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

      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.

      Keywords

      Two or more antihypertensive medications may be required to control blood pressure in a substantial number of patients with hypertension;
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      Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).
      thus, adherence to therapy can be a challenge. Fixed-dose combinations have been documented to improve adherence with therapy.
      • Gupta A.K.
      • Arshad S.
      • Poulter N.R.
      Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
      • Bangalore S.
      • Kamalakkannan G.
      • Parkar S.
      • Messerli F.H.
      Fixed-dose combinations improve medication compliance: a meta-analysis.
      Drugs acting through different mechanisms and on different receptors have been shown to have an incremental effect at reducing blood pressure but at the same time mitigate some of the drug-related adverse effects.
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      2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension.
      • Fagan T.C.
      Remembering the lessons of basic pharmacology.
      • Calcium channel blockers are one of the most commonly used antihypertensive drug classes; however, peripheral edema is one of the major adverse effects thought to result from preferential arteriolar dilatation.
      • The combination of ACE inhibitors or ARBs with calcium channel blockers reduces the incidence by 38% and withdrawal rate due to peripheral edema by 62% when compared with calcium channel blocker monotherapy. ACE inhibitors seem to be more efficacious than ARBs in reducing calcium channel blocker-associated peripheral edema.
      • However, head-to-head studies are need to prove this association.
      Calcium channel blockers are one of the most commonly used antihypertensive drug classes, and peripheral edema is a common dose-dependent adverse effect. Peripheral edema is thought to result from preferential arteriolar dilatation, thus increasing the pressure gradient between arteriolar and venule capillaries, leading to extravasation of intravascular fluid.
      • Pedrinelli R.
      • Dell'Omo G.
      • Mariani M.
      Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension.
      • Messerli F.H.
      Vasodilatory edema: a common side effect of antihypertensive therapy.
      • Messerli F.H.
      • Grossman E.
      Pedal edema—not all dihydropyridine calcium antagonists are created equal.
      Peripheral edema is also a major cause for discontinuation of therapy.
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      • Palmer C.R.
      • Castaigne A.
      • et al.
      Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).
      Renin-angiotensin system blockers are increasingly used for the treatment of hypertension in combination with calcium channel blockers. They not only improve the antihypertensive efficacy but also reduce peripheral edema by decreasing post-capillary resistance, thus normalizing intracapillary pressure and reducing fluid extravasation.
      • Messerli F.H.
      Vasodilatory edema: a common side effect of antihypertensive therapy.
      • Messerli F.H.
      • Grossman E.
      Pedal edema—not all dihydropyridine calcium antagonists are created equal.
      The combination has also been shown to reduce the risk of cardiovascular events.
      • Jamerson K.
      • Weber M.A.
      • Bakris G.L.
      • et al.
      Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients.
      The present study's objective was 2-fold: 1) to evaluate the risk of peripheral edema (incidence and withdrawal) in patients receiving calcium channel blocker/renin-angiotensin system combination therapy compared with channel blocker monotherapy; and 2) to evaluate the difference in reducing the risk for peripheral edema among renin-angiotensin system blockers (ACE inhibitor, ARB, and direct renin inhibitor).

      Materials and Methods

      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 identified by the electronic search to find other potentially eligible articles. Trials in the abstract form without a published manuscript were not considered for the analysis.

      Study Selection and Data Extraction

      Two authors (HJ and JR) searched the data independently and in duplicate. Data were extracted using standardized protocol and reporting form. Disagreements were resolved by consensus. We extracted the publication year, baseline characteristics of the study population, sample size, type of the medication used along with the dose, mean age, study duration, mean baseline blood pressure, incidence of peripheral edema, and withdrawal rates due to peripheral edema. Information was obtained regarding the method of reporting peripheral edema in each trial (self-reported, obtained by symptom questionnaire or measurement of ankle edema by the examiner).

      Selection Criteria

      Trials were screened for eligibility using the following criteria: 1) randomized controlled trials comparing calcium channel blocker with the combination of calcium channel blocker with an ACE inhibitor, an ARB, or a direct renin inhibitor; 2) data on incidence of peripheral edema or withdrawal of patient because of edema; 3) follow-up of at least 4 weeks; 4) sample size of at least 100; and 5) cohort enrolled with hypertension. Studies were excluded if equivalent doses of calcium channel blocker were not used in both comparison arms.

      Quality Assessment and Sensitivity Analysis

      The criteria used for quality assessment were sequence generation of allocation, allocation concealment, masking of participants, personnel, and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias, as recommended by the Cochrane Collaboration.
      • Higgins J.
      • Green S.
      Assessing risk of bias in included studies.
      Studies with high or unclear risk of bias for any of the first 3 components were classified as low quality.

      Statistical Analysis

      The statistical analysis was performed in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines
      • Moher D.
      • Cook D.J.
      • Eastwood S.
      • et al.
      [Improving the quality of reports of meta-analyses of randomized controlled trials: the QUOROM Statement].
      using Review Manager (RevMan), Version 5.0.23, The Cochrane Collaboration, 2008. Heterogeneity was assessed using the I
      • Gupta A.K.
      • Arshad S.
      • Poulter N.R.
      Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
      statistics. I
      • Gupta A.K.
      • Arshad S.
      • Poulter N.R.
      Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
      is the proportion of total variation observed between the trials attributable to differences between trials rather than sampling error (chance), and we considered I
      • Gupta A.K.
      • Arshad S.
      • Poulter N.R.
      Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
      less than 25% as low and I
      • Gupta A.K.
      • Arshad S.
      • Poulter N.R.
      Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
      greater than 75% as high. The random-effects model of DerSimonian and Laird
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      was used to calculate the effect sizes if I
      • Gupta A.K.
      • Arshad S.
      • Poulter N.R.
      Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis.
      was greater than 25% or heterogeneity P value was less than .05. All analyses were performed using the intention-to-treat principle. Results were calculated by relative risk (RR) ratio and 95% confidence intervals (CIs) with the use of the Mantel–Haenszel method. Head-to-head comparison was made between the calcium channel blocker group and the combination of calcium channel blocker with renin-angiotensin system blocker for the incidence of edema and patient withdrawal because of edema. We also assessed the incidence of peripheral edema for both calcium channel blocker monotherapy and calcium channel blocker/renin-angiotensin system blocker combination on the basis of the inverse variance weighted mean method. Indirect comparison was made for the comparison of calcium channel blocker/ACE inhibitor versus calcium channel blocker/ARBs versus calcium channel blocker/aliskiren combinations on the incidence of edema. Publication bias was estimated visually by funnel plots or use of the Begg's test and the weighted regression test of Egger.
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      Individual trials were excluded to observe the influence of the trial on overall heterogeneity of the analysis.
      Sensitivity analysis was performed between calcium channel blocker monotherapy and calcium channel blocker combined with ACE inhibitor and ARB for various subgroups (age, gender, calcium channel blocker dose, duration, and quality of studies), and the difference between the subgroups was estimated on the basis of tests for interaction.
      • Altman D.G.
      • Bland J.M.
      Interaction revisited: the difference between two estimates.

      Results

      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 criteria
      • Chan P.
      • Lin C.N.
      • Tomlinson B.
      • et al.
      Additive effects of diltiazem and lisinopril in the treatment of elderly patients with mild-to-moderate hypertension.
      • Chrysant S.G.
      • Bakris G.L.
      Amlodipine/benazepril combination therapy for hypertensive patients nonresponsive to benazepril monotherapy.
      • Frishman W.H.
      • Ram C.V.
      • McMahon F.G.
      • et al.
      Comparison of amlodipine and benazepril monotherapy to amlodipine plus benazepril in patients with systemic hypertension: a randomized, double-blind, placebo-controlled, parallel-group study The Benazepril/Amlodipine Study Group.
      • Gradman A.H.
      • Cutler N.R.
      • Davis P.J.
      • et al.
      Combined enalapril and felodipine extended release (ER) for systemic hypertension Enalapril-Felodipine ER Factorial Study Group.
      • Jamerson K.A.
      • Nwose O.
      • Jean-Louis L.
      • et al.
      Initial ACE inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension.
      • Kuschnir E.
      • Acuna E.
      • Sevilla D.
      • et al.
      Treatment of patients with essential hypertension: amlodipine 5 mg/benazepril 20 mg compared with amlodipine 5 mg, benazepril 20 mg, and placebo.
      • Messerli F.
      • Frishman W.H.
      • Elliott W.J.
      Effects of verapamil and trandolapril in the treatment of hypertension Trandolapril Study Group.
      • Messerli F.H.
      • Oparil S.
      • Feng Z.
      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.
      • Miranda R.D.
      • Mion Jr, D.
      • Rocha J.C.
      • 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.
      • Neutel J.M.
      • Smith D.H.
      • Weber M.A.
      • et al.
      Efficacy of combination therapy with amlodipine besylate/benazepril hydrochloride for lowering systolic blood pressure in stage 2 hypertension.
      • Persson B.
      • Widgren B.R.
      • Fox A.
      • Stimpel M.
      Antihypertensive effects of moexipril, a new ACE inhibitor, as add-on therapy to nifedipine in patients with essential hypertension.
      • Poisson P.
      • Bauer B.
      • Schueler E.
      • Rangoonwala B.
      Ramipril and felodipine: a comparison of the efficacy and safety of monotherapy versus combination therapy.
      • Pool J.
      • Kaihlanen P.
      • Lewis G.
      • et al.
      Once-daily treatment of patients with hypertension: a placebo-controlled study of amlodipine and benazepril vs amlodipine or benazepril alone.
      • Scholze J.
      • Bauer B.
      • Massaro J.
      Antihypertensive profiles with ascending dose combinations of ramipril and felodipine ER.
      • Steiner G.
      • Pauly N.C.
      Comparison of the efficacy and safety of trandolapril and nifedipine SR in mild-to-moderate hypertension Investigator Study Group.
      • Chrysant S.G.
      • Melino M.
      • Karki S.
      • 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.
      • Destro M.
      • Luckow A.
      • Samson M.
      • 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.
      • Flack J.M.
      • Calhoun D.A.
      • Satlin L.
      • et al.
      Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study.
      • Kuschnir E.
      • Bendersky M.
      • Resk J.
      • et al.
      Effects of the combination of low-dose nifedipine GITS 20 mg and losartan 50 mg in patients with mild to moderate hypertension.
      • Littlejohn 3rd, T.W.
      • Majul C.R.
      • Olvera R.
      • et al.
      Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study.
      • Philipp T.
      • Smith T.
      • Glazer R.
      • 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.
      • Schunkert H.
      • Glazer R.D.
      • Wernsing M.
      • et al.
      Efficacy and tolerability of amlodipine/valsartan combination therapy in hypertensive patients not adequately controlled on amlodipine monotherapy.
      • Sharma A.
      • Bagchi A.
      • Kinagi S.B.
      • 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.
      • Volpe M.
      • Brommer P.
      • Haag U.
      • Miele C.
      Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: a randomized, double-blind, parallel-group, multicentre study.
      • Drummond W.
      • Munger M.A.
      • Rafique Essop M.
      • et al.
      Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy.
      (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 with calcium channel blocker combination with an ACE inhibitor,
      • Chan P.
      • Lin C.N.
      • Tomlinson B.
      • et al.
      Additive effects of diltiazem and lisinopril in the treatment of elderly patients with mild-to-moderate hypertension.
      • Chrysant S.G.
      • Bakris G.L.
      Amlodipine/benazepril combination therapy for hypertensive patients nonresponsive to benazepril monotherapy.
      • Frishman W.H.
      • Ram C.V.
      • McMahon F.G.
      • et al.
      Comparison of amlodipine and benazepril monotherapy to amlodipine plus benazepril in patients with systemic hypertension: a randomized, double-blind, placebo-controlled, parallel-group study The Benazepril/Amlodipine Study Group.
      • Gradman A.H.
      • Cutler N.R.
      • Davis P.J.
      • et al.
      Combined enalapril and felodipine extended release (ER) for systemic hypertension Enalapril-Felodipine ER Factorial Study Group.
      • Jamerson K.A.
      • Nwose O.
      • Jean-Louis L.
      • et al.
      Initial ACE inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension.
      • Kuschnir E.
      • Acuna E.
      • Sevilla D.
      • et al.
      Treatment of patients with essential hypertension: amlodipine 5 mg/benazepril 20 mg compared with amlodipine 5 mg, benazepril 20 mg, and placebo.
      • Messerli F.
      • Frishman W.H.
      • Elliott W.J.
      Effects of verapamil and trandolapril in the treatment of hypertension Trandolapril Study Group.
      • Messerli F.H.
      • Oparil S.
      • Feng Z.
      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.
      • Miranda R.D.
      • Mion Jr, D.
      • Rocha J.C.
      • 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.
      • Neutel J.M.
      • Smith D.H.
      • Weber M.A.
      • et al.
      Efficacy of combination therapy with amlodipine besylate/benazepril hydrochloride for lowering systolic blood pressure in stage 2 hypertension.
      • Persson B.
      • Widgren B.R.
      • Fox A.
      • Stimpel M.
      Antihypertensive effects of moexipril, a new ACE inhibitor, as add-on therapy to nifedipine in patients with essential hypertension.
      • Poisson P.
      • Bauer B.
      • Schueler E.
      • Rangoonwala B.
      Ramipril and felodipine: a comparison of the efficacy and safety of monotherapy versus combination therapy.
      • Pool J.
      • Kaihlanen P.
      • Lewis G.
      • et al.
      Once-daily treatment of patients with hypertension: a placebo-controlled study of amlodipine and benazepril vs amlodipine or benazepril alone.
      • Scholze J.
      • Bauer B.
      • Massaro J.
      Antihypertensive profiles with ascending dose combinations of ramipril and felodipine ER.
      • Steiner G.
      • Pauly N.C.
      Comparison of the efficacy and safety of trandolapril and nifedipine SR in mild-to-moderate hypertension Investigator Study Group.
      9 trials with 7224 patients compared calcium channel blocker with calcium channel blocker combination with an ARB,
      • Chrysant S.G.
      • Melino M.
      • Karki S.
      • 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.
      • Destro M.
      • Luckow A.
      • Samson M.
      • 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.
      • Flack J.M.
      • Calhoun D.A.
      • Satlin L.
      • et al.
      Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study.
      • Kuschnir E.
      • Bendersky M.
      • Resk J.
      • et al.
      Effects of the combination of low-dose nifedipine GITS 20 mg and losartan 50 mg in patients with mild to moderate hypertension.
      • Littlejohn 3rd, T.W.
      • Majul C.R.
      • Olvera R.
      • et al.
      Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study.
      • Philipp T.
      • Smith T.
      • Glazer R.
      • 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.
      • Schunkert H.
      • Glazer R.D.
      • Wernsing M.
      • et al.
      Efficacy and tolerability of amlodipine/valsartan combination therapy in hypertensive patients not adequately controlled on amlodipine monotherapy.
      • Sharma A.
      • Bagchi A.
      • Kinagi S.B.
      • 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.
      • Volpe M.
      • Brommer P.
      • Haag U.
      • Miele C.
      Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: a randomized, double-blind, parallel-group, multicentre study.
      and 1 trial with 545 patients compared calcium channel blocker with calcium channel blocker combination with aliskiren.
      • Drummond W.
      • Munger M.A.
      • Rafique Essop M.
      • et al.
      Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy.
      In all, 25 trials reported the incidence of peripheral edema and 7 trials reported patient withdrawal because of edema. Three trials were excluded because of lack of data about the incidence of peripheral edema with total patient population more than 100,
      • Fitscha P.
      • Meisner W.
      • Hitzenberger G.
      Evaluation of isradipine and captopril alone or in combination for the treatment of hypertension.
      • Levine J.H.
      • Ferdinand K.C.
      • Cargo P.
      • et al.
      Additive effects of verapamil and enalapril in the treatment of mild to moderate hypertension.
      Effects of verapamil SR, trandolapril, and their fixed combination on 24-h blood pressure: the Veratran Study.
      2 trials were duplicate studies,
      • Neutel J.M.
      • Smith D.H.
      • Weber M.A.
      • et al.
      Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study.
      • Littlejohn 3rd, T.W.
      • Majul C.R.
      • Olvera R.
      • et al.
      Results of treatment with telmisartan-amlodipine in hypertensive patients.
      and 6 trials had unequal doses of calcium channel blocker in both comparison groups of calcium channel blocker monotherapy and calcium channel blocker/renin-angiotensin system blockers.
      • Karlberg B.E.
      • Andrup M.
      • Oden A.
      Efficacy and safety of a new long-acting drug combination, trandolapril/verapamil as compared to monotherapy in primary hypertension Swedish TARKA trialists.
      • Kohlmann Jr, O.
      • Oigman W.
      • Mion Jr, D.
      • et al.
      [The “LOTHAR” study: evaluation of efficacy and tolerability of the fixed combination of amlodipine and losartan in the treatment of essential hypertension].
      • Pittrow D.B.
      • Antlsperger A.
      • Welzel D.
      • et al.
      Evaluation of the efficacy and tolerability of a low-dose combination of isradipine and spirapril in the first-line treatment of mild to moderate essential hypertension.
      • Saito I.
      • Saruta T.
      Controlled release nifedipine and valsartan combination therapy in patients with essential hypertension: the adalat CR and valsartan cost-effectiveness combination (ADVANCE-combi) study.
      • Schrader J.
      • Salvetti A.
      • Calvo C.
      • et al.
      The combination of amlodipine/valsartan 5/160 mg produces less peripheral oedema than amlodipine 10 mg in hypertensive patients not adequately controlled with amlodipine 5 mg.
      • Ueng K.C.
      • Lin L.C.
      • Voon W.C.
      • et al.
      An eight-week, multicenter, randomized, double-blind study to evaluate the efficacy and tolerability of fixed-dose amlodipine/benazepril combination in comparison with amlodipine as first-line therapy in Chinese patients with mild to moderate hypertension.
      Figure thumbnail gr1
      Figure 1Selection of studies. ACE=ACE inhibitor; ARB=ARB; CCB=calcium channel blocker; RAS=renin-angiotensin system.
      Of 25 studies that were included, 8 reported adequate generation of allocation sequence and adequate allocation concealment, and 17 reported adequate masking of participants, personnel, and outcome assessors. On the basis of quality assessment, 8 were deemed as low bias risk trials and the rest as high bias risk.
      Of the 15 studies that compared calcium channel blocker monotherapy with the combination of calcium channel blocker and ACE inhibitor, peripheral edema was self-reported in 9 trials, by both self-reporting and patient questionnaire in 4 trials and by measurement of ankle edema in 2 trials. In 9 studies comparing calcium channel blocker monotherapy with combination of calcium channel blocker and ARB, peripheral edema was self-reported in 3 trials, by both self-reporting and patient questionnaire in 5 trials and by measurement of ankle edema in 1 trial. In the only trial comparing calcium channel blocker monotherapy with the combination of calcium channel blocker and aliskiren, peripheral edema was reported by both self-reporting and patient questionnaire.

      Risk of Peripheral Edema

      At similar doses of calcium channel blocker, the risk of edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than with calcium channel blocker monotherapy (RR 0.62; 95% CI, 0.53-0.74; P<.00001) (Figure 2). Individually, the risk of edema was 54% lower for calcium channel blocker/ACE inhibitor combination compared with calcium channel blocker monotherapy (RR 0.46; 95% CI, 0.37-0.58; P<.00001) and 21% lower for the calcium channel blocker/ARB combination compared with calcium channel blocker monotherapy (RR 0.79; 95% CI, 0.64-0.97; P=.02). For the calcium channel blocker/aliskiren combination, there was a trend toward reduction in edema compared with calcium channel blocker monotherapy, although this did not reach statistical significance (RR 0.64; 95% CI, 0.18-2.22; P=.48).
      Figure thumbnail gr2
      Figure 2Head-to-head comparison of calcium channel blocker with calcium channel blocker/renin-angiotensin-receptor blocker combination on the incidence of peripheral edema. ACEI = ACE inhibitor; CCB = calcium channel blocker; CI = confidence interval; RAS = renin-angiotensin system.
      Test of publication bias was negative for this comparison (Egger's P=.27). There was modest heterogeneity among the studies when comparing calcium channel blocker alone with calcium channel blocker/ARB combination (I2 = 38%). By excluding Flack et al's
      • Flack J.M.
      • Calhoun D.A.
      • Satlin L.
      • et al.
      Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study.
      study from the analysis, heterogeneity was resolved. The risk of edema after excluding this study was 24% lower for calcium channel blocker/ARB combination compared with calcium channel blocker monotherapy (RR 0.76; 95% CI, 0.66-0.88; P=.0003).
      Pooled weighted incidence of peripheral edema was 6.0% with calcium channel blocker monotherapy compared with 3.2% with calcium channel blocker/renin-angiotensin system blocker combination (P<.0001) (Figure 3). On indirect comparison, the incidence of edema with the calcium channel blocker/ACE inhibitor combination (2.7%) was significantly lower than with the calcium channel blocker/ARB combination (3.7%) (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84). Similarly, the incidence with the calcium channel blocker/aliskiren combination (2.1%) was lower than with the calcium channel blocker/ARB combination (3.7%) (P=.04) (ratio of RR 0.57, 95% CI, 0.33-0.98) (indirect comparison). However, there was no significant difference between calcium channel blocker/ACE inhibitor and calcium channel blocker/aliskiren combination on edema (P=.37) (indirect comparison).
      Figure thumbnail gr3
      Figure 3Pooled incidence of peripheral edema and withdrawal due to edema with calcium channel blocker and calcium channel blocker/renin-angiotensin-receptor blocker combination. *P < .05 comparing calcium channel blocker with calcium channel blocker/renin-angiotensin-receptor combination. CCB = calcium channel blocker; RAS = renin-angiotensin system.

      Patient Withdrawal Because of Peripheral Edema

      Risk of withdrawal because of edema was 62% lower for the calcium channel blocker/renin-angiotensin system combination compared with calcium channel blocker monotherapy (RR 0.38; 95% CI, 0.22-0.66; P=.006) (Figure 4). For the calcium channel blocker/ACE inhibitor combination, the risk of withdrawal was 58% lower compared with calcium channel blocker monotherapy (RR 0.42; 95% CI, 0.22-0.80; P=.008). For the calcium channel blocker/ARB combination, the risk of withdrawal was 73% lower than with calcium channel blocker monotherapy (RR 0.27; 95% CI, 0.09-0.81; P=.02). However, this was based on a single study and the CI was wide. For the calcium channel blocker/aliskiren combination, none of the studies included in this analysis reported data on withdrawal due to peripheral edema.
      Figure thumbnail gr4
      Figure 4Head-to-head comparison of calcium channel blocker with calcium channel blocker/renin-angiotensin-receptor blocker combination on the withdrawal due to peripheral edema. ACEI = ACE inhibitor; CCB = calcium channel blocker; CI = confidence interval; RAS = renin-angiotensin system.
      Test of publication bias was negative (Egger's P=.52), and there was no evidence of heterogeneity for this comparison. Sensitivity analyses for various subgroups were consistent with the main results.

      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 inhibitor was significantly more efficacious than ARB or aliskiren in reducing peripheral edema associated with calcium channel blocker monotherapy. Thus, it seems that not all renin-angiotensin system blockers are created equal with regard to antagonizing calcium channel blocker-associated edema. However, this statement has to be qualified by the fact that there are no head-to-head comparisons of ACE inhibitors versus ARBs. Moreover, all ACE inhibitor studies were done more than a decade earlier than the ARB studies. Thus, to some extent we are dealing with “historic” comparisons that clearly are of limited validity.
      Peripheral edema is one of the most common adverse effects of a calcium channel blocker. Peripheral edema has been observed with all available dihydropyridine agents, but it also seems to occur to a lesser extent with verapamil and diltiazem. The incidence of peripheral edema is clearly dose-dependent and may exceed 80% with very high doses of dihydropyridine calcium channel blocker.
      • Messerli F.H.
      Vasodilatory edema: a common side effect of antihypertensive therapy.
      With starting doses of amlodipine or felodipine, only approximately 5% of patients will have swelling of the feet or ankles.
      • Messerli F.H.
      • Oparil S.
      • Feng Z.
      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.
      Peripheral edema is not associated with salt and water retention, because dihydropyridine calcium channel blocker has been shown to be natriuretic
      • Epstein M.
      Natriuretic effect.
      and therefore does not respond well to diuretic therapy.
      • Weir M.R.
      • Rosenberger C.
      • Fink J.C.
      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.
      In susceptible patients with peripheral edema, capillary permeability may increase to the extent that erythrocytes are leaked from the capillary into the interstitium and cause a petechial rash with prolonged exposure to calcium channel blocker. The petechial rash can lead to hyperpigmentation and discoloration in the edematous area.
      The 4 main determinants of the capillary fluid filtration into the interstitium are 1) intracapillary pressure, 2) interstitial oncotic pressures, 3) capillary permeability, and 4) lymphatic drainage. With change from the supine to the standing posture, capillary fluid filtration is held constant by the veno-arteriolar reflex, causing postural vasoconstriction in both the arteriolar and the venous limb.
      • Pedrinelli R.
      • Dell'Omo G.
      • Mariani M.
      Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension.
      • Messerli F.H.
      • Grossman E.
      Pedal edema—not all dihydropyridine calcium antagonists are created equal.
      The precapillary vasoconstriction is selectively diminished by a calcium channel blocker. As a consequence of attenuated arteriolar constriction, intracapillary pressure increases. Capillary hypertension will lead to a net capillary fluid filtration into the interstitium. Thus, gravitational factors clearly have a permissive role in promoting or favoring peripheral edema formation with calcium channel blocker.
      • Pedrinelli R.
      • Dell'Omo G.
      • Mariani M.
      Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension.
      • Messerli F.H.
      • Grossman E.
      Pedal edema—not all dihydropyridine calcium antagonists are created equal.
      Calcium channel blockers seem to block the myogenic component of the reflex control of skin blood flow, which is independent of neural, metabolic, and other hormonal influences.
      • Bellet M.
      • Sassano P.
      • Guyenne T.
      • et al.
      Converting-enzyme inhibition buffers the counter-regulatory response to acute administration of nicardipine.
      Calcium channel blockers also cause activation of both the sympathetic nervous system and the renin-angiotensin system, which can attenuate the blood pressure-lowering effects.
      • Bellet M.
      • Sassano P.
      • Guyenne T.
      • et al.
      Converting-enzyme inhibition buffers the counter-regulatory response to acute administration of nicardipine.
      • Cappuccio F.P.
      • Markandu N.D.
      • Sagnella G.A.
      • et al.
      Effects of amlodipine on urinary sodium excretion, renin-angiotensin-aldosterone system, atrial natriuretic peptide and blood pressure in essential hypertension.
      This action can be buffered by renin-angiotensin system blockers.
      • Bellet M.
      • Sassano P.
      • Guyenne T.
      • et al.
      Converting-enzyme inhibition buffers the counter-regulatory response to acute administration of nicardipine.
      Antihypertensive effect of a renin-angiotensin system blocker is enhanced by the negative sodium balance created by diuretic and natriuretic properties of a calcium channel blocker.
      • Burges R.
      • Gardiner D.
      • Carter A.
      • McKay F.
      Amlodipine: long-term natriuretic and antihypertensive activity in spontaneously hypertensive rats with developing and established hypertension.
      Because peripheral edema with calcium channel blocker is caused by capillary hypertension during upright posture, it stands to reason that a drug that would normalize intracapillary pressure should diminish this edema. Capillary hypertension can be reduced by venous dilation, and both ACE inhibitors
      • Messerli F.H.
      • Oparil S.
      • Feng Z.
      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.
      and ARBs have been shown to counteract the effects of a calcium channel blocker in this regard. In our study, ACE inhibitors were considerably more efficacious than ARBs in reducing peripheral edema. The reason for this difference is unclear but may be related to greater activation of the bradykinin/prostaglandin system by ACE inhibitors.
      The incidence of peripheral edema with calcium channel blocker (6.0%) in our study is lower than that in major studies. The reason may be related to the shorter duration of most studies (mean average 9.2 weeks) and the lower dose of calcium channel blocker. Newer membranophilic calcium channel blockers, such as manidipine, lacidipine, and lercanidipine, have a reduced incidence of peripheral edema compared with conventional calcium channel blockers, such as nifedipine or amlodipine,
      • Makarounas-Kirchmann K.
      • Glover-Koudounas S.
      • Ferrari P.
      Results of a meta-analysis comparing the tolerability of lercanidipine and other dihydropyridine calcium channel blockers.
      and their combination with renin-angiotensin system blockers may further reduce the incidence of edema.
      • Fogari R.
      • Malamani G.
      • Zoppi A.
      • 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.

      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 drugs and because all the studies show that combining drugs from 2 different groups enhances the antihypertensive efficacy. Indirect comparison was made between the calcium channel blocker/ACE inhibitor and calcium channel blocker/ARB combination on reduction of peripheral edema, and this comparison is best defined as hypothesis-generating only. Because of the limited number of studies with non-dihydropyridines combined with ACE inhibitors, ARBs, or aliskiren, the exact effect could not be determined.

      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.

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