Correspondence

Possibly Disappointing Results of Treatment with Gemfibrozil

N Engl J Med 1993; 328:139-140January 14, 1993

Article

To the Editor:

Many readers may have missed one of the most interesting items in the September 3 issue of the Journal: the fine print on the back of an advertisement for the Lopid brand of gemfibrozil. Gemfibrozil reduced the incidence of coronary events in the landmark Helsinki Heart Study, reported in the Journal in 19871. However, additional information about gemfibrozil that has since become available has received much less attention.

The Warnings section of the prescribing information begins with a reminder that gemfibrozil is chemically, pharmacologically, and clinically similar to clofibrate, which was found in a World Health Organization study to increase total mortality by 29 percent in a nine-year follow-up. With 3.5 years of additional follow-up after the initial 5-year period of the Helsinki Heart Study, the results are beginning to look remarkably similar: 101 deaths in the Lopid group as compared with 83 in the placebo group -- an excess of 20 percent that is not quite statistically significant.

If we strain our eyes further, we learn that there were actually two Helsinki heart studies: the primary-prevention study reported in 1987 and a secondary-prevention study conducted in parallel at the same centers in the men excluded from the first study because of previous coronary heart disease. The secondary-prevention study, the results of which have for some reason still not been published, found an increase in adverse outcomes in the gemfibrozil group, including an increase in cardiac events (hazard ratio, 1.47; 95 percent confidence interval, 0.88 to 2.44), especially deaths from cardiac disease (hazard ratio, 2.18; 95 percent confidence interval, 0.94 to 5.05). No data are provided on total mortality and mortality from other than cardiac causes.

These results, thus far reported only in the summary of prescribing information for Lopid, have important implications. First, the available evidence suggests that gemfibrozil may increase total mortality in settings of both primary and secondary prevention. If this information were widely known, it might dampen enthusiasm for prescribing the drug. Second, recent meta-analyses of the effects of cholesterol reduction on primary and secondary prevention will need to be revised. Evidence of increased mortality from other than cardiac causes, already strong in primary-prevention studies,2,3 will be strengthened further, and the borderline decrease in total mortality in secondary-prevention trials4 will no longer be statistically significant. Finally, it appears that methods for the dissemination of unfavorable results of clinical trials may need improvement.

Thomas B. Newman, M.D., M.P.H.
University of California, San Francisco, San Francisco, CA 94143

4 References

1
Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-1245
Full Text | Web of Science | Medline

2
Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ 1990;301:309-314
CrossRef | Web of Science | Medline

3
Criqui MH. Cholesterol, primary and secondary prevention, and all-cause mortality. Ann Intern Med 1991;115:973-976
Web of Science | Medline

4
Rossouw JE, Lewis B, Rifkind BM. The value of lowering cholesterol after myocardial infarction. N Engl J Med 1990;323:1112-1119
Full Text | Web of Science | Medline

Author/Editor Response

Parke-Davis, the manufacturer of Lopid, replies:

To the Editor: We are surprised that Dr. Newman would reach such sweeping conclusions on as important an issue as the prevention of coronary disease from a package insert intended only to provide guidance on the safe use of a medication.

The five-year results of the Helsinki Heart Study1-3 showed a relative reduction of 34 percent in serious coronary events, leading to the statement on the package insert that, when used as adjunctive therapy to diet, Lopid reduces the risk of coronary heart disease in certain types of patients. In the 3.5-year open-label phase that followed the 5-year randomized study, the patients in both the placebo group and the Lopid group had two opportunities to switch to or stop treatment with Lopid. Two thirds of the patients in the original placebo group switched to Lopid at the beginning of the open-label phase, and one third of those in the original Lopid group took no active drug in the follow-up period, making comparisons between groups (or, indeed, comparisons with any other long-term trial, such as the World Health Organization study) problematic at best. It is important to note that Lopid remains indicated for the primary prevention of coronary heart disease.

The secondary-prevention study referred to was reviewed extensively at a public Food and Drug Administration Advisory Panel meeting in March 1991. The study was undertaken at the request of union and management authorities in the civil service and in industry, to afford some possibility of treatment for patients ineligible for the primary-prevention Helsinki Heart Study. Several factors, including the much smaller size of the study, the large percentage of patients with an ill-defined history and severity of cardiac disease, and the time lag between the discontinuation of Lopid and the occurrence of cardiac events, led the FDA Advisory Panel to conclude that the study results were uninterpretable and did not relate to the landmark findings of the primary-prevention Helsinki Heart Study.

Dr. Newman wrongly implies that one needs to “strain” to find the results he discusses and that there has been a problem with the dissemination of this information. When recent changes to the Lopid package insert were made, Parke-Davis sent a “Dear Doctor” letter to 170,000 physicians and 63,000 pharmacists. We also published this letter in 12 leading medical journals. Publication of the studies rests with the investigators, as it should. The results of the secondary-prevention study have been accepted for publication and will appear shortly. The first of two manuscripts about the 8.5-year follow-up is currently being submitted for publication.

David Canter, M.B., F.R.C.S.
Lawrence Perlow, M.D.
Parke-Davis, Morris Plains, NJ 07950

3 References

1
Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-1245
Full Text | Web of Science | Medline

2
Manninen V, Elo MO, Frick MH, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988;260:641-651
CrossRef | Web of Science | Medline

3
Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37-45
Web of Science | Medline

Citing Articles (1)