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By William T. Elliott, MD, FACP
November was a good month for ace inhibitors. the New England Journal of Medicine took the unusual step of publishing an early release of data from The Heart Outcomes Prevention Evaluation (HOPE) on its Web site because of potential therapeutic implications. The study of more than 9000 patients was performed at 129 centers in Canada, 27 in the United States, 76 in Europe, and 35 in Mexico and South America on patients aged 55 years and older with cardiac risk factors such as coronary artery disease, diabetes, or a previous stroke. Patients with heart failure or weak heart function were excluded from the study. In the critical part of the study, 4645 patients were randomized to receive the ACE inhibitor ramipril (Altace) (Hoechst—Marion Roussel) while 4652 received placebo. Treatment with ramipril resulted in a 25% reduction in death from all cardiovascular causes, 20% reduction in MI, and 30% reduction in stroke risk. The proportion of patients who required either coronary or noncoronary revascularization procedures was 16% lower in the ramipril group than in controls. The rates of cardiac arrest, heart failure, and complications of diabetes were 37%, 22% and 16% less with ramipril therapy, respectively. The drug also reduced the new development of diabetes by 30%, the first drug to be effective in this role. The full paper will be published in a January issue of the New England Journal of Medicine.
Angiotension receptor blockers (ARBs) such as losartin (Cozaar—Merck) are becoming popular antihypertensive agents because of their effectiveness and lack of cough commonly associated with ACE inhibitors. There has been some suggestion that ARBs may be more effective than ACE inhibitors for treating congestive heart failure as well. Much of this evidence was from the head-to-head, double-blind ELITE trial, comparing losartin to captopril in patients with heart failure. ELITE enrolled only 700 patients and early results suggested a significant survival benefit for patients on losartin. The follow-up ELITE II trial enrolled more than 3000 patients in the same design. The results of ELITE II, reported in November to the 72nd scientific sessions of the American Heart Association, came up with a far different conclusion—the mortality curves were superimposable, with 250 deaths in the captopril group and 280 in the losartin group—a non-significant difference. The investigators suggest that the early findings were due to chance and the small number of patients in the original study.
Yet another ACE inhibitor study for the treatment of chronic heart failure (CHF) suggests that most CHF patients may be receiving subtherapeutic doses. The study, entitled ATLAS (Assessment of Treatment with Lisinopril and Survival), enrolled 3000 patients with heart failure, all with ejection fractions less than 30%. Two groups were given either low-dose lisinopril (2.5-5 mg/d) or high-dose (32.5-35 mg/d) along with standard CHF therapy. During the five-year study period, the high-dose group had a 12% lower risk of death or hospitalization. There was no improvement in symptoms with high-dose lisinopril and, surprisingly, there was a higher rate of cough in the low-dose group. The results of the study were published as a "rapid track" by the American Heart Association, and the full results are in the December 1999 issue of Circulation.
Glaxo’s drug lamivudine may be effective in preventing liver fibrosis associated with chronic hepatitis B infections. A multicenter, placebo-controlled, randomized trial of 137 patients studied 100 mg of lamivudine daily vs. placebo. The active treatment group was significantly more likely to have a reduction in liver inflammation (64% vs 34%) or progressive fibrosis (5% vs 20%) compared to placebo. HBV DNA levels became undetectable after lamivudine therapy, but quickly returned to half of pretreatment levels within four months (N Engl J Med 1999;341:1256-1263). In phase III studies of lamivudine, a lower 25 mg/d dose was also found to be effective (59% reduction in inflammation, and 10% progressive fibrosis). Lamivudine is marketed for HIV treatment under tradenames Epivir and Combivir, and for HBV therapy as Epivir-HBV.
Do lipid-lowering medications cause more accidental injuries? Ever since the Helsinki Heart Study was published in 1987, concern has lingered on whether lipid-lowering medications may increase total mortality even if they reduce cardiovascular events. Some studies seemed to suggest that these medications might increase depression and hostility, thereby leading to an increase in accidental deaths or injuries. A new study suggests that not only is this not the case, but that patients on these drugs may be at a lower risk of accidental injury as nonusers. The population-based, case-control study showed that injured patients are about half as likely to be on lipid-lowering medications as nonusers (J Clin Epidemiol 1999;52:1197-1200).
The FDA has approved the combination drug aspirin/dipyridamole for the prevention of recurrent CVAs and TIAs. The drug will be marketed as Aggrenox by Boehringer. Approval of the drug combination was based on data from the European Stroke Prevention Study in which it was compared to 50 mg of aspirin/d, showing a modest benefit.
The Agency has also approved Teva Pharmaceutical’s generic version of Glaxo’s antidepressant bupropion (Wellbutrin) in the 75 and 100 mg dose form. Bupropion is also marketed under the trade name Zyban for smoking cessation.
The FDA’s Gastrointestinal Drugs Advisory Committee has recommended approval of alosetron, a 5-HT3 antagonist, for the treatment of symptoms of irritable bowel syndrome (IBS). The drug is recommended only for women with IBS who have diarrhea as the predominant symptom. Once approved by the FDA, it will be marketed under the name Lotronex by Glaxo.
UCB Pharmahas received approval to market their antiepileptic agent levetiracetam (Keppra). The drug, which is approved for the treatment of partial-onset seizures in adults, should be available this spring.