Initiating Sacubitril/Valsartan in HFrEF
Sacubitril/valsartan should replace your patient's current ACE inhibitor or ARB to reduce cardiovascular death and heart failure hospitalization, starting at 49/51 mg twice daily after a mandatory 36-hour washout period from the ACE inhibitor. 1, 2
Pre-Initiation Requirements
Before switching to sacubitril/valsartan, you must:
- Discontinue lisinopril or valsartan and wait exactly 36 hours before giving the first dose of sacubitril/valsartan to prevent angioedema 1, 2
- Review and potentially reduce diuretic doses 24 hours before initiation to minimize hypotension risk 1
- Verify baseline blood pressure ≥100 mmHg systolic, potassium <5.5 mEq/L, and creatinine clearance adequate 1
- Confirm no history of angioedema with prior ACE inhibitor or ARB use 1, 2
Dosing Protocol
Start sacubitril/valsartan 49/51 mg orally twice daily, then:
- Double the dose to 97/103 mg twice daily after 2-4 weeks if the patient tolerates the initial dose without symptomatic hypotension, hyperkalemia, or worsening renal function 1, 2
- The target maintenance dose is 97/103 mg twice daily 2
- Uptitrate gradually with small increments every 1-2 weeks, monitoring one parameter at a time 1
Monitoring Schedule
Check the following parameters:
- Blood pressure, serum creatinine, potassium, and eGFR at 1-2 weeks after each dose change, then at 3 months, then every 6 months 1
- Expect a modest increase in urinary albumin/creatinine ratio, which does not predict worse outcomes and should not prompt discontinuation 3
- The eGFR typically declines more slowly with sacubitril/valsartan than with enalapril despite increased albuminuria 3
Absolute Contraindications
Do not prescribe sacubitril/valsartan if:
- History of angioedema with any ACE inhibitor or ARB 1, 2
- Concomitant use with ACE inhibitors (requires 36-hour washout) 1, 2
- Pregnancy (causes fetal injury and death) 2
- Severe hepatic impairment 2
Managing Hypotension
If systolic blood pressure drops below 90-100 mmHg:
- Reduce or temporarily hold diuretics first if the patient shows no signs of congestion 1
- Consider reducing non-essential antihypertensive medications (alpha-blockers for benign prostatic hyperplasia, calcium channel blockers) 1
- Do not reduce sacubitril/valsartan dose unless symptomatic hypotension persists after optimizing other medications 1
- Transient asymptomatic hypotension or mild dizziness upon standing does not require dose reduction—patient education and reassurance are usually sufficient 1
Combination Therapy Warnings
Never combine sacubitril/valsartan with:
- ACE inhibitors (increased angioedema risk) 1
- Additional ARBs (sacubitril/valsartan already contains valsartan) 1
- The triple combination of ACE inhibitor + ARB + MRA (causes life-threatening hyperkalemia and renal dysfunction) 1, 4
Evidence Basis
Sacubitril/valsartan reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 20% compared to enalapril in the PARADIGM-HF trial, with consistent benefits across all prespecified subgroups including those with chronic kidney disease 1, 5, 6. The 2022 ACC/AHA guidelines give this a Class 1 recommendation for symptomatic chronic HFrEF patients with NYHA Class II-III symptoms who tolerate ACE inhibitors or ARBs 1. The 2016 ESC guidelines similarly recommend sacubitril/valsartan as replacement therapy to further reduce hospitalization and death risk 1.
Practical Implementation
- Sacubitril/valsartan can be initiated de novo (without prior ACE inhibitor/ARB exposure) in hospitalized patients before discharge, which simplifies management and improves NT-proBNP levels 1
- The drug is generally well-tolerated with symptomatic hypotension being the most common adverse effect, occurring at similar rates to enalapril 1, 7
- Avoid NSAIDs during treatment as they interfere with renal protective effects 1