In heart failure with reduced ejection fraction, should sacubitril/valsartan (Entresto) be started before empagliflozin (Jardiance) as the preferred therapy hierarchy?

HFrEF Therapy Hierarchy: Start SGLT2i and Beta-Blocker First, Then Add Entresto

In HFrEF, initiate empagliflozin (Jardiance) and a beta-blocker simultaneously as first-line therapy, followed 1-2 weeks later by sacubitril/valsartan (Entresto), rather than prioritizing Entresto first. This rapid sequencing approach is supported by current evidence showing independent efficacy of each drug class and the need to achieve therapeutic doses of all foundational medications within 2-4 weeks rather than the traditional 6+ month approach 1.

The Four Foundational Drug Classes

The 2022 AHA/ACC/HFSA guidelines establish that HFrEF management requires four drug classes, all with Class 1 recommendations 2:

• SGLT2 inhibitors (empagliflozin or dapagliflozin)
• Beta-blockers (evidence-based for HFrEF)
• ARNI (sacubitril/valsartan) or ACE-I/ARB
• Mineralocorticoid receptor antagonists (MRA)

Recommended Sequencing Strategy

Step 1 (Day 1): Start SGLT2i + Beta-blocker simultaneously

• Empagliflozin 10 mg daily (Jardiance) 2
• Evidence-based beta-blocker at low dose

Step 2 (1-2 weeks later): Add sacubitril/valsartan

• Start Entresto 49/51 mg twice daily 3
• Requires 36-hour washout if switching from ACE-I 3

Step 3 (1-2 weeks later): Add MRA

• Spironolactone or eplerenone at low dose

Why This Sequence?

SGLT2i First Makes Clinical Sense

1. Rapid mortality benefit: SGLT2 inhibitors work quickly and independently of other HF medications 1
2. Excellent tolerability: Minimal titration needed, can start at therapeutic dose 2
3. Enhances safety of subsequent drugs: May improve blood pressure and volume status, making Entresto better tolerated 1
4. No drug interactions: Unlike Entresto, which requires ACE-I washout 3

Comparative Efficacy Data

Network meta-analysis shows SGLT2 inhibitors ranked as most effective therapy overall, with a trend toward superiority over sacubitril/valsartan for the composite endpoint of CV death or HF hospitalization (HR 0.92,95% CI 0.81-1.05) 4. For HF hospitalization specifically, SGLT2i demonstrated the greatest effect (HR 0.69,95% CI 0.62-0.77) compared to standard of care 4.

Critical point: The efficacy of each foundational drug is independent of the others—you don't need to start one before the other for it to work 1. This contradicts the historical approach of sequential titration.

Entresto-Specific Considerations

When to Start Entresto

• After 1-2 weeks of SGLT2i + beta-blocker, when volume status and blood pressure are optimized 1
• Requires 36-hour washout if patient is on ACE-I 3
• Can be used as initial therapy even without prior ACE-I exposure 5

Entresto Dosing

• Start: 49/51 mg twice daily 3
• Target: 97/103 mg twice daily 3
• Reduce starting dose to 24/26 mg twice daily if:
  • Not currently on ACE-I/ARB or on low doses 3
  • Severe renal impairment 3
  • Moderate hepatic impairment 3

Contraindications to Entresto

• History of angioedema with ACE-I or ARB 3
• Concomitant ACE-I use 3
• Pregnancy 3
• Concomitant aliskiren in diabetics 3

Common Pitfalls to Avoid

1. Waiting months between drug initiations: The traditional approach of starting one drug, titrating to target over months, then adding the next is outdated. Low doses of all four classes provide substantial benefit 1.

2. Prioritizing up-titration over breadth: Getting patients on low doses of all four foundational drugs takes precedence over achieving target doses of fewer drugs 1.

3. Forgetting the ACE-I washout: Must wait 36 hours between stopping ACE-I and starting Entresto to avoid angioedema risk 3.

4. Assuming you need ACE-I first: Entresto can be initiated de novo without prior ACE-I exposure 5.

5. Therapeutic inertia: Real-world data shows cardiologists prescribe only 23.3% of sacubitril/valsartan and 10% of SGLT2i, with most prescriptions from ancillary staff 6. Don't delay—primary care and HF nurses can initiate these medications.

Real-World Outcomes

Recent observational data demonstrates that systematic introduction of both ARNI and SGLT2i (2017-2021 cohort) versus older therapy (2011-2016) resulted in 7:

• Higher mean LVEF at one year (44.3% vs 42.1%, p=0.004)
• Reduced 2-year mortality (5.9% vs 9.4%, p=0.023)
• Decreased ICD implantation rates (7.2% vs 11.1%, p=0.016)

The Bottom Line

Start SGLT2i and beta-blocker together on day 1, add Entresto 1-2 weeks later, then add MRA 1-2 weeks after that. This gets patients on all four foundational therapies within one month rather than six months, maximizing early mortality and morbidity benefits. The sequence can be compressed or reordered based on individual patient factors (blood pressure, renal function, volume status), but the principle remains: achieve low doses of all four classes quickly rather than target doses of fewer classes slowly 1.