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Antianginal Efficacy and Safety of Ivabradine Compared with Amlodipine in Patients with Stable Effort Angina Pectoris

A 3-Month Randomised, Double-Blind, Multicentre, Noninferiority Trial

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Abstract

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.

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References

  1. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J Gen Physiol 2002; 120: 1–13

    Article  PubMed  CAS  Google Scholar 

  2. Simon L, Ghaleh B, Puybasset L, et al. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther 1995; 275: 659–66

    PubMed  CAS  Google Scholar 

  3. Ragueneau I, Laveille C, Jochemsen R, et al. Pharmacokinetic pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin Pharmacol Ther 1998, 64: 192–203

    Article  PubMed  CAS  Google Scholar 

  4. Vilaine JP, Bidouard JP, Lesage L, et al. Anti-ischemic effects of ivabradine, a selective heart rate-reducing agent, in exercise-induced myocardial ischemia in pigs. J Cardiovasc Pharmacol 2003; 42: 688–96

    Article  PubMed  CAS  Google Scholar 

  5. Borer JS, Fox K, Jaillon P, et al., for the Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentred, placebo-controlled trial. Circulation 2003; 107: 817–23

    Article  PubMed  Google Scholar 

  6. Tardif JC, Ford I, Tendera M, et al. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005 Dec; 26 (23): 2529–36

    Article  PubMed  CAS  Google Scholar 

  7. ACC/AHA 2002. Guideline update for the management of patients with chronic stable angina [online]. Available from URL: http://www.acc.org/clinical/guidelines/stable [Accessed 2003 Aug 22]

  8. Committee for Proprietary Medicinal Products (CPMP). Note for guidance on the clinical investigation of anti-anginal medicinal products in stable angina pectoris. London: European Agency for the Evaluation of Medicinal Products, 1996. CPMP/EWP/234/95

    Google Scholar 

  9. Morganroth J. Proarrhythmic effects of antiarrhythmic drugs: evolving concepts. Am Heart J 1992; 123: 1137–9

    Article  PubMed  CAS  Google Scholar 

  10. Pepine CJ, Abrams J, Marks RG, et al. Characteristics of a contemporary population with angina pectoris. TIDES investigators. Am J Cardiol 1994; 74: 226–31

    Article  PubMed  CAS  Google Scholar 

  11. Bois P, Bescond J, Renaudon B, et al. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol 1996; 118: 1051–7

    Article  PubMed  CAS  Google Scholar 

  12. Kannel WB, Kannel C, Paffenbarger RS, et al. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987; 113: 1489–94

    Article  PubMed  CAS  Google Scholar 

  13. Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005; 26: 967–74

    Article  PubMed  Google Scholar 

  14. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J 1999; 1 Suppl.: H64–9

    Google Scholar 

  15. Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Guidelines on the management of stable angina pectoris. Eur Heart J 2006; 27: 1341–81

    Article  Google Scholar 

  16. Thackray S, Ghosh J, Wright G, et al. The effect of altering heart rate on ventricular function in patients with heart failure trated with β-blockers. Am Heart J 2006; 152 (4): 713.e9-13

    Article  PubMed  CAS  Google Scholar 

  17. Cucherat M. Relationship between heart rate lowering and benefits on cardiac and sudden death observed with beta-blockers in post MI patients: a meta-regression of randomized clinical trials. Eur Heart J 2006; 27 (Abstract Suppl.): 590

    Google Scholar 

  18. Asirvatham S, Sebastian C, Thadani U. Choosing the most appropriate treatment for stable angina: safety considerations. Drug Saf 1998; 19: 23–44

    Article  PubMed  CAS  Google Scholar 

  19. Fox KM, Jespersen CM, Ferrari R, et al. How European cardiologists perceive the role of calcium antagonists in the treatment of stable angina. Eur Heart J 1997; 18 Suppl. A: A113–6

    Article  PubMed  Google Scholar 

  20. Ezekowitz MD, Hossack K, Mehta JL, et al. Amlodipine in chronic stable angina: results of a multicenter double-blind crossover trial. Am Heart J 1995; 129: 527–35

    Article  PubMed  CAS  Google Scholar 

  21. Pehrsson SK, Ringqvist I, Ekdahl S, et al. Monotherapy with amlodipine or atenolol versus their combination in stable angina pectoris. Clin Cardiol 2000; 23: 763–70

    Article  PubMed  CAS  Google Scholar 

  22. Hjalmarson A, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol 1990; 65: 547–53

    Article  PubMed  CAS  Google Scholar 

  23. Hjalmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol 1998; 21 (12 Suppl.): II3–7

    PubMed  CAS  Google Scholar 

  24. Guth BD, Heusch G, Seitelberger R, et al. Mechanism of beneficial effect of β-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ Res 1987; 60: 738–46

    Article  PubMed  CAS  Google Scholar 

  25. Demontis GC, Moroni A, Gravante B, et al. Functional characterisation and subcellular localisation of HCN1 channels in rabbit retinal rod photoreceptors. J Physiol 2002; 542 (Pt 1): 89–97

    Article  PubMed  CAS  Google Scholar 

  26. Demontis GC, Gargini C, Paoli GT, et al. Ivabradine inhibits the hyperpolarization-activated inward current (Ih) in mouse rod photoreceptors. Documenta Ophthalmol 2006; 112: 102–3

    Google Scholar 

  27. Gargini C, Demontis GC, Delia Santina L, et al. Effects of acute and chronic ivabradine administration on retinal function and morphology in pigmented rats. Documenta Ophthalmol 2006; 112 (133): S2–16

    Google Scholar 

  28. Fox K, Ferrari R, Tendera M, et al. Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) Study. Am Heart J 2006; 152: 860–6

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

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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Ruzyllo, W., Tendera, M., Ford, I. et al. Antianginal Efficacy and Safety of Ivabradine Compared with Amlodipine in Patients with Stable Effort Angina Pectoris. Drugs 67, 393–405 (2007). https://doi.org/10.2165/00003495-200767030-00005

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  • DOI: https://doi.org/10.2165/00003495-200767030-00005

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