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

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

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:

1. Does intensive medication optimization reduce death or hospital readmissions for heart failure within one year?
2. Do women benefit as much as men from intensive and full-dose heart failure therapy?
3. Is this treatment protocol safe and feasible also in women?

Researchers will compare two groups of women hospitalized for heart failure:

• 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).

PopS-HF is a phase IV, low-interventional, multicenter randomized controlled trial designed to test whether intensive optimization of guideline directed medical therapy (GDMT), following the STRONG-HF (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing of Heart Failure Therapies) titration strategy, improves outcomes in women hospitalized for heart failure (HF).

The study also includes a retrospective analysis of national healthcare databases and specialized HF registries from 2018-2023 to evaluate how GDMT are prescribed in real-world practice and to identify sex-related differences in treatment patterns and outcomes.

Eligible patients are women aged 18-85 years hospitalized for acute HF with evidence of congestion and hemodynamic stability before discharge. Exclusion criteria include severe comorbidities, pregnancy, and inability to follow up.

The prospective component randomizes 368 patients to an intensive strategy or usual care, with follow-up visits at 2, 4, 6, 12, 24, 36, and 52 weeks.

The primary endpoint is a composite of all-cause mortality, HF readmission, or worsening HF within 1 year.

Secondary endpoints assess optimization of therapy, side effects, biomarkers (NT-proBNP), and quality of life.

Inclusion Criteria:

1. Female patients >18 <85 years.

2. 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.

3. All measures within 24 hours prior to Randomization of systolic blood pressure ≥ 100 mmHg, and of heart rate ≥ 60 bpm.

4. All measures within 24 hours prior to Randomization of serum potassium ≤ 5.0 mEq/L (mmol/L).

5. Biomarker criteria for persistent congestion:

   5.1. 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).

6. 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.

7. Written informed consent to participate in the study.

Exclusion Criteria:

1. Male patients
2. Age < 18 or > 85 years.
3. Mechanical ventilation (not including CPAP/BIPAP) in the 24 hours prior to Screening.
4. 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.
5. 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.
6. Index Event (admission for Acute Heart Failure) triggered primarily by a correctable aetiology such as significant arrhythmia (e.g., sustained ventricular tachycardia, or atrial fibrillation/flutter with sustained ventricular response >130 beats per minute, or bradycardia with sustained ventricular arrhythmia <45 beats per minute), infection, severe anaemia, acute coronary syndrome, pulmonary embolism, exacerbation of Chronic Obstructive Pulmonary Disease (COPD), planned admission for device implantation or severe non-adherence leading to very significant fluid accumulation prior to admission and brisk diuresis after admission. Troponin elevations without other evidence of an acute coronary syndrome are not an exclusion.
7. Uncorrected thyroid disease, active myocarditis, or known amyloid or hypertrophic obstructive cardiomyopathy.
8. History of heart transplant or on a transplant list or using or planned to be implanted with a ventricular assist device.
9. Sustained ventricular arrhythmia with syncopal episodes within the 3 months prior to screening that is untreated.
10. 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
11. Active infection at any time during the AHF hospitalization prior to Randomization based on abnormal temperature and elevated WBC or need for intravenous antibiotics.
12. Stroke or Transient Ischemic Attack (TIA) within the 3 months prior to Screening.
13. Primary liver disease considered to be life threatening.
14. Renal disease or eGFR < 30 mL/min/1.73m2 (as estimated by the simplified MDRD formula) at Screening or history of dialysis.
15. Psychiatric or neurological disorder, cirrhosis, or active malignancy leading to a life expectancy < 6 months.
16. 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.
17. Discharge for the AHF hospitalization anticipated to be >14 days from admission, or to a long-term care facility. Randomization must occur within 12 days following admission and at 1-2 days prior to anticipated discharge.
18. Inability to comply with all study requirements, due to major co-morbidities, social or financial issues or a history of noncompliance with medical regimens, that might compromise the patient's ability to understand and/or comply with the protocol instructions or follow-up procedures.
19. Pregnant or nursing (lactating) women.
20. Hypersensitivity to the active substance or to any of the excipients as indicated in Summary of Product Characteristics of Investigational Medicinal Product (IMPs).
21. Angioedema.
22. Severe heart failure (NYHA class IV).