Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin–angiotensin system

Abstract

This review is aimed at examining calcium channel blocker (CCB)-related oedema and how this can be attenuated through the use of agents that inhibit the renin-angiotensin system. CCBs are effective antihypertensive agents, but their propensity for causing oedema may reduce compliance. A review of the literature has indicated that the absolute incidence of this side effect is difficult to determine because reported rates vary widely, a factor that may stem from differences in the surveillance technique (active vs passive). In a recent trial incorporating active surveillance, 25% of patients who received amlodipine 10 mg per day experienced oedema. CCB-induced oedema is caused by increased capillary hydrostatic pressure that results from preferential dilation of pre-capillary vessels. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) cause postcapillary dilation and normalize hydrostatic pressure, and are thus ideally suited for prevention/reversal of CCB-induced oedema. The efficacy of this strategy was proven using both subjective and objective techniques. ARB/CCB and ACEI/CCB combination therapy is also more effective than CCB monotherapy in controlling blood pressure. These combinations represent an important advance in the management of hypertension.

Nifedipine GITS/Candesartan Combination Therapy Lowers Blood Pressure Across Different Baseline Systolic and Diastolic Blood Pressure Categories: DISTINCT Study Subanalyses

“…Rates of vasodilatory events were lower for nifedipine GITS and candesartan combinations than for nifedipine GITS monotherapy in all baseline BP subgroups, and the incidence of these events was similar across the 4 subgroups. This finding is consistent with other studies of CCB/RAS blocker combination therapies, which show that RAS blockers predictably attenuate the vasodilatory side effects associated with CCBs through decreasing postcapillary resistance 20, 28, 35. As noted by other reviewers, CCB‐associated peripheral edema may be more common in clinical practice than is recorded in clinical trials, and these distressing effects are a common reason for lack of compliance with CCB therapy, especially among patients who require high doses to gain BP control 35, 36.…”

“…This finding is consistent with other studies of CCB/RAS blocker combination therapies, which show that RAS blockers predictably attenuate the vasodilatory side effects associated with CCBs through decreasing postcapillary resistance 20, 28, 35. As noted by other reviewers, CCB‐associated peripheral edema may be more common in clinical practice than is recorded in clinical trials, and these distressing effects are a common reason for lack of compliance with CCB therapy, especially among patients who require high doses to gain BP control 35, 36. Therapy with a combination such as nifedipine GITS/candesartan is therefore likely to be of particular benefit for individuals with high baseline BP, who may be able to achieve significant reductions in BP while avoiding unwanted side effects associated with higher CCB doses.…”

“…Compliance is likely to be further enhanced by the use of a simplified therapeutic regimen that incorporates a fixed‐dose combination of the CCB and RAS blocker 32, 35. Increased compliance through these means is likely to improve antihypertensive efficacy and reduce hypertension‐associated morbidity and mortality.…”

Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile

“…In the current study, it is possible that active reporting and increased focus on vasodilatory side effects could have contributed to the higher rate of headache (11.0%) and oedema (14.2%) than previous data on nifedipine GITS. CCBs are known to cause arteriolar vasodilation, but the addition of a RAS blocker may mitigate this by increasing venous vasodilation, resulting in normalization of intra-capillary pressure [41]. However, ARB therapy has been associated with a substantial reduction in the incidence of headache (of around one-third) compared with placebo, and is being highlighted as a potential prophylactic treatment for patients with migraine [42,43].…”

Leg edema with (S)-amlodipine vs conventional amlodipine given in triple therapy for hypertension: a randomized double blind controlled clinical trial

“…The incidence of edema reported in the literature can also be dependent on the method of edema assessment in the clinical trials [13, 14]. …”