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. 2002 Nov;10(11):455–461.

Combination and triple therapy in patients with stable angina pectoris not adequately controlled by optimal β-blocker therapy

WEM Kok, FC Visser, CA Visser
PMCID: PMC2499810  PMID: 25696045

Abstract

In 60 to 80% of patients with stable angina pectoris at low risk for future coronary events, monotherapy with a β-blocker is an effective treatment. When patients with stable angina pectoris and low risk for events do not respond adequately to optimal β-blocker monotherapy, combination therapy or even triple therapy is may be recommended, but little is known of the actual benefit of such a strategy. We reviewed the evidence from the literature on the effectiveness of combination and triple therapy. Combination therapy with a calcium antagonist or nitrate was found to be more effective than β-blocker monotherapy in the majority of studies, but only an estimated 30% of patients objectively benefit from these combination therapies. Direct comparison shows that combination therapy of a β-blocker with a calcium antagonist is more effective than the combination of a β-blocker with a nitrate. An inadequate response to β-blocker monotherapy is more effectively improved by addition of a calcium antagonist than by alternative use of a calcium antagonist. The use of triple therapy is controversial and not recommended in patients with mild angina pectoris, while for patients with severe angina pectoris not responding to combination therapy of a β-blocker with a nitrate, triple therapy may be of advantage, although the number of patients studied has been small.

Keywords: angina pectoris, β-blocker, calcium antagonist, nitrate, medical therapy

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akhras F., Jackson G. Efficacy of nifedipine and isosorbide mononitrate in combination with atenolol in stable angina. Lancet. 1991 Oct 26;338(8774):1036–1039. doi: 10.1016/0140-6736(91)91900-f. [DOI] [PubMed] [Google Scholar]
  2. Benditt D. G., Mianulli M., Fetter J., Milstein S., Buetikofer J., Molina E., Wibel F., Markowitz T. An office-based exercise protocol for predicting chronotropic response of activity-triggered, rate-variable pacemakers. Am J Cardiol. 1989 Jul 1;64(1):27–32. doi: 10.1016/0002-9149(89)90647-4. [DOI] [PubMed] [Google Scholar]
  3. Blasini R., Brügmann U., Reiniger G., Rudolph W. Langzeittherapie der Belastungs-Angina-pectoris durch einmal tägliche Verabreichung von 120 mg Isosorbiddinitrat in retardierter Form. Vergleich von Monotherapie und Kombinationstherapie mit Atenolol und Nifedipin. Herz. 1985 Jun;10(3):163–171. [PubMed] [Google Scholar]
  4. Boden W. E., Bough E. W., Reichman M. J., Rich V. B., Young P. M., Korr K. S., Shulman R. S. Beneficial effects of high-dose diltiazem in patients with persistent effort angina on beta-blockers and nitrates: a randomized, double-blind, placebo-controlled cross-over study. Circulation. 1985 Jun;71(6):1197–1205. doi: 10.1161/01.cir.71.6.1197. [DOI] [PubMed] [Google Scholar]
  5. Crake T., Quyyumi A. A., Wright C., Mockus L., Fox K. M. Treatment of angina pectoris with nifedipine: a double blind comparison of nifedipine and slow-release nifedipine alone and in combination with atenolol. Br Heart J. 1987 Dec;58(6):617–620. doi: 10.1136/hrt.58.6.617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dargie H. J., Ford I., Fox K. M. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET Study Group. Eur Heart J. 1996 Jan;17(1):104–112. doi: 10.1093/oxfordjournals.eurheartj.a014668. [DOI] [PubMed] [Google Scholar]
  7. Dargie H. J., Lynch P. G., Krikler D. M., Harris L., Krikler S. Nifedipine and propranolol: a beneficial drug interaction. Am J Med. 1981 Oct;71(4):676–682. doi: 10.1016/0002-9343(81)90238-2. [DOI] [PubMed] [Google Scholar]
  8. Donaldson K. M., Dawkins K. D., Waller D. G. A comparison of nisoldipine and nifedipine, in combination with atenolol, in the management of myocardial ischaemia. Eur Heart J. 1993 Apr;14(4):534–539. doi: 10.1093/eurheartj/14.4.534. [DOI] [PubMed] [Google Scholar]
  9. Dunselman P. H., van Kempen L. H., Bouwens L. H., Holwerda K. J., Herweijer A. H., Bernink P. J. Value of the addition of amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade. Am J Cardiol. 1998 Jan 15;81(2):128–132. doi: 10.1016/s0002-9149(97)00877-1. [DOI] [PubMed] [Google Scholar]
  10. Dunselman P., Liem A. H., Verdel G., Kragten H., Bosma A., Bernink P. Addition of felodipine to metoprolol vs replacement of metoprolol by felodipine in patients with angina pectoris despite adequate beta-blockade. Results of the Felodipine ER and Metoprolol CR in Angina (FEMINA) Study. Working Group on Cardiovascular Research, The Netherlands (WCN). Eur Heart J. 1997 Nov;18(11):1755–1764. doi: 10.1093/oxfordjournals.eurheartj.a015170. [DOI] [PubMed] [Google Scholar]
  11. Ekelund L. G., Ulvenstam G., Walldius G., Aberg A. Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris. Am J Cardiol. 1994 Apr 1;73(9):658–660. doi: 10.1016/0002-9149(94)90929-6. [DOI] [PubMed] [Google Scholar]
  12. Emanuelsson H., Ahlström P., Kujacic V., Lundkvist L., Rosenqvist U., Tisell A., Angman K. Felodipine versus placebo in stable effort-induced angina pectoris in patients inadequately controlled with metoprolol--a dose-finding study. J Cardiovasc Pharmacol. 1994 Aug;24(2):303–309. [PubMed] [Google Scholar]
  13. Foale R. A. Atenolol versus the fixed combination of atenolol and nifedipine in stable angina pectoris. Eur Heart J. 1993 Oct;14(10):1369–1374. doi: 10.1093/eurheartj/14.10.1369. [DOI] [PubMed] [Google Scholar]
  14. Folland E. D., Hartigan P. M., Parisi A. F. Percutaneous transluminal coronary angioplasty versus medical therapy for stable angina pectoris: outcomes for patients with double-vessel versus single-vessel coronary artery disease in a Veterans Affairs Cooperative randomized trial. Veterans Affairs ACME InvestigatorS. J Am Coll Cardiol. 1997 Jun;29(7):1505–1511. doi: 10.1016/s0735-1097(97)00097-1. [DOI] [PubMed] [Google Scholar]
  15. Fox K. M., Mulcahy D., Findlay I., Ford I., Dargie H. J. The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group. Eur Heart J. 1996 Jan;17(1):96–103. doi: 10.1093/oxfordjournals.eurheartj.a014699. [DOI] [PubMed] [Google Scholar]
  16. Gould A. L., Rossouw J. E., Santanello N. C., Heyse J. F., Furberg C. D. Cholesterol reduction yields clinical benefit: impact of statin trials. Circulation. 1998 Mar 17;97(10):946–952. doi: 10.1161/01.cir.97.10.946. [DOI] [PubMed] [Google Scholar]
  17. Heidenreich P. A., McDonald K. M., Hastie T., Fadel B., Hagan V., Lee B. K., Hlatky M. A. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999 May 26;281(20):1927–1936. doi: 10.1001/jama.281.20.1927. [DOI] [PubMed] [Google Scholar]
  18. Henderson R. A., Pocock S. J., Sharp S. J., Nanchahal K., Sculpher M. J., Buxton M. J., Hampton J. R. Long-term results of RITA-1 trial: clinical and cost comparisons of coronary angioplasty and coronary-artery bypass grafting. Randomised Intervention Treatment of Angina. Lancet. 1998 Oct 31;352(9138):1419–1425. doi: 10.1016/s0140-6736(98)03358-3. [DOI] [PubMed] [Google Scholar]
  19. Humen D. P., Kostuk W. J. Clinical response and effects on left ventricular function of isosorbide dinitrate added to propranolol or diltiazem monotherapy in patients with chronic stable angina. Can J Cardiol. 1991 Mar;7(2):74–80. [PubMed] [Google Scholar]
  20. Humen D. P., O'Brien P., Purves P., Johnson D., Kostuk W. J. Effort angina with adequate beta-receptor blockade: comparison with diltiazem alone and in combination. J Am Coll Cardiol. 1986 Feb;7(2):329–335. doi: 10.1016/s0735-1097(86)80500-9. [DOI] [PubMed] [Google Scholar]
  21. Hung J., Lamb I. H., Connolly S. J., Jutzy K. R., Goris M. L., Schroeder J. S. The effect of diltiazem and propranolol, alone and in combination, on exercise performance and left ventricular function in patients with stable effort angina: a double-blind, randomized, and placebo-controlled study. Circulation. 1983 Sep;68(3):560–567. doi: 10.1161/01.cir.68.3.560. [DOI] [PubMed] [Google Scholar]
  22. Jackson G. Combination therapy in angina: a review of combined haemodynamic treatment and the role for combined haemodynamic and cardiac metabolic agents. Int J Clin Pract. 2001 May;55(4):256–261. [PubMed] [Google Scholar]
  23. Jenkins R. M., Nagle R. E. The symptomatic and objective effects of nifedipine in combination with beta-blocker therapy in severe angina pectoris. Postgrad Med J. 1982 Nov;58(685):697–700. doi: 10.1136/pgmj.58.685.697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jensen G., Trautner F., Rasmussen S., Hesse B. Haemodynamic and clinical effects of isosorbide-dinitrate in patients with severe effort angina on beta-blocking treatment. Eur J Clin Pharmacol. 1983;24(2):169–172. doi: 10.1007/BF00613812. [DOI] [PubMed] [Google Scholar]
  25. Johnston D. L., Lesoway R., Humen D. P., Kostuk W. J. Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine and diltiazem in exertional angina pectoris: a placebo-controlled, double-blind, randomized, crossover study. Am J Cardiol. 1985 Mar 1;55(6):680–687. doi: 10.1016/0002-9149(85)90136-5. [DOI] [PubMed] [Google Scholar]
  26. Julian D. G. Comparisons and combinations in anti-anginal therapy. Eur Heart J. 1985 Jan;6 (Suppl A):37–52. doi: 10.1093/eurheartj/6.suppl_a.37. [DOI] [PubMed] [Google Scholar]
  27. Knight C. J., Fox K. M. Amlodipine versus diltiazem as additional antianginal treatment to atenolol. Centralised European Studies in Angina Research (CESAR) Investigators. Am J Cardiol. 1998 Jan 15;81(2):133–136. doi: 10.1016/s0002-9149(97)00893-x. [DOI] [PubMed] [Google Scholar]
  28. Mark D. B., Shaw L., Harrell F. E., Jr, Hlatky M. A., Lee K. L., Bengtson J. R., McCants C. B., Califf R. M., Pryor D. B. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med. 1991 Sep 19;325(12):849–853. doi: 10.1056/NEJM199109193251204. [DOI] [PubMed] [Google Scholar]
  29. Meluzín J., Stejfa M., Novák M., Zeman K., Spinarová L., Julínek J., Toman J., Simek P. Amlodipine in patients with stable angina pectoris treated with nitrates and beta-blockers. The influence on exercise tolerance, systolic and diastolic functions of the left ventricle. Int J Cardiol. 1992 Oct;37(1):101–109. doi: 10.1016/0167-5273(92)90137-r. [DOI] [PubMed] [Google Scholar]
  30. Meluzín J., Zeman K., Stetka F., Simek P. Effects of nifedipine and diltiazem on myocardial ischemia in patients with severe stable angina pectoris treated with nitrates and beta-blockers. J Cardiovasc Pharmacol. 1992 Dec;20(6):864–869. doi: 10.1097/00005344-199212000-00003. [DOI] [PubMed] [Google Scholar]
  31. Morse J. R. Comparison of combination nifedipine-propranolol and diltiazem-propranolol with high dose diltiazem monotherapy for stable angina pectoris. Am J Cardiol. 1988 Nov 15;62(16):1028–1032. doi: 10.1016/0002-9149(88)90542-5. [DOI] [PubMed] [Google Scholar]
  32. Morse J. R., Nesto R. W. Double-blind crossover comparison of the antianginal effects of nifedipine and isosorbide dinitrate in patients with exertional angina receiving propranolol. J Am Coll Cardiol. 1985 Dec;6(6):1395–1401. doi: 10.1016/s0735-1097(85)80231-x. [DOI] [PubMed] [Google Scholar]
  33. Nademanee K., Christenson P. D., Intarachot V., Robertson H. A., Mody F. V. Variability of indexes for myocardial ischemia: a comparison of exercise treadmill test, ambulatory electrocardiographic monitoring and symptoms of myocardial ischemia. J Am Coll Cardiol. 1989 Mar 1;13(3):574–579. doi: 10.1016/0735-1097(89)90595-0. [DOI] [PubMed] [Google Scholar]
  34. O'Hara M. J., Khurmi N. S., Bowles M. J., Raftery E. B. Diltiazem and propranolol combination for the treatment of chronic stable angina pectoris. Clin Cardiol. 1987 Feb;10(2):115–123. doi: 10.1002/clc.4960100207. [DOI] [PubMed] [Google Scholar]
  35. O'Keefe J. C., Creamer J. E., Banim S. O. Efficacy of nisoldipine combined with beta-adrenergic-blocking drugs in the treatment of chronic stable angina. Clin Cardiol. 1987 Jun;10(6):345–350. doi: 10.1002/clc.4960100609. [DOI] [PubMed] [Google Scholar]
  36. Packer M. Drug therapy. Combined beta-adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med. 1989 Mar 16;320(11):709–718. doi: 10.1056/NEJM198903163201107. [DOI] [PubMed] [Google Scholar]
  37. Parker J. D., Parker J. O. Nitrate therapy for stable angina pectoris. N Engl J Med. 1998 Feb 19;338(8):520–531. doi: 10.1056/NEJM199802193380807. [DOI] [PubMed] [Google Scholar]
  38. Quyyumi A. A., Crake T., Wright C. M., Mockus L. J., Fox K. M. Medical treatment of patients with severe exertional and rest angina: double blind comparison of beta blocker, calcium antagonist, and nitrate. Br Heart J. 1987 Jun;57(6):505–511. doi: 10.1136/hrt.57.6.505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Ridker P. M., Manson J. E., Gaziano J. M., Buring J. E., Hennekens C. H. Low-dose aspirin therapy for chronic stable angina. A randomized, placebo-controlled clinical trial. Ann Intern Med. 1991 May 15;114(10):835–839. doi: 10.7326/0003-4819-114-10-835. [DOI] [PubMed] [Google Scholar]
  40. Rossinen J., Partanen J., Nieminen M. S. Amlodipine in patients with stable angina pectoris treated with beta-blockers. Double-blind comparison with placebo. Scand Cardiovasc J. 1998;32(1):41–48. doi: 10.1080/14017439850140337. [DOI] [PubMed] [Google Scholar]
  41. Rønnevik P. K., Silke B., Ostergaard O. Felodipine in addition to beta-adrenergic blockade for angina pectoris. a multicentre, randomized, placebo-controlled trial. Eur Heart J. 1995 Nov;16(11):1535–1541. doi: 10.1093/oxfordjournals.eurheartj.a060774. [DOI] [PubMed] [Google Scholar]
  42. Savonitto S., Ardissiono D., Egstrup K., Rasmussen K., Bae E. A., Omland T., Schjelderup-Mathiesen P. M., Marraccini P., Wahlqvist I., Merlini P. A. Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) Study. J Am Coll Cardiol. 1996 Feb;27(2):311–316. doi: 10.1016/0735-1097(95)00489-0. [DOI] [PubMed] [Google Scholar]
  43. Silber S., Vogler A., Theisen K. Equal anti-ischemic properties of isosorbide dinitrate plus verapamil and isosorbide dinitrate plus propranolol. A randomized, double-blind and crossover study. Z Kardiol. 1986;75 (Suppl 3):100–105. [PubMed] [Google Scholar]
  44. Siu S. C., Jacoby R. M., Phillips R. T., Nesto R. W. Comparative efficacy of nifedipine gastrointestinal therapeutic system versus diltiazem when added to beta blockers in stable angina pectoris. Am J Cardiol. 1993 Apr 15;71(11):887–892. doi: 10.1016/0002-9149(93)90901-n. [DOI] [PubMed] [Google Scholar]
  45. Stone P. H., Ware J. H., DeWood M. A., Gore J. M., Eich R. H., Pietro D. A., Parisi A. F., Nesto R. W., Boden W. E., Sharma S. C. The efficacy of the addition of nifedipine in patients with mixed angina compared to patients with classic exertional angina: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Am Heart J. 1988 Oct;116(4):961–971. doi: 10.1016/0002-8703(88)90146-9. [DOI] [PubMed] [Google Scholar]
  46. Svendsen J. H., Aldershvile J., Abildgaard U., Amtorp O. Efficacy of controlled-release isosorbide-5-mononitrate as adjunctive treatment to beta-blocking agents in patients with stable angina pectoris. J Cardiovasc Pharmacol. 1989 Sep;14(3):358–363. doi: 10.1097/00005344-198909000-00002. [DOI] [PubMed] [Google Scholar]
  47. TIME Investigators Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial. Lancet. 2001 Sep 22;358(9286):951–957. doi: 10.1016/S0140-6736(01)06100-1. [DOI] [PubMed] [Google Scholar]
  48. Thadani U. Medical therapy of stable angina pectoris. Cardiol Clin. 1991 Feb;9(1):73–87. [PubMed] [Google Scholar]
  49. Tolins M., Weir E. K., Chesler E., Pierpont G. L. "Maximal" drug therapy is not necessarily optimal in chronic angina pectoris. J Am Coll Cardiol. 1984 Apr;3(4):1051–1057. doi: 10.1016/s0735-1097(84)80366-6. [DOI] [PubMed] [Google Scholar]
  50. Uusitalo A., Keyriläinen O., Härkönen R., Rautio P., Rehnqvist N., Engvall J., Rosenqvist U., Nyberg G., Aberg A., Ulvenstam G. Anti-anginal efficacy of a controlled-release formulation of isosorbide-5-mononitrate once daily in angina patients on chronic beta-blockade. Acta Med Scand. 1988;223(3):219–225. doi: 10.1111/j.0954-6820.1988.tb15790.x. [DOI] [PubMed] [Google Scholar]
  51. White H. D., Polak J. F., Wynne J., Holman B. L., Antman E. M., Nesto R. W. Addition of nifedipine to maximal nitrate and beta-adrenoreceptor blocker therapy in coronary artery disease. Am J Cardiol. 1985 May 1;55(11):1303–1307. doi: 10.1016/0002-9149(85)90493-x. [DOI] [PubMed] [Google Scholar]
  52. de Vries R. J., Dunselman P. H., van Veldhuisen D. J., van den Heuvel A. F., Wielenga R. P., Lie K. I. Comparison between felodipine and isosorbide mononitrate as adjunct to beta blockade in patients > 65 years of age with angina pectoris. Am J Cardiol. 1994 Dec 15;74(12):1201–1206. doi: 10.1016/0002-9149(94)90548-7. [DOI] [PubMed] [Google Scholar]
  53. van der Vring J. A., Daniëls M. C., Holwerda N. J., Withagen P. J., Schelling A., Cleophas T. J., Hendriks M. G. Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers. The Netherlands Working Group on Cardiovascular Research (WCN). Angiology. 1999 Jun;50(6):447–454. doi: 10.1177/000331979905000602. [DOI] [PubMed] [Google Scholar]

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