"In the neutral megatrials some of the patients did not have HFPEF but had other disorders such as deconditioning and obesity – things that cannot be helped by treatments directed at the heart. We need to identify the patients who will respond to the treatment," said Dr. Burkert M. Pieske, professor and director of cardiology at the Medical University of Graz, Austria.
The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) results reported last November exemplified the problem of patient heterogeneity. The study enrolled more than 3,400 patients in six countries: Argentina, Brazil, Canada, Russia, the Republic of Georgia, and the United States. Retrospective analysis showed that among patients in the placebo group, the primary endpoint of death or heart failure hospitalization during follow-up occurred at a rate of 12.6 events/100 patient-years among the 881 patients treated in the four Western Hemisphere countries, and at a rate of 2.3 events/100 patient-years among the 842 patients treated in Russia or Georgia, a greater than fivefold difference between the two subgroups.
"As a whole, the patients in Russia and Georgia had a lower event rate and were certainly less severely ill than the other patients, but they supposedly still had heart failure. Defining this disorder is difficult, and when a patient has signs and symptoms of heart failure and preserved ejection fraction you may not be certain that heart failure is causing the symptoms. That’s why many people think that we should use another criterion" to define HFPEF in trials, such as elevated serum level of some form of natriuretic peptide, said Dr. Solomon, a TOPCAT coinvestigator. By design, patients could enter TOPCAT either because of a recent heart failure hospitalization, which is how 72% of patients got in, or by having a threshold level of natriuretic peptide, the way the remaining 28% entered the study. Within the subgroup enrolled by natriuretic peptide level, spironolactone treatment had a statistically significant effect in reducing the primary endpoint, while in the other 72% the drug produced no discernable benefit over placebo.
Dr. Barry A. Borlaug
"TOPCAT had funding problems, recruitment problems, and monitoring problems. There was not enough money for good monitoring," said Dr. Pieske, who did not participate in TOPCAT. The patients enrolled in Russia and Georgia were "unbelievably stable," with their 2.3/100 patient-years event rate. "Even if the drug works, it can’t exert an effect if there are no events."
Dr. Pieske ran a much smaller study of spironolactone involving 422 patients with HFPEF, the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial, which showed efficacy for the endpoint of improved diastolic function but not for the co-endpoint of improved exercise capacity (JAMA 2013;309:781-91).
"If you look at TOPCAT and Aldo-DHF together and ask, does spironolactone work, the answer is yes if you select the right patients, those with clear evidence of cardiac functional abnormalities and increased natriuretic peptide levels or documented hospitalization for heart failure. The drug clearly works in these patients, but there were enough inconsistencies in these trials so that this will not get into the treatment guidelines," Dr. Pieske said in an interview.
"Spironolactone provides most benefit in patients who are volume overloaded, have right-heart failure, or both. These are also the patients most likely to have elevated natriuretic peptide. Spironolactone does not seem to benefit as much early-stage HFPEF," noted Dr. Shah.
Dr. Scott D. Solomon
Several experts cautioned that because the TOPCAT results failed to produce a statistically significant benefit for the study’s primary endpoint, any other conclusions from the results must be made very cautiously, and several also said that they wanted to see the full, published results which had not appeared as of late February. They also noted that many patients with HFPEF, most likely a majority, do not have elevated blood levels of natriuretic peptide.
Where HFPEF management stands now
Evidence-based guidelines for the specific treatment of HFPEF are simple. There aren’t any.
The American Heart Association/American College of Cardiology heart failure management guidelines released last October made no disease-specific treatment recommendations (J. Amer. Coll. Cardiol. 2013;62:e147-e239). They call for controlling hypertension in patients who need intervention by prevailing standards, treatment with a diuretic in patients with volume overload, coronary revascularization if coronary disease is present, and management of atrial fibrillation if that’s present. The European Society of Cardiology’s guidelines issued in 2012 say pretty much the same (Eur. J. Cardiol. 2012;33:1787-1847), except they add this statement: "No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFPEF."