Captopril reduced exercise tolerance and increased angina in patients with angina pectoris and heart failure
ACP J Club. 1991 Sept-Oct;115:44. doi:10.7326/ACPJC-1991-115-2-044
Cleland JG, Henderson E, McLenachan J, Findlay IN, Dargie HJ. Effect of captopril, an angiotensin-converting enzyme inhibitor, in patients with angina pectoris and heart failure. J Am Coll Cardiol. 1991 March 1;17:733-9.
To examine the effects of treatment with an angiotensin-converting enzyme (ACE) inhibitor, captopril, for patients with both angina and chronic heart failure.
Randomized, double-blind, crossover trial, with 2 6-week treatment periods.
Hospital outpatient clinics in the United Kingdom.
18 patients (14 men and 4 women, mean age 63 y) were included. All patients had confirmed heart failure, a history of myocardial infarction, and stable angina pectoris. One patient died (while receiving placebo) and another was withdrawn because of hypotension and progressive hyponatremia and uremia (while receiving captopril).
Patients received either placebo or captopril (25 mg 3 times daily). After 2 weeks, the dose was increased to 50 mg 3 times daily for 5 patients whose symptoms remained unchanged and whose systolic blood pressure was > 100 mm Hg. At the end of 6 weeks, patients received the alternate therapy. Concurrent medications included digoxin, nitrates, nifedipine, and diuretics.
Main outcome measures
Patients rated symptoms of breathlessness, fatigue, and angina using visual analog scales at baseline and during each treatment period. Cardiovascular variables were measured at peak exercise for each of 2 (fast and slow) treadmill protocols. Left ventricular ejection fraction and ventricular extrasystoles were assessed.
Scores on visual analog scales for the captopril and placebo treatment periods were similar for breathlessness (45 vs 42) and tiredness (39 vs 46). Scores for angina favored placebo (57 for captopril and 40 for placebo, P < 0.01). With the fast treadmill protocol, captopril and placebo scores differed for systolic blood pressure (123 vs 148 mm Hg, P < 0.001), exercise rate-pressure product (16.4 vs 19.5, P < 0.01), and exercise time (213 vs 255 s, P < 0.01). Heart rate (133 vs 132 beats/min) and maximal oxygen consumption (14.9 vs 15.7 mL/kg of body weight per min) did not differ. Similar results were observed for the slow protocol except for exercise time which did not differ (9.6 vs 10.9 s). Ejection fractions were not altered substantially with either therapy but ventricular extrasystoles during 48-hour ECG ambulatory monitoring were decreased in patients on captopril (median, 686 vs 1424 per 48 h), and ventricular salvos was also reduced (median 2 vs 6, P < 0.05).
Captopril reduced exercise tolerance and increased angina in patients with angina pectoris and heart failure.
Source of funding: In part, Bristol Myers-Squibb (UK).
Address for article reprint: Dr. J.G. Cleland, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, England, UK.
Although several studies have documented that ACE inhibitor therapy improves functional status, survival, or both in patients with moderate-to-severe congestive heart failure (1), this study is one of the first to evaluate specifically the effects of ACE inhibitors in patients with both heart failure and chronic stable angina. Important features of the study population were that all patients had previous myocardial infarctions and presumably had underlying ischemic disease as the prime cause of their heart failure, and many were receiving concurrent medications such as nitrates and nifedipine.
The study results are interesting because some potentially desirable metabolic effects and decreases in ventricular extrasystoles were seen with captopril, but angina symptoms and exercise tolerance were worsened. Differences in survival outcomes and potential factors associated with worsening angina such as low diastolic blood pressure or particular therapy combinations (e.g., captopril and nifedipine) could not be evaluated because of the small study size and short follow-up period.
Clinicians should be aware that therapy with ACE inhibitors in patients with ischemic congestive heart failure and coexisting angina may be associated with worsening chest pain. Whether the increased pain is related to the ACE inhibitor therapy, particular combinations of therapy, or associated blood pressure reductions is not known. More studies are needed to define the benefit/risk ratios in particular subsets of patients before recommendations can be made to withhold ACE inhibitors for those patients. Regardless, excessive lowering of blood pressure in patients with congestive heart failure and angina seems unwise.
Cynthia D. Mulrow, MD, MSc
The University of Texas Health Science CenterSan Antonio, Texas, USA