In patients on chronic dialysis with heart failure with reduced ejection fraction, which medication class has the strongest evidence for improving outcomes?

Beta-Blockers Have the Strongest Evidence in Dialysis Patients with HFrEF

Among dialysis patients with heart failure with reduced ejection fraction, beta-blockers have the highest quality evidence for improving outcomes, particularly carvedilol, bisoprolol, and metoprolol. 1, 2

Evidence Hierarchy in Dialysis-Specific HFrEF Populations

Beta-Blockers: Strongest Evidence

• Beta-blockers are the only medication class with randomized controlled trial data specifically in dialysis patients with HFrEF. 1, 3
• Carvedilol demonstrated improved survival in hemodialysis patients with systolic heart failure receiving four sessions per week in a dedicated RCT. 2
• Large retrospective cohorts of hemodialysis patients with new-onset heart failure showed better survival when treated with carvedilol, bisoprolol, or metoprolol. 2
• Beta-blockers have been shown to improve outcomes in patients with HFrEF across all stages of CKD, including those on dialysis—the only drug class with this distinction. 1

SGLT2 Inhibitors: Limited to Moderate CKD

• SGLT2 inhibitors improved mortality and hospitalization in HFrEF patients with CKD stages 3 and 4 (eGFR >20 mL/min per 1.73 m²). 1, 4
• Dialysis patients (CKD stage 5) were excluded from all major SGLT2 inhibitor trials, leaving no evidence for efficacy or safety in this population. 4
• The DAPA-HF and EMPEROR trials that established SGLT2 inhibitor benefits did not include dialysis-dependent patients. 5

ARNI (Angiotensin Receptor-Neprilysin Inhibitors): Insufficient Evidence

• ARNI therapy was successfully used in randomized trials in patients with eGFR as low as 20 mL/min per 1.73 m², but not in dialysis patients. 1
• No data exist on ARNI use in dialysis-dependent patients (eGFR <15 mL/min or on dialysis). 4
• The PARADIGM-HF trial excluded patients with severe renal impairment. 5

MRA (Mineralocorticoid Receptor Antagonists): Contraindicated in Severe CKD

• Studies of HFrEF selected patients with creatinine <2.5 mg/dL for MRAs, explicitly excluding patients with severe CKD and dialysis. 1
• MRAs carry prohibitive risks of life-threatening hyperkalemia in dialysis patients and lack safety data in this population. 6, 4
• The EMPHASIS-HF trial that established MRA benefits excluded advanced CKD patients. 5

ACEIs/ARBs: Weak Evidence, Common Use

• ACE inhibitor studies selected patients with creatinine <2.5 mg/dL, and ARB studies used <3.0 mg/dL cutoffs, excluding severe CKD. 1
• Despite limited evidence, ACE inhibitor or ARB use is common in dialysis practice, but this reflects clinical inertia rather than robust data. 3
• There is no high-quality randomized trial evidence supporting ACEIs/ARBs specifically in dialysis-dependent HFrEF patients. 4

Critical Clinical Considerations

Practical Implementation in Dialysis Patients

• Start beta-blockers at low doses and titrate carefully, monitoring for intradialytic hypotension and bradycardia. 2
• Avoid beta-blockers in patients with intradialytic hypotension associated with bradycardia, as this combination is linked to sudden cardiac death. 2
• Carvedilol appears superior to metoprolol in some dialysis cohorts, though recent data suggest metoprolol may have lower all-cause mortality. 2

The Evidence Gap

• Major HFrEF trials (PARADIGM-HF, DAPA-HF, EMPEROR, EMPHASIS-HF) systematically excluded dialysis patients, creating a critical knowledge void. 3, 5, 4
• Data for any HFrEF therapy in CKD stage 5 (dialysis) are lacking for both mortality and hospitalization endpoints. 4
• The comprehensive four-pillar therapy (ARNI + beta-blocker + MRA + SGLT2 inhibitor) recommended for general HFrEF populations has zero evidence in dialysis patients. 6, 5

Dialysis-Specific Factors

• Peritoneal dialysis and more frequent hemodialysis may be better tolerated due to slower ultrafiltration rates and better volume control. 3
• Dialysate cooling and higher dialysate calcium may provide additional cardiovascular benefits. 3
• Combined cardiology-nephrology clinics may improve implementation of evidence-based therapy in this complex population. 1

Device Therapy Considerations

• Implantable cardiac defibrillators (ICDs) and cardiac resynchronization therapy that benefit non-dialysis HFrEF patients have not consistently shown benefit in limited dialysis studies. 3
• Leadless pacemakers and subcutaneous ICDs can mitigate future hemodialysis access limitations. 3

Bottom Line for Clinical Practice

In the absence of trial data for most HFrEF medications in dialysis patients, beta-blockers remain the only class with dedicated randomized evidence and consistent observational support. 1, 2 While guidelines recommend comprehensive four-pillar therapy for general HFrEF populations 6, 7, this recommendation cannot be extrapolated to dialysis patients where only beta-blockers have proven safety and efficacy. 4 The use of other medication classes in dialysis-dependent HFrEF patients represents off-label extrapolation from non-dialysis populations and should be approached with extreme caution, particularly for MRAs given hyperkalemia risk. 6, 1