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Study of Sacubitril/ValsarTan on MyocardIal OxygenatioN and Fibrosis in Heart Failure With Preserved Ejection Fraction (PRISTINE-HF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04128891
Recruitment Status : Not yet recruiting
First Posted : October 16, 2019
Last Update Posted : October 16, 2019
Information provided by (Responsible Party):
Joseph Selvanayagam, Flinders University

Tracking Information
First Submitted Date  ICMJE August 21, 2019
First Posted Date  ICMJE October 16, 2019
Last Update Posted Date October 16, 2019
Estimated Study Start Date  ICMJE February 1, 2020
Estimated Primary Completion Date February 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 15, 2019)
• To study the effects of Sacubitril/Valsartan on microvascular function and ischaemia in HFpEF patients. [ Time Frame: 12 Months ]
The HFpEF participants on Sacubitril/valsartan with improvement in microvascular function and ischaemia, as assessed by OS-CMR at rest and stress (ΔSI: signal intensity change, at baseline and at 12 months).
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2019)
  • 2.1 Incidence of microvascular dysfunction in HFpEF [ Time Frame: 12 Months ]
    The proportion of HFpEF patients with microvascular dysfunction, as assessed by OS-CMR ΔSI.
  • 2.2 Extent of myocardial fibrosis in HFpEF [ Time Frame: 12 Months ]
    Baseline assessment of myocardial fibrosis in HFpEF patients and assess the response to Sacubitril/Valsartan by measuring changes in myocardial ECV
  • 2.3 Assessment of left ventricular diastolic function in HFpEF [ Time Frame: 12 Months ]
    Baseline echocardiographic assessment of left ventricular diastolic function in HFpEF patients and assess the response to Sacubitril/Valsartan.
  • 2.4 New York Heart Association (NYHA) class [ Time Frame: 12 Months ]
    Baseline evaluation of NYHA class and change in NYHA class at 12 months following Sacubitril/Valsartan therapy.
  • 2.5 Functional assessment [ Time Frame: 12 Months ]
    Baseline computation of functional status by 6-minute walk test and evaluate the response to Sacubitril/Valsartan therapy
  • 2.6 Number of heart failure related hospitalisations [ Time Frame: 12 Months ]
    The number of HFpEF patients admitted with heart failure during the study period.
  • 2.7 Cardiac mortality [ Time Frame: 12 Months ]
    Cardiac mortality during the study period
  • 2.8 All-cause mortality. [ Time Frame: 12 Months ]
    All-cause mortality during the study period.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Study of Sacubitril/ValsarTan on MyocardIal OxygenatioN and Fibrosis in Heart Failure With Preserved Ejection Fraction
Official Title  ICMJE PRospectIve Study of Sacubitril/ValsarTan on MyocardIal OxygenatioN and Fibrosis in PatiEnts With Heart Failure and Preserved Ejection Fraction
Brief Summary To assess the effect of ARNI on myocardial deoxygenation at stress and myocardial fibrosis, and correlate this to changes in myocardial systolic and diastolic function in HFpEF patients.
Detailed Description

Heart failure with preserved ejection fraction (HFpEF) is increasing in incidence and accounts for one third to one half of all heart failure admissions worldwide. It portrays a significant burden in terms of prevalence, morbidity and mortality. It is a complex clinical syndrome characterized by multiple pathophysiological mechanisms affecting the cardiac structure and function culminating to increased ventricular filling pressures. The definition of HFpEF remains an evolving concept and the exact definition by various learned societies is not uniform. The recent ANZ heart failure guidelines defines HFpEF as the presence of typical symptoms with or without signs of heart failure, with a measured left ventricular ejection fraction of at least 50% and objective evidence of relevant structural heart disease or diastolic dysfunction without an alternative cause. Despite some common clinical features, there is heterogeneity in the causes of HFpEF, and it is likely that it represents a broad cohort of patients with a range of comorbid conditions. In addition to clinical variability, there is morphological and functional variability at the myocardial level. For instance, whilst left ventricular hypertrophy and left atrial dilatation are traditionally considered morphological hallmarks, they are not universally present, and one third to one half of patients do not demonstrate one or both of these features. Furthermore whilst diastolic dysfunction is considered a sine qua non of the disease, and is recognised in the current guidelines, up-to one third of HFpEF patients in echocardiographic sub-studies have normal diastolic function even in the presence of elevated natriuretic peptides.

The heterogeneous phenotypes in HFpEF have potentially confounded previous trials. Therefore, the identification of various structural phenotypes capable of segmenting the HFpEF population into relevant pathophysiologic categories represents a promising approach. Post-mortem endomyocardial biopsy studies from HFpEF patients have suggested that some of the cardiac structural phenotypes are related to myocyte hypertrophy, interstitial fibrosis, myocardial inflammation due to oxidative stress and epicardial coronary artery disease. In addition, a better understanding of the mechanisms that contribute to the pathophysiology of HFpEF is emerging from pre-clinical, interventional and mechanistic studies. In HFpEF, proinflammatory cardiovascular and non-cardiovascular coexisting conditions (e.g., hypertension, obesity) lead to systemic microvascular endothelial inflammation. This results in myocardial inflammation and fibrosis, increases in oxidative stress and alterations in cardiomyocyte signalling pathways. These alterations promote cardiomyocyte remodeling and dysfunction as well as coronary microvascular dysfunction. A recent study showed that there is a high prevalence of coronary microvascular dysfunction in HFpEF even in the absence of unrevascularized macrovascular coronary artery disease and was correlated with markers of heart failure severity.

Cardiac imaging is pivotal in the evaluation of patients with suspected HFpEF. 2D Echocardiography is able to non-invasively measure left ventricular systolic and diastolic dysfunction, as well as characterise left ventricular filling pressures. Echocardiographic data adds incremental prognostic information in patients with HFpEF. These include assessment of left ventricular hypertrophy, left atrial volume, E/e' ratio, tricuspid regurgitation velocity, right ventricular function and global longitudinal strain. However, echocardiography is unable to easily characterise myocardial tissue nor assess myocardial microvascular function. The application of Cardiovascular Magnetic Resonance (CMR) imaging is increasingly recognised and is currently the standard modality for assessing atrial / ventricular volumes, quantifying ejection fraction and left ventricular mass. It is uniquely able to provide information on morphology, function, perfusion, viability, and tissue characterization in a single examination. Hence, CMR is an ideal tool to delineate the various cardiac structural phenotypes that have been described in HFpEF patients. In addition to routinely used CMR parameters, there are a number of emerging CMR applications that have the potential in advancing our understanding of HFpEF. The important amongst them are the assessment of myocardial oxygenation using Oxygen Sensitive CMR (OS-CMR) and diffuse myocardial fibrosis using T1 mapping. OS-CMR can directly assess the myocardial tissue oxygenation and potentially measure mismatches in myocardial oxygen demand and supply. OS-CMR is based on the principle of changes of paramagnetic properties of haemoglobin due to the effects of oxygenation. The change from oxygenated to de-oxygenated haemoglobin leads to a change in the magnetic resonance signal intensity (SI). An increased myocardial de-oxygenation is reflected as a drop in SI on the T2 weighted CMR images. Hence, this allows in vivo assessment of myocardial ischaemia at the tissue level, relying on accumulation of de-oxyhaemoglobin following vasodilator stress. The change in SI is quantified as a percentage of signal change. Myocardial fibrosis has been implicated in the pathophysiology of HFpEF. Both focal replacement fibrosis and interstitial fibrosis promote adverse ventricular remodelling in HFpEF. The pattern of interstitial fibrosis is diffuse in HFpEF and cannot be detected using the late gadolinium enhancement technique. Recent improvements in parametric mapping techniques (such as T1, T2 and T2*) has made non-invasive assessment of diffuse interstitial and fibrotic changes clinically feasible. CMR T1 parametric mapping techniques enable quantification of the extracellular volume (ECV), a surrogate marker of diffuse fibrosis, and have been validated histologically. Hence it is possible that CMR along with OS-CMR, parametric imaging and late gadolinium enhancement represents the ideal non-invasive modality to study and understand the various pathophysiological mechanisms in HFpEF patients.

A number of biomarkers associated with heart failure are well recognized and measuring their concentrations in circulation can provide valuable information about the diagnosis, prognosis, and management. These biomarkers have significantly enhanced the understanding of the pathophysiology of HFpEF, however only a few are currently being used in clinical practice. The measurement of natriuretic peptides (BNP or NT-proBNP) is recommended by current guidelines as they provide incremental value. Cardiac troponin testing is recommended to establish prognosis in acute heart failure and may be used for prognostication in chronic heart failure as well. Novel biomarkers are increasingly becoming validated and recognized in the care of patients with heart failure. These include galectin-3, ST2, renin and cGMP and they alter in response to cardiac remodelling and fibrosis. However, the role of these biomarkers in microvascular dysfunction has not been systematically studied in HFpEF.

Currently, there are no proven pharmacological therapies for patients with HFpEF. This is evident on HFpEF patients trial on beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers which have failed to demonstrate a significant clinical benefit. The first-in-class angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan holds promise based on its pharmacodynamic profile. It simultaneously blocks the renin-angiotensin-aldosterone system and the endopeptidase neprilysin. Neprilysin is a ubiquitous enzyme that is responsible for the breakdown of many vasoactive peptides, including the biologically active natriuretic peptides. Sacubitril/valsartan has reduced cardiovascular and all-cause mortality in patients with heart failure and reduced ejection fraction, compared with enalapril. In addition, the biomarkers associated with profibrotic signalling are significantly decreased with ARNI therapy in patients with reduced ejection fraction. In HFpEF patients, the PARAMOUNT-HF Phase II trial has demonstrated significant reduction of NT-proBNP with ARNI in comparison with Valsartan.However, in the recently published PARAGON-HF trial, sacubitril/valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with HFpEF. In patients with HFpEF, the effect of ARNI therapy on the various emerging pathophysiological mechanisms remains unknown. Myocardial fibrosis is an important pathophysiological mechanism in HFpEF. Treatment options to block or reverse fibrosis in HFpEF have proven elusive. Angiotensin-receptor blockers have been shown to induce regression of severe myocardial fibrosis in hypertensive patients. In mouse models, ARNI ameliorates maladaptive cardiac remodeling and fibrosis in pressure overload-induced hypertrophy. Although not approved for use in HFpEF, ARNI is an attractive option to mitigate myocardial hypertrophy, fibrosis, ischaemia, and impaired ventricular-arterial coupling, which are all closely related to increased left ventricular filling pressures, a common hallmark of this multifaceted syndrome.

Thus, there remains an enormous unmet need for effective therapy in the group of HFpEF patients. HFpEF is a heterogeneous syndrome, with different degrees of contribution from various pathophysiological processes. In patients with HFpEF, the effect of ARNI therapy on the various postulated structural phenotypes remain unexplored. ARNI has the potential to reduce both ischaemia and fibrosis, and both can be accurately measured utilizing CMR. Therefore, by combining CMR with echocardiography, the investigators aim to assess the effect of ARNI on myocardial deoxygenation at stress and myocardial fibrosis, and correlate this to changes in myocardial systolic and diastolic function in HFpEF patients.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure With Preserved Ejection Fraction
Intervention  ICMJE Drug: Sacubitril-Valsartan
Cardiomagnetic Resonance Imaging
Other Name: Valsartan
Study Arms  ICMJE
  • Experimental: Sacubitril/Valsartan
    30 participants to be administered Sacubitril/Valsartan (Entresto) tablets, minimum dose of 49/51mg or maximum dose of 97/103 mg twice daily for the duration of the study (two years).
    Intervention: Drug: Sacubitril-Valsartan
  • Active Comparator: Valsartan
    30 participants to be administered Valsartan tablets, minimum dose 80 mg or maximum dose of 160 mg twice daily for the duration of the study (two years).
    Intervention: Drug: Sacubitril-Valsartan
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: October 15, 2019)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2024
Estimated Primary Completion Date February 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent will be obtained before any assessment is performed
  2. ≥ 40 years of age, male or female
  3. LVEF ≥45% by echocardiography during the screening period
  4. Symptom(s) of heart failure requiring treatment with diuretic(s) for at least 30 days prior to screening visit
  5. Current symptom(s) of heart failure (NYHA functional class II to IV)
  6. Structural heart disease evidenced by at least 1 of the following echocardiography findings:

    1. Left atrial (LA) enlargement defined by at least 1 of the following: LA width (diameter) ≥3.8 cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 ml or LA volume index ≥29 ml/m2
    2. Left ventricular hypertrophy defined by septal thickness or posterior wall thickness ≥1.2 cm
  7. Elevated NT-proBNP (atleast 1 of the following)

    1. NT-proBNP >300 pg/ml for patients not in atrial fibrillation or >900 pg/ml for patients in atrial fibrillation during initial screening
    2. Heart failure hospitalization (defined as heart failure listed as the major reason for hospitalization) within 9 months prior to screening visit and NT-proBNP >200 pg/ml for patients not in atrial fibrillation or >600 pg/ml for patients in atrial fibrillation during initial screening

Exclusion Criteria:

  1. Any prior echocardiographic measurement of LVEF <45%
  2. Acute coronary syndrome (including myocardial infarction), cardiac surgery, other major cardiovascular surgery, or percutaneous coronary intervention within 3 months
  3. Known unrevascularized epicardial coronary artery disease (> 50% stenosis in any major epicardial coronary artery)
  4. Current acute decompensated heart failure requiring augmented therapy with intravenous diuretic agents, vasodilator agents, and/or inotropic drugs
  5. Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, or a renin inhibitor
  6. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
  7. Patients with a known history of angioedema
  8. Probable alternative diagnoses that in the opinion of the investigator could account for the patient's heart failure symptoms such as significant pulmonary disease (including primary pulmonary hypertension), anaemia, or obesity. Specifically, patients with the following are excluded:

    1. Severe pulmonary disease including chronic obstructive pulmonary disease (i.e., requiring home oxygen therapy, chronic oral steroid therapy or hospitalized for pulmonary decompensation within 12 months) or
    2. Haemoglobin <10 g/dl, or
    3. Body mass index >40 kg/m2
  9. Patients with any of the following:

    1. Systolic blood pressure (SBP) ≥180 mm Hg at entry, or
    2. SBP >150 mm Hg and <180 mm Hg at entry unless the patient is receiving 3 or more antihypertensive drugs.
    3. SBP <110 mm Hg at entry
  10. Current participation in another investigational drug or device.
  11. Patients with history of any dilated cardiomyopathy, including peripartum cardiomyopathy, chemotherapy-induced cardiomyopathy, or viral myocarditis
  12. Evidence of right-sided heart failure in the absence of left-sided structural heart disease
  13. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy
  14. Clinically significant congenital heart disease that could be the cause of the patient's symptoms and signs of heart failure
  15. Presence of hemodynamically significant valvular heart disease in the opinion of the investigator
  16. Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within the 3 months
  17. Carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention during the trial
  18. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or atrial flutter with a resting ventricular rate >110 beats per minute
  19. Patients with a cardiac resynchronization therapy device
  20. Patients with prior major organ transplant or intent to transplant (i.e., on transplant list)
  21. Any surgical or medical condition that in the opinion of the investigator may place the patient at higher risk from his/her participation in the study or is likely to prevent the patient from complying with the requirements of the study or completing the study
  22. Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following: any history of pancreatic injury, pancreatitis, or evidence of impaired pancreatic function/injury within the past 5 years
  23. Evidence of hepatic disease as determined by any 1 of the following: SGOT (AST) or SGPT (ALT) values exceeding 3× the upper limit of normal, bilirubin >1.5 mg/dl at entry
  24. Patients with severe renal impairment of the following: eGFR <30 ml/min/1.73 m2 as calculated by the Modification in Diet in Renal Disease (MDRD) formula at entry
  25. Presence of known functionally significant bilateral renal artery stenosis
  26. Patients with serum potassium >5.2 mmol/l (mEq/l) at entry
  27. History or presence of any other disease with a life expectancy of <3 years
  28. History of noncompliance to medical regimens and patients who are considered potentially unreliable
  29. History or evidence of drug or alcohol abuse within the past 12 months
  30. Persons directly involved in the execution of this protocol
  31. History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
  32. Pregnant or nursing (lactating) women
  33. Women of child-bearing potential
  34. Contraindications to CMR (claustrophobia, implanted medical devices like pacemakers / defibrillators, cochlear implants, intracranial clips, iron fragments in eyes, inability to lie flat for the scanning period)
  35. Contraindications to Gadolinium (eGFR <30 ml/min/1.73 m2 as calculated by the MDRD formula at entry or previous know serious allergy)
  36. Contraindications to Adenosine (second or third-degree atrioventricular block, asthma, concurrent dipyridamole use)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Professor Selvanayagam 0984045619 ext 65619
Contact: Tonia Bromley 0984042852 ext 62852
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT04128891
Other Study ID Numbers  ICMJE FlindersU
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Joseph Selvanayagam, Flinders University
Study Sponsor  ICMJE Flinders University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Carmine De Pasquale, Assoc Prof Flinders Medical Centre
Principal Investigator: Majo Joseph, Doctor Flinders Medical Centre
Principal Investigator: Rajiv Ananthakrishna, Doctor Flinders Medical Centre
Principal Investigator: Michael Stokes, Doctor Royal Adelaide Hospital
Principal Investigator: Sean Lal, Doctor Royal Prince Alfred
Principal Investigator: David Kaye, Professor Baker Institute/ Alfred Hospital
PRS Account Flinders University
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP