Risk of valvular heart disease associated with use of fenfluramine

Abstract

Background: Estimates of excess risk of valvular heart disease among prior users of fenfluramine and dexfenfluramine have varied widely. Two major forms of bias appear to contribute to this variability and also result in a systematic under-estimation of risk. The first, a form of nondifferential misclassification, is the result of including background, prevalent cases among both exposed and unexposed persons in calculations of risk. The second bias results from not considering the relatively short duration of exposure to drugs.

Methods: We examined data from all available echocardiographic studies reporting the prevalence of aortic regurgitation (AR) and mitral regurgitation (MR) among persons exposed to fenfluramine or dexfenfluramine and a suitable control group. We also included one study in which previously existing AR or MR had been excluded. We corrected for background prevalent cases, estimated incidence rates in unexposed persons, and performed a person-years analysis of apparent incidence rates based on exposure time to provide an unbiased estimate of relative risk.

Results: Appearance of new AR was strongly related to duration of exposure (R2 = 0.75, p < 0.0001). The summary relative risk for mild or greater AR was 19.6 (95% CI 16.3-23.5, p < 0.00001); for moderate or greater MR it was 5.9 (95% CI 4.0-8.6, p < 0.00001).

Conclusion: These findings provide strong support for the view that fenfluramine and dexfenfluramine are potent causal factors in the development of both aortic and mitral valvular heart disease.

Figure 1

Effect of adding cases from competing causes on the odds ratio in a case control study. In this hypothetical example of 500 exposed and 500 unexposed persons, when no extra cases were added (far left) there were 18 cases of disease in the exposed and 2 cases among the unexposed yielding an odds ratio of 9.30 (p value = 0.0007). Adding an equal number of cases due to unrelated causes to both the exposed and unexposed groups results in dilution of the odds ratio. The odds ratio drops below 2 after 16 cases are added and becomes non-significant after 21 cases are added (representing just 4.2% of exposed or unexposed groups).

Figure 2

a. Prevalence of mild or greater aortic regurgitation by duration of exposure compared with controls. Adapted from data presented in Jollis, et al (reference [13]). b. Rationale for present study using data from figure 2a. The controls are considered to provide an estimate of the background or baseline risk of AR prior to exposure (shown in dark grey). Prevalent cases beyond this estimated background rate were considered to have arisen during the period of drug exposure, thus providing an estimate of incidence (white portion of bars).

Figure 3

Estimated percent of incident cases with mild or greater AR arising during the exposure period (± 95% confidence intervals) versus duration of exposure to fenfluramine or dexfenfluramine. Some studies provided multiple point estimates based on different exposure times. The midpoint of the duration interval was used to plot these observations. Expected incident cases were calculated using the pooled estimate described in the text.

Figure 4

Estimated percent of incident cases with moderate or greater MR arising during the exposure period (± 95% confidence intervals) versus duration of exposure to fenfluramine or dexfenfluramine.