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.
