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

Abstract

Objectives:DISTINCT (reDefining Intervention with Studies Testing Innovative Nifedipine GITS – Candesartan Therapy) aimed to determine the dose–response and tolerability of nifedipine GITS and/or candesartan cilexetil therapy in participants with hypertension.Methods:In this 8-week, multinational, multicentre, randomized, double-blind, placebo-controlled study, adults with mean seated DBP of at least 95 to less than 110 mmHg received combination or monotherapy with nifedipine GITS (N) 20, 30 or 60 mg and candesartan cilexetil (C) 4, 8, 16 or 32 mg, or placebo. The primary endpoint, change in DBP from baseline to Week 8, was analysed using the response surface model (RSM); this analysis was repeated for mean seated SBP.Results:Overall, 1381 participants (mean baseline SBP/DBP: 156.5/99.6 mmHg) were randomized. Both N and C contributed independently to SBP/DBP reductions [P < 0.0001 (RSM)]. A positive dose–response was observed, with all combinations providing statistically better blood pressure (BP) reductions from baseline versus respective monotherapies (P < 0.05) and N60C32 achieving the greatest reduction [–23.8/–16.5 mmHg; P < 0.01 versus placebo (–5.3/–6.7 mmHg) and component monotherapies]. Even very low-dose (N20 and C4) therapy provided significant BP-lowering, and combination therapy was similarly effective in different racial groups. N/C combination demonstrated a lower incidence of vasodilatory adverse events than N monotherapy (18.3 versus 23.6%), including headache (5.5 versus 11.0%; P = 0.003, chi-square test) and peripheral oedema over time (3.6 versus 5.8%; n.s.).Conclusion:N/C combination was effective in participants with hypertension and showed an improved side effect profile compared with N monotherapy.

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

“…Response surface modeling showed that nifedipine GITS/candesartan combinations provided greater SBP and DBP lowering after 8 weeks of treatment compared with respective component monotherapies or placebo in all SBP and DBP subgroups, consistent with the main study results24 (Figure 1). For example, mean ± SE reductions in SBP in the N60C32, N60, C32, and placebo treatment groups were 29.8 ± 2.5, 23.0 ± 2.7, 20.3 ± 2.8, and 8.0 ± 2.7 mm Hg, respectively, in the SBP ≥160 mm Hg subgroup and were 20.0 ± 2.1, 13.1 ± 2.0, 14.3 ± 1.9, and 35 ± 1.9 mm Hg, respectively, in the SBP <160 mm Hg subgroup.…”

Effectiveness of two‐drug therapy versus monotherapy as initial regimen in hypertension: A propensity score‐matched cohort study in the UK Clinical Practice Research Datalink

“…Therefore, there is no debate about the effectiveness of the combination strategy, but the question is more whether it should always be preceded by monotherapy, or whether combination therapy may be the initial approach . RCTs tend to confirm that initial two‐drug combination strategies achieve earlier BP control when compared with strategies that add a second drug after monotherapy . Similar evidence has accumulated in observational studies to some extent .…”

Fixed-dose combination of nifedipine gastrointestinal therapeutic system and candesartan cilexetil in patients with moderate-to-severe essential hypertension: an open-label, long-term safety and efficacy study

“…Pharmacokinetic analyses demonstrated that steady‐state concentrations of nifedipine and candesartan were reached by week 28. Although there was a tendency for candesartan concentrations to be higher in Black than other groups, there was no difference in the efficacy of the FDC for BP reduction between racial subgroups, as noted also in the DISTINCT main study (although efficacy analyses in DISTINCT did not take into account addition of a third drug) …”

“…This multinational, multicentre, open‐label study evaluated, for the first time, the long‐term safety and efficacy of FDC N/C once daily in a large population ( n = 508) with moderate‐to‐severe essential hypertension. The target dose of N60/C32 was selected based on outcomes from the DISTINCT study, and the majority of patients attained this dose following titration (87·2% at weeks 44–52).…”

“…Nifedipine is a dihydropyridine CCB available in the gastrointestinal therapeutic system (GITS) formulation, which delivers controlled drug release over 24 h. Candesartan cilexetil is a prodrug that converts to the ARB, candesartan, during gastrointestinal tract absorption. Although nifedipine GITS (N) and candesartan cilexetil (C) are both effective monotherapies for lowering BP, the recent DISTINCT study showed that combining these agents (in ‘loose combination’) provided greater BP reduction than monotherapies alone . The DISTINCT study was an 8‐week, dose‐finding, phase II study in 1381 patients with mild‐to‐moderate hypertension.…”