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Heart Failure* / drug therapy

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

Management of Chronic Heart Failure with Reduced Ejection Fraction

Author/s: 
Brandon Williamson, Carl Tong

Heart failure with reduced ejection fraction (HFrEF) is a commonly seen clinical entity in the family physician's practice. This clinical review focuses on the pharmacologic management of chronic HFrEF. Special attention is paid to the classification of heart failure and the newest recommendations from the American Heart Association concerning the use of guideline-directed medical therapy. β blockers, ACE inhibitors, ARBs, mineralocorticoid receptor antagonists are discussed in detail. The new emphasis on sacubitril-valsartan and SGLT2i's as therapies for HFrEF are reviewed, followed by a brief discussion of more advanced therapies and comorbidity management.

Keywords 
heart failure Reduced Ejection Fraction CHF pharmacotherapy HFrEF

Revisiting Race and the Benefit of RAS Blockade in Heart Failure: A Meta-Analysis of Randomized Clinical Trials

Author/s: 
Li Shen, Matthew M Y Lee, Pardeep S Jhund, Christopher B Granger, Inder S Anand

Importance: Concerns have arisen that renin-angiotensin system (RAS) blockers are less effective in Black patients than non-Black patients with heart failure and reduced ejection fraction (HFrEF).

Objective: To determine whether the effects of RAS blockers on cardiovascular outcomes differ between Black patients and non-Black patients with HFrEF.

Data sources: MEDLINE and Embase databases through December 31, 2023.

Study selection: Randomized trials investigating the effect of RAS blockers on cardiovascular outcomes in adults with HFrEF that enrolled Black and non-Black patients.

Data extraction and synthesis: Individual-participant data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses Independent Personal Data (PRISMA-IPD) reporting guidelines. Effects were estimated using a mixed-effects model using a 1-stage approach.

Main outcome and measure: The primary outcome was first hospitalization for HF or cardiovascular death.

Results: The primary analysis, based on the 3 placebo-controlled RAS inhibitor monotherapy trials, included 8825 patients (9.9% Black). Rates of death and hospitalization for HF were substantially higher in Black than non-Black patients. The hazard ratio (HR) for RAS blockade vs placebo for the primary composite was 0.84 (95% CI, 0.69-1.03) in Black patients and 0.73 (95% CI, 0.67-0.79) in non-Black patients (P for interaction = .14). The HR for first HF hospitalization was 0.89 (95% CI, 0.70-1.13) in Black patients and 0.62 (95% CI, 0.56-0.69) in non-Black patients (P for interaction = .006). Conversely, the corresponding HRs for cardiovascular death were 0.83 (95% CI, 0.65-1.07) and 0.84 (95% CI, 0.77-0.93), respectively (P for interaction = .99). For total hospitalizations for HF and cardiovascular deaths, the corresponding rate ratios were 0.82 (95% CI, 0.66-1.02) and 0.72 (95% CI, 0.66-0.80), respectively (P for interaction = .27). The supportive analyses including the 2 trials adding an angiotensin receptor blocker to background angiotensin-converting enzyme inhibitor treatment (n = 16 383) gave consistent findings.

Conclusions and relevance: The mortality benefit from RAS blockade was similar in Black and non-Black patients. Despite the smaller relative risk reduction in hospitalization for HF with RAS blockade in Black patients, the absolute benefit in Black patients was comparable with non-Black patients because of the greater incidence of this outcome in Black patients.

Keywords 
RAS blocker heart failure renin-angiotensin system
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