Fenfluramines, idiopathic pulmonary primary hypertension and cardiac valve disorders: facts and artifacts.

The fenfluramines saga began in 1963 and ended in 1997. Fenfluramines are anorexigenic agents recommended, in April 1996, for the long-term treatment of obesity in USA, before being suddenly withdrawn from the market in September 1997. Over 34 years, about 60 million people were exposed to these drugs worldwide, mainly in Europe. The aim of this critical review is not to attempt to rehabilitate these appetite suppressants but to launch a plea for a more rational and rigorous approach to what might be called objective medical knowledge. Idiopathic primary pulmonary hypertension and cardiac valve disorders which have been both associated with fenfluramines have in common many puzzling features. The metamorphosis of facts into artifacts is only a hypothesis, but seems conceivable from a scientific point of view. Medicine is not only an art, it is also a science, which, like the others, implies adhesion to certain fundamental rules, such as refutation or verification of all experimental results by rigorous and standardized methods, before considering them as established facts. Firstly, a single study, moreover a case-control study like the International Primary Pulmonary Hypertension Study, is not sufficient to establish a causal relationship between exposure to appetite-suppressants and idiopathic pulmonary hypertension, because of the numerous biases which characterize even the best analytical research. Secondly, Doppler-echocardiography cannot be considered as a laboratory test, because of the poor interoperator reproducibility observed in obese patients. The use of this technique in pharmaco-epidemiology implies standardized procedures concerning not only reading data, but also their acquisition, because of possible uncontrolled interactions between sonographers, patients and sophisticated machines. In the case of the fenfluramines saga, numerous methodological artifacts concerning acquisition, processing and interpretation of epidemiologic and echocardiographic data might have contributed to distortion of reality. Let us recall how Webster's dictionary defines artifact: "a spurious observation or result arising from preparatory or investigative procedures or any feature that is not naturally present but is a product of an extrinsic agent, method, or the like".