Correspondence
Calcium-Channel Blockade and Hypertension
N Engl J Med 1999; 341:372-373July 29, 1999
- Article
To the Editor:
Tuomilehto and colleagues present a post hoc analysis (March 4 issue)1 of a trial of nitrendipine-based treatment for older patients with isolated systolic hypertension.2 The authors evaluated the outcome in patients with diabetes, a group that accounted for 10 percent of the population originally studied. It is difficult and often misleading to make meaningful conclusions on the basis of an analysis of small subgroups chosen after the study design has been established and the results recorded. However, the authors conclude that antihypertensive treatment with dihydropyridine calcium-channel blockers may be particularly helpful for patients with diabetes, not harmful as mounting evidence suggests.3
The active-treatment group in the study received various combinations of nitrendipine, enalapril, and hydrochlorothiazide, and the control group received placebo alone. Only half the patients in the active-treatment group, including diabetic and nondiabetic patients, received nitrendipine alone, and the number of cardiovascular events in this subgroup did not differ significantly from the number in the placebo group (75 vs. 77 events), despite a substantial reduction in systolic and diastolic blood pressure. It is unfortunate that the authors chose not to provide more details on the effect of nitrendipine alone, including statistically significant differences, in the original article or in a subsequent subgroup analysis.2,4 The other half of the patients in the active-treatment group, who received other study medications (enalapril, hydrochlorothiazide, or both), with or without nitrendipine, had substantially fewer cardiovascular events than the placebo group (62 vs. 109 events).
The authors contend that the rate of cardiovascular events among the patients with diabetes was reduced to a similar extent with nitrendipine alone and with the other study medications. However, the numbers of events recorded in these subgroups were very small, and no statistical information was provided, making this conclusion questionable. It is quite possible that treatment with nitrendipine reduced the risk of stroke by lowering systolic blood pressure but actually increased the risk of cardiac events such as myocardial infarction, heart failure, and sudden death. The main benefit in the diabetic patients in this study may be related to the significant reductions in risk associated with the use of angiotensin-converting–enzyme inhibitors and diuretics.5,6
6 ReferencesShelley Salpeter, M.D.
Santa Clara Valley Medical Center, San Jose, CA 951281
Tuomilehto J ,Rastenyte D ,Birkenhager WH , et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999;340:677-684
Full Text | Web of Science | Medline2
Staessen JA ,Fagard R ,Thijs L , et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757-764
CrossRef | Web of Science | Medline3
Pahor M ,Kritchevsky SB ,Zuccala G ,Guralnik JM . Diabetes and risk of adverse events with calcium antagonists. Diabetes Care 1998;21:193-194
Web of Science | Medline4
Staessen JA ,Fagard R ,Thijs L , et al. Subgoups and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. Arch Intern Med 1998;158:1681-1691
CrossRef | Web of Science | Medline5
Curb JD ,Pressel SL ,Cutler JA , et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-1892[Erratum, JAMA 1997;277:1356.]
CrossRef | Web of Science | Medline6
UK Prospective Diabetes Study Group
CrossRef | Web of Science
Author/Editor Response
The authors reply:
To the Editor: Subgroup analyses must be interpreted cautiously, because they deviate from the lines of randomization. Dr. Salpeter's comments in this regard are equally applicable to our trial and to the Systolic Hypertension in the Elderly Program study.1 However, the comparison of these two independent trials mutually reinforces their conclusions. In the two studies, the nondiabetic patients had the same risks and similar benefits from treatment. Diabetes at base line increased the cardiovascular risk to the same extent in the control groups in the two trials, and active treatment resulted in similar reductions in systolic pressure in the nondiabetic and diabetic patients. The main differences between the two trials were the first-line antihypertensive drug used and the outcome in the diabetic patients.
As we have previously reported,2 the patients in our trial who continued to receive monotherapy with nitrendipine had the full benefit of active treatment. Moreover, our findings in diabetic patients were recently confirmed in the placebo-controlled Systolic Hypertension in Elderly Chinese (Syst-China) trial,3 in which active treatment was also initiated with nitrendipine. Confirmation of the observation that hypertensive patients with diabetes fare better with a dihydropyridine than with a thiazide is required, but data bearing on the question will be available in 2002, when the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial is completed. This trial compares amlopidine, lisinopril, and doxazosin with chlorthalidone. Of the 40,000 patients who have been randomly assigned to a treatment group, one third have diabetes mellitus.
3 ReferencesJaakko Tuomilehto, M.D.
National Public Health Institute, FIN-00300 Helsinki, FinlandJan A. Staessen, M.D., Ph.D.
University of Leuven, B-3000 Leuven, BelgiumWillem H. Birkenhäger, M.D., Ph.D.
Erasmus University, 3015 GE Rotterdam, the Netherlands1
Curb JD ,Pressel SL ,Cutler JA , et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996;276:1886-1892[Erratum, JAMA 1997;277:1356.]
CrossRef | Web of Science | Medline2
Staessen JA ,Thijs L ,Fagard RH , et al. Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension. Hypertension 1998;32:410-416
Web of Science | Medline3
Syst-China trial. Arch Intern Med (in press).
