Correspondence
Nisoldipine and Myocardial Infarction
N Engl J Med 1998; 339:126-127July 9, 1998
- Article
To the Editor:
Estacio et al. (March 5 issue)1 report an increased incidence of fatal and nonfatal myocardial infarction in patients with hypertension and diabetes who received nisoldipine, in a randomized, prospective, blinded study of moderate as compared with intensive control of hypertension and nisoldipine as compared with enalapril. The increased incidence of fatal and nonfatal myocardial infarction could be due to a deleterious effect of nisoldipine, a protective role of enalapril, or both, but the study design does not allow for further conclusions. Since, as the authors state, the incidence of myocardial infarction in the nisoldipine group was not significantly higher than that in previous studies, a protective effect of enalapril is plausible.
There were no follow-up data on changes in therapeutic insulin doses, antidiabetic-drug requirements, or basal insulin levels in the groups, which could differ significantly because of enhanced insulin sensitivity during treatment with angiotensin-converting–enzyme (ACE) inhibitors.2 Hyperinsulinemia, a common finding in patients with type 2 diabetes mellitus, is an independent risk factor for coronary heart disease,3 and plasma insulin levels are known to decrease with ACE-inhibitor therapy.4 Hence, if enalapril treatment was associated with a significant reduction in insulin requirements or oral antidiabetic-drug requirements, or both, or in basal insulin levels, it could have a protective role by reducing not only hypertension but also hyperinsulinemia, an effect that nisoldipine may not have.
4 ReferencesJulio I. Osende, M.D.
Mount Sinai Medical Center, New York, NY 100291
Estacio RO ,Jeffers BW ,Hiatt WR ,Biggerstaff SL ,Gifford N ,Schrier RW . The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645-652
Full Text | Web of Science | Medline2
Haenni A ,Berglund L ,Reneland R ,Andersson PE ,Lind L ,Lithell H . The alterations in insulin sensitivity during angiotensin converting enzyme inhibitor treatment are related to changes in the calcium/magnesium balance. Am J Hypertens 1997;10:145-151
CrossRef | Web of Science | Medline3
Despres J-P ,Lamarche B ,Mauriege P , et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-957
Full Text | Web of Science | Medline4
Zehetgruber M ,Beckmann R ,Gabriel H ,Christ G ,Binder BR ,Huber K . The ACE-inhibitor lisinopril affects plasma insulin levels but not fibrinolytic parameters. Thromb Res 1996;83:143-152
CrossRef | Web of Science | Medline
To the Editor:
Despite the authors' care not to make excessive claims, the report on the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial seems incomplete. The data and safety monitoring committee noted a difference between nisoldipine and enalapril, but only in hypertensive patients. We are told, but not shown, that there was no adverse effect of treatment with calcium-channel blockers in normotensive subjects. Although there was no hypothesis that adverse effects would be limited to patients with hypertension, Estacio et al. detailed only the most worrisome part of the findings.
Could Journal readers be shown the rest of the data?
Alexander M. Walker, M.D., Dr.P.H.
Harvard School of Public Health, Boston, MA 02115To the Editor:
One of the major risk factors for cardiovascular disease in patients with type 2 diabetes is the presence of microalbuminuria (≥20 μg of albumin per minute),1-5 but there were no data on urinary albumin levels or the percentages of subjects with microalbuminuria in either Table 1 or Table 2 in the article by Estacio et al. Overt albuminuria is listed in Table 2, but it is clear that the cardiovascular risk extends to the microalbuminuric range as well. Could the authors let us know whether the percentages of subjects with microalbuminuria in the two groups were significantly different?
5 ReferencesMark E. Molitch, M.D.
Northwestern University Medical School, Chicago, IL 60611-30081
Stehouwer CD ,Nauta JJ ,Zeldenrust GC ,Hackeng WH ,Donker AJ ,den Ottolander GJ . Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 1992;340:319-323
CrossRef | Web of Science | Medline2
Mattock MB ,Morrish NJ ,Viberti G ,Keen H ,Fitzgerald AP ,Jackson G . Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 1992;41:736-741
CrossRef | Web of Science | Medline3
Neil A ,Hawkins M ,Potok M ,Thorogood M ,Cohen D ,Mann J . A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM. Diabetes Care 1993;16:996-1003
CrossRef | Web of Science | Medline4
MacLeod JM ,Lutale J ,Marshall SM . Albumin excretion and vascular deaths in NIDDM. Diabetologia 1995;38:610-616
CrossRef | Web of Science | Medline5
Stephenson JM ,Kenny S ,Stevens LK ,Fuller JH ,Lee E . Proteinuria and mortality in diabetes: the WHO Multinational Study of Vascular Disease in Diabetes. Diabetic Med 1995;12:149-155
CrossRef | Web of Science | Medline
To the Editor:
In 1989, my colleagues and I reported1 that although nicardipine was associated with an improvement in exercise performance and a decrease in exercise-induced ischemia in 46 patients with stable angina, 6 patients (13 percent) had an ischemic event, unstable angina, or a non–Q-wave myocardial infarction over a relatively short period during treatment with nicardipine. During the placebo period, none of the patients had an ischemic event. Scheidt et al.,2 using a comparable protocol, reported similar findings: 7 of 66 patients with stable angina had a cardiac event while receiving nicardipine therapy, as compared with 1 patient given placebo. Thadani et al.3 found that during two weeks of therapy with nisoldipine, 6 of 137 patients with stable coronary disease had a myocardial infarction or unstable angina. No coronary events occurred in the placebo group. In the Holland Interuniversity Nifedipine/Metoprolol Trial, the risk of myocardial infarction within 48 hours was two times higher among the patients with unstable angina who were randomly assigned to treatment with nifedipine than among those assigned to placebo.4
I agree with Dr. Cutler's statement, in his editorial,5 that the ABCD results need to be confirmed by additional randomized trials. However, on the basis of the available data, it is probably prudent not to use, or to use with extreme caution, short-acting dihydropyridines in patients with symptomatic coronary artery disease, particularly since many other therapies are available.
5 ReferencesMihai Gheorghiade, M.D.
Northwestern University Medical School, Chicago, IL 60611-29501
Gheorghiade M ,Weiner DA ,Chakko S ,Lessem JN ,Klein MD . Monotherapy of stable angina with nicardipine hydrochloride: double-blind, placebo-controlled, randomized study. Eur Heart J 1989;10:695-701
Web of Science | Medline2
Scheidt S ,LeWinter MM ,Hermanovich J ,Venkataraman K ,Freedman D . Efficacy and safety of nicardipine for chronic, stable angina pectoris: a multicenter randomized trial. Am J Cardiol 1986;58:715-721
CrossRef | Web of Science | Medline3
Thadani U ,Zellner SR ,Glasser S , et al. Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine: a new second-generation calcium channel blocker in angina pectoris. Circulation 1991;84:2398-2408
Web of Science | Medline4
Report of the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group
CrossRef | Web of Science | Medline5
Cutler JA . Calcium-channel blockers for hypertension -- uncertainty continues. N Engl J Med 1998;338:679-681
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In response to Dr. Walker: the results we reported were generated by the findings of our data and safety monitoring committee with regard to the difference in the incidence of myocardial infarction between the nisoldipine and enalapril groups in the cohort with hypertension. These findings led to the early termination of the drug comparison in the group with hypertension. The data and safety monitoring committee did not recommend early termination of the drug comparison in the cohort with normotension. These results will therefore be reported later (the study ended on June 30). It is theoretically possible that the difference between the drugs was observed only in the cohort of patients with hypertension because of their exposure to this cardiovascular risk factor for a mean of eight years, whereas the blood pressure was less than 140/90 mm Hg in the cohort with normotension.
We examined factors that may have influenced the incidence of cardiovascular events during the study. In this regard, the enalapril group had a statistically lower level of high-density lipoprotein cholesterol and a higher proportion of subjects with abnormal ankle–brachial indexes. These factors should have placed the patients in the enalapril group at higher risk for cardiovascular events. We agree with Dr. Osende's comments regarding plasma insulin levels and their possible influence on the rate of myocardial infarction in our study. Although plasma insulin levels were not measured, analyses of the use of exogenous insulin and oral hypoglycemic agents during the course of the study did not reveal any differences between the nisoldipine and enalapril groups. In response to Dr. Molitch's comments: the prevalence of microalbuminuria at base line did not differ significantly between the two groups (nisoldipine, 34 percent; enalapril, 28 percent).
The studies cited by Dr. Gheorghiade are interesting, including the study by Thadani et al.,1 who used the short-acting form of nisoldipine. We agree that “short-acting” calcium antagonists should be used cautiously or should even be avoided, especially in patients at risk for coronary artery disease. Our study, however, used a sustained-release form of the calcium-channel antagonist (nisoldipine CC), which has been demonstrated to have a more blunted sympathetic-activation response than the short-acting forms of the medication.2
2 ReferencesRobert W. Schrier, M.D.
Raymond O. Estacio, M.D.
Barrett W. Jeffers, M.S.
University of Colorado Health Sciences Center, Denver, CO 802621
Thadani U ,Zellner SR ,Glasser S , et al. Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine: a new second-generation calcium channel blocker in angina pectoris. Circulation 1991;84:2398-2408
Web of Science | Medline2
Fodor JG . Nisoldipine CC: efficacy and tolerability in hypertension and ischemic heart disease. Cardiovasc Drugs Ther 1997;10:Suppl 3:873-879
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Domenico Acanfora, Mihai Gheorghiade, Luigi Trojano, Giuseppe Furgi, Antimo Papa, Francesco Cacciatore, Luisa Viati, Francesca Mazzella, Franco Rengo. (2004) A Randomized, Double-Blind Comparison of Lercanidipine 10 and 20 mg in Patients with Stable Effort Angina. American Journal of Therapeutics 11:6, 423-432
CrossRef2
D ACANFORA, M GHEORGHIADE, D ROTIROTI, L TROJANO, G RENGO, G FURGI, A PAPA, C PICONE, A NICOLINO, L ODIERNA. (2000) Acute dose-response, double-blind, placebo-controlled pilot study of lercanidipine in patients with angina pectoris. Current Therapeutic Research 61:5, 255-265
CrossRef
