The Azimilide Post-Infarct Survival Evaluation (ALIVE) demonstrated that azimilide had neither beneficial nor adverse effects on reducing all-cause mortality in patients who had had a recent myocardial infarction, according to A. John Camm, MD, of St George’s Hospital Medical School in London, UK. He noted, however, that further study needs to be directed toward the drug’s primary use as an antiarrhythmia medication. Dr Camm presented the study on November 14, 2001, at the 2001 Scientific Sessions of the American Heart Association in Anaheim, Calif.⇓
The study enrolled 3381 patients who had had a myocardial infarction in the previous 5 to 21 days and randomized them to either azimilide at 100 mg per day or placebo, in addition to the medications regularly given after a heart attack. Patients had a low left ventricular ejection fraction (15% to 35%) and were defined to be at risk for sudden death. A subpopulation of 1264 patients with low heart rate variability were defined to be at very high risk of sudden death and were studied separately.
The trial, conducted in 26 countries with 483 institutions, involved 3717 patients. A total of 336 patients randomized to 75 mg azimilide were not part of the overall analysis, although they were continued in safety studies. Baseline characteristics of both groups of patients were the same. There were 1690 patients in the placebo group and 1691 in the 100-mg azimilide group. There were 642 patients in the high-risk subgroup of the placebo group and 622 in the high-risk subgroup of the 100-mg azimilide group.
At the end of the study, 196 patients in the placebo group and 197 in the treatment group had died. There were 96 deaths in the high-risk placebo group and 88 in the high-risk treatment group. “Any way you parsed it, there was no difference,” said Dr Camm. He found a glimmer of hope in the fact that more than twice as many patients in the placebo group developed atrial fibrillation as in the treatment group, even though the numbers were low (19 and 8 patients, respectively).
The trial’s discussant during a plenary session at the American Heart Association’s 2001 Scientific Session in Anaheim, Calif, was Douglas Zipes, MD, Distinguished Professor of Medicine at the University of Indiana School of Medicine in Indianapolis. “I’d summarize this as the best of results and the worst of results,” said Dr Zipes. “The best is that there was no increase in mortality and the worst was that there was no decrease in mortality.”
He pointed out that the patients in the study were exceedingly well treated, with three fourths of them receiving β-blockers and >80% receiving aspirin. “We don’t know whether that excellent care might have blunted a negative effect of azimilide.”
Dr Zipes was concerned about reported neutropenia and Torsade de Pointes, even though the rates were low (0.9% and 0.4%, respectively), and he did not think that the trial establishes the drug’s benefit on atrial fibrillation. “The claims for atrial fibrillation need to be demonstrated in a well-run trial,” said Dr Zipes.
The Impact of Nicorandil in Angina (IONA) study demonstrated that use of the antianginal agent nicorandil reduced the risk of death from coronary heart disease, myocardial infarction, or unplanned hospitalization for cardiac-related chest pain by 17%, according to Henry Dargie, MD, of the University of Glasgow, Scotland. Dr Dargie described the study, which included >5000 patients, at the 2001 Scientific Sessions of the American Heart Association in Anaheim, Calif.⇓
Dr Dargie’s presentation on November 14, 2001, involved a disease that the trial’s discussant, Lionel Opie, MD, Director of the Cape Heart Centre, University of Cape Town Medical School, South Africa, called “the Cinderella” of coronary heart disease. “This is the first outcome study in this disease,” said Dr Opie.
“Our object was to investigate the impact of nicorandil on outcomes when it is added to existing treatment,” said Dr Dargie. The hypothesis was that it would reduce the incidence of the primary end points of coronary heart disease death, myocardial infarction, or unplanned hospitalization for chest pain by 25%, a target that the trial missed. The trial, carried out exclusively in the United Kingdom, enrolled only patients not being considered for revascularization.
The placebo group totaled 2451 patients and the treatment group, 2565 patients. Treatment with nicorandil was initiated at 10 mg and raised to 20 mg after 2 weeks, said Dr Dargie. Patients were followed up for an average of 1.6 years or until they died of coronary heart disease, had a heart attack, or were admitted to the hospital for angina. Of the patients in the placebo group, 396 reached one of the primary end points, compared with 335 in the treatment group, giving a hazard ratio of 0.83. However, 134 patients in the placebo group and 107 in the treatment group reached the secondary end point of coronary heart disease death or myocardial infarction, a difference that was not statistically significant.
Nicorandil is a potassium channel activator that reduces myocardial demand and increases coronary blood flow, said Dr Dargie. He said it is also believed that the drug is cardioprotective because it involves ischemic preconditioning. The drug is not available in the United States because the US Food and Drug Administration has not approved it. It has been used in Europe and Japan for at least a decade.
Dr Opie did not think that drug is responsible for ischemic preconditioning because it did not protect against myocardial infarction, as shown by the results for the primary and secondary end points. “Are there other mechanisms involved?” he asked. One of Dr Opie’s reservations about the study was that it involved only white patients. “There are no minority groups as there would be in an American study.” He was also concerned about the effect of excluding patients under consideration for a revascularization procedure and by the fact that patients were not receiving maximum treatment. Only 55% received either a β-blocker or calcium-channel blocker. A study of the graph of the drug’s effect, however, “leads me to suppose that nicorandil is altering the fundamental mechanism in unstable angina,” he said.
The drug fondaparinux proved as effective as enoxaparin (low–molecular weight heparin) in the Double-Blind dose-ranging study of Fondaparinux (Pentasaccharide) in Unstable Angina (PENTUA) study, said its principal investigator, Maarten L. Simoons, MD, of the Thoraxcenter in Rotterdam, the Netherlands. Dr Martin and his colleagues at 66 hospitals in 5 European countries enrolled 1147 patients with acute coronary syndromes in the study, which was presented November 14, 2001, at the 2001 Scientific Sessions of the American Heart Association in Anaheim, Calif.⇓
The analysis presented by Dr Simoons involved data from 929 patients who had at least 12 hours of continuous 12-lead ECG recording. Two thirds of the patients were male, with an average age of 62 years. Of the 929 patients, 80% had ECG abnormalities at enrollment, and 41% had elevated cardiac troponin levels.
Fondaparinux was tested at 2.5 mg, 4 mg, 8 mg, and 12 mg and was compared to enoxaparin at 1 mg/kg body weight twice a day. The main end points of the study were death, myocardial infarction, or recurrent ischemia. The treatment was administered for 3 to 8 days or until coronary revascularization. Patients were on different kinds of treatment: All had had aspirin, 95% were on nitrates and β-blockers, and more than half were taking lipid-lowering drugs.
There was no significant difference among the groups with regard to major end points. In the lowest-dose group (2.5 mg), 30% of patients reached the end point in 9 days and 33.8% in 30 days. At 4 mg, 43.5% of patients reached an end point in 9 days and 44.9% in 30 days. At 8 mg, 41.0% of patients reached an end point in 9 days and 42.4% in 30 days. At 12 mg, 34.8% of patients reached an end point in 9 days and 37.8% in 30 days. In the enoxaparin group, 40.2% of patients reached an end point in 9 days and 43.6% in 30 days. There was no dose-response, and in fact, the best results were reached with the lowest dose of fondaparinux.
Fondaparinux is a pentasaccharide with 5 sugar molecules. The drug was developed for the prevention of deep vein thrombosis and has been beneficial in orthopedic treatments. “It is intriguing that the lowest dose was the most effective, said Dr Simoons.
“None of us have an explanation for the dose-response effect,” said Robert M. Califf, MD, of the Duke Clinical Research Institute in Durham, NC. One problem, he noted, is that there are no surrogate end points in acute coronary syndromes, and a phase III trial of this drug would require a very large set of clinical trials “to generate the statistics needed to avoid doing harm to patients.”
In addition, Dr Califf said, fondaparinux will not exist in isolation. Similar drugs, including fractionated heparin and low–molecular weight heparin, are already in clinical use. “This is a wonderful phase II study, but it in no way tells us we should use this treatment, but gives the green light for further studies.”
The Combination Assessment of Ranolazine in Stable Angina (CARISA) trial is the first study of ranolazine in patients already taking antianginal medications, including antenolol, diltiazem CD, or amlodipine, according to Bernard R. Chaitman, MD, of St Louis University Medical Center in Missouri. The study enrolled 823 patients in 15 countries. Patients had a history of angina and documented coronary artery disease and were receiving at least one antianginal drug. Patients were enrolled in a double-blind, placebo-controlled, 3-arm study. They received either placebo, 750 mg ranolazine twice a day, or 1000 mg ranolazine twice a day.⇓
Those in the study underwent exercise testing at trough levels of the drug on weeks 2, 6, and 12 and at peak levels of the drug on weeks 2 and 12. The primary end point was exercise duration at 12 weeks. A total of 731 patients completed the study.
Patients on ranolazine could exercise on the treadmill 24 seconds longer than could those on placebo at trough after 12 weeks of treatment. The change was similar at both dosages, said Dr Chaitman. Patients on placebo increased their exercise times by 92 seconds compared with 115 seconds on 750 mg of ranolazine and 116 seconds on 1000 mg of ranolazine. In addition, said Dr Chaitman, frequency of angina attacks decreased by ≈1 per week. The average number of attacks was 4 per week.
Ranolazine is one of a new class of compounds called partial fatty acid oxidation (pFOX) inhibitors, a new class of antianginal drugs still under study. In animal studies, the drug increases the efficiency of oxygen use by the heart, using both fatty acids and sugar to make energy.
William Weintraub, MD, of Emory University School of Medicine (Atlanta, Ga) was formal discussant of the study during the plenary late-breaking session. He said the study involved a new drug and a new mechanism of treatment and pointed out that although the study showed that the drug has a good safety profile, questions remain.
“Who are the patients who are more appropriate for ranolazine?” asked Dr Weintraub. “Are we going to see problems with adverse events with wider use? This is an interesting drug and a trial with provocative findings, but there are more questions than answers.”