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Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis

Author/s: 
Pardeep S Jhund, Atefeh Talebi, Alasdair D Henderson, Brian L Claggett, Muthiah Vaduganathan

Background: Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction.

Methods: This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487.

Findings: 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72-0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59-0·73]) compared with HFmrEF or HFpEF (0·87 [0·79-0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55-0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74-0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63-0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80-1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65-0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85-1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02-2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45-0·57]; 7% vs 14%).

Interpretation: Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF.

Funding: None.

Keywords 
mineralocorticoid mineralocorticoid receptor antagonist heart failure

Screening for primary aldosteronism in primary care

Author/s: 
Dubrofsky, L., Hundemer, G. L.

Primary aldosteronism (PA) is common among patients with hypokalemia and hypertension. Patients with PA are at an increased risk of chronic disease if undiagnosed or untreated. Expert consensus recommends screening for PA in high-risk populations. Most antihypertensive medications can be continued during the work-up for PA. An elevated aldosterone-to-renin ratio is suggestive of PA.

Keywords 
Hypokalemia Aldosterone primary aldosteronism primary care screening

Management of Heart Failure

Author/s: 
Belkin, M. N., Cifu, A. S., Pinney, S.

GUIDELINE TITLE 2022 American College of Cardiology
(ACC)/American Heart Association AHA)/Heart Failure
Society of America (HFSA) Guidelines for the Management
of Heart Failure
RELEASE DATE April 1, 2022
PRIOR VERSIONS 2017 ACC/AHA/HFSA Focused Update
of the 2013 ACCF/AHA Guideline for the Management of
Heart Failure and 2013 ACCF/AHA Guideline for the
Management of Heart Failure
DEVELOPER AND FUNDING SOURCE ACC/AHA Joint
Committee on Clinical Practice Guidelines
TARGET POPULATION Adult patients with a diagnosis of
or at risk for heart failure (HF)
MAJOR RECOMMENDATIONS
• Classifications for HF are separated into 4 categories based
on ejection fraction (EF) and disease history: HF with
reduced EF (EF 40%), HF with mildly reduced EF
(EF 41%-49%), HF with preserved EF (EF 50%), and HF
with improved EF (EF previously 40% with improvement
to >40%).
• In patients with chronic HF with reduced EF, angiotensin
receptor–neprilysin inhibitors (ARNIs) are preferred over
angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin II receptor blockers (ARBs). If ARNI use is not
feasible, ACEIs are preferred over ARBs, unless there is
significant cough or angioedema (class 1, level of
evidence [LOE] A).
• Sodium-glucose cotransporter 2 (SGLT2) inhibitors should
be included across all HF categories (symptomatic HF with
reduced EF [class 1, LOE A]; HF with mildly reduced EF and
HF with preserved EF [class 2a, LOE B-R]).
• Patients with HF with improved EF should continue to
receive medical therapy originally indicated for HF with
reduced EF (class 1, LOE B-R).
• Evidence-based treatment of HF with preserved EF
includes blood pressure control (class 1, LOE C-LD),
SGLT2 inhibitors (class 2a, LOE B-R), mineralocorticoid
antagonists, ARBs, and ARNIs (class 2b, LOE B-R).

Keywords 
Stroke Volume American Heart Association Cardiology heart failure Sodium

Estimating Lifetime Benefits of Comprehensive Disease-Modifying Pharmacological Therapies in Patients With Heart Failure With Reduced Ejection Fraction: A Comparative Analysis of Three Randomised Controlled Trials

Author/s: 
Vaduganathan, M., Claggett, BL, Jhund, PS, Cunningham, JW, Ferreira, JP, Zannad, F, Packer, M, Fonarow, GC, McMurray, JJV, Solomon, S.D.

Background: Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.

Methods: In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).

Findings: The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.

Interpretation: Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.

Funding: None.

Keywords 
CHF patients heart failure pharmacologic management

Primary Prevention of Sudden Cardiac Death

Author/s: 
Beaser, A.D., Cifu, A.S.

  • In patients with heart failure with reduced ejection fraction (<40%), guideline-directed medical therapy (GDMT) is recommended to reduce sudden cardiac death and all-cause mortality; GDMT includes β-blockers; mineralocorticoid receptor antagonists; and angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor–neprilysin inhibitors (class I, level A recommendation).

  • In patients with left ventricular ejection fraction (LVEF) of 35% or less due to ischemic heart disease at least 40 days after myocardial infarction, at least 90 days after revascularization, and with New York Heart Association (NYHA) class II or III heart failure despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).

  • In patients with LVEF of 30% or less due to ischemic heart disease at least 40 days after myocardial infarction, at least 90 days after revascularization, and with NYHA class I heart failure symptoms despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).

  • In patients with nonischemic cardiomyopathy, NYHA class II to III symptoms, and LVEF of 35% or less despite GDMT, an ICD is recommended if expected survival is greater than 1 year (class I, level A recommendation).

Keywords 
cardiac sudden cardiac death risk reduction risk factors heart failure
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