Prevention of atherosclerotic complications: Controlled trial of ketanserin

Study objective - To determine whether ketanserin, an antagonist at the serotonin receptor, prevents important vascular events such as death, myocardial infarction, major stroke, and amputation of a leg in patients with claudication. Design - Double blind, randomised, placebo controlled trial after a single blind run in period of placebo treatment for one month. Setting - One hundred and forty seven outpatient clinics in 14 countries. Patients - Total of 3899 patients over 40 years old who had had documented intermittent claudication for at least two months and in whom the ratio of systolic blood pressure in the ankle to that in the arm was ≤ 0.85 in both arteries of at least one foot. Intervention - After the one month placebo run in period patients were randomly allocated to take 20 mg ketanserin three times daily for the first month and 40 mg three times daily thereafer or to take the same number of placebo tablets. Five months after the onset of the trial, on the recommendation of the ethical and safety committee, four patients stopped taking ketanserin and two stopped taking placebo because they had a corrected QT interval > 500 ms. Four months later the committee recommended that all patients taking diuretics should stop receiving trial treatment (167 of those taking ketanserin and 144 of those taking placebo). End point - The first primary event after randomisation. Primary event were definite myocardial infarction, major stroke, amputation above the ankle, excision of ischaemic viscera, and death due to other vascular causes. Measurements and main results - There were 136 study end points in the 1930 patients treated with ketanserin, who were followed up for 2063 patient years, and 132 study end points in the 1969 patients treated with placebo, who were followed up for 2129 patient years. A harmful interaction of ketanserin and potassium losing diuretics resulted in an increase in the number of deaths. After patients taking potassium losing diuretics or antiarrhythmic agents were included a secondary analysis showed that there were 65 end points in 1514 patients taking ketanserin and 87 in 1557 patients taking placebo, a reduction of 23% in the number of study end points in those taking ketanserin. Conclusions - Ketanserin can prolong the corrected QT interval, and the combined use of ketanserin and potassium losing diuretics can be harmful. A secondary analysis suggested a protective effects of ketanserin against cardiovascular complications in patients with claudication.