Should guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) be initiated simultaneously or sequentially?

GDMT Initiation Strategy for HFrEF

Step 1 medications for HFrEF should be started simultaneously at low initial doses, rather than waiting to achieve target dosing of one medication before initiating the next. 1

Simultaneous vs Sequential Initiation

The 2022 ACC/AHA/HFSA guidelines explicitly state that all four foundational GDMT medications (ARNI/ACEi/ARB, beta-blocker, MRA, and SGLT2 inhibitor) may be started simultaneously at initial low doses. 1 Alternatively, these medications may be started sequentially with the sequence guided by clinical factors, but critically, there is no need to achieve target dosing before initiating the next medication. 1

Evidence Supporting Simultaneous Initiation

• Combined quadruple therapy reduces mortality risk by approximately 73% over 2 years compared to no treatment, with transitioning from traditional dual therapy to quadruple therapy extending life expectancy by approximately 6 years. 2

• The 2021 ESC guidelines shifted the paradigm from stepwise escalation to rapid simultaneous initiation of quadruple therapy, with Norwegian registry data showing fourfold acceleration in MRA use and substantial SGLT2i uptake following this approach, accompanied by declining mortality rates after 2021. 3

• Achievement of partial doses of all four pillars of GDMT is superior to achieving target dosing of only a couple medications. 4

Practical Implementation Algorithm

Initial Approach (First 4-6 Weeks)

Start all four medication classes simultaneously or in rapid sequence: 5

1. SGLT2 inhibitors first (empagliflozin or dapagliflozin) - minimal BP effect, no titration needed, rapid benefits within weeks 2, 5

2. MRA concurrently (spironolactone 12.5-25 mg or eplerenone 25 mg daily) - minimal BP-lowering effects 2, 5

3. Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) at low dose if HR >70 bpm 5

4. ARNI preferred (sacubitril/valsartan 25-50 mg twice daily) over ACEi for NYHA class II-III; use ACEi if ARNI not tolerated 5

Uptitration Strategy

Uptitrate medications every 1-2 weeks until target doses are achieved, with monitoring of BP, renal function, and electrolytes at each increment. 2 The forced-titration approach involves starting all four classes at low doses with uptitration at specific intervals, typically every 1-2 weeks. 2

Special Clinical Scenarios

Low Blood Pressure (SBP <100 mmHg)

If patient has adequate organ perfusion, do not withhold GDMT. 1, 5 Instead:

• Discontinue non-HF hypotensive medications 5
• Prioritize SGLT2 inhibitors and MRAs first (minimal BP impact) 1, 2
• Use selective β₁ receptor blockers (lesser BP-lowering effects) 2, 5
• Start very low-dose ARNI or ACEi 1, 5
• Consider ivabradine if beta-blockers not hemodynamically tolerated 1, 2

Hospitalized Patients

Continue GDMT in hospitalized patients except when hemodynamically unstable or contraindicated. 2 The STRONG-HF trial demonstrated that intensive treatment strategy with uptitration to 100% of recommended doses within 2 weeks of discharge significantly reduced mortality and HF readmissions at 180 days. 1

In-hospital initiation substantially improves post-discharge medication use compared to deferring initiation to outpatient setting. 1

Common Pitfalls to Avoid

• Do not use the traditional step-by-step approach that delays one drug class until another is optimized - this outdated strategy unnecessarily delays mortality benefits. 5

• Do not discontinue GDMT for asymptomatic hypotension - patients with adequate perfusion can tolerate systolic BP 80-100 mmHg. 2

• Modest creatinine increases (up to 30% above baseline) are acceptable and should not prompt discontinuation of RAS inhibitors. 2

• Temporary symptoms of fatigue and weakness with dose increases usually resolve within days - do not prematurely discontinue. 2

Monitoring Requirements

Monitor at 1-2 weeks after each dose increment: 2

• Blood pressure (both supine and standing)
• Renal function (eGFR, serum creatinine)
• Electrolytes (particularly potassium)
• Volume status
• Heart rate

More frequent monitoring needed in elderly patients and those with chronic kidney disease. 2

Clinical Context

The evidence strongly favors simultaneous or rapid sequential initiation over the outdated sequential approach. Less than one-quarter of eligible patients currently receive all three medications concurrently (pre-SGLT2i era), and only 1% receive target doses of all medications. 1 This represents a massive treatment gap that simultaneous initiation directly addresses by ensuring patients benefit from proven therapies without unnecessary delays.