Current issues of ACP Journal Club are published in Annals of Internal Medicine


Combination therapy for stable angina

ACP J Club. 1992 Mar-April;116:44. doi:10.7326/ACPJC-1992-116-2-044

Source Citation

Akhras F, Jackson G. Efficacy of nifedipine and isosorbide mononitrate in combination with atenolol in stable angina. Lancet. 1991 Oct 26;338:1036-9.



To determine the optimal second-step drug to add to β-blockade in patients with symptomatic, stable angina.


Randomized, double-blind, multiple crossover trial.


Cardiac Department, Guy's Hospital, London, England.


22 selected patients with proven coronary artery disease ( ≥ 70% luminal narrowing in at least 1 major vessel). All had had positive exercise stress electrocardiograms (ECGs) and experienced ≥ 3 episodes per week of exertional angina pectoris on adequate β-blockade. The subjects averaged 60 years of age, and 13 had survived a previous myocardial infarction. 21 had multivessel disease, and 21 were men. {Information on the referral pattern and sample size calculations was not given.}


All patients participated in 4, fixed-dose, 4-week regimens in a randomly allocated sequence. The regimens consisted of atenolol (50 mg twice daily) alone or combined with either isosorbide mononitrate (20 mg twice daily, separate pills), long-acting nifedipine (20 mg twice daily mixed in capsules with atenolol), or both. Patients took 2 pills twice daily during all periods. Nitroglycerine tablets were taken as needed. All antianginal medications except atenolol were withdrawn at least 24 hours before study entry. {There were no washout periods.} (Information provided by authors.)

Main outcome measures

Performance was assessed on symptom-limited exercise testing (Bruce protocol) and 24-hour ambulatory ECG monitoring at the end of each 4-week period; the number of anginal episodes and amount of nitroglycerine consumed during each treatment period were determined.

Main results

4 patients dropped out of the study (3 with intolerable headache while taking mononitrate; 1 with acute myocardial infarction). Mean exercise duration was longest for atenolol and isosorbide mononitrate and was longer than for atenolol alone (486 vs. 440 s; 95% CI for the difference, 18 to 88 s, P = 0.005) or atenolol and nifedipine (difference 35 s; CI, 2 to 71 s; P = 0.047). No other significant differences were found between groups in other exercise test results, episodes of ischemia on ambulatory ECG monitoring, frequency of angina, or consumption of nitroglycerine.


The addition of isosorbide mononitrate, nifedipine, or both to atenolol confers no substantial advantage compared with atenolol alone in the treatment of stable angina. Isosorbide mononitrate with atenolol offers a slight advantage over other combinations.

Source of funding: ICI Pharmaceuticals.

Address for article reprint: Dr. G. Jackson, Cardiac Department, Guy's Hospital, St. Thomas Street, London SE1 9RT, United Kingdom.


The conclusion of this study is probably correct, but there were several important methodologic shortcomings. Baseline exercise duration varied widely. A washout period would have permitted knowledge of untreated status. Because all patients remained on atenolol, the background benefit of β-blockade is unknown. Baseline angina was mild as reflected in low attack frequency and use of nitroglycerine; thus the indications for additional therapy were questionable. Mean time between nitrate dosing (7.72 h) and testing was rather close to the nitrate's duration of action. Treatment differences were small and certainly not clinically important, but the estimates of benefit were somewhat unreliable because of the small sample size. 12 patients were actually worse when nifedipine was added!

Conventional wisdom on angina pathogenesis and antianginal drug action predicts additive if not synergistic drug interactions. Observations, however, do not convincingly demonstrate this. Packer's extensive review (1) concluded: "The present trend of routinely prescribing multiple antianginal agents to patients with coronary artery disease needs to be critically re-evaluated." Packer observed that adding a β-blocker enhanced nifedipine effects, but adding nifedipine failed to augment β-blockade. It appears more likely that these drugs interact to limit rather than to potentiate each other's antianginal effects.

Angina sufferers already well controlled with β-blocker monotherapy gain little from addition of oral nitrates or calcium blockers. Consider alternative monotherapy before adding medications in patients with persistent angina. Obvious benefits include simpler, more convenient, less costly treatment with reduced risk for adverse events from polypharmacy.

S. George Carruthers, MD
Dalhousie University Halifax, Nova Scotia