Acute renal failure and open heart surgery.

SIR,-I can understand and have some sympathy with the irritated comments of Dr. P. M. S. Gillam (11 March, p. 685) on the two trials of clofibrate in the treatment of ischaemic heart disease. One finds that not only patients but also some doctors (who cannot have read the two papers) are expecting that the symptom of angina will improve as soon as the drug is consumed. There is no evidence and has been no claim for this whatever. But I must answer his criticism of the Newcastle trial, for which I bear much responsibility. Regarding "the most important criticism"-namely, that non-cardiac deaths have not been reported-the facts are that I have records of seven patients who withdrew because of illness and later died-four of them in the clofibrate group (three dying of cancer) and three in the placebo (one dying of cancer). If these figures, which are I suspect incomplete, are added to the Scottish ones, which are believed to be complete, then we have 12 known deaths in the clofibrate group (six from cancer and four from cerebrovascular accidents) and 13 in the placebo (six from cancer and two from cerebrovascular accidents). Doubtless some patients in both trials who withdrew for reasons other than illness died later of non-cardiac causes before the 51 years of the trials were completed, the most frequent causes being, as in the above list, cancer and cerebrovascular accidents. One can only say that there is no evidence at all that clofibrate either prevents or precipitates these maladies. The wisdom of admitting patients to the trial on the basis of history alone can indeed be questioned. but less than a quarter of the patients had normal E.C. G.s, and it is hard to believe that when all of them were personally selected by experienced consultant physicians as suitable for a trial more than a tiny fraction would be wrongly diagnosed. Regarding status on entry, some of the parameters were so obviously similar in the treated and controlled groups as not to need statistical analysis. In the remainder, including for example smoking habits on entry, statistical tests were applied, and in no instances were differences significant at the 5% level discovered. Regarding the subsequent fate of the clofibrate patients who withdrew from the trial, it is difficult to see how this can have much bearing on the conclusions. The great majority of them certainly discontinued the drug. If they fared better than the placebo group it would strengthen the trial results in which Dr. Gillan does not believe. If they fared worse it could, as with anticoagulant therapy, be attributed to a rebound ill effect from stopping treatment. It seemed to us best just to disregard them. Finally Dr. M. F. Oliver and I were well aware of the dubiety of combining the results of two trials whose criteria of entry differed. We did not therefore combine the figures, except in one instance-the nonfatal infarcts. We simply set them close together for easy comparison, and for the same reason preceded them with a full exposition of those differing criteria. Dr. W. H. S. St. John-Brooks's strictures (18 March, p. 750) cover some of the same points, but he also refers to others of some importance. He states that in the relatively few females in the trial and in those patients on anticoagulants the causative factors and the course of their ischaemic heart disease might well differ significantly from what they would be in the uncoagulated males. This is very true, and it is one of our regrets that in the design of the trial females were included. It was our hope that patients on anticoagulants would not be included but the trial was mounted at a time when there was more confidence in their value than there is today, and several physicians did not care for that treatment to be discontinued on entry, and some patients were put on it during the course of the trial when they were doing badly. Because of this, as Dr. St. John-Brooks noted, the mortality of those on anticoagulants was greater than that of the remainder. It was also, he may note, equal in the clofibrate and the placebo groups. Because this anticoagulant group comprised so many with a poor prognosis it seemed to us wisest in the analysis to include them. For the same reason we included against Dr. St. John-Brocks's objections, those who withdrew from the trial up to the time of that withdrawal. If clofibrate had made the patients so much worse from repeated infarcts and/or angina that they had insisted on withdrawingwould Dr. St. John-Brocks have wished them still to be excluded? One cannot have it both ways. Finally his composite statement of some of the Newcastle results is founded on the selection of those where the advantage to clofibrate attained statistical significance. There were several others where owing to lack of numbers the advantage, though clear and consistent, did not attain this level. In the same way, though it is true that some of the advantageous results could have been thrown up by chance, it is unlikely that this would have happened to the same results in both the Newcastle and Scottish trials, and it is for this reason that we think that the protection, especially against sudden death, afforded to patients with angina is probably genuine. Like Dr. Oliver I would be delighted if a new trial of male patients with angina only could be mounted to confirm this point. -I am, etc.,