A COMPARATIVE STUDY OF EFFICACY AND TOLERABILITY OF ANTIANGINAL DRUGS OF DIFFERENT GROUPS — NITROVASODILATATOR (ISOSORBIDE-5-MONONITRATE SUSTAINED RELEASE) AND BETA-BLOCKER WITH VASODILATING ACTION (NEBIVOLOL) — IN PATIENTS WITH STABLE ANGINA

Aim. To compare the efficacy and safety of the slow-release isosorbide-5-mononitrate and of the nebivolol in patients with stable angina. Material and Methods. Patients (n=19) with ischemic heart disease (stable angina) were enrolled into randomized, double-blind, placebo-controlled, crossover study. They alternatively received nebivolol 5 mg QD or slow-release isosorbide-5-mononitrate 50 mg QD. The drug efficacy was assessed by changes in symptoms, angina attack number , sublingual nitroglycerin need, and treadmill test duration. Results. Patients treated with isosorbide-5-mononitrate shown significant increase in heart rate (HR) at rest in all time check-points in comparison with patients receiving placebo. HR significantly decreased 2 hours after nebivolol intake both single one and after 30 days of treatment (p<0.001). Duration of treadmill exercise significantly increased (vs placebo) 2 hours after a single intake of both isosorbide-5-mononitrate (454.3±37.1 vs 310.6±13.3 s; p <0.001) and nebivolol (428.6±33.3 vs 310.6±13.3 s; p<0.01). In one month of treatment isosorbide- 5-mononitrate and nebivolol reduced a number of angina episodes vs placebo (5.6±2.1 and 4.3±1.4, respectively , vs 8.6±2.4 episodes per month; p<0.05), the need for nitroglycerin (5.5±2.6 and 3.1±1.2, respectively , vs 6.7±2.2 sublingual tablets/month; p>0.05). No significant differences of these indicators were found between studied drugs. Conclusion. Nebivolol 5 mg daily is not inferior to slow-release isosorbide-5-mononitrate 50 mg daily in antianginal efficacy , significantly reduces HR, and much less causes headache and other side effects.

1. Treatment of stable angina. The recommendations of a special commission of the European Society of Cardiology. Russkiy meditsinskiy zhurnal 2006;14(20):1402-6. Russian (Лечение стабильной стенокардии. Рекомендации специальной комиссии Европейского общества кардиологов. Русский медицинский журнал 2006;14(20):1402-6).

2. Chazov EI. Problems in the treatment of patients with ischemic heart disease. Ter Arkh. 2000;72(9):5-

3. Russian (Чазов Е.И. Проблема лечения больных ишемической болезнью сердца. Терапевтический архив 2000;(9):5–9).

4. Metelitsa V.I. Handbook of clinical pharmacology of cardiovascular drugs. Moscow: MIA; 2005. Russian (Метелица В.И. Справочник по клинической фармакологии сердечно–сосудистых лекарственных средств. М.: МИА; 2005).

5. Davies R.F., Goldberg A.D., Forman S. et al. Asymptomatic Cardiac Ischemia Pilot (ACIP) study two-year follow-up: outcomes of patients randomized to initial strategies of medical therapy versus revascularization. Circulation. 1997; 95: 2037-2043.

6. Boden W.E., O’Rourke R.A., Teo K.K. et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356:1503—1516.

7. Velazquez E., Lee K., Deja M. et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011; 364: 1607-1616.

8. Fox K., Garcia M.A., Ardissino D. et al. Guidelines on the management of stable angina pectoris: executive summary: the Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J 2006;27:1341–1381.

9. Daly C.A., Clemens F., Sendon J.L. et al. The clinical characteristics and investigations planned in patients with stable angina presenting to cardiologists in Europe: from the Euro Heart Survey of Stable Angina. Eur Heart J 2005;26:996–1010.

10. Packer M., Bristow M.R., Cohn J.N. et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group . N Engl J Med 1996;334:1349– 1355.

11. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet 999;353:9–13.

12. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Inter-vention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–2007.

13. Elkayam U., Johnson J.V., Shotan A. et al. Intermittent large dose nitrates added to standard therapy, improves left ventricular function and exercise capacity in patients with chronic heart failure. J Am Coll Cardiol 1999;33:188A.

14. Sussex B.A., Campbell N.R., Raju M.K., McKay D.W. The antianginal efficacy of isosorbide dinitrate therapy is maintained during diuretic treatment. Clin Pharmacol Ther 1994;56:229–234.

15. Darius H. Role of nitrates for the therapy of coronary artery disease patients in the years be-yond 2000. J Cardiovasc Pharmacol 1999;34 Suppl 2:S15–20.

16. ACC/AHA/ACP-ACIM Guidelines for the management of patients with chronic stable angina. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. JACC 2003;41:159-168.

17. Van Nueten L., Walgraeve H. Pharmacodynamic effects of Nebivolol. JRF Clinical Research Report on R67555. January 1995.

18. Cheymol G., Woestenborghs R., Snoeck E. et al. Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects. Eur J Clin Pharmacol 1997;51:493-8.

19. Cherchi A. et al. Antianginal and antiischemic activity of nebivolol in stable angina of effort. Drug Invest 1991;3(Suppl 1):86-98.

20. Ruf G., Trenk D., Jahnchen E., Roskamm H. Determination of the antiischemic activity of nebivolol in comparison with atenolol. Int J Cardiol 1994;43:279-85.

21. Ulvenstam G. A single blind dose-ranging study of the effect of nebivolol in patients with angina pectoris. Drug Invest 1991;3( Suppl.1):199-200.

22. Makolkin V.I. Nebivolol - a new generation of beta-blockers. Kardiologiia 2000;(12):69-71. Russian (Маколкин В.И. Небиволол — представитель нового поколения b-адреноблокатров. Кардиология 2000;(12):69-71).

23. Munzel T., Gori T. Nebivolol. The somewhat-different β-adrenergic receptor blocker. JACC 2009;54:1491–9

24. Martsevich S.Iu., Semenova Iu.E., Alimova E.V. et al. Selection of therapy with nitrates in patients with stable effort angina: results of comparative study of common isosorbide dinitrate and long acting preparation of isosorbide-5-mononitrate. Kardiologiia. 2005;45(11):42-5. Russian (Марцевич С.Ю., Се-менова Ю.Э., Алимова Е.В. и др. Выбор терапии нитратами у больных со стенокардией напряжения: сравнительное исследование обычных таблеток изосорбид диниграта и препарата изосорбида-5-мононитрата пролонгированного действия. Кардиология 2005;45(11): 42-45).

25. Gavrilov Y.V., Sulimov V.A., Makolkin V.I. Nebivolol in treatment of stable exertional angina pectoris. Rational Pharmacother Card 2007; 2:11-15. Russian (Гаврилов Ю.В., Сулимов В.А., Маколкин В.И. Небиволол в лечении стабильной стенокардии напряжения. РФК 2007; 2:11-15).

26. Fox K., Ford I., Steg P.G. et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372(9641):817-821.