Mortality Risk in Patients with Hypertension Treated with Calcium Antagonists
Mortality Risk in Patients with Hypertension Treated with Calcium Antagonists
Abstract & Commentary
Synopsis: Until such time as the results of these studies are available, it certainly would appear to be prudent to avoid the use of short-acting nifidipines in all circumstances and to use long-acting calcium antagonists cautiously.
Source: Abascal V, et al. Arch Int Med 1998;158:1882-1886.
Meta-analyses of several clinical trials (2-4) have clearly demonstrated reductions in cardiovascular mortality among patients who were treated for hypertension with diuretics and/or beta blockers alone or in combination. However, a prospective analysis of a health maintenance organization’s pharmacy database on drug therapy for hypertension by Psaty and associates in August 1995 revealed a higher mortality rate among the patients who were given medium and high doses of short-acting calcium channel blockers compared to patients who were administered other classes of drugs.1
Because the negative results noted in the Psaty data occurred with the use of medium and high doses of short-acting calcium channel blockers, most physicians who use calcium channel blockers have altered their prescribing pattern to use long-acting second- and third-generation drugs rather than the short-acting, first-generation agents. Abascal and associates from the National Heart, Lung and Blood Institute’s Framingham Heart Study reported the results of stratifying 3539 patients who had hypertension at routine clinic examinations according to their use of calcium antagonists and the presence of coronary artery disease at the baseline examination.5 Subjects were then reclassified every 2-4 years with regard to the use of calcium antagonists. All models were adjusted for age, sex, current smoking habits, systolic and diastolic blood pressure, use of beta blockers, and the use of other antihypertensive medications. A total of 970 deaths occurred during the follow-up period. Hazard ratios for mortality associated with the use of calcium antagonists for the treatment of hypertension were 0.93 for subjects without coronary artery disease and 0.92 for those patients with coronary artery disease at baseline. In addition, there was no difference in mortality among subjects using calcium antagonists compared with nonusers.
Comment by Harold L. Karpman, MD, FACP
The data published by Psaty in 1995 revealed that the risk of myocardial infarction in relation to antihypertensive therapy using moderate and/or high doses of short-acting calcium channel blockers was 58% higher among users of the calcium antagonists compared with those patients using diuretics alone.1 This increased risk for myocardial infarction among users of the short-acting calcium antagonists was similar in patients with and without cardiovascular disease. Similar results have been reported by other authors.6,7
Most prior studies associated with the use of calcium antagonists have reported on the use primarily of short-acting preparations. These drugs, in particular short-acting nifedipine, have been noted to produce vasodilatation with reflex sympathetic activation,7 a phenomenon that is less pronounced with the use of long-acting preparations.8 In the Framingham study, prescribing data revealed that physicians had gradually shifted from short-acting to long-acting preparations and that 80% of the calcium antagonists used at baseline were short-acting whereas 64% of patients on the last examination were using long-acting calcium antagonists. The study design was excellent since the authors followed a prospective cohort with routine and consistent ascertainment of hypertension status, provided aggressive hypertension treatment, and analyzed risk factors and clinical characteristics at each follow-up visit. In addition, the longer follow-up time provided the necessary statistical power to detect an effect on survival. However, it must be clearly recognized that this was an observational study and not a randomized clinical trial and that, although information was obtained on the type of calcium antagonist used and its duration of action, the effect of different drug doses was not analyzed. Although there was no difference in mortality among subjects using calcium antagonists compared with nonusers in the 3539 patients treated with these drugs for their hypertensive condition, there was a suggestion of an increased risk of mortality associated with the use of short-acting vs. long-acting calcium antagonists. These findings must be contrasted with the recently published, randomized, double-blind, placebo-controlled trial using a calcium antagonist (nitrendipine), which demonstrated a 42% reduction in risk of stroke and a 31% reduction in the risk of fatal and nonfatal cardiac end points in patients on active therapy.9
Physicians are still concerned as to whether they should consider using calcium channel blockers for the treatment of vascular hypertension and whether only long-acting drugs in this category are safe for use in these patients. There is no current data available that suggests that the long-acting calcium channel blockers have any untoward effects and it must, therefore, be recognized that these agents may be excellent drugs for the treatment of chronic stable angina, variant angina, and hypertension. However, final data on whether these drugs can be used safely will have to await the results of two large, randomized, long-term trials that are now in progress. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attacks Trial (ALLHAT)10 and the Swedish Trial in Old Patients with Hypertension (STOP-hypertension)11 results are being eagerly awaited since these studies have been designed to examine differences in morbidity and mortality for different antihypertensive drugs including calcium antagonists. Until such time as the results of these studies are available, it certainly would appear to be prudent to avoid the use of short-acting nifidipines in all circumstances and to use long-acting calcium antagonists cautiously. Though, as indicated above, there are no solid data currently available that demonstrate that they have any untoward effect in patients with hypertension and/or other cardiovascular problems.
References
1. Psaty BM et al. JAMA 1995;274:620-625.
2. MacMahon S, et al. Lancet 1990;335:765-744.
3. Collins R, et al. Lancet 1990;335:827-838.
4. Cutler J, et al. Public Health Issues in Hypertension Control: What has been Learned from Clinical Trials. In: Laragh JR, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press; 1995:253-270.
5. Abascal VM, et al. Arch Int Med 1998;158:1882-1886.
6. Pahor M, et al. J Am Geriatr Soc 1995;43:1191-1197.
7. Furberg CD, et al. Circulation 1995;92:1326-1331.
8. Frolich Ed, et al. Am J Cardiol 1991;68:1346-1350.
9. Straessen JA, et al, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757-764.
10. Davis BR, et al. Am J Hypertens 1996;9:342-360.
11. Dahlof B, et al. Blood Press 1993;2:136-141.
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