Peripheral edema associated with calcium channel blockers: incidence and withdrawal rate--a meta-analysis of randomized trials

Abstract

Objective: Peripheral edema is considered to be a common and annoying adverse effect of calcium channel blockers (CCBs). It has been thought to occur secondary to arteriolar dilatation causing intracapillary hypertension and fluid extravasation. We aimed to evaluate the incidence and withdrawal rate of peripheral edema with CCBs.

Methods: A systematic search was made in PubMed, EMBASE and CENTRAL from 1980 to January 2011 for randomized clinical trials reporting peripheral edema with CCBs in patients with hypertension. Trials enrolling at least 100 patients in the CCB arm and lasting at least 4 weeks were included in the analysis. Both the incidence and withdrawal rate due to edema were pooled by weighing each trial by the inverse of the variance. Head-to-head comparison was done to evaluate the risk of edema between newer lipophilic dihydropyridine (DHP) CCBs and older DHPs.

Results: One hundred and six studies with 99 469 participants, mean age 56 ± 6 years, satisfied our inclusion criteria and were included in this analysis. The weighted incidence of peripheral edema was significantly higher in the CCBs group when compared with controls/placebo (10.7 vs. 3.2%, P < 0.0001). Similarly, the withdrawal rate due to edema was higher in patients on CCBs compared with control/placebo (2.1 vs. 0.5%, P < 0.0001). Both the incidence of edema and patient withdrawal rate due to edema increased with the duration of therapy with CCBs reaching 24 and 5%, respectively, after 6 months. The risk of peripheral edema with lipophilic DHPs was 57% lower than with traditional DHPs (relative risk 0.43; 95% confidence interval 0.34-0.53; P < 0.0001). Incidence of peripheral edema in patients on DHPs was 12.3% compared with 3.1% with non-DHPs (P < 0.0001). Edema with high-dose CCBs (defined as more than half the usual maximal dose) was 2.8 times higher than that with low-dose CCBs (16.1 vs. 5.7%, P < 0.0001).

Conclusion: The incidence of peripheral edema progressively increased with duration of CCB therapy up to 6 months. Over the long term, more than 5% of patients discontinued CCBs because of this adverse effect. Edema rates were lower with both non-DHPs and lipophilic DHPs.