About This Guide

This guide provides supplementary clinical information for the Sacubitril-Valsartan Start and Titration calculator. It explains the tool's inputs, outputs, and the clinical framework it uses to generate dosing recommendations for patients with heart failure with reduced ejection fraction (HFrEF).

Outputs Explained

The calculator provides one of two primary recommendations based on the selected mode:

• New Start Initiation: The tool calculates the appropriate starting dose (either 24/26 mg or 49/51 mg twice daily). It provides a clear rationale based on the patient's prior therapy, renal function (eGFR), and hepatic status. It also includes critical safety alerts, such as the 36-hour washout period for patients previously on an ACE inhibitor.
• Dose Titration: For patients already on therapy, the tool recommends whether to proceed with dose titration. It advises titrating to the next dose level (e.g., from 24/26 mg to 49/51 mg) if the patient is stable. If key parameters like systolic blood pressure (SBP) or serum potassium are outside of acceptable ranges, it recommends holding titration and re-assessing the patient.

How to Use the Calculator

To ensure accurate recommendations, enter the following information based on the clinical scenario.

For New Start Initiation

1. Previous RAS Inhibitor Therapy: Specify if the patient was on an ACE inhibitor (ACEi), ARB, or was naive to both. This is crucial for determining the starting dose and washout requirements.
2. Dose Level of Previous Therapy: If on an ACEi/ARB, classify the prior dose as "Low" (e.g., ≤10 mg enalapril daily) or "Moderate to High" (e.g., >10 mg enalapril daily).
3. Renal Function (eGFR): Enter the patient's estimated glomerular filtration rate. An eGFR <30 mL/min/1.73 m² requires a lower starting dose.
4. Hepatic Function: Select the patient's liver function status based on the Child-Pugh classification. Moderate impairment requires a lower starting dose, and severe impairment is a contraindication.

For Dose Titration

1. Current Sacubitril-Valsartan Dose: Select the patient's current dose (24/26 mg or 49/51 mg twice daily).
2. Current Systolic Blood Pressure: Enter the patient's current SBP. A value <95 mmHg is a caution against titration.
3. Current Serum Potassium: Enter the latest potassium level. A value >5.5 mmol/L (or mEq/L) is a caution against titration.
4. Symptomatic Hypotension: Check the box if the patient reports symptoms like dizziness or lightheadedness.

Dosing Overview

The administration of sacubitril-valsartan follows a structured initiation and titration schedule to ensure patient safety and tolerability.

• Available Strengths: 24/26 mg, 49/51 mg, and 97/103 mg of sacubitril/valsartan.
• Starting Dose: The typical starting dose is 49/51 mg twice daily. A reduced starting dose of 24/26 mg twice daily is recommended for patients not currently taking an ACEi/ARB, those on low doses of these agents, or those with severe renal or moderate hepatic impairment.
• Titration Schedule: The dose should be doubled approximately every 2-4 weeks, as tolerated by the patient, with the goal of reaching the target maintenance dose.
• Target Maintenance Dose: The target dose for most patients is 97/103 mg twice daily.

Switching Patients to Sacubitril-Valsartan

Proper washout periods are critical to minimize the risk of angioedema.

• From an ACE Inhibitor: Do NOT co-administer with an ACEi. The patient must stop the ACEi for at least 36 hours before initiating sacubitril-valsartan.
• From an ARB: No washout period is required. The patient can start sacubitril-valsartan at the next scheduled dose time after stopping the ARB.

Missed Dose Information

If a patient misses a dose, they should take it as soon as they remember. However, if it is close to the time of their next scheduled dose, they should skip the missed dose and resume their regular dosing schedule. Advise patients not to take two doses at the same time to make up for a missed one.

Safety Alerts

• Angioedema: There is a higher risk of angioedema in patients with a prior history, especially with ACE inhibitors. Do not use in patients with a known history of angioedema related to previous ACEi or ARB therapy.
• Hypotension: Symptomatic hypotension can occur, particularly in volume-depleted patients. Monitor blood pressure closely after initiation and during dose titration.
• Renal Function Impairment: Worsening renal function may occur. Monitor serum creatinine periodically, especially in patients with risk factors.
• Hyperkalemia: Increases in serum potassium can occur. Monitor potassium levels, especially in patients with renal impairment, diabetes, or those on potassium-sparing diuretics.

Frequently Asked Questions

Why does the calculator recommend a 24/26 mg starting dose?

A lower starting dose of 24/26 mg twice daily is recommended to improve tolerability in specific patient populations. The calculator selects this dose if the patient is not currently taking an ACEi/ARB, was on a low-dose equivalent of one, has an eGFR <30 mL/min/1.73 m², or has moderate hepatic impairment (Child-Pugh B).

What is the 36-hour washout rule?

Sacubitril inhibits neprilysin, which breaks down bradykinin. ACE inhibitors also increase bradykinin levels. Concomitant use significantly increases the risk of life-threatening angioedema. A 36-hour washout period after stopping an ACE inhibitor allows its effects to diminish before starting sacubitril-valsartan.

What blood pressure triggers a "Hold Titration" warning?

The calculator flags a systolic blood pressure (SBP) of less than 95 mmHg as a reason to hold a dose increase. This threshold is based on clinical guidelines to avoid symptomatic hypotension.

Can I use this calculator for a patient with severe liver disease?

No. The calculator reflects prescribing information which states that sacubitril-valsartan is contraindicated in patients with severe hepatic impairment (Child-Pugh C) as drug exposure is significantly increased.

What is considered a "low dose" of a previous ACEi or ARB?

The tool defines a low dose as a total daily dose equivalent to ≤10 mg of enalapril or ≤160 mg of valsartan, consistent with clinical trial criteria.

How often should labs be checked after a dose change?

The calculator recommends re-assessing blood pressure, eGFR, and serum potassium within 1-2 weeks of initiating therapy or after any dose titration to ensure patient safety and tolerability.

What is the final target maintenance dose?

The target maintenance dose for sacubitril-valsartan is 97/103 mg taken twice daily, as tolerated by the patient.

What should a patient do if they feel dizzy after a dose increase?

Dizziness can be a symptom of hypotension. The patient should be advised to sit or lie down and contact their healthcare provider. The calculator accounts for this by asking about symptomatic hypotension before recommending titration.

References

1. ENTRESTO® (sacubitril and valsartan) Prescribing Information. U.S. Food and Drug Administration.
2. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Journal of the American College of Cardiology.
3. ENTRESTO® Dosing & Administration Guide. Novartis Pharmaceuticals Corporation.