Inhaled Iloprost and Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction

NCT ID: NCT03620526

Last Updated: 2019-08-14

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-29
• Study Completion Date: 2020-01-01

Brief Summary

BACKGROUND There is no effective medical treatment for heart failure with preserved ejection fraction (HFpEF). Increases in pulmonary capillary wedge pressure (PCWP) develop in patients with HFpEF. Prostacyclin analogo can possible reduced PA pressure along with PWCP pressure, as with exercise.

OBJECTIVES This study try to determine whether inhlalation of iloprost improves exercise hemodynamics and cardiac reserve in HFpEF.

METHODS In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF underwent invasive cardiac catheterization with simultaneous expired gas analysis at rest and during exercise, before and 15 min after treatment with either inhaled iloprost or matching placebo.

Detailed Description

Study participants and study design The ILO-HOPE trial is a prospective, randomized, double-blind, single center trial conducted at the National Taiwan University Hospital (NTUH). This study was performed in accordance with the Declaration of Helsinki and was approved by the institutional review board of the National Taiwan University Hospital, and all subjects provided their written informed consent prior to participation in the study. Patients referred to National Taiwan University Hospital cardiac catheterization laboratory for invasive hemodyanamic exercise stress testing were enrolled. HFpEF was defined according to 2016 European society of cardiology heart failure guidelines and our previous studies. In brief, HFpEF was determined by (1) presence of typical HF symptoms and signs (2) LV ejection fraction ≥ 50 (3) elevated levels of NT-proBNP (at least >125 pg/ml) (4) echocardiographic structural (a left atrial volume index > 34 mL/m2 or a left ventricular mass index ≥115 g/m2 for males and ≥95 g/m2 for females) or functional alterations (E/e'≥13 and a mean e' septal and lateral wall < 9 cm/s). The exclusion criteria were chronic renal failure (creatinine > 250 μmol/L), significant hepatic disease, secondary hypertension, pericardial disease, valvular heart disease (echocardiographic evidence of at least mild stenosis or at least moderate regurgitation), cancer, cor pulmonale, congenital heart disease, left-to-right shunt, myocardial infarction within 60 days, high-output heart failure, long-term treatment with phosphodiesterase 5 inhibitors, and chronic atrial fibrillation. The patients will be asked to hold nitrate for 3 days before the test if they receive any oral nitrate.

Trial protocol Investigators will perform cardiac catheterization with simultaneous expired gas analysis at rest and during supine exercise at a 20-W workload for 6 min, as previously described. Hemodynamic values will be recorded for the first exercise phase (before any drug administration) and after return to steady state baseline hemodynamic values, and the second exercise phase (after drug administration). Subjects will be randomized 1:1 to inhalation of placebo (normal saline solution) or iloprost (50 mg/kg/min) (Bayer Pharmaceuticals, Scottsdale, Ari-zona) for 5 min. The iloprost/placebo inhalation will be identical in appearance and prepared by the research pharmacy, ensuring double-blinding of inhalation content. After finishing inhalation process for 10 min, hemodynamic measurements will be repeated at rest, followed by repeat supine exercise at a 20-W workload for 6 min, identical to the study's first phase. Arterial and venous blood samples and hemodynamic and expired gas data will be acquired during each stage of the protocol. Right heart catheterization will be performed through a 7-F sheath via the internal jugular vein. Transducers were zeroed at mid-axilla. Right atrial pressure (RAP), pulmonary artery (PA) pressure, and PCWP will be measured at end-expiration using swan-Ganz catheter 2-F, high-fidelity micromanometer-tipped cathe-ters (Millar Instruments, Houston, Texas) advanced through the lumen of a 7-F, fluid-filled catheter (Arrow, Teleflex, Morrisville, North Carolina)(). Mean RAP and PCWP will be taken at mid A wave. Arterial blood pressure (BP) will be measured continuously through a 5-F radial arterial cannula. Oxygen consumption (VO2) will be measured from expired gas analysis (MedGraphics, St. Paul, Minnesota) taken as the average from the 60 s preceding arterial and mixed venous blood sampling. Ventilatory efficiency will be assessed by the increase in minute ventilation relative to carbon dioxide production (VE/VCO2). CO and stroke volume (SV) will be determined by the direct Fick method and heart rate as previous described. Investigators also will calculate pulmonary vascular resistance, PA compliance (SV/PA pulse pressure), and systemic vascular resistance (SVR) using standard formulas. LV systolic performance will be assessed by LV stroke work using standard formula as well.

Assessments of outcomes The primary endpoint of the trial is the PCWP during exercise. Secondary endpoints are changes of other hemodynamic data including alterations in resting PCWP, rest and exercise changes in RAP, PA pressure, PVR, PA compliance, systemic BP, heart rate, SV, stroke work.

Statistical analysis Statistical analyses will be done on an intention to treat basis. Results are reported as mean ± SD, median (interquartile range) or n (%).Within-group differences are assessed by the paired Student t test. Between-group differences in rest or exercise hemodynamic responses were compared by an unpaired Student t test., Wilcoxon rank sum test, or Fisher exact test. Linear regression will be performed to compare hemodynamic responses to exercise before and after study drug inhalation, with variables log-transformed as necessary for analysis. All tests were 2-sided, with p < 0.05 considered significant. We used G-power (version 3.1.9.2, Heinrich-Heine-Universität Düsseldorf, Germany; http://www.gpower.hhu.de/) to calculate the sample size. A sample size of 34 total patients would be needed to provide 80% power (assuming a SD of 2.76 mmHg) to detect a 2 mmHg difference in the primary efficacy parameter, change in exercising PCWP, with a 5% type I error rate for a 2-sided test.

Conditions

Heart Failure With Normal Ejection Fraction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Iloprost

patients received inhaled iloprost 10 mcg/mL x 1 dose after baseline and exercise test and then received measurements for hemodynamic data again for both baseline and after exercise test.

Group Type: EXPERIMENTAL

Iloprost

Intervention Type: DRUG

Investigators performed cardiac catheterization as previously described. Hemodynamic values were recorded for the first exercise phase (before any drug administration) and after return to steady state baseline hemodynamic values, and the second exercise phase (after drug administration). Subjects were randomized 1:1 to inhalation of placebo (normal saline solution) or iloprost (50 mg/kg/min) (Bayer Pharmaceuticals, Scottsdale, Ari-zona) for 5 min. The iloprost/placebo inhalation were identical in appearance and prepared by the research pharmacy, ensuring double-blinding of inhalation content. After finishing inhalation process for 10 min, hemodynamic measurements were repeated at rest, followed by repeat supine exercise at a 20-W workload for 6 min, identical to the study's first phase.

Placebo

patients received inhaled normal saline with the same amount x 1 dose after baseline and exercise test and then received measurements for hemodynamic data again for both baseline and after exercise test.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Investigators performed cardiac catheterization as previously described. Hemodynamic values were recorded for the first exercise phase (before any drug administration) and after return to steady state baseline hemodynamic values, and the second exercise phase (after drug administration). Subjects were randomized 1:1 to inhalation of placebo (normal saline solution) or iloprost (50 mg/kg/min) (Bayer Pharmaceuticals, Scottsdale, Ari-zona) for 5 min. The iloprost/placebo inhalation were identical in appearance and prepared by the research pharmacy, ensuring double-blinding of inhalation content. After finishing inhalation process for 10 min, hemodynamic measurements were repeated at rest, followed by repeat supine exercise at a 20-W workload for 6 min, identical to the study's first phase.

Interventions

Iloprost

Investigators performed cardiac catheterization as previously described. Hemodynamic values were recorded for the first exercise phase (before any drug administration) and after return to steady state baseline hemodynamic values, and the second exercise phase (after drug administration). Subjects were randomized 1:1 to inhalation of placebo (normal saline solution) or iloprost (50 mg/kg/min) (Bayer Pharmaceuticals, Scottsdale, Ari-zona) for 5 min. The iloprost/placebo inhalation were identical in appearance and prepared by the research pharmacy, ensuring double-blinding of inhalation content. After finishing inhalation process for 10 min, hemodynamic measurements were repeated at rest, followed by repeat supine exercise at a 20-W workload for 6 min, identical to the study's first phase.

Intervention Type: DRUG

Placebo

Investigators performed cardiac catheterization as previously described. Hemodynamic values were recorded for the first exercise phase (before any drug administration) and after return to steady state baseline hemodynamic values, and the second exercise phase (after drug administration). Subjects were randomized 1:1 to inhalation of placebo (normal saline solution) or iloprost (50 mg/kg/min) (Bayer Pharmaceuticals, Scottsdale, Ari-zona) for 5 min. The iloprost/placebo inhalation were identical in appearance and prepared by the research pharmacy, ensuring double-blinding of inhalation content. After finishing inhalation process for 10 min, hemodynamic measurements were repeated at rest, followed by repeat supine exercise at a 20-W workload for 6 min, identical to the study's first phase.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. presence of typical HF symptoms and signs

2. LV ejection fraction ≥ 50

3. elevated levels of NT-proBNP (at least >125 pg/ml)

4. echocardiographic structural (a left atrial volume index > 34 mL/m2 or a left ventricular mass index ≥115 g/m2 for males and ≥95 g/m2 for females) or functional alterations (E/e'≥13 and a mean e' septal and lateral wall < 9 cm/s).

Exclusion Criteria

1. chronic renal failure (creatinine > 250 μmol/L)

2. significant hepatic disease, significant coronary artery disease (CAD) (coronary artery stenosis >70% without intervention or positive stress test),

3. secondary hypertension,

4. pericardial disease

5. significant valvular heart disease (>mild stenosis, >moderate regurgitation),

6. active cancer,

7. cor pulmonale

8. congenital heart disease

9. high-output heart failure

10. subjects receiving long-term treatment with phosphodiesterase 5 in-hibitors

11. chronic atrial fibrillation.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Taiwan University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

CHO-KAI WU, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

National Taiwan University Hospital

Locations

National Taiwan University Hospital

Taipei, , Taiwan

Site Status: RECRUITING

Countries

Taiwan

Central Contacts

CHO-KAI WU, MD, PhD

Role: CONTACT

chokaiwu@yahoo.com.tw

886-23123456 ext. 62152

Facility Contacts

CHO-KAI WU, MD, PhD

Role: primary

References

Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015 Oct 13;66(15):1672-82. doi: 10.1016/j.jacc.2015.07.067.

Reference Type: RESULT

PMID: 26449137 (View on PubMed)

Chen ZW, Huang CY, Cheng JF, Chen SY, Lin LY, Wu CK. Stress Echocardiography-Derived E/e' Predicts Abnormal Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction. Front Physiol. 2019 Dec 3;10:1470. doi: 10.3389/fphys.2019.01470. eCollection 2019.

Reference Type: DERIVED

PMID: 31849715 (View on PubMed)

Huang CY, Lee JK, Chen ZW, Cheng JF, Chen SY, Lin LY, Wu CK. Inhaled Prostacyclin on Exercise Echocardiographic Cardiac Function in Preserved Ejection Fraction Heart Failure. Med Sci Sports Exerc. 2020 Feb;52(2):269-277. doi: 10.1249/MSS.0000000000002145.

Reference Type: DERIVED

PMID: 31479003 (View on PubMed)

Other Identifiers

201704075MIND

Identifier Type: -

Identifier Source: org_study_id