Clinical trial NCT04753112: Treatment of PH With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF Patients With CardioMEMS Device
Official title: Treatment of Pulmonary Hypertension With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in Patients With Heart Failure With Preserved Ejection Fraction Monitored With the CardioMEMS Device (ARNIMEMS-HFpEF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Hypertension
Keywords: Pulmonary Hypertension
preserved ejection fraction
heart failure
Lead sponsor: Germans Trias i Pujol Hospital
Sponsor class: OTHER
First posted: 2021-02-15
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 14 participants (the sample size was calculated accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided contrast, to detect a mean PAP difference equal or greater than 4mmHg, assuming a standard deviation of 5mmHg and a 10% loss to follow-up)
Primary purpose: TREATMENT

Brief summary: This study will assess the impact of sacubitril/valsartan on elevated pulmonary artery (PA) pressures in patients with heart failure (HF) with preserved ejection fraction (HFpEF), measured using a previously implanted hemodynamic monitoring device (CardioMEMS).

Detailed description: Fluid overload leading to increased PA pressure is one of the primary causes of HF related hospitalizations in HFpEF. Signs and symptoms of fluid overload are not sensitive enough to reflect early pathophysiologic changes that increase the risk of decompensation. Elevations in PA pressure may increase several days or weeks before signs and symptoms manifest.

The CardioMEMS device is a small wireless sensor that is permanently implanted in the PA via a catheter inserted through the femoral vein. The sensor measures PA pressure and is paired with a portable electronic transmitter. The system allows patients to wirelessly transmit pressure readings to a secure online database from which treating physicians can access the data and adjust medication in response to PA pressure changes.

The CHAMPION trial was a single blind randomized clinical trial that showed a significant and large reduction in hospitalizations in patients with NYHA class III HF who were managed with a the CardioMEMS device.

More recently, real life clinical practice has confirmed the value of PA pressure-guided therapy for HF. PA pressures were reduced, lower rates of HF hospitalizations and all-cause hospitalization, and low rates of adverse events across a broad range of patients with symptomatic HF and prior HF hospitalizations were reported.

The angiotensin receptor-neprilysin inhibitor (ARNI) led to a reduced risk of hospitalization for HF or death from cardiovascular causes among patients with HF and reduced ejection fraction in the PARADIGM-HF trial. However it did not result in a significantly lower rate of total hospitalizations for HF and death from cardiovascular causes among patients with HF and an ejection fraction of 45% or higher in the PARAGON-HF trial, despite there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women.

ARNI reduced pulmonary pressures and vascular remodeling in an animal model of pulmonary hypertension (PH) and may be appropriate for treatment of PH and right ventricle dysfunction. Data are lacking on the hemodynamic effects of ARNI on pulmonary hypertension in patients with HFpEF.

This study will assess the impact of sacubitril/valsartan on PA pressures measured using an implanted PA monitoring device. The device will be used according to approved indications.

Eligibility criteria: Inclusion Criteria:

* Patients able to provide written informed consent.
* Patients ≥18 years of age, male or female, in NYHA Class II- III HFpEF with LVEF \> 45% (measured within the past year), and who have no previous LVEF\<45%.
* NT-proBNP \>200 pg/ml if HF hospitalization in the previous 9 months and\> 300 pg/ml if there was no previous HF hospitalization; Three times the values were required in patients with atrial fibrillation.
* CardioMEMS HF System implanted and patient transmitting information regularly and system functioning appropriately.
* Average PAPm \>20mm Hg during the 7 days prior to enrollment, including at least 5 daily measurements.
* Systolic BP \> 100 mm Hg at most recent clinical assessment.
* Stable, ambulatory patients without the need for change in diuretics and other HF drugs during last week.

Exclusion Criteria:

* eGFR \< 30 ml/min/1.73 m2 as measured by CKD-EPI.
* Sacubitril/Valsartan treatment within the past 30 days.
* History of hypersensitivity, intolerance or angioedema to previous renin-angiotensin system (RAS) blocker, ACE inhibitor, ARB, or Entresto.
* Serum potassium \> 5.4 mmol/L.
* Acute coronary syndrome, stroke, transient ischemic attack, cardiovascular surgery, PCI, or carotid angioplasty within the preceding 3 months.
* Coronary or carotid artery disease likely to require surgical or percutaneous intervention within 3 months after trial entry.
* Non-cardiac condition(s) as the primary cause of dyspnea.
* Documented untreated ventricular arrhythmia with syncopal episodes within the prior 3 months.
* Symptomatic bradycardia or second or third degree heart block without a pacemaker.
* Hepatic dysfunction, as evidenced by total bilirubin \> 3 mg/dl.
* Pregnancy.
* Women who are breastfeeding

Primary outcomes:
measure: Change in mPAP With Sacubitril/Valsartan compared to Standard therapy
timeFrame: Time Frame: 0-18 weeks
Secondary outcomes:
measure: Mean Change in mPAP
timeFrame: 7 days
measure: Change in Distance Walked
timeFrame: Baseline, 6 weeks, 12 weeks, 18 weeks
measure: Change in NT-proBNP concentration
timeFrame: 6-12-18 weeks
measure: Change in CA-125 concentration
timeFrame: 6-12-18 weeks
measure: Change in Soluble ST2 concentration
timeFrame: 6-12-18 weeks
measure: Change in the European Quality of Life-5 Dimensions scale
timeFrame: Baseline, 18 weeks
measure: Change in the short version of the Kansas City Cardiomyopathy Questionnaire (KCCQ-12)
timeFrame: Baseline, 18 weeks
measure: Change in Daily Diuretic Dose
timeFrame: Baseline-6-12-18 weeks
measure: Change in E/e'
timeFrame: 6 weeks, 12 weeks, 18 weeks
measure: Change in septal e' velocity
timeFrame: 6 weeks, 12 weeks, 18 weeks
measure: Change in lateral e' velocity
timeFrame: 6 weeks, 12 weeks, 18 weeks
measure: Change in diastolic dysfunction echocardiography parameter tricuspid regurgitation velocity
timeFrame: 6 weeks, 12 weeks, 18 weeks
measure: Change in diastolic dysfunction echocardiography parameter left atrium volumen index
timeFrame: 6 weeks, 12 weeks, 18 weeks
measure: Change in the number of B-lines in lung ultrasound LUS
timeFrame: 6 weeks, 12 weeks, 18 weeks
measure: Decline in renal function
timeFrame: Baseline-18 weeks
measure: Prespecified adverse events of interest
timeFrame: Baseline-18 weeks
Other outcomes:
Locations:
city: Badalona
country: Spain
facility: Germans Trias i Pujol University Hospital
state: Barcelona
Study officials:
References: