What evidence based medical therapies are available for patients with heart failure with preserved ejection fraction?

Approximately 6.5 million Americans have heart failure currently, and this number is expected to rise in coming years. One half of these patients have heart failure with preserved ejection fraction (HFpEF). HFpEF is a clinical syndrome characterized by the signs and symptoms of heart failure but with echocardiographic evidence of a left ventricular ejection fraction (LVEF) greater than 50%. These patients usually have normal LV volumes and evidence of diastolic dysfunction. Notably, there are other heart failure syndromes characterized by a normal LVEF that do not fall under the definition of HFpEF. These include valvular diseases like mitral regurgitation, pericardial disease, and high output heart failure. The proportion of patients with HFpEF appears to be increasing, perhaps due to an aging population and increased rates of obesity – both factors strongly associated with HFpEF. Hypertension is the most comorbid cardiovascular disease in these patients. In fact, it is so commonly seen in these patients that HFpEF is often thought of as an end-stage manifestation of hypertensive heart disease. Perhaps the most agreed upon characteristic of HFpEF is that it is a poorly understood disease entity, and further basic, translational, and clinical research is needed. The body of evidence for HFrEF is extremely robust, with countless large randomized controlled trials (RTCs) and a plethora of proven mortality-reducing medical and procedural treatments. Unfortunately, this is not the case for HFpEF, where there are far fewer landmark trials, and results to date have been less encouraging than with HFrEF. 

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By the end of this post, you should have a basic understanding of a few of these trials and how you might counsel David. 

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The Trials

• I-PRESERVE (2008)
• TOPCAT (2014)
• PARAGON HF (2019)

I-PRESERVE (2008)

Population (N = 4,128)

• Patients older than 60 years with symptomatic heart failure + recent hospitalization, or severe symptoms (NYHA class III or IV) without recent hospitalization. All patients were required to have an LVEF greater than 45%.

Intervention

• Irbesartan 300 mg daily
• Placebo daily

Outcomes

• No significant difference in primary composite outcome of death from any cause or hospitalization for a cardiovascular cause over median follow-up of 4.1 years (36% irbesartan vs. 37% placebo)
• No significant difference in overall mortality (secondary outcome)
• No significant difference in rate of hospitalization for a cardiovascular cause (secondary outcome)

Criticism

• The degree of renal impairment and anemia were considerably lower than generally seen in this population
• There was a high rate of study drug discontinuation, which reached 34% by the end of the study
• There was a high rate of concomitant use of ACE inhibitors and spironolactone which may have left little room for further benefit from the addition of irbesartan

Other points

• Results similar to earlier CHARM-Preserved trial with candesartan and PEP-CHF with perindopril
• Majority of patients had NYHA class III symptoms
• 60% of patients were female
• Average LVEF was 60%

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TOPCAT (2014)

Population (N = 3,445)

• Patients older than 50 with symptomatic heart failure and a left ventricular ejection fraction greater than 45% 

Intervention

• Spironolactone 15-45mg daily
• Placebo daily

Outcomes

• No significant difference in composite prima19ry outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure over mean follow-up of 3.3 years (18.6% spironolactone vs. 20.4% placebo)
• No significant difference in cardiovascular mortality (secondary outcome)
• No significant difference in all-cause mortality (secondary outcome)
• Small but statistically significant reduction in hospitalizations for heart failure (secondary outcome)

Criticism

• High rate of drug discontinuation for adverse events
• Unclear if all patients actually had HFpEF
• Significant differences in practice across multinational sites 

Other points

• 2017 ACC/AHA/HFSA guidelines give aldosterone antagonists level IIb support to decrease hospitalizations in HFpEF patients with EF>45%, elevated BNP levels or recent CHF hospitalization, Cr less than 2.5, and potassium less than 5.0mEq/L
• Spironolactone was associated with significantly more hyperkalemia and increased serum creatinine, though no overall increase in serious adverse events or highly elevated Cr requiring dialysis 
• Average LVEF was 56%
• 52% of patients were female
• Majority of patients had NYHA class II symptoms

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PARAGON-HF (2019)

Population (N=10,251)

• Patients older than 50 with symptomatic heart failure and a left ventricular ejection fraction greater than 45% 

Intervention

• Sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) 
• Valsartan (target dose, 160 mg twice daily).

Outcomes

• No significant difference in primary composite outcome of total hospitalizations for heart failure and death from CV causes after a median duration of 2.9 years (12.8 vs. 14.6 events per 100 patient years)
• No significant difference in death from a CV causes (secondary outcome)
• No significant difference in hospitalizations for HF (secondary outcome)
• Significant decrease in a renal composite outcome in sacubitril-valsartan group (secondary outcome)

Other points

• Reason that sacubitril-valsartan was compared to valsartan rather than placebo is that in the community most HFpEF patients are already on an ACEi or ARB (for reasons other than HF, ie HTN, CKD)
• The trial “just”missed statistical significance
• Sacubitril-valsartan was associated with a reduction of the primary outcome in women, but not in men
• This trial contrasts with the PARADIGM-HF trial, which documented benefit from sacubitril-valsartan among patients with HF with reduced EF.

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The Bottom Line

Multiple medical therapies have proven beneficial in patients with HFrEF, but the same cannot be said for HFpEF. The large, well conducted RCTs above looked at ACE inhibitors, aldosterone antagonists, and angiotension-neprolysin inhibitors in patients with HFpEF, and all failed to show a primary outcome benefit. It should be noted that similarly robust data on beta blockers in HFpEF patients do not exist; the limited studies available do not suggest a benefit. There are hints of a positive effect throughout these trials – decreases in HF hospitalization with spironolactone and reduced mortality/hospitalization in woman with sacubitril–valsartan, in particular – but, these findings require further study in large RTCs. In the meantime, the main tools in our HFpEF arsenal remain diuretics for symptomatic overload, aggressive hypertension management, and changes in lifestyle.

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Expert’s Opinion

Arnold S. Baas, MD, FACC, FACP

Professor of Medicine, Division of Cardiology
Fellowship Director, Advanced Heart Failure and Transplant Cardiology

Ahmanson Cardiomyopathy Center
David Geffen School of Medicine at UCLA

My approach to heart failure with preserved ejection fraction: HFpEF occurs when right and left ventricular filling pressures are elevated in the setting of preserved ejection fraction – essentially significant and symptomatic diastolic dysfunction. HFpEF is a very common and heterogenous clinical entity. In fact over 50% of congestive heart failure (CHF) consists of HFpEF.  It is mostly observed in patients as they age, and is seen more often in women, those with atrial fibrillation, valvular heart disease, CKD, diabetes, and other risk factors for cardiovascular disease. 

Unfortunately the plethora of medications with strong randomized clinical trial data supporting their use in HFrEF (beta-blockers, ACE-I, ARB, ARNI, aldosterone antagonists, and ivabradine) have not translated into meaningful positive results in patients with HFpEF, as the graveyard of negative clinic trials above illustrates. While it can be tempting to use subgroup analysis and secondary outcomes to guide management, it should not be done. The trails above are negative. Recently, SGLT2 inhibitors have demonstrated positive outcomes in HFrEF. Clinical trials using SGLT2 inhibitors in HFpEF are currently underway, including EMPEROR-preserved, DELIVER , and DETERMINE.

My main approach to patients with HFpEF is to control symptoms of volume excess by use of loop diuretics or adequate dialysis in patients with renal failure. Next, I make sure their blood pressure and cardiovascular risk factors are well controlled and that they are assessed for occult CAD, valvular heart disease, and uncontrolled atrial fibrillation, all potential treatable causes of HFpEF. I do not use aldosterone antagonists in these patients for outcomes reduction, but rather as potassium sparing agents if needed for that indication. I encourage exercise as there is data to suggest it improves diastolic dysfunction. 

When cardiomyopathy with preserved ejection fraction is diagnosed, certain underlying conditions for which we actually have treatments need to be considered. These include certain infiltrative and genetic cardiomyopathies such as sarcoidosis (corticosteroids, followed by a steroid sparing regimen), hemochromatosis (iron chelation/phlebotomy), hypertrophic cardiomyopathy (negative inotropic therapy with beta-blockers, verapamil, disopyramide or septal reduction therapies such as myomectomy and alcohol septal ablation), and amyloidosis (hydroxyurea, bortezomib, or bone marrow transplant for AL amyloid or tafamadis for TTR amyloid).

Finally, if patient’s volume status is difficult to manage, placement of a CardioMems device has been shown to assist with diuretic management improving symptoms and reducing heart failure related hospitalizations. 

No conflicts of interest.

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