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IIIa receptor blockers in acute coronary syndromes
CORRESPONDENCE
two principles might help to avoid conflicting results. *Thomas Störk, Eckhart Fröhlich, Martin Möckel Departments of *Cardiology and Intensive Care, and Gastroenterology, Karl-OlgaKrankenhaus Stuttgart, Teaching Hospital, University of Ulm, 70022 Stuttgart, Germany; and Department of Cardiology, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin 1
2
3
4
5
The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001; 357: 1915–24. Heeschen C, van den Brand MJ, Hamm CK, Simoons ML, for the CAPTURE investigators. Angiographic findings in patients with refractory unstable angina according to Troponin T status. Circulation 1999; 104: 1509–14. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: executive summary and recommendations. Circulation 2000; 102: 193–209. Pope HJ, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000; 342: 1163–70. Störk T, Wu AHB, Müller-Bardorff M, et al, for the NOWIS Group. Diagnostic and prognostic role of myoglobin in patients with suspected acute coronary syndrome. Am J Cardiol 2000; 86: 1371–74.
Sir—To general disappointment, the results of the GUSTO IV-ACS trial1 were negative. The investigators offer many possible explanations (population characteristics, trial design, dose duration of abciximab administration, sample size, proinflammatory effects of abciximab), yet no reason is satisfying, as Marc Cohen recognises in the accompanying June 16 Commentary.2 We are left, therefore, with the puzzling observation that abciximab seems to work in coronary intervention, but not in the more general population of patients with ACS admitted to the coronary-care unit. Is there any difference between spontaneous thrombi and thrombi developing during or after coronary intervention? Probably yes. Thrombi occurring during intervention are fragmented by the procedure, exposing a larger total surface area, and are washed by the brisk flow after lumen enlargement. Spontaneous thrombi are smaller, exposing only a tiny surface area to the blood and arise in a context of stagnant flow. Therefore, such a large molecule as abciximab might gain easier access to thrombi developing during coronary intervention. This possible explanation
THE LANCET • Vol 358 • December 8, 2001
could also reconcile the observation that small-molecule glycoprotein IIb/IIIa inhibitors (tirofiban, eptifibatide) seem to work in ACS and coronary intervention.3,4 Giovanni Melandri Dipartimento Cardiovascolare, Ospedale S Orsola, Bologna, Italy 1
2
3
4
The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IVACS randomised trial. Lancet 2001; 357: 1915–24. Cohen M. Glycoprotein IIb/IIIa receptor blockers in acute coronary syndromes: Gusto IV-ACS. Lancet 2001; 358: 1899–1900. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000; 356: 2037–44. Bhatt DL, Topol EJ. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA 2000; 284: 1549–58.
Author’s reply Sir—In the GUSTO-IV ACS study we note no benefit with abciximab in patients admitted with ACS who did not undergo early coronary revascularisation. These findings contrast with early results with abciximab in selected patients during 1 day before percutaneous coronary intervention,1 and findings with other glycoprotein IIb/IIIa receptor blockers in patients with ACS.2,3 The lack of benefit is not fully understood, and several explanations have been suggested particularly related to selection of patients and to the studydrug regimen, as we address in the discussion section. Thomas Störk and colleagues remind us that patients with suspected ACS might have other disorders, from gastrointestinal, pulmonary, skeletal, or other origins. To select patients with true ACS, our protocol specified that the clinical suspicion should be supported by additional objective findings, in particular ST-segment depression, or raised concentrations of cardiac troponin T or I. These requirements were intended to be more strict than in earlier studies, in which less-specific electrocardiography abnormalities were also accepted, such as negative T waves.2,3 We did not record the final discharge diagnoses of patients. In fact, this feature is not done in most large clinical trials, and it is a useful suggestion to do so in the future. Nevertheless, inclusion of a proportion of patients with a false diagnosis of ACS does not fully explain the trial results, unless a systematic negative
effect of abciximab in such patients would have balanced or outweighed a positive effect in patients with true thrombosis-related ACS. We give one suggestion in our report of such negative effect: a possible improvement of an inflammatory response by abciximab through P-selectin-mediated leucocyte adhesion. Giovanni Melandri suggests that the large antibody molecule of abciximab might penetrate into clots less effectively than small-molecule glycoprotein IIb/IIIa receptor blockers. Abciximab, and the other glycoprotein IIb/IIIa receptor blockers, are most effective to prevent platelet aggregation and to prevent further aggregation at the surface of existing clots. Additionally, Collet and colleagues4 have shown that abciximab facilitates dissolution or fragmentation of plateletrich clots through loosening of the matrix of platelet-fibrin and fibrinogen. We are not aware of comparative studies of clot resolution with the different glycoprotein IIb/IIIa receptor blockers. In laboratory experiments, different glycoprotein IIb/IIIa receptor blockers, including abciximab facilitate clot lysis in the presence of fibrinolytic drugs. The unexpected negative outcome of GUSTO IV-ACS has led to modification and refinement of the ACS guidelines by the European Society of Cardiology and the American College of Cardiology/ American Heart Association, and will further stimulate discussion and trigger investigation in this intriguing field of cardiology. Maarten L Simoons, for the GUSTO-IV ACS investigators Thoraxcenter, Room H 560, University Hospital Rotterdam, PO Box 2040, 3000 CA Rotterdam, Netherlands 1
2
3
4
The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997; 349: 1429–35. PRISM-PLUS. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction: Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISMPLUS) Study Investigators. N Engl J Med 1998; 338: 1488–97. PURSUIT investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: platelet glycoprotein IIb/IIIa in unstable angina—receptor suppression using integrilin therapy. N Engl J Med 1998; 339: 436–43. Collet JP, Montalescot G, Lesty C, et al. Effects of abciximab on the architecture of platelet-rich clots in patients with acute myocardial infarction undergoing primary coronary intervention. Circulation 2001; 103: 2328–31.
1997
For personal use. Only reproduce with permission from The Lancet Publishing Group.
two principles might help to avoid conflicting results. *Thomas Störk, Eckhart Fröhlich, Martin Möckel Departments of *Cardiology and Intensive Care, and Gastroenterology, Karl-OlgaKrankenhaus Stuttgart, Teaching Hospital, University of Ulm, 70022 Stuttgart, Germany; and Department of Cardiology, Charité, Campus Virchow-Klinikum, Humboldt University, Berlin 1
2
3
4
5
The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001; 357: 1915–24. Heeschen C, van den Brand MJ, Hamm CK, Simoons ML, for the CAPTURE investigators. Angiographic findings in patients with refractory unstable angina according to Troponin T status. Circulation 1999; 104: 1509–14. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: executive summary and recommendations. Circulation 2000; 102: 193–209. Pope HJ, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000; 342: 1163–70. Störk T, Wu AHB, Müller-Bardorff M, et al, for the NOWIS Group. Diagnostic and prognostic role of myoglobin in patients with suspected acute coronary syndrome. Am J Cardiol 2000; 86: 1371–74.
Sir—To general disappointment, the results of the GUSTO IV-ACS trial1 were negative. The investigators offer many possible explanations (population characteristics, trial design, dose duration of abciximab administration, sample size, proinflammatory effects of abciximab), yet no reason is satisfying, as Marc Cohen recognises in the accompanying June 16 Commentary.2 We are left, therefore, with the puzzling observation that abciximab seems to work in coronary intervention, but not in the more general population of patients with ACS admitted to the coronary-care unit. Is there any difference between spontaneous thrombi and thrombi developing during or after coronary intervention? Probably yes. Thrombi occurring during intervention are fragmented by the procedure, exposing a larger total surface area, and are washed by the brisk flow after lumen enlargement. Spontaneous thrombi are smaller, exposing only a tiny surface area to the blood and arise in a context of stagnant flow. Therefore, such a large molecule as abciximab might gain easier access to thrombi developing during coronary intervention. This possible explanation
THE LANCET • Vol 358 • December 8, 2001
could also reconcile the observation that small-molecule glycoprotein IIb/IIIa inhibitors (tirofiban, eptifibatide) seem to work in ACS and coronary intervention.3,4 Giovanni Melandri Dipartimento Cardiovascolare, Ospedale S Orsola, Bologna, Italy 1
2
3
4
The GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IVACS randomised trial. Lancet 2001; 357: 1915–24. Cohen M. Glycoprotein IIb/IIIa receptor blockers in acute coronary syndromes: Gusto IV-ACS. Lancet 2001; 358: 1899–1900. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000; 356: 2037–44. Bhatt DL, Topol EJ. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA 2000; 284: 1549–58.
Author’s reply Sir—In the GUSTO-IV ACS study we note no benefit with abciximab in patients admitted with ACS who did not undergo early coronary revascularisation. These findings contrast with early results with abciximab in selected patients during 1 day before percutaneous coronary intervention,1 and findings with other glycoprotein IIb/IIIa receptor blockers in patients with ACS.2,3 The lack of benefit is not fully understood, and several explanations have been suggested particularly related to selection of patients and to the studydrug regimen, as we address in the discussion section. Thomas Störk and colleagues remind us that patients with suspected ACS might have other disorders, from gastrointestinal, pulmonary, skeletal, or other origins. To select patients with true ACS, our protocol specified that the clinical suspicion should be supported by additional objective findings, in particular ST-segment depression, or raised concentrations of cardiac troponin T or I. These requirements were intended to be more strict than in earlier studies, in which less-specific electrocardiography abnormalities were also accepted, such as negative T waves.2,3 We did not record the final discharge diagnoses of patients. In fact, this feature is not done in most large clinical trials, and it is a useful suggestion to do so in the future. Nevertheless, inclusion of a proportion of patients with a false diagnosis of ACS does not fully explain the trial results, unless a systematic negative
effect of abciximab in such patients would have balanced or outweighed a positive effect in patients with true thrombosis-related ACS. We give one suggestion in our report of such negative effect: a possible improvement of an inflammatory response by abciximab through P-selectin-mediated leucocyte adhesion. Giovanni Melandri suggests that the large antibody molecule of abciximab might penetrate into clots less effectively than small-molecule glycoprotein IIb/IIIa receptor blockers. Abciximab, and the other glycoprotein IIb/IIIa receptor blockers, are most effective to prevent platelet aggregation and to prevent further aggregation at the surface of existing clots. Additionally, Collet and colleagues4 have shown that abciximab facilitates dissolution or fragmentation of plateletrich clots through loosening of the matrix of platelet-fibrin and fibrinogen. We are not aware of comparative studies of clot resolution with the different glycoprotein IIb/IIIa receptor blockers. In laboratory experiments, different glycoprotein IIb/IIIa receptor blockers, including abciximab facilitate clot lysis in the presence of fibrinolytic drugs. The unexpected negative outcome of GUSTO IV-ACS has led to modification and refinement of the ACS guidelines by the European Society of Cardiology and the American College of Cardiology/ American Heart Association, and will further stimulate discussion and trigger investigation in this intriguing field of cardiology. Maarten L Simoons, for the GUSTO-IV ACS investigators Thoraxcenter, Room H 560, University Hospital Rotterdam, PO Box 2040, 3000 CA Rotterdam, Netherlands 1
2
3
4
The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997; 349: 1429–35. PRISM-PLUS. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction: Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISMPLUS) Study Investigators. N Engl J Med 1998; 338: 1488–97. PURSUIT investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: platelet glycoprotein IIb/IIIa in unstable angina—receptor suppression using integrilin therapy. N Engl J Med 1998; 339: 436–43. Collet JP, Montalescot G, Lesty C, et al. Effects of abciximab on the architecture of platelet-rich clots in patients with acute myocardial infarction undergoing primary coronary intervention. Circulation 2001; 103: 2328–31.
1997
For personal use. Only reproduce with permission from The Lancet Publishing Group.