Key result
Quadruple therapy with ARNI, BB, MRA, and SGLT-2i improves LVEF by ~6% over ACEI-based triple therapy.
Why the study?
Although SGLT-2is are included in HFrEF treatment guidelines alongside ARNIs, ACEIs, ARBs, BBs, and MRAs, their comparative effects in HFrEF had not yet been systematically evaluated.
Does the addition of SGLT-2 inhibitors to standard heart failure therapies (ARNI/ACEI + BB + MRA) improve cardiac remodeling parameters in patients with HFrEF?
Meta-Analysis (n=16,425)
Does the addition of SGLT-2 inhibitors to standard heart failure therapies (ARNI/ACEI + BB + MRA) improve cardiac remodeling parameters in patients with HFrEF?
Effect estimate: MD 5.83% (95% CI 0.53% to 11.14%)
Adding SGLT-2 inhibitors to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling, and the new quadruple drug regimen is superior to the traditional triple therapy in improving LVEF.
Supports quadruple therapy over ACEI-based triple regimens for HFrEF remodeling; extends meta-analytic evidence for SGLT2i addition.
BACKGROUND: Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI). RESULTS: We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI + BB + MRA + SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI + BB + MRA + SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI + BB + MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle ACEI + BB + MRA in improving LVEF. ACEI + BB + MRA + SGLT-2i was better than ACEI + BB + MRA (-8.05 mL/m 2 , 95% CI: -14.88 to -1.23 mL/m 2 ) and ACEI + BB + SGLT-2i (-18.94 mL/m 2 , 95% CI: -36.97 to -0.61 mL/m 2 ) in improving LVEDVI. ACEI + BB + MRA + SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB + BB + MRA in reducing NT-proBNP. CONCLUSIONS: Adding SGLT-2i to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI + BB + MRA + SGLT-2i" is superior to the golden triangle "ACEI + BB + MRA" in improving LVEF. REGISTRATION: PROSPERO; No. CRD42022354792.
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Tang et al. (2024) conducted a meta-analysis in Heart failure with reduced ejection fraction (HFrEF) (n=16,425). ARNI + BB + MRA + SGLT-2i vs. ACEI + BB + MRA was evaluated on Change in left ventricular ejection fraction (LVEF) (MD 5.83%, 95% CI 0.53% to 11.14%). Quadruple therapy with ARNI, BB, MRA, and SGLT-2i was superior to ACEI, BB, and MRA in improving left ventricular ejection fraction (MD 5.83%; 95% CI 0.53% to 11.14%).
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