Captopril was not more effective than conventional treatment in hypertension and led to an increase in stroke
ACP J Club. 1999 July-Aug;131:18. doi:10.7326/ACPJC-1999-131-1-018
Hansson L, Lindholm LH, Niskanen L, et al., for the Captopril Prevention Project (CAPPP) study group. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999 Feb 20;353:611-6.
In patients with hypertension, does captopril reduce morbidity and mortality better than conventional therapy (diuretics or β-blockers)?
Randomized, single-blind, controlled trial with a mean follow-up of 6.1 years.
536 Swedish and Finnish health centers.
10 985 patients who were 25 to 66 years of age (mean age 53 y, 53% men) and had primary hypertension with diastolic blood pressure ≥ 100 mm Hg on 2 occasions. Exclusion criteria were secondary hypertension, serum creatinine level > 150 mmol/L, or a disorder that required treatment with β-blockers. Follow-up was 99.8%.
Patients were allocated to captopril, 50 mg daily in 1 or 2 doses (n = 5492), or conventional antihypertensive treatment, which consisted of diuretics (most commonly hydrochlorothiazide, 25 mg once daily, or bendrofluazide, 2.5 mg once daily), β-blockers (most commonly atenolol or metoprolol, 50 to 100 mg once daily), or both (n = 5493). To reach the treatment goal (supine diastolic blood pressure ≤ 90 mm Hg), captopril could be increased to 100 mg once or twice daily and, if necessary, a diuretic could be added; a calcium antagonist could be added to the regimen in either group.
Main outcome measures
Combined end point of fatal and nonfatal myocardial infarction (MI), stroke, and other types of cardiovascular death.
Analysis was by intention to treat. The groups did not differ for the combined end point (P = 0.52), fatal cardiovascular events (P = 0.09), or MI (P = 0.68); captopril led to more strokes than did conventional treatment (P = 0.04) (Table).
In patients with hypertension, captopril did not reduce morbidity and mortality better than conventional treatment and led to an increase in stroke.
Source of funding: Bristol-Myers Squibb.
For correspondence: Professor L. Hansson, Division of Clinical Hypertension Research, Department of Public Health and Social Sciences, University of Uppsala, Box 609, S-751 25 Uppsala, Sweden. FAX 46-18-177973.
Table. Captopril vs conventional treatment for hypertension at mean 6.1-year follow-up*
|Outcomes||Captopril||Control||Adjusted RRI† (95% CI)||NNH (CI)|
|Combined end point||6.9%||6.1%||5% (-10 to 22)||Not significant|
|Stroke||3.5%||2.7%||25% (1 to 55)||125 (69 to 651)|
|Adjusted RRR (CI)||NNT (CI)|
|Myocardial infarction||3.0%||3.0%||4% (-19 to 23)||Not significant|
|Cardiovascular mortality||1.4%||1.7%||23% (-4 to 43)||Not significant|
*Abbreviations defined in Glossary; NNT, NNH, and CI calculated from data in article.
†Adjusted for age, sex, diabetes, systolic blood pressure, and previous treatment.
Angiotension-converting enzyme (ACE) inhibitors lower blood pressure to a similar extent as diuretics and β-blockers (1). Their effects on major cardiovascular outcomes, such as MI and stroke, have not been previously assessed in a randomized controlled trial. Nevertheless, superiority over β-blockers and diuretics has been claimed on the basis of improved intermediate outcomes, such as lipid profile and plasma potassium and glucose levels.
The main results of the CAPPP study refute these claims: The ACE inhibitor captopril did not prevent the primary end point more often than conventional therapy and increased risk for stroke.
The authors' conclusion that this drug may be useful in patients with diabetes is not sufficiently supported by their subgroup analysis. They did not state that this analysis was planned in the study design, and they reported a flaw in the randomization procedure that resulted in unbalanced groups. Moreover, their conclusion conflicts with firmer evidence shown by the U.K. Prospective Diabetes Study 40 in which 1148 hypertensive patients with diabetes were randomly allocated to captopril or atenolol (2). In that study, captopril was not more effective than atenolol for preventing major cardiovascular outcomes.
The mean difference between groups in baseline blood pressure levels could be large enough to explain the difference in efficacy for stroke prevention. Therefore, this first trial of ACE inhibitors in middle-aged, hypertensive patients is not definitive. Future trials may show that these drugs are equivalent to diuretics and β-blockers in the prevention of stroke but are unlikely to be proved superior.
Meanwhile, diuretics and β-blockers remain the first line of treatment for uncomplicated hypertension.
Edmond Walma, MD
Siep Thomas, MDErasmus UniversityRotterdam, The Netherlands