Clinical research study
Effect of Renin-Angiotensin System Blockade on Calcium Channel Blocker-Associated Peripheral Edema

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Abstract

Background

Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way.

Methods

We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis.

Results

We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P < .00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P = .002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P < .0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison).

Conclusion

In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this.

Section snippets

Search Strategy

Trials were searched in PubMed and the Cochrane Central Register of Clinical Trials (Cochrane Library Issue 2, 2009) using the key terms “calcium channel blockers” OR “calcium antagonists” OR “CCBs” OR using the names of individual calcium channel blockers. We restricted our search to randomized controlled trials in human beings and in peer-reviewed journals from 1980 to March 2010. No language restriction was applied. We checked the reference lists of the reviewed articles and original studies

Study Selection and Patient Characteristics

We identified 36 trials comparing calcium channel blocker monotherapy with calcium channel blocker combination with renin-angiotensin system blockers, of which 25 met the inclusion criteria16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 (Figure 1). The 25 trials enrolled 17,206 patients (55% ± 9% were male) with a mean age of 56 ± 5 years who were followed up for 9.2 ± 3 weeks. Of these, 15 trials with 9437 patients compared calcium channel blocker

Discussion

The present study compared the incidence of peripheral edema and the withdrawal of patients because of peripheral edema with calcium channel blocker monotherapy and with calcium channel blocker/renin-angiotensin system blocker combination. Both incidence and withdrawal rates were significantly lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy at similar doses of the calcium channel blocker in both arms. ACE

Study Limitations

As with other meta-analyses, given the lack of data in each trial, we did not adjust our analysis for adherence to therapy. Also, the results are subject to limitations inherent to any meta-analysis based on pooling of data from different trials with different duration, different definitions for peripheral edema, and different patient groups. We did not assess the antihypertensive efficacy of all groups because this meta-analysis was mainly performed to compare the safety of the combination

Conclusions

The combination of ACE inhibitors or ARBs with calcium channel blockers reduces calcium channel blocker-associated peripheral edema. ACE inhibitors seem to be more efficacious than ARBs in reducing calcium channel blocker-associated peripheral edema (based on indirect comparison), but further head-to-head studies are needed to conclusively test this association.

References (58)

  • F.H. Messerli et al.

    Comparison of efficacy and side effects of combination therapy of ACE inhibitor (benazepril) with calcium antagonist (either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension

    Am J Cardiol

    (2000)
  • R.D. Miranda et al.

    An 18-week, prospective, randomized, double-blind, multicenter study of amlodipine/ramipril combination versus amlodipine monotherapy in the treatment of hypertension: the assessment of combination therapy of amlodipine/ramipril (ATAR) study

    Clin Ther

    (2008)
  • S.G. Chrysant et al.

    The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study

    Clin Ther

    (2008)
  • M. Destro et al.

    Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized, double-blind, multicenter study: the EX-EFFeCTS Study

    J Am Soc Hypertens

    (2008)
  • T. Philipp et al.

    Two mulicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension

    Clin Ther

    (2007)
  • A. Sharma et al.

    Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension

    Clin Ther

    (2007)
  • J.H. Levine et al.

    Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension

    Am J Hypertens

    (1995)
  • M.R. Weir et al.

    Pilot study to evaluate a water displacement technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity edema due to dihydropyridine calcium antagonists

    Am J Hypertens

    (2001)
  • K. Makarounas-Kirchmann et al.

    Results of a meta-analysis comparing the tolerability of lercanidipine and other dihydropyridine calcium channel blockers

    Clin Ther

    (2009)
  • R. Fogari et al.

    Effect on the development of ankle edema of adding delapril to manidipine in patients with mild to moderate essential hypertension: a three-way crossover study

    Clin Ther

    (2007)
  • W.C. Cushman et al.

    Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT)

    J Clin Hypertens (Greenwich)

    (2002)
  • A.K. Gupta et al.

    Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis

    Hypertension

    (2010)
  • G. Mancia et al.

    2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension

    J Hypertens

    (2007)
  • T.C. Fagan

    Remembering the lessons of basic pharmacology

    Arch Intern Med

    (1994)
  • R. Pedrinelli et al.

    Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension

    J Hum Hypertens

    (2001)
  • F.H. Messerli

    Vasodilatory edema: a common side effect of antihypertensive therapy

    Curr Cardiol Rep

    (2002)
  • K. Jamerson et al.

    Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients

    N Engl J Med

    (2008)
  • J. Higgins et al.

    Assessing risk of bias in included studies

    Cochrane Handbook for Systematic Reviews of Interventions

    (2008)
  • D. Moher et al.

    [Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM Statement]

    Rev Esp Salud Publica

    (2000)
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    Funding: None.

    Conflict of Interest: HM, SB, JR, OW-P: none. FHM.: Ad hoc consultant/speaker for the following organizations: Novartis, Boehringer Ingelheim, Forest, Daiichi Sankyo, Sanofi, and Savient Pharmaceuticals. Grant support from GSK, Novartis, Forest, Daiichi Sankyo, and Boehringer Ingelheim. None of the authors received any compensation for their work on this manuscript.

    Authorship: All authors had access to the data and played a role in writing this manuscript.

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