The PACK trial: morbidity and mortality effects of ketanserin. Prevention of Atherosclerotic Complications.

A total of 3899 patients over 40 years old who had documented intermittent claudication for at least 2 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 were recruited in a double-blind, randomized, placebo-controlled trial after a single-blind run-in period of placebo treatment for 1 month. Trial drug was ketanserin 40 mg three times daily. The first primary event after randomization was the endpoint. Primary events were definite myocardial infarction, major stroke, amputation above the ankle, excision of ischaemic viscera, and death due to other vascular causes. There were 136 study endpoints in the 1930 patients treated with ketanserin, who were followed up for 2063 patient-years, and 132 study endpoints 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 excluded, a secondary analysis showed that there were 65 endpoints in 1514 patients taking ketanserin and 87 in 1577 patients taking placebo, a reduction of 23% in the number of study endpoints in those taking ketanserin. The treadmill walking distance and ankle systolic pressure were measured in a predetermined subset of 594 patients. Complete datasets at the beginning and end of 1 year's treatment with ketanserin or placebo were available in 436 patients. There was no difference between the groups in the improvement in pain-free treadmill walking distance. The placebo effect on treadmill walking distance increased continuously for at least 1 year at the rate of about 15% every 6 months. There was no significant change in either group in the ankle systolic pressure at the end of the treatment period, but, in the group given ketanserin, brachial systolic pressure was decreased and the ankle/arm systolic pressure ratio therefore increased.