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Captopril

Captopril is an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) used for the treatment of hypertension and some types of chronic heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the revolutionary development process. The original innovator drug Bristol-Myers Squibb's Capoten®. more...

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Clinical Use

Development of captopril

Captopril was invented in 1975 by three researchers at the American drug company Squibb (now Bristol-Myers Squibb) , Miguel Ondetti, Bernard Rubin and David Cushman. Squibb filed for American patent protection on the drug in February 1976 and U.S. Patent was 4,046,889 was granted in September 1977.

The development of captopril was amongst the earliest successes of the revolutionary concept of structure-based drug design. The renin-angiontensin-aldosterone system had been extensively studied in the mid-20th century and it had been decided that this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were renin and ACE. Captopril was the culmination of efforts by Squibb's laboratories to develop an ACE inhibitor.

Ondetti, Cushman and colleagues built on work that had been done in the 1960s by the British Nobel laureate Sir John Vane when he was a researcher at the Royal College of Surgeons. Working with a Brazilian colleage, Sérgio Ferreira, Vane discovered a peptide in Brazilian viper venom which was a 'collected-product inhibitor' of angiotensin II. Captopril was developed from this peptide after it was found via QSAR-based modification that the terminal sulfhydryl-moiety of the peptide provided a high potency of ACE inhibition.

Capoten gained FDA approval in June 1981. The drug went generic in the U.S. in February 1996 as a result of the end of market exclusivity for Bristol-Myers Squibb.

Shortcomings

During Phase III/IV trials of captopril, it was found that captopril had some undesirable adverse effects. The most predominant of which included cough, rash and taste disturbances (metallic or loss of taste). Cough is an adverse effect common to all of the ACE inhibitors, but the rash and taste disturbances were attributed to the very sulfhydryl moiety which granted captopril its potency. An additional shortcoming of captopril is the short half-life, necessitating 2-3 times daily dosing.

The development of longer-acting ACE inhibitors lacking the sulfhydryl-moiety such as enalapril proved to be the downfall of captopril and, whilst it is still used, it is no longer amongst the more widely used ACE inhibitors.

Reference

Smith CG, Vane JR. The discovery of captopril. FASEB J 2003;17:788-9. Fulltext. PMID 12724335.

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Is losartan superior to captopril in reducing all-cause mortality in elderly patients with symptomatic heart failure?
From Journal of Family Practice, 8/1/00 by Thomas H. Trojian

Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomized trial-the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355:1582-87.

* BACKGROUND Because of their beneficial effects on mortality risk and functional status, angiotensin-converting-enzyme (ACE) inhibitors should be prescribed for all patients with heart failure and systolic left ventricular dysfunction unless specific contraindications exist. However, some physicians do not prescribe them because of fear of adverse effects. Angiotensin II type 1 receptor blockers ([AT.sub.1]RBs) may be better tolerated than ACE inhibitors. A secondary analysis of 49 deaths in the original Evaluation of Losartan in the Elderly (ELITE) study, in which the primary end point was the effect of treatment on renal function, showed an unexpected survival benefit for the [AT.sub.1]RB losartan over captopril, an ACE inhibitor. ELITE II was a larger trial designed to confirm whether losartan is superior to captopril in reducing all-cause mortality in elderly heart failure patients.

* POPULATION STUDIED The study included 3152 patients aged 60 years or older with New York Heart Association class II to IV heart failure and an ejection fraction of 40% or less. Most of the patients recruited from the 289 outpatient centers in 46 countries were white men aged older than 65 years who had never received an ACE inhibitor or an [AT.sub.1]RB. Exclusion criteria included previous intolerance or contraindication to either the study drug, systolic blood pressure greater than 90 mm Hg, uncontrolled hypertension, obstructive valvular heart disease, recent cardiac procedure or event, anticipated cardiac surgery, or recent cerebrovascular event.

* STUDY DESIGN AND VALIDITY This study was a prospective randomized double-blind trial funded by the manufacturer of losartan. Designed as an event-driven superiority trial, the study had 90% power to detect a relative 25% difference in all-cause mortality between treatments. At each study center, randomization was stratified on the basis of use of [Beta]-blockers. After a single-blind run-in period of 1 to 28 days, 1578 patients were allocated to losartan (12.5 mg titrated to a maximum of 50 mg once daily) and 1574 to captopril (12.5 mg titrated to a maximum of 50 mg 3 times daily). Clinical assessments were done weekly during dose titration and then every 4 months. Periodic laboratory assessments were also performed.

The appropriate study design and intention-to-treat analysis were used for this efficacy trial. Neither the patients, those assessing clinical outcomes, nor the drug safety monitoring committee were aware of treatment status. Concealed allocation to treatment group at each study site was assured through central block randomization. The results are only applicable to elderly patients.

* OUTCOMES MEASURED The primary outcome was all-cause mortality, and the secondary end point was the composite of sudden cardiac death or resuscitated cardiac arrest.

* RESULTS Treatment groups were well matched demographically and for confounding variables that might affect response to treatment. Only 1 patient from each group was lost to follow-up during a median follow-up period of 18 months. A total of 280 deaths (17.5%) occurred in the losartan group compared with 250 (15.9%) in the captopril group, with an annual mortality rate of 11.7% and 10.4%, respectively (hazard ratio=l.13; 95.7% confidence interval, 0.95-1.35; /2=-.16). Neither of these differences was statistically significant, but power may have been an issue. Similarly, there was no significant difference in the composite of sudden death or resuscitated arrests (9.0% vs 7.3%). Fewer patients in the losartan group (excluding those who died) discontinued treatment because of side effects (9.7% vs 14.7%, P [is less than] .001).

RECOMMENDATIONS FOR CLINICAL PRACTICE

Clinicians should continue to prescribe ACE inhibitors as initial treatment for elderly patients with symptomatic heart failure. Losartan was clearly not superior (or even Equivalent) to captopril in reducing all-cause mortality and should not be used as first-line therapy for these patients.

Thomas H. Trojian, MD Eric A. Jackson, PharmD University of Connecticut School of Medicine Saint Francis Hospital and Medical Center Hartford, Connecticut E-mail: ejackson2@stfranciscare.org

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