Heart Failure With Normal Ejection Fraction Clinical Trial
Official title:
Inhaled Iloprost and Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction - the ILO-HOPE Clinical Trial
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.
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.
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