LETTER TO THE EDITOR
Reply
Andrew J. Burger, MDa
a BI Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
Phentermine and Fenfluramine (phen-fen) were popular medications for the treatment of obesity. After the Mayo clinic report (1), numerous anecdotal reports and several small, nonrandomized observational surveys (2) described significant, unsuspected cardiac pathology in patients formerly on these drugs. Although the methodology of these surveys differed, the prevalence of valvular disease meeting the Food and Drug Administration case definition for significant valvular regurgitation was similar in all five surveys and ranged from 30 to 38% (overall: 32.8%). These findings alarmed both the medical community and the general public. There was a great concern that a "virtual epidemic" of valvular disease was upon us.
In our study (3) only 18 subjects (8%) had significant valvular regurgitation as defined by Food and Drug Administration criteria. The most common finding was mild or greater aortic insufficiency in 15 subjects and 3 subjects with moderate mitral regurgitation. No subjects had severe regurgitation of any valve. The dose or duration of medications did not appear to be significant.
Our study is just another piece of the puzzle; it is not the final answer. Our data showed a much lower prevalence of valvular heart disease. As stated in the article, our study has multiple limitations. First, all subjects did not have an echocardiographic evaluation. However, all patients were followed clinically. All patients were asymptomatic; no new murmurs were found, and no subjects underwent cardiac surgery. No significant clinical differences were found between subjects who had echocardiograms performed and those who did not. Our study could be biased to overestimate the prevalence of valve disease because subjects who returned for an echocardiogram may have been concerned about a heart problem, while those who did not return were not.
Second, our study noted the inherent inaccuracies that exist in differentiating relatively mild degrees of valvular regurgitation, that is, trace versus mild aortic regurgitation (since most studies to date have found mild aortic regurgitation to be the problem). The differentiation of trace from mild degrees of valvular regurgitation is subjective and problematic, especially when trace is considered normal and mild is considered a "disease." Furthermore, it is very important to distinguish between a clinical diagnosis and an echocardiographic finding.
Third, heart valves degenerate over time and become "leaky." A significant proportion of healthy men and women have detectable valvular regurgitation by color Doppler. This is not a disease, and these subjects will probably never develop a clinical syndrome. These valvular abnormalities represent age-related degenerative changes. The Food and Drug Administration’s criteria for valvular regurgitation are too narrow and arbitrary, and the case definition for pathologic regurgitation needs to be modified and age-specific.
Fourth, our study did not have a control group. Our informal comparison to the Framingham study (4) was done only to assist the reader’s understanding of the prevalence of valvular regurgitation in phen-fen users and in the normal population. After reproducing Doctors Moye and Annegers’ analysis, we then used our study population to estimate the expected prevalence of valve disease based on the published Framingham data. We found the prevalence ratio for mitral and aortic regurgitation to be 0.67 and 1.29, respectively. However, we found an error in their calculation of the total expected prevalence, which should have been a weighted average expected prevalence. With this correction, the prevalence ratio for mitral and aortic regurgitation becomes 1.34 and 3.13, respectively (Table 1).
Finally, the true risk of diet drugs to cause pathologic valvular regurgitation is still unknown. Initial reports suggested a possible epidemic of valve disease with the prevalence up to 38% of users. Our study questions the degree to which phen-fen therapy contributes to valvular regurgitation. Long-term, prospective, randomized, controlled investigations with a sufficient number of patients are needed. However, the general public and the medical community should be reassured by our study that the severity of the problem is probably much less than initially thought.
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References
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1. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med. 1997;337:581–588[Abstract/Free Full Text]
2. Bowen R, Glicklich A, Khan M, et al. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health Recommendations. Morb Mortal Wkly Rep. 1997;46:1061–1066[Medline]
3. Burger AJ, Sherman HB, Charlamb MJ, et al. Low prevalence of valvular heart disease in 226 phentermine-fenfluramine protocol subjects prospectively followed for up to 30 months. J Am Coll Cardiol. 1999;34:1153–1158[Abstract/Free Full Text]
4. Singh JP, Evans JC, Levy D, et al. Prevalence of valvular regurgitation in a population based cohort: Framingham heart study. Am J Cardiol. 1999;83:897–902[CrossRef][Medline]
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