Evidence-Based Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) as identified by a reduced estimated glomerular filtration rate (eGFR) is a common comorbidity in patients with heart failure with reduced ejection fraction (HFrEF). The presence of CKD is associated with more severe heart failure, and CKD itself is a strong independent risk factor of poor cardiovascular outcome. Furthermore, the presence of CKD often influences the decision to start, uptitrate, or discontinue possible life-saving HFrEF therapies. Because pivotal HFrEF randomized clinical trials have historically excluded patients with stage 4 and 5 CKD (eGFR <30 mL/min/1.73 m²), information on the efficacy and tolerability of HFrEF therapies in these patients is limited. However, more recent HFrEF trials with novel classes of drugs included patients with more severe CKD. In this review on medical therapy in patients with HFrEF and CKD, we show that for both all-cause mortality and the combined end point of cardiovascular death or heart failure hospitalization, most drug classes are safe and effective up to CKD stage 3B (eGFR minimum 30 mL/min/1.73 m²). For more severe CKD (stage 4), there is evidence of safety and efficacy of sodium glucose cotransporter 2 inhibitors, and to a lesser extent, angiotensin-converting enzyme inhibitors, vericiguat, digoxin and omecamtiv mecarbil, although this evidence is restricted to improvement of cardiovascular death/heart failure hospitalization. Data are lacking on the safety and efficacy for any HFrEF therapies in CKD stage 5 (eGFR < 15 mL/min/1.73 m² or dialysis) for either end point. Last, although an initial decline in eGFR is observed on initiation of several HFrEF drug classes (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/mineralocorticoid receptor antagonists/angiotensin receptor blocker neprilysin inhibitors/sodium glucose cotransporter 2 inhibitors), renal function often stabilizes over time, and the drugs maintain their clinical efficacy. A decline in eGFR in the context of a stable or improving clinical condition should therefore not be cause for concern and should not lead to discontinuation of life-saving HFrEF therapies.

Keywords: chronic kidney disease; evidence-based treatment; heart failure with reduced ejection fraction.

Figure 1.. Overview of the potential mechanisms through which evidence based treatments influence renal function in HFrEF

This schematic gives an overview of the potential mechanisms via which evidence based treatments impact renal function in HFrEF. Renin angiotensin system inhibitors (and probably SGLT2i) cause efferent vasodilation, leading to higher RBF, lower GFR and lower FF. It is postulated that SGLT2i have effects on afferent arteriolar tone, causing lower RBF, lower GFR and stable FF. ARNIs may vasodilate the afferent arteriole causing slightly increased RBF and possibly more preserved GFR (as compared with ACEi/ARB alone). ARNIs also influence podocyte function which may be a factor in the modest albuminuria associated with these drugs. It is unclear how MRA influence GFR. Finally, many therapies influence blood pressure, improve contractility and have direct cardiac effects, all of which influence mean arterial pressure and cardiac output/congestion, thereby influencing renal hemodynamics. Abbreviations: ACEi: Angiotensin Converting Enzyme Inhibitor, ARB: Angiotensin II Receptor Blocker, ARNI: Angiotensin Blocker Neprilysin Inhibitor, BBL: Beta Blocker, CVP, central venous pressure; FF, filtration fraction; GFR, glomerular filtration rate; H-ISDN: Hydralazine-Isosorbidedinitrate, HFrEF, heart failure with reduced ejection fraction; MAP, mean arterial pressure; MRA: Mineralocorticoid Receptor Antagonist, RBF, renal blood flow; SGLT2i: Sodium-glucose co-transporter-2 inhibitor; TGF, tubuloglomerular feedback.

Figure 2.. Clinical Summary Figures of class I guideline recommended medical therapies

A) ACEi B) ARB C) MRA D) Beta-Blocker E) ARNI F) SGLT2i Each figure panel provides evidence of the pivotal scientific background of the drug class overall, for different endpoints and stratified for CKD stages. It summarizes the known (and unknown) effect of each drug class on renal function and how to approach a patient with either worsening renal function and/or hyperkalemia. Abbreviations: ACM: All Cause Mortality, CI: Confidence Interval, CKD: Chronic Kidney Disease, CrCl: Creatinine Clearance, CV: Cardiovascular, eGFR: estimated Glomerular Filtration Rate, HF: Heart Failure, HR: Hazard Ratio, RRR: Relative Risk Reduction, WRF: Worsening Renal Function. For study acronyms see Supplementary Table 1.

Figure 2.. Clinical Summary Figures of class I guideline recommended medical therapies

A) ACEi B) ARB C) MRA D) Beta-Blocker E) ARNI F) SGLT2i Each figure panel provides evidence of the pivotal scientific background of the drug class overall, for different endpoints and stratified for CKD stages. It summarizes the known (and unknown) effect of each drug class on renal function and how to approach a patient with either worsening renal function and/or hyperkalemia. Abbreviations: ACM: All Cause Mortality, CI: Confidence Interval, CKD: Chronic Kidney Disease, CrCl: Creatinine Clearance, CV: Cardiovascular, eGFR: estimated Glomerular Filtration Rate, HF: Heart Failure, HR: Hazard Ratio, RRR: Relative Risk Reduction, WRF: Worsening Renal Function. For study acronyms see Supplementary Table 1.

Figure 2.. Clinical Summary Figures of class I guideline recommended medical therapies

A) ACEi B) ARB C) MRA D) Beta-Blocker E) ARNI F) SGLT2i Each figure panel provides evidence of the pivotal scientific background of the drug class overall, for different endpoints and stratified for CKD stages. It summarizes the known (and unknown) effect of each drug class on renal function and how to approach a patient with either worsening renal function and/or hyperkalemia. Abbreviations: ACM: All Cause Mortality, CI: Confidence Interval, CKD: Chronic Kidney Disease, CrCl: Creatinine Clearance, CV: Cardiovascular, eGFR: estimated Glomerular Filtration Rate, HF: Heart Failure, HR: Hazard Ratio, RRR: Relative Risk Reduction, WRF: Worsening Renal Function. For study acronyms see Supplementary Table 1.

Figure 2.. Clinical Summary Figures of class I guideline recommended medical therapies

A) ACEi B) ARB C) MRA D) Beta-Blocker E) ARNI F) SGLT2i Each figure panel provides evidence of the pivotal scientific background of the drug class overall, for different endpoints and stratified for CKD stages. It summarizes the known (and unknown) effect of each drug class on renal function and how to approach a patient with either worsening renal function and/or hyperkalemia. Abbreviations: ACM: All Cause Mortality, CI: Confidence Interval, CKD: Chronic Kidney Disease, CrCl: Creatinine Clearance, CV: Cardiovascular, eGFR: estimated Glomerular Filtration Rate, HF: Heart Failure, HR: Hazard Ratio, RRR: Relative Risk Reduction, WRF: Worsening Renal Function. For study acronyms see Supplementary Table 1.

Figure 2.. Clinical Summary Figures of class I guideline recommended medical therapies

A) ACEi B) ARB C) MRA D) Beta-Blocker E) ARNI F) SGLT2i Each figure panel provides evidence of the pivotal scientific background of the drug class overall, for different endpoints and stratified for CKD stages. It summarizes the known (and unknown) effect of each drug class on renal function and how to approach a patient with either worsening renal function and/or hyperkalemia. Abbreviations: ACM: All Cause Mortality, CI: Confidence Interval, CKD: Chronic Kidney Disease, CrCl: Creatinine Clearance, CV: Cardiovascular, eGFR: estimated Glomerular Filtration Rate, HF: Heart Failure, HR: Hazard Ratio, RRR: Relative Risk Reduction, WRF: Worsening Renal Function. For study acronyms see Supplementary Table 1.

Figure 2.. Clinical Summary Figures of class I guideline recommended medical therapies

A) ACEi B) ARB C) MRA D) Beta-Blocker E) ARNI F) SGLT2i Each figure panel provides evidence of the pivotal scientific background of the drug class overall, for different endpoints and stratified for CKD stages. It summarizes the known (and unknown) effect of each drug class on renal function and how to approach a patient with either worsening renal function and/or hyperkalemia. Abbreviations: ACM: All Cause Mortality, CI: Confidence Interval, CKD: Chronic Kidney Disease, CrCl: Creatinine Clearance, CV: Cardiovascular, eGFR: estimated Glomerular Filtration Rate, HF: Heart Failure, HR: Hazard Ratio, RRR: Relative Risk Reduction, WRF: Worsening Renal Function. For study acronyms see Supplementary Table 1.

Figure 3.. Conceptual overview of evidence based treatments in HFrEF according to baseline CKD status

With more severe CKD stages, prognosis worsens, and scientific evidence becomes scarce. There is more evidence for CKD stage 1–4 for preventing CV Death/HF Hospitalization with evidence based treatments as compared with preventing all-cause mortality. Among treatments there is some evidence for efficacy of SGLT2i, omecamtiv-mecarbil, ACEi, digoxin and vericiguat in CKD stage 4. Overall the renal safety profile in all classes of CKD with essentially all treatments is good, if the clinical status is taken into account and renal function and potassium are checked regularly. Loop Diuretics are not depicted in the absence of large randomized placebo controlled trials. Abbreviations: ACEi: Angiotensin Converting Enzyme Inhibitor, ARB: Angiotensin II Receptor Blocker, ARNI: Angiotensin Receptor blocker neprilysin Inhibitor, Beta-blocker: Beta-Blocker, CV: Cardiovascular, eGFR: Estimated Glomerular Filtration Rate, H-ISDN: Hydralazine IsosorbideDinitrate, HR: Hazard Ratio, HF: Heart Failure, MRA: Mineralocorticoid Receptor Antagonist, SGLT2i: Sodium glucose co-transporter 2 inhibitor.