Heart Failure Therapy What Should Clinicians Believe

HEART FAILURE WITH PRESERVED EJECTION FRACtion is a syndrome of volume overload and exertional intolerance marked by myocardial stiffness. Sophisticated investigations have also delineated multiple other pathophysiologic mechanisms, including vascular and renal dysfunction, chronotropic incompetence, energetic and metabolic derangements, and contractile abnormalities. However, other than the clinical similarities with heart failure with reduced ejection fraction, there is little evidence to support the notion that the 2 conditions are related pathophysiologically. Moreover, these disorders appear to be distinct and not part of a continuum of disease. Although basic science, observational studies, and clinical trials support heart failure with reduced ejection fraction as a condition of neurohormonal activation, the same is not true for heart failure with preserved ejection fraction. In fact, renin-angiotensin system antagonism with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in heart failure with preserved ejection fraction has not been effective—although not harmful—in randomized trials to date. Yet, these trials have significant limitations, including issues of power, selection bias, and crossovers. In this issue of JAMA, Lund and colleagues use a large, well-characterized registry to further explore the use of ACE inhibitors and ARBs in heart failure with preserved ejection fraction. Using the Swedish Heart Failure registry of 41 791 patients (n=16 216 with heart failure with preserved ejection fraction), the authors report that use of renin-angiotensin system antagonists in heart failure with preserved ejection fraction was associated with a statistically significant reduction in mortality (HR, 0.91; 95% CI, 0.85-0.98, P= .008) after the necessary adjustments for confounding factors, such as differences in baseline characteristics between those treated and not treated with renin-angiotensin system antagonists. The authors also use clinical trial techniques, eg, calculation of sample size to strengthen their analysis. Strengths of the study include the size of the cohort, the completeness and rigor of data collection, and careful propensity matching. In addition, the investigators provide consistency analyses that demonstrated both a dose-response association and confirmation of renin-angiotensin system antagonist benefit in a population with heart failure with reduced ejection fraction who were drawn from the same registry. Importantly, the authors also note that, in contrast to randomized trials involving patients with heart failure with preserved ejection fraction, the patients in their registry more accurately reflect those treated in routine clinical practice. However, there are important limitations that should be considered in the interpretation of the study by Lund et al. For example, the heart failure with preserved ejection fraction population studied was defined by a left ventricular ejection fraction (LVEF) of 40%, which represents significant systolic dysfunction. Despite the lack of an interaction between LVEF and the mortality benefit of renin-angiotensin system inhibition, the authors note that the nominal benefits were attenuated among patients with LVEF of more than 50%. Furthermore, heart failure was defined clinically by a large number of practitioners who had variable specialty training, thereby calling into question who was being treated. Also, it is not known whether renin-angiotensin system antagonists were specifically prescribed for the treatment of heart failure per se or for another condition, such as hypertension. In fact, there was a significant interaction P value noted for blood pressure in the analysis. A concomitant analysis using a different class of antihypertensive agents would have been of interest. At the heart of the matter is whether any set of sophisticated statistical techniques can ever fully account for confounding in an observational study. Variability among health care practitioners, time-dependent changes in health status and medical therapy, and differences in socioeconomic status are all important sources of confounding that are not fully accounted for by measured covariates and not only influence the decision to use specific drugs but are known to independently be related to outcomes. In fact, as further statistical adjustments are made to the findings, the magnitude of the benefit declines. The limitations that the au-