Drug Investigation

, Volume 3, Issue 4, pp 210–219 | Cite as

Randomised Double-Blind Comparison of Isosorbide-5-Mononitrate and Sustained Release Nifedipine in Patients with Stable Exercise-Induced Angina

  • H. J. Überbacher
  • W. D. Patyna
  • H. P. Krepp
  • J. Puespoek
  • R. Neuhaus
  • K. Hilbich
  • M. Bulitta
  • R. Rittinghausen
Original Research Article
First Online:

Summary

The therapeutic effects of isosorbide-5-mononitrate (IS-5-MN) and sustained release (SR) nifedipine for 2 weeks were, investigated in this double-blind randomised comparative multicentre study in 252 patients with well documented coronary artery disease and stable reproducible exercise-induced angina. After 1 week’s treatment with IS-5-MN 20mg twice daily, 50% of the patients were responders, showing an increase in total exercise time (to onset of moderately severe angina) of ⩾ 20% in comparison with the placebo run-in phase. The corresponding rate after SR nifedipine 20mg twice daily was 45%. By increasing the dose in the nonresponders to 20mg 3 times daily for IS-5-MN and 40mg twice daily for SR nifedipine (double-dummy technique), and continuing lower dose treatment in responders for an additional week, the responder rate increased to 61 and 53%, respectively. Both IS-5-MN and SR nifedipine significantly increased total exercise time, time to angina onset and ⩾ 1 mm ST-segment depression, and significantly reduced the rate-pressure product and ST-segment depression at peak exercise compared with the placebo run-in. However, differences between treatments were not significant. The improvement in quality of life, indicated by the reduction in angina episodes and intake of short-acting nitrates, was similar for the 2 drugs. During IS-5-MN treatment, 8 patients were withdrawn prematurely because of adverse events (7 for headache, 1 for tachycardia, vertigo and dizziness). In the SR nifedipine group, 1 patient withdrew because of headache and tachycardia, and another because of a lack of increase in diastolic blood pressure during exercise. Adverse events were reported more frequently in the IS-5-MN group than in the SR nifedipine group (17 and 3.9%, respectively, for transient headache). The pattern and incidence of all adverse effects were as expected in the 2 active treatment groups. Daily treatment costs for a 20mg twice daily dosing regimen for both drugs in the Federal Republic of Germany was 64% higher for SR nifedipine than for IS-5-MN.

This well controlled study confirmed the tolerability of both drugs and their therapeutic value in the majority of patients with stable reproducible exercise-induced angina.

Keywords

Nifedipine Coronary Flow Reserve Drug Invest Peak Exercise Isosorbide Dinitrate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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References

  1. Biamino G, Oeff M, Anderson D, et al. Hemodynamic effects of isosorbide-5-mononitrate in patients with coronary artery disease, at rest and under exercise. In Cohn & Rittinghausen (Eds) Mononitrates, p. 277, Springer Verlag, Berlin, 1985CrossRefGoogle Scholar
  2. Boden WE, Korr KS, Bough EW. Nifedipine induced hypotension and myocardial ischemia in refractory angina pectoris. Journal of the American Medical Association 253: 1311, 1985CrossRefGoogle Scholar
  3. Brand S, Überbacher HJ, Tartini R, Steinbrunn W. Hämodyn-amische Effekte und diastolische Funktion von Patienten mit koronarer Herzkrankheit nach 20 mg IS-5-MN im Vergleich zu Placebo. Medizinische Welt 40: 1419–1423, 1989Google Scholar
  4. Brown BG. Response of normal and diseased epicardial coronary arteries to vasoactive drugs: quantitative arteriographic studies. American Journal of Cardiology 56 (Suppl. E): 23E–29E, 1985PubMedCrossRefGoogle Scholar
  5. Brügmann U. Unterscheidliches Ansprechen von Patienten mit stabiler Belastungs-Angina-Pectoris auf Nifedipin. Herz 7: 117, 1982PubMedGoogle Scholar
  6. Dirschinger J, Fleck E, Redl A, Rudolph W. Regionale Myokard-durchblutung unter der Wirkung von Nifedipin in Abhängigkeit von Lumenänderung im Stenosebereich und Kollateralversorgung. Zeitschrift für Kardiologie 72 (Suppl. 40): 14, 1983Google Scholar
  7. Distante A, Lombardi M, Morscarelli E, et al. The therapeutic role of isosorbide-5-mononitrate in stable and unstable angina pectoris. Zeitschrift für Kardiologie 75 (Suppl. 3): 38, 1986PubMedGoogle Scholar
  8. Distante A, Lombardi M, Moscarelli E, et al. Acute study with isosorbide-5-mononitrate in vasospastic angina. In Julian et al. (Eds) Mononitrate II, p. 153, Springer Verlag, Berlin, 1987CrossRefGoogle Scholar
  9. Ekelund LG, Orö L. Antianginal efficiency of Adalat® with and without a β-blocker: a subacute study with exercise tests. In Jatene & Lichtlen (Eds) 3rd International Adalat® Symposium: new therapy of ischemic heart disease, p. 218, Excerpta Medica, Amsterdam, 1976Google Scholar
  10. Emanuelsson H, Holmberg S. Mechanisms of angina relief after nifedipine: a hemodynamic and myocardial metabolic study. Circulation 68: 124–130, 1983PubMedCrossRefGoogle Scholar
  11. Engel HJ, Lichtlen PR. Beneficial enhancement of coronary blood flow by nifedipine: comparison with nitroglycerin and beta blocking agents. American Journal of Medicine 71: 658, 1981PubMedCrossRefGoogle Scholar
  12. Erlemeier HH, Kupper W, Hempel NB, Bleifeld W. Anti-ischemic effects of slow-release formulations of nifedipine, isosorbide-5-mononitrate and their combination in patients with coronary heart disease. Cardiology 75: 409, 1988PubMedCrossRefGoogle Scholar
  13. Fuchs RM, Brinker JA, Maughan WL, et al. Coronary flow limitation during the development of ischemia. American Journal of Cardiology 48: 1029, 1981PubMedCrossRefGoogle Scholar
  14. Harris PJ, Behar VS, Conley MJ, Harrel FE, Lee KL, et al. The prognostic significance of 50% coronary stenosis in medically treated patients with coronary artery disease. Circulation 62: 240, 1980PubMedCrossRefGoogle Scholar
  15. Hill JA, Feldman RL, Pepine CJ, et al. Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm. American Journal of Cardiology 49: 431, 1982PubMedCrossRefGoogle Scholar
  16. Imai S. Effects of nifedipine on heart and coronary circulation. In Hashimoto et al. (Eds) New therapy of ischaemic heart disease, p. 23, University of Tokyo Press, Tokyo, 1975Google Scholar
  17. Isbary J, Doering W, Wauer B, et al. Hämodynamische Veränderungen in Ruhe und während Belastung nach 20mg Isosorbid-5-Mononitrat bei Patienten mit koronarer Herzerkrankung. Medizinische Welt 32: 530, 1981PubMedGoogle Scholar
  18. Jansen W, Tauchert M, Osterspey A, et al. Systemische und koronare Hämodynamik bei Elantan 20 und 50. In Hochrein et al. (Eds) Mononitrat, p. 38, Universitätsdruckerei und Verlag Dr C. Wolf und Sohn, München, 1984Google Scholar
  19. Jansen W, Tauchert MA, Osterspey A, et al. Comparison of the hemodynamic effects of various doses of isosorbide-5-mononitrate following single dose and long-term administration in patients with coronary heart disease. In Cohn & Rittinghausen (Eds) Mononitrates, p. 171, Springer Verlag, Berlin, 1985CrossRefGoogle Scholar
  20. Koch G. Beta-receptor and calcium blockade in ischemic heart disease: effects on systemic and pulmonary hemodynamics and on plasma catecholamine at rest and during exercise. In Puech & Krebs (Eds) 4th International Adalat® Symposium: new therapy of ischemic heart disease, p. 131, Excerpta Medica, Amsterdam, 1980Google Scholar
  21. Koch G, Fransson L, Karlegärd L, et al. Double-blind comparison of the effects of nifedipine and isosorbide-5-mononitrate on the circulatory response to exercise, exercise tolerance and ST-segment depression in patients with ischemic heart disease. In Cohn & Rittinghausen (Eds) Mononitrates, p. 245, Springer Verlag, Berlin, 1984Google Scholar
  22. Kochsiek K, Neubaur J. Die Wirkung von Nifedipin auf den Myokardstoffwechsel, die Hämodynamik, die Blutgase und den allgemeinen Stoffwechsel des Menschen. Arzneimittel Forschung 22: 353, 1972PubMedGoogle Scholar
  23. Kramer PH, Chatterjee K, Schwartz A, Swedberg K, Rouleau JL, et al. Alterations in angina threshold with nifedipine during pacing induced angina. British Heart Journal 52: 308, 1984PubMedCrossRefGoogle Scholar
  24. Lombardi M, Distante A, Moscarelli E, et al. Preventive effects of isosorbide-5-mononitrate on myocardial ischemia induced by hand-grip test: an echocardiographic study. In Julian et al. (Eds) Mononitrate II, p. 159, Springer Verlag, Berlin, 1987CrossRefGoogle Scholar
  25. Maseri A, Chierchia S. A new rationale for the clinical approach to the patient with angina pectoris. American Journal of Medicine 71: 639, 1981PubMedCrossRefGoogle Scholar
  26. Maseri A, Chierchia S, Kaski JC. Mixed angina pectoris. American Journal of Cardiology 56 (Suppl. E): 30E–33E, 1985PubMedCrossRefGoogle Scholar
  27. Maseri A, L’Abbate A, Pessola A, et al. Regional myocardial perfusion in patients with atherosclerotic coronary artery disease at rest and during angina pectoris induced by tachycardia. Circulation 55: 423, 1977PubMedCrossRefGoogle Scholar
  28. Mehmel HC, Ruffmann K, Schwarz F, et al. Die Wirkung von Isosobid-5-Mononitrat (IS-5-MN) auf die linksventrikuläre Hämodynamik. Medizinische Welt 32: 527, 1981PubMedGoogle Scholar
  29. Müller G, Überbacher HJ, Glocke M. Koronartherapeutische Wirkamkeit von niedrig dosiertem IS-5-MN im Vergleich zur Kombination IS-5-MN + Metipranolol und Plazebo. Medizinische Welt 34: 321, 1983PubMedGoogle Scholar
  30. Nakashima T, Inoki M, Nakanishi Y. Nifedipine serum concentration: effects upon blood pressure and heart rate in normotensive volunteers. European Journal of Drug Metabolism and Pharmacokinetics 9: 73, 1984PubMedCrossRefGoogle Scholar
  31. Raff WK, Kosche F, Lochner W. Untersuchungen mit Nifedipin, einer koronargefässerweiternden Substanz mit schneller sublingualer Wirkung. Arzneimittel Forschung 22: 367, 1972Google Scholar
  32. Rennhak U, Riebesel T, Biamino G. A double-blind crossover study on the effectiveness and possible development of tolerance during long-term therapy with isosorbide-5-mononitrate or isosorbide dinitrate slow-release in coronary artery disease. In Cohn & Rittinghausen (Eds) Mononitrates, p. 147, Springer Verlag, Berlin, 1985CrossRefGoogle Scholar
  33. Rocco MB, Barry J, Campbell S, Nabel E, Cook EF, et al. Circadian variation of transient myocardial ischemia in patients with coronary artery disease. Circulation 75: 395, 1987PubMedCrossRefGoogle Scholar
  34. Rubartelli P, Abbadessa L, Badano L, et al. Effects of isosorbide-5-mononitrate on hemodynamic parameters and left-ventricular function in patients with coronary heart disease. In Juliann et al. (Eds) Mononitrate II, p. 129, Springer Verlag, Berlin, 1987CrossRefGoogle Scholar
  35. Russo G, Tolaro S, Monaco O, Greco G, Grassi R, et al. Effetti emodinamici dell’isosorbide 5 mononitrato nella cardiopatia ischemica. Cardiologia 33: 291, 1988PubMedGoogle Scholar
  36. Schmidt-Thrun A, Mentzel W. Exercise response of patients with coronary artery disease during treatment with isosorbide-5-mononitrate and slow release nifedipine. In Julian et al. (Eds) Mononitrate II, p. 187, Springer Verlag, Berlin, 1987CrossRefGoogle Scholar
  37. Schnellbacher K, Samek L, Blasenke H-J, et al. Efficacy of isosorbide-5-mononitrate and diltiazem in patients with myocardial ischemia. In Julian et al. (Eds) Mononitrates II, p. 205, Springer Verlag, Berlin, 1987CrossRefGoogle Scholar
  38. Schulz W. Antianginöse Wirksamkeit des Kalziumantagonisten Nifedipin in Abhängigkeit von Koronarbefall. Zeitschrift für Kardiologie 72: 657, 1983PubMedGoogle Scholar
  39. Schulz W, Kaltenbach M. Antianginal effect of nifedipine after intracoronary and intravenous administration judged by reduction of ischemic ST-segment depression in exercise tests. Cardiology 68 (Suppl. 2): 200–208, 1981PubMedCrossRefGoogle Scholar
  40. Schulz W, Kober G, Bamberg E, Kaltenbach M. Kardiale und periphere Effekte von Nifedipin. Zeitschrift für Kardiologie 67: 196, 1978Google Scholar
  41. Schwarzkopf HJ, Schäfer J, Schöttler M, Sedlmeyer I, Nordmann KJ. Der Einfluss von Nifedipin auf die Koronarvenöse Sauer-Stoffsättigung des Menschen bei konstanten Herzfrequenzen. Arzneimittel Forschung 22: 367, 1972PubMedGoogle Scholar
  42. Sehnert W. A comparison of isosorbide-5-mononitrate and transdermal glyceryl trinitrate: acute effects and tolerance development during chronic therapy. In Julian et al. (Eds) Mononitrates II, p. 69, Springer Verlag, Berlin, 1987CrossRefGoogle Scholar
  43. Steinorth G, Seidel U, Glocke M, et al. Zur koronatherapeutischen Wirksamkeit von IS-5-MN und ISDN retard. Medizinische Welt 36: 359, 1985Google Scholar
  44. Überbacher HJ, Glocke M, Abshagen U. Langzeitverträglichkeit und koronartherapeutische Wirksamkeit von Isosorbid-5-Mononitrat: Offene Multicenter Studie unter Praxisbedingungen mit ISMO. Münchener Medizinische Wochenschrift 125: 76, 1983aPubMedGoogle Scholar
  45. Überbacher HJ, Steinorth G, Glocke M, et al. An open long-term, multicentre study of the antianginal efficacy and safety of isosorbide-5-mononitrate at low doses in patients with coronary heart disease. Pharmatherapeutica 3: 331, 1983bPubMedGoogle Scholar
  46. Wiechmann HW, Lenga P, Odenthal H, et al. Haemodynamic and anti-ischaemic effects of isosorbide-5-mononitrate and verapamil. In Julian et al. (Eds) Mononitrate II, p. 196, Springer Verlag, Berlin, 1987CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1991

Authors and Affiliations

  • H. J. Überbacher
    • 1
  • W. D. Patyna
    • 2
  • H. P. Krepp
    • 3
  • J. Puespoek
    • 4
  • R. Neuhaus
    • 5
  • K. Hilbich
    • 1
  • M. Bulitta
    • 1
  • R. Rittinghausen
    • 1
  1. 1.Clinical ResearchBoehringer Mannheim GmbHMannheimGermany
  2. 2.LVA Westfalen LippeBad NauheimGermany
  3. 3.Arzt für Innere MedizinSport und SozialmedizinGross SaitingenGermany
  4. 4.Rehabilitationszentrum für Herz- und KreislauferkrankungenGrossgerungsGermany
  5. 5.Abt. Rhein-Ruhr-Klinik NordrheinBad NauheimGermany

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