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New approaches needed for clinical trials in HF
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Arguably, the modern era of heart failure diagnosis and management began in the mid-1960s. It was a short time ago.
Indeed, furosemide was made available for HF therapy in 1967 and this dramatically changed the approach to dropsical patients admitted to the hospital for decompensated congestive HF. That same year, Drs. Braunwald, Ross and Sonnenblick published a seminal series in The New England Journal of Medicine on the physiology of HF that was in five parts, 50 pages, and 30 figures. It was an extraordinary work and many figures from this series have been shown, and morphed in hundreds of presentations in a variety of venues (with the authors sometimes even given credit).
In 1971, data were published from the Framingham Study and emphasized that congestive HF patients had extraordinarily poor survival rates. They looked as if they had metastatic cancer. The stage was set for dozens of randomized clinical trials that clarified the best therapeutic strategies.
Challenges of HF trials
The compendium of HF clinical trials has driven substantial improvement in outcomes for patients with HF syndromes. Nonetheless, we find ourselves wanting in the sense that HF morbidity and mortality overall is still high and unacceptable.
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Furthermore, clinical trials, important as they may be, have created a substantial problem for the clinician because most of the studies have been driven by add-on concepts with digoxin and loop diuretics originally used as baseline therapy. Subsequent piling on occurred with ACE inhibitors, beta-blockers, aldosterone antagonists, and angiotensin II receptor antagonists demonstrating that, in properly selected patient populations, morbidity and mortality could be significantly attenuated.
This philosophy of clinical trial design has generated tremendous challenge and difficulty as new concepts regarding HF therapies emerge. Have we reached the limit of baseline polypharmacy that can be tolerated?
Coupled to this has been another important and seminal change. The acceptance of the concept that HF is a broad syndrome that does not simply include patients with substantive fluid retention and congestion has allowed study of a broader spectrum of patients. Furthermore, HF does not mean that patients solely have systolic left ventricular dysfunction. The understanding that a variety of degrees of left ventricular systolic and diastolic dysfunction contribute to the syndrome was an important step forward.
One of the most significant recent accomplishments was the development of HF descriptive stages by the American College of Cardiology and American Heart Association. Controversial is the fact that Stage A HF included those patients only at risk for developing HF without having structural heart disease or traditional symptoms of HF. Stages B, C and D are a bit less controversial in that structural heart disease can be found with symptomatic presentation varying with syndrome severity.
Accepting this staging system turns appropriate attention to the prevention of syndrome development in the first place, or progression from asymptomatic HF states to ones with substantive symptomatology associated with higher morbidity and mortality.
Improving HF trials
As mentioned, clinical trials play an important role in the every cycling evidenced-based medical practice we now tout so much. Still, however, clinical trials have many problems in addition to the polypharmacy challenge already noted. Clinical trials are rigid and inflexible tools. It is hard to evaluate the art of medicine in a clinical trial, and we must remember that clinical trials can only address a limited number of questions with some, perhaps, not particularly important.
Furthermore, the lengthy duration of most clinical trials means intercurrent advances are often ignored.
One can also argue that clinical trial study populations are highly biased and a large sample size is often required to show small but statistically significant results. Obviously the cost is enormous and the studies are performed largely by the health care industry to pursue regulatory approval of therapies. Surgical and intervention trials have their own set of challenges.
Nonetheless, clinical trials do provide the most precise and valid study of treatment outcomes while characterizing risk/benefit ratio and defining adverse events. Indeed, the importance of clinical trials is affirmed by the fact that all therapeutic guidelines issued to date have been based on clinical trial outcomes. What should we do and where should we go?
We cannot abandon such an important tool as the clinical trial. However, to have a broader effect on HF morbidity and mortality we will have to think more about how evidence leading to truthful conclusions is obtained. Perhaps relying more on natural history studies, including large registry efforts, will be helpful. Certainly we hope to see fewer add-on clinical drug trials as polypharmaceutical approaches to any disease or syndrome limits patient compliance and is clinically problematic.
Since most agents studied in this fashion have hemodynamic effects, we are limited with respect to the number of vaso-active medications we can give. Perhaps we will be brave enough one day to pit one strategy against another. Is a beta-blocker and aldosterone antagonist as good as an ACE inhibitor coupled to an AII receptor antagonist? Is one approach superior to the other? Additionally, blocking individual receptor sites may not be adequate to force a beneficial de-remodeling in HF, as the number of receptors is great, heterogeneous and redundant.
Perhaps we should drive our clinical trials with better patient selection. Unfortunately only about 30% of a study population in HF clinical trials today seem to respond to therapy even though overall the trial is positive. This is vastly different than in trials of many antimicrobials. By gaining more insight into HF pathophysiology, hopefully we will be able to define more specifically which patients benefit from which specific therapy. Exploring the pharmacogenetic and genominic issues seem essential to accomplishing this particular mission.
Also important is the fact that we usually study a highly heterogeneous group of patients, and some might argue that there is no reason to believe that a patient with HF due to ischemia and CAD will behave in the same fashion as a HF patient with mitral regurgitation being the primary etiology. Along this line we need to do a better job of studying patients with diastolic HF or HF clinical syndromes in a setting of preserved LV systolic function. Though representing half of all patients admitted to the hospital with decompensated congestive HF, we have yet to study these patients adequately.
Finally, future HF clinical trials must better represent a real world clinical practice and have patient entry specifically linked to older, female, and multiple comorbidity groups. Clinical trials generally have not done a good job of characterizing comorbidities in the HF setting and, in particular, diabetes, renal insufficiency, and anemia have been largely ignored.
The future may be bright for new approaches to prevent and treat HF syndrome, but it is clear that new and creative approaches are mandatory for best defining therapeutic safety and efficacy and better driving future guideline development.
James B. Young, MD, is Chairman of the Division of Medicine at the Heart and Vascular Institute at the Cleveland Clinic and Section Editor of the Myocardial Disorders, Heart Failure and Transplantation section of Cardiology Today.