April 11th, 2013
Treatment of Heart Failure with Preserved Ejection Fraction: Why Have All the Clinical Trials Failed, and What Can We Do About It?
We invited Sanjiv Shah, MD, author of a recent editorial in JACC:HF on heart failure with preserved ejection fraction (HFpEF) to answer some of our questions on what we do and don’t understand about this condition and how we are closing the gap.
Dr. Ryan: Are the negative trials that are seen in HFpEF a result of the disease process or the trials?
Dr. Shah: I think it’s a little bit of both, but primarily a problem of trial design. HFpEF is a heterogeneous syndrome with multiple etiologies and pathophysiologies, and it is also a syndrome of the elderly who typically have many competing risks for morbidity and mortality. I like to use the analogy of cancer to describe the problem with HFpEF clinical trials. Imagine a world where we designed clinical trials to tests new drugs for “cancer” regardless of type. That would seem silly to us, and yet that’s what we do for HFpEF. We take a heterogeneous syndrome and we try to use a “one size fits all” approach. I believe that if we are able to come up with a categorization system for HFpEF, we may have better luck designing clinical trials for therapies targeted at specific subsets of HFpEF.
Dr. Ryan: You mention in your editorial that we need “an established paradigm for the routine testing” of patients with HFpEF. Why have we failed to define a standardized work up for HFpEF patients?
Dr Shah: The first problem is that HFpEF is not easy to diagnose. There is no low ejection fraction to easily spot and call it “heart failure”. HFpEF is a common syndrome but I believe that it is often missed because so many other disease processes can present like HFpEF. So there has to be a low threshold to think about the diagnosis so that we can diagnose it more routinely and then work it up in a standardized fashion. The next problem is that currently several types of providers care for patients like HFpEF (which is necessary because HFpEF is common). However, family practice physicians, internists, cardiologists, and heart failure specialists may work up HFpEF patients in very different ways, and no one type of physician is necessarily more correct than the other. Nevertheless, until we have good evidence-based diagnosis and management protocols for HFpEF, we need dedicated HFpEF clinical programs to facilitate clinical trials and other research in this area. Such research would help us develop the standardized protocols that physicians sorely need when diagnosing and managing these patients.
Dr. Ryan: What is your idea to improve the trials and outcomes in HFpEF and why is it important?
Dr. Shah: As I alluded to above, I think the most important first step would be to develop a rational classification system for HFpEF, and then develop targeted therapies for HFpEF subgroups based on etiology and pathophysiology. In addition, I believe that clinical trials would benefit from more specific enrollment criteria for HFpEF patients. However, adding additional inclusion criteria for HFpEF clinical trials (e.g., requiring a certain degree of left atrial enlargement, the presence of elevated pulmonary artery pressure, or a specific cut-off for tissue Doppler e’ velocity) would likely make enrollment more difficult. It is therefore critically important to develop dedicated HFpEF clinical programs simultaneously with more targeted clinical trials. In our own HFpEF program at Northwestern, we have shown that having a dedicated HFpEF program facilitates enrollment into clinical trials. In addition to establishing HFpEF specialty centers that can enroll large numbers of patients, my hope is that we can harness the power of deep phenotyping of HFpEF patients (in multiple phenotypic domains) and that these results will allow us to match the right treatments to the right patients, thereby improving the outcomes for this common and morbid syndrome.