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Peripheral edema and headache associated with amlodipine treatment

a meta-analysis of randomized, placebo-controlled trials

Vukadinović, Davora; Scholz, Sean S.a; Messerli, Franz H.b; Weber, Michael A.c; Williams, Bryand; Böhm, Michaela; Mahfoud, Felixa

doi: 10.1097/HJH.0000000000002145
Original Article: PDF Only

Objective: Use of amlodipine for treatment of arterial hypertension and stable coronary artery disease (CAD) is sometimes limited by occurrence of peripheral edema and headache. We aimed to explore the true magnitude of this phenomenon by determining the rate and placebo-adjusted rate of these side effects.

Methods: We performed a meta-analysis by including all randomized, placebo-controlled trials reporting edema and headache with amlodipine in patients with arterial hypertension and CAD. Placebo-adjusted rate (%) was determined as follows: (SE amlodipine % − SE placebo %)/SE amlodipine %.

Results: Data from 7226 patients of 22 trials were analyzed. Rate of edema was higher on amlodipine vs. placebo (16.6 vs. 6.2%, risk ratio: 2.9, 95% CI: 2.50–3.36, P < 0.0001). The placebo-adjusted rate was 63%, indicating that 37% of edema cases were unrelated to amlodipine. Treatment with low/medium doses (2.5–5 mg) resulted in lower rates of edema (risk ratio: 2.01, 95% CI: 1.41–2.88, P = 0.0001) vs. high dose (10 mg) (risk ratio: 3.08, 95% CI 2.62–3.60, P < 0.0001, Pforinteraction = 0.03). Incidence of headache was reduced using amlodipine vs. placebo (7.9 vs. 10.9%, risk ratio: 0.77, 95% CI: 0.65–0.90, P = 0.002) and was driven by use of low/medium doses (risk ratio: 0.52, 95% CI: 0.40–0.69, P < 0.00001 vs. risk ratio: 0.92, 95%-CI: 0.74–1.15, P = 0.45, for high doses, Pforinteraction = 0.002).

Conclusion: Although risks of peripheral edema are three-fold higher on amlodipine, up to one-third of edema cases on amlodipine might not be induced by amlodipine. Headache is reduced on amlodipine treatment, mainly driven by use of this drug at low/medium doses.

aUniversitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany

bDepartment of Cardiology and Clinical Research, University Hospital, Inselspital, Freiburgstrasse, CH-3010 Bern, Switzerland

cState University of New York Downstate College of Medicine, Brooklyn, New York, USA

dInstitute of Cardiovascular Science, University College London, London, UK

Correspondence to Davor Vukadinović, Universitätsklinikum des Saarlandes, Saarland University, Homburg/Saar, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Kirrberger Strasse 1, IMED, D-66421 Homburg, Germany. Tel: +49 6841 16 15000; e-mail:

Received 17 March, 2019

Revised 10 April, 2019

Accepted 10 April, 2019

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