Guillaume Lefèvre

BACKGROUND: Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS: In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS: The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS: Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. (Funded by Programme Hospitalier de Recherche Clinique and Arrow Génériques; BEZURSO ClinicalTrials.gov number, NCT01654731 .).

To investigate disturbances in the coronary circulation and myocardial metabolism during septic shock, we examined coronary sinus blood flow and myocardial substrate extraction in 40 patients with septic shock and 13 control patients. Patients with coronary artery disease were excluded from this study. The global hemodynamic pattern of the septic patients was characterized by a lower stroke volume, despite an elevated cardiac index. Coronary sinus blood flow was high (187 +/- 47 vs 130 +/- 21 ml/min in the control group, p less than .001) due to marked coronary vasodilation, especially in the subgroup of nonsurvivors. In contrast to the control group, myocardial lactate uptake was elevated, while that of free fatty acids, glucose, and ketone bodies was diminished in patients with septic shock. These findings were especially prominent in the nonsurvivors. Expressed as oxygen equivalents, the contribution of free fatty acids as an energy source of the myocardium was markedly diminished in septic patients (12% vs 54% in the control group, p less than .005), while that of lactate was increased (36% vs 12%, p less than .01). The observed shift in myocardial substrate extraction was associated with a discrepancy between measured myocardial oxygen consumption and that calculated chemically from commonly available exogenous substrates: 41% of myocardial oxygen consumption was not explained by the utilization of commonly available substrates extracted from coronary circulation in all patients with septic shock.(ABSTRACT TRUNCATED AT 250 WORDS)

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OBJECTIVE: Pulmonary hypertension (PH) is a frequent and life-limiting complication of systemic sclerosis (SSc). However, data on survival rates and their evolution over time, as well as prognostic factors in SSc complicated by PH, are still conflicting. The aim of this study was to conduct a systematic review and meta-analysis of cohort studies to assess pooled survival and prognostic factors for survival in patients with SSc-associated PH. METHODS: For this systematic review and meta-analysis, we searched the Medline and EMBase databases (January 1960 to January 2012). All cohort studies in which survival and/or prognostic factors for SSc-associated PH were reported were included in the analysis. We calculated the pooled survival rates and analyzed their evolution over time and identified prognostic factors for survival. RESULTS: Twenty-two studies were included, representing a total of 2,244 patients with SSc-associated PH. The pooled 1-, 2-, and 3-year survival rates were 81% (95% confidence interval [95% CI] 79-84%), 64% (95% CI 59-69%), and 52% (95% CI 47-58%), respectively. Meta-regression did not reveal a significant change in survival over time, while baseline hemodynamic measures of PH severity were significantly correlated with survival. In patients with SSc complicated by pulmonary arterial hypertension (PAH), age, male sex, diffusing capacity for carbon monoxide (DLCO), pericardial effusion, and the parameters classically associated with the severity of idiopathic PAH, including the 6-minute walk distance, mean pulmonary artery pressure, cardiac index, and right atrial pressure, were significant prognostic factors. DLCO and pericardial effusion were the only prognostic factors in patients with interstitial lung disease-related PH. CONCLUSION: Our meta-analysis revealed a poor pooled 3-year survival rate of 52% in patients with SSc-associated PH. Baseline hemodynamic measures of PAH severity, but not the period of time during which patients were included in the studies, correlated significantly with survival in patients with SSc-associated PAH. All of the prognostic factors typically observed in idiopathic PAH, including the 6-minute walk distance and right atrial pressure, were also prognostic factors in SSc-associated PAH.