A Randomized Double-Blind Trial of Enalapril in Older Patients With Heart Failure and Preserved Ejection Fraction

Abstract

Background-Exercise intolerance is the primary symptom in older patients with heart failure and preserved ejection fraction (HFPEF); however, little is known regarding its mechanisms and therapy. Methods and Results-Seventy-one stable elderly (70Ϯ1 years) patients (80% women) with compensated HFPEF and controlled blood pressure were randomized into a 12-month follow-up double-blind trial of enalapril 20 mg/d versus placebo. Assessments were peak exercise oxygen consumption; 6-minute walk test; Minnesota Living with HF Questionnaire; MRI; Doppler echocardiography; and vascular ultrasound. Compliance by pill count was excellent (94%). Twenty-five patients in the enalapril group versus 34 in the placebo group completed the 12-month follow-up. During follow-up, there was no difference in the primary outcome of peak exercise oxygen consumption (enalapril, 14.5Ϯ3.2 mL/kg/min; placebo, 14.3Ϯ3.4 mL/kg/min; Pϭ0.99), or in 6-minute walk distance, aortic distensibility (the primary mechanistic outcome), left ventricle mass, or neurohormonal profile. The effect size of enalapril on peak exercise oxygen consumption was small (0.7%; 95% CI, 4.2% to 5.6%). There was a trend toward improved Minnesota Living with HF Questionnaire total score (Pϭ0.07), a modest reduction in systolic blood pressure at peak exercise (Pϭ0.02), and a marginal improvement in carotid arterial distensibility (Pϭ0.04). Conclusions-In stable, older patients with compensated HFPEF and controlled blood pressure, 12 months of enalapril did not improve exercise capacity or aortic distensibility. These data, combined with those from large clinical event trials, suggest that angiotensin inhibition does not substantially improve key long-term clinical outcomes in this group of patients. This finding contrasts sharply with observations in HF with reduced EF and highlights our incomplete understanding of this important and common disorder. (Circ Heart Fail. 2010;3:477-485.)

Prognostic Impact of Myocardial Interstitial Fibrosis in Non-Ischemic Heart Failure - Comparison Between Preserved and Reduced Ejection Fraction Heart Failure -

“…Although ARB and ACEI could decrease myocardial fibrosis in HFPEF, 4,35,36 large clinical trials failed to demonstrate any beneficial effects of ARB or ACEI (eg, irbesartan, candesartan, enalapril, and valsartan) in patients with HFPEF. [37][38][39][40] This is consistent with the present finding that no significant correlation was noted between myocardial fibrosis and cardiac events in the HFPEF group, suggesting that the prognostic impact of myocardial fibrosis might be small in HFPEF. It has been previously reported, however, that in approximately 20% of patients with HFPEF, LVEF was significantly decreased during the 3-month follow-up period, 41 which is consistent with the present study, in which LVEF was significantly decreased in 11% of patients with HFPEF during follow-up.…”

Clinical Phenotypes in Heart Failure With Preserved Ejection Fraction

“…Lowering neurohormonal activation has unexpectedly failed to improve clinical outcome in large, placebo‐controlled, randomized HFpEF trials 20, 21, 22, 23, 24. Diagnostic uncertainties may partially account for the lack of therapeutic benefit 29, 76, 77.…”

“…The large, all‐inclusive, randomized, placebo‐controlled therapeutic trials approach that led to great therapeutic progress in HFrEF has not worked so far in HFpEF 20, 21, 22, 23, 24, 25, 26, 27. Such discrepancy is, in part, attributable to overt differences in the pathogenesis and progression of HFpEF and HFrEF.…”

“…However, little therapeutic progress was made 20, 21, 22, 23, 24, 25, 26, 27. Among the issues that may account for the modest therapeutic progress, one appears to be overwhelming: HFpEF is not a well‐defined clinical entity: It is an amalgam of cardiovascular, metabolic, renal, and geriatric conditions 28, 29.…”

Global dyssynchrony correlates with compromised left ventricular filling and stroke volume but not with ejection fraction or QRS duration in HFpEF

“…Furthermore, HFpeF has been shown to share similar mortality to that of HFreF 4 urging the need for serious identification of stringent treatment polices. Randomized clinical trials have succeeded in establishing the important role of pharmacological treatment of HF with reduced eF, but they failed to do so in patients with HFpeF [5][6][7] suggesting the lack of clear understanding of the pathophysiology of the syndrome as well as various mechanisms for symptom development. likewise, cardiac resynchronization therapy (CRt) has proved successful in improving HFreF patient's symptoms and survival [8][9][10] , particularly in those with clear evidence for electrical and mechanical dyssynchrony.…”