Invited Editorial Suggests Protocol Changes for Federally-Funded Studies

November 2, 2010

A cardiologist and heart failure researcher at Wake Forest University Baptist Medical Center has published an editorial calling for new mandates by the National Institutes of Health (NIH) and U.S. Food and Drug Administration (FDA) for all federally-funded studies.

The suggestion draws on the idea that studies in heart failure are not painting a truly accurate picture of the disease, often excluding the kinds of participants who are most commonly afflicted, according to the editorial, published in the Nov. 3 issue of the Journal of the American Medical Association (JAMA)

In the article, Dalane W. Kitzman, M.D., suggests funding by the NIH be tied to a requirement that investigators include in their grant applications the expected age range of study participants and clearly defined plans to enroll people in age ranges relevant to the specific disease, as it occurs in the general population. The suggestion mimics a similar step, controversial at the time, taken by the NIH in 1992 to address disparities in medical research for women and minorities. The mandate prohibited male-only studies and required researchers applying for federal funding to demonstrate that at least 50 percent of the participants would be women.

Kitzman’s invited editorial coincides with the American Heart Association’s fall Scientific Sessions to be held in Chicago later this month.  

“Heart failure (HF) affects more than 5 million Americans, accounts for nearly $40 billion in annual health care expenditures in the United States, is associated with severely increased morbidity, mortality, and reduced health-related quality of life, and is the only major cardiac disorder that is increasing in the U.S.,” Kitzman explained in his editorial. “Importantly, HF is overwhelmingly a disorder of the older population. HF prevalence increases inexorably from middle to old age, with no abatement even into the 10th decade of life. It is the most common reason for hospitalization among Medicare recipients, and its lethality and complications increase progressively with age.” 

Yet, despite the enormous public health implications of HF, there has been relatively little progress over the past 20 years in improving outcomes for older patients with the condition, Kitzman said, explaining that one reason for this is that there are actually two different types of heart failure, one of which wasn’t recognized or acknowledged as a true form until recently. Heart failure with preserved left ventricular ejection fraction (HFPEF), the most common form of HF, has largely gone unrecognized as a genuine condition until just a few years ago.  

As a result, much of the HF research conducted to date has been concentrated on HF with reduced ejection fraction (HFREF), the kind of heart failure most common among middle-aged individuals, mostly men. These studies are often designed with upper age limits as part of the exclusion criteria, preventing people above a certain age from participating in the trials. The focused efforts have resulted in about 100 randomized clinical trials among more than 50,000 participants in just over two decades.  

In contrast, during the same period, only one large clinical trial was reported in patients with HFPEF, which exists most often in the general public, and is almost exclusively seen in people 60 years and older, and mostly in women. As of 2010, only four trials in HFPEF have been reported, yet more than two-thirds of women over 60 who have HF have this form, which is nearly non-existent in middle-aged men, the most studied group.  

“We’ve ended up in the seemingly bizarre situation where most of the data to guide heart failure treatment from the last two decades are not applicable to the majority of patients with this condition,” Kitzman said. “We have enormous amounts of data, literature and recommendations pertaining to HFREF, which is the less common form of HF and occurs most often in a subgroup of people who aren’t the most likely to be affected by HF. Yet we are still left with very few answers about HFPEF, which is the form that will affect the most people. A doctor who takes care of the typical patient with HF constantly has to wonder if the available data and guidelines for treatment are applicable.” 

Often, Kitzman explained, individuals over the age of 60 who have HF, also have several other conditions or diseases, called comorbidities, which may muddy research results and that is why they have traditionally been excluded from study enrollment. However, since the vast majority of HF patients have multiple co-morbidities, he said, excluding patients who have other conditions further promotes research results that do not apply to the majority of the patients who have HF. In the editorial, invited by JAMA, Kitzman challenges the NIH and the FDA to consider taking positive measures when evaluating requests for research funding:  

  • Require that all federal grant applicants determine the true age distribution of people who have the disorder to be studied in the general population, and require them to include in their proposals clearly defined plans for how they intend to enroll participants that reflect that distribution. For example, if a condition most commonly occurs in the elderly, a study proposal should include more recruitment effort and funds to be dedicated toward reaching out to seniors in the community to ensure participation. Kitzman is calling for the NIH to mandate that federally funded research include representation by the types of people who actually have the disorder, an act similar to that taken in addressing the disparities in women and minorities in the past.
  • Lift age cutoffs on research proposals so as to get a good look at the disorder being studied across all age ranges, even if the results in older individuals with more comorbidities may ultimately need further follow-up to clearly understand findings in these subgroups.
  • Scrutinize the frequently long list of exclusion criteria to include broader representation. Kitzman said excluding participants from studies because they have multiple health issues and comorbidities leads to findings that may not apply to most patients. The most valid reason for excluding patients with a particular comorbidity is if participation by those individuals would present a safety concern, he said.

“This approach would lead to new insights into diseases that can be immediately applied to helping the patients who actually have them,” Kitzman said. “No longer would clinicians have to wonder whether a newly released medication or device is applicable to the typical patients seen in their clinics.” 

Kitzman calls for support from the research community for his proposal, adding that such requirements would, undoubtedly, spark objections much like those heard when the NIH mandated attention to the inclusion of women and minorities. Investigators quickly learned how to achieve the new goals back then, he points out, as they surely would for age-appropriate inclusions today. 

In the end, Kitzman said, when it comes to HFPEF, “we have a lot of catching up to do. The current system lacks integrity when it uses public funds to produce research results that do not apply to a large majority of the population affected. Future trials should do better, and a modest investment in effort and cost could pay great dividends.”  

The editorial was coauthored by another leading researcher in heart disease among older individuals, Michael W. Rich, M.D., from Washington University in St. Louis.   

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