Valvular heart disease associated with fenfluramine-phentermine
Other reportsIn the same issue of the New England Journal of Medicine is a letter to the editor from the Graham and Green of the FDA detailing further cases of valvular heart disease associated with appetite suppressants. 28 patients had taken fenfluramine-phentermine; 6 of these underwent surgery. They also mention several cases associated with fenfluramine alone, dexfenfluramine alone and dexfenfluramine plus phentermine.
Another letter to editor describes a single case of valvular disease associated with dexfenfluramine use.
In a brief report, elsewhere in the same issue, Mark et al describe a case of fatal pulmonary hypertension associated with short term (23 day) use of fenfluramine-phentermine.
CommentThe study by Connolly et al provides two types of evidence implicating the combination fenfluramine-phentermine in the pathogenesis of valvular heart disease. These are pathological findings similar to those seen in patients with carcinoid tumors and ergotamine toxicity, and echocardiographic evidence. The pathologic findings are convincing because of the specific lesions seen, but only 5 cases are presented. The echocardiographic findings are far less specific, but there were 19 cases. Taken together, along with a plausible mechanism (serotonin-related), the evidence is persuasive and worrisome.
Since this was not a study with a well-defined means for recruiting cases and without "controls", it is subject to bias. One way these findings could be spurious is if the cases had been actively recruited. If, for example, surgeons who had heard about this problem had referred 5 cases with "peculiar valve morphology" who had taken fenfluramine-phentermine, while failing to report 100 other cases with similar valve morphologies who had not taken these drugs, and if the use of these agents was prevalent in 5% of the population, then the association would be purely due to chance.
This is certainly not the case here. The authors specifically state that no attempt was made to recruit cases. It is unlikely that many other patients with such a distinctive surgical pathology went unreported, although the authors do not address this point specifically.
Because of the specificity of the pathology, these few surgical cases are more convincing than the echocardiographic cases, although these were more numerous.
I had planned to discuss the implications of these findings for drugs other than the fenfluramine-phentermine combination, in particular for monotherapy with dexfenfluramine, but as I was starting to write about this, television news reported that both fenfluramine and dexfenfluramine are being taken off the market in the United States.
The question that will now arise is how to evaluate the many patients who have taken these drugs recently. How many people are at risk for the development of valvular disease? Hopefully, more epidemiologic data will soon become available to help answer this question.
September 15, 1997
September 16, 1997
In today's New York Times there is further information on the decision to recall dexfenfluramine and fenfluramine. It is reported that in one recent study of 291 asymptomatic women who had taken fen-phen, echocardiography revealed valvular abnormalities in one third of them. Furthermore, in a subset of 24 women who had had prior normal echocardiograms, abnormalities were discovered in 8. These are obviously remarkable numbers, if they are confirmed.