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.
aOslo University Hospital Ullevaal, University of Oslo, Oslo, Norway
bVirginia Commonwealth University, Richmond, Virginia, USA
cHannover Medical School, Hannover, Germany
dKRK Medical Research Institute, Dallas, Texas, USA
eHospital Universitario San Cecilio, Granada, Spain
fThe Crouch Oak Family Practice, Surrey, UK
gHuisartsenpraktijk De Regenboog, Antwerp, Belgium
hNational Research Institute, Los Angeles, California, USA
iFondazione S. Maugeri - IRCCS, Pavia
jUniversity of Milano-Bicocca, Milan, Italy
Correspondence to Professor Sverre E. Kjeldsen, MD, PhD, Department of Cardiology, Ullevaal Hospital, N-0407 Oslo, Norway. Tel: +47 22119100; fax: +47 22119181.
Abbreviations: ACE, angiotensin-converting enzyme; ANCOVA, analysis of covariance; ARB, angiotensin receptor blocker; C, candesartan cilexetil; CCB, calcium channel blocker; DISTINCT, reDefining Intervention with Studies Testing Innovative Nifedipine GITS – Candesartan Therapy; FDC, fixed-dose combination; GCP, good clinical practice; GFR, glomerular filtration rate; GITS, gastrointestinal therapeutic system; ICH, International Conference on Harmonization; IEC, independent ethics committee; IRB, institutional review board; LOCF, last observation carried forward; MedDRA, Medical Dictionary for Regulatory Activities; N, nifedipine GITS; RSM, response surface model; TEAE, treatment-emergent adverse event
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Received March 7, 2014
Received in revised form July 7, 2014
Accepted July 8, 2014