Statins Might Help in HFpEF—Even in the Absence of ASCVD

Starting a statin may improve outcomes in patients with heart failure with preserved ejection fraction (HFpEF) who are initially free from atherosclerotic cardiovascular disease (ASCVD), according to a study of US military veterans.

Over a median follow-up of 6 years, new statin users had lower risks of all-cause mortality, MACE, any hospitalization, and HF-related hospitalization compared with those who didn’t start a statin, researchers led by Ariela Orkaby, MD (VA Boston Healthcare System and Brigham and Women’s Hospital, Boston, MA), and Parag Goyal, MD (Weill Cornell Medicine, New York, NY), report in a study published recently in JACC: Advances.

The definite conclusion, he said, “is that if you have a HFpEF patient and they have an indication for a statin, you have to really make sure the patient takes a statin if at all possible.”

Beyond that, “this does indicate that statins may be useful for HFpEF even without high risk, but that needs to be tested in a randomized clinical trial,” Joseph added.

Indeed, despite the fact that the study was well done, it remains an observational analysis with all of the inherent limitations, commented Mary Norine Walsh, MD (Ascension St. Vincent Heart Center, Indianapolis, IN), a past president of the American College of Cardiology. In particular, the vast majority of patients (96%) were men and even with statistical adjustments, it’s difficult to account for the fact that clinicians decided that statin therapy was warranted in some patients and not others, she pointed out.

“So I don’t know that there’s any kind of take-home message like we should be thinking of statins in general for HFpEF patients,” Walsh said. “We should probably think of statins for HFpEF patients who have high risk of cardiovascular disease.”

And she agreed that “the only way to really answer this question is a randomized trial.”

Groundwork for a New RCT

Though statins have proven their effectiveness for the primary and secondary prevention of ASCVD, their benefits in patients with heart failure are unclear. Two statin trials have focused on patients with preexisting heart failure, CORONA and GISSI-HF, with both demonstrating no significant impact on outcomes. Thus, guidelines don’t recommend statins for patients with heart failure in the absence of other indications.

Most of the patients in those two trials, however, had heart failure with reduced ejection fraction (HFrEF), and there is observational evidence—albeit with the usual limitations—suggesting that statins may be beneficial in patients with preserved ejection fraction.

To further explore this issue, the investigators conducted a study that incorporated Veterans Health Administration electronic medical record data, Medicare and Medicaid claims and pharmaceutical data, and information from the National Death Index. The analysis included 7,970 veterans (mean age 69 years; 96% men) with a diagnosis of HFpEF between 2002 and 2012 who were followed through April 8, 2016; all had no known history of ASCVD or statin use. Mean ejection fraction was 60%.

Slightly fewer than half of patients (47%) initiated statin therapy during follow-up. The most commonly prescribed statin was simvastatin (76%), followed by lovastatin (9%), atorvastatin (7%), and pravastatin (6%). Others were used by fewer than 1% of patients.

There were two co-primary outcomes: all-cause mortality and MACE (CABG/PCI, incident MI, MI-related mortality, incident stroke/TIA, and stroke-related mortality). After adjusting for baseline differences between statin users and nonusers with propensity score overlap weighting, statin initiation was associated with lower risks of both all-cause mortality (HR 0.78; 95% CI 0.73-0.83) and MACE (HR 0.79; 95% CI 0.74-0.84).

If you have a HFpEF patient and they have an indication for a statin, you have to really make sure the patient takes a statin if at all possible. Jacob Joseph

Results were consistent across subgroups for mortality, but for MACE, there were significant interactions with sex and ASCVD risk category indicating a benefit among men, but not women, and a greater effect among those with an ASCVD risk of 5% to 9.9% versus patients with a lower or higher risk.

Patients who started taking a statin during follow-up also had lower risks of all-cause hospitalization (rate ratio 0.69; 95% CI 0.60-0.80) and HF hospitalization (rate ratio 0.72; 95% CI 0.59-0.88), with results that did not differ significantly across subgroups.

The study, the researchers say, “has important implications on a two-decade search for a therapy to improve survival in HFpEF; in particular, it strengthens the foundation for a potential RCT to examine the effect of statins in HFpEF.”

Potential Mechanisms

How statins might be positively impacting outcomes in HFpEF isn’t clear, the investigators say. They note that because there appeared to be benefits irrespective of ASCVD risk, it indicates that statins may be helping in ways other than addressing atherosclerosis. They suggest statins could be easing inflammation, a key issue for patients with HFpEF, or providing benefits mediated by reduced risks of atrial fibrillation and improvements in frailty.

“Taken together, our work here further supports the need for additional mechanistic studies that include detailed cardiovascular imaging data and biomarkers, as well as extracardiac markers of aging such as physical frailty,” they write.

They also call for a trial of statins in patients with HFpEF and no prior ASCVD, noting that the drugs “have a unique mechanism of action compared to other guideline-directed agents for HFpEF, most of which were not in routine use for HFpEF during the study period. This provides additional rationale for statins to serve as add-on therapy for patients with HFpEF, though more evidence is needed.”

I don’t know that there’s any kind of take-home message like we should be thinking of statins in general for HFpEF patients. Mary Norine Walsh

Speculating about why statins may have a greater benefit in HFpEF than in HFrEF, Joseph said one possibility is that “heart failure with preserved ejection fraction as we currently define it is a condition that is associated with a lot of comorbidities that may later contribute to the increased incidence of cardiovascular and other events.” But, he added, it’s difficult to draw firm conclusions without randomization and without mechanistic substudies.

The Likelihood of a Future Trial

In an accompanying editorial, Varun Sundaram, MD, PhD (Louis Stokes Cleveland Veteran Affairs Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH), and colleagues say “this well-conducted study has yielded important hypothesis-generating observations on the clinical efficacy of statin for primary prevention in a well-defined real-world HFpEF cohort with reliable long-term follow-up.”

They also see a need for an RCT to confirm any potential benefit of statins in this setting but point to the challenges of conducting such a study, since it would need to exclude patients with no prior statin indication. They note, for example, that 69% of patients in the EMPEROR-Preserved trial of empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) in HFpEF were already taking statins when they entered the study.

Walsh agreed that a trial of statins in patients with HFpEF and no established ASCVD would be difficult, pointing out, too, that outside of the veteran population, patients with HFpEF are generally elderly and more frail. “So a randomized trial would have to be really large and very well done to account for some of the confounding issues that you’d find in that patient population,” she said.

For now, though, the message is that “as in all our patients, if they don’t have known vascular disease, their risk for vascular disease should be analyzed closely, and those that are at high risk should be on statins,” Walsh said. “And looking at primary prevention indications for statins, they apply to HFpEF patients as well as all patients, and so attention to assessing lipid status in HFpEF patients is important.”