Diastolic Heart Failure Has Increased While Survival Stalls

ROCHESTER, Minn., July 19 -- Although the prevalence of heart failure with preserved ejection fraction has increased, survival rates for these patients with diastolic heart failure remain similar to those with a reduced ejection fraction, according to two studies.

In the first study, Mayo Clinic physicians here found that over 15 years (1987 to 2001) at a single institution, the prevalence of heart failure with a preserved ejection fraction (50% or higher) increased, while the death rate from this disorder remained unchanged, they reported in the July 20 New England Journal of Medicine.

In a comment on the terminology used in this study, Margaret Redfield, M.D., and colleagues wrote that because the American College of Cardiology and the American Heart Association use the nomenclature "preserved ejection fraction" (diastolic heart failure) and "reduced ejection fraction" (systolic heart failure), this nomenclature was employed, although it is controversial.

In the study of 4,596 consecutive heart-failure patients with available ejection fraction data, 53% had a reduced ejection fraction (less than 50%) and 47% had a preserved ejection fraction (50% or higher). Patients were classified as community or referral patients.

The prevalence of preserved-ejection-fraction patients with a discharge diagnosis of heart failure increased over time, going from a mean 38% to 47% to 54% in the three consecutive five-year study periods, the researchers said.

This increase was also seen when the preserved ejection fraction was defined as greater than 60%. In addition, the increase was significantly higher among community patients than among referral patients.

The increase was because of a rise in the number of patients admitted with preserved ejection fraction, with no significant change in the number of patients admitted with reduced ejection fraction, the researchers pointed out.

The survival rate was slightly higher among patients with preserved ejection fraction versus those with lower ejection fractions (unadjusted hazard ratio for death, 0.96; P=0.01). The rates remained even after adjustments for baseline characteristics.

On the other hand, the survival rates for patients with a preserved-ejection fraction did not change significantly over time. By contrast, survival rates for patients with a reduced ejection fraction improved throughout the study, with an unadjusted hazard ratio for death of 0.98 per year (95% CI 0.97-1.00; P=0.005). Trends were similar when ejection fraction cut-offs were changed to 60% versus less than 40%, the researchers said.

During this period, the hypertension rates for all the patients increased from 48% to 53% to 63% in the three consecutive study periods (r=0.98, P<0.001); atrial fibrillation rose from 29% to 33% to 41% (r=0.90, P=0.001), and diabetes increased from 32% to 33% to 36% (r=0.65 P =0.008). By comparison, the prevalence of coronary artery disease was stable at 59%, 58%, and 59%.

Overall, the prevalence of preserved ejection fraction among all patients with a discharge diagnosis of heart failure was 49% among patients age 65 or older and 40% among those under age 65. Patients with a preserved ejection fraction were older, more likely to be female, and had a higher mean body-mass index.

Speculating on possible causes for the increase in heart-failure patients with a preserved ejection fraction, the researchers suggested that the increase could be related to changes associated cardiovascular disease, such as atrial fibrillation. Hypertension and diabetes, which increase over time in these patients, are also common in heart failure patients with preserved ejection fraction.

Changes in physician behavior with an increased propensity to diagnose heart failure in these patients may also account for the increase, they said.

Referring to variable, often conflicting reports from other studies, the investigators pointed to a variety of methodologic differences in other studies, such as the inclusion of patients with milder heart failure and the lack of uniformity of patients in some cohorts.

As for their own study, the researchers noted that it is subject to the limitations inherent in all retrospective studies. They also cited the restriction of the study to hospitalized patients and the lack of ejection fraction data from some patients.

In summing up, Dr. Redfield said, the increase in the prevalence of heart failure with preserved ejection fraction over time and the continued stability of the death rates, underscore the need for studies to determine the pathophysiology of this form of heart failure and the development of therapeutic strategies.

"Because no proven therapy for heart failure with preserved ejection fraction currently exists, there is a need for coordinated efforts to address this growing problem," she concluded.

Dr. Redfield reported having received grant support from Biosite, Scios, Medtronic, Guidant, Alteon, and St. Jude Medical.

In similar findings from a second study in the same NEJM issue, survival of patients with heart failure and a preserved ejection fraction could not be distinguished from that of patients with a reduced ejection fraction, according Peter Liu, M.D., at the University of Toronto and colleagues there and at the Framingham (Mass.) Heart Study.

Between 1999 and 2001, the researchers studied 2,802 patients admitted to 103 hospitals in the province of Ontario, with a discharge diagnosis of heart failure and an available ejection fraction. Patients (13%) with borderline ejection fractions of 40% to 50% were excluded for the most part to permit clearer distinctions, the researchers explained.

In a comparison of those with an ejection fraction of less than 40% (56% of patients) and those with a fraction of more than 50% (31% of patients), the unadjusted mortality rates for the patients with a preserved ejection fraction were not significantly different from those for patients with a reduced fraction at 30 days (5% vs. 7%, P=0.08) and at one year (22% vs. 26%, P= 0.07), the Dr. Liu reported.

Adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; CI, 0.94-1.36; P=0.18). In addition, the rates of readmission for heart failure and for in-hospital complications did not differ between the two groups, the researchers said.

Patients with a preserved ejection fraction were older (75 versus 72), were more likely to be female (66% versus 37%), and had a significantly higher rate of hypertension (55% vs. 49%) than those with a reduced ejection fraction. They also had significantly higher rates of atrial fibrillation and chronic obstructive pulmonary disease. On the other hand, they had lower rates of other modifiable cardiac risk factors, including smoking, diabetes, and hyperlipidemia.

A strength of this study, Dr. Liu said, is that it included only patients admitted to the hospital during the first episode of heart failure, and all subjects were required to meet the Framingham criteria for heart failure, so that the study compared patients at the same point in the evolution of the disease. Also, the study included patients from small and large community hospitals as well as academic teaching institutions.

Other clinical trials have found a large difference in mortality between the two ejection-fraction groups, with an advantage for patients with a preserved ejection fraction, the researchers said.

However, the largest of these, the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trials, enrolled patients who were significantly younger (average age 67 versus 75), were predominantly male, were more heterogeneous, and were enrolled at different points in their disease, they noted.

In reviewing the limitations of their own study, the researchers mentioned that only 42% of possible patients had a documented assessment of left ventricular function, the assessment of ejection fraction could not be standardized, they could not control for the decision-making process that led to the admission of the patient in the first place, and the possibility that physicians were less likely to admit a patient with a normal ejection fraction.

Summing up, Dr. Liu said that the approximately one-third of patients admitted with heart failure had an ejection fraction of more than 50%, and such patients could not be reliably distinguished from those with an ejection fraction of less than 40% on clinical grounds.

The one-year mortality rates in the two groups, he said, were similar; the morbidity rates were similar; and the absolute mortality rates among patient with a preserved ejection fraction were higher than previously reported.

In an accompanying editorial, Gerard Aurigemma, M.D., of the University of Massachusetts in Worcester, started with a few words about the terminology controversy. He wrote that although the currently preferred term "heart failure with preserved ejection fraction" is not incorrect, he prefers the term "diastolic heart failure," saying that it better describes the "underlying pathophysiological features and has connotations familiar to the clinician."

The principal conclusions of these studies, he said, may come as a surprise. "These data challenge the widely held perception that the survival among most patients is inversely related to the ejection fraction, or at least for ejection fractions below 45%."

Asking how one can reconcile these findings with the apparently contradictory results of large earlier studies, he suggests that the differences may relate to patient characteristics and the growing recognition of diastolic heart failure by clinicians.

In both studies, Dr. Aurigemma noted, the mean age was older for those with diastolic failure so that these patients were more likely to have co-existing medical conditions. Also, he said, the Mayo physicians studied only patients who survived long enough to be discharged, thereby overlooking a possible higher rate of in-hospital mortality among the systolic-failure patients.

"I concur with the authors' observations that owing to increasing awareness, clinicians are more likely to admit a patient to the hospital in 2001 than previously," Dr. Aurigemma wrote. The bad news, he said, is the finding that there has been little improvement in survival rates among patients with diastolic heart failure, in contrast to the improvement in survival over time among patients with systolic heart failure.

He pointed out that 22% to 29% of patients with diastolic heart failure die within one year of hospital discharge, and 65% die within five years -- a reminder that this is a lethal condition.

The improvement in the survival rates of patients with systolic heart failure suggests that emerging treatment strategies for diastolic heart failure, such as the use of angiotensin-receptor blockers, might eventually have a clinical effect, he said. Among preventive measures, he mentions antihypertensive therapy and the prevention of a myocardial infarction as the best means of keeping the ejection fraction "preserved."

Above all, Dr. Aurigemma said, "the development of specific, effective management approaches for diastolic heart failure must also become a high priority."

Dr. Aurigemma reported receiving consulting fees and grant support from Novartis and grant support from Biosite.