PRIMA-HF: Predicting Myocardial Recovery in Heart Failure Using Cardiac Imaging HAI-HF: High Dosing vs. Standard Dosing Adenosine During Myocardial Perfusion in Heart Failure

NCT07243119 | Enrolling By Invitation Phase 4

• 1 other identifier: 1-10-72-126-25
• Study Type: interventional
• Target: 180
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Heart failure with reduced ejection fraction (HFrEF) is a heterogeneous condition with variable potential for left ventricular ejection fraction (LVEF) recovery. While LVEF improvement and reverse remodeling predict better outcomes, the determinants that predict left ventricular recovery remain poorly understood. An expert panel of the Journal of American College of Cardiology highlighted the need for improved HFrEF phenotyping to clarify recovery patterns and support personalized management and risk stratification. Methods: PRIMA-HF is a prospective prediction study designed to determine whether baseline cardiac multimodality imaging can predict LVEF recovery in patients with de novo HFrEF (n=180). The imaging protocol includes cardiac magnetic resonance (CMR), coronary computed tomography and \[¹⁵O\]H₂O positron emission tomography (\[¹⁵O\]H₂O-PET) and echocardiography. Patients will also undergo a six-minute walk test, blood volume measurement, and blood sampling. The primary outcome is the change in LVEF from baseline to approx. after 3-12 months (or after full optitration in GDMT), assessed by CMR. In 60 patients from the PRIMA-HF cohort, the randomized, double-blind study High Dose Adenosine During Perfusion Imaging in Heart Failure (HAI-HF) will be conducted. HAI-HF evaluates whether high-dose adenosine (210 µg/kg/min) versus standard-dose (140 µg/kg/min) during \[¹⁵O\]H₂O-PET changes the stress myocardial blood flow, which is the primary endpoint. Aim: The PRIMA-HF study comprehensively characterizes patients with newly diagnosed HFrEF through multimodality imaging and systematically assesses change in LVEF using CMR. The study's deep phenotyping approach integrates clinical, imaging, biomarker, and functional data to capture disease heterogeneity, rather than relying on traditional measures such as LVEF or symptom class. This enables the identification of distinct patient subgroups with shared pathophysiological mechanisms. The HAI-HF trial examines whether higher adenosine doses improve \[¹⁵O\]H₂O-PET perfusion imaging in HFrEF. Together, the studies will advance understanding of myocardial recovery, improve perfusion assessment, and support development of a predictive model for HFrEF prognosis.

Conditions

Heart Failure; Heart Failure and Reduced Ejection Fraction

Keywords

LVEF; HFrEF; HFrecEF; Perfusion Imaging; Adenosine; Cardiac Magnetic Resonance Imaging

Outcome Measures

Primary Outcomes (2)

• PRIMA-HF: Left ventricular ejection fraction (LVEF)

  Change in LVEF (continuous variable, absolute change in LVEF in percent points)

  PRIMA-HF: Baseline through study completion, an average of 3 months

• HAI-HF: Stress Myocardial Blood Flow (MBF)

  Change in stress MBF (continuous variable, ml/min/g)

  Baseline and periprocedural

Secondary Outcomes (2)

• PRIMA-HF: Kansas City Cardiomyopathy Questionaire (KCCQ-12)

  Baseline through study completion, an average of 3 months

• PRIMA-HF: 6 minutes-walk-test

  Baseline through study completion, an average of 3 months

Other Outcomes (2)

• PRIMA-HF: Blood volume

  Baseline through study completion, an average of 3 months

• PRIMA-HF: NT-Pro-BNP

  Baseline through study completion, an average of 3 months

Study Arms (2)

Low-dose then High-dose Adenosine

EXPERIMENTAL

Diagnostic Test: HAI-HF: Adenosine Stress [¹⁵O]H₂O PET Imaging; Drug: Two different doses of adenosine

High-dose then Low-dose Adenosine

EXPERIMENTAL

Diagnostic Test: HAI-HF: Adenosine Stress [¹⁵O]H₂O PET Imaging; Drug: Two different doses of adenosine

Interventions

HAI-HF: Adenosine Stress [¹⁵O]H₂O PET Imaging DIAGNOSTIC_TEST

HAI-HF: Patients will be randomized in a 1:1 ratio to one of two dosing sequences: high-dose followed by low-dose adenosine, or low-dose followed by high-dose adenosine.

High-dose then Low-dose Adenosine; Low-dose then High-dose Adenosine

Two different doses of adenosine DRUG

Testing if high dose adenosine (210 ug/kg/min) during perfusion imaging results in a higher myocardial blood flow compared to standard dose (140 ug/kg/min) in patients with HFrEF

High-dose then Low-dose Adenosine; Low-dose then High-dose Adenosine

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years
• Capable and has provided written informed consent
• LVEF ≤ 40% by echocardiography in connection with hospitalization for heart failure or in connection with outpatient evaluation for heart failure

You may not qualify if:

• Previous diagnosis of heart failure
• Unable to understand the patient information
• Pregnancy, as the study involves ionizing radiation.
• Current severe valvular disease (as defined by the Danish national treatment guidelines on cardio.dk)
• Acute exacerbation of existing chronic obstructive pulmonary disease
• Severe asthma or chronic obstructive pulmonary disease with FEV1 \< 1L
• any contraindication for adenosine stress testing
• Severe renal failure \< 15 mL/min/1.73m² or dialysis
• Advanced liver disease (Child-Pugh class C)
• Isolated right-sided heart failure
• Malignant disease treated with chemotherapy or radiotherapy, or expected life expectancy under 1 year

Sponsors & Collaborators

• Gødstrup Hospital: lead

Study Sites (1)

University Clinic of Cardiovascular Reseach

Herning, 7400, Denmark

Location

Related Publications (23)

• Funaya H, Kitakaze M, Node K, Minamino T, Komamura K, Hori M. Plasma adenosine levels increase in patients with chronic heart failure. Circulation. 1997 Mar 18;95(6):1363-5. doi: 10.1161/01.cir.95.6.1363.

  PMID: 9118500 BACKGROUND

• Kim IC, Yoo BS. Multidimensional Approach of Heart Failure Diagnosis and Prognostication Utilizing Cardiac Imaging with Biomarkers. Diagnostics (Basel). 2022 Jun 1;12(6):1366. doi: 10.3390/diagnostics12061366.

  PMID: 35741176 BACKGROUND

• Wilcox J, Yancy CW. Stopping medication for heart failure with improved ejection fraction. Lancet. 2019 Jan 5;393(10166):8-10. doi: 10.1016/S0140-6736(18)32825-3. Epub 2018 Nov 11. No abstract available.

  PMID: 30429051 BACKGROUND

• Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel. J Am Coll Cardiol. 2020 Aug 11;76(6):719-734. doi: 10.1016/j.jacc.2020.05.075.

  PMID: 32762907 BACKGROUND

• Postnov DD, Tuchin VV, Sosnovtseva O. Estimation of vessel diameter and blood flow dynamics from laser speckle images. Biomed Opt Express. 2016 Jun 22;7(7):2759-68. doi: 10.1364/BOE.7.002759. eCollection 2016 Jul 1.

  PMID: 27446704 BACKGROUND

• Borges JP, Lopes GO, Verri V, Coelho MP, Nascimento PM, Kopiler DA, Tibirica E. A novel effective method for the assessment of microvascular function in male patients with coronary artery disease: a pilot study using laser speckle contrast imaging. Braz J Med Biol Res. 2016 Sep 1;49(10):e5541. doi: 10.1590/1414-431X20165541.

  PMID: 27599202 BACKGROUND

• Strobeck JE, Feldschuh J, Miller WL. Heart Failure Outcomes With Volume-Guided Management. JACC Heart Fail. 2018 Nov;6(11):940-948. doi: 10.1016/j.jchf.2018.06.017. Epub 2018 Oct 10.

  PMID: 30316941 BACKGROUND

• Bello D, Shah DJ, Farah GM, Di Luzio S, Parker M, Johnson MR, Cotts WG, Klocke FJ, Bonow RO, Judd RM, Gheorghiade M, Kim RJ. Gadolinium cardiovascular magnetic resonance predicts reversible myocardial dysfunction and remodeling in patients with heart failure undergoing beta-blocker therapy. Circulation. 2003 Oct 21;108(16):1945-53. doi: 10.1161/01.CIR.0000095029.57483.60. Epub 2003 Oct 13.

  PMID: 14557364 BACKGROUND

• Dewey M, Siebes M, Kachelriess M, Kofoed KF, Maurovich-Horvat P, Nikolaou K, Bai W, Kofler A, Manka R, Kozerke S, Chiribiri A, Schaeffter T, Michallek F, Bengel F, Nekolla S, Knaapen P, Lubberink M, Senior R, Tang MX, Piek JJ, van de Hoef T, Martens J, Schreiber L; Quantitative Cardiac Imaging Study Group. Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia. Nat Rev Cardiol. 2020 Jul;17(7):427-450. doi: 10.1038/s41569-020-0341-8. Epub 2020 Feb 24.

  PMID: 32094693 BACKGROUND

• Tersalvi G, Beltrani V, Grubler MR, Molteni A, Cristoforetti Y, Pedrazzini G, Treglia G, Biasco L. Positron Emission Tomography in Heart Failure: From Pathophysiology to Clinical Application. J Cardiovasc Dev Dis. 2023 May 17;10(5):220. doi: 10.3390/jcdd10050220.

  PMID: 37233187 BACKGROUND

• Graversen CB, Rasmussen LD, Sundboll J, Wurtz M, Kragholm KH, Bottcher M, Winther S. Cardiac computed tomography for rule-out of ischaemic heart disease in patients with new-onset heart failure. Eur Heart J Cardiovasc Imaging. 2025 Apr 30;26(5):794-801. doi: 10.1093/ehjci/jeaf090.

  PMID: 40085773 BACKGROUND

• Burger PM, Savarese G, Tromp J, Adamson C, Jhund PS, Benson L, Hage C, Tay WT, Solomon SD, Packer M, Rossello X, McEvoy JW, De Bacquer D, Timmis A, Vardas P, Graham IM, Di Angelantonio E, Visseren FLJ, McMurray JJV, Lam CSP, Lund LH, Koudstaal S, Dorresteijn JAN, Mosterd A; European Society of Cardiology's Cardiovascular Risk Collaboration (ESC CRC). Personalized lifetime prediction of survival and treatment benefit in patients with heart failure with reduced ejection fraction: The LIFE-HF model. Eur J Heart Fail. 2023 Nov;25(11):1962-1975. doi: 10.1002/ejhf.3028. Epub 2023 Sep 18.

  PMID: 37691140 BACKGROUND

• Perera D, Clayton T, O'Kane PD, Greenwood JP, Weerackody R, Ryan M, Morgan HP, Dodd M, Evans R, Canter R, Arnold S, Dixon LJ, Edwards RJ, De Silva K, Spratt JC, Conway D, Cotton J, McEntegart M, Chiribiri A, Saramago P, Gershlick A, Shah AM, Clark AL, Petrie MC; REVIVED-BCIS2 Investigators. Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction. N Engl J Med. 2022 Oct 13;387(15):1351-1360. doi: 10.1056/NEJMoa2206606. Epub 2022 Aug 27.

  PMID: 36027563 BACKGROUND

• Kjaerulff MLG, Tolbod LP, Pryds K, Nielsen R, Madsen S, Luong TV, Gormsen LC. Clinical use of [15O]H2O/[18F]FDG viability positron emission tomography does not reliably predict left ventricular ejection fraction improvement or survival after revascularization. Eur Heart J Cardiovasc Imaging. 2025 May 30;26(6):969-979. doi: 10.1093/ehjci/jeaf041.

  PMID: 39901814 BACKGROUND

• Basuray A, French B, Ky B, Vorovich E, Olt C, Sweitzer NK, Cappola TP, Fang JC. Heart failure with recovered ejection fraction: clinical description, biomarkers, and outcomes. Circulation. 2014 Jun 10;129(23):2380-7. doi: 10.1161/CIRCULATIONAHA.113.006855. Epub 2014 May 5.

  PMID: 24799515 BACKGROUND

• Punnoose LR, Givertz MM, Lewis EF, Pratibhu P, Stevenson LW, Desai AS. Heart failure with recovered ejection fraction: a distinct clinical entity. J Card Fail. 2011 Jul;17(7):527-32. doi: 10.1016/j.cardfail.2011.03.005. Epub 2011 May 6.

  PMID: 21703523 BACKGROUND

• Swat SA, Cohen D, Shah SJ, Lloyd-Jones DM, Baldridge AS, Freed BH, Vorovich EE, Yancy CW, Jonnalagadda SR, Prenner S, Kim D, Wilcox JE. Baseline Longitudinal Strain Predicts Recovery of Left Ventricular Ejection Fraction in Hospitalized Patients With Nonischemic Cardiomyopathy. J Am Heart Assoc. 2018 Oct 16;7(20):e09841. doi: 10.1161/JAHA.118.009841.

  PMID: 30371257 BACKGROUND

• Solomon SD, Anavekar N, Skali H, McMurray JJ, Swedberg K, Yusuf S, Granger CB, Michelson EL, Wang D, Pocock S, Pfeffer MA; Candesartan in Heart Failure Reduction in Mortality (CHARM) Investigators. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation. 2005 Dec 13;112(24):3738-44. doi: 10.1161/CIRCULATIONAHA.105.561423. Epub 2005 Dec 5.

  PMID: 16330684 BACKGROUND

• Solomon SD, Skali H, Anavekar NS, Bourgoun M, Barvik S, Ghali JK, Warnica JW, Khrakovskaya M, Arnold JM, Schwartz Y, Velazquez EJ, Califf RM, McMurray JV, Pfeffer MA. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation. 2005 Jun 28;111(25):3411-9. doi: 10.1161/CIRCULATIONAHA.104.508093. Epub 2005 Jun 20.

  PMID: 15967846 BACKGROUND

• St John Sutton M, Pfeffer MA, Moye L, Plappert T, Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B, Braunwald E. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation. 1997 Nov 18;96(10):3294-9. doi: 10.1161/01.cir.96.10.3294.

  PMID: 9396419 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

• Bozkurt B, Coats AJS, Tsutsui H, Abdelhamid CM, Adamopoulos S, Albert N, Anker SD, Atherton J, Bohm M, Butler J, Drazner MH, Michael Felker G, Filippatos G, Fiuzat M, Fonarow GC, Gomez-Mesa JE, Heidenreich P, Imamura T, Jankowska EA, Januzzi J, Khazanie P, Kinugawa K, Lam CSP, Matsue Y, Metra M, Ohtani T, Francesco Piepoli M, Ponikowski P, Rosano GMC, Sakata Y, Seferovic P, Starling RC, Teerlink JR, Vardeny O, Yamamoto K, Yancy C, Zhang J, Zieroth S. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail. 2021 Mar;23(3):352-380. doi: 10.1002/ejhf.2115. Epub 2021 Mar 3.

  PMID: 33605000 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, Systolic; Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, MD, PhD student

Study Record Dates

• First Submitted: November 17, 2025
• First Posted: November 21, 2025
• Study Start: December 8, 2025
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029
• Last Updated: December 26, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Data sharing is planned after the enrollment of 200 patients in PRIMA-HF, which is anticipated to be achieved by the end of 2027. Approximately two months thereafter, we expect to have completed the necessary analyses, at which point the availability of individual participant data will cease. Upon completion of the project, collaborating partners will destroy all data in accordance with our agreements and applicable requirements.
• Access Criteria: We plan to send biological material for proteomics measurements for further analysis to either deCODE, Reykjavik, Iceland, or Olink, Uppsala, Sweden. This will only take place after legal approval has been obtained in the Central Denmark Region.

Locations

DK (1)