Antianginal Efficacy and Safety of Ivabradine Compared with Amlodipine in Patients with Stable Effort Angina Pectoris
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Background and objective: Current medical therapies for the symptoms of angina pectoris aim to improve oxygen supply and reduce oxygen demand in the myocardium. Not all patients respond to current antianginal monotherapy, or even combination therapy, and a new class of antianginal drug that complements existing therapies would be useful. This study was undertaken to compare the antianginal and anti-ischaemic effects of the novel heart-rate-lowering agent ivabradine and of the calcium channel antagonist amlodipine.
Patients and methods: Patients with a ≥3-month history of chronic, stable effortinduced angina were randomised to receive ivabradine 7.5mg (n = 400) or 10mg (n = 391) twice daily or amlodipine 10mg once daily (n = 404) for a 3-month, double-blind period. Bicycle exercise tolerance tests were performed at baseline and monthly intervals. The primary efficacy criterion was the change from baseline in total exercise duration after 3 months of treatment. Secondary efficacy criteria included changes in time to angina onset and time to lmm ST-segment depression, rate-pressure product at trough drug activity, as well as short-acting nitrate use and anginal attack frequency (as recorded in patient diaries).
Results: At 3 months, total exercise duration was improved by 27.6 ± 91.7, 21.7 ± 94.5 and 31.2 ± 92.0 seconds with ivabradine 7.5 and 10mg and amlodipine, respectively, both ivabradine groups were comparable to amlodipine (p-value for noninferiority < 0.001). Similar results were observed for time to angina onset and time to lmm ST-segment depression. Heart rate decreased significantly by 11–13 beats/min at rest and by 12–15 beats/min at peak of exercise with ivabradine but not amlodipine, and rate-pressure product decreased more with ivabradine than amlodipine (p-value vs amlodipine <0.001, at rest and at peak of exercise). Anginal attack frequency and short-acting nitrate use decreased substantially in all treatment groups with no significant difference between treatment groups. The most frequent adverse events were visual symptoms and sinus bradycardia with ivabradine (0.8% and 0.4% withdrawals, respectively) and peripheral oedema with amlodipine (1.5% withdrawals).
Conclusions: In patients with stable angina, ivabradine has comparable efficacy to amlodipine in improving exercise tolerance, a superior effect on the reduction of rate-pressure product (a surrogate marker of myocardial oxygen consumption) and similar safety.
KeywordsAmlodipine Stable Angina Ivabradine Calcium Channel Antagonist Daily Group
This study was supported by Servier, France. Each of the authors has received an honorarium for committee membership in association with this study.
List of investigators:
Czech Republic: Dr J. Widimsky, Dr O. Jerabek, Dr J. Florian, Dr J. Ulman, Dr M. Rubacek, Dr Z. Lorenc, Dr O. Mayer, Dr I. Oral, Dr J. Nagel, Dr L. Berka, Dr H. Krejcova, Dr K. Kamenik, Dr T. Brabec, Dr J. Kost’ak
Denmark: Prof. J. Aldershvile, Dr P. Grande, Dr K. Egstrup, Dr H. Nielsen, Dr K.E. Pedersen, Dr T. Nielsen, Dr P. Hildebrandt, Dr L. Kober, Dr H. Ulriksen, Dr D.J. Markenvard, Dr K. Skagen, Dr H. Rickers
Finland: Dr J. Hartikainen, Dr K. Peuhkurinnen, Dr P.-E. Wingren, Dr J. Juvonan, Dr A. Karkkainen, Dr M. Huttunen, Dr H. Sodervik, Dr J. Melin, Dr A. Kokko, Dr T. Hamalainen, Dr P. Kettunen, Dr S. Pohjola-Sintonen, Dr J. Karmakoski, Dr M. Niemela
Hungary: Dr S. Timar, Dr F. Lakatos, Dr A. Papp, Dr C. Toth, Dr E. Kalo, Prof. J. Tenczer, Dr G. Veress, Prof. I. Preda, Prof. E. Kekes, Dr B. Barsi, Prof. I. Edes, Prof. C. Balazs, Dr J. Tomcsanyi, Dr A. Matoltsy, Dr A. Cziraki, Dr J. Tarjan, Dr D. Apro
Norway: Dr K. Gjesdal, Dr T. Indrebo, Dr D. Torvik, Dr A. Nesvold, Dr A. Andersen, Dr S. Njalla, Dr E. Hauge, Dr T. Holm, Dr K. Loland-Jacobsen, Dr O. Vikesdal, Dr J. Kjekshus, Dr H. Istad, Dr F. Kontny, Dr F. Wandel
Poland: Prof. Adamus, Prof. M. Krzeminska-Pakula, Prof. W. Ruzyllo, Dr Trojnar, Dr Chmielinski, Dr Kozlowski, Dr Sinkiewicz, Dr Achremczyk, Dr K. Janik, Dr T. Marczyk, Dr W. Piotrowski, Prof. K. Kawecka-Jaszcz, Prof. J. Dubiel, Dr S. Malinowski, Prof. A. Pluta, Prof. Cieslinski, Dr W. Pluta, Dr K. Jaworska, Dr M. Piepiorka, Prof. W. Banasiak, Dr Kleinrok, Dr Kurowski, Dr Malinski, Prof. M. Dluzniewski
Russia: Prof. V. Tsyrline, Prof. E. Kuleshova, Prof. Konstantinov, Prof. E. Shliakhto, Dr E. Nifontov, Dr B. Goloschekin, Dr S. Minkin, Prof. E. Zemtsovsky, Dr E. Varga, Dr M. Balyuzek, Dr A. Kuchinsky, Dr G. Katashkova, Dr E. Zhukova, Dr A. Ronzhin, Dr V. Kostenko, Prof. S. Churina, Prof. Y. Lukjanov, Prof. A. Obrezan, Dr D.A. Zverev, Dr A.V. Strekalovsky, Dr S. Dobrodeev, Prof. O.L. Barbarash, Dr P. Yakhontova, Dr A.A. Kolomiets, Dr V.I. Fialkovsky, Dr E. Pavlyukova, Dr G.A. Choumakova
Slovak Republic: Dr S. Filipova, Dr J. Sirotiakova, Dr G. Kamensky, Dr J. Mazur, Dr A. Banikova, Dr T. Duris
Sweden: Dr B. Karlson, Dr J. Herlitz, Dr B. Persson, Dr M. Dellborg, Dr G. Ulvenstam, Dr P. Hardhammer, Dr T. Johansson, Dr L. Kareld, Dr P. Pettersson, Dr A. Sjostrand, Dr T. Carlsson, Dr L. Erhardt, Dr P. Lofdahl, Dr J. Perk, Dr G. Stehn, Dr A. Tisell, Dr A. Torp, Dr U. Ahremark, Dr B. Petersson, Dr C. Hoglund, Dr J.E. Frisell, Dr H. Nilsson, Dr T. Fraser, Dr J. Ellstrom, Dr L. Juntti, Dr A. Andersson, Dr M. Henning, Dr V. Engblom
The Netherlands: Dr G.C.M. Linssen, Dr R. Dijkgraaf, Dr Kuijer, Dr A. Withagen, Dr P. Van Rossum, Dr R.F. Veldkamp.
Expert Committee: Prof. K. Fox, Royal Brompton Hospital (London, UK), Prof. M. Tendera, Silesian School of Medicine (Katowice, Poland), Prof. I. Ford, Robertson Centre for Biostatistics (Glasgow, UK).
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