Effect of benazepril addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients

Abstract

The aim of this study was to evaluate the effect of benazepril addition to amlodipine antihypertensive treatment on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP), two objective measures of ankle oedema. A total of 32 mild to moderate essential hypertensives (DBP490 and o110 mmHg), aged 30-70 years were studied. After a 4-week placebo period, they were randomized to amlodipine 5 mg o.d. or benazepril 10 mg o.d. or amlodipine 5 mg plus benazepril 10 mg o.d. for 4 weeks, according to a crossover design. At the end of the placebo period and of each active treatment period, blood pressure,AFV and PSTP were evaluated. AFV was measured using the principle of water displacement. PSTP was assessed using a system, the subcutaneous pretibial interstitial enviroment with a water manometer. Both amlodipine and benazepril monotherapy significantly reduced SBP (À18.2 7 4 and À17.8 7 4 mmHg, respectively, Po0.01 vs baseline) and DBP (À12.1 7 3 and À11.7 7 3 mmHg, respectively, Po0.01); the reduction was increased by the combination (À24.2 7 5 mmHg for SBP, Po0.001 and À16.8 7 4 mmHg for DBP, Po0.001). Amlodipine monotherapy significantly increased both AFV (+17.1%, Po0.001 vs baseline) and PSTP (+56.6%, Po0.001 vs baseline). As compared to amlodipine alone, the combination produced a less pronounced increase in AFV (+5.5%, Po0.05 vs baseline and Po0.01 vs amlodipine) and PSTP (+20.5%, Po0.05 vs baseline and Po0.01 vs amlodipine). Ankle oedema was clinically evident in 11 patients with amlodipine monotherapy and in three patients with the combination. These results suggest that ACE-inhibitors partially counteract the microcirculatory changes responsible for Ca-antagonists-induced oedema formation.

Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients

“…These findings are similar to previous observations with the ACE-I/CCB combination, both based on spontaneously reported side effects in clinical trials [9][10][11][12] and also on the use of the water displacement technique. 13,14 The mechanisms by Valsartan-amlodipine combination and ankle oedema R Fogari et al which ARB may attenuate the CCB-induced oedema are not clear but possibly resemble those hypothesized for ACE-I. [4][5][6][7][8] Thus, RAAS blockade by both ACE-I and ARB is likely to result in venous capacitance vessels vasodilation with consequent intracapillary pressure normalization and reduced fluid exudation from the intracapillary space into the interstitium.…”

“…PSTP was measured directly using the balancing open system, described by Lauderer 17 in 1884 and modified by Burch and Sodeman 18 in 1937 and the Malamani device, 19,20 according to a method already described in detail in a previous paper, based on the connection of the pretibial subcutaneous environment to a water manometer. 13 Also in this test, three successive recordings were performed with a good reproducibility (coefficient of variation 0.25%).…”

“…6 By contrast, adding an angiotensin-converting enzyme inhibitor (ACE-I) to the treatment with a CCB has been shown to reduce the incidence and the entity of ankle oedema. [9][10][11][12][13] The mechanisms by which ACE-I attenuate the CCBinduced oedema are not clear, but their ability to dilate venous capacitance vessels seems to play a major role by normalizing intracapillary pressure and reducing fluid exudation from the intracapillary space into the interstitium. 6,14 Whether this ability is peculiar of ACE-I or extends to the other drugs interfering with the renin-angiotensin-aldosterone system (RAAS), that is the angiotensin receptor blockers (ARB), remains to be established.…”

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

“…10,12,22 This theoretical concept is borne out by the results of individual clinical trials that have shown that the incidence of oedema is substantially lower in patients who receive ACEI/ CCB or ARB/CCB combination therapy than in those treated with CCB monotherapy. 6,[15][16][17][18][19][20][21][22] Moreover, a meta-analysis of 82 studies that compared the safety and efficacy of benazepril/amlodipine therapy with that of nine monotherapy regimens concluded that this combination was associated with a lower overall rate of side effects and of side effects that led to withdrawal than either amlodipine or nifedipine monotherapy. Table 1 shows the rates of oedema from eight relevant clinical trials.…”

“…13,14 The incidence of oedema in CCB-treated patients can be substantially reduced by addition of an inhibitor of the renin-angiotensin system (RAS), that is, an ARB or an angiotensin-converting enzyme inhibitor (ACEI). 5,6,[15][16][17][18][19][20][21][22] This review discusses the pharmacological mechanisms that underlie CCB-induced oedema formation and mitigation of this side effect by ACEIs and ARBs. The data cited in this review were selected for relevance by the author from searches performed using PubMed without specific considerations to patient populations.…”