Efficacy and Tolerability of Delapril Plus Indapamide Versus Lisinopril Plus Hydrochlorothiazide Combination Treatments in Mild to Moderate Hypertension: A Multicenter, Randomized Clinical Study

Abstract

Background: Several studies have shown that antihypertensive monotherapy is commonly insufficient to control blood pressure (BP) in hypertensive patients and that concomitant use of Ն2 drugs is necessary in ∼50% of these patients. The combination of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic, delapril plus indapamide (DϩI), has been shown to be effective and tolerable, with no interaction between the 2 components. Another widely used combination of ACE inhibitor and diuretic is lisinopril plus hydrochlorothiazide (LϩH).Objectives: The aims of this study were to confirm the antihypertensive efficacy and tolerability of the fixed combination of DϩI in mild to moderate hypertension, and to compare its therapeutic efficacy and tolerability with that of LϩH.Methods: The antihypertensive efficacy and tolerability of a fixed combination of DϩI (30-mg ϩ 2.5-mg tablets once daily) or LϩH (20-mg ϩ 12.5-mg tablets once daily) in patients with mild to moderate hypertension were compared in a multinational, multicenter, randomized, 2-armed, parallel-group study. Eligible patients were aged 18 to 75 years and had a diastolic blood pressure (DBP) 95 to 115 mm Hg and a systolic blood pressure (SBP) Յ180 mm Hg, both measured in the sitting position. After a single-blind, placebo run-in period of 2 weeks, patients were randomized to receive 1 of the 2 treatments for a 12-week period. The primary efficacy end point was the BP normalization Key words: hypertension, delapril, indapamide, lisinopril, hydrochlorothiazide, combination therapy. INTRODUCTIONHypertension represents one of the most common risk factors for cardiovascular disease, the major cause of mortality and disability in industrialized countries. The results of 2 clinical studies 1,2 have demonstrated that blood pressure (BP) reduction provides benefits in terms of reduced cardiovascular mortality and morbidity, and the scientific community recommends early diagnosis and aggressive therapy for hypertension. 3,4 The major goal in the treatment of hypertensive patients should be normalization of BP; 1 trial 5 also has shown that the incidence of cardiovascular complications is often higher in treated hypertensive patients than in matched normotensive subjects.Several studies 3,4,6 conducted to identify the ideal antihypertensive drug have shown that monotherapy is commonly insufficient to control BP in hypertensive patients and that concomitant use of Ն2 drugs is necessary in ∼50% of these patients. Moreover, in addition to the superior therapeutic efficacy of this approach, the concomitant administration of antihypertensive drugs with different mechanisms of action allows dose decreases with the associated advantage of reduction of adverse events (AEs). 3,4 Among antihypertensive therapies, angiotensin-converting enzyme (ACE) inhibitors have become widely used therapeutic agents; in particular, a common approach is the combined administration of an ACE inhibitor and a diuretic. 7

Efficacy and safety of delapril/indapamide compared to different ACE-inhibitor/hydrochlorothiazide combinations: a meta-analysis

“…Responder patients were defined as: (a) showing a reduction in sitting DBP of 15 mmHg after 1 month of treatment, compared to baseline values;27 (b) showing a reduction in sitting DBP of 10 mmHg compared to baseline values or DBP ≤ 90 mmHg after 12 weeks of treatment;28,30 or (c) demonstrating a reduction in sitting DBP of 10 mmHg from baseline after 1 month of treatment 29. Leonetti27 reported two definitions of patient responders: (a) patients with reduction in sitting DBP of 15 mmHg and (b) a second, wider definition, which also included the definition of normalized patients.…”

“…Since outcome measures were similar for all four studies 27 – 30 included in the meta-analysis, we considered the definitions used in each study as follows: normalized patients were defined as showing a reduction in sitting DBP ≤ 90 mmHg at the 4-week visit 27 , 29 or at the end of the 12-week period of treatment. 28 , 30 Responder patients were defined as: (a) showing a reduction in sitting DBP of 15 mmHg after 1 month of treatment, compared to baseline values; 27 (b) showing a reduction in sitting DBP of 10 mmHg compared to baseline values or DBP ≤ 90 mmHg after 12 weeks of treatment; 28 , 30 or (c) demonstrating a reduction in sitting DBP of 10 mmHg from baseline after 1 month of treatment. 29 Leonetti 27 reported two definitions of patient responders: (a) patients with reduction in sitting DBP of 15 mmHg and (b) a second, wider definition, which also included the definition of normalized patients.…”

“…In studies from Leonetti 27 and Cremonesi et al, 28 the variation in both sitting SBP and DBP between visits was estimated graphically. From studies by Rosei and Rizzoni 29 and Cremonesi et al, 30 the variation between visits was provided, including 90% or 95% confidence intervals (CI).…”

“…To determine the reduction in DBP, the difference compared to baseline was evaluated. If the confidence interval of the difference over time was reported, the standard deviation was derived by simple calculations, 29 , 30 otherwise 27 it was conservatively estimated by the worst coefficient of variation (SD/mean) among the studies that had reported both values. The mean difference between groups, along with its measure of dispersion was then calculated.…”

“…23 , 24 Although several clinical studies have examined the efficacy and safety of the D+I combination to placebo, 18 , 23 – 26 only a few head-to-head clinical trials have been undertaken. 27 – 30 Although efficacy data emerging from these trials would appear to slightly favor the use of the D+I combination over ACEi + hydrochlorothiazide (HCTZ) combinations, 27 – 29 no definitive evidence is currently available that can verify this. To address this clinically relevant issue, we have therefore performed a meta-analysis of head-to-head randomized controlled trials (RCTs), to compare the efficacy and safety of the fixed combination D+I compared to different ACEi and HCTZ combinations in hypertensive patients.…”