Illustrations From Other Types Of Research Studies

Many of the methodological issues of randomised clinical trials also apply to other types of research studies. The latter studies are susceptible to additional problems/biases caused by lack of randomisation, comparable control groups, and blinding. This is illustrated by the following example.

In early July 1997, the US Food and Drug Administration (FDA) reported that it had received 33 reports of unusual valvar morphology and regurgitation among users of combined fenfluramine and phentermine, "fen-phen".1516 Half of the cases, all women, who had used the drug combination from one month to more than 16 months (mean 10 months) also had pulmonary hypertension.

To determine the magnitude of the problem nationwide, the FDA strongly encouraged all healthcare professionals to report suspected cased of cardiac valvar disease associated with fen-phen use. It was know that between 1.2-4.7 million persons had been "exposed" (14 million prescriptions). Obesity clinics from five states reported echocardiographic findings from 284 subjects. The prevalence of valvulopathy was a staggering 32.8%; 22% in those with exposures < 6 months and 35% in those with longer exposures. Multiplying the number of persons exposed with the risk of valvulopathy gives a number of persons affected ranging from 130 000-500 000. These estimates, of epidemic proportions, raised several questions regarding their reliability.

A closer look at the data revealed a sampling bias. The cases in the Mayo Clinic report15 and the FDA sample had a much longer exposure than the 1.2-4.7 million users. Expectation bias created by all the publicity was another factor. The sono-graphers and the readers were not blinded and the readings were subjective (non-standardised). No consideration was given to the fact that valvulopathy is not uncommon in obese, middle aged persons.

Interestingly, the Wall Street Journal11 subsequently conducted its own survey, which among 746 persons found 57 leaky valves (8%). Subsequent scientific studies confirmed an even lower prevalence and also concluded that most cases were mild, with a large majority of confirmed cases having an exposure duration > 3 months.

Several methodologic lessons were learned: (1) defined cohorts, including unexposed persons, are more reliable sources of data than case series, (2) random sampling is preferable to self selection, (3) standardisation (explicit diagnostic criteria) trumps non-standardisation, and (4) blinded readings are superior to unblinded readings. Adjustment for "background noise" is another important consideration. Routine clinical echocardiograms are rarely of the highest scientific quality and should not be relied on for estimation of prevalence rates.

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