Pharmacological Optimization in Prevention in Heart Failure: A Sex-gap?

NCT07295522 | Not Yet Recruiting Phase 4

• 2 other identifiers: PopS-HF2025-520660-18
• Study Type: interventional
• Target: 368
• Locations: 1 country
• Sites: 13

Brief Summary

The goal of this clinical trial is to learn whether a rapid and intensive optimization of heart failure medications in women can improve outcomes after hospitalization for heart failure. It will also investigate the safety and the tolerance of these treatments when given at full guideline-recommended doses. The main questions it aims to answer are:

• High-intensity care: starting and increasing all recommended heart-failure medications as quickly as possible and monitoring patients closely during the first weeks after discharge.
• Usual care: medications are started and adjusted gradually, according to the judgment of the treating cardiologist and the patient's usual care team. The study will follow participants for 12 months to see whether the high-intensity strategy reduces death, hospital readmission for heart failure, or worsening symptoms. It will also evaluate side effects, medication tolerance, and quality of life. Participants will be randomly assigned to one of the two groups, attend regular follow-up visits for one year, complete a short quality-of-life questionnaire (EQ-5D). This study will include about 360 women from 13 hospitals in Italy. It is sponsored by IRCCS Policlinico San Donato and funded by the Italian Medicines Agency (AIFA).

Conditions

Heart Failure; Acute Heart Failure; Heart Failure With Reduced Ejection Fraction (HFrEF); Heart Failure With Preserved Ejection Fraction (HFPEF); Heart Failure With Mildly Reduced Ejection Fraction

Keywords

heart failure; women; GDMT; Pharmacological Optimization; phase IV; High intensity up-titration; Secondary prevention; Sex differences; Real world data

Outcome Measures

Primary Outcomes (1)

• Composite of all-cause mortality, heart failure (HF) readmission, or worsening HF within 1 year.

  Composite endpoint including occurrence of (1) death from any cause, (2) hospital readmission for heart failure, or (3) clinically assessed worsening of heart failure.

  12 months

Secondary Outcomes (10)

• Optimization of Beta-blocker Therapy

  12 months

• Optimization of ACEi/ARB/ARNI Therapy

  12 months

• Optimization of Mineralocorticoid Receptor Antagonists (MRAs)

  12 months

• Optimization of SGLT2 Inhibitors

  12 months

• Discontinuation of GDMT due to side effects

  12 months

Other Outcomes (1)

• Proportion of participants experiencing the composite endpoint of all-cause mortality, heart failure hospitalization, or worsening heart failure at 12 months

  12 months

Study Arms (2)

Usual care

NO INTERVENTION

Participants in the usual care arm will receive sequential introduction and adjustment of guideline-directed medical therapy (GDMT) according to the treating cardiologist or general physician's clinical judgment, following routine practice. Follow-up will occur at weeks 6, 12, 24, 36, and 52 after randomization, with clinical visits and intermediate phone contacts as per standard care.

High-intensity care

EXPERIMENTAL

Participants assigned to the high-intensity arm will begin rapid initiation and optimization of guideline-directed medical therapy (GDMT) according to the STRONG-HF protocol. During hospitalization, eligible therapies (beta-blockers (BB), Angiotensin converting enzyme inhibitor(ACEi) /Angiotensin II receptor blocker (ARB)/Angiotensin Receptor-Neprilysin Inhibitors(ARNI), Mineralocorticoid Receptor Antagonists (MRA), and Sodium-Glucose Co-Transporter inhibitor 2 (SGLT2i) for HFrEF/HFmrEF; MRA and SGLT2i for HFpEF will be prescribed at least at half of the recommended target dose. Further titration toward full optimal doses will be performed within the first 6 weeks if clinically appropriate. Participants will undergo clinical assessments at weeks 2, 4, 6, 12, 24, 36, and 52, with safety monitoring including vital signs, physical examination, and laboratory evaluation (NT-proBNP, electrolytes, kidney function). Additional visits may occur after any up-titration if needed for safety.

Drug: Guideline-Directed Medical Therapy (GDMT)

Interventions

Guideline-Directed Medical Therapy (GDMT) DRUG

Guideline-directed medical therapy (GDMT) including beta-blockers, ACE inhibitors or ARBs or ARNIs, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, all approved and commercially available, used according to current ESC guidelines. Participants in the high-intensity care arm are assigned to a strategy of rapid initiation and optimization of GDMT based on the STRONG-HF protocol. Eligible therapies (beta-blockers, ACEi/ARB/ARNI, mineralocorticoid receptor antagonists, and SGLT2 inhibitors for HFrEF/HFmrEF; MRA and SGLT2 inhibitors for HFpEF) are started during hospitalization at least at half of the recommended target dose, followed by frequent clinical assessments and dose titration, when clinically appropriate, within 6 weeks. Safety monitoring includes clinical examination, vital signs, laboratory tests (NT-proBNP, electrolytes, kidney function), and additional visits after each titration if needed.

High-intensity care

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female patients \>18 \<85 years.
• Hospital admission within the 72 hours prior to Screening for acute heart failure with dyspnea at rest and pulmonary congestion on chest X-ray, and other signs and/or symptoms of heart failure such as edema and/or positive rales on auscultation.
• All measures within 24 hours prior to Randomization of systolic blood pressure ≥ 100 mmHg, and of heart rate ≥ 60 bpm.
• All measures within 24 hours prior to Randomization of serum potassium ≤ 5.0 mEq/L (mmol/L).
• Biomarker criteria for persistent congestion:
• At Screening, NT-proBNP \>1,800 pg/mL (2,350 pg/mL in case of atrial fibrillation) 5.2. At the time of Randomization (1-2 days prior to discharge), NT-proBNP \>1,000 pg/mL (1,300 pg/mL in case of Atrial Fibrillation) to ensure the persistence of congestion and the acuity of the index episode).
• At 1 week prior to admission, at Screening, and at Visit 2 6.1. If EF\<50% (ie HFrEF or HFmrEF) either \<½ the optimal dose of ACEi/ARB/ARNi and MRA and BB or no SGLT2i (see Table) must have been prescribed 6.2. If EF\>50% (ie HFpEF): \<½ the optimal dose of MRA (see Table) or no SGLT2i.
• Written informed consent to participate in the study.

You may not qualify if:

• Male patients
• Age \< 18 or \> 85 years.
• Mechanical ventilation (not including CPAP/BIPAP) in the 24 hours prior to Screening.
• Significant pulmonary disease contributing substantially to the patients' dyspnoea such as FEV1 \<1 liter or need for chronic systemic or nonsystemic steroid therapy, or any kind of primary right heart failure such as primary pulmonary hypertension or recurrent pulmonary embolism.
• Myocardial infarction, unstable angina or cardiac surgery within 3 months, or cardiac resynchronization therapy (CRT) device implantation within 3 months, or percutaneous transluminal coronary intervention (PTCI), within 1 month prior to Screening or during the index event.
• Uncorrected thyroid disease, active myocarditis, or known amyloid or hypertrophic obstructive cardiomyopathy.
• History of heart transplant or on a transplant list or using or planned to be implanted with a ventricular assist device.
• Sustained ventricular arrhythmia with syncopal episodes within the 3 months prior to screening that is untreated.
• Presence at Screening of any hemodynamically significant valvular stenosis or regurgitation, except mitral or tricuspid regurgitation secondary to left ventricular dilatation, or the presence of any hemodynamically significant obstructive lesion
• Active infection at any time during the AHF hospitalization prior to Randomization based on abnormal temperature and elevated WBC or need for intravenous antibiotics.
• Stroke or Transient Ischemic Attack (TIA) within the 3 months prior to Screening.
• Primary liver disease considered to be life threatening.
• Renal disease or eGFR \< 30 mL/min/1.73m2 (as estimated by the simplified MDRD formula) at Screening or history of dialysis.
• Psychiatric or neurological disorder, cirrhosis, or active malignancy leading to a life expectancy \< 6 months.
• Prior (defined as less than 30 days from screening) or current enrollment in a CHF trial or participation in an investigational drug or device study within the 30 days prior to screening or 5 half-lives of the study drug, whichever is longer.

Sponsors & Collaborators

• IRCCS Policlinico S. Donato: lead
• Agenzia Italiana del Farmaco: collaborator

Study Sites (13)

IRCCS Policlinico San Donato

San Donato Milanese, MILANO, 20097, Italy

Location

Azienda Ospedaliero Universitaria Delle Marche

Ancona, Italy

Location

Azienda Sanitaria Locale Bari

Bari, Italy

Location

Azienda USL Toscana Nord Ovest - Cecina

Cecina, Italy

Location

Ospedale Universitario di Ferrara

Ferrara, Italy

Location

Azienda USL Toscana Centro

Florence, Italy

Location

Centro Cardiologico Monzino

Milan, Italy

Location

Istituto Auxologico Italiano

Milan, Italy

Location

Fondazione Toscana Gabriele Monasterio

Pisa, Italy

Location

Ospedale S. Maria delle Croci

Ravenna, Italy

Location

Azienda USL IRCCS Di Reggio Emilia

Reggio Emilia, Italy

Location

Fondazione Policlinico Universitario Campus Bio-medico

Roma, Italy

Location

Ospedale San Camillo Forlanini

Roma, Italy

Location

Related Publications (12)

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  PMID: 27143684 BACKGROUND

• Brotons C, Falces C, Alegre J, Ballarin E, Casanovas J, Cata T, Martinez M, Moral I, Ortiz J, Perez E, Rayo E, Recio J, Roig E, Vidal X. Randomized clinical trial of the effectiveness of a home-based intervention in patients with heart failure: the IC-DOM study. Rev Esp Cardiol. 2009 Apr;62(4):400-8. doi: 10.1016/s1885-5857(09)71667-6. English, Spanish.

  PMID: 19401125 BACKGROUND

• Mebazaa A, Davison B, Chioncel O, Cohen-Solal A, Diaz R, Filippatos G, Metra M, Ponikowski P, Sliwa K, Voors AA, Edwards C, Novosadova M, Takagi K, Damasceno A, Saidu H, Gayat E, Pang PS, Celutkiene J, Cotter G. 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 Dec 3;400(10367):1938-1952. doi: 10.1016/S0140-6736(22)02076-1. Epub 2022 Nov 7.

  PMID: 36356631 BACKGROUND

• Dewan P, Rorth R, Jhund PS, Shen L, Raparelli V, Petrie MC, Abraham WT, Desai AS, Dickstein K, Kober L, Mogensen UM, Packer M, Rouleau JL, Solomon SD, Swedberg K, Zile MR, McMurray JJV. Differential Impact of Heart Failure With Reduced Ejection Fraction on Men and Women. J Am Coll Cardiol. 2019 Jan 8;73(1):29-40. doi: 10.1016/j.jacc.2018.09.081.

  PMID: 30621948 BACKGROUND

• Lainscak M, Milinkovic I, Polovina M, Crespo-Leiro MG, Lund LH, Anker SD, Laroche C, Ferrari R, Coats AJS, McDonagh T, Filippatos G, Maggioni AP, Piepoli MF, Rosano GMC, Ruschitzka F, Simic D, Asanin M, Eicher JC, Yilmaz MB, Seferovic PM; European Society of Cardiology Heart Failure Long-Term Registry Investigators Group. Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry. Eur J Heart Fail. 2020 Jan;22(1):92-102. doi: 10.1002/ejhf.1645. Epub 2019 Dec 20.

  PMID: 31863522 BACKGROUND

• Butler J, Yang M, Sawhney B, Chakladar S, Yang L, Djatche LM. Treatment patterns and clinical outcomes among patients <65 years with a worsening heart failure event. Eur J Heart Fail. 2021 Aug;23(8):1334-1342. doi: 10.1002/ejhf.2252. Epub 2021 Jun 17.

  PMID: 34053163 BACKGROUND

• Fiuzat M, Ezekowitz J, Alemayehu W, Westerhout CM, Sbolli M, Cani D, Whellan DJ, Ahmad T, Adams K, Pina IL, Patel CB, Anstrom KJ, Cooper LS, Mark D, Leifer ES, Felker GM, Januzzi JL, O'Connor CM. Assessment of Limitations to Optimization of Guideline-Directed Medical Therapy in Heart Failure From the GUIDE-IT Trial: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol. 2020 Jul 1;5(7):757-764. doi: 10.1001/jamacardio.2020.0640.

  PMID: 32319999 BACKGROUND

• Kapelios CJ, Murrow JR, Nuhrenberg TG, Montoro Lopez MN. Effect of mineralocorticoid receptor antagonists on cardiac function in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials. Heart Fail Rev. 2019 May;24(3):367-377. doi: 10.1007/s10741-018-9758-0.

  PMID: 30618017 BACKGROUND

• Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW; ACC/AHA Joint Committee Members. 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 May 3;145(18):e895-e1032. doi: 10.1161/CIR.0000000000001063. Epub 2022 Apr 1.

  PMID: 35363499 BACKGROUND

• Najafi F, Jamrozik K, Dobson AJ. Understanding the 'epidemic of heart failure': a systematic review of trends in determinants of heart failure. Eur J Heart Fail. 2009 May;11(5):472-9. doi: 10.1093/eurjhf/hfp029. Epub 2009 Feb 27.

  PMID: 19251729 BACKGROUND

• Piepoli MF, Adamo M, Barison A, Bestetti RB, Biegus J, Bohm M, Butler J, Carapetis J, Ceconi C, Chioncel O, Coats A, Crespo-Leiro MG, de Simone G, Drexel H, Emdin M, Farmakis D, Halle M, Heymans S, Jaarsma T, Jankowska E, Lainscak M, Lam CSP, Lochen ML, Lopatin Y, Maggioni A, Matrone B, Metra M, Noonan K, Pina I, Prescott E, Rosano G, Seferovic PM, Sliwa K, Stewart S, Uijl A, Vaartjes I, Vermeulen R, Verschuren WM, Volterrani M, Von Haehling S, Hoes A. Preventing heart failure: a position paper of the Heart Failure Association in collaboration with the European Association of Preventive Cardiology. Eur J Prev Cardiol. 2022 Feb 19;29(1):275-300. doi: 10.1093/eurjpc/zwab147.

  PMID: 35083485 BACKGROUND

• McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available.

  PMID: 34447992 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Central Study Contacts

Massimo Piepoli, MD

CONTACT

0252774966; MASSIMO.PIEPOLI@GRUPPOSANDONATO.IT

Giovanna Landi, PharmD

CONTACT

0252774885; GIOVANNA.LANDI@GRUPPOSANDONATO.IT

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: A parallel-group design is used, with participants randomized 1:1 to receive either high-intensity optimization of guideline-directed medical therapy or usual care.

Study Record Dates

• First Submitted: December 1, 2025
• First Posted: December 19, 2025
• Study Start: April 8, 2026
• Primary Completion (Estimated): June 8, 2027
• Study Completion (Estimated): June 8, 2028
• Last Updated: March 30, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (13)