Diastolic heart failure and TOPCAT

The TOPCAT study, reported at the recent American Heart Association meeting in Dallas, examined the murky world of our understanding of heart failure occurring in patients with preserved left ventricular ejection fraction.

That seeming paradox has been the subject of physiologic and therapeutic controversy for some time. The realization that at least half of the patients admitted to the hospital with heart failure have normal or even supernormal left ventricular ejection fraction (HFpEF) has raised the therapeutic importance of this clinical entity. Of even more importance is the fact that patients with HFpEF exhibit morbidity and mortality similar to those heart failure patients with reduced left ventricular ejection fraction (HFrEF).

In an epidemiologic study in Olmsted County, Minnesota (N. Engl. J. Med. 2006;355:251-9), the 1-year mortality was 29% for HFpEF and 32% for HFrEF. Patients with HFpEF were more likely to be female (65.7% vs. 34.6%) and to have hypertension and atrial fibrillation than were those with HFrEF (62.7% vs. 48% and 41.3% vs. 28.5%, respectively).

Although we have significantly impacted mortality in patients who have HFrEF with the use of cardiac resynchronization therapy, implantable cardiac defibrillators, and medical therapy with beta-blockers and renin angiotensin inhibitors, we have failed to modify clinical outcomes in patients with HFpEF.

This has not been for a lack of trying. Several randomized clinical trials have been conducted with all of the drugs currently being used for HFrEF without any definitive results. An important problem in treating this population has been the heterogeneity of patients and multiple comorbidities, including chronic renal and pulmonary disease, acute hypertension, and atrial fibrillation that patients with HFpEF experience with the acute event. In addition, many of these patients are already receiving a multiplicity of concurrent therapies that have been approved for HFrEF for management.

Our understanding of the pathophysiology of HFpEF also remains cloudy. Both left and right ventricular hypertrophy with concomitant decrease in ventricular diastolic relaxation is the common observed echocardiographic abnormality. We have not as yet developed therapy for the treatment of diastolic dysfunction. Aldosterone antagonists, previously shown to be beneficial in patients with HFrEF, have emerged as likely candidates to improve HFpEF. Small clinical studies have shown improvement in diastolic function in elderly patients with hypertension and chronic renal disease. Consequently, the National Heart, Lung, and Blood Institute embarked on the TOPCAT study in 2006.

TOPCAT randomized 3,345 symptomatic heart failure patients who had a heart failure hospitalization in the previous year and with evidence of fluid retention, a left ventricular ejection fraction of more than 45%, controlled systolic blood pressure of less than 140 mm Hg, and elevated brain natriuretic peptide to treatment with placebo or spironolactone at 25 or 50 mg daily. A history of hypertension was present in 91%, coronary artery disease in 57%, atrial fibrillation in 35%, chronic renal disease in 35%, and diabetes in 32%. Patients included in the study had a mean LVEF of 56%; two thirds were in New York Heart Association class II and one third were in NYHA class III.

Over 80% of patients were receiving an ACE inhibitor or angiotensin receptor blocker, beta-blockers, and a diuretic. The mean dose of spironolactone was 25 mg. There was no significant difference in the primary outcome of cardiovascular death, nonfatal hospitalization or resuscitated cardiac arrest in the placebo and treated groups (20.4% and 18.6%, respectively). There was a significant decrease in heart failure hospitalization in the placebo compared to spironolactone patients (14.2% vs. 12.0%; P = .042). Both hyperkalemia greater than 5.5 mmol/L and an increase in serum creatinine were observed in the treated patients.

The striking observation in this trial, as it has been in previous trials, is the disparity between the epidemiologic mortality and the randomized controlled trial experience: 29% annual mortality in Olmsted County, compared with the 10.2% three-year mortality in TOPCAT. It appears that we are studying two separate diseases. And we are. After all the exclusion criteria included in the design of TOPCAT, we are unable to encapsulate the population at risk in this complex heart failure syndrome.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.