Editor—The conundrum of the HOPE (heart outcomes prevention evaluation) study is resolved.1 Why was there no relation between blood pressure and outcome? Answer: Because ramipril was taken at bedtime.
Separate papers in the BMJ and Lancet reported that risk reduction for stroke and cardiovascular end points in the HOPE study were much greater than could be accounted for by the small reduction in measured blood pressure.2,3 Both papers suggested that ramipril had brought about a specific beneficial effect unrelated to blood pressure lowering. However, neither paper mentioned when the ACE inhibitor dose was taken in relation to blood pressure measurement.
A previous report by an overlapping authorship reported that HOPE “is the only large trial in which an antihypertensive agent, according to the study protocol, has been recommended to be given at bedtime” and that blood pressure was measured on the following day, between 12 and 18 hours later.4 This report of 24 hour blood pressure monitoring on a subset of HOPE subjects confirmed that the bedtime dose of ramipril brought about a pronounced effect on overnight blood pressure (decrease of 17/8 mm Hg) but no significant reduction in blood pressure when measured the following day. The time course of action of ramipril was clearly demonstrated, with a peak effect between 3 and 6 hours after administration. The effect had waned by 12 hours after administration.
There is no reason to believe that the pharmacodynamics of ramipril observed in the 38 Swedish patients studied over 24 hours would differ appreciably from that of the rest of the subjects. This is so even though they were slightly older, had more vascular disease, and were taking fewer blood pressure lowering drugs than the rest of the HOPE study population.
Unfortunately lack of clarity remains. A subsequent letter by the authors stated that “in some people (but not all) ramipril was taken at night.”5 The authors must come clean. Just how many of their subjects followed the original protocol and took ramipril at night? What was the fall in office blood pressure in those who did take their treatment in the morning? Does this change the conclusions of their BMJ and Lancet papers?2,3
Competing interests: None declared.
References
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