Clinical trial NCT03412201: Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies
Official title: Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Heart Failure
Keywords: Disease management
Medication therapy management
Biomarkers
Lead sponsor: Heart Initiative
Sponsor class: OTHER
Collaborators: name: Hôpitaux Universitaires Saint-Louis-Lariboisière
name: Momentum Research, Inc.
name: Roche Diagnostics GmbH
name: INSERM UMR-942, Paris, France
First posted: 2018-01-26
Enrollment: 1800
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: multicenter, randomized, parallel group study
Primary purpose: TREATMENT

Brief summary: STRONG-HF is a multicenter, randomized, parallel group study designed to evaluate the efficacy and safety of up-titration of standard oral heart failure medications during hospitalization for acute heart failure. Patients admitted for acute heart failure will be randomized within 2 days before discharge to either usual care or intensification of treatment with a beta-blocker, a renin-angiotensin system blocker, and a mineralocorticoid receptor blocker ("high intensity care" arm). In the "high intensity care" arm, patients' clinical signs and symptoms of heart failure will be assessed, and routine laboratory measures and biomarkers will be measured, at frequent post-discharge visits. When these measures indicate that it is safe to do so, the doses of the oral heart failure medications will be increased to optimal levels. Patients will be followed through 180 days from randomization. Patients assigned to the usual care group will be followed by their general physician and/or cardiologist according to local medical standards. Patients who were screened but did not meet eligibility criteria will be followed for 90-day outcome. Randomized patients will be contacted at 180 days to assess outcomes.

Detailed description: STRONG-HF is a multicenter, randomized, parallel group study designed to evaluate the efficacy and safety of up-titration of standard of care medical therapy including beta-blockers; angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blocker (ARB) or angiotensin receptor neprolysin inhibitor (ARNi); and mineralocorticoid receptor antagonist (MRAs), on morbidity and mortality when initiated and up-titrated early during hospitalization for acute heart failure (AHF). Optimal safety conditions will allow physicians to introduce and/or continue oral HF therapies during this "vulnerable phase" in AHF patients. Patients admitted for AHF with clinical signs of congestion and elevated circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP) and who are not treated with optimal doses of oral heart failure (HF) therapies within 2 days before hospital discharge for AHF and who are hemodynamically stable will be randomized in a 1:1 ratio to either usual care (named "usual care" arm) or intensification of treatment with beta-blockers, and ACEi (or ARB) or ARNi and a MRA (named "high intensity care" arm). In the latter arm, repeated assessments of clinical signs and symptoms of heart failure, routine clinical laboratory measures including potassium, sodium, and creatinine as well as NT-ProBNP will foster, encourage and ensure the safety of the optimization of oral heart failure therapies. AHF patients who were screened but did not meet inclusion criteria, including low circulating NT-proBNP at visit 2, will be followed for 90-day outcome. Randomized patients will be contacted at 180 days to assess outcomes.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. All measures within 24 hours prior to Randomization of systolic blood pressure ≥ 100 mmHg, and of heart rate ≥ 60 bpm.
3. All measures within 24 hours prior to Randomization of serum potassium ≤ 5.0 mEq/L (mmol/L).
4. Biomarker criteria for persistent congestion:
5. At Screening, NT-proBNP \> 2,500 pg/mL.
6. At the time of Randomization (within 2 days prior to discharge), NT-proBNP \> 1,500 pg/mL (to ensure the persistence of congestion) that has decreased by more than 10% compared to Screening (to ensure the acuity of the index episode).
7. At 1 week prior to admission, at Screening, and at Visit 2 (just prior to Randomization) either (a) \<= ½ the optimal dose of ACEi/ARB/ARNi (see Table) prescribed, no beta-blocker prescribed, and \<= ½ the optimal dose of MRA prescribed or (b) no ACEi/ARB/ARNi prescribed, \<= ½ the optimal dose of beta-blocker prescribed, and \<= ½ the optimal dose of MRA prescribed.
8. Written informed consent to participate in the study.

Exclusion Criteria:

1. Age \< 18 or \> 85 years.
2. Clearly documented intolerance to high doses of beta-blockers.
3. Clearly documented intolerance to high doses of renin-angiotensin system (RAS) blockers (both ACEi and ARB).
4. Mechanical ventilation \[not including continuous positive airway pressure (CPAP)/bilevel positive airway pressure (BIPAP)\] in the 24 hours prior to Screening.
5. Significant pulmonary disease contributing substantially to the patients' dyspnea such as forced expiratory volume during the 1st second (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.
6. 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.
7. Index Event (admission for AHF) triggered primarily by a correctable etiology 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 anemia, 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.
8. Uncorrected thyroid disease, active myocarditis, or known amyloid or hypertrophic obstructive cardiomyopathy.
9. History of heart transplant or on a transplant list, or using or planned to be implanted with a ventricular assist device.
10. Sustained ventricular arrhythmia with syncopal episodes within the 3 months prior to screening that is untreated.
11. 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 of the left ventricular outflow tract.
12. Active infection at any time during the AHF hospitalization prior to Randomization based on abnormal temperature and elevated white blood cells (WBC) or need for intravenous antibiotics.
13. Stroke or transient ischemic attack (TIA) within the 3 months prior to Screening.
14. Primary liver disease considered to be life threatening.
15. Renal disease or estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m2 \[as estimated by the simplified Modification of Diet in Renal Disease (MDRD) formula\] at Screening or history of dialysis.
16. Psychiatric or neurological disorder, cirrhosis, or active malignancy leading to a life expectancy \< 6 months.
17. Prior (defined as less than 30 days from screening) or current enrollment in a congestive heart failure (CHF) trial or participation in an investigational drug or device study within the 30 days prior to screening
18. 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 within 2 days prior to anticipated discharge.
19. 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
20. Pregnant or nursing (lactating) women.

Primary outcomes:
measure: 180-day all-cause mortality or heart failure readmission
timeFrame: 180 days
Secondary outcomes:
measure: Change in quality of life
timeFrame: 90 days
measure: 180-day all-cause mortality
timeFrame: 180 days
measure: 90-day all-cause mortality or heart failure readmission
timeFrame: 90 days
Other outcomes:
measure: 180-day cardiovascular death
timeFrame: 180 days
measure: 90-day cardiovascular death
timeFrame: 90 days
measure: 90-day all-cause mortality
timeFrame: 90 days
measure: 180-day heart failure readmission
timeFrame: 180 days
measure: 90-day heart failure readmission
timeFrame: 90 days
measure: Finkelstein-Schoenfeld hierarchical composite
timeFrame: 90 days
measure: Change in NT-proBNP
timeFrame: 90 days
measure: Change in weight
timeFrame: 90 days
measure: Changes in signs and symptoms of congestion: NYHA class
timeFrame: 90 days
measure: Changes in signs and symptoms of congestion: orthopnea
timeFrame: 90 days
measure: Changes in signs and symptoms of congestion: peripheral edema
timeFrame: 90 days
measure: Changes in signs and symptoms of congestion: rales
timeFrame: 90 days
measure: Changes in signs and symptoms of congestion: JVP
timeFrame: 90 days
Locations:
city: Villa María
country: Argentina
facility: Sanatorio de la Canada
state: Cordoba
city: Córdoba
country: Argentina
facility: Chutro Srl Clinic
city: Córdoba
country: Argentina
facility: Del Prado Private Clinic
city: Córdoba
country: Argentina
facility: San Roque Hospital
city: Rosario
country: Argentina
facility: Rosario Cardiovascular Institute
city: Rosario
country: Argentina
facility: Rosario Clinical Research Institute - Delta
city: San Miguel De Tucumán
country: Argentina
facility: Modelo Cardiology Center
city: Santa Fe
country: Argentina
facility: Diagnostic and Treatment Medical Clinic SA
city: Santa Rosa
country: Argentina
facility: Santa Rosa Hospital
city: Venado Tuerto
country: Argentina
facility: San Martin SA Clinic
city: Villa María
country: Argentina
facility: Fusavim Privada SRL Clinic
city: Braunau Am Inn
country: Austria
facility: Internal Med. 1, St. Josef Hospital Braunau
city: St. Poelten
country: Austria
facility: Clin. Dep. Internal Med 3, University Hospital St. Poelten
city: Villach
country: Austria
facility: Internal Med., LKH Villach
city: Wien
country: Austria
facility: 1. Med. Dep, Donauspital
city: Wien
country: Austria
facility: Cardiology Department at Hietzing Hospital with Neurological Center Rosenhugel
city: Wien
country: Austria
facility: Dep. Of Cardiology, Medical Univ. Vienna
city: Cartagena
country: Colombia
facility: Cardiovascular Diagnostic Center
state: Bolivar
city: Armenia
country: Colombia
facility: CEQUIN Cardiomet Foundation
state: Quindio
city: Pereira
country: Colombia
facility: Cardiomet Pereira Clinical Research Center Foundation
state: Risaralda
city: Bucaramanga
country: Colombia
facility: Santander Ophthalmological Foundation
state: Santander
city: Auxerre
country: France
facility: Auxerre Hospital Center
city: Béziers
country: France
facility: University Hospital of Beziers
city: Chambray-lès-Tours
country: France
facility: Center Hospital Regional University of Tours Trousseu Hospital
city: Creil
country: France
facility: University Hospital Henri Mondor
city: Dijon
country: France
facility: CHU Dijon Burgundy F. Mitterand
city: Paris
country: France
facility: Hôpitaux Universitaires Saint-Louis-Lariboisière, University Paris Diderot
city: Toulon
country: France
facility: Center Hospital of Toulon
city: Budapest
country: Hungary
facility: Buda Hospital of the Hospitaller Order of Saint John of God
city: Nagykanizsa
country: Hungary
facility: Kanizsai Dorottya Hospital
city: Zalaegerszeg
country: Hungary
facility: St. Rafael Hospital in Zala County
city: Ashkelon
country: Israel
facility: Barzilay MC Ashkelon
city: Zerifin
country: Israel
facility: Asaf Harofe MC
city: Maputo
country: Mozambique
facility: Dept of Medicine Research unit, Maputo Central Hospital
city: Maputo
country: Mozambique
facility: Mavalane Hospital, National Institute of Health
city: Kano
country: Nigeria
facility: Amino Kano Teaching Hospital
city: Kano
country: Nigeria
facility: Murtala Muhammad Specialist Hospital
city: Arkhangel'sk
country: Russian Federation
facility: State Budget HealthCare Institution "First City clinical hospital named after E.E. Volosevich"
city: Ivanovo
country: Russian Federation
facility: Regional budget Healthcare Institution "Cardiological dispensary"
city: Moscow
country: Russian Federation
facility: Federal State Budget Educational Institution of Higher Education "Moscow State Medico-Dental University n.a. A.I. Evdokimov", under Ministry of Health of the Russian Federation
city: Moscow
country: Russian Federation
facility: Federal State Budget Educational Institution of Higher Education "Moscow State University n.a. M.V. Lomonosov", independent division Medical research Educational Centre
city: Moscow
country: Russian Federation
facility: Moscow City Hospital # 81, Moscow
city: Moscow
country: Russian Federation
facility: Moscow State Budget Healthcare Institution City clinical Hospital 52 of Moscow Healthcare Department
city: Moscow
country: Russian Federation
facility: Primary Healthcare Unit of the RF Ministry of Internal Affairs in Moscow
city: Moscow
country: Russian Federation
facility: Russian National Research Medical University n.a. N.I.Pirogov based at City Clinical hospital n.a. V.M.Buyanov DZM
city: Moscow
country: Russian Federation
facility: SBHI of Moscow City clinical hospital 64 of Moscow Healthcare department
city: Moscow
country: Russian Federation
facility: State Budget HealthCare Institution of Moscow "City clinical hospital 15 n.a. O.M. Filatov under Department of HealthCare of Moscow"
city: Moscow
country: Russian Federation
facility: State Budget HealthCare Institution of Moscow "City clinical hospital 29 n.a. N.E. Bauman under Department of HealthCare of Moscow"
city: Moscow
country: Russian Federation
facility: State Budget HealthCare Institution of Mosocw "City clinical hospital 51 under Department of HealthCare of Moscow"
city: Pushkin
country: Russian Federation
facility: Saint-Petersburg State Budget HealthCare Institution "City hospital 38 n.a. N.A. Semashko"
city: Rostov-on-Don
country: Russian Federation
facility: Municipal Government-financed Institution of Healthcare "City Emergency Hospital" of Rostov-on-Don City
city: Ryazan'
country: Russian Federation
facility: Federal State Budgetary Educational Institution of Higher Education "Ryazan State Medical University named after academician I.P. Pavlov"
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budget Educational Institution of Higher Education "North-West state medical university n.a. I.I. Mechnikov under the Ministry of Health of the Russian Federation"
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg State Budget Healthcare Institution Pokrovskaya City Hospital
city: Saint Petersburg
country: Russian Federation
facility: Saint-Petersburg State Budget Healthcare Institution City Hospital 15
city: Saint Petersburg
country: Russian Federation
facility: State Budget Institution "Saint Petersburg state budget research institution of first aid named after I. I. Dzhanelidze"
city: Vladimir
country: Russian Federation
facility: State Budget HealthCare Institution of Vladimir Region "City Hospital 4 of Vladimir"
city: Yaroslavl
country: Russian Federation
facility: State Institution of Healthcare of Yaroslavl Region "Clinical Hospital 8"
city: Bratislava
country: Slovakia
facility: National Institute of Cardio and Vascular Diseases
city: Bratislava
country: Slovakia
facility: V. Internal Clinic, LFUK and UNB Bratislava
city: Brezno
country: Slovakia
facility: Internal Department, Hospital with Polyclinic Brezno
city: Dolný Kubín
country: Slovakia
facility: Internal Department, Dolnooravian Hospital of Dr. L.N.Jege
city: Lučenec
country: Slovakia
facility: Internal Department, Hospital with Polyclinic Lucenec
city: Nové Zámky
country: Slovakia
facility: First Internal Clinic, Faculty Hospital with Polyclinic Nove Zamky
city: Rimavská Sobota
country: Slovakia
facility: Department of Internal Medicine Hospital Rimavska Sobota
city: Ružomberok
country: Slovakia
facility: Department of Internal Medicine UVN SNP-FN
city: Spišská Nová Ves
country: Slovakia
facility: Internal Department, NsP Spisska Nova Ves
city: Svidník
country: Slovakia
facility: Internal Department Hospital Arm General L. Svobodu Svidnik
city: Cape Town
country: South Africa
facility: Groote Schuur Hospital
city: Mthatha
country: South Africa
facility: Nelson Mandela Academic Hospital, Walter Sisulu University
city: Bizerte
country: Tunisia
facility: Habib Bougatfa Hospital
city: Jendouba
country: Tunisia
facility: Regional Hospital of Jendouba
city: Monastir
country: Tunisia
facility: Fattouma Bourguiba Hospital
city: Sfax
country: Tunisia
facility: Hedi chaker Hospital
city: Tunis
country: Tunisia
facility: Charles Nicolle Hospital
city: Tunis
country: Tunisia
facility: Habib Thameur Hospital
city: Tunis
country: Tunisia
facility: La Rabta Hospital
city: Tunis
country: Tunisia
facility: Military Hospital
Study officials:
affiliation: Inserm UMRS 942; Hôpitaux Universitaires Saint-Louis-Lariboisière, University Paris Diderot
name: Alexandre Mebazaa, MD PhD FESC
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Cotter G, Davison B, Metra M, Sliwa K, Voors AA, Addad F, Celutkiene J, Chioncel O, Cohen Solal A, Diaz R, Damasceno A, Duengen HD, Filippatos G, Goncalvesova E, Merai I, Ponikowski P, Privalov D, Sani MU, Takagi K, Shogenov Z, Saidu H, Mebazaa A. Amended STRONG-HF study design. Eur J Heart Fail. 2021 Nov;23(11):1981-1982. doi: 10.1002/ejhf.2348. Epub 2021 Oct 4. No abstract available.
citation: Kimmoun A, Cotter G, Davison B, Takagi K, Addad F, Celutkiene J, Chioncel O, Solal AC, Diaz R, Damasceno A, Duengen HD, Filippatos G, Goncalvesova E, Merai I, Metra M, Ponikowski P, Privalov D, Sliwa K, Sani MU, Voors AA, Shogenov Z, Mebazaa A. Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP and GDF-15, of Heart Failure therapies (STRONG-HF): rationale and design for a multicentre, randomized, parallel-group study. Eur J Heart Fail. 2019 Nov;21(11):1459-1467. doi: 10.1002/ejhf.1575. Epub 2019 Aug 19.