Recommendations:
Uusitalo et al. (1986) studied 62 patients taking metoprolol 100 mg twice daily, nifedipine 10 mg three times daily and the combination in a randomised double blind crossover study. Metoprolol was better than nifedipine; the combination was better again.
Pedersen and Kantor (1990) studied nisoldipine 20 mg once daily or nifedipine 20 mg three times daily added to atenolol 100 mg. Exercise time and workload increased with nifedipine but not nisoldipine.
Sangiorgio et al. (1990) compared the effect of Felodipine 5 mg twice daily or placebo in patients already on beta-blockers. It decreased angina attacks but had no effect on glyceryl trinitrate consumption. There was a 0.7 minutes increase in exercise time (9.3 minutes v 8.6 minutes).
DiBianco et al. (1992) studied beta-blocker plus amlodipine versus beta-blocker alone. With dose titration of amlodipine a dose response effect was detected; an increase in exercise time (505 against 481 seconds) but no effect on angina attacks or glyceryl trinitrate usage.
el-Tamimi and Davies (1992) compared atenolol versus nifedipine versus the combination. Atenolol was slightly better than nifedipine on exercise time. The combination was slightly better for decreasing the number of attacks.
Donaldson et al. (1993) studied atenolol 100 mg plus either nifedipine SR 20 mg twice daily or nisoldipine 10 mg twice daily. There was no effect on angina days, glyceryl trinitrate consumption, severity of angina, subjective rating scale, treatment preference.
Foale (1993) compared atenolol 50 mg twice daily with atenolol 50 mg once daily plus nifedipine SR 20 mg twice daily. The combination produced 120 seconds extra (over 320s) before pain and patients preferred the combination. There was no difference in terms of ST depression, exercise duration, adverse reactions, angina attacks and glyceryl trinitrate use.
Siu et al. (1993) compared nifedipine GITS in a titrated dose against diltiazem in a titrated dose in patients already on maximum dose of a
beta-blocker. Active treatment produced a 25% increase in exercise tolerance compared with baseline, but there was no difference between diltiazem and nifedipine GITS.
Donaldson, K.M., Dawkins, K.D. and Waller, D.G. (1993) A comparison of nisoldipine and nifedipine in combination with atenolol, in the management of myocardial ischaemia. European Heart Journal 14:534-539.
el-Tamimi, H. and Davies, G.J. (1992) Optimal control of myocardial ischaemia: the benefit of a fixed combination of atenolol and nifedipine in patients with chronic stable angina. British Heart Journal 68:291-295.
Foale, R.A. (1993) Atenolol versus the fixed combination of atenolol and nifedipine in stable angina pectoris. European Heart Journal 14:1369-1374.
Pedersen, T.R. and Kantor, M. (1990) Nisoldipine tablets once daily versus nifedipine capsules three times daily in patients with stable effort angina pectoris pre-treated with atenolol. Cardiovascular Drugs and Therapy 4:451-456.
Sangiorgio, P., Di Pasquale, G., Savonitto, S., Urbinati, S., Rubboli, A., Cavallotti, G., Pinelli, G. and Bracchetti, D. (1990) Felodipine in chronic stable angina: a randomised, double-blind, placebo-controlled crossover study. European Heart Journal 11:1011-1017.
Siu, S.C., Jacoby, R.M., Phillips, R.T. and Nesto, R.W. (1993) Comparative efficacy of nifedipine gastrointestinal therapeutic system versus diltiazem when added to
beta-blockers in stable angina pectoris. American Journal of Cardiology 71:887-892.
Uusitalo, A., Arstila, M., Bae, E.A., Harkonen, R., Keyrilainen, O., Rytkonen, U., Schjelderup-Mathiesen, P.M. and Wendelin, H. (1986) Metroprolol, nifedipine, and the combination in stable effort angina pectoris. American Journal of Cardiology 57:733-737.
Humen et al. (1986) studied patients with angina already on propranolol in three groups of: propranolol alone, propranolol plus low dose diltiazem and propranolol plus high dose diltiazem. There was less angina and better exercise tolerance with the high dose. High dose diltiazem/propranolol was more effective than low dose diltiazem/propranolol which was more effective than propranolol alone. The combination was preferred by patients
Siu et al. (1993) compared nifedipine GITS in a titrated dose against diltiazem in a titrated dose in patients already on maximum dose of a
beta-blocker. Active treatment produced a 25% increase in exercise tolerance compared with baseline, but no difference between diltiazem and nifedipine GITS.
Steffensen et al. (1993) studied atenolol 100 mg once daily versus diltiazem 120 mg SR twice daily versus the combination (the latter single blind) using the end points of exercise duration, number of angina attacks and glyceryl trinitrate use. The combination halved the number of angina attacks (4.5 to 2.9) and the amount of glyceryl trinitrate use (3.4 to 1.8). They concluded that while atenolol worked slightly better than diltiazem, the combination was better again.
Siu, S.C., Jacoby, R.M., Phillips, R.T. and Nesto, R.W. (1993) Comparative efficacy of nifedipine gastrointestinal therapeutic system versus diltiazem when added to
beta-blockers in stable angina pectoris. American Journal of Cardiology 71:887-892.
Steffensen, R., Grande, P., Pedersen, F. and Haunso, S. (1993) Effects of atenolol and diltiazem on exercise tolerance and ambulatory ischaemia. International Journal of Cardiology 40:143-153.
beta-blockers produce no additional benefit. Adding isosorbide mononitrate to beta-blockers is effective (I).
Uusitalo et al. (1988) studied the effect of adding long-acting isosorbide mononitrate in patients already on beta-blockers. There was an increase in exercise duration (9 minutes to 9.5 minutes or 0.8 minutes median) and a 28% decrease in the use of glyceryl trinitrate tablets.
Waters et al. (1989) studied the effect of a 10 mg nitrate patch against placebo (single blind) in a group of patients, 26 out of 40 of whom were on beta-blockers. They used two different nitrate free intervals. There was no effect on exercise time; lots of patients complained of headache (25/36). They concluded that the intermittent use of 10 mg patch produced no additional benefit.
Friedensohn et al. (1991) studied isosorbide dinitrate SR 120 mg, verapamil SR and the combination of the two drugs. They found no difference in walking time, all regimes being better than placebo with a 60 to 80 second increase over 520 seconds. The combination was as effective compared to placebo as the two drugs singly. This study did not compare active treatments against each other.
Humen and Kostuk (1991) studied the effect of adding isosorbide dinitrate to diltiazem or propranolol. There was no extra effect from adding isosorbide dinitrate in doses of up to 180 mg per day. Diltiazem and propranolol were both better than placebo, diltiazem slightly better than propranolol.
Thadani et al. (1994) studied the asymmetrical use of isosorbide mononitrate 20 mg twice daily (08.00 hours, 15.00 hours) in a group of patients, 55-60% of whom were on beta-blockers. There was a 15-20% increase in exercise time and no rebound or early morning angina.
Humen, D.P. and Kostuk, W.J. (1991) Clinical response and effects on left ventricular function of isosorbide dinitrate added to propranolol or diltiazem monotherapy in patients with chronic stable angina. Canadian Journal of Cardiology 7:74-80.
Thadani, U., Maranda, C.R., Amsterdam, E., Spaccavento, L., Friedman, R.G., Chernoff, R., Zellner, S., Gorwit, J. and Hinderaker, P.H. (1994) Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate. Annals of Internal Medicine 120:353-359.
Uusitalo, A., Keyrilainen, O., Harkonen, R., Rautio, P., Rehnqvist, N., Engvall, J., Rosenqvist, U., Nyberg, G., Aberg, A., Ulventstam, G. et al. (1988) Anti-anginal efficacy of a controlled-release formulation of isosorbide-5-mononitrate once daily in angina patients on chronic -blockade. Acta Medica Scandinavica 223:219-225.
Waters, D.D., Juneau, M., Gossard, D., Choquette, G. and Brien, M. (1989) Limited usefulness of intermittent nitroglycerin patches in stable angina. Journal of the American College of Cardiology 13:421-425.
Recommendations:
Such patients should be referred rather than given a third drug (C)
Meluzin et al. (1992) studied the effect of adding nifedipine or diltiazem (both in titrated doses) or placebo to beta-blockers and nitrates (isosorbide dinitrate). Both were better than placebo.
Pellinen et al. (1992) studied SR verapamil 200 mg twice daily versus verapamil 120 mg three times daily added to beta-blockers and nitrates (isosorbide dinitrate). Exercise time increased 20% with either verapamil preparation.
Woodmansey et al. (1993) added amlodipine 10 mg daily or placebo to atenolol (in maximum dose) and oral nitrate. Amlodipine reduced glyceryl trinitrate use (due to high placebo use). However, there was no good evidence that in the important comparison of amlodipine against placebo, there was any difference.
Pellinen, T.J., Lukkala, K., Sundberg, S., Heikkila, J. and Frick, M.H. (1992) Efficacy of conventional and sustained-release verapamil in stable angina pectoris. Annals of Medicine 24:49-53.
Woodmansey, P.A., Stewart, A.G., Morice, A.H. and Channer, K.S. (1993) Amlodipine in patients with angina uncontrolled by atenolol. A double blind placebo controlled cross over trial. European Journal of Clinical Pharmacology 45:107-111.