Chronic Heart Failure Clinical Trial
Official title:
Multimodal Approach of Undernutrition in Chronic Heart Failure : a Controlled, Randomized Trial
The treatment of chronic heart failure (CHF) is a key challenge in public health. Despite
medical advances, 1-year mortality of NYHA III-IV CHF is 28%. Undernutrition is an
independent risk factor for mortality and complications. Up-to-date, interventional studies
involving nutrition are scarce in CHF. Academic societies are recommending the use of oral
nutritional supplements (ONS) in case of weight loss, without defining the modalities. ONS
could improve nutritional status in undernourished CHF patients, but solely administered,
have a limited impact on undernutrition, physical performance and prognosis. A multimodal
approach integrating physical exercise, nutritional intakes, polyunsaturated n-3 fatty acids
(n-3 PUFA), and anabolizing hormones, has to be privileged. A recent trial has shown the
clinical benefits of such an approach in patients with chronic respiratory insufficiency
(CRI), who have similar nutritional and muscular characteristics.
Exercise rehabilitation is well validated in CHF patients, but has never been validated in
case of undernutrition. Exercise rehabilitation allows improving exercise capacity, quality
of life and cardiovascular outcomes including mortality.
N-3 PUFA supplementation improves muscle strength and endurance in CRI patients. n-3 PUFA
supplementation decreases by 30% cardiovascular mortality of CHF patients. n-3 PUFA could be
useful for CHF patients rehabilitation.
Androgenopenia is a prognostic factor in CHF. Androgen substitution improves significantly
muscle strength, walking endurance and quality of life. In the context of a multimodal
approach, Androgen substitution together with exercise rehabilitation and ONS could have a
beneficial effect on muscle mass, strength and endurance of CHF patients, as already
described in CRI, elderly and HIV patients.
The study hypotheses that a 3-month multimodal approach associating exercise rehabilitation,
androgen substitution, n-3 PUFAs and ONS improves exercise capacity of undernourished CHF
patients.
Study aims :
Main study aim :
To evaluate the impact of a 3-month multimodal approach associating exercise rehabilitation,
androgen substitution, n-3 PUFAs and ONS on exercise capacity of undernourished CHF
patients.
Secondary study aims :
To Evaluate the impact of the 3-month multimodal approach on :
heart function muscle strength exercise endurance body composition and nutritional status
quality of life drugs compliance number of hospital stays during one year 1-year survival.
Experimental protocol
Undernourished CHF patients will be randomized into two groups:
1) The 'intervention' group: 3-month multimodal approach associating exercise
rehabilitation, ONS, n-3 PUFAs and androgen substitution. 2) The 'control' group: no
multimodal approach but the treatment currently recommended: heart rehabilitation and
dietary counseling during 3 months.
Both groups will receive by the oral route for 3 months:
vitamin D : 100 000UI/month if plasma 25-OH vitamin D <30 ng/l, ubiquinone : 250 mg/jour in
all patients. Both groups will benefit of dietary counseling. A monthly follow-up of
compliance will be performed during the 3- month treatment period.
The overall follow-up period will be 15 months, including the 3-month treatment period.
Considering a recruitment period of 18 months and a 15-month follow up, the total study
duration will be 33 months.
Primary endpoint: measurement of VO2 at the ventilatory level.
The study hypothesis is to demonstrate in a population of malnourished CHF patients a 10%
difference (with a 15% standard error) of the level of VO2 variation between the two groups,
measured during the maximal cycle exercise capacity test coupled with respiratory exchanges.
VO2 will be measured by the same operators, at baseline and after the 3-month multimodal
approach.
Number of subjects to be included :
50 patients per group are needed to demonstrate a 10% difference (with a 15% standard error)
if 1st and 2nd error risks respectively fixed at 5% (bilateral) and 10%. Considering the
potential studies dropouts, 120 patients will be included.
Inclusion criteria :
Stable patients with CHF, defined by the absence of acute episodes since 2 months, and
absence of exercise rehabilitation in the two last months NYHA III Heart failure VO2 peak <
18 ml/kg/min Left ventricle ejection fraction ≤ 40% Age ≥ 18 years, informed, having given
their consent Absence of acute disease
Undernutrition, defined by :
Involuntary weight loss ≥5% during the 12 last months, without any increase of diuretics
doses or body mass index <20 or fat-free mass index assessed by BIA <18 in men, and <15 in
women.
Exclusion criteria :
Heart failure related to pulmonary hypertension Heart failure treatable by surgery or
angioplasty Patients eligible to ventricular resynchronisation Instable heart failure
Patients waiting for transplantation On-going imunosuppressant or corticosteroids Disease
affecting 6-month survival (end-stage cancer, or chronic disease,…) Positive VIH or
hepatitis C serology Liver failure Respiratory insufficiency End-stage (stage 5) renal
failure (creatinine clearance ≤15ml/kg/min) Acute disease Previous history of hormonal
cancer (breast, prostate) Suspected or proved hormonal cancer (breast, prostate)
Hypersensibility to testosterone or components of testosterone patch Liver tumor or previous
history of liver tumor Unability or contra-indication to rehabilitation program (defined by
the French society of Cardiology including contra-indication to physical exercise)
Orthopedical limitations to exercise Type 2 diabetes requiring insulin since less than 3
months Patients having not giving their consent.
Statistical analysis STATA V10 (Stata Corp) will be used. The analysis will be performed by
intention-to-treat, and, secondly per-protocol. All statistical tests (except for
intermediary analysis) will be performed considering a 5% α error risk.
Continuous variables will be presented as mean and standard deviation if normal distribution
(Shapiro-Wilk test), and as median, quartiles and extremes, if not. Qualitative variables
will be expressed as n (%).
Comparisons between groups will be (1) systematic without any adjustment, and (2) with
adjustment on factors not equally distributed between groups despite randomization.
Main endpoint, i.e. ventilatory peak VO2, wil be compared between randomization groups by
Student or Kruskal-Wallis tests. Variances equality will be tested with the Fisher-Snedecor
test.
In case of adjustment on factors (stratification and treatments), a linear regression model
will be performed in the context of a secondary analysis.
Secondary endpoints will be compared according to the same tests and by Chi2 test or exact
Fisher test for qualitative parameters.
To measure the variation through time of the different collected parameters, a longitudinal
data analysis with ANOVA for repeated data, or Friedman test, followed by a post-hoc test
and by mixt models allowing to study inter- or intra-patient variabilities.
Intra-group comparisons will be performed with paired-t Student or Wilcoxon tests for
quantitative parameters and Stuart-Maxwell test for qualitative parameters.
12-month survival analysis will be performed according to: univariate analysis: comparison
of survival curves with Kaplan-Meier method by log-rank test multivariate analysis with Cox
model.
Multivariate analysis models of quality of life (e.g. SF36) will consider the group effect
and the patient's demographical/clinical data. To keep a 5% risk for every analysed area, a
procedure of 1st species risk correction will be done to calculate the level of significancy
of each test.
The rate of expected missing data of the main endpoint was estimated to 20%. A sensitivity
analysis of these data will be performed to evaluate its statistical nature: MAR or MCAR
and, if necessary it will be decided to use the most appropriate method.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label
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