Clinical trials in cardiovascular medicine: are we looking for statistical significance or clinical relevance? | Heart

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Clinical trials in cardiovascular medicine: are we looking for statistical significance or clinical relevance?

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Application of clinical trial results
Pitt O Lim
Published on: 9 January 2022

Published on: 9 January 2022
Application of clinical trial results
- Pitt O Lim, Lecturer in Cardiovascular Medicine
Dear Editor:
I read with interest Kübler’s review[1] and Willenheimer and colleagues’ viewpoint[2] on a similar theme about the application of drug trial results in clinical practice, an area that remains controversial.
Florey’s penicillin trial in the 1940s only involved 8 mice. The mice were inoculated with streptococci and only the four that were treated survived. Such simplistic demonstration of a positive...
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Dear Editor:
I read with interest Kübler’s review[1] and Willenheimer and colleagues’ viewpoint[2] on a similar theme about the application of drug trial results in clinical practice, an area that remains controversial.
Florey’s penicillin trial in the 1940s only involved 8 mice. The mice were inoculated with streptococci and only the four that were treated survived. Such simplistic demonstration of a positive drug effect is unfortunately not possible in preventative cardiovascular medicine where multiple factors are at work. The advent of modern drug trials however has allowed the efficacy of many cardiac drugs to be proved, but only with an assumption of homogeneity in large numbers of study patients. The call for more “overly” inclusive trials by Willenheimer and colleagues such as the HOPE study could potentially be problematic. This empirical approach “treats the many to benefit the few”. This invariably removes the need for any understanding of the individual pathophysiologic process resulting in unnecessary multiple drug therapy in many patients. Also, this encourages an unhealthy “pill-pushing” culture and not enough on the need for lifestyle modification. For example, the benefit of cholesterol lowering with a statin is completely negated by smoking.[3]
For a given drug trial, theoretically there will be 4 outcome groups:
(a) those who survive because of a positive drug effect
(b) the vast majority whose survivals are not dependent on treatment
(c) those whose deaths are contributed by adverse drug reactions
(d) those whose deaths are inevitable; either due to inadequate drug effect or alternate pathophysiology.
If (a) > (c) then (a) divided by (a) + (c) + (d) gives the relative risk reduction, in many positive cardiovascular trials, this being greater than 25%. The problem is, it is necessary to treat a large number of patients to uncover a drug effect.
As pointed out by Willenheimer and colleagues, the survival of “32” out of 696 heart failure patients treated in the US carvedilol trial established the statistical efficacy of the drug. In other words, 19 out of every 20 patients treated did not benefit from the drug as a whole (the inverse of number needed to treat). Unfortunately, it is not possible to distinguish (a) from (b) patients. There is therefore room to find reliable markers of drug efficacy (or the lack of) to monitor the progress of drug treatment. The lack of drug efficacy in (c) and (d) patients should perhaps be more carefully explored clinically, and post-mortems should be carried out if feasible. Some would argue that the (b) patient population would also benefit from drug-induced alteration of the disease process. This however has not yet been borne out in population mortality curves which appear to have flattened out.[4]
Pitt O Lim
Department of Clinical Pharmacology and Therapeutics
Ninewells Hospital
Dundee, DD1 9SY UK
References
(1) Kubler W. Treatment of cardiac diseases: evidence based or experience based medicine? Heart 2000;84:134-6.
(2) Willenheimer R, Dahlof B, Gordon A. Clinical trials in cardiovascular medicine: are we looking for statistical significance or clinical relevance? Heart 2000;84:129-33.
(3) Isles CG, Norrie J. Lipid lowering drugs for patients who continue to smoke? Heart 2000;83:619-20.
(4) Fuster V. Epidemic of cardiovascular disease and stroke: the three main challenges: presented at the 71st scientific sessions of the American Heart Association - Dallas, Texas. Circulation 1999;99:1132-7.
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Conflict of Interest:
None declared.
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