The following presentations were given at the 69th Scientific Sessions of the American Heart Association in New Orleans, La, November 10-13, 1996.
Paul Dudley White International Lecture
Since 1950, the United States and other developed countries have seen massive declines in death rates from coronary artery disease, by as much as 65% in those 44 to 55 years of age. The Nobel Prize winners Michael S. Brown and Joseph L. Goldstein predict that “Exploitation of recent breakthroughs…may well end coronary disease as a major public health problem early in the next century.”1 So has the time come to cut back on research and the employment of cardiologists? On the contrary, declared Dr David Kelly (Sydney, Australia) in his Paul Dudley White International Lecture at the start of the Scientific Sessions. Over the same 46 years, the number of coronary deaths actually rose by nearly two-thirds; he warned that the coming decades will bring a large increase in the burden of heart disease.
The reason for this paradox is the aging of the population. Today, >80% of coronary artery disease is seen in patients >65 years old, a group in which the modest decline in coronary death rates has been overshadowed by vast numerical growth, most strikingly in the very old. Thus, in the United States, the number of persons >85 years old was 1 million in 1970, is 3.5 million today, and is expected to reach 16 to 23 million 30 years hence. In this age group, the prevalence of heart failure alone is 10% to 15%, so there need be no worries about a shortage of work for physicians. What ought to worry us, says Dr Kelly, is a widespread failure to grasp the implications reflected in the low priority given to research on heart disease (in research dollars per death, cancer gets 4 times more and AIDS 38 times more) and a continuing neglect of the persons >65 years of age in clinical trials. The real challenge in an aging society, he said, will not be to prevent death but to enable the old to live in comfort. Some of the work reported in New Orleans will, we hope, contribute to this goal.
Radiation Therapy for Restenosis
Dr Paul Teirstein from the Scripps Clinic in La Jolla, Calif, presented the preliminary results of the SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting) trial. In this landmark study, 55 patients undergoing balloon angioplasty and stent implantation were randomized to receive either radiation treatment to the involved coronary segment or similar treatment with a placebo radiation source. Radiation treatment was delivered using an 192Ir-γ source; the total dose of radiation delivered was estimated to be between 8 and 30 Gy. Exposure times varied from 20 to 45 minutes.
At 6 months, the incidence of angiographic restenosis was 16.7% in the radiation-treated group and 53.6% in the untreated group. By 12 months, the incidence of death, myocardial infarction, and repeat revascularization was 15.4% in the radiation-treated group and 48.3% in the untreated group. The differences between the two groups were so dramatic in these 55 patients that the trial was halted prematurely by the Data Safety Monitoring Committee. A subsequent similar study will evaluate the efficacy of radiation therapy in patients with more extensive coronary disease.
At the same session, Dr Philip Urban from University Hospital in Geneva, Switzerland, reported somewhat less encouraging results with the β-emitter 90Y, which was used with a special centering balloon to give homogeneous irradiation within the coronary artery (18 Gy at the luminal surface). In this series of 15 patients, the radiotherapy was applied immediately after angioplasty and stents were implanted in 4 patients afterward. At 6 months, the dichotomous incidence of restenosis (diameter stenosis >50% at follow-up) was 40%. The authors plan to look at other radiation doses in subsequent studies.
Dr Patrick Serruys from the Thoraxcenter in Rotterdam, the Netherlands, presented the results of the BENESTENT II study, a randomized trial of a heparin-coated stent versus balloon angioplasty in patients (both stable and unstable) undergoing coronary intervention. A total of 827 patients were enrolled between September 1995 and March 1996 in 55 clinical centers in 16 countries; in 55 of 414 patients randomized to balloon angioplasty, crossover to stent was necessary because of a suboptimal result. Stent patients were treated after the procedure with aspirin and ticlopidine. Procedural success was 97% in the stent group and 86% in the PTCA group. Length of hospital stay was similar between groups.
At day 15 after the procedure, there were no significant differences between groups in the combined end point of death, myocardial infarction, or reintervention (4.1% in the stent group, 4.8% in the PTCA group). At 6 months, the incidence of combined clinical events was 14.5% in the stent group and 19.9% in the PTCA group (relative risk, .73; 95% CI, .54 to .99). There was a relative decrease of 36% in the need for revascularization (8.9% in the stent group, 14% in the PTCA group). Preliminary cost analyses showed an increased cost of approximately $3100 in the stent group.
Dr Serruys concluded that the use of heparin-coated stents is associated with a significant decrease in the incidence of combined clinical events compared with the use of PTCA. He noted that there has been significant improvement in the outcomes of the control PTCA group compared with prior studies. Complete cost-effectiveness and follow-up angiographic data will be available in the future.
Dr Martin Leon from Washington Hospital Center in Washington, DC, presented the results of STARS (Stent Anticoagulation Regimen Study). This trial compared three anticoagulant regimens (aspirin alone, aspirin plus ticlopidine, and aspirin plus coumadin) in 1652 patients after “optimal” elective Palmaz-Schatz stent placement (final angiographic stenosis <10%) in native coronary arteries. The primary end point of the trial was a hierarchical composite of the following at 30 days: death, emergency CABG, Q-wave myocardial infarction, and subacute closure with repeat revascularization. With regard to the primary end point, the incidence of adverse events was 3.6% in the aspirin alone group (n=555), 2.4% in the aspirin plus coumadin group (n=553), and 0.6% in the aspirin plus ticlopidine group (n=544; P=.001). The significant benefit of aspirin plus ticlopidine therapy arose largely from a reduction in Q-wave myocardial infarction (P=.014) and subacute closure with revascularization (P=.007). There were no differences between groups in quantitative coronary angiography–measured postprocedure minimal lumen diameter of percent diameter stenosis. There was a trend toward more frequent bleeding and vascular complications with aspirin plus coumadin (3.4% versus 1.3% with aspirin alone and 2.2% with aspirin plus ticlopidine; P=.057). A separate group of 509 STARS registry patients who had suboptimal angiographic results were treated with aspirin, ticlopidine, and other pharmacological agents as necessary; these patients had a primary event rate >10 times higher than randomized patients, largely as a result of more frequent in-laboratory closure, emergency CABG, and procedure-related death.
Dr Leon concluded that aspirin plus ticlopidine therapy is significantly better than aspirin alone or aspirin plus coumadin; this benefit derives from a lower incidence of Q-wave myocardial infarction and subacute closure with revascularization. He noted that the incidence of CK-MB elevation is ≈20% in this population of patients with optimal stenting; this rate was not influenced by any of the pharmacological regimens.
Dr Eric Topol from the Cleveland Clinic in Cleveland, Ohio, presented the 6-month follow-up of patients enrolled in the EPILOG study at a Cleveland Clinic Satellite Symposium, “INTERVENT: Interventional Cardiology and Pharmacology at the Crossroads.” Low- and high-risk patients were randomized in this placebo-controlled trial of the platelet glycoprotein IIb/IIIa receptor antagonist ReoPro in patients undergoing PTCA to standard heparin (100 U/kg bolus; titrated to activated clotting times of 300 to 350 seconds) plus placebo, standard heparin plus ReoPro (0.25 mg/kg bolus, 10 μg/kg per minute infusion for 12 hours), or low-dose heparin (70 U/kg titrated to activated clotting times >200 seconds) plus ReoPro. The EPILOG trial, conducted at 65 US and Canadian centers, originally was designed to include 4800 patients but was halted prematurely, because of excessive efficacy, in December 1995 after 2792 patients had been enrolled.
The primary end point of the study, death, myocardial infarction, or any revascularization, was significantly decreased at 6 months (25.8% with placebo, 22.3% with standard heparin plus ReoPro, and 22.8% with low-dose heparin plus ReoPro). The major events causing this difference were myocardial infarction (9.9%, 5.3%, and 5.0%, respectively) and urgent revascularization (6.7%, 3.5%, and 3.1%, respectively). There were no significant differences in target-vessel revascularization between groups at 6 months (18.1%, 16.2%, and 17.0%, respectively). By 6 months, the composite outcome event rates in diabetic patients were no different with ReoPro than with placebo because of an excess of target vessel revascularization. One very provocative observation was that both low- and high-risk patients appeared to benefit significantly. Furthermore, lowering the heparin dose and removing sheaths early resulted in much lower bleeding events, which were now equal to those in the control group, than in the prior EPIC study. Another interesting observation was the significant improvement in target vessel revascularization in the EPILOG versus the EPIC study control group.
Dr Topol concluded that ReoPro is associated with significant early (30-day) benefit in death, myocardial infarction, and emergency revascularization. This early benefit is highly durable and appears consistent across all clinical subgroups. No procedure-related increases in bleeding were associated with ReoPro. At 6 months, the initial benefit is generally durable overall, but use of ReoPro led to no reduction in target vessel revascularization.
Dr Donald Baim from Beth Israel Hospital in Boston, Mass, presented the long-term results of BOAT (Balloon versus Optimal Atherectomy Trial). In this study conducted at 39 clinical centers in the US, Canada, and Europe, 989 patients with de novo lesions in native coronary arteries were randomized to undergo either balloon angioplasty or optimal directional atherectomy (directional atherectomy plus adjunctive balloon angioplasty, when necessary, to achieve a final angiographic diameter stenosis of <20% by quantitative coronary angiography). Enrollment took place between May 1994 and November 1995; 80% of study patients underwent follow-up angiography. The previously presented short-term results demonstrated that optimal atherectomy was associated with higher lesion success (98.8% versus 96.5%), higher procedural success (93% versus 86.7%), and lower postprocedural residual diameter stenosis (14% versus 28%) compared with balloon angioplasty. Dr Baim now reports that, at 6 months, optimal atherectomy and balloon angioplasty, respectively, were associated with minimal lumen diameters of 1.86 and 1.69 mm, residual diameter stenoses of 41% and 46%, and dichotomous restenosis rates (the primary end point of BOAT) of 32% and 40% (P=.017). Overall, 1-year mortality rates were low (0.6% for atherectomy, 1.6% for balloon angioplasty; P=.14) despite the higher incidence of CK-MB greater than three times normal (14% for DCA, 7% for PTCA). Moreover, there was no association between postprocedural creatine phosphokinase elevations and 1-year mortality. Surprisingly, target-vessel revascularization was low for both groups (17.1% for atherectomy, 19.7% for balloon angioplasty; P=.33), as was the incidence of any revascularization (22.9% versus 24.2%; P=.65), suggesting that the small relative benefit of atherectomy was largely due to improvements in the clinical outcome of angioplasty (with ≥10% crossover to stenting) compared with the 24% incidence of target-vessel revascularization seen for angioplasty in CAVEAT.
Dr Baim concluded that optimal atherectomy appears to be superior to balloon angioplasty. This procedure has a higher short-term success rate and results in a larger lumen in the short term, a lower incidence of 8-month angiographic restenosis, fewer late clinical events, and no increase in adverse events at 30 days and 1 year. He cautioned that procedural technique is at least as important as the device used in determining long-term outcome.
Vesnarinone and Heart Failure
Dr Jay Cohn, from the University of Minnesota in Minneapolis, presented the results of VEST (VESnarinone Trial), a multicenter, randomized, placebo-controlled trial of vesnarinone (an oral phosphodiesterase inhibitor) in patients with New York Heart Association class III or IV heart failure. A total of 3833 patients who had already been treated with an angiotensin-converting enzyme inhibitor and diuretic (with or without digitalis) were randomized at 189 clinical centers to receive either 60 mg/d vesnarinone, 30 mg/d vesnarinone, or placebo. The trial was designed with a 90% power to detect a 30% relative reduction in all-cause mortality, the primary end point of the study. Enrollment took place between January 1995 and March 1996. The study was terminated as planned, on July 31, 1996, after 232 deaths in the placebo group.
Vesnarinone therapy was associated with a dose-dependent increase in mortality: the 30 mg/d vesnarinone group had a relative mortality increase of 12%; the 60 mg/d vesnarinone group had a relative mortality increase of 23%. This increase in mortality was not a consequence of deaths attributable to worsening heart failure (which were equal between groups). There was, however, a dose-dependent increase in sudden death.
From the perspective of quality-of-life (QOL) indices, vesnarinone was associated with a modest improvement in QOL at 8 weeks that persisted at 16 weeks. However, at 6 months, there was no difference in QOL scores between groups. There was also no difference between groups in the time to first hospitalization (requiring intravenous support) or death. A number of instances of drug-induced agranulocytosis (some fatal) were reported.
Dr Cohn concluded that vesnarinone treatment is associated with a dose-dependent increase in mortality in patients with New York Heart Association class III or IV heart failure that was largely attributable to an increase in sudden death. There is early improvement in QOL scores with vesnarinone that is not maintained at 6 months. No subgroups were identified in whom vesnarinone provided safe, effective therapy and sustained QOL benefit.
Dr Michael Gent from Hamilton, Ontario, Canada, presented the results of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial, a multicenter study conducted in 384 clinical centers in 16 countries. In CAPRIE, three groups of patients (recent stroke, recent myocardial infarction, and peripheral vascular disease patients) were randomized to receive either clopidogrel (chemically related to ticlopidine) 75 mg/d or aspirin 325 mg/d. Recruitment took place over 3 years; the mean follow-up was 1.91 years. The primary end point of the study was a composite of ischemic stroke, myocardial infarction, or vascular death. The trial originally was designed to include 15 000 patients; enrollment was extended when overall event rates were noted to be lower than expected. A total of 19 185 patients were randomized. The annual incidence of the primary outcome cluster was 5.32% in the clopidogrel group versus 5.83% in the aspirin group, a relative risk reduction of 8.7% in favor of clopidogrel (95% CI, 0.3% to 16.5%; P=.043). No major differences in safety were observed between aspirin and clopidogrel. Importantly, the incidence of neutropenia with clopidogrel was at least as low as that seen with aspirin.
Dr Gent concluded that clopidogrel is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death in patients with atherosclerotic vascular disease. The safety profile of clopidogrel is at least as favorable as that of medium-dose aspirin.
Low-Molecular-Weight Heparin for Unstable Angina/Non–Q-Wave Myocardial Infarction
Dr Marc Cohen from Allegheny University–Hahnemann Division in Philadelphia, Pa, presented the results of the ESSENCE trial. ESSENCE was a controlled trial of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in patients with unstable angina and non–Q-wave myocardial infarction. A total of 3171 qualifying patients were enrolled at 176 clinical centers in North and South America and Europe and randomized to receive either aspirin plus enoxaparin (1 mg/kg every 12 hours) or aspirin plus unfractionated heparin (adjusted to the activated partial thromboplastin time). The primary end point of the trial was the combined incidence of death, myocardial infarction, and recurrent angina at 14 days. The mean duration of therapy was 3.1 days. At 48 hours, the combined incidence of major events was 7.4% in the heparin group and 6.2% in the enoxaparin group (P=.11); at 14 days it was 19.8% in the heparin group and 16.6% in the enoxaparin group (P=.019); by 30 days it was 23.3% in the heparin group and 19.8% in the enoxaparin group (P=.016). There was no significant increase in major hemorrhages with enoxaparin, although there were slightly more minor bleeding events (primarily injection site ecchymoses).
Dr Cohen concluded that, compared with unfractionated heparin, low-molecular-weight heparin significantly reduces the combined incidence of death, myocardial infarction, and recurrent angina in patients with unstable angina and non–Q-wave myocardial infarction. This benefit is sustained through 30 days and is achieved without an increase in major bleeding events.
Dr Frans Van de Werf from the University Hospital Gasthuisberg in Leuven, Belgium, presented the results of COBALT, a randomized, double-blind trial of double-bolus versus front-loaded TPA in patients with acute myocardial infarction. COBALT was designed as an equivalence trial; equivalence was defined as an upper bound of the difference in 30-day mortality (the primary end point of the trial) between the two agents that did not exceed 0.4%. COBALT was to have included 4000 patients in each of the two arms of the trial but was terminated early, January 5, 1996, when adverse outcomes were noted in the double-bolus group; given the very low likelihood of equivalence in the overall trial, it was stopped. At 30 days, mortality was 7.98% in the double-bolus group and 7.53% in the front-loaded group. The 90% CI for the difference in mortality was 0.6% to 1.49%. Hence, according to the protocol definition, the two treatment arms were not equivalent; the double-bolus TPA–treated patients had worse 30-day outcomes. The 30-day incidence of total stroke (1.92% versus 1.53%), hemorrhagic stroke (1.12% versus 0.81%), and death or nonfatal stroke (8.8% versus 8.3%) all tended to be higher with double-bolus TPA. Retrospective analysis suggested that there was a greater likelihood for adverse outcomes in older (>75 years of age) patients, especially those treated with double-bolus TPA. Conversely, there did not appear to be 30-day outcome differences between treatment regimens in patients <75 years of age.
Dr Van de Werf concluded that, from a statistical viewpoint, double-bolus treatment with TPA is not equivalent to accelerated TPA; it results in a slightly higher 30-day mortality. The results of COBALT do not suggest any advantage to the use of double-bolus TPA besides the ease of administration, although the retrospective data raise the question as to whether the two dosing strategies may be equivalent in selected populations.
Reprint requests to James J. Ferguson, MD, Cardiology Research, 1-191, Texas Heart Institute, PO Box 20345, Houston, Texas 77225-0345.
- Copyright © 1997 by American Heart Association