Highlights of the 70th Scientific Sessions of the American Heart Association
The following trials were presented at the 70th Scientific Sessions of the American Heart Association, November 10–13, 1997, in Orlando, Fla.
The Trial: AFCAPS/TEXCAPS
Presenter: Antonio Gotto, MD, Cornell University, New York, NY.
The study: A randomized, placebo-controlled trial of the HMG-CoA reductase inhibitor lovastatin in 6605 patients with average LDL cholesterol (130 to 190 mg/dL) and relatively low HDL (<50 mg/dL), with an HDL/LDL ratio of <0.5. No patients had clinical evidence of coronary artery disease. Patients were randomized to placebo or lovastatin (mean dose, 30 mg) and followed up. The primary end point of the trial was the new development of unstable angina, fatal or nonfatal MI, or sudden cardiac death. The study was stopped when the result crossed the prespecified stopping boundaries after a total of 267 events.
The results: Overall, treatment with lovastatin resulted in a 36% relative decrease in the incidence of primary-end-point events. In the placebo group, the total number of primary-end-point events at long-term follow-up (≥5 years) was 182, compared with 105 in the lovastatin group. Lovastatin therapy was associated with a relative decrease of 34% in new unstable angina admissions, 35% in fatal or nonfatal MI, and 33% in revascularization procedures. The degree of benefit was independent of the absolute level of LDL.
Summary: In men and women free of clinical signs of cardiovascular disease, with average total cholesterol and LDL and low HDL, treatment with lovastatin results in a significant decrease in the incidence of new cardiovascular events.
The Trial: LIPID
Presenter: Andrew Tonkin, MD, University of Melbourne and National Heart Foundation of Australia, Melbourne.
The study: A multicenter, randomized, placebo-controlled trial of the HMG-CoA reductase inhibitor pravastatin in patients (men and women 31 to 75 years old) after a heart attack or those admitted with unstable angina with average (155 to 270 mg/dL) cholesterol levels. A total of 9014 patients were randomized to pravastatin (40 mg/d) or placebo. The primary end point of the trial was coronary heart disease mortality. The study was originally designed to take place over a 7-year period. However, at a mean follow-up of 60 months, the mortality curves crossed the prespecified boundary (3 SD) for stopping the trial, and the study was terminated.
The results: Pravastatin therapy was associated with significant reductions in death from coronary heart disease (6.4% versus 8.3%, 24% relative decrease), total mortality (11.0% versus 14.1%, 23% relative decrease), stroke (20% relative decrease), need for CABG (8.9% versus 11.3%, 24% relative decrease), and fatal and nonfatal MI (7.4% versus 10.1%, 29% relative decrease).
Summary: In patients with unstable angina or a history of MI with average cholesterol levels, cholesterol-lowering therapy with pravastatin significantly reduces mortality.
The Trial: PAMI Stent Pilot
Presenter: Gregg W. Stone, MD, El Camino Hospital, Mountain View, Calif.
The study: An open-label pilot trial of the safety and efficacy of primary stenting (stenting all target lesions possible) in patients with acute MI. There were no age restrictions, and treatment of both native vessels and saphenous vein grafts was allowed. In-hospital outcomes were compared with the outcomes of primary PTCA in the PAMI-2 study.
The results: Of 312 consecutively enrolled patients, 240 (77%) underwent successful stent implantation. Procedural success (TIMI-3 flow with <50% stenosis) was slightly but not significantly better in the PAMI stent pilot than in PAMI-2 (95% versus 92%, P=.08). PAMI stent patients had a significantly lower incidence of reinfarction (1.3% versus 4.8%), recurrent ischemia (3.5% versus 11.8%), and in-hospital mortality (0.6% versus 2.8%). There was also a nonsignificant trend toward lower repeat target lesion PTCA (2.9% versus 6.0%, P=.06) and similar rates of CABG (5.1% versus 6.9%) and stroke (0.3% versus 0.8%).
Summary: A primary stent strategy in patients with acute MI is safe and feasible and results in better in-hospital outcomes than primary PTCA in previous studies.
The Trial: TIMI 14
Presenter: Elliott Antman, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass.
The study: A prospective, multicenter, randomized, controlled trial of combined therapy with thrombolytic agents and the platelet GP IIb/IIIa antagonist abciximab in patients with acute MI. An interim report was presented on a total of 444 patients who were randomized to standard front-loaded t-PA (100 mg), low-dose t-PA (20, 35, or 50 mg) plus abciximab, low-dose streptokinase (500 000, 750 000, or 1 250 000 U) plus abciximab, or abciximab alone. The primary end point of the study is the incidence of TIMI grade III flow at 90-minute angiography.
The results: At 90 minutes, the incidence of TIMI III flow was 52% in the t-PA–alone arm; 32% in the abciximab-alone arm; 53%, 63%, and 61% in the respective t-PA plus abciximab groups; and 42%, 38%, and 48% in the respective streptokinase plus abciximab groups. The incidence of major hemorrhage was 7% in the t-PA–alone arm; 6% in the abciximab-alone arm; 5%, 0%, and 8% in the respective t-PA plus abciximab groups; and 5%, 8%, and 12% in the respective streptokinase plus abciximab groups.
Summary: The combination of thrombolytic therapy and GP IIb/IIIa receptor blockade appears to result in facilitated thrombolysis. Abciximab alone was not as effective as t-PA alone. Bleeding may be somewhat increased with combination therapy when higher doses of streptokinase are used.
The Trial: HIT 4
Presenter: Professor Karl-Ludwig Neuhaus, Staedtische Kliniken, Kassel, Germany.
The study: A multicenter, randomized, controlled trial of heparin versus r-hirudin (a direct thrombin inhibitor) in 1211 patients with acute MI treated with streptokinase. An angiographic substudy examined patency rates in 447 patients undergoing 90-minute angiography.
The results: There were no significant differences in 30-day mortality (6.8% with r-hirudin versus 6.4% with heparin) or reinfarction (4.4% with r-hirudin versus 4.9% with heparin). There were no significant differences in TIMI 3 flow rates between groups (40.7% with r-hirudin versus 33.5% with heparin). The r-hirudin group had more complete resolution of ST-segment changes (28% versus 22%).
Summary: The combination of r-hirudin and streptokinase does not dramatically enhance the efficacy of thrombolytic therapy as assessed by mortality, reinfarction, and 90-minute angiographic patency.
The Trial: PRIME
Presenter: Gregory Barsness, MD, Duke University Medical Center, Durham, NC.
The study: A prospective, multicenter, randomized, controlled trial of the direct thrombin inhibitor efegatran versus heparin in patients with acute MI after thrombolytic therapy. A total of 336 MI patients treated with t-PA were randomized to heparin or efegatran. All patients underwent 90-minute angiography; a subset of 152 patients without previous intervention had follow-up angiography a median of 5 days later.
The results: Efegatran-treated patients had shorter activated partial thromboplastin times but longer peak thrombin times. In patients with matched studies, the 90-minute TIMI III flow rates (66% versus 73%; P=.4) and reduction in infarct artery stenosis at follow-up (4% versus 1%; P=.16) were not significantly different for heparin and efegatran. There was no significant difference in reocclusion rates for heparin and efegatran (8% versus 10%; P=1.0).
Summary: In patients with acute MI treated with accelerated t-PA, efegatran appears to provide no angiographic improvement in acute or subsequent infarct artery stenosis.
The Trial: AMISTAD
Presenter: Kenneth W. Mahaffey, MD, Duke University Medical Center, Durham, NC.
The study: A multicenter, randomized, placebo-controlled trial of adenosine (70 μg · kg−1 · min−1 for 3 hours) in 236 patients with acute MI treated with thrombolytic therapy. To qualify for the study, patients had to be enrolled within 6 hours of their MI; patients in cardiogenic shock were excluded. Separate randomization schemes were used for anterior and nonanterior infarcts. The primary end point of the study was myocardial infarct size (adjusted for covariates), as determined by 99mTc-sestamibi single-photon emission computed tomographic imaging 6±1 days after enrollment. Clinical follow-up was also obtained at 4 to 6 weeks.
The results: The principal finding was a 33% relative reduction in infarct size (P=.03 using prespecified multivariable regression modeling that adjusted for covariate (22 adenosine patients vs 16 placebo patients). There was a 67% (15 vs 45.5%; P=.014) relative reduction in infarct size in patients with anterior infarcts, but no reduction (11.5 vs 11.5%) in infarct size in patients with nonanterior infarcts. There was a tendency toward more adverse clinical events (death, infarction, CHF, shock, and/or stroke) in the adenosine group, although the overall number of events was small.
Summary: Adenosine may significantly reduce infarct size; the results of this study are encouraging and support the need for a large clinical outcome study.
The Trial: ERASER
Presenter: Stephen Ellis, MD, Cleveland Clinic, Cleveland, Ohio.
The study: A prospective, randomized, placebo-controlled, multicenter study of the platelet GP IIb/IIIa receptor antagonist abciximab in patients undergoing coronary stent placement. After successful stent placement, a total of 225 patients were randomized to receive either placebo, a bolus and 12-hour infusion of abciximab, or a bolus and 24-hour infusion of abciximab. The primary end point of the study was the percent volume obstruction by IVUS at 6-month follow-up catheterization; 152 patients underwent 6-month follow-up IVUS examination.
The results: At 6 months, the mean IVUS percent volume obstruction was 32.4% in the placebo group, 32.7% in the 12-hour abciximab group, and 34.2% in the 24-hour abciximab group. The incidence of death, MI, and target vessel revascularization at 6 months was 25.4% in the placebo group, 20.3% in the 12-hour abciximab group, and 22.7% in the 24-hour abciximab group.
Summary: Treatment with abciximab did not result in a significant decrease in intimal hyperplasia after intracoronary stent placement.
The Trial: ORBIT
Presenter: Dean Kereiakes, MD, Lindner Center for Cardiovascular Research, Cincinnati, Ohio.
The study: A phase II, multicenter, randomized, placebo-controlled trial of the oral platelet GP IIb/IIIa antagonist xemilofiban in patients after percutaneous coronary intervention. A total of 549 patients were randomized to one of three treatment groups: xemilofiban 15 mg TID for 2 weeks, then BID for 2 weeks; xemilofiban 20 mg TID for 2 weeks, then BID for 2 weeks; or placebo. Abciximab patients were included but received lower doses of xemilofiban (10 mg TID) for the first 2 weeks. All patients received aspirin (325 mg/d). The primary end points of the study were pharmacokinetic/pharmacodynamic parameters and the safety and tolerability of xemilofiban.
The results: There was a dose-dependent increase in plasma concentration and degree of platelet inhibition; both xemilofiban doses were able to achieve between 50% and 80% inhibition of platelet aggregation in response to 20 μmol/L ADP. There was no increase in serious bleeding events in the xemilofiban groups. Xemilofiban was associated with an increase in insignificant and mild bleeding events that did not require discontinuation of study drug or treatment. There were no significant differences in clinical outcome events at 90 days for the entire study population.
Summary: After percutaneous coronary intervention, prolonged (1-month) therapy with xemilofiban does not increase the incidence of major bleeding complications, although insignificant and minor bleeding complications are more common. Although clinical events were not significantly different at 90 days, the trial was not powered for a clinical events end point; longer-term outcomes will be assessed in larger phase III trials.
The Trial: Argatroban in HIT Patients Undergoing PTCA
Presenter: Bruce Lewis, MD, Loyola University, Chicago, Ill.
The study: A controlled, open-label trial of the direct thrombin inhibitor argatroban in 50 patients with a history of HIT undergoing PTCA. Outcomes were compared with a registry control of 5832 non-HIT patients undergoing PTCA who were treated with heparin.
The results: Adequate procedural anticoagulation (activated coagulation time >300 seconds) with argatroban was achieved in 98% of the HIT patients. Among HIT patients, there were 1 patient who developed abrupt closure requiring bypass surgery and 1 patient with a retroperitoneal hematoma. Acute procedural success was slightly better in the argatroban/HIT group (98% versus 94%; P=.03).
Summary: Argatroban anticoagulation for PTCA in patients with a history of HIT appears to be comparable to heparin anticoagulation in non-HIT patients.
The Trial: ACUTE
Presenter: Uri Rosenschein, MD, The Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
The study: A prospective, uncontrolled, multicenter trial of percutaneous coronary ultrasound thrombolysis in 31 consecutive patients presenting with acute anterior MI.
The results: Patency was achieved in 29 of 31 patients (94%); TIMI 3 flow was achieved in 26 (84%). The mean residual stenosis after ultrasound therapy alone was 54±26%. There were no dissections, perforations, embolism, no-reflow, or spasm. Subsequent adjunct PTCA resulted in a mean residual stenosis of 15%. Stents were deployed in 7 patients (22%). After the procedure, 1 patient (3%) developed reinfarction and 3 patients (10%) had recurrent ischemia and repeat target-vessel revascularization.
Summary: Ultrasound thrombolysis appears to be a useful reperfusion technique in patients with acute MI.
The Trial: ARREST
Presenter: Peter Kudenchuk, MD, University of Washington, Seattle.
The study: A prospective, double-blind study of amiodarone in patients with nontraumatic out-of-hospital cardiac arrest and refractory ventricular arrhythmias not responding to three initial shocks. A total of 3954 patients were screened for the study; 667 met study inclusion criteria, and 504 were enrolled. Of these, 246 received amiodarone and 258 received placebo. All patients were pulseless at the time of treatment with amiodarone or placebo, and all patients were subsequently treated with standard advanced cardiac life support protocols. The primary end point of the study was the number of patients admitted alive to the hospital.
The results: Of the patients treated with amiodarone, 44% survived to hospital admission, compared with 35% of the placebo-treated patients, a relative increase of 27%. One subgroup with particular benefit was those patients who transiently had a return of spontaneous cardiac function before treatment with the study drug. In these patients, 64% of the amiodarone patients survived to hospital admission, compared with 41% of the placebo-treated patients.
Summary: Amiodarone appears to be an effective form of therapy in patients with cardiac arrest due to shock-refractory ventricular fibrillation.
The Trial: CABG-PATCH
Presenter: Thomas Bigger, MD, Columbia University, New York, NY.
The study: A multicenter, randomized, controlled trial of ICD therapy in high-risk patients (ejection fraction <36%, abnormal signal-averaged ECG) undergoing CABG surgery. A total of 900 patients were randomized to ICD (n=446) or no ICD (n=454) and followed clinically for an average of 3 years. The primary end point of the trial was all-cause mortality.
The results: There was no difference between the two treatment groups in all-cause mortality. The use of drugs for angina, heart failure, and arrhythmias did not differ between groups; there were no differences in the use of antiarrhythmic drugs and β-blockers.
Summary: In the high-risk group of patients studied in this trial, who were undergoing CABP, ICD therapy did not decrease mortality. ICD prophylaxis does not appear to benefit all high-risk subgroups.
The Trial: DIAMOND-MI
Presenter: Poul Erik Bloch-Thomsen, MD, PhD, University of Copenhagen, Denmark.
The study: A multicenter, randomized, placebo-controlled trial of the class III antiarrhythmic drug dofetilide in patients after MI. A total of 1510 patients were randomized to dofetilide (n=749; target dose, 0.5 mg BID) or placebo (n=761) and followed up for at least 1 year. All randomized patients were continuously monitored by telemetry for 3 days after therapy was initiated. The primary end point of the study was all-cause mortality.
The results: There were 230 total deaths in the dofetilide group, compared with 243 total deaths in the placebo group (P=NS). There were no differences in cardiac mortality or arrhythmic death between groups. The drug was generally well tolerated, although there was a slight increase in the early incidence of torsades de pointes in the dofetilide group.
Summary: In post-MI patients, dofetilide is well tolerated, but it has no significant effect on mortality.
Congestive Heart Failure
The Trial: RESOLVD
Presenter: Salim Yusuf, MD, McMaster University, Hamilton, Ontario, Canada.
The study: A multicenter, prospective, randomized, controlled trial of Candesartan (a direct angiotensin II subtype I receptor antagonist) in 768 patients with congestive heart failure. Patients were randomized to 1 of 3 doses of Candesartan (4, 8, or 16 mg/d), enalapril alone (20 mg/d), enalapril 10 mg/d plus Candesartan 4 mg/d, or enalapril 10 mg/d plus Candesartan 8 mg/d. The primary end point of the study was exercise tolerance; the secondary end point was ventricular function.
The results: There were no differences among groups in exercise capacity, symptomatic deterioration, or quality of life; combination therapy resulted in lower levels of serum aldosterone, greater blood pressure reduction, improved ejection fraction, decreased cardiac dilatation, and a reduction in atrial natriuretic peptide and brain natriuretic peptide than either therapy alone. There were no significant differences in mortality, clinical deterioration of heart failure, or hospitalizations.
Summary: Candesartan appears to be comparable to enalapril in terms of clinical outcome. Combination therapy results in greater suppression of aldosterone, prevention of ventricular dilatation, and a greater reduction in natriuretic peptides.
Selected Abbreviations and Acronyms
|CABG||=||coronary artery bypass graft surgery|
|HMG-CoA||=||hydroxymethylglutaryl coenzyme A|
|PTCA||=||percutaneous transluminal coronary angioplasty|
|t-PA||=||tissue plasminogen activator|
Reprint requests to James J. Ferguson, MD, Cardiology Research, MC1–191, St Luke’s Episcopal Hospital, PO Box 20269, Houston, TX 77225.
- Copyright © 1998 by American Heart Association