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Expanded Methods
Study design
RALI-DHF was a prospective, single-center, randomized, double-blind, placebo-controlled
proof-of-concept study (NCT01163734, EudraCT 2009-017168-17) funded by a scientific
grant from Gilead (Foster City, CA, USA). The trial was approved by the local ethics
committee and by the German Federal Institute for Drugs and Medical Devices BfArM.
Patients with clinical symptoms of heart failure (NYHA class II-III) undergoing cardiac
catheterization as part of the routine diagnostic procedure for standard care were screened
for inclusion into the study. Inclusion criteria consisted of LVEF≥45%, E/E′>15 or NT-proBNP>220pg/mL at screening and, as continued eligibility criteria, average resting LVEDP≥18
mm Hg, as well as resting time-constant of relaxation (tau) ≥50 ms at time of cardiac
catheterization.1,2
Study conduct and procedures
Administration of the study drug was performed in a 1.5:1 ratio (ranolazine vs. placebo). The
study treatment began with an intravenous bolus injection of 92 mg (in 10 mL over 2
minutes). A second bolus injection of 92 mg was administered 15 minutes thereafter.
Continuous infusion of ranolazine or placebo at a dose of 92 mg/hour (23 mL/hour) was
started 5 minutes after the start of the second bolus injection and continued for 24 hours.
This dosing regimen was designed to achieve and maintain a therapeutic target ranolazine
plasma concentration of ~2500 ng/mL (average concentration achieved by oral dose of 1000
mg twice daily) at the time of post-baseline measurements i.e., 30 minutes after the start of
the initial bolus injection. One hour prior to the end of the 24-hour infusion, patients were
started on oral study drug 1000 mg (extended release tablets, 2 x 500 mg) twice daily and
continued until the end of the study on day 14 (Fig. 1a of the main paper). To assess
pharmacokinetic (PK) parameters, PK blood samples were drawn at 10, 20, 30 minutes, and
22 hours after start of intravenous study drug administration.
Invasive hemodynamic measurements were initially performed before the first
intravenous bolus of study drugs. Pacing was then performed at 120 beats per minute for
better comparison between patients and hemodynamic and pressure measurements were
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again collected.3 These measurements were repeated 30 minutes after the initial
intravenous bolus administration at both resting and paced conditions. Three measurements
were taken at each time and averaged. Hemodynamic parameters were assessed during rest
and pacing for two reasons: First, the goal was to further impair diastolic filling and secondly,
we wanted to exclude differences in heart rate as a confounder.
Tissue Doppler echocardiography was performed at before catheterization, repeated
60 minutes prior to administration of oral study drug, and at the end of study (Day 14).
Cardiopulmonary exercise test (CPET) was performed at baseline and on Day 14. The 12-lead
ECG was collected at baseline, prior to start of oral study drug, and at Day 14.
Patients were asked to return to the clinic for the End of Study visit on Day 14 (±2
days). The End of Study visit procedures were performed within 2-6 hours after the morning
dose. The following key assessments were performed: Complete physical examination
including vital signs and weight measurements, 12-lead ECG, echocardiography (prior to
CPET), NT-pro-BNP determination and safety labs, CPET, adverse events and concomitant
medications.
Endpoints
The exploratory endpoints were: i) change from baseline to 30 minutes in hemodynamic
parameters at both resting and paced conditions including LVEDP, dP/dtmin, tau (derived
from a mono-exponential pressure decay fit),3 and ii) change from baseline to Day 14 in
echocardiographic parameters including E/E´, CPET parameters including VO 2max, and NTpro-BNP.
Statistical considerations
The safety analysis set included all patients who received at least one dose of study
medication. The full analysis set (FAS) included all patients in the safety analysis set who had
at least one post-baseline efficacy measurement. Exploratory efficacy endpoints were
analyzed using the FAS, and safety analyses were performed on the safety analysis set. One
patient, who was randomized to the ranolazine treatment group and received ranolazine
intravenous infusion, was erroneously dispensed placebo tablets. This patient was included
only in the 30 minutes and 2-hour time points for analyses of exploratory endpoints, but was
included in all safety analyses, both in the ranolazine group.
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Between-treatment comparisons of all exploratory efficacy endpoints were analyzed
using the Wilcoxon rank sum test. Within-treatment comparisons were analyzed using the
Wilcoxon signed rank test. Change from baseline was analyzed. Due to the exploratory
nature of this study, there were no multiplicity adjustments when testing exploratory
endpoints. Therefore, p-values need to be interpreted with caution. Data are presented as
mean±SEM.
Supplemental Table
Parameter
LVEDP [mmHg]
LVESP [mmHg]
PCWP [mmHg]
mPAP [mmHg]
sPAP [mmHg]
dP/dt min [mmHg/s]
Tau [ms]
t relax [ms]
SVR [dyn*s*cm-5]
PVR [dyn*s*cm-5]
CO [l/min]
dP/dt max [mmHg/s]
t sys [ms]
t sys [%]
t dias [ms]
stroke vol [ml]
Placebo
Baseline
30 min
17.7±3.5
14.3±2.3
137.5±12.3
140.9±11.0
19.0±4.4
17.5±3.5
30.2±4.0
28.6±3.9
38.7±5.3
37.3±4.8
-1807.5±134.2
-1851.0±115.7
59.5±2.9
60.7±3.9
165.7±14.2
165.0±12.7
2086.6±273.3
2401.4±336.0
209.5±36.4
224.3±44.2
5.2±1.0
4.8±1.0
1741.1±146.4
1765.4±134.4
234.9±31.6
237.4±21.0
44.2±5.8
44.3±4.7
486.1±23.8
484.0±22.0
46.4±9.3
42.9±9.1
P -value
0.03
0.22
0.41
0.31
0.23
0.64
0.55
0.95
0.04
0.46
0.15
0.95
0.92
0.46
0.95
0.14
Ranolazine
P -value
P -value
Baseline
30 min
Plac vs Ran
14.7±2.1
11.0±1.15
0.02
0.97
141.1±7.8
135.7±6.9
0.63
0.30
14.2±2.1
12.3±1.4
0.12
0.80
26.5±2.7
25.2±2.5
0.02
1.00
36.6±3.7
35.3±3.4
0.05
1.00
-2030.8±97.2
-2013.8±84.1
0.90
0.60
52.1±2.6
53.6±2.6
0.07
0.54
133.3±4.9
140.4±5.55
0.01
0.43
1760.9±133.5
1915.5±118.6
0.01
0.21
196.0±10.8
235.5±17.7
0.06
0.71
4.9±0.2
4.3±0.2
<0.01
0.39
2024.1±167.7
1706.2±74.3
0.01
0.04
236.1±15.9
238.2±14.2
0.53
0.84
46.6±3.7
44.9±2.6
0.24
0.54
472.1±21.0
475,09⁺₋21,69
0.32
0.71
42.4±2.1
37.5±2.3
<0.01
0.39
Hemodynamic parameters during catheterization at paced conditions (120 beats per
minute). LVEDP=Left ventricular end-diastolic pressure, LVESP=Left ventricular end-systolic
pressure, PCWP=Pulmonary capillary wedge pressure, mPAP mean pulmonary arterial
pressure, sPAP=systolic pulmonary arterial pressure, tau=time constant for relaxation, t
relax=time for relaxation, SVR=systemic vascular resistance, PVR=pulmonary vascular
resistance, CO=cardiac output, t sys=time in systole, t dias=time in diastole, stroke
vol=stroke volume. All values are mean±SEM. P-value compares baseline vs. 30 min. P-value
Plac vs. Ran compares 30 min values between groups.
REFERENCES
1. Paulus WJ, Tschöpe C, Sanderson JE, et al. How to diagnose diastolic heart failure: a
consensus statement on the diagnosis of heart failure with normal left ventricular ejection
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fraction by the heart failure and echocardiography associations of the European Society of
Cardiology. Eur Heart J 2007;28:2539–50.
2. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and
preserved ejection fraction. N Engl J Med 2009;359:2456–67.
3. Wachter R, Schmidt-Schweda S, Westermann D, et al. Blunted frequency-dependent
upregulation of cardiac output is related to impaired relaxation in diastolic heart failure. Eur
Heart J 2009;30:3027–36.
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