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HFpEF: Clinical trial data through the years

HF with preserved ejection fraction is recognized as a major contributor to CV morbidity and mortality and a growing health problem worldwide.

The prevalence of HF with preserved EF (HFpEF) is estimated at approximately 50% of the HF population and is associated with similar readmission and mortality rates as HF with reduced EF (HFrEF). Unfortunately, for clinicians, physicians and patients, the knowledge regarding appropriate treatment and management of HFpEF is limited.

Disease state and clinical problems

The 2012 European Society of Cardiology and 2013 American College of Cardiology Foundation/American Heart Association Guidelines for HF similarly define HFpEF as patients exhibiting signs and symptoms of HF, the presence of a normal or preserved EF ( 50%) and evidence of abnormal left ventricular diastolic dysfunction. Despite these clear criteria, diagnosis remains a challenge and is often made after excluding noncardiac causes.

HFpEF affects an elderly patient population burdened by multiple comorbid conditions. Compared with HFrEF, patients with a preserved EF will more frequently die of noncardiac causes. Current ACC/AHA treatment guidelines for stage C HFpEF include CV risk factor management and treatment of volume overload with loop diuretics. BP management has the most robust evidence regarding reducing HF hospitalization in HFpEF. Other recommendations include treating CAD and atrial fibrillation according to respective guidelines, although there has been little evidence to support these recommendations. Drug therapies used in HFrEF have had little success in reducing outcomes in HFpEF, which raises question regarding our understanding of the pathophysiology of HFpEF.

Clinical trials

ACE inhibitors/angiotensin receptor blockers/mineralocorticoid receptor antagonists

The backbone to HFrEF treatment includes targeting the renin-angiotensin-aldosterone system (RAAS) to prevent the negative effects of angiotensin II and aldosterone in HF, such as ventricular remodeling, fibrosis and hypertrophy. Although there are also neurohormonal increases in HFpEF, these targets have not yielded similar results in clinical trials.

Carolyn Hempel, PharmD, BCPS
Carolyn Hempel
Kendra Nielsen, PharmD candidate
Kendra Nielsen

The first multicenter, randomized controlled trial to be conducted in HFpEF assessed the angiotensin receptor blocker candesartan vs. placebo in the CHARM-Preserved trial. The primary outcome of CV death or HF hospitalization showed no significant difference, but there was significantly less HF hospitalization in patients assigned candesartan.

Unfortunately, these results were not replicated in I-PRESERVE, the largest randomized controlled trial in HFpEF looking at angiotensin receptor blockers comparing irbesartan vs. placebo. There was no difference in primary (death or CV hospitalization) and secondary outcomes.

PEP-CHF trial was the only study comparing ACE inhibitors vs. placebo, but results were limited due to the study being underpowered.

After two small trials in 2011 and 2013 (RAAM-PEF and Aldo-DHF) comparing mineralocorticoid receptor antagonists vs. placebo in patients with HFpEF, hope for a promising drug treatment was generated after finding improved LV diastolic function, despite the lack of improved outcomes. Clinicians anticipated results of the TOPCAT trial, a large randomized controlled trial, and the most recent trial published in HFpEF, comparing spironolactone vs. placebo with a primary outcome of composite CV death, HF hospitalization or aborted cardiac arrest. However, results showed no difference in the primary outcome, but a significant difference in HF hospitalization.

Beta-blockers and calcium channel blockers

With the success of beta-blockers in producing improved outcomes in HFrEF and promising results in a smaller trial looking at nebivolol vs. placebo patients with HFpEF, beta-blockers were later studied in two randomized controlled trials. These trials compared nebivolol and carvedilol vs. placebo, but did not find a significant difference in primary and secondary outcomes.

Verapamil has been the only calcium channel blocker studied in HFpEF. In a small, randomized, placebo-controlled study in 1990, verapamil significantly improved exercise capacity, peak filling rate and objective HF score. No study has specifically assessed the outcomes related to verapamil use in HFpEF. Unlike HFrEF, verapamil may safely be used in HFpEF and is an option for treatment as a rate-controlling agent in AF.

Other therapies

With standard pharmacotherapies for HFrEF failing to demonstrate improved outcomes in HFpEF, researchers turned to a novel class of drugs: phosphodiesterase type 5 (PDE5) inhibitors. These agents enhance nitric oxide and natriuretic peptide actions in the heart, thereby potentially enhancing vascular function and reversing cardiac remodeling.

In the RELAX trial, sildenafil (Viagra, Pfizer; Revatio, Pfizer) was compared with placebo in patients with NYHA class II to IV HF and EF of at least 50%. No significant differences were found between the two groups in the primary outcome of change in peak VO2 or secondary outcomes, leading researchers to conclude that chronic PDE5 inhibition in patients with HFpEF and no pulmonary hypertension had no effect on outcomes.

There have been many other drugs and interventions that have also been studied such as exercise training, digoxin, statins and ranolazine (Ranexa, Gilead), and although there were some beneficial findings, overall outcomes studies have not been assessed or have been limited.

A look at prior trials

There are a few reasons why there has been inconsistent evidence regarding therapies in HFpEF.

One, HFpEF is difficult to diagnose, making it difficult to enroll a consistent patient population between each trial.

Two, inclusion criteria for these studies varies between each trial and is not consistent with the guideline definitions of HF. For example, CHARM-Preserved included a HF population with an EF of at least 40%, whereas I-PRESERVE had a stricter cut off of an EF of at least 50% and no history of an EF of less than 40%. Although I-PRESERVE had less favorable results, this could indicate the inclusion of patients with systolic dysfunction in CHARM-Preserved and a population that is not well understood (HFpEF, borderline).

Three, the outcomes being evaluated include CV morbidity and mortality, but it is possible that due to the high non-CV burden of HFpEF that trials are not evaluating appropriate outcomes.

Current recommendations

The ACC/AHA guidelines include the use of angiotensin receptor blockers as an option (class IIb, level of evidence B recommendation) to decrease hospitalizations in HF.

Guidelines were published before the results of the TOPCAT trial, but it would be expected that aldosterone antagonists do not have enough evidence to support their use in HFpEF alone, especially due to the significant increase in risk for hyperkalemia.

Conclusions

One conclusion that we can draw from these studies is that although these agents may not reduce CV morbidity and mortality in HF, these agents are not harmful to use for other indications such as AF and hypertension.

The newly approved combination product sacubitril/valsartan (Entresto, Novartis) had promising results in chronic HFrEF, as seen by the PARADIGM-HF trial. In the phase 2, proof-of-concept trial PARAMOUNT, sacubitril/valsartan reduced N-terminal pro–B-type natriuretic peptide (NT-proBNP) to a greater extent than valsartan in patients with HFpEF. The drug is now currently being studied in the phase 3 trial PARAGON-HF. It is estimated that this trial will be completed by May 2019.

Based on historical information of the success of drugs that have improved outcomes in HFrEF, we should have cautious expectations of these results. Studies addressing novel targets of this disease must be done to better understand the pathophysiology and progression of HFpEF.

Disclosure: The authors report no relevant financial disclosures.

HF with preserved ejection fraction is recognized as a major contributor to CV morbidity and mortality and a growing health problem worldwide.

The prevalence of HF with preserved EF (HFpEF) is estimated at approximately 50% of the HF population and is associated with similar readmission and mortality rates as HF with reduced EF (HFrEF). Unfortunately, for clinicians, physicians and patients, the knowledge regarding appropriate treatment and management of HFpEF is limited.

Disease state and clinical problems

The 2012 European Society of Cardiology and 2013 American College of Cardiology Foundation/American Heart Association Guidelines for HF similarly define HFpEF as patients exhibiting signs and symptoms of HF, the presence of a normal or preserved EF ( 50%) and evidence of abnormal left ventricular diastolic dysfunction. Despite these clear criteria, diagnosis remains a challenge and is often made after excluding noncardiac causes.

HFpEF affects an elderly patient population burdened by multiple comorbid conditions. Compared with HFrEF, patients with a preserved EF will more frequently die of noncardiac causes. Current ACC/AHA treatment guidelines for stage C HFpEF include CV risk factor management and treatment of volume overload with loop diuretics. BP management has the most robust evidence regarding reducing HF hospitalization in HFpEF. Other recommendations include treating CAD and atrial fibrillation according to respective guidelines, although there has been little evidence to support these recommendations. Drug therapies used in HFrEF have had little success in reducing outcomes in HFpEF, which raises question regarding our understanding of the pathophysiology of HFpEF.

Clinical trials

ACE inhibitors/angiotensin receptor blockers/mineralocorticoid receptor antagonists

The backbone to HFrEF treatment includes targeting the renin-angiotensin-aldosterone system (RAAS) to prevent the negative effects of angiotensin II and aldosterone in HF, such as ventricular remodeling, fibrosis and hypertrophy. Although there are also neurohormonal increases in HFpEF, these targets have not yielded similar results in clinical trials.

Carolyn Hempel, PharmD, BCPS
Carolyn Hempel
Kendra Nielsen, PharmD candidate
Kendra Nielsen

The first multicenter, randomized controlled trial to be conducted in HFpEF assessed the angiotensin receptor blocker candesartan vs. placebo in the CHARM-Preserved trial. The primary outcome of CV death or HF hospitalization showed no significant difference, but there was significantly less HF hospitalization in patients assigned candesartan.

Unfortunately, these results were not replicated in I-PRESERVE, the largest randomized controlled trial in HFpEF looking at angiotensin receptor blockers comparing irbesartan vs. placebo. There was no difference in primary (death or CV hospitalization) and secondary outcomes.

PEP-CHF trial was the only study comparing ACE inhibitors vs. placebo, but results were limited due to the study being underpowered.

After two small trials in 2011 and 2013 (RAAM-PEF and Aldo-DHF) comparing mineralocorticoid receptor antagonists vs. placebo in patients with HFpEF, hope for a promising drug treatment was generated after finding improved LV diastolic function, despite the lack of improved outcomes. Clinicians anticipated results of the TOPCAT trial, a large randomized controlled trial, and the most recent trial published in HFpEF, comparing spironolactone vs. placebo with a primary outcome of composite CV death, HF hospitalization or aborted cardiac arrest. However, results showed no difference in the primary outcome, but a significant difference in HF hospitalization.

Beta-blockers and calcium channel blockers

With the success of beta-blockers in producing improved outcomes in HFrEF and promising results in a smaller trial looking at nebivolol vs. placebo patients with HFpEF, beta-blockers were later studied in two randomized controlled trials. These trials compared nebivolol and carvedilol vs. placebo, but did not find a significant difference in primary and secondary outcomes.

Verapamil has been the only calcium channel blocker studied in HFpEF. In a small, randomized, placebo-controlled study in 1990, verapamil significantly improved exercise capacity, peak filling rate and objective HF score. No study has specifically assessed the outcomes related to verapamil use in HFpEF. Unlike HFrEF, verapamil may safely be used in HFpEF and is an option for treatment as a rate-controlling agent in AF.

Other therapies

With standard pharmacotherapies for HFrEF failing to demonstrate improved outcomes in HFpEF, researchers turned to a novel class of drugs: phosphodiesterase type 5 (PDE5) inhibitors. These agents enhance nitric oxide and natriuretic peptide actions in the heart, thereby potentially enhancing vascular function and reversing cardiac remodeling.

In the RELAX trial, sildenafil (Viagra, Pfizer; Revatio, Pfizer) was compared with placebo in patients with NYHA class II to IV HF and EF of at least 50%. No significant differences were found between the two groups in the primary outcome of change in peak VO2 or secondary outcomes, leading researchers to conclude that chronic PDE5 inhibition in patients with HFpEF and no pulmonary hypertension had no effect on outcomes.

There have been many other drugs and interventions that have also been studied such as exercise training, digoxin, statins and ranolazine (Ranexa, Gilead), and although there were some beneficial findings, overall outcomes studies have not been assessed or have been limited.

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A look at prior trials

There are a few reasons why there has been inconsistent evidence regarding therapies in HFpEF.

One, HFpEF is difficult to diagnose, making it difficult to enroll a consistent patient population between each trial.

Two, inclusion criteria for these studies varies between each trial and is not consistent with the guideline definitions of HF. For example, CHARM-Preserved included a HF population with an EF of at least 40%, whereas I-PRESERVE had a stricter cut off of an EF of at least 50% and no history of an EF of less than 40%. Although I-PRESERVE had less favorable results, this could indicate the inclusion of patients with systolic dysfunction in CHARM-Preserved and a population that is not well understood (HFpEF, borderline).

Three, the outcomes being evaluated include CV morbidity and mortality, but it is possible that due to the high non-CV burden of HFpEF that trials are not evaluating appropriate outcomes.

Current recommendations

The ACC/AHA guidelines include the use of angiotensin receptor blockers as an option (class IIb, level of evidence B recommendation) to decrease hospitalizations in HF.

Guidelines were published before the results of the TOPCAT trial, but it would be expected that aldosterone antagonists do not have enough evidence to support their use in HFpEF alone, especially due to the significant increase in risk for hyperkalemia.

Conclusions

One conclusion that we can draw from these studies is that although these agents may not reduce CV morbidity and mortality in HF, these agents are not harmful to use for other indications such as AF and hypertension.

The newly approved combination product sacubitril/valsartan (Entresto, Novartis) had promising results in chronic HFrEF, as seen by the PARADIGM-HF trial. In the phase 2, proof-of-concept trial PARAMOUNT, sacubitril/valsartan reduced N-terminal pro–B-type natriuretic peptide (NT-proBNP) to a greater extent than valsartan in patients with HFpEF. The drug is now currently being studied in the phase 3 trial PARAGON-HF. It is estimated that this trial will be completed by May 2019.

Based on historical information of the success of drugs that have improved outcomes in HFrEF, we should have cautious expectations of these results. Studies addressing novel targets of this disease must be done to better understand the pathophysiology and progression of HFpEF.

Disclosure: The authors report no relevant financial disclosures.