Calcium Channel Blockers: Effective for Isolated Systolic Hypertension

By Sally Beattie, MS, RN, CS, GNP

Summary—Isolated systolic hypertension (ISH) in an aging population carries an increased risk of cardiovascular (CV) diseases, including stroke and death.1 Calcium channel blockers (CCB) often are prescribed for hypertension, but some studies suggest an increased risk of myocardial infarction concomitant with using CCBs. The present analysis explored the effect of nitrendipine alone on cardiovascular complications. Only six months into the study, researchers noted a net blood pressure reduction of 7.7 mmHg systolic and 3.3 mmHg diastolic and a reduction of all cardiovascular end points by 55%. By the end of the analysis, investigators concluded that the dihydropyridine CCB, nitrendipine, independent of other anti-hypertensive agents, is effective in preventing CV complications in patients with ISH.2

Hypertension affects 25-30 million Americans and accounts for 56-81% of all hemorrhagic strokes, one of the most feared complications of older patients with ISH.3 The incidence of ISH, defined as systolic blood pressure > 140 mmHg and diastolic blood pressure < 90 mmHg, is increasing as the population ages. ISH increases the risk of stroke, other CV diseases, and death for those with ISH.1 Scientists continue to search for therapies that decrease blood pressure as well as the catastrophic sequelae of hypertension (HTN). A study analysis published recently in Hypertension revealed that nitrendipine, a long-acting CCB, decreased CV mortality by 41%, all CV end points by 33%, and fatal and nonfatal cardiac end points by 33%.2 Although nitrendipine is not available in the United States, other long-acting dihydropyridine CCBs are considered to be appropriate alternatives.4

Although CCBs are among the most frequently prescribed anti-hypertensive agents, controversy in the mid-1990s questioned their safety. Studies in 1995 suggested CCBs were associated with an increased risk of myocardial infarction (MI) when compared with diuretics and beta-blockers (BB).5,6 The study authors speculated this might be secondary to a reflex increase in sympathetic activity related to rapid-release formulations. The validity of these analyses has been criticized, however, because two of three CCBs prescribed at the time were short-acting formulations no longer in widespread use and not approved by the U.S. Food and Drug Administration for treatment of HTN. Selection bias also might have influenced the use of these agents in patients already at a higher risk for MI.

Study Methodology

The recently published analysis2 was undertaken to address this question in view of ongoing concerns about the use of CCBs as first-line antihypertensive drugs. The above allegations prompted authors of the present analysis to explore the extent to which nitrendipine alone prevented cardiovascular complications A randomized, double-blind, placebo-controlled European trial (referred to as Syst-Eur) studied whether active first-line drug treatment with the long-acting dihydropyridine CCB nitrendipine reduced the incidence of stroke and other CV complications in older patients with ISH.2,7 Investigators recruited 4,695 patients with ISH. Study subject characteristics included:

• ages 60-98 (mean age at randomization averaged 70.2 ± 6.7 years);

• sitting blood pressure at entry; range 160-218 systolic, 49-94 diastolic (mean systolic 173.8 ± 10.0 mmHg, diastolic 85.5 ± 5.9 mmHg);

• > number of women than men (66.8%);

• 1402 subjects had cardiovascular complications at entry (29.9%);

• and equal distribution of subjects with pre-existing cardiac complications.

A total of 2398 study subjects were randomized to active treatment with nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day) and/or hydrochlorothiazide (12.5-25 mg/day) titrated or combined to decrease sitting blood pressure by at least 20 mmHg to < 150 mmHg. Matching placebos were used similarly in the control group of 2297 subjects.

The present analysis of the study findings elicited some interesting results:

• Fewer patients remained on treatment with only the first-line placebo when compared with active treatment patients:

• These control patients progressed more frequently to second- or third-line medication than did patients on the first-line study medication.

• At six months, most active-treatment patients still were using the CCB as monotherapy (1829).

• This active-treatment group showed a net blood pressure reduction of 7.7 mmHg systolic and 3.3 mmHg diastolic.

Active treatment, at this point, reduced all cardiovascular end points by 55%. End points were defined as death, stroke, myocardial infarction, or heart failure.2 These reductions were of the same magnitude as at two or four years of follow-up.

Study Results

The two-year median follow-up showed net blood pressure reductions averaged 12.9 mmHg systolic and 5.7 mmHg diastolic in patients receiving monotherapy with active nitrendipine (average daily dose 23.4 ± 11.5 mg), when compared with the whole placebo group. There was a 25% lower incidence of fatal and nonfatal cardiovascular end points in the 1327 patients receiving nitrendipine monotherapy.

In all patients who progressed to second- or third-line medications (enalapril or hydrochlorothiazide), the net blood pressure reduction averaged 10.3 mmHg systolic and 4.9 mmHg diastolic. Patients receiving active treatment with second- or third-line medications had a 40% reduction in mortality, a 39% reduction in all cardiovascular end points, a 59% reduction in fatal and nonfatal stroke, and a 29% reduction in all cardiac end points.2

In a companion study after a median follow-up of two years, the CCB group experienced a 42% reduction in the primary end point, stroke. In addition, all fatal and nonfatal cardiac end points, including sudden death, decreased by 26%; nonfatal cardiac end points decreased by 33%, and all fatal and nonfatal CV end points decreased by 31%.7

The investigators firmly concluded that the dihydropyridine CCB nitrendipine, independent of other anti-hypertensive agents, is effective in the prevention of CV complications in patients with ISH.2

Implications for Practice

In response to the results of this trial, the Sixth Report of the Joint National Committee on Prevention, Detec tion, Evaluation, and Treatment of High Blood Pressure (JNC-VI) modified its algorithm for treating HTN and now recommends long-acting dihydropyridine CCBs as an alternative in older ISH patients. "Because nitren d i pine is not available in the United States, other long-acting dihydropyridine CCBs are considered to be appropriate alternatives in these patients," JNC-VI states.4

Supporting JNC-VI recommendations, a recent Fram ing ham Heart Study analysis found no differences in mortality among subjects (mean age 64 ± 13 years) with HTN using a long-acting CCB vs. those who were not. Results were similar in subjects who had HTN with and without known coronary artery disease.8 Investi gators did report a trend toward higher mortality associated with short- vs. long-acting CCB formulations. Another analysis of the Pfi zer HTN clinical trial databases for amlodipine and nifedipine XL did not reveal an excessive risk of death or CV events for hypertensive patients.9

Randomized, placebo-controlled trials investigating the effects of long-acting CCBs in the treatment of all classifications of HTN in comparison with ACE-inhibitors, diuretics, or alpha-blockers on mortality, morbidity, and heart attack end points are ongoing to solidify the favorable results with long-acting CCBs found by the Syst-Eur investigators. Preliminary reports are positive and comforting, and they appear to contradict previous warnings related to the short-acting or immediate-release formulations.

Practitioners should continue using therapies tailored to patients’ clinical presentations. The current level of understanding indicates providers need not fear the use of long-acting CCBs while considering strategies for managing ISH. These agents are effective in hypertensive patients of all ages and races, and they appear to be effective in decreasing the incidence of stroke, the most dreaded complication of older ISH patients.

References

1. Materson BJ. Isolated systolic hypertension (editorial). Arch Intern Med 1994;154:2128-2129.

2. 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.

3. Jorde L. Genes, environment, and common diseases. In: McCance K, Huether S, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. St Louis: Mosby; 1998:162.

4. The sixth report of the Joint National Committee on Pre vention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-2443

5. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620-625.

6. Furberg CD, Psaty BM, Meyer JV. Nifedipine: Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-1331.

7. Staessen JA, Fagard RH, Thijs L, et al. Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757-764.

8. Abascal VM, Larson MG, Evans JC, et al. Calcium antagonists and mortality risk in men and women with hypertension in the Framingham Heart Study. Arch Intern Med 1998;158:1882-1886.

9. Kloner RA, Vetrovec GW, Materson BJ, et al. Safety of long-acting dihydropyridine calcium channel blockers in hypertensive patients. Am J Card 1998;81:163-169.