Heart failure guidelines: What you need to know about the 2017 focused update

Cleveland Clinic Journal of Medicine. 2019 February;86(2):123-139 | 10.3949/ccjm.86a.18022
February 1, 2019|Cleveland Clinic Journal of Medicine
Lee Rodney Haselhuhn, MD;Daniel J. Brotman, MD;Ilan Shor Wittstein, MD
Author and Disclosure Information

Lee Rodney Haselhuhn, MD
Department of Medicine, Johns Hopkins University, Baltimore, MD

Daniel J. Brotman, MD
Department of Medicine, Johns Hopkins University, Baltimore, MD

Ilan Shor Wittstein, MD
Departments of Medicine and Cardiology, Johns Hopkins University, Baltimore, MD

Address: Lee Rodney Haselhuhn, MD, Division of General Internal Medicine, Johns Hopkins Hospitalist Program, Johns Hopkins Hospital, 600 N. Wolfe St., Meyer 8-134M, Baltimore, MD 21287; lhaselh1@jhmi.edu

Dr. Brotman has disclosed consulting for Portola Pharmaceuticals.

Release date: February 1, 2019
Expiration date: January 31, 2020
Estimated time of completion: 1 hour

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ABSTRACT

The 2017 focused update of the 2013 ACC/AHA guideline on heart failure contains new and important recommendations on prevention, novel biomarker uses, heart failure with preserved ejection fraction (HFpEF), and comorbidities such as hypertension, iron deficiency, and sleep-disordered breathing. Potential implications for management of acute decompensated heart failure will also be explored.

KEY POINTS

  • Despite advances in treatment, heart failure remains highly morbid, common, and costly. Prevention is key.
  • Strategies to prevent progression to clinical heart failure in high-risk patients include new blood pressure targets (< 130/80 mm Hg) and B-type natriuretic peptide screening to prompt referral to a cardiovascular specialist.
  • An aldosterone receptor antagonist might be considered to decrease hospitalizations in appropriately selected stage C HFpEF patients. Routine use of nitrates or phosphodiesterase-5 inhibitors in such patients is not recommended.
  • Outpatient intravenous iron infusions are reasonable in persistently symptomatic New York Heart Association stage II to III heart failure with reduced ejection fraction (HFrEF) to improve functional capacity and quality of life.
  • The new systolic blood pressure target is less than 130 mm Hg for stage A heart failure, stage C HFrEF, and stage C HFpEF.

PHARMACOLOGIC TREATMENT FOR STAGE C HFpEF

Although the 2013 guidelines2 contain many class I recommendations for various medications in chronic HFrEF, not a single such recommendation is found for chronic HFpEF. A review by Okwuosa et al7 covered HFrEF, including the most recent additions on which the 2016 update was based, sacubitril-valsartan and ivabradine. The 2016 update was similarly devoid of recommendations regarding specific medications in HFpEF, leaving only the 2013 class IIb recommendation to consider using an ARB to decrease hospitalizations in HFpEF.

Evidence behind this recommendation came from the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity program’s randomized controlled trial in 3,025 patients with New York Heart Association (NYHA) class II to IV heart failure and left ventricular ejection fraction over 40%, who were treated with candesartan or placebo.14 Over a median follow-up of 36.6 months, there was no significant difference in the primary composite outcome of cardiovascular death or admission for heart failure, but significantly fewer patients in the candesartan arm were admitted (230 vs 270, P = .017). Thus the recommendation.

Although this finding was encouraging, it was clear that no blockbuster drug for HFpEF had been identified. Considering that roughly half of all heart failure patients have preserved ejection fraction, the discovery of such a drug for HFpEF would be met with much excitement.15 Subsequently, other medication classes have been evaluated in the hope of benefit, allowing the 2017 update to provide specific recommendations for aldosterone antagonists, nitrates, and phosphodiesterase-5 inhibitors in HFpEF.

ALDOSTERONE ANTAGONISTS FOR HFpEF

Mineralocorticoid receptor antagonists had previously been shown to significantly reduce morbidity and mortality rates in patients with HFrEF.16 In addition to aldosterone’s effects on sodium retention and many other pathophysiologic mechanisms relating to heart failure, this hormone is also known to play a role in promoting myocardial fibrosis.17 Accordingly, some have wondered whether aldosterone antagonists could improve diastolic dysfunction, and perhaps outcomes, in HFpEF.

The Aldo-DHF trial

The Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial investigated whether the aldosterone antagonist spironolactone would improve diastolic function or maximal exercise capacity in chronic HFpEF.18 It randomized 422 ambulatory patients with NYHA stage II or III heart failure, preserved left ventricular ejection fraction (≥ 50%), and echocardiographic evidence of diastolic dysfunction to receive spironolactone 25 mg daily or placebo.

Although no significant difference was seen in maximal exercise capacity, follow-up over 1 year nevertheless showed significant improvement in echocardiographic diastolic dysfunction (E/e') and perhaps reverse remodeling (decreased left ventricular mass index). These improvements spurred larger trials powered to detect whether clinical outcomes could also be improved.

The TOPCAT trial

The Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial19 was a large, multicenter, international, double-blind, placebo-controlled trial that investigated whether spironolactone could improve clinical outcomes in HFpEF. It randomized 3,445 patients with symptomatic heart failure and left ventricular ejection fraction of 45% or more to spironolactone 15 to 45 mg daily or placebo.

The effect on a composite primary outcome of death from cardiovascular cause, aborted cardiac arrest, or hospitalization for heart failure was evaluated over a mean follow-up of 3.3 years, with only a small (HR 0.89), nonclinically significant reduction evident. Those in the spironolactone group did have a significantly lower incidence of hospitalization for heart failure (12.0% vs 14.2%, P = .04).

Although the results were disappointing in this essentially negative trial, significant regional variations evident on post hoc analysis prompted further investigation and much controversy since the trial’s publication in 2014.

Participants came in roughly equal proportions from the Americas (United States, Canada, Brazil, and Argentina—51%) and from Russia and Georgia (49%), but outcomes between the two groups were markedly different. Concern was first raised when immediate review discovered a 4-fold lower rate of the primary outcome in the placebo groups from Russia and Georgia (8.4%), a rate in fact similar to that in patients without heart failure.19 This led to further exploration that identified other red flags that called into question the data integrity from the non-American sites.20

Not only did patients receiving spironolactone in Russia and Georgia not experience the reduction in clinical outcomes seen in their American counterparts, they also did not manifest the expected elevations in potassium and creatinine, and spironolactone metabolites were undetectable in almost one-third of patients.21

These findings prompted a post hoc analysis that included only the 51% (1,767 patients) of the study population coming from the Americas; in this subgroup, treatment with spironolactone was associated with a statistically significant 18% relative risk reduction in the primary composite outcome, a 26% reduction in cardiovascular mortality, and an 18% reduction in hospitalization for heart failure.20

New or modified recommendations on aldosterone receptor antagonists

Recommendations for patients with heart failure with preserved ejection fraction
Recognizing both the encouraging data above and the limitations of post hoc analyses, the 2017 focused update provides a class IIb (weak) recommendation stating that aldosterone receptor antagonists might be considered to decrease hospitalizations in appropriately selected patients with HFpEF (Table 3).1

Nitrates and phosphodiesterase-5 inhibitors

Earlier studies indicated that long-acting nitrates are prescribed in 15% to 50% of patients with HFpEF, perhaps based on extrapolation from studies in HFrEF suggesting that they might improve exercise intolerance.22 Some have speculated that the hemodynamic effects of nitrates, such as decreasing pulmonary congestion, might improve exercise intolerance in those with the stiff ventricles of HFpEF as well, prompting further study.