CHAPTER 4

RESEARCH METHODOLOGY

1.1. Research Design

This is a double blinded randomized experimental study.

1.1.1. Randomization

Randomization is done by simple randomization method using computer program from

website https://www.randomizer.org/.

1.1.2. Incognito

Incognito is done with double blind where researchers or participants do not know the
given drug. Drugs tested will be packaged into trimetazidine 35 mg per capsule and
placebo per capsule. The drug is labeled A or B. The giving is done after the informed
consent is filled and signed. Trimetazidine group maintenance doses will be given 2
capsules daily taken morning and night (both trimetazidine 35 mg) while the placebo
group will be given 2 capsules daily taken morning and night (both placebo).

1.2. Place and research time

The research was conducted at the Department of Cardiology and Vascular Medicine FKUI /
Heart and Blood Vessel Hospital Harapan Kita (RSJPDHK), from June 2017 to December
2017.

1.3. Study Population

1.3.1. Population Target

Precapillary HP patients

1.3.2. Affordable Population

Precapillary HP patients who come to the RSJPDHK clinic in June 2017 to December 2017.

1.4. Inclusion and exclusio criteria

1.4.1. Inclusion criteria

Age 18-65 years old

Willing to follow research and sign informed consent approval.
Evidence of increased mPAP> 25mmHg and PCWP or left atrial pressure <15 mmHg
from KJK.
 In cases of pulmonary hypertension associated with right-to-left shunting there is
evidence of PARI> 5 WU / m2 with a non-reactive oxygen test from KJK.
Willing to follow the research.

1.4.2. Exclusion criteria

Post-capillary HP marked with mPAP> 25mmHg and PCWP> 15 mmHg from

KJK.
Pregnant or breastfeeding
LFG <30 ml / min / 1.73 m 2 or undergo routine hemodialysis
Malignant arrhythmia: total AV block (TAVB) or ventricular arrhythmia (VT /
VF) before or after therapy.
Left ventricular dysfunction with FEVKI <55%.
Parkinson's disease.
Severe chronic obstructive pulmonary disease
Psychiatric disorders that may hamper informed consent approval.
History of intolerance or contraindications to trimetazidine.

1.5. Sampling Frame

1.5.1. Sampling Size

The sample size was calculated using the large numerical comparative sample samples for the
two unpaired groups. Initial sample:

2
n1=n2= 2 (Z + Z)SD
m1 - m2

Explanation :

n1n2 = sample size of each group

= type I error set 5%
= type II error set 10%
Z = for 5%, two-tailed Z = 1.96
Z = for 20% Z = 0.84
m1-m2 = FEVKA difference from significant cardiac MRI. Set at 5%.
SD = standard deviation of MCA post cardiac MRI standard deviation (sildenafil). Defined
6%.
Based on the above formula obtained a sample:

2
n1 = n2 = 2 (1.96 + 0.84) 6
5
n1 = n2 = 22.5

To keep the possibility of drop out, the number of samples added becomes:

n1 + (10% x n1)
n1 = n2 = 22.5 + 2.25 = 24.75 25 samples

1.5.2. Sampling Technique

Samples were chosen by using consecutive sampling technique.

1.1. Variable Identification

1.1.1. Independent Variables

Provision of trimetazidine 2x35 mg in addition to HAP therapy

Provision of placebo in addition to HAP therapy
1.1.2. Dependent Variables

Differences of post cardiac MRI FEVKA post 3 months of treatment

Differences in native T1 and extracellular volume fraction of post cardiac MRI 3
months of treatment.
Differences in serum levels of lactate dehydrogenase after 3 months of treatment.
1.1.3. Confouding Variables

Demographic: Age, sex, race, weight (BW), height (TB), body mass index (BMI).
Clinical: WHO functional class, kidney function, comorbid disease, HAP drug type,
and HAP drug dose.
1.2. Research Procedure

Subjects meeting the inclusion criteria will be evaluated demographic, clinical, and
FEVKA data from cardiac MRI. Data taken include gender, race, last education, body
weight (kg), age (year), height (cm), body mass index (kg / m2), traditional factors of
 cardiovascular disease, family history, which is still to be drunk, the duration of HP
precursor diagnosed, FEVKA (%), native T1, extracellular volume fraction of cardiac
MRI, and serum lactate dehydrogenase level.
Randomization is performed by drawing patients using www.randomizer.org to obtain
A or B capsules whose contents are unknown to the subjects, examiners, or
researchers (randomized double blind).
Patients who have been randomized will receive A or B capsule therapy for 12 weeks.
Provision of A or B capsules will be given every 4 weeks along with the evaluation of
functional classes and possible side effects.
At week 12, the patient will undergo cardiac MRI examination to determine changes
in EDV (ml), ESV (ml), FEVKA (%), native T1, and extracellular volume fraction
and serum lactate dehydrogenase examination.

1.3. Statistical Analysis

Statistical analysis using SPSS computer program (version 23, SPSS Inc., IBM, Armonk,
New York). Data from dependent variables in the form of numerical scales are analyzed
using independent t-test if normal data distribution, if abnormal data distribution data is
analyzed by non-parametric test. The results of analysis are presented in the form of mean
standard deviation if the distribution of normal data or the middle value with the
minimum range value - maximum if the data distribution is not normal.

1.4. Operational Definition

Preecapillary pulmonary hypertension increased pulmonary artery pressure> 25
mmHg and PCWP <15mmHg ang measured by KJK.
Standard Precapillary HP Therapy: standard therapies available in Indonesia
include oral (oral-root) phosphodiesteras -5 oral (sildenafil) or oral prostacyclin
(oral-throst) oral blockers.
WHO functional class: clinical classification of heart failure during examination
that has a usefulness for predicting mortality.
a) Class I: lung hypertensive patients without impaired physical activity
where routine physical activity does not cause fatigue, shortness of breath,
chest pain or syncope.
b) Class II: patients with pulmonary hypertension with mild physical activity
disorders. Patients have no complaints at rest but have complaints of
 fatigue, shortness of breath, chest pain, or near-syncope during routine
day-to-day activities.
c) Class III: patients with pulmonary hypertension with significant activity
disorders. Patients have no complaints at rest. Patients have complaints of
fatigue, shortness of breath, chest pain, or near-syncope during light
activity.
d) Class IV: patients with pulmonary hypertension with inability to activity
without complaint. Patients have symptoms and signs of right heart failure.
Complaints of shortness of breath or fatigue can arise during breaks that
increase with the activity.
Right ventricular ejection fraction (RVEF) taken by cardiac MRI examination by
formula (EDV-ESV) / EDV x 100%.
End diastolic volume (EDV): measurement of RV volume at the end of diastolic
measured by cardiac MRI.
Systolic end volume (ESV): measurement of end-systolic RV volume as
measured by cardiac MRI.
Native T1 mapping: the measurement of the longitudinal relaxation time (spin-
lattice) that can be elevated in various pathological conditions of the heart such as
myocardial fibrosis.
Extracellular volume fraction: calculation of cardiac extracellular volume
calculated based on different native values of T1 and contrast-enhanced T1 in blood
and tissue.
Glomerular filtration rate (LFG)
The LFG value is calculated using the Cockroft-Gault formula: eLFG = (140 - age)
body weight / plasma creatinine (mg / dl) 72 ( 0.85 if female) It is said to be
normal if the LFG value is> 90 ml / min / 1.73m2, mild LFG decrease if the value is
60-89 ml / min / 1.73m2, moderate LFG decline if the value is 30-59 ml / min /
1.73m2, and LFG decrease if its value <30 mL / min / 1.73m2