The following are key points to remember from this state-of-the-art review on phenotype-guided initiation of drug layering in heart failure:

1. Current guidelines for heart failure with reduced ejection fraction (HFrEF) recommend a stepwise initiation and titration to maximally tolerated doses of key therapies. This is a slow process and may delay the start of prognostically beneficial treatments, many of which have shown early improvement in outcomes.
2. Many have advocated for simultaneous or rapid initiation of the four key HFrEF therapies (angiotensin receptor-neprilysin [ARN] inhibitor or angiotensin-converting enzyme [ACE] inhibitor or angiotensin-receptor blocker [ARB], beta-blocker, mineralocorticoid receptor antagonist [MRA], sodium-glucose cotransporter type 2 [SGLT2] inhibitor), though this may lead to more adverse effects (e.g., bradycardia, hypotension, worsening renal function, hyperkalemia).
3. Unfortunately, there are a lack of data regarding the best order and strategy for HFrEF medication initiation and titration.
4. The authors propose a strategy of initially starting of all four key therapies (likely at low doses) followed by personalized drug layering or titration based on HFrEF phenotypes (incorporating heart rate [HR], blood pressure [BP], presence of atrial fibrillation [AF]).
5. Phenotype 1: normal to high HR/low BP → titrate beta-blockers, consider ivabradine.
6. Phenotype 2: low HR/low BP → consider dopamine/norepinephrine or left ventricular assist device.
7. Phenotype 3: low HR/normal BP → titrate beta-blocker and ARN inhibitor.
8. Phenotype 4: normal to high HR/normal to high BP → titrate beta-blocker and ARN inhibitor, consider ivabradine.
9. Phenotype 5: normal HR/normal BP → titrate beta-blocker and ARN inhibitor, consider isosorbide mononitrate.
10. Phenotype 6: AF/low BP → titrate beta-blocker, use anticoagulation, consider digoxin.
11. Phenotype 7: AF → titrate ARN inhibitor, use anticoagulation, consider digoxin.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Mechanical Circulatory Support

Keywords: Adrenergic beta-Antagonists, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Blood Pressure, Diabetes Mellitus, Type 2, Digoxin, Dopamine, Heart Failure, Heart Rate, Heart-Assist Devices, Hyperkalemia, Hypotension, Ivabradine, Maximum Tolerated Dose, Mineralocorticoid Receptor Antagonists, Neprilysin, Norepinephrine, Pharmaceutical Preparations, Sodium-Glucose Transporter 2 Inhibitors, Stroke Volume

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