BACKGROUND: Long-acting anti-angina agents have theoretical advantages over short-acting options. They offer more consistent blood levels, which could result in fewer side effects, as well as more sustained control of symptoms. This randomized controlled trial addressed the effectiveness of a strategy of converting to long-acting antianginal medication.
POPULATION STUDIED: The investigators enrolled 100 male outpatients at a Veterans Administration (VA) Health Systems Clinic who had known coronary disease or angina and who were taking at least 2 antianginal drugs. They were identified by clinician or a pharmacy database. Patients were excluded from the study if they had a recent hospitalization, aortic stenosis, an ejection fraction of less than 40%, significant conduction defects, or limited life expectancy. Most of the men (81%) were white and the average age was 65 years. The men had several concomitant diseases: 39% had diabetes, 28% congestive heart failure, and 68% had a prior myocardial infarction. These patients seem similar to the sicker patients in a typical family practice, but caution should be exercised in generalizing the results to women and to settings different from the VA.
STUDY DESIGN AND VALIDITY: The study was a single-blind, prospective randomized trial using concealed allocation. A nurse practitioner evaluated all patients weekly for 4 weeks and then monthly for 2 months. In the “once a day” group, all previous antianginal medications were withdrawn and then restarted one at a time in this order: long-acting diltiazem (up to 360 mg/day), nitroglycerin patches (up to 0.8 mg/hour) and atenolol (up to 100 mg/day). Doses were maximized prior to the addition of the next drug. In contrast, no drugs were stopped in “usual care”; instead, baseline medications were increased on the basis of symptoms to maximum doses following alphabetical order. For both groups, an algorithm was used to adjust medications. Data were analyzed according to intention-to-treat using t tests, with logistic regression to control for baseline frequency of angina. The methodology of this study was pragmatic and appropriate. Strengths included randomization, concealed allocation and complete follow-up. A major limitation of the design was that the intervention was complex, involving frequent visits along with a specific care algorithm, complete withdrawal of medication at the beginning and a specified order of medication re-introduction. The consequence is that it is difficult to determine which component of the intervention led to the results. Other important limitations include short duration (3 months); inattention to important confounding variables such as diabetes, congestive heart failure, or which specific drugs the patients were taking; lack of statistical power to assess confounding; and lack of attention to multiple comparisons.
OUTCOMES MEASURED: Primary outcomes were functional status, treatment satisfaction, and quality of life, measured by the Seattle Angina Questionnaire, a validated disease-specific measure for patients with coronary artery disease. The study did not address cost, side-effects, morbidity/mortality, or any long-term outcomes.
RESULTS: At the end of the trial, the once-a-day group had fewer symptoms than the usual care group (difference of averages: 12.3 points, P <.002; 5-8 points is considered clinically significant). Controlling for baseline frequency of angina did not change this result. There was no significant difference between groups in treatment satisfaction or quality of life. By the end of the trial, the patients in the once-a-day group were taking fewer medications (average 1.55 vs 2.14, P <.001).
This report provides good evidence that a strategy of withdrawing antianginal medications and replacing them with once-a-day medications reduces overall medications and provides improved symptom relief. Which medications to use, how to adjust them, and in which settings remains unclear, although these data suggest that switching to once-a-day medications is itself beneficial. Clinicians should not necessarily be locked into a traditional strategy of gradually increasing medications for patients with angina; rather, this trial shows that very different approaches, such as trials of withdrawal and substitution of different classes of medications, can be effective.