Highlights of the 20th Congress of the European Society of Cardiology
The following studies were presented at the 20th Congress of the European Society of Cardiology, August 22–26, 1998, in Vienna, Austria.
Acute Coronary Syndromes
Presenter: Elliott Antman, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
The study: A large-scale (200 centers, 10 countries), randomized, controlled trial comparing unfractionated heparin with low-molecular-weight heparin (enoxaparin) in patients with unstable angina and non–Q-wave infarction. Patients were randomized to intravenous unfractionated heparin (70-U/kg bolus, 15 U · kg−1 · h−1 titrated to activated partial thromboplastin times [aPTTs]) of 1.5 to 2× control; n=1957) or enoxaparin (30-mg IV bolus, 1 mg/kg SC every 12 hours; n=1953). In-hospital therapy was continued for 2 to 8 days. After discharge, patients in the unfractionated-heparin group received placebo and enoxaparin patients continued active therapy through 43 days. Initially, unstable angina patients could be enrolled in the study if they had a known history of coronary artery disease or had documented ECG changes (ST-segment depression) or positive cardiac markers. Ten months into the study, because of a lower-than-projected outcome event rate, the inclusion criteria were amended to include only the higher-risk group with documented ECG changes or elevated serum cardiac markers. At the end of the trial, 83% of patients enrolled had these high-risk characteristics. All patients received aspirin. The primary end point of the study was the composite incidence of death/MI and urgent, ischemia-driven revascularization.
The results: At 14 days, primary outcome events occurred in 14.2% of the patients taking enoxaparin and 16.7% of those taking unfractionated heparin (P=0.029). Individual components of the end points all tended to be lower with enoxaparin: death, 2.2% versus 2.8%; MI, 4.2% versus 5.4%; death/MI, 5.7% versus 6.9%; and revascularization, 9.6% versus 11.1%. After the chronic treatment phase (through day 43), composite outcome events occurred in 17.3% of the enoxaparin group and 19.6% of the unfractionated-heparin group. Major bleeding events at 72 hours (0.8% with enoxaparin versus 0.7% with unfractionated heparin) and during the in-hospital phase (1.5% versus 1.0%) were not significantly increased; during the chronic phase, they were significantly higher with enoxaparin (2.9% versus 1.5%; P=0.02). A meta-analysis combining the results of TIMI 11B with the ESSENCE trial showed a significant 20% reduction of death and cardiac ischemic events in unstable angina/non–Q-wave MI patients treated with enoxaparin.
Summary: In TIMI 11B, enoxaparin was superior to unfractionated heparin in reducing the occurrence of composite outcome events. The initial benefits are sustained, but a prolonged course of therapy provides no additional relative increase in benefit and is associated with an increase in major bleeding events.
Presenter: Salim Yusuf, McMaster University, Hamilton, Ontario, Canada.
The study: A large-scale (360 centers in 16 countries; n=5058), randomized, controlled trial of heparin versus the direct thrombin antagonist hirudin in patients with unstable angina or MI without ST-segment elevation. Qualifying patients were randomized to receive either heparin (5000-U bolus, 15-U/kg infusion, titrated to aPTTs of 60 to 100 seconds) or hirudin (0.4 μg/kg bolus; 0.15 μg · kg−1 · h−1 infusion; n=5083). Study-drug therapy was intended to be continued for up to 72 hours. The primary end point of the trial was the composite incidence of cardiovascular death and new MI at 7 days. The secondary end point was the composite of cardiovascular death, new MI, and refractory ischemia.
The results: More than 90% of patients received >48 hours of study-drug therapy. Mean plateau aPTTs were ≈80 seconds in the heparin group and slightly higher in the hirudin group. Only ≈5% of the patients in the trial underwent angioplasty during the initial hospitalization.
The incidence of the composite of cardiovascular death and MI at 7 days was 4.2% in the heparin group and 3.6% in the hirudin group (P=0.069) The composite incidence of cardiovascular death, MI, and refractory ischemia at 7 days was 6.7% with heparin and 5.5% with hirudin (P=0.009). There was no evidence of a “rebound” phenomenon after discontinuation of the study drug. Revascularization was required significantly less frequently in the hirudin group (6.8% versus 8.1% with heparin; P=0.01). Major bleeding was slightly increased with hirudin (1.2% versus 0.7% with heparin). Combined analysis of OASIS-I and OASIS-2 showed a significant reduction (of ≈20%) in cardiovascular death/MI (P=0.03), the composite of cardiovascular death/MI/refractory ischemia (P=0.003), and need for intervention (P=0.007).
Summary: The use of hirudin may be associated with moderate advantages in composite clinical outcome over unfractionated heparin for the treatment of patients with unstable angina.
Presenter: A. Leizorovicz, Lyons, France.
The study: A large-scale (179 centers in 17 countries), randomized, controlled trial comparing unfractionated heparin (n=1151) with 1 of 2 treatment regimens with the low-molecular-weight heparin compound Fraxiparine (a short course of 6±2 days of therapy [n=1166] and a long course of 14 days of therapy [n=1151]) in patients with unstable angina and non–Q-wave MI. The primary end point of the study was the composite incidence of cardiovascular death/MI/recurrent angina at 14 days.
The results: Primary end-point events occurred in 15.1% of the heparin group, 17.8% of the short-course Fraxiparine group, and 20% of the long-course Fraxiparine group. At 6 days, occurrence rates for the respective composite end points were 14.9%, 13.8%, and 15.8%. At 3 months, the long-course Fraxiparine group tended to do worse than the unfractionated-heparin group; incidence rates for composite end points were 22.2%, 22.3%, and 26.2%, respectively, and the incidence of death/MI was 7.9%, 8.6%, and 8.9%. Overall mortality at 3 months was 3.6%, 4.2%, and 4.4%, respectively. There was no difference among groups in the incidence of revascularization at 3 months. There was a significantly higher incidence of hemorrhage in the long-course Fraxiparine group (3.5% at 14 days; 4.0% at 3 months).
Summary: A 6-day course of Fraxiparine is associated with clinical outcomes comparable to those seen with unfractionated heparin. A longer course of Fraxiparine therapy results in no added clinical benefit, a trend toward worse clinical outcomes, and a significantly increased risk of bleeding.
Presenter: F.W.H.M. Bär, Maastricht, Netherlands.
The study: A study comparing a bolus alone versus a bolus plus infusion of the thrombolytic agent saruplase in patients with acute MI. A total of 2410 patients presenting within 6 hours of an MI were randomized to standard therapy with saruplase (20-mg bolus plus 60-mg infusion over 1 hour [n=1214]) or a single 80-mg bolus (n=1196). The primary end point of the study was 30-day mortality. BIRD was designed as an equivalence study to show that the new bolus regimen was associated with end-point events that were no worse than 2.5% higher than with standard saruplase therapy.
The results: Thirty-day mortality was 6.0% with standard saruplase therapy and 5.9% with single-bolus saruplase therapy. Other 30-day end points included reinfarction (5.0% with standard therapy versus 6.5% with single-bolus therapy), recurrent angina (25.9% versus 24.7%, respectively), hemorrhagic stroke (0.7% versus 0.8%), and major bleeding events (2.4% versus 2.8%).
Summary: In BIRD, single-bolus therapy with saruplase was clinically equivalent to standard-bolus-plus-infusion treatment.
GISSI-3: Long-Term Follow-Up
Presenter: Luigi Tavazzi, Pavia, Italy.
The study: GISSI-3 was a large-scale (n=19 394) randomized study (conducted from 1991 to 1993) that evaluated the potential benefit of early lisinopril therapy on the combined end point of survival and left ventricular function in patients with acute myocardial infarction (MI). The initial results showed a significant relative reduction of 11% in overall 6-week mortality (6.4% with lisinopril versus 7.2% with placebo); at 6 months, there was a nonsignificant trend favoring lisinopril (9.1% versus 9.6%). Follow-up has been extended to 4 years (in 95% of the original cohort) to determine whether this survival benefit persists.
The results: Over time, out to 4 years of follow-up, the survival curves continue to track in parallel. At 4 years, mortality was 20.9% in the lisinopril group and 21.7% in the placebo group (P=NS). Subgroup analysis suggested that most of the benefit was manifested in patients with diabetes and patients with anterior infarction. Whatever mortality benefit was present was mostly manifested early in the course of therapy. A substudy analysis of 687 patients that examined echocardiographic remodeling suggested a complex, heterogeneous process. Early remodeling was not significantly impacted by lisinopril, but there was a trend toward reduction of late remodeling.
Summary: The mortality benefit of ACE-inhibitor therapy in acute MI is mainly manifested early; the absolute degree of benefit appears to be maintained over time but is not statistically significant at 4 years. Late ventricular remodeling (but not early remodeling) may be favorably influenced by long-term ACE-inhibitor therapy.
EPISTENT: 6-Month Follow-Up
Presenter: Eric Topol, MD, Cleveland Clinic, Cleveland, Ohio.
The study: A randomized trial comparing stenting without a glycoprotein IIb/IIIa antagonist, stenting with a glycoprotein IIb/IIIa antagonist (abciximab), and PTCA with a glycoprotein IIb/IIIa antagonist (abciximab) in 2499 patients eligible for coronary stenting. Patients in the 2 abciximab arms received low-dose heparin (70 U/kg) for procedural anticoagulation. Previously reported 30-day data demonstrated significant improvement in the composite end point of death, MI, and revascularization in the 2 abciximab groups compared with the stent-alone control arm. The present report documents longer-term 6-month follow-up outcomes.
The results: At 6 months, the combined incidence of death, MI, and urgent revascularization was 12.1% in the stent-alone group, 6.4% in the stent-plus-abciximab group, and 9.2% in the PTCA-plus-abciximab group. The respective rates for the composite end point of death, MI, and total repeat revascularization were 18.3% in the stent-alone group, 13.0% in the stent-plus-abciximab group, and 20.5% in the PTCA-plus-abciximab group. Every component of the composite end point in stent patients was significantly improved with adjunctive abciximab (death, 0.5% versus 1.2%; MI, 5.2% versus 10.3%; and target vessel revascularization, 8.7% versus 10.6%). In the subgroup of patients in the trial who had diabetes (n=491), the composite end point of death, MI, and target vessel revascularization was reduced from 25.2% to 13.0%, and repeat revascularization was reduced from 16.6% to 8.1% when stent alone was compared with stent plus abciximab, contrasted with 23.4% in the PTCA-plus-abciximab group. The use of abciximab was not associated with an increase in major bleeding.
Summary: The initial benefits associated with the use of the IIb/IIIa antagonist abciximab in coronary stent patients are sustained at 6 months. There was a very low incidence of target vessel revascularization in the stent-plus-abciximab group. Diabetics treated with stents appear to be 1 subgroup in whom adjunctive IIb/IIIa antagonist therapy may be particularly effective in reducing long-term events, including repeat revascularization.
Presenter: Patrick Serruys, Thoraxcentrum, Rotterdam, Netherlands.
The study: A randomized, double-blind, placebo-controlled trial evaluating the efficacy of trapidil in preventing in-stent neointimal hyperplasia. A total of 319 patients undergoing placement of a coronary Wallstent for single de novo lesions in native coronary arteries were randomized to placebo (n=155) or trapidil (200 mg TID; n=148) for 6 months. The primary end point of the study was an intravascular ultrasound (IVUS)–derived measurement of neointimal volume within the deployed stent.
The results: There was no significant difference in the primary end point between treatment groups. Clinical events (death, MI, and revascularization) also did not differ between groups. On quantitative coronary angiography analysis at 6-month follow-up, lumen size tended to be slightly but not significantly lower with trapidil (1.63±0.61 versus 1.74±0.69 mm). Binary restenosis rates tended to be slightly but not significantly higher with trapidil (31% versus 24%).
Summary: In patients undergoing coronary Wallstent implantation, the use of trapidil does not result in any clinical, angiographic, or IVUS benefit.
Presenter: Nico Pijls, Eindhoven, Netherlands.
The study: A randomized trial evaluating deferred versus immediate angioplasty in patients admitted for coronary intervention without clearly documented ischemia. A total of 303 patients from 40 clinical centers in 7 countries scheduled for elective coronary interventions in native coronary vessels underwent evaluation of fractional flow reserve (FFR) with a 0.014-in pressure wire and maximal hyperemia with adenosine. Patients with an FFR <0.75 (n=140) proceeded to intervention; patients with an FFR ≥0.75 (n=163) were randomized to no intervention or “optimal intervention” (stents were used in 53% of this group). The primary end point of the study was the composite incidence of death, MI, or repeat revascularization at 12 months. Complete follow-up data are not yet available.
The results: At the time of the present analysis, all patients had completed 30-day follow-up, 50% had completed 6-month follow-up, and 25% had completed 1-year follow-up. The incidence of composite outcome events was 14% in the group with an FFR <0.75 who proceeded to intervention, 9% in the group with an FFR ≥0.75 who were randomized to intervention, and 5% in the group with an FFR ≥0.75 who were randomized to no intervention. Angiographic characteristics were not a good predictor of FFR.
Summary: In the DEFER study, ≈50% of patients without a clearly documented history of ischemia had inducible ischemia as manifested by an FFR ≤0.75. Angiography was not a good predictor of inducible ischemia. The question of whether optimal intervention is of long-term benefit in patients without inducible ischemia cannot be answered definitively until complete follow-up data are available.
Presenter: J. Dens, Leuven, Belgium.
The study: A single-center, placebo-controlled trial of the calcium channel blocker nisoldipine in patients undergoing coronary intervention. Patients undergoing successful PTCA procedures in native coronary arteries were randomized to nisoldipine (20 mg/d for 2 weeks, then 40 mg/d for 3 years) or placebo. Patients undergoing stent procedures and patients with familial homozygotic hypercholesterolemia were excluded. A total of 826 patients were enrolled, 772 of whom composed the intention-to-treat population and 646 of whom completed follow-up (308 nisoldipine, 338 placebo). The current presentation focused on the effects of nisoldipine on restenosis after intervention. An ongoing part of the trial will look at the effect of nisoldipine on the progression of minor lesions in nondilated segments.
The results: At 6 months, there was no significant difference between treatment groups in minimum lumen diameter, initial gain, late loss, or diameter stenosis. The minimum lumen diameter cumulative distribution curves were virtually superimposable for the 2 treatment groups. There did appear to be somewhat fewer repeat revascularizations in the nisoldipine group.
Summary: Nisoldipine does not significantly influence the incidence of angiographic restenosis after balloon angioplasty. Nisoldipine is associated with somewhat lower subsequent revascularization rates, probably because of its anti-ischemic effects rather than a primary effect on restenosis.
Presenter: Michael Kutryk, Rotterdam, Netherlands.
The study: A single-center, randomized, placebo-controlled trial of the feasibility, safety, and efficacy of the local delivery of LR3280 (c-myc antisense oligonucleotide) for the inhibition of intimal proliferation. Patients undergoing elective stent implantation for a single lesion, de novo or restenotic, were randomized to LR3280 or placebo, given via a Transport catheter after stent implantation with a self-expanding Wallstent. The primary end point of the study was the percent intimal volume as determined by follow-up IVUS examination at 6 months.
The results: There were no significant differences between groups in volumetric IVUS analysis, in-stent volume, percent diameter stenosis, minimum lumen diameter at follow-up, late loss, and binary restenosis rate. There was also no difference in clinical outcomes between groups.
Summary: In lesions undergoing coronary stenting with a self-expanding Wallstent, treatment with LR3280 does not result in improvement of clinical, angiographic, or IVUS parameters.
Congestive Heart Failure
Presenter: Henry J. Dargie, Glasgow, Scotland.
The study: A large-scale (200 centers in 18 countries in Europe), randomized, placebo-controlled trial of bisoprolol (a selective β1-blocker) in patients with symptomatic congestive heart failure (CHF). The trial was originally designed to include 2500 patients with New York Heart Association (NYHA) class III or IV CHF and an ejection fraction ≤35%. Patients were randomized to bisoprolol (1.5 mg up to a maximum of 10 mg/d) or placebo. The primary end point was all-cause mortality. The trial was terminated prematurely because of excess benefit.
The results: At the time the study was stopped, a total of 2647 patients had been recruited (83% NYHA class III, 16% NYHA class IV; ≈60% ischemic, 40% nonischemic). At a mean follow-up of 1.4 years, all-cause mortality was 11.8% in the bisoprolol group and 17.3% in the placebo group, a 32% relative decrease (P=0.00005).
There appeared to be benefit in patients irrespective of age or cause of heart failure, although patients with very severe nonambulatory class IV heart failure were not included in the study. The incidence of sudden death was dramatically reduced with bisoprolol. (3.6% versus 6.4% with placebo). There were also significant reductions in the total number of hospitalizations and hospitalizations for worsening heart failure. Bisoprolol appeared to be as well tolerated as placebo.
Summary: In patients with NYHA class III and IV CHF, bisoprolol therapy is associated with a significant reduction in sudden death, all-cause mortality, mortality, and subsequent hospitalizations.
Presenter: E. Lindberg, Basel, Switzerland.
The study: A randomized, multicenter, placebo-controlled trial of the T-type calcium antagonist mibefradil in 2590 patients with symptomatic heart failure. The primary end point of the trial was overall mortality.
The results: There was no significant difference in survival between placebo and mibefradil. There was a tendency toward worse outcomes with mibefradil in a number of subgroups (women, patients with atrial fibrillation, and patients taking arrhythmic therapy, particularly amiodarone). When the effects of amiodarone were controlled for, mortality was equal in the placebo and mibefradil groups.
Summary: The use of mibefradil in patients with symptomatic CHF is not associated with any improvement in outcome. Mibefradil was associated with increased mortality in certain subgroups; there is a suggestion that there may be an adverse interaction between mibefradil and amiodarone.
Coronary Artery Disease
The WHO MONICA Project
Presenter: Hugh Tunstall-Pedoe, Dundee, UK.
The study: The WHO MONICA project monitored trends in incidence and outcome of cardiovascular disease over 10 years in 38 populations worldwide (predominantly in Europe). Two key questions being addressed are (1) do observed trends in the changing incidence of cardiovascular disease relate to changes in risk factors and (2) do observed trends in survival relate to changes in treatment?
The results: Preliminary analyses do not show a good quantitative relationship across populations between changes in risk factors and trends in incidence of coronary disease, although most trends are downward. On the other hand, there is a strong but possibly nonspecific relationship between implementation of new treatments and decline in fatality from acute coronary events.
Summary: Preliminary analyses appear to show a strong relationship between changing treatment and survival and no strong relationship of concurrent trends in risk factors with incidence of coronary disease, but additional analyses need to consider possible geographic polarization of results and evaluate further the quality, lack of heterogeneity of the data, and possible time lags in the relationship of trends.
Presenter: Michael F. Oliver, London, UK.
The study: A randomized, placebo-controlled trial of mivazerol (a drug with α2-agonist properties that decreases postganglionic noradrenaline output) to determine whether it can favorably influence the incidence of perioperative complications in patients undergoing noncardiac surgery. A total of 2854 patients undergoing major noncardiac surgery were enrolled in the overall trial in 61 clinical centers in Europe; 1897 patients had known coronary artery disease, and 957 were at risk for coronary artery disease. The latter group was not included in the present presentation. Qualifying patients were randomized to mivazerol (IV infusion beginning 20 minutes before anesthesia and continuing for 72 hours postoperatively; drug administered as a 4-μg/kg bolus over 10 minutes, then a 1.5-μg · kg−1 · h−1 infusion). The primary end point was the perioperative composite incidence of death and MI.
The results: The perioperative incidence of death/MI in the total population of 1897 patients with coronary artery disease was 10.6% in the placebo group and 9.5% in the mivazerol group (P=NS). When patients were stratified by type of surgery (vascular, thoracoabdominal, or orthopedic), mivazerol therapy did provide significant benefit in patients undergoing vascular surgery (n=904). In this group, incidence of death/MI was 9.7% in the mivazerol group versus 14.2% in the placebo group; both all-cause mortality (1.8% versus 4.4%; P=0.024) and cardiovascular mortality (1.3% versus 4.0%; P=0.017) were also significantly reduced with mivazerol. The divergence of events in the vascular surgery group took place largely in the first 6 hours after surgery. There were no significant differences among patients undergoing nonvascular thoracoabdominal surgery and orthopedic surgery.
Summary: Mivazerol appears to reduce mortality and the composite of death and MI in patients with coronary artery disease undergoing vascular surgery. It does not appear to provide significant benefit in patients with coronary artery disease undergoing nonvascular thoracoabdominal or orthopedic surgical procedures.
Presenter: Elieser Kaplinsky, MD, Tel Hashomer, Israel.
The study: A multicenter, randomized, placebo-controlled trial of bezafibrate (a fibric acid derivative whose primary actions are to decrease triglyceride and increase HDL levels) in 3090 patients with a prior MI and symptomatic coronary artery disease. The trial was conducted in 18 clinical centers in Israel. Qualifying patients (with a history of MI from 6 months to 5 years before enrollment and with angina for the past 2 years) were randomized to bezafibrate 400 mg/d (n=1548) or placebo (n=1542) and followed up for 5 to 7 years. The primary end point of the study was the composite incidence of fatal or nonfatal MI and sudden death.
The results: Bezafibrate therapy resulted in an ≈15% increase in HDL, a 20% decrease in triglyceride, and a 6% decrease in LDL. The composite primary end point tended to be lower with bezafibrate, although this did not achieve statistical significance. In the subpopulation of patients with high triglyceride levels (≥200 mg/dL), bezafibrate therapy was associated with a significant reduction in primary outcome events. Patients who raised their HDL by ≥5 mg/dL or reduced their triglycerides by ≥28 mg/dL (not mutually exclusive groups) showed the most benefit.
Summary: In the overall cohort of patients with prior MI and symptomatic coronary artery disease, bezafibrate does not significantly reduce outcome events. Bezafibrate does appear to reduce events in the subpopulation of patients with high baseline triglyceride levels, many of whom may have low levels of HDL.
Reprint requests to James J. Ferguson, MD, Cardiology Research, MC1-191, Texas Heart Institute, PO Box 20345, Houston, TX 77225.
- Copyright © 1999 by American Heart Association