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

Abstract

The aim of this study was to assess the effect of valsartan addition to amlodipine on ankle foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP), two objective measures of ankle oedema. After a 4-week placebo period, 80 grade 1-2 hypertensive patients (diastolic blood pressure (DBP)490 mm Hg and o110 systolic blood pressure (SBP)4140 mm Hg) were randomized to amlodipine 10 mg or valsartan 160 mg or amlodipine 10 mg plus valsartan 160 mg for 6 weeks according to an open-label, blinded end point, crossover design. At the end of the placebo period and of each treatment period, blood pressure, AFV and PSTP were evaluated. AFV was measured using the principle of water displacement. PSTP was assessed connecting the subcutaneous pretibial interstitial environment with a water manometer. Both amlodipine and valsartan monotherapy significantly reduced SBP (À16.9 and -14.5 mm Hg, respectively, Po0.01 vs baseline), and DBP (À12.9 and À10.2 mm Hg, respectively, Po0.01 vs baseline) but the reduction was greater with the combination (À22.9 mm Hg for SBP, Po0.01 vs monotherapy; À16.8 mm Hg for DBP, Po0.01 vs monotherapy). Amlodipine monotherapy significantly increased both AFV ( þ 23%, Po0.01 vs baseline) and PSTP ( þ 75.5%, Po0.001 vs baseline) whereas valsartan monotherapy did not influence them. As compared to amlodipine alone, the combination produced a less marked increase in AFV ( þ 6.8%, Po0.01 vs amlodipine) and PSTP ( þ 23.2%, Po0.001 vs amlodipine). Ankle oedema was clinically evident in 24 patients with amlodipine and in six patients with the combination. These results suggest that angiotensin receptor blockers partially counteract the microcirculatory changes responsible for calcium channel blockers induced oedema formation.

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

“…5 In an additional study, the incidence rate of peripheral oedema was lower with valsartan and amlodipine in combination (5.4%) than with amlodipine monotherapy (8.7%). 6 Moreover, in the trials summarized in Table 1 that recorded the highest incidences of oedema in CCB monotherapy-treated patients, addition of an ACEI or an ARB to the daily therapeutic regimen (benazepril 10 mg added to amlodipine 5 mg; 16 valsartan 160 mg added to amlodipine 10 mg 17 ) reduced the incidence of ankle oedema significantly.…”

“…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.…”

“…Determinations regarding the presence or absence of peripheral oedema have 15,17,41,42 Subcutaneous tissue pressure has been measured using the balancing open system, in which the subcutaneous environment is connected to a water manometer through a saline-filled needle and graduated capillary tube. 15,16 Once the needle has been threaded into the subcutaneous space, tissue pressure causes movement of the meniscus in the capillary tube.…”

Targeting mechanisms of hypertensive vascular disease with dual calcium channel and renin–angiotensin system blockade

“…76 However, few trials have been designed to test the effect of specific antihypertensive combinations on cardiovascular or renal end points. [77][78][79][80][81] Dual RAS/CCB blockade would seem a propitious combination, since these classes of antihypertensive agents target multiple mechanisms involved in hypertensive vascular disease progression.…”