HFrEF: Four Pillars, Rapid Titration and Follow-Up

1. Slide 1 · HFrEF: Four Pillars, Rapid Titration, Close Follow-Up

   HFrEF: Four Pillars, Rapid Titration, Close Follow-Up

   From guideline evidence to a practical outpatient titration strategy

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   Speaker notes

   Good morning, everyone. Today we focus on one of the most actionable areas in cardiology: reduced ejection fraction heart failure. We know what works. Four drug classes together change prognosis. Our weak point is implementation. Patients leave hospital on low doses, or missing whole classes, and titration stalls for months. We will cover three things. First, the evidence for quadruple therapy and the doses we aim for. Second, how fast we can safely titrate, using STRONG-HF as our model. Third, how to organise outpatient follow-up and when to refer. My goal is that you leave with a concrete plan for your next patient.

2. Slide 2 · Quadruple therapy: largest mortality benefit in HFrEF

   Quadruple therapy: largest mortality benefit in HFrEF

   HR 0.39

   All-cause mortality, ARNI+BB+MRA+SGLT2i vs placebo (network meta-analysis)

   5.3 years

   Additional life-years for a representative 70-year-old vs no treatment

   +15.6%

   LVEF improvement with ARNI+BB+MRA+SGLT2i vs placebo

   89 RCTs

   103,754 patients in the 2025 updated network meta-analysis

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   [1, 2]

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   Speaker notes

   Let's start with the size of the prize. The 2025 network meta-analysis in JACC pooled 89 randomised trials and more than one hundred thousand patients. Quadruple therapy with an ARNI, a beta-blocker, an MRA and an SGLT2 inhibitor reduced all-cause mortality with a hazard ratio of about 0.39 versus placebo. Adding vericiguat moved it slightly further, to 0.35. In absolute terms, a typical 70-year-old gains over five life-years. A separate meta-analysis shows the same combination produces the largest reverse remodelling, with LVEF gains around 15 points. Practical point: when you tell a patient this is worth five extra years, adherence conversations become much easier.

3. Slide 3 · The four pillars: starting and target doses

   The four pillars: starting and target doses

   Pillar	Agent	Starting dose	Target dose
   ARNI	Sacubitril/valsartan	24/26–49/51 mg twice daily	97/103 mg twice daily
   Beta-blocker	Bisoprolol / carvedilol / metoprolol succinate	1.25 mg od / 3.125 mg bid / 12.5–25 mg od	10 mg od / 25 mg bid (50 mg bid if >85 kg) / 200 mg od
   MRA	Spironolactone / eplerenone	12.5–25 mg od / 25 mg od	25–50 mg od / 50 mg od
   SGLT2i	Dapagliflozin / empagliflozin	10 mg od	10 mg od (no titration)

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   Speaker notes

   Here are the four pillars with trial-proven doses, aligned with the 2022 AHA/ACC/HFSA guideline and the 2024 ACC decision pathway. ARNI is preferred over ACE inhibitor or ARB in symptomatic patients; if switching from an ACE inhibitor, respect the 36-hour washout. Only the three evidence-based beta-blockers belong here. MRA dosing depends on potassium and renal function. And the SGLT2 inhibitor is the easiest pillar: one dose, no titration, minimal blood pressure effect. Practical tip: the target dose is the trial dose, not a suggestion. Document the current percentage of target for each class at every visit, so the gap stays visible.

4. Slide 4 · Start all four pillars early, not sequentially

   Start all four pillars early, not sequentially

   Legacy sequential approach

   ACEi first, then BB, then MRA, each to target before adding next

   Full regimen takes many months to assemble

   Many patients never receive all classes

   Early events occur while therapy is incomplete

   Contemporary parallel approach

   Initiate all four classes at low doses within weeks

   SGLT2i and MRA add little blood pressure burden

   Presence of every class outweighs maximising one

   Begin in hospital once haemodynamically stable

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   Speaker notes

   The old teaching was to introduce drugs one by one, pushing each to target before adding the next. That historical order reflects when trials were published, not biology. The benefits of each class appear within weeks, so delaying a class means losing benefit. The 2024 ACC decision pathway endorses rapid, flexible sequencing: get all four classes on board at low doses, then titrate. A useful order in a borderline-pressure patient is SGLT2 inhibitor and MRA first, since they barely lower blood pressure, then beta-blocker and ARNI. Hospital admission is the ideal moment: the patient is monitored and motivated.

5. Slide 5 · Rapid titration: lessons from STRONG-HF

   Rapid titration: lessons from STRONG-HF

   How fast is safe after an acute admission?

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   Speaker notes

   So we know what to give. The next question is how fast. For years we lacked randomised data on the pace of titration, and many of us were cautious, especially in older or frail patients. STRONG-HF changed that. It tested an intensive strategy right after an acute heart failure admission, the highest-risk window, and measured both efficacy and safety. Let's look at what it showed and how it translates to your clinic.

6. Slide 6 · STRONG-HF: full doses within two weeks

   STRONG-HF: full doses within two weeks

   1,078 patients randomised before discharge after acute HF, 87 centres

   High-intensity care: 100% target doses within 2 weeks of discharge

   Four visits over 2 months guided by clinical status, labs, NT-proBNP

   180-day death or HF readmission: 15.2% vs 23.3% with usual care

   Benefit consistent across age, sex, baseline eGFR and LVEF; better quality of life

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   Speaker notes

   STRONG-HF randomised over a thousand patients just before discharge. The high-intensity arm aimed for full doses within two weeks, with visits checking congestion, blood pressure, heart rate, potassium, creatinine and NT-proBNP. The primary endpoint of death or heart failure readmission at 180 days fell from about 23 to 15 percent. Subanalyses are reassuring: no meaningful interaction with age over 65, sex, baseline kidney function, or ejection fraction above or below 40 percent, and quality of life improved more with intensive care. Adverse events were somewhat more frequent but serious events were not. Take-home: the elderly patient is not a reason to go slow by default.

7. Slide 7 · Rapid up-titration applies to all patients

   “

   Rapid up-titration applies to all patients

   A rapid up-titration of GDMT immediately after an AHF hospitalization can and should be implemented similarly in men and women

   STRONG-HF sex-specific analysis, Eur J Heart Fail 2023

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   [7, 8]

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   Speaker notes

   This sentence from the STRONG-HF sex-specific analysis captures the message well. Women are historically undertreated and underdosed in heart failure, often because of concerns about lower body weight or blood pressure. In STRONG-HF, women and men had similar benefit and similar safety. The same was true for older patients. So the default should be to titrate everyone, and to individualise only when there is a specific clinical reason. Let's now look at those reasons, the common barriers that stall titration, and how to handle them without abandoning therapy.

8. Slide 8 · Managing common titration barriers

   Managing common titration barriers

   Issue	Interpretation	Action
   Low BP, asymptomatic	Usually tolerated; not a reason to stop	Continue GDMT; recheck at next visit
   Symptomatic hypotension	More frequent with ARNI-based regimens	Reduce diuretic if euvolaemic; stop non-HF antihypertensives; stagger dosing
   Early eGFR decline	Often haemodynamic; may signal congestion	Do not stop GDMT reflexively; reassess volume; recheck labs
   Hyperkalaemia	Mainly MRA and ARNI related	K+ >5.5 mmol/L: reduce or hold MRA; consider potassium binder
   Bradycardia	HR <50 bpm or symptomatic	Reduce beta-blocker; review other rate-slowing drugs

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   [9, 12, 13, 14]

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   Speaker notes

   These are the barriers that most often stop titration. Asymptomatic low blood pressure is not a contraindication; many patients run systolic pressures in the nineties without problems. If symptomatic, cut the diuretic in a euvolaemic patient and stop non-heart-failure antihypertensives before touching GDMT. The KDIGO conference emphasised that small eGFR declines after starting these drugs are usually haemodynamic and do not require discontinuation. In STRONG-HF, an early eGFR drop was linked to residual congestion and subsequently lower GDMT doses, so think decongestion, not withdrawal. Note also that SGLT2 inhibitors protect against renal adverse events and help limit hyperkalaemia.

9. Slide 9 · Structured follow-up and timely specialist referral

   Structured follow-up and timely specialist referral

   Every titration visit (1–2 weekly)

   Congestion, weight, BP including orthostatic, heart rate

   Potassium, creatinine/eGFR, NT-proBNP trend

   One dose step per visit; adjust loop diuretic

   Adherence, education, record % of target dose

   Refer to HF specialist when

   Persistent NYHA III–IV or recurrent HF admissions

   Intolerance prevents reaching meaningful GDMT doses

   LVEF ≤35% after ≥3 months optimised GDMT: ICD/CRT evaluation

   Advanced HF markers: worsening renal function, hypotension, cachexia

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   Speaker notes

   How do we make this work in practice? Borrow the STRONG-HF structure: early visits after discharge, roughly weekly or fortnightly, each with a short checklist. Assess congestion, vital signs, potassium, creatinine and natriuretic peptide, then make one change. Nurse-led or telephone visits can cover many steps. Refer early when titration stalls because of intolerance, when symptoms persist, or after repeated admissions. And remember device timing: reassess LVEF after about three months of optimised therapy, since many patients improve enough to avoid an ICD. Practical tip: a pre-printed titration plan given at discharge saves weeks.

10. Slide 10 · References

    References

    1. 1.van Essen BJ, Ceelen DCH, Ouwerkerk W, et al. Pharmacologic Treatment of Heart Failure With Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis. J Am Coll Cardiol. 2025. doi:10.1016/j.jacc.2025.08.054
    2. 2.Tang J, Wang P, Liu C, et al. Pharmacotherapy in patients with heart failure with reduced ejection fraction: A systematic review and meta-analysis. Chin Med J (Engl). 2025. doi:10.1097/CM9.0000000000003118
    3. 3.Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022. doi:10.1161/CIR.0000000000001063
    4. 4.Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022. doi:10.1016/j.jacc.2021.12.012
    5. 5.Maddox TM, Januzzi JL Jr, Allen LA, et al. 2024 ACC Expert Consensus Decision Pathway for Treatment of Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2024. doi:10.1016/j.jacc.2023.12.024
    6. 6.Mebazaa A, Davison B, Chioncel O, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial. Lancet. 2022. doi:10.1016/S0140-6736(22)02076-1
    7. 7.Arrigo M, Biegus J, Asakage A, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure in elderly patients: A sub-analysis of the STRONG-HF randomized clinical trial. Eur J Heart Fail. 2023. doi:10.1002/ejhf.2920
    8. 8.Čerlinskaitė-Bajorė K, Lam CSP, Sliwa K, et al. Sex-specific analysis of the rapid up-titration of guideline-directed medical therapies after a hospitalization for acute heart failure: Insights from the STRONG-HF trial. Eur J Heart Fail. 2023. doi:10.1002/ejhf.2882
    9. 9.Ter Maaten JM, Mebazaa A, Davison B, et al. Early changes in renal function during rapid up-titration of guideline-directed medical therapy following an admission for acute heart failure. Eur J Heart Fail. 2023. doi:10.1002/ejhf.3074
    10. 10.Čelutkienė J, Čerlinskaitė-Bajorė K, Cotter G, et al. Impact of Rapid Up-Titration of Guideline-Directed Medical Therapies on Quality of Life: Insights From the STRONG-HF Trial. Circ Heart Fail. 2024. doi:10.1161/CIRCHEARTFAILURE.123.011221
    11. 11.Arrigo M, Davison B, Edwards C, et al. Characteristics, treatment, and outcomes of early vs. late enrollees of the STRONG-HF trial. Am Heart J. 2024. doi:10.1016/j.ahj.2024.04.019
    12. 12.Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges: Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC Heart Fail. 2026. doi:10.1016/j.jchf.2026.102943
    13. 13.Jiang N, Zhang Y, Tang Y, et al. Comparative efficacy and safety of different SGLT2 inhibitor-based combination strategies in HFrEF: a systematic review and network meta-analysis. Front Endocrinol (Lausanne). 2025. doi:10.3389/fendo.2025.1742128
    14. 14.Writing Committee, Maddox TM, Januzzi JL Jr, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021. doi:10.1016/j.jacc.2020.11.022

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11. Slide 11 · Questions?

    Questions?

    Start all four pillars early, reach target doses within weeks, follow closely

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    Speaker notes

    To summarise: quadruple therapy offers the largest survival benefit we have in HFrEF, measured in years of life. Start all four classes early and in parallel, ideally before discharge. Titrate rapidly, as STRONG-HF showed, across ages and sexes, with structured visits checking congestion, vitals and labs. Manage hypotension, kidney function changes and potassium thoughtfully rather than stopping drugs. And refer when titration stalls or advanced features appear. I'm happy to take questions or discuss difficult cases from your practice.

This presentation was generated automatically to show what Doctoria can do and has not been reviewed as clinical guidance. Clinical cases in the examples are fictional.