Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile: DISTINCT randomized trial results

Sverre E Kjeldsen, Domenic Sica, Hermann Haller, Gloria Cha, Blas Gil-Extremera, Peter Harvey, Frank Heyvaert, Andrew J Lewin, Giuseppe Villa, Giuseppe Mancia, DISTINCT Investigators, J Agaiby, N Aggarwal, P Ainsworth, R Akhras, V Amaluan, A Ballarin, L Bardauskiene, F C Berra, M Blagden, B Bodalia, C Borghi, C Bundy, L Burgess, R Buynak, A Cafferata, T Cahill, L Capiau, V Capuano, R Casanova, J Cecil, G Cha, J Chapman, M Chilvers, S Christensen, Y-H Cho, W-B Chung, F Cipollone, A Coca, H Colombo, E M Contreras, D Crowley, B Cusco-Prieto, F Decarlini, J-H Doh, P Dzongowski, G Dzyak, A Ellery, B G Extremera, E Farias, C Farrington, J Fidelholtz, L Fouche, A Gabito, M Gainza, M Gani, R Gaunt, E Gelersztein, M Giuliano, A Glazunov, N Glorioso, B Goloschekin, M Gumbley, A Gupta, L Guzman, J-W Ha, R Hart, P Harvey, D Haworth, S Henein, D Henry, S-H Her, F Heyvaert, G Hollanders, M Hominal, B-K Hong, T-J Hong, K-K Hwang, A Jacovides, J Jacqmein, H K Jeon, N Jones, S Kanani, H Kang, O Karpenko, D Kenton, N Kimzey, S E Kjeldsen, V Kovalenko, M Kushnir, B Lasko, K J Lee, N Lee, A Lewin, M Litvak, D Luksiene, C Majul, E Mannarino, O Manuale, A Marcadis, D Miller, R Mills, K Misik, J Mortelmans, M O'Mahony, W O'Mahony, C Park, R Pedrinelli, Z Petrulioniene, F Pettyjohn, D Piskorz, G Poss, K Pudi, W B Pyun, G Raad, G Raila, M F Ramirez Espinosa, P Ramlachan, M Rhee, L Rudenko, T S Ruiz, J Ryan, G Schacter, J-H Shin, D Short, D Sica, Y Sirenko, R Slapikas, R Somani, M Stanislavchuk, R Stewart, Y Svishchenko, O Sychov, I Teitelbaum, V Tseluyko, D J Van Rensburg, J V Vaquer Perez, L M Via, M Vico, G Villa, V Vizir, D Vogel, H Wellmann, B S Yoo, Sverre E Kjeldsen, Domenic Sica, Hermann Haller, Gloria Cha, Blas Gil-Extremera, Peter Harvey, Frank Heyvaert, Andrew J Lewin, Giuseppe Villa, Giuseppe Mancia, DISTINCT Investigators, J Agaiby, N Aggarwal, P Ainsworth, R Akhras, V Amaluan, A Ballarin, L Bardauskiene, F C Berra, M Blagden, B Bodalia, C Borghi, C Bundy, L Burgess, R Buynak, A Cafferata, T Cahill, L Capiau, V Capuano, R Casanova, J Cecil, G Cha, J Chapman, M Chilvers, S Christensen, Y-H Cho, W-B Chung, F Cipollone, A Coca, H Colombo, E M Contreras, D Crowley, B Cusco-Prieto, F Decarlini, J-H Doh, P Dzongowski, G Dzyak, A Ellery, B G Extremera, E Farias, C Farrington, J Fidelholtz, L Fouche, A Gabito, M Gainza, M Gani, R Gaunt, E Gelersztein, M Giuliano, A Glazunov, N Glorioso, B Goloschekin, M Gumbley, A Gupta, L Guzman, J-W Ha, R Hart, P Harvey, D Haworth, S Henein, D Henry, S-H Her, F Heyvaert, G Hollanders, M Hominal, B-K Hong, T-J Hong, K-K Hwang, A Jacovides, J Jacqmein, H K Jeon, N Jones, S Kanani, H Kang, O Karpenko, D Kenton, N Kimzey, S E Kjeldsen, V Kovalenko, M Kushnir, B Lasko, K J Lee, N Lee, A Lewin, M Litvak, D Luksiene, C Majul, E Mannarino, O Manuale, A Marcadis, D Miller, R Mills, K Misik, J Mortelmans, M O'Mahony, W O'Mahony, C Park, R Pedrinelli, Z Petrulioniene, F Pettyjohn, D Piskorz, G Poss, K Pudi, W B Pyun, G Raad, G Raila, M F Ramirez Espinosa, P Ramlachan, M Rhee, L Rudenko, T S Ruiz, J Ryan, G Schacter, J-H Shin, D Short, D Sica, Y Sirenko, R Slapikas, R Somani, M Stanislavchuk, R Stewart, Y Svishchenko, O Sychov, I Teitelbaum, V Tseluyko, D J Van Rensburg, J V Vaquer Perez, L M Via, M Vico, G Villa, V Vizir, D Vogel, H Wellmann, B S Yoo

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.

Trial registration: ClinicalTrials.gov NCT01303783.

Figures

FIGURE 1
FIGURE 1
Disposition of study participants. FAS, full analysis set.
FIGURE 2
FIGURE 2
Significant (P < 0.0001) reduction in SBP and DBP (mmHg) from baseline to Week 8 following treatment with nifedipine GITS (0, 20, 30, 60 mg) and/or candesartan cilexetil (0, 4, 8, 16, 32 mg) [LS means from final RSM (n = 1362)]. BP, blood pressure; LS, least squares; RSM, response surface model.
FIGURE 3
FIGURE 3
Patients reaching blood pressure targets. Figure showing (a) control rates (%) (BP 20 mmHg or DBP 10 mmHg) at Week 8 following treatment with nifedipine GITS (N0, 20, 30, 60 mg) and/or candesartan cilexetil (C0, 4, 8, 16, 32 mg) (n = 1362). BP, blood pressure.
FIGURE 4
FIGURE 4
The mean change in SBP and DBP (+SD), and control and response rates from baseline to Week 8 for patients of different race who received treatment with placebo, candesartan cilexetil, nifedipine GITS or nifedipine GITS-candesartan cilexetil combination (n = 1332). SD, standard deviation. aThirty patients were of other racial origins.
FIGURE 5
FIGURE 5
The incidence rate of headache (%) during 8 weeks of treatment with nifedipine GITS monotherapy (20, 30, 60 mg), candesartan cilexetil monotherapy (4, 8, 16, 32 mg), combination or placebo (n = 1381).
FIGURE 6
FIGURE 6
The incremental incidence of peripheral oedema (%) during 8 weeks of treatment with nifedipine GITS monotherapy (20, 30, 60 mg), candesartan cilexetil monotherapy (4, 8, 16, 32 mg), combination or placebo (n = 1381).

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