In a patient with heart failure with reduced ejection fraction, how should dapagliflozin (Farxiga) and sacubitril/valsartan (Entresto) be initiated and titrated as part of guideline‑directed medical therapy, including appropriate dosing, monitoring parameters, and contraindications?

Initiating and Titrating Dapagliflozin (Farxiga) and Sacubitril/Valsartan (Entresto) in HFrEF

Start all four foundational medication classes—including dapagliflozin 10 mg daily and sacubitril/valsartan—simultaneously as soon as possible after HFrEF diagnosis, rather than sequentially, to maximize survival benefit and gain approximately 5.3 additional life-years compared to no disease-modifying therapy. 1

Core Principle: Quadruple Therapy as Standard of Care

• The four foundational medication classes for all HFrEF patients are: an SGLT2 inhibitor (dapagliflozin or empagliflozin), a mineralocorticoid receptor antagonist (spironolactone or eplerenone), a beta-blocker (carvedilol, metoprolol succinate, or bisoprolol), and an ARNI/ACE-inhibitor/ARB. This regimen reduces all-cause mortality by 61% (HR 0.39,95% CI: 0.32–0.49) over 2 years. 1

• Each of these four classes provides at least 20% mortality reduction and reduces sudden cardiac death, making them essential and non-interchangeable. 2

• Sacubitril/valsartan is the preferred renin-angiotensin system inhibitor over ACE inhibitors for symptomatic patients (NYHA class II–IV), providing superior mortality reduction. 2, 1

Dapagliflozin (Farxiga) Initiation

Dosing and Administration

• Start dapagliflozin 10 mg once daily immediately—no titration is required. This single dose provides maximal benefit without dose-response relationship in HFrEF. 2, 1

• Dapagliflozin can be initiated if eGFR ≥20 mL/min/1.73 m² (empagliflozin requires eGFR ≥30 mL/min/1.73 m²). 2, 1

• A mild, transient drop in eGFR may occur soon after initiation but offers long-term kidney protection; do not discontinue for modest creatinine increases up to 30% above baseline. 2, 1

Unique Advantages for Early Initiation

• Dapagliflozin has minimal blood pressure effect (average decrease only –1.50 mmHg in patients with baseline SBP 95–110 mmHg, diminishing to <1 mmHg after 4 months), making it ideal as the first agent in patients with borderline BP. 2, 1

• Benefits occur within weeks of initiation, independent of age, sex, diabetes status, or background medical therapy. 2, 1

• Dapagliflozin reduces cardiovascular death and HF hospitalization regardless of whether patients are taking sacubitril/valsartan, with similar efficacy and safety in both groups. 3

• Dapagliflozin does not increase hypovolemia risk when combined with sacubitril/valsartan. 3

Monitoring

• Monitor renal function and volume status at baseline and 1–2 weeks after initiation, but do not discontinue for asymptomatic mild eGFR decline. 2, 1

• No potassium monitoring is specifically required for dapagliflozin alone, as it does not affect potassium levels. 2

Sacubitril/Valsartan (Entresto) Initiation

Patient Selection Criteria

• Initiate sacubitril/valsartan in patients with HFrEF (EF ≤40%) and NYHA class II–IV symptoms who remain symptomatic despite optimal therapy. 1, 4

• Systolic BP ≥100 mmHg is preferred, but lower BP is not an absolute contraindication if the patient has adequate perfusion. 1, 4

• Confirm eGFR >30 mL/min/1.73 m² and serum potassium <5.0 mEq/L before initiation. 1, 4

Critical Safety Requirements

• If switching from an ACE inhibitor, observe a mandatory 36-hour washout period to avoid angioedema. 4

• No washout period is required when switching from an ARB. 4

• Never combine sacubitril/valsartan with an ACE inhibitor—this is absolutely contraindicated. 1, 4

Initial Dosing Strategy

• For patients previously on high-dose ACE inhibitors (equivalent to enalapril 10 mg twice daily), start sacubitril/valsartan 49/51 mg twice daily. 1, 4

• For patients on low/medium-dose ACE inhibitors or ARBs, or treatment-naïve patients, start 24/26 mg twice daily. 1, 4

• For patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), moderate hepatic impairment (Child-Pugh B), age ≥75 years, or systolic BP <100 mmHg, start with the lowest dose (24/26 mg twice daily). 1, 4

Titration Protocol

• Double the dose every 2–4 weeks as tolerated until reaching the target dose of 97/103 mg twice daily, which provides maximum mortality benefit. 1, 4

• Monitor blood pressure, renal function, and serum potassium at baseline and 1–2 weeks after each dose increment. 1, 4

• If symptomatic hypotension occurs, reduce diuretic dose first in non-congested patients before reducing sacubitril/valsartan. 1, 4

• If temporary dose reduction is necessary, 40% of patients can subsequently be restored to target doses—do not accept permanent sub-optimal dosing. 4

Monitoring Parameters

• Monitor blood pressure, serum creatinine/eGFR, and serum potassium regularly, with particular vigilance when combined with mineralocorticoid receptor antagonists. 1, 4

• Exercise caution when serum potassium >5.0 mEq/L; consider potassium binders (e.g., patiromer) rather than discontinuing life-saving medications. 1, 4

• Sacubitril/valsartan actually reduces hyperkalemia risk compared to ACE inhibitor plus MRA combinations. 1

Sequencing Strategy for Simultaneous Initiation

Optimal Order When Starting All Four Classes

• Start dapagliflozin 10 mg daily and spironolactone 25 mg daily first, as they have minimal blood pressure effects. 2, 1

• Then initiate low-dose beta-blocker (if heart rate >70 bpm) or low-dose sacubitril/valsartan (24/26 mg twice daily). 2, 1

• Up-titrate one drug at a time every 1–2 weeks using small increments until target or maximally tolerated dose is achieved, prioritizing SGLT2 inhibitor and MRA first, then beta-blocker, then ARNI. 1

Managing Low Blood Pressure During Optimization

• Never discontinue or reduce GDMT for asymptomatic hypotension with adequate perfusion—GDMT medications maintain efficacy and safety even in patients with baseline SBP <110 mmHg. 2, 1

• For symptomatic hypotension (SBP <80 mmHg or major symptoms), address reversible non-HF causes first: stop alpha-blockers (tamsulosin, doxazosin), discontinue other non-essential BP-lowering medications, and evaluate for dehydration, infection, or acute illness. 2, 1

• Non-pharmacological interventions include compression leg stockings for orthostatic symptoms, exercise and physical training programs, and adequate salt and fluid intake if not volume overloaded. 2, 1

• If symptoms persist after addressing reversible causes, reduce GDMT in this specific order: if heart rate >70 bpm, reduce ACEi/ARB/ARNI dose first; if heart rate <60 bpm, reduce beta-blocker dose first; always maintain SGLT2 inhibitor and MRA. 1

Contraindications and Precautions

Dapagliflozin Contraindications

• eGFR <20 mL/min/1.73 m² is the only renal contraindication for dapagliflozin. 2, 1

• History of diabetic ketoacidosis is a relative contraindication, though risk is low in HFrEF patients. 2

Sacubitril/Valsartan Contraindications

• History of angioedema related to previous ACE inhibitor or ARB therapy is a precaution (not absolute contraindication) for sacubitril/valsartan use. 4

• Pregnancy and lactation are absolute contraindications. 4

• Severe hepatic impairment (Child-Pugh C) is a contraindication. 4

• Concomitant use with ACE inhibitors is absolutely contraindicated. 1, 4

Triple RAAS Blockade Warning

• Never combine ACE inhibitor + ARB + MRA simultaneously due to extreme hyperkalemia and renal dysfunction risk. 2, 1

• Sacubitril/valsartan + MRA is safe and recommended; the ARNI actually reduces hyperkalemia risk compared to ACE inhibitor + MRA. 1

Common Pitfalls to Avoid

• Delaying initiation of all four medication classes—start simultaneously, not sequentially. 1

• Accepting suboptimal doses due to unfounded BP concerns—clinical trials demonstrated benefits at target doses, not low doses. 1

• Stopping medications for asymptomatic hypotension—adverse events occur in 75–85% of HFrEF patients regardless of treatment, with no substantial difference between GDMT and placebo arms. 1

• Inadequate monitoring of renal function and electrolytes, particularly when combining sacubitril/valsartan with MRAs. 1, 4

• Using non-evidence-based beta-blockers (e.g., atenolol, metoprolol tartrate) instead of carvedilol, metoprolol succinate, or bisoprolol. 1

• Discontinuing RAASi after hypotension or hyperkalemia—this is associated with two- to fourfold higher risk of subsequent adverse events compared to continuing therapy. 2, 1

• Failing to educate patients about transient dizziness as a side effect of life-prolonging drugs, which improves compliance. 2