meta-analyses of 6 ACS trials—PARAGON A, PARAGON B, PURSUIT, PRISM-PLUS, Platelet Receptor
Antman S19
Figure 2
A, Graph showing the difference in effectiveness between GP IIb/ IIIa inhibitors and placebo/control found by the Boersma et al meta-analysis of GP IIb/IIIa in ACS. B, Results from 2 strata of the Boersma et al meta-analysis of GP IIb/IIIa in ACS. D, Death; OR, odds ratio. Reprinted with permission from Elsevier (Lancet 2002;359:189 –98).
Inhibition for Ischemic Syndrome Management (PRISM), and Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries Trial IV in Acute Coronary Syndromes (GUSTO IV-ACS)— have recently been published. Boersma et al reviewed data from all 31,402 patients enrolled in the 6 trials.3 However, the meta-analysis by Roffi et al excluded 345 patients from the arm not containing heparin in the PRISM-PLUS trial, as well as 1487 patients from the low-dose eptifibatide arm in the PURSUIT trial.4 Only 21% of the patients in the Roffi et al meta-analysis underwent PCI; the rest were treated medically. The Boersma et al meta-analysis revealed a 9% reduction in the odds ratio of death or MI in those patients receiving GP IIb/IIIa inhibitors (Figure 2, A).3 When the analysis was stratified according to whether patients underwent PCI within 5 days or did not undergo PCI, the magnitude of the treatment effect was found to be greater in those who underwent PCI within 5 days (Figure 2, B). The Roffi et al meta-analysis was stratified 3 ways according to whether patients were managed exclusively medically, underwent PCI after the drug had been discontinued, or underwent PCI while GP IIb/IIIa was being administered. The odds ratio plot (Figure 3) shows a gradient of the treatment effect of GP IIb/IIIa, which ranges from small and not statistically significant in exclusively medically managed patients, to a very strong effect when PCI was performed with concomitant GP IIb/IIIa inhibitor administration. The Roffi et al meta-analysis also calculated that for every 1000 patients treated, 30 events (death or MI)
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Figure 3
Treatment effect observed across 3 strata of the Roffi et al metaanalysis of GP IIb/IIIa in ACS trials.
Figure 4
Site for GP IIb/IIIa inhibitor administration An analysis of the CAPTURE, PURSUIT, and PRISMPLUS trials showed a 1.4% absolute risk reduction in adverse events in patients receiving GP IIb/IIIa inhibitors upstream of the thrombus.6 Around 22% of those patients went on to receive PCI. While these results are encouraging, there are few other data to support the use of upstream GP IIb/IIIa inhibitors. In the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18) trial, all patients received upstream GP IIb/IIIa inhibitor therapy and were randomized to either early invasive or early conservative treatment,7 so the design did not permit a definitive statement to be made as to whether upstream GP IIb/IIIa inhibition is helpful in patients who progress to an early invasive strategy. It is difficult to draw any conclusions from previous trials because there is no uniformity in the trial design or the study drugs used. Also, there has been no randomized trial in which patients were actually randomized to an early invasive strategy or were selected for an early invasive strategy and randomized to receive upstream GP IIb/IIIa inhibitors or GP IIb/IIIa inhibitors in the laboratory. There are also only limited data from randomized trials involving clopidogrel combined with GP IIb/IIIa inhibitors.
GP IIb/IIIa inhibitors: A double-edged sword A, Number of adverse events prevented per 1000 patients treated across three strata of the Roffi et al meta-analysis of GP IIb/IIIa in ACS. B, Number needed to treat (NNT) to prevent 1 adverse event across 3 strata of the Roffi et al meta-analysis of GP IIb/IIIa in ACS.
are prevented if PCI is performed concurrent to administration of GP IIb/IIIa inhibitors (Figure 4, A).4,5 If PCI is performed after GP IIb/IIIa inhibitor administration has been discontinued, only 14 events are prevented per 1000 patients treated. This figure drops to 4 events per 1000 patients treated if a GP IIb/IIIa inhibitor is used exclusively to amplify another medical treatment (usually aspirin and an antithrombin). From an alternative viewpoint, the number needed to treat to prevent 1 event in patients undergoing PCI while receiving GP IIb/IIIa therapy is 32, which increases to 71 if PCI is performed after the drug has been discontinued, and reaches 250 if the patients receive only medical treatment (Figure 4, B).4,5
Despite the recent positive findings that GP IIb/IIIa inhibitor therapy in combination with PCI reduces the absolute risk of death or MI, an apparently harmful thrombotic effect has been seen with suboptimal doses of GP IIb/IIIa inhibitors in some trials (eg, GUSTO IV-ACS) (Figure 5). It is known that atheroma-associated cells such as activated platelets express a variety of receptors, including CD40 ligand (CD40L), an important prothrombotic and proinflammatory protein with GP IIb/IIIa binding activity.8,9 When a patient undergoes PCI after receiving a dose of intravenous GP IIb/IIIa inhibitor that is sufficient to occupy at least 80% of the GP IIb/ IIIa receptors, CD40L release is inhibited, blood flow improves, shear forces diminish, and platelet activation decreases, thus decreasing the risk of adverse events.10,11 If, during the course of a prolonged infusion of GP IIb/IIIa inhibitors in patients who are treated nonsurgically, there is ⬍80% occupancy of the GP IIb/IIIa receptors for a period of time and no PCI is performed, the GP IIb/IIIa inhibitors can, paradoxically, increase the risk of thrombosis via an increase in serum CD40L and a variety of other mechanisms that
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Figure 5
Under certain conditions, suboptimal doses of platelet GP IIb/IIIa inhibitors can, in the absence of PCI, increase the risk of thrombosis. Reprinted with permission from: Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation 2002;106:379 – 85.
are still poorly understood.11 Therefore, it is important that a sufficient dose of GP IIb/IIIa inhibitor is administered.
ACC/AHA guidelines The results from these recent ACS clinical trials have been used to formulate updated ACC/AHA guidelines for the management of patients with ACS.1 These guidelines and recommendations relate to the usefulness and applicability of certain treatments in particular situations. All recommendations are given ‘Class’ and ‘Level of Evidence’ classifications, which are defined as follows: ● Class I recommendations are given in situations where an intervention is useful and effective. ● Class IIa recommendations are made when the weight of evidence/opinion is in favor of the usefulness/ efficacy of an intervention in a given situation. ● Class IIb recommendations are made when the usefulness/efficacy of an intervention in a given situation is less well established by evidence/opinion. ● Class III recommendations are made when an intervention is not useful/effective in a given situation and may be harmful.
● Level of Evidence A is based on data from many large randomized, controlled trials. ● Level of Evidence B is based on data from a few smaller, randomized, controlled trials or careful analysis of nonrandomized studies or observational registries. ● Level of Evidence C, the most frequently used level, is based on expert consensus opinion.
Interpreting the updated ACC/AHA 2002 guidelines The main difference between the new ACC/AHA recommendations and the older ones is that the updated guidelines favor an early invasive strategy in the management of patients with suspected ACS and those without ST-segment elevation after the acute ischemic insult.1 The early invasive strategy is preferred for patients with high-risk indicators, and has a Class I, Level A recommendation. The high-risk indicators in this case include the following: ● recurrent ischemia on treatment ● elevated troponin levels ● new ST-segment depression
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● hemodynamic compromise with ischemia ● high-risk noninvasive test results ● depressed left ventricular function (ejection fraction ⬍40%) ● hemodynamic instability ● sustained ventricular tachycardia ● PCI within 6 months, before coronary artery bypass grafting The new ACC/AHA guidelines have also been updated to recommend that GP IIb/IIIa inhibitors, unfractionated heparin, aspirin, and clopidogrel should be administered to patients without ST-segment elevation when PCI is planned.1 This is a Class IIa, Level B recommendation because there is uncertainty about whether GP IIb/IIIa inhibitors should be given just before PCI. In patients with continued ischemia and elevated troponin levels— or other features of high risk—in whom PCI is not planned, eptifibatide or tirofiban, together with aspirin and either low-molecular–weight heparin or unfractionated heparin, can be used (Class IIa, Level A).1 Under the same conditions, abciximab carries a Class III, Level A recommendation.1 Although it is tempting to use the comparisons of placebo and GP IIb/IIIa inhibitors from recently published clinical trials to draw conclusions about the relative efficacy of various agents, the ACC/AHA guidelines on the management of unstable angina and NSTEMI suggest that this is an inappropriate exercise.1 Each trial varies in its definition of the enrolled populations, the elements of the composite end point, and the duration of treatment with the agents, and the trials do not necessarily compare equally potent doses of GP IIb/IIIa inhibitors with respect to their ability to inhibit platelet aggregation.
Conclusions Clinical trials are the best source of data on which to base therapeutic decisions. Although it is logical to use published trial results to continually update one’s knowledge about the use of GP IIb/IIIa inhibitors in patients with unstable angina/NSTEMI, it is also important to read and understand the ACC/AHA guidelines because they have been created from careful analysis of trial data and expert opinion, and have a very useful
weighting system to indicate the importance of each recommendation.
References 1. ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366 –74. 2. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999;353:227–31. 3. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189 – 98. 4. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes: gradient of benefit related to the revascularization strategy. Eur Heart J 2002;23:1441– 8. 5. Antman EM. ’I can see clearly now’: a new view on the use of IV GP IIb/IIIa inhibitors in acute coronary syndromes. Eur Heart J 2002;23:1408 –11. 6. Boersma E, Akkerhuis KM, Theroux P, et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation 1999;100:2045– 8. 7. Cannon CP, Weintraub WS, Demopoulos LA, et al. Invasive versus conservative strategies in unstable angina and non-Q-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 Trial. Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy. Thrombolysis In Myocardial Infarction. Am J Cardiol 1998;82:731– 6. 8. Mach F, Schonbeck U, Libby P. CD40 signaling in vascular cells: a key role in atherosclerosis? Atherosclerosis 1998;137(Suppl):S89 – 95. 9. Andre P, Prasad KS, Denis CV, et al. CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat Med 2002;8:247–52. 10. Nannizzi-Alaimo L, Alves VL, Phillips DR. Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation. Circulation 2003;107: 1123– 8. 11. Quinn MJ, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword? Circulation 2002;106: 379 – 85.