HFpEF: The Therapeutic Mystique Preserved

Updated:Jul 28,2014

Disclosure: None.
Pub Date: Thursday, January 22, 2009
Author: John B. O'Connell, MD, FAHA&
Article: HFpEF: The Therapeutic Mystique Preserved


Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A.,  Irbesartan in patients with heart failure and preserved ejection fraction.,  The New England journal of medicine,  359 (23) 2456-67. View in PubMed

Article Text

Heart failure with preserved ejection fraction (HFpEF) is a confusing condition of multiple etiologies and presentations. Known variously as "diastolic heart failure" or "heart failure with normal ejection fraction," it is a conundrum that is essentially defined as heart failure (HF) in the absence of obvious depression of left ventricular systolic function (EF ≥ 45%). Despite the confusion, HFpEF accounts for nearly 50% of the one-million HF hospitalizations in the US.[1] While initially viewed as a relatively benign condition, HFpEF has been shown to have mortality at least as high as, if not exceeding that of HF with demonstrable systolic dysfunction.[2,3] Multiple comorbidities contribute to this condition and the patient profile differs from those with systolic dysfunction. Patients with HFpEF tend to be older (mean age approximately 75 years) and two-thirds are women. Hypertension is the most common comorbidity (approximately 75%) and coronary artery disease less prevalent (approximately 35%). Other common comorbidities include atrial fibrillation, diabetes mellitus, chronic renal disease, and cerebrovascular disease.

Common treatment approaches incorporate therapy applied to other forms of HF. In particular, diuretics are the mainstay of therapy, yet the necessity of maintaining filling pressure to maintain cardiac output frequently results in a narrow balance between congestion and overdiuresis, resulting in potentiation of the cardiorenal syndrome. Other drugs commonly applied include beta blockade, calcium channel blockers, and angiotensin converting enzyme inhibitors (ACEI). Although digoxin has been suggested in the past, the Ancillary Digitalis Investigation Group (DIG) Trial showed no difference compared to placebo in those with HFpEF.[4] Treatments designed to ameliorate hypertension have been shown to be efficacious. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), improved blood-pressure control correlated with a reduction in hospitalizations for HF.[5] In the Hypertension in the Very Elderly Trial (HYVET), reduction in blood pressure was associated with a decrease in cardiovascular events and improved survival.[6] Controlling blood pressure is a Class 1 recommendation of the ACC/AHA Heart Failure Guidelines.[7]

The renin-angiotensin system has been deemed important in this condition because activation of this system results in hypertension, left ventricular hypertrophy, fibrosis, and vascular dysfunction. However, the Candesartan in Heart Failure (CHARM)-Preserved Trial did not detect a difference between the subjects with HFpEF receiving candesartan, an angiotensin receptor blocker (ARB), or placebo. Neither could a difference in treatment arms be detected in the Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) Trial.

Despite these negative results, enthusiasm for drugs affecting the renin-angiotensin system remains high. In that light, the much anticipated results of the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) Trial was reported to the American Heart Association's Scientific Sessions 2008 as a Late Breaking Clinical Trial by one of the co-principal investigators, Peter Carson, MD and later published in the New England Journal of Medicine.[8] Four-thousand, one-hundred and twenty-eight subjects with HFpEF (EF ≥ 45%) with current HF symptoms (NYHA Cl II-IV) and who were ≥ 60 years of age were randomized to irbesartan (titrated to 300 mg/d) or placebo in a double-blind trial. Subjects were followed out to 4.5 years with a primary end point of all-cause mortality and protocol-specified CV hospitalizations (for HF, myocardial infarction, stroke, arrhythmia). The baseline characteristics of the subjects were similar to the general HFpEF population, with 60% women, mean age 72 years, mean EF 59%, and 88% were hypertensive with a mean BP of 136/79 mmHg, while only 24% had a prior myocardial infarction. At the completion of the study, the primary end point and each of the component events showed no difference between the two arms.

While these results are disconcerting and perhaps counter intuitive, this trial does corroborate the results of CHARM-Preserved and PEP-CHF, in that it does not appear that ACEIs or ARBs will be indicated to treat the HF in this population. These agents may very well be indicated to reduce the blood pressure, which may ultimately reduce the morbidity, including HF associated with hypertension. The equally anticipated clinical trial of spironolactone in HFpEF, Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT), is ongoing and may offer more specific therapy. Until a specific agent is proven effective, HFpEF remains a therapeutic enigma.


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  5. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme or calcium channel blocker or diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT). JAMA 2002;288:2981-2997.
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  8. Massie BM, Carson PE, McMurray JJ, et al., for the I-PRESERVE Investigators. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-2467.

-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association

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