TY - JOUR
AU - Fink, Jeffrey, C.
AB - Abstract Combination therapy is required in many patients to achieve goal blood pressure (BP). Calcium antagonists are highly effective antihypertensive drugs in a broad range of demographic groups. Yet, higher doses are associated with an increased frequency of lower extremity edema. The purpose of our open label, single-center clinical trial was to evaluate the use of concomitant pharmacologic therapies to attenuate the lower extremity edema associated with dihydropyridine calcium antagonists therapy using a water displacement technique. Forty-seven patients received 5 mg/day of oral amlodipine for a period of 6 weeks after a 4-week wash-out off of all antihypertensive medications to establish baseline BP. They were then randomized to receive either an additional 5 mg of amlodipine, 25 mg of hydrochlorothiazide (HCTZ), or 20 mg of benazepril for an additional 6 weeks. Blood pressure determinations and water displacement measurements were obtained at the end of the 4-week placebo wash-out period, after 6 weeks of 5 mg/day of oral amlodipine therapy, and after an additional 6 weeks of 5 mg of amlodipine and randomized drug therapy. Adjusted BP reductions (based on pretreatment BP) were −6.8/−3.8 mm Hg for the 10-mg amlodipine group, −9.9/−8.2 mm Hg for the amlodipine (5 mg)/HCTZ (25 mg) group, and −26.2/−16.4 mm Hg for the amlodipine (5 mg)/benazepril (20 mg) group (P < .0167, group 3 v group 1 diastolic BP, which was statistically significant by the improved Bonferroni method). Seventeen of the 47 patients developed at least a 10% increase in lower extremity edema water displacement in response to 5 mg/day of oral amlodipine therapy (36.2%). Adding 5 mg of amlodipine to a baseline of 5 mg of amlodipine resulted in no net change in lower extremity edema (+58.0 mL, +0.6% change, n = 5). Adding 25 mg of HCTZ reduced lower extremity edema by a mean of 136.3 mL (−11.1% change, n = 4). Benazepril reduced water displacement by 204.4 mL (−14.3% change, n = 8). Our pilot study indicates that adding an angiotensin converting enzyme inhibitor to a dihydropyridine calcium channel blocker is the most effective way to not only reduce systolic and diastolic BP but also attenuate lower extremity edema. Due to the inherent daily variability of lower extremity edema, power calculations indicate many patients (n = 702, 356 in each group) would be needed to compare the antiedema efficacy of the angiotensin converting enzyme inhibitor and the thiazide diuretic. Am J Hypertens 2001;14:963–968 © 2001 American Journal of Hypertension, Ltd. Edema, calcium antagonists, ACE inhibitors, diuretics Current approaches to the treatment of hypertension are less than optimal. Less than 50% of patients receiving medication achieve a diastolic blood pressure (BP) <90 mm Hg.1 Even fewer achieve a systolic BP of <140 mm Hg. Despite these observations, newer recommendations suggest that even more aggressive efforts should be made to reduce both systolic and diastolic BP, particularly in patients with diabetes or evidence of target organ damage.1 There are options in clinical practice to remedy this situation. One could increase the dose of medication, substitute an agent from another drug class, add a second agent from another class, or use a fixed-dose combination. Angiotensin converting enzyme (ACE) inhibitors and calcium antagonists are widely used antihypertensive medications with somewhat different mechanisms of action. Although both are vasodilators, mechanistically they are entirely different.2,3 Each drug class has a somewhat different efficacy profile. Calcium antagonists have been demonstrated to be effective in the low renin, salt-sensitive hypertensive individual and manifest more robust antihypertensive properties in the face of a high salt diet relative to other commonly used therapies.4,5 The ACE inhibitors in lower doses are more effective in patients with higher plasma renin activity such as younger patients and Caucasians. When used in higher doses, they do provide incremental antihypertensive activity.6 Calcium antagonists, although highly effective antihypertensive drugs, do present a clinical challenge in that a sizable percentage of patients will develop the side effect of lower extremity edema. This is more common, particularly in women and in obese hypertensives.7 Mechanistically, this lower extremity edema is likely due to distal arteriolar dilation with capillary leak as opposed to salt and water retention, which is common with the direct-acting vasodilators like hydralazine and minoxidil. Clinicians have struggled with therapeutic strategies to reduce the pedal edema and facilitate better BP control in patients receiving calcium antagonists by experimenting with other antihypertensive drug classes like ACE inhibitors or diuretics. The purpose of our clinical trial was to evaluate a water displacement technique to objectively evaluate the effect of a thiazide diuretic or an ACE inhibitor to attenuate the lower extremity edema associated with the dihydropyridine antagonist amlodipine. Methods Study design This was a single-center, open label, randomized clinical study to evaluate the antihypertensive properties and impact on water displacement of the lower extremity in hypertensive patients by adding either 5 mg of amlodipine, 25 mg of hydrochlorothiazide (HCTZ), or 20 mg of benazepril in hypertensives already receiving 5 mg/day of oral amlodipine. Newly diagnosed hypertensives or hypertensives receiving antihypertensive medication were observed for a period of 4 weeks off all medication to determine baseline, untreated BP and lower extremity water displacement (phase 1). All patients were started on 5 mg/day of oral amlodipine for a period of 6 weeks, after which time BP and water displacement were determined (phase 2). All patients were subsequently randomized to receive either an additional 5 mg of oral amlodipine, 25 mg/day of oral HCTZ, or 20 mg/day of oral benazepril (phase 3). After an additional 6 weeks of therapy, patients had their BP determined and lower extremity water displacement measured. Patients Male and female outpatients between the ages of 21 and 80 years with uncomplicated diastolic essential hypertension where eligible. Women were at least 1 year postmenopausal or surgically sterilized. Entry criteria required that patients have either stage I or stage II diastolic hypertension (mean sitting diastolic BP of ≥90 mm Hg and <110 mm Hg off all antihypertensive medication). Patients were excluded from the study if they had any evidence of clinically significant concurrent medical conditions including cardiac, renal, hepatic, gastrointestinal, or endocrinologic disease. Also excluded were patients with known hypersensitivity or serious drug reactions to calcium antagonists or ACE inhibitors. Patients were also excluded if there were differences in lower extremity size or any evidence of prior deep vein thrombosis, lymphatic disease, or concurrent requirement for medications that could effect BP or salt and water retention (eg, nonsteroidal antiinflammatory drugs, estrogen containing drugs). Informed consent as approved by the Institutional Review Board of the University of Maryland School of Medicine was obtained from each patient. Study procedures Study procedures included a baseline medical history and physical examination, laboratory examination including complete blood count and chemistry, and electrocardiogram. Visits were conducted every 2 weeks and included brief physical examination, measurement of systolic and diastolic BP using a mercury sphygmomanometer on the same arm in sitting and standing positions. Three consecutive sitting BP measurements were taken at no less than 30-sec intervals. The recorded BP was the average of three measurements. One-minute pulse rate was recorded after BP measurements. All BP and pulse measurements throughout the study were made at trough, approximately the same time of day, always between 8 and 10 AM, approximately 24 h after the last dose. A physical examination and laboratory evaluation was performed at the midpoint and at study conclusion. All medications were given once daily in an open label fashion. Patients received instructions on how to take the medications. Pill counts were conducted at each study visit. Less than 90% compliance with medication resulted in study termination. No effort was made to adjust the diet of the patients participating in the study. Water displacement measurements were made by using a large tub (52 cm long, 37 cm wide, and 33 cm deep). The tub was filled to 23 cm. Patients were instructed to immerse their right leg into the tub after standing for 4 min. Water was removed down to the 23-cm level while the foot was in the tub and measured with a graduated cylinder to assess water displacement. All measurements were performed at room temperature (20° to 22°C) during trough blood pressure measurements approximately 22 to 24 h dosing. Statistical analysis Descriptive statistics were used to summarize water displacement and BP at the end of each phase. Changes and percent changes in these outcomes within phases were also described by descriptive statistics. A phase 2 versus phase 3 within treatment group analysis (not shown) was performed by applying the Wilcoxon signed rank statistic to the change during phase 3 minus the change during phase 2. The primary efficacy variable was percent change in water displacement during phase 3 assessed by using the water immersion method. Secondary efficacy variables were percent change in diastolic and systolic BP during phase 3. In this analysis, ANOVA was performed. Pairwise treatment group comparisons were performed using Tukey's simultaneous 95% confidence intervals. Additionally water displacement, diastolic and systolic BP at the end of phase 3 in the treatment groups were compared using analysis of covariance (ANCOVA) with the readings at the end of phase 1 and phase 2 as covariates. Holm's multiple comparison procedure was used to compare the pairwise differences in this ANCOVA model. Results Patient demographics Seventy-four patients were enrolled in phase 1 (4-week wash-out phase). Nineteen of these 74 patients discontinued to study during phase 1 and 55 patients were enrolled in phase 2 (5 mg/day of amlodipine for 6 weeks). Eight patients discontinued the study during phase 2 (one withdrew consent and seven withdrew for other reasons). The remaining 47 patients were enrolled in phase 3. There were a total of 25 men and 22 women who completed the study of whom 23 were Caucasian and 24 of African American descent. The mean age was 49.9 years and mean body mass index was 33 kg/m2. Mean systolic and diastolic BP at the end of phase I (4-week wash-out period) was 149.5 ± 21.1 and 96.6 ± 8.7 mm Hg. As depicted in Table 1, the baseline BP after the 4-week wash-out was lower in group 1 and group 2 compared to group 3. Table 1 Diastolic and systolic blood pressure changes (mm Hg) during the study . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline after 4 week washout (phase 1) 142.7 ± 9.6/93.8 ± 6.9 142.6 ± 14.5/96.3 ± 8.8 164.3 ± 28.1/99.7 ± 9.7 BP reduction (mm Hg) with amlodipine 5 mg (phase 2) −2.4/−0.1 6.4/−5.1 −15.9/−8.5 Incremental BP reduction (mm Hg) with amlodipine 5 mg + randomized therapy (phase 3) −4.4/−3.7 −3.5/−3.1 −10.3/−7.9 Total BP reduction −6.8/−3.8 −9.9/−8.2 −26.2/−16.4* . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline after 4 week washout (phase 1) 142.7 ± 9.6/93.8 ± 6.9 142.6 ± 14.5/96.3 ± 8.8 164.3 ± 28.1/99.7 ± 9.7 BP reduction (mm Hg) with amlodipine 5 mg (phase 2) −2.4/−0.1 6.4/−5.1 −15.9/−8.5 Incremental BP reduction (mm Hg) with amlodipine 5 mg + randomized therapy (phase 3) −4.4/−3.7 −3.5/−3.1 −10.3/−7.9 Total BP reduction −6.8/−3.8 −9.9/−8.2 −26.2/−16.4* * P < .016, group 3 v group 1, statistically significant by the improved Bonferroni method. Open in new tab Table 1 Diastolic and systolic blood pressure changes (mm Hg) during the study . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline after 4 week washout (phase 1) 142.7 ± 9.6/93.8 ± 6.9 142.6 ± 14.5/96.3 ± 8.8 164.3 ± 28.1/99.7 ± 9.7 BP reduction (mm Hg) with amlodipine 5 mg (phase 2) −2.4/−0.1 6.4/−5.1 −15.9/−8.5 Incremental BP reduction (mm Hg) with amlodipine 5 mg + randomized therapy (phase 3) −4.4/−3.7 −3.5/−3.1 −10.3/−7.9 Total BP reduction −6.8/−3.8 −9.9/−8.2 −26.2/−16.4* . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline after 4 week washout (phase 1) 142.7 ± 9.6/93.8 ± 6.9 142.6 ± 14.5/96.3 ± 8.8 164.3 ± 28.1/99.7 ± 9.7 BP reduction (mm Hg) with amlodipine 5 mg (phase 2) −2.4/−0.1 6.4/−5.1 −15.9/−8.5 Incremental BP reduction (mm Hg) with amlodipine 5 mg + randomized therapy (phase 3) −4.4/−3.7 −3.5/−3.1 −10.3/−7.9 Total BP reduction −6.8/−3.8 −9.9/−8.2 −26.2/−16.4* * P < .016, group 3 v group 1, statistically significant by the improved Bonferroni method. Open in new tab Blood pressure efficacy The secondary goal of this study was to compare the efficacy of the randomized therapies added to 5 mg/day of amlodipine to lower BP. As illustrated in Table 1, the optimal therapy was adding 20 mg of benazepril to 5 mg of amlodipine, which provided clinically meaningful improvements (−10.3/−7.9 mm Hg) in both systolic and diastolic BP compared to increasing the dose of amlodipine from 5 to 10 mg (−4.4/−3.7 mm Hg) or adding 25 mg of HCTZ to 5 mg of amlodipine (−3.5/−3.1 mm Hg). However, the BP reduction in group 3 would be expected to be greater due to the higher pretreatment BP (164.3/99.7 mm Hg). Yet, even after statistical adjustment for the higher pretreatment blood pressure in group 3, the diastolic BP reduction was statistically significantly superior in group 3 than in group 1 (adjusted estimate 7.3 mm Hg lower). Diagnostic plots did not reveal departures from ANCOVA model assumptions. The adjusted estimate of diastolic BP at the end of phase 3 was 5.7 mm Hg lower in group 3 than in group 2 (not significant by the improved Bonferroni method). Percent change in diastolic BP reduction during phase 3 was also analyzed by ANOVA with Tukey's simultaneous confidence intervals. Although not statistically significant, the adjustment indicates a trend with close to a 5% greater reduction in group 3 than in the other two groups. Water displacement measurements Tables 2 and 3summarize the effects of phase 2 therapy (5 mg/day of oral amlodipine) and the phase 3 randomized therapy on the water displacement results for the whole group (Table 2) and only for those patients who had a 10% increase in water displacement in response to 5 mg/day of amlodipine therapy (Table 3). In Table 2, one can see the data for all randomized patients (n = 47). There was no significant change from baseline in group 1 with 5 mg of amlodipine, but with the increase in dose from 5 to 10 mg, there was an incremental change of 6.6% (P = NS). In group 2, there was a slight decrease in water displacement during phase 2 and no significant increase with the randomized therapy of 25 mg/day of HCTZ. In group 3, 5 mg/day of amlodipine did result in a 14.1% increase in water displacement during phase 2. Subsequent therapy with 20 mg of benazepril reduced that by almost 100 mL, a decrease of about 6.8%. For the whole group, 5 mg of amlodipine did not result in a statistical change in water displacement (1307.0 to 1299.5 mL). However, of the 47 patients, 17 (36.2%) had an increase in water displacement of at least 10% over baseline. Table 3 Water displacement results in patients with at least a 10% increase in volume during phase 2 . Group 1: Amlopidine 10 mg (n = 5) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 4) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 8) . Baseline (phase 1) 1298.0 ± 83.7 mL 907.5 ± 208.9 mL 1085.1 ± 106.4 mL Amlodipine 5 mg (phase 2) 1640.0 ± 215.7 mL 1281.3 ± 120.6 mL 1522.5 ± 94.2 mL Amlodipine 5 mg and randomized therapy (phase 3) 1698.0 ± 318.8 mL 1145.0 ± 222.3 mL 1318.1 ± 138.9 mL Net change (phase 2 to 3) +58.0 mL −136.3 mL −204.4 mL % Change (phase 2 to 3) +0.6 −11.1 −14.3 . Group 1: Amlopidine 10 mg (n = 5) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 4) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 8) . Baseline (phase 1) 1298.0 ± 83.7 mL 907.5 ± 208.9 mL 1085.1 ± 106.4 mL Amlodipine 5 mg (phase 2) 1640.0 ± 215.7 mL 1281.3 ± 120.6 mL 1522.5 ± 94.2 mL Amlodipine 5 mg and randomized therapy (phase 3) 1698.0 ± 318.8 mL 1145.0 ± 222.3 mL 1318.1 ± 138.9 mL Net change (phase 2 to 3) +58.0 mL −136.3 mL −204.4 mL % Change (phase 2 to 3) +0.6 −11.1 −14.3 Open in new tab Table 3 Water displacement results in patients with at least a 10% increase in volume during phase 2 . Group 1: Amlopidine 10 mg (n = 5) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 4) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 8) . Baseline (phase 1) 1298.0 ± 83.7 mL 907.5 ± 208.9 mL 1085.1 ± 106.4 mL Amlodipine 5 mg (phase 2) 1640.0 ± 215.7 mL 1281.3 ± 120.6 mL 1522.5 ± 94.2 mL Amlodipine 5 mg and randomized therapy (phase 3) 1698.0 ± 318.8 mL 1145.0 ± 222.3 mL 1318.1 ± 138.9 mL Net change (phase 2 to 3) +58.0 mL −136.3 mL −204.4 mL % Change (phase 2 to 3) +0.6 −11.1 −14.3 . Group 1: Amlopidine 10 mg (n = 5) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 4) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 8) . Baseline (phase 1) 1298.0 ± 83.7 mL 907.5 ± 208.9 mL 1085.1 ± 106.4 mL Amlodipine 5 mg (phase 2) 1640.0 ± 215.7 mL 1281.3 ± 120.6 mL 1522.5 ± 94.2 mL Amlodipine 5 mg and randomized therapy (phase 3) 1698.0 ± 318.8 mL 1145.0 ± 222.3 mL 1318.1 ± 138.9 mL Net change (phase 2 to 3) +58.0 mL −136.3 mL −204.4 mL % Change (phase 2 to 3) +0.6 −11.1 −14.3 Open in new tab Table 2 Water displacement results in all randomized patients (n = 47) . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline (phase 1) 1385.7 ± 212.5 mL 1293.8 ± 355.8 mL 1244.0 ± 384.4 mL Amlodipine 5 mg (phase 2) 1394.3 ± 359.3 mL 1110.3 ± 260.4 mL 1419.0 ± 300.7 mL Amlodipine 5 mg and randomized therapy (phase 3) 1485 ± 595.2 mL 1135.6 ± 351.0 mL 1322.7 ± 315.6 mL Net change +91.4 mL +25.3 mL −96.3 mL % Change (phase 2 to 3) 6.6% 2.3% −6.8% . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline (phase 1) 1385.7 ± 212.5 mL 1293.8 ± 355.8 mL 1244.0 ± 384.4 mL Amlodipine 5 mg (phase 2) 1394.3 ± 359.3 mL 1110.3 ± 260.4 mL 1419.0 ± 300.7 mL Amlodipine 5 mg and randomized therapy (phase 3) 1485 ± 595.2 mL 1135.6 ± 351.0 mL 1322.7 ± 315.6 mL Net change +91.4 mL +25.3 mL −96.3 mL % Change (phase 2 to 3) 6.6% 2.3% −6.8% Data expressed as mean ± SEM. Open in new tab Table 2 Water displacement results in all randomized patients (n = 47) . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline (phase 1) 1385.7 ± 212.5 mL 1293.8 ± 355.8 mL 1244.0 ± 384.4 mL Amlodipine 5 mg (phase 2) 1394.3 ± 359.3 mL 1110.3 ± 260.4 mL 1419.0 ± 300.7 mL Amlodipine 5 mg and randomized therapy (phase 3) 1485 ± 595.2 mL 1135.6 ± 351.0 mL 1322.7 ± 315.6 mL Net change +91.4 mL +25.3 mL −96.3 mL % Change (phase 2 to 3) 6.6% 2.3% −6.8% . Group 1: Amlodipine 10 mg (n = 15) . Group 2: Amlodipine 5 mg + HCTZ 25 mg (n = 17) . Group 3: Amlodipine 5 mg + Benazepril 20 mg (n = 15) . Baseline (phase 1) 1385.7 ± 212.5 mL 1293.8 ± 355.8 mL 1244.0 ± 384.4 mL Amlodipine 5 mg (phase 2) 1394.3 ± 359.3 mL 1110.3 ± 260.4 mL 1419.0 ± 300.7 mL Amlodipine 5 mg and randomized therapy (phase 3) 1485 ± 595.2 mL 1135.6 ± 351.0 mL 1322.7 ± 315.6 mL Net change +91.4 mL +25.3 mL −96.3 mL % Change (phase 2 to 3) 6.6% 2.3% −6.8% Data expressed as mean ± SEM. Open in new tab Table 3 illustrates the water displacement results in those patients (n = 17) who demonstrated at least a 10% increase over baseline. Note that during phase 3, group 1 (10 mg of amlodipine) had a continued increase in volume displacement, whereas in groups 2 and 3 a reduction in water displacement occurred. Note, that no increase in edema occurred when 5 mg was increased to 10 mg. Increased edema was not seen likely because these patients were preselected for already having at least a 10% increase on 5 mg alone. Adding HCTZ resulted in a 136.3 mL reduction (−11.1%), and adding 20 mg/day of benazepril resulted in a 204.4 mL water displacement reduction, a decrease of 14.3%. Safety The drug therapies during the course of the study were extremely well tolerated. There were no drop outs due to intolerability or evidence of serious adverse reactions. There were no reported laboratory adverse events. Discussion In this pilot study, the impact of adjunctive therapies, either HCTZ or ACE inhibitor was evaluated with regard to their ability to attenuate lower extremity edema (with a water displacement technique) and facilitate reduction in systolic and diastolic BP in patients already receiving the dihydropyridine calcium antagonist amlodipine. We demonstrated that the optimal strategy to reduce both systolic and diastolic BP and attenuate edema is to combine an ACE inhibitor with a calcium antagonist. Essential hypertension remains a complicated and complex illness to treat. The disease is largely symptomless, and medications, particularly those titrated to higher doses frequently cause adverse events. In an effort to facilitate better BP control, an effort has been made to develop low-dose fixed combinations, not only to facilitate efficacy, but improve compliance and ease of administration. The recent Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure consensus report has endorsed this approach.1 In this clinical trial, we have successfully demonstrated that there are two therapies that demonstrate benefit in attenuating the lower extremity edema associated with dihydropyridine calcium antagonists. Although the number of patients are small in our pilot study, 2 of 4 patients receiving amlodipine had their lower extremity edema improved when adding a thiazide diuretic (25 mg of HCTZ). Similarly, 6 of 8 patients receiving 20 mg/day of benazepril had their lower extremity edema improved. Moreover, the addition of these medications besides attenuating lower extremity edema, also facilitated better BP reduction. Thus, this type of therapeutic strategy provides a more rational approach to facilitate BP control when adequate BP control is not achieved on a dihydropyridine calcium antagonist. Besides better BP control and improved tolerability, ACE inhibitors may provide additional opportunities with regard to reducing proteinuria,8 attenuating sympathetic nervous system activity, which may be important in patients with heart disease,9 as well as has been shown to provide secondary risk reduction in patients with heart disease10 and kidney disease.11,12 The combination of the better BP reduction and attenuation of lower extremity edema would argue that the ACE inhibitor may be the ideal strategy to combine with the calcium antagonist. The mechanism of thiazide diuretic- or ACE inhibitor-induced reduction in water displacement is not easily described. Thiazide diuretics primary reduce BP through only subtle changes in blood volume and act primarily through vasorelaxation (over the long term). Short-term studies demonstrate mild volume reduction associated with the use of thiazides.13 However, that is not likely to explain the observations seen in our studies where water displacement measurements were carried out 6 weeks apart. The ACE inhibitors are a class of drugs that provide both preload and afterload reduction.3 The ability to dilate venous capacitance vessels may explain why ACE inhibitors reduce the lower extremity edema associated with the calcium antagonists. Because calcium antagonists provide potent vasodilation, even in distal arteriolar beds, this may lead to a capillary leak syndrome. Thus, venous capacitance dilation and reduction in venular pressure may modify this effect and explains the mechanism of ACE inhibitors in reducing the increased lower extremity water displacement associated with dihydropyridine calcium antagonists. Unfortunately our pilot study did not provide the statistical power to differentiate between the ability of thiazide diuretic or the ACE inhibitor to reduce lower extremity edema using our water displacement technique. However, some useful information can be gleaned from this new, previously not reported technique that can assist in the design of larger clinical trials. There is an inherent variability in the lower extremity edema measurements, perhaps related to age, gender, weight, time of day of measurement, and even dietary salt consumption. Although not studied in our clinical trial, this is not uncommonly observed in clinical practice where patients report changes in lower extremity edema. Using power calculations based on the data in Table 3 to detect a significant difference (with 90% power) between the HCTZ group and the ACE inhibitor, one would need to study 702 patients (356 in each group). On the other hand, many fewer patients would need to be studied (16, 8 in each group) to achieve statistical significance with 90% power between the calcium antagonist group alone and the ACE inhibitor/calcium antagonist combination. In summary, we have demonstrated in a pilot study that thiazide diuretics or ACE inhibitors may provide an opportunity to reduce lower extremity edema in patients receiving the dihydropyridine calcium antagonist amlodipine. This benefit is seen in at least 50% of the patients and remains evident at 6 weeks after concomitant therapy. Moreover, both therapies provide incremental reduction in BP in conjunction with the calcium antagonist. This was most notable with the ACE inhibitor. Consequently, the latter approach appears to be the ideal strategy to combine with a calcium antagonist for BP control and avoidance of lower extremity edema. We thank Vondalee Cowling for her excellent secretarial support. References 1. Joint National Committee The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure . Arch Intern Med 1997 ; 157 : 2413 – 2446 . Crossref Search ADS PubMed WorldCat 2. Romero JC , Raij L, Granger JP, Ruilope LM, Rodicio JL: Multiple effects of calcium entry blockers on renal function in hypertension . Hypertension 1987 ; 10 : 140 – 151 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Zusman RM : Effects of converting enzyme inhibitors on the renin-angiotensin aldosterone, bradykinin, and arachidonic acid-prostaglandin systems: correlation of chemical structure and biologic activity . Am J Kidney Dis 1987 ; 10 ( suppl 1 ): 13 – 23 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 4. Weir MR , Hall PS, Behrens MT, Flack JM: Salt and blood pressure responses to calcium antagonism in hypertensive patients . Hypertension 1997 ; 30 ( part 1 ): 422 – 427 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Weir MR , Chrysant SG, McCarron DA, Canossa-Terris M, Cohen JD, Gunter PA, Lewin AJ, Mennella RF, Kirkegaard LW, Hamilton JH, Weinberger MH, Weder AB: Influence of race and dietary salt on the antihypertensive efficacy of an angiotensin-converting enzyme inhibitor or a calcium channel antagonist in salt-sensitive hypertensives . Hypertension 1998 ; 31 : 1088 – 1096 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Weir MR , Gray JM, Paster R, Saunders E: Differing mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. The Trandolapril Multicenter Study Group . Hypertension 1995 ; 26 : 124 – 130 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Messerli FH , Oparil S, Feng Z: Comparison of efficacy and side effects of low-dose combination therapy of angiotensin-converting enzyme inhibitor (benazepril) with calcium antagonist (either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension . Am J Cardiol 2000 ; 86 : 1182 – 1187 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Gansevoort RT , deZeeuw D, deJong PE: Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin-angiotensin system? . Kidney Inter 1994 ; 45 : 861 – 867 . Google Scholar Crossref Search ADS WorldCat 9. Ligtenberg G , Blankestijn PJ, Oey PL, Klein IH, Dijkhorst-Oei LT, Boomsma F, Wieneke GH, Van Huffelen AC, Koomans HA: Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure . N Engl J Med 1999 ; 340 : 1321 – 1328 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients . N Engl J Med 2000 ; 342 : 145 – 153 . Crossref Search ADS PubMed WorldCat 11. Lewis EJ , Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy: the Collaborative Study Group . N Engl J Med 1993 ; 329 : 1456 – 1562 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Giatras I , Lan J, Levey AS: Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials . Ann Intern Med 1997 ; 127 : 337 – 345 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Conway J , Lauwers P: Hemodynamic and hypotensive effects of long-term therapy with chlorothiazide . Circulation 1960 ; 21 : 21 – 27 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes * This research project was supported by a grant from Novartis Pharmaceuticals, Inc. © 2001 by the American Journal of Hypertension, Ltd. American Journal of Hypertension, Ltd.
TI - 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
JF - American Journal of Hypertension
DO - 10.1016/S0895-7061(01)02167-7
DA - 2001-09-01
UR - https://www.deepdyve.com/lp/oxford-university-press/pilot-study-to-evaluate-a-water-displacement-technique-to-compare-1YUmMmzu1m
SP - 963
EP - 968
VL - 14
IS - 9
DP - DeepDyve
ER -