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HF with recovered ejection fraction underscores importance of reverse remodeling
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A recent study in JAMA Cardiology proposes that HF with recovered ejection fraction is a new phenotype of HF, and patients with this type of HF appear to have better outcomes than those with HF with reduced ejection fraction or HF with preserved ejection fraction.
Mary Norine Walsh, MD, FACC, medical director, heart failure and cardiac transplantation of St. Vincent Heart Center of Indiana, told Cardiology Today that the study appears to show that reverse remodeling provides a survival benefit, and the new classification could be helpful in future research. “We have long wondered what differentiates [those with recovered EF] from patients who show no response to medical or device therapies,” Walsh said.
Although these findings offer insight into the importance of reverse remodeling for patient survival, experts told Cardiology Today that the limitations of the study are a concern.
“Not enough is known or presented by the authors about baseline cardiac function other than simply [left ventricular] EF in these patients when they initially presented (eg, [right ventricular] systolic function, pulmonary artery systolic pressures, etc.) to determine whether they had a milder degree of HF than the other groups,” John T. Barron, MD, PhD, professor of medicine at Loyola University Chicago, Stritch School of Medicine, said in an interview.
Examination of a new phenotype
Andreas P. Kalogeropoulos, MD, MPH, PhD, from the division of cardiology, department of medicine, Emory University School of Medicine, and colleagues reviewed the medical records of 2,166 patients with HF (median age, 65 years; 415 women; 49% white) who received outpatient care in the Emory Healthcare system from January to April 2012. Patients were classified as having HF with reduced EF (HFrEF), HF with preserved EF (HFpEF) or HF with recovered EF (HFrecEF), defined as current LVEF greater than 40% but a previously documented LVEF of 40% or less.
Primary endpoints included mortality; a composite of death or first hospitalization for any cause; a composite of death or first hospitalization for CV causes; and a composite of death or first HF-related hospitalization. Median follow-up was 3 years.
The researchers classified 350 patients with HFpEF as having HFrecEF (16.2%; 95% CI, 14.6-17.8). Compared with those with HFpEF, patients with HFrecEF were more likely to be younger and male (P < .001 for both); less likely to have CAD (P = .004), diabetes (P < .001) and chronic kidney disease (P = .02); and more likely to have lower systolic BP (P < .001). They also were more likely, according to the researchers, to receive an ACE inhibitor or angiotensin receptor blocker regimen (P < .001), but not loop diuretics (P < .001) or digoxin (P < .001).
During the study period, patients with HFrecEF experienced reduced rates of mortality and hospitalization. Mortality occurred in 13.3% of the total cohort. During the first year of follow-up, no differences in mortality were observed between the three groups of patients with HF. However, in the second and third year, patients with HFrecEF had lower mortality rates compared with those with HFpEF (HR = 0.56; P = .02) and HFrEF (HR = 0.55; P = .01). At 3 years, age- and sex-adjusted mortality rates were 16.3% in those with HFrEF, 13.2% in those with HFpEF and 4.8% in those with HFrecEF (P for HFrecEF < .01 vs. HFrEF and HFpEF).
Compared with patients with HFpEF, those with HFrEF had less all-cause hospitalization (adjusted rate ratio = 0.71; 95% CI, 0.55-0.91), less CV hospitalization (adjusted rate ratio = 0.5; 95% CI, 0.35-0.71) and HF-related hospitalization (adjusted rate ratio = 0.48; 95% CI, 0.3-0.76), according to the researchers.
Compared with patients with HFrEF, those with HFrecEF were at lower risk for death or all-cause hospitalization (HR = 0.63; 95% CI, 0.52-0.75), death or CV hospitalization (HR = 0.34; 95% CI, 0.26-0.44) or death or HF hospitalization (HR = 0.29; 95% CI, 0.21-0.39), the researchers wrote.
Kalogeropoulos and colleagues wrote that the retrospective design of the study did not allow them “to provide insights into potential predictors of LVEF recovery, including clinical and genetic characteristics. That would require a different, longitudinal study design because our present cross-sectional approach of HF group assignment does not allow us to causally link characteristics to LVEF recovery.”
Reaction mixed
Due to the limitations of the study design, response to the data from the medical community has been cautious.
One of the study’s most important limitations was the absence of a concurrent comparator group or inception cohort, Jane E. Wilcox, MD, MSc, and Clyde W. Yancy, MD, MSc, both from the division of cardiology, department of medicine at Northwestern University Feinberg School of Medicine, wrote in a related editorial. This “could very well represent a survival bias alone, which leads us to interpret the data with interest but not yet with conviction.”
However, Wilcox and Yancy, who is deputy editor of JAMA Cardiology, wrote that the existence of this new category cannot be denied.
“It is our opinion that myocardial recovery exists, as evidenced by clinical trials, observational data and recent integration into current guidelines. Now is the time to recognize recovery as a clinical reality for patients with HFrEF and to begin a deliberate pursuit of the underlying mechanisms and future clinical considerations,” they wrote.
Barron said he does not agree with the authors that HFrecEF is a new kind of HF; rather, he said, it could reflect a less severe degree of HFrEF.
“It is well known and reported that there is incremental benefit in titrating ACE inhibitors and beta-blockers to maximally tolerated doses, so it is not surprising that this group of patients would have better outcomes,” he said.
Barron added that a major concern is the cutoff value of 40% for LVEF the authors used to categorize the patient groups. “I don’t know any cardiologist who thinks an LVEF of 40% is a ‘normal’ or ‘preserved’ ejection fraction,” he said. “Even though the authors had a supplemental analysis using 50% LVEF as a cutoff value, the main analysis utilized 40%. Remember, an LVEF of 35%, slightly less than 40% and certainly within the range of error of LVEF measurement by echocardiography, qualifies a patient for an automatic implantable cardioverter defibrillator. Future research should entail a prospective study where the patients are better matched and medical regimens are optimized.”
What everyone appears to agree upon, however, is that more study is needed.
“HFrecEF is a relatively newly defined population of patients with HF, but not a newly discovered population,” Walsh, president-elect of the American College of Cardiology, told Cardiology Today. “The investigators have rightly turned their focus to this population of patients.”
Regardless of whether HFrecEF is a new category or a milder degree of HFrEF, the data highlight the importance of providing optimal therapy to this population, Walsh said.
“These data should compel clinicians to redouble their efforts at providing HFrEF patients with optimization of guideline-directed medical therapy,” she said. – by Tracey Romero
- References:
- Kalogeropoulos AP, et al. JAMA Cardiol. 2016;doi:10.1001/jamacardio.2016.1325.
- Wilcox JE, Yancy CW. JAMA Cardiol. 2016;doi:10.1001/jamacardio.2016.1356.
- For more information:
- John T. Barron, MD, PhD, can be reached at Loyola University Chicago, Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153; email: jbarron@lumc.edu.
- Mary Norine Walsh, MD, FACC, can be reached at St. Vincent Heart Center of Indiana, 8333 Naab Road, Suite 400, Indianapolis, IN 46260; email: macwalsh@iquest.net.
Disclosures: The researchers, Barron, Walsh, Wilcox and Yancy report no relevant financial disclosures.