Circulation, Vol 84, 2398-2408, Copyright © 1991 by American Heart Association
U Thadani, SR Zellner, S Glasser, N Bittar, R Montoro, AB Miller, B Chaitman, P Schulman, A Stahl and R DiBianco
BACKGROUND. Nisoldipine is a potent 1:4 dihydropyridine calcium channel
antagonist, and doses of 5 or 10 mg administered either once or twice daily
have been claimed to exert antianginal effects. There is, however, little
information regarding the dose-response relation and whether the drug
exerts any consistent effects throughout the dosing interval. In this
placebo-controlled, parallel-design study, the dose- response relation of
monotherapy with nisoldipine administered twice daily was studied in
patients with stable angina pectoris. METHODS AND RESULTS. Two hundred
thirty-one patients received single-blind placebo for 2 weeks; of these,
185 patients who reproducibly stopped treadmill exercise because of angina
of moderate severity and had greater than or equal to 1 mm ST segment
depression during exercise and experienced an average of three episodes of
anginal attacks per week were randomized in a double-blind manner to one of
the four treatment groups: placebo (n = 48), nisoldipine 2.5 mg (n = 47),
nisoldipine 5 mg (n = 44), or nisoldipine 10 mg (n = 46). Nisoldipine or
placebo was administered twice daily for 4 weeks and symptom-limited
exercise tests were repeated at 2 and 10-14 hours after the double-blind
medication. One hundred sixty-eight patients completed the study and 181
patients were valid for efficacy analysis. Compared with double-blind
placebo, there were marginally significant trends toward increases for time
to onset of angina for the 10-mg-b.i.d. group (83 versus 108 seconds, p =
0.08), time to 1 mm ST segment depression for the 5-mg-b.i.d. group (54
versus 83 seconds, p = 0.08), and total exercise time for the 5- (30 versus
50 seconds, p = 0.10) and 10-mg-b.i.d. (30 versus 58 seconds, p = 0.06)
groups at 2 hours after the dose (peak effect) after 4 weeks of therapy. At
10-14 hours after the dose (trough effect), no differences between placebo
and any of the nisoldipine doses on any of the exercise parameters were
found after 4 weeks of therapy. A subset analysis of patients who stopped
exercise within 10 minutes because of angina of moderate severity during
single-blind placebo therapy (n = 123) revealed significant increase in
total exercise duration and time to 1 mm ST segment depression at 2 hours
after the dose in the 5- and 10-mg- b.i.d. dose groups compared with
double-blind placebo (p less than 0.04). No significant trough effects,
however, were observed even in this subgroup after any of the doses of
nisoldipine. The frequency of anginal attacks decreased by 44%, 41%, 30%,
and 41% after twice-daily therapy with 2.5 mg, 5 mg, 10 mg nisoldipine, and
placebo groups, respectively (p = NS, nisoldipine versus placebo). The
incidence of adverse events (minor and major) was 43.8% in the placebo
group and 42.6%, 45.5%, and 56.5% in the nisoldipine 2.5-, 5-, and
10-mg-b.i.d. groups, respectively (p = NS compared with placebo). However,
four patients developed unstable angina while on nisoldipine therapy (two
in the 2.5-mg, one in the 5-mg, and one in the 10-mg-b.i.d. group) and two
patients died suddenly in the nisoldipine 10-mg-b.i.d. group. CONCLUSIONS.
Monotherapy with 2.5, 5, and 10 mg nisoldipine twice a day was not superior
to placebo therapy in treating patients with angina pectoris, and the
10-mg-b.i.d. therapy resulted in a statistically insignificant but
clinically important increase in the incidence of serious adverse events.
ARTICLES
Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine. A new second-generation calcium channel blocker in angina pectoris
Cardiovascular Section, Oklahoma University Health Sciences Center, Oklahoma City 73190.
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