Can a patient with heart failure, particularly with reduced ejection fraction, take Entresto (sacubitril/valsartan) and Kerendia (finerenone) simultaneously?

Can Patients with Heart Failure Take Entresto and Kerendia Together?

Yes, patients with heart failure with reduced ejection fraction can and should take Entresto (sacubitril/valsartan) and Kerendia (finerenone) simultaneously as part of comprehensive guideline-directed medical therapy. Both medications are recommended components of the modern quadruple therapy approach for HFrEF and work through complementary mechanisms without contraindication to concurrent use 1, 2.

Evidence Supporting Concurrent Use

Complementary Roles in HFrEF Treatment

• Entresto (ARNI) is a foundational first-line therapy that provides at least 20% mortality reduction superior to ACE inhibitors, reducing cardiovascular death and heart failure hospitalization 1, 2.

• Kerendia (finerenone) is a non-steroidal mineralocorticoid receptor antagonist that should be used alongside other GDMT medications, as MRAs provide at least 20% mortality reduction and reduce sudden cardiac death 2.

• The current treatment paradigm for HFrEF emphasizes initiating four foundational medication classes simultaneously: an SGLT2 inhibitor, a mineralocorticoid receptor antagonist (like Kerendia), a beta-blocker, and an ARNI (like Entresto), along with diuretics for volume management 2.

Safety Profile of Combination Therapy

• Entresto actually reduces the risk of hyperkalemia when combined with MRAs compared to ACE inhibitors plus MRAs, making the combination safer than traditional RAAS inhibitor approaches 1.

• The combination requires monitoring but is not contraindicated - check renal function and electrolytes within 1-2 weeks after initiation and with each dose increase 3.

Practical Implementation Algorithm

Step 1: Verify Patient Eligibility

• Confirm HFrEF diagnosis (EF ≤40%) with NYHA class II-IV symptoms 1.
• Ensure eGFR >30 mL/min/1.73 m² for both medications 2.
• Verify potassium <5.0 mEq/L before initiating MRA 2.

Step 2: Initiate Both Medications

• Start Entresto: Use 24/26 mg twice daily for patients with severe renal impairment, or 49/51 mg twice daily for standard patients 4, 3.
• Start Kerendia: Follow standard dosing based on renal function per product labeling.
• If transitioning from ACE inhibitor to Entresto, observe mandatory 36-hour washout period 3.

Step 3: Titration Strategy

• Titrate Entresto every 2-4 weeks to target dose of 97/103 mg twice daily as tolerated 4, 3.
• Uptitrate one drug at a time using small increments, prioritizing SGLT2 inhibitor and MRA first, then beta-blocker, then ARNI 2.

Step 4: Monitoring Requirements

• Check potassium and creatinine at 1-2 weeks after each dose change 2, 3.
• Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation 2.
• Monitor blood pressure closely, especially during initiation 3.

Managing Common Concerns

Hyperkalemia Risk

• The combination of Entresto plus MRA carries lower hyperkalemia risk than ACE inhibitor plus MRA 1.
• If hyperkalemia develops (K >5.5 mmol/L), consider potassium binders like patiromer rather than discontinuing life-saving medications 1.
• Discontinuation of RAAS inhibitors after hyperkalemia is associated with two to fourfold higher risk of adverse events 2.

Hypotension Management

• Do not withhold therapy for asymptomatic low blood pressure with adequate perfusion 2.
• If symptomatic hypotension occurs, address reversible non-HF causes first (stop alpha-blockers, evaluate for dehydration) before reducing GDMT doses 2.
• Consider temporary dose reduction rather than discontinuation - 40% of patients who required temporary dose reduction were subsequently restored to target doses 3.

Renal Function Changes

• Changes in kidney function during GDMT optimization must be interpreted in the context of decongestion 1.
• Worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function 1.

Critical Contraindications to Avoid

• Never combine Entresto with ACE inhibitors - this is an absolute contraindication due to angioedema risk 2, 3.
• Avoid triple combination of ACE inhibitor + ARB + MRA, but Entresto + MRA is appropriate 2.
• Do not use Entresto in patients with history of angioedema related to previous ACE inhibitor or ARB therapy 4.

Common Pitfalls

• Delaying initiation of all four medication classes - start simultaneously when possible 2.
• Accepting suboptimal doses due to concerns about laboratory changes or asymptomatic hypotension 2.
• Stopping medications for asymptomatic hypotension - GDMT provides mortality benefit even with lower blood pressure 2.
• Permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate 4.
• Inadequate monitoring of renal function and electrolytes during uptitration 2.