Correspondence
Platelet Glycoprotein IIb/IIIa Receptor Blockade after Coronary Angioplasty
N Engl J Med 1997; 337:1243-1245October 23, 1997
- Article
To the Editor:
Although antagonists of the platelet glycoprotein IIb/IIIa receptor are undoubtedly efficacious in selected patients undergoing angioplasty, we believe there is an alternative perspective to that of the Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) investigators (June 12 issue)1 and Dr. Holmes, who wrote the accompanying editorial.2 The investigators concluded that this agent may have “potentially broad clinical use” in patients undergoing percutaneous transluminal coronary angioplasty (PTCA), and Dr. Holmes designated the trial a “home run.”
The primary finding in the EPILOG trial was a reduction in the need for urgent revascularization and in non–Q-wave myocardial infarction. At six months there was no reduction in death or Q-wave myocardial infarction. Although the incidence of urgent revascularization was reduced, the incidence of nonurgent revascularization was higher in both abciximab groups than in the placebo group, resulting in similar overall rates of revascularization at six months. Consequently, revascularization was not prevented, it was merely delayed. Thus, the only events that were prevented were non–Q-wave myocardial infarctions. The definition of non–Q-wave infarction was an elevation of threefold or greater in creatine kinase or its MB isoenzyme while the patient was in the hospital or an elevation of twofold or greater after discharge from the hospital. As the authors note, the clinical significance of these periprocedural enzyme elevations “remains somewhat controversial,” and their effect on prognosis is unclear.
Although we understand a further economic analysis is planned, a “back of the napkin” analysis can be performed with the data given in the article. At $1,407 per patient, treatment with abciximab of 100 patients undergoing PTCA would cost $140,700 and would result in the prevention of 4.5 non–Q-wave myocardial infarctions at six months (incidence of non–Q-wave myocardial infarctions, 8.4 percent in the placebo group, as compared with 3.9 percent in both abciximab groups). A skeptic might argue that the prevention of modest enzyme elevations in 4.5 of 100 treated patients at a cost of $140,700 may not justify the “broad clinical use” of abciximab.
2 ReferencesSteven S. Khan, M.D.
James Forrester, M.D.
Cedars–Sinai Medical Center, Los Angeles, CA 90048-18651
The EPILOG Investigators
Full Text | Web of Science | Medline2
Holmes DR Jr . Preventing coronary restenosis and complications. N Engl J Med 1997;336:1748-1749
Full Text | Web of Science | Medline
To the Editor:
The EPILOG study provides conclusive evidence that blockade of the platelet glycoprotein IIb/IIIa receptor with abciximab, given together with low-dose heparin, is an effective and safe strategy to reduce early ischemic complications in patients undergoing percutaneous coronary revascularization, mostly angioplasty (PTCA).
This study confirms the findings of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) study1 and adds another indication for the use of platelet-receptor antagonists. However, the authors' statement that the magnitude of the observed abciximab benefit was consistent among the various subgroups of patients seems to overlook some potentially important differences. Indeed, it seems that the treatment benefit does not extend to elderly patients. The hazard ratio for the 30-day primary efficacy end point among patients 65 years of age or older was about 0.8, with wide confidence intervals in both abciximab groups. In the EPIC study the event rates of the primary end point among patients 70 years of age or older was 12.6 percent in the placebo group and 11.1 percent in the group of patients treated with abciximab; the hazard ratio was 0.9 (95 percent confidence interval, 0.5 to 1.7). The therapeutic strategy in elderly patients probably needs to be revisited.
1 ReferencesGiovanni Gambassi, M.D.
Brown University, Providence, RI 02912Raffaele Landolfi, M.D.
Roberto Bernabei, M.D.
Università Cattolica del Sacro Cuore, 00168, Rome, Italy1
The EPIC Investigators
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Drs. Khan and Forrester question the value of six months of abciximab therapy, suggesting that the only durable effect was on the incidence of non–Q-wave myocardial infarctions. In fact, the absolute treatment effect of abciximab on the composite end point of death, myocardial infarction, or urgent intervention was maintained without attenuation between 30 days and 6 months (64 events prevented per 1000 patients treated at each time point), as was the treatment effect for each of the components of that end point. The relative risk reductions for the infrequent events of death and Q-wave infarction were not expected to reach statistical significance, since the trial could not practically be given sufficient power to detect such differences (particularly in view of its early termination due to a finding of efficacy at the first interim analysis). Nevertheless, the concordance of the direction and the magnitude of the reduction in all these end points provided sufficient evidence of a common pathogenesis of these ischemic complications and a consistent beneficial influence of abciximab therapy. The findings at 6 months differed from those at 30 days only in that abciximab did not prevent elective revascularization procedures, events that are driven primarily by restenosis, not by acute platelet-thrombus formation. We do not agree, however, with the interpretation that abciximab “merely delayed” revascularization; urgent revascularization procedures, which often occur unexpectedly and require hospitalization for unstable ischemic symptoms, are usually not equivalent from the patient's or the physician's standpoint to elective revascularizations performed for restenosis.
Finally, it is surprising that the importance of periprocedural non–Q-wave myocardial infarction continues to be questioned. Every contemporary study that has examined the impact of creatine kinase release over an adequate follow-up period has demonstrated an association between periprocedural enzyme release and an increased risk of late ischemic events.1-4 Moreover, most of the non–Q-wave infarctions prevented in the EPILOG trial were marked by creatine kinase elevations to more than five times the control value (typically to >1000 IU per liter); it is difficult to understand how such enzyme elevations could be interpreted as anything other than clinically relevant myocardial infarctions.
Dr. Gambassi and colleagues observed that the reduction in risk appeared to be less for elderly patients than for their younger counterparts, but point estimates of treatment effect are imprecise, with wide confidence intervals for any subgroup owing to sample size. The common direction of the effects, however, supports our statement that the treatment effect was homogeneous among all groups of patients.
4 ReferencesA. Michael Lincoff, M.D.
Eric J. Topol, M.D.
Cleveland Clinic Foundation, Cleveland, OH 44195Robert M. Califf, M.D.
Duke University, Durham, NC 277051
Abdelmeguid AE ,Topol EJ ,Whitlow PL ,Sapp SK ,Ellis SG . Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996;94:1528-1536
Web of Science | Medline2
Kong TQ ,Davidson CJ ,Meyers SN ,Tauke JT ,Parker MA ,Bonow RO . Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 1997;277:461-466
CrossRef | Web of Science | Medline3
Topol EJ ,Ferguson JJ ,Weisman HF , et al. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin β3 blockade with percutaneous coronary intervention. JAMA 1997;278:479-484
CrossRef | Web of Science | Medline4
Harrington RA ,Lincoff AM ,Califf RM , et al. Characteristics and consequences of myocardial infarction after percutaneous coronary intervention: insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). J Am Coll Cardiol 1995;25:1693-1699
CrossRef | Web of Science | Medline
Author/Editor Response
Drs. Khan and Forrester make some important points. They are troubled by the phrase “potentially broad clinical use.” Current estimates are that abciximab is used in approximately 30 percent of coronary interventions. Certainly, an approach that results in a 56 percent decrease in the hard end points of death, infarction, or urgent revascularization at 30 days is an important advance that should at least be considered for broad clinical use. Few patients, if given the option, would elect not to receive such a beneficial treatment. There are clearly issues that still need to be addressed; although the EPILOG investigators reported an impressive reduction in bleeding as compared with the EPIC trial, it is still a potential concern, particularly in centers that are not as familiar with the technique of adjusting the heparin dose according to the patient's weight and early sheath removal. Thrombocytopenia is also a potential concern. Appropriately, Drs. Khan and Forrester echo the concern about costs, which are pointed out in both the article and my editorial. One can only hope that as alternative drugs become available economic competition will lead to a decrease in cost. In addition, it may become possible to direct abciximab therapy to the patients at highest risk.
Drs. Khan and Forrester are also troubled by my use of the term “home run.” It must be remembered that a home run does not always win the game, but it is a great start. Approaches that lead to an improvement in initial outcome can be valuable whether or not they improve the longer-term outcome. There are few truly curative treatments for coronary artery disease. However, to have a successful long-term outcome you must start with an initial success. The use of abciximab in the EPILOG trial was not associated with a reduced rate of repeated revascularization, as it was in the EPIC trial. The reason for this is not clear. The point remains, however, that early events were dramatically decreased with this treatment. The challenge for the future is to prolong and extend those benefits — whether that be through the use of orally administered blockers of platelet glycoprotein IIa/IIIb receptor, which are currently being tested, or combinations of drugs and devices, which are also being tested, remains to be determined.
David R. Holmes, Jr., M.D.
Mayo Clinic, Rochester, MN 55905
