Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial

Jean-Claude Tardif, Piotr Ponikowski, Thomas Kahan, ASSOCIATE Study Investigators, J-C Tardif, J E Tronje, R A Ahuad Guerrero, M Machado Cesar, N N Gotcheva, M Vejar, V Chaloupka, W Delius, I Edes, F Crea, P-K Ronnevik, M Banasiak, A Swed, C Macarie, Y Karpov, D Pella, P J Commerford, T Kahan, J J Alonso Martin, A Parshomenko, A Timmis, R A Ahuad Guerrero, F J Sokn, O A Allall, L R Cartasegna, L L del V Lobo Marquez, A Hirschson Prado, A D Hrabar, J O Ibañez, J J Fuselli, H L Luciardi, S M Macin, M Rusculleda, A C Piombo, M S Sanjurjo, F L Gadaleta, J C Pomposiello, R M Colgue, M Hominal, E Kuschnir, H A Luquez, R Ronderos, A C Amico, L A Machado Cesar, M Maranhao, O R Coelho, E Manenti, A H Herdy, J F Kerr Saraiva, D B Precoma, J P Ribeiro, I Castro, J R C de B Silveira, V Baycheva, S Denchev, D Raev, A Tschirkov, A Dzhurdzhev, A Penev, M Tzekova, P Ma, G Bailey, R Saint-Hilaire, D Desai, M F J O'Mahony, M Vejar, F Lanas, R Lamich, J Abadal, L Lucio, M Rubacek, O Jerabek, E Zidkova, K Gorican, J Danczik, A Al Zoebi, A Förster, W Rein, A Nagy, A Katona, J Takacs, F Magel, J Lippai, B Nyuzo, A Kovacs, G Polak, J Nagy, T Sydo, A Papp, K Toth, M Sereg, S Timar, J Tenczer, F Lakatos, A Gaspardone, C Vitale, P Ronnevik, H Istad, P A Sirnes, W Banasiak, A Budaj, M Dluzniewski, H Szwed, K Kawecka-Jaszcz, W Piwowarska, P Achremczyk, J Kwiecien, M Szpajer, J Kopaczewski, K Szymczak, A Kowalisko, W Pluta, R Trojnar, A Drzewiecki, C Macarie, M M Vintila, A G Dan, R Capalneanu, D D Ionescu, I Manitiu, M Popescu, G Aaron, Y A Karpov, D Aronov, S A Boytsov, N A Gratsiansky, A Y Konyakhin, A K Starodubtsev, S N Tereschenko, O P Shevchenko, Y N Grishkin, A S Svistov, N Khasanov, V Naumov, E A Zharova, S Martsevitch, E Kokourina, M G Glezer, A Y Ivleva, Y Lukjanov, S Tchurina, L Ermoshkina, T Treshkur, G Usova, E Volkova, I Shaposhnik, A Timofeev, G A Chumakova, A Masin, O L Barbarash, P Yakhontova, A Kolomiets, D Pella, A Dzupina, S Filipova, P Loviska, J Mazur, J Bayat, M M de V Basson, M Mpe, D P Naidoo, J J Alonso Martin, V Manuel, I Plaza, R Krittayaphong, A Parkhomenko, A Bazilevich, B Goloborodko, I Krayz, V Lyzogub, V Tseluyko, M Vlasenko, V Volkov, A Pell, Jean-Claude Tardif, Piotr Ponikowski, Thomas Kahan, ASSOCIATE Study Investigators, J-C Tardif, J E Tronje, R A Ahuad Guerrero, M Machado Cesar, N N Gotcheva, M Vejar, V Chaloupka, W Delius, I Edes, F Crea, P-K Ronnevik, M Banasiak, A Swed, C Macarie, Y Karpov, D Pella, P J Commerford, T Kahan, J J Alonso Martin, A Parshomenko, A Timmis, R A Ahuad Guerrero, F J Sokn, O A Allall, L R Cartasegna, L L del V Lobo Marquez, A Hirschson Prado, A D Hrabar, J O Ibañez, J J Fuselli, H L Luciardi, S M Macin, M Rusculleda, A C Piombo, M S Sanjurjo, F L Gadaleta, J C Pomposiello, R M Colgue, M Hominal, E Kuschnir, H A Luquez, R Ronderos, A C Amico, L A Machado Cesar, M Maranhao, O R Coelho, E Manenti, A H Herdy, J F Kerr Saraiva, D B Precoma, J P Ribeiro, I Castro, J R C de B Silveira, V Baycheva, S Denchev, D Raev, A Tschirkov, A Dzhurdzhev, A Penev, M Tzekova, P Ma, G Bailey, R Saint-Hilaire, D Desai, M F J O'Mahony, M Vejar, F Lanas, R Lamich, J Abadal, L Lucio, M Rubacek, O Jerabek, E Zidkova, K Gorican, J Danczik, A Al Zoebi, A Förster, W Rein, A Nagy, A Katona, J Takacs, F Magel, J Lippai, B Nyuzo, A Kovacs, G Polak, J Nagy, T Sydo, A Papp, K Toth, M Sereg, S Timar, J Tenczer, F Lakatos, A Gaspardone, C Vitale, P Ronnevik, H Istad, P A Sirnes, W Banasiak, A Budaj, M Dluzniewski, H Szwed, K Kawecka-Jaszcz, W Piwowarska, P Achremczyk, J Kwiecien, M Szpajer, J Kopaczewski, K Szymczak, A Kowalisko, W Pluta, R Trojnar, A Drzewiecki, C Macarie, M M Vintila, A G Dan, R Capalneanu, D D Ionescu, I Manitiu, M Popescu, G Aaron, Y A Karpov, D Aronov, S A Boytsov, N A Gratsiansky, A Y Konyakhin, A K Starodubtsev, S N Tereschenko, O P Shevchenko, Y N Grishkin, A S Svistov, N Khasanov, V Naumov, E A Zharova, S Martsevitch, E Kokourina, M G Glezer, A Y Ivleva, Y Lukjanov, S Tchurina, L Ermoshkina, T Treshkur, G Usova, E Volkova, I Shaposhnik, A Timofeev, G A Chumakova, A Masin, O L Barbarash, P Yakhontova, A Kolomiets, D Pella, A Dzupina, S Filipova, P Loviska, J Mazur, J Bayat, M M de V Basson, M Mpe, D P Naidoo, J J Alonso Martin, V Manuel, I Plaza, R Krittayaphong, A Parkhomenko, A Bazilevich, B Goloborodko, I Krayz, V Lyzogub, V Tseluyko, M Vlasenko, V Volkov, A Pell

Abstract

Aims: To evaluate the anti-anginal and anti-ischaemic efficacy of the selective I(f) current inhibitor ivabradine in patients with chronic stable angina pectoris receiving beta-blocker therapy.

Methods and results: In this double-blinded trial, 889 patients with stable angina receiving atenolol 50 mg/day were randomized to receive ivabradine 5 mg b.i.d. for 2 months, increased to 7.5 mg b.i.d. for a further 2 months, or placebo. Patients underwent treadmill exercise tests at the trough of drug activity using the standard Bruce protocol for randomization and at 2 and 4 months. Total exercise duration at 4 months increased by 24.3 +/- 65.3 s in the ivabradine group, compared with 7.7 +/- 63.8 s with placebo (P < 0.001). Ivabradine was superior to placebo for all exercise test criteria at 4 months (P < 0.001 for all) and 2 months (P-values between <0.001 and 0.018). Ivabradine in combination with atenolol was well tolerated. Only 1.1% of patients withdrew owing to sinus bradycardia in the ivabradine group.

Conclusion: The combination of ivabradine 7.5 mg b.i.d. and atenolol at the commonly used dosage in clinical practice in patients with chronic stable angina pectoris produced additional efficacy with no untoward effect on safety or tolerability.

Figures

Figure 1
Figure 1
Summary of study design.
Figure 2
Figure 2
Disposition of patients throughout the study. AE, adverse event; ETT, exercise tolerance test.
Figure 3
Figure 3
Changes in exercise tolerance test criteria between baseline and M2 visit and between baseline and end of study (M4) in the full analysis set.

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Source: PubMed

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