Diet-Drug-Related Cardiac Valve Disease: Surveillance Methods for Obesity Clinical Research

By Toni Bransford, M.D., FACC Senior Medical Director, Medical & Scientific Affairs, Cardiovascular Disease, Worldwide Clinical Trials,

Prevalence of obesity has reached and surpassed epidemic proportions, with trends in cardiovascular risk factors such as hypertension, hyperlipidemia, and diabetes, rising in parallel leading to an excess of cardiovascular events.

Obesity Clinical Research, Diet Drug Valvulopathy

Thus the need not only exists but is increasing for treatment that can effectively reduce body mass index. However, using anorexigens comes with a price. The most common ”go-to” drug-associated method of weight loss utilizes serotonin pathways to suppress appetite and thus lower weight. Yet these agents have been shown to lead to valvular heart disease similar to carcinoid heart disease. This was never more graphically demonstrated than with the observational Connolly et al, report of 24 obese/ overweight subjects with mitral and aortic regurgitation associated with the fenfluramine-phentermine combination(1). The FDA subsequently received additional reports from requests to over 700,000 physicians and institutions ultimately leading to the request for voluntary withdrawal of fenfluramine and dexfenfluramine(2).

However these agents are still available, can be used in research for other indications, and newer, more sophisticated iterations of these diet drugs are under evaluation. Thus there is still potential for valvulopathy risk. This writing reflects on case definitions of significant valvular disease, and appropriate surveillance measures for cardiac valve disease, and medical management.

Case Definitions of Diet Drug Valvulopathy

Although valvular lesions are noted on both right and left sides of the heart, a left-heart valve is affected in virtually all cases, therefore case definitions are focused on left heart valvular lesions, and particularly regurgitation. Minimal degrees of regurgitation are seen frequently in the general population, and are not considered abnormal. Minimal regurgitation is considered trace aortic regurgitation and trace to mild mitral regurgitation. Moderate or greater mitral regurgitation and mild or greater aortic regurgitation meets the FDA Criteria for the case definition of diet-drug associated valvulopathy after exposure to these agents.

Surveillance measures for Diet-Drug Induced Valvular Lesions

Echocardiography (echo) provides a simple, easy to perform, and accurate method of documenting and quantifying cardiac valvular disease and thus is the method of choice for valvulopathy surveillance. Both 2D and Doppler echo should be performed to examine for cardiac valvular disease. 2D echo can be used to assess for vavlular fibrosis, the histopathological lesion that occurs with increased serotonin activity affecting the serotonin receptors on cardiac valves. With valvular fibrosis comes valvular insufficiency because of the restricted, abnormal valve closure resulting from this fibrosis. Additionally, 2D allows for optimization of the angle of inference for your Doppler probe (both Color and pulse wave) examination, which can have a significant effect on how accurately the valvular regurgitation is quantified. Quantification of regurgitant lesions should be in accordance with the American Society of Echocardiogrpahy guidance, which notes use of the jet area, PISA, or vena contracta methods of quantification into mild, moderate, or severe(3). One or a combination can be used to quantify the lesion and all are more accurate than the”eyeball method” or simple planimetry of the jet lesion without comparison to the 2D area.

This full echo examination should be performed at baseline for all patients that will be administered these agents. Repeat echo examinations should be performed within 6 months and again within 9-12 months for patients that are on the drugs for longer than 3 months(2). Data has established that diet drug use for less than 6 months is associated with a much lower prevalence of valvular lesions than diet drug use of 6 months or greater. If this surveillance will be part of an observational or randomized controlled study, which will be reviewed by health authorities, then echo readings should be performed by an echo core reading lab facility rather than a central reader(4). Echo care labs will have quality control measures in place that will prevent temporal reader drift. Additionally, the readings can be organized so that completed blinded paired echo readings (baseline, 6 months, end of treatment, follow-up) can be performed rather than reading each component separately. This will allow for a better comparison of valvular lesion trends for an individual blinded patient and thus increases accuracy. This type of reading is better than simple batch reading, although a combination batch-paired reading may actually be the best method, as it combines the best features of paired reading with the reduction in temporal drift seen with batch reading.

Management of Diet-Drug Valvulopathy

In the vast majority of these cases, valvular lesions stabilized or regressed when the diet drug is discontinued and therefore, it is enough to continue to monitor the valvular lesion similar to monitoring non-diet drug valvular lesions, as long as the lesion is not severe. Severe regurgitation should be treated similar to non-diet drug associated valvulopathy with medication and/ or surgery as needed. There are no guidelines for management of diet-drug valvulopathy, therefore until specific guidelines are available, the clinician should consider managing these patients using the standard valvular regurgitation section of the ACC/AHA guidelines for the management of valvular heart disease.

This data will most certainly impact current and future research with obesity drugs and obesity drugs used for alternate indications. Our Worldwide Clinical Trials experts are well-versed in managing complex cardiovascular disease trials for these types of drugs and in guiding the appropriate regulatory entities and sponsors in disease monitoring and management.

References

  1. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581–8.
  2. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997;46:1061–6.
  3. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003 Jul;16:777-802.
  4. Douglas PS, DeCara JM, Devereux RB et al. ASE Expert Consensus Statement: Echocardiographic Imaging in Clinical Trials; ASE Standards for Echocardiography Core Laboratories. J Am Soc Echocardiogr. 2009 Jul;22:755-65.

Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:2438-88.