Impact of fingolimod therapy on magnetic resonance imaging outcomes in patients with multiple sclerosis.

OBJECTIVE: To assess the impact of fingolimod (FTY720) therapy on magnetic resonance imaging measures of inflammatory activity and tissue damage in patients participating in a 2-year, placebo-controlled, phase 3 study. DESIGN: Patients with active relapsing-remitting multiple sclerosis were randomized to receive fingolimod, 0.5 mg; fingolimod, 1.25 mg; or placebo for 2 years. Standardized magnetic resonance imaging scans were obtained at months 0, 6, 12, and 24 and centrally evaluated for number and volume of T1 gadolinium-enhancing, T2 hyperintense, and T1 hypointense lesions and for percentage of brain volume change. Findings were compared across subgroups by treatment and baseline characteristics. SETTING: Worldwide, multicenter clinical trial. PATIENTS: Patients were part of the fingolimod FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial for relapsing-remitting multiple sclerosis (N=1272). MAIN OUTCOME MEASURES: We measured the effect of therapy on acute inflammatory activity, burden of disease, and irreversible loss of brain volume. RESULTS: Fingolimod therapy resulted in rapid and sustained reductions in inflammatory lesion activity as assessed by gadolinium-enhancing and new/newly enlarged T2 lesions after 6, 12, and 24 months of therapy (P.001, all comparisons vs placebo). Changes in T2 hyperintense and T1 hypointense lesion volume also significantly favored fingolimod (P.05, all comparisons). Fingolimod, 0.5 mg (licensed dose), significantly reduced brain volume loss during months 0 to 6, 0 to 12, 12 to 24, and 0 to 24 (P.05, all comparisons) vs placebo, and subgroup analyses confirmed these effects over 2 years irrespective of the presence/absence of gadolinium-enhancing lesions, T2 lesion load, previous treatment status, or level of disability. CONCLUSION: These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00289978

The effect of carvedilol on mortality risk in heart failure patients with diabetes: results of a meta-analysis.

BACKGROUND: Although beta-blocker therapy has been shown to improve survival in patients with chronic heart failure, this class of drugs tends to be underutilized in diabetic patients due to concerns about adverse metabolic effects, especially on glycemic control. No randomized clinical trial has specifically evaluated the effect of beta-blocker therapy on mortality in diabetic patients with heart failure. Previous meta-analyses combining results of heart failure trials with pharmacologically diverse beta-blockers suggest that the survival benefit in diabetic patients may be diminished compared to benefits in non-diabetic patients. However, some trial results indicate that carvedilol, which blocks beta1-, beta2-, and alpha1-receptors and is a potent antioxidant, may produce at least comparable effects in both patient groups. OBJECTIVES: To evaluate the effect of carvedilol in patients with heart failure and diabetes, specifically to determine if the survival benefit of carvedilol demonstrated in heart failure trials was as great in the subgroups of patients with diabetes. METHODS: A meta-analysis was performed that included 5757 patients with heart failure, 25% of whom had diabetes, from seven large placebo-controlled randomized trials with carvedilol. All large (> 100 patients) placebo-controlled, randomized trials with carvedilol in heart failure were included. The endpoint of all-cause mortality was examined in the overall population, patients without diabetes, and patients with diabetes. The number of patients needed to treat (NNT) for 1 year to prevent one death associated with carvedilol use in diabetic versus non-diabetic patients was also calculated. The log-rank test and the Cox proportional hazards regression were used to compare the event time distributions of carvedilol versus placebo with respect to the outcome of mortality. RESULTS: Similar survival benefits were seen with carvedilol use in diabetic and non-diabetic patients (relative risk reductions of 28% [95% confidence interval (CI) 3-46%; p = 0.03] and 37% [95% CI 22-48%; p < 0.001], respectively). There were no significant differences between the relative mortality risk reductions or the NNT with carvedilol use in diabetic versus non-diabetic patients. The NNT for 1 year to prevent one death was 23 for all patients, as well as for non-diabetic patients, and 25 for the diabetic group. CONCLUSIONS: This meta-analysis provides evidence that the same survival benefit may occur with carvedilol in heart failure patients with and without diabetes. The low NNT in the severe heart failure trial, COPERNICUS, and the diabetic subgroup in this meta-analysis suggests that severe heart failure patients and heart failure patients with diabetes may particularly derive benefit from therapy with carvedilol.

Pharmacokinetics and pharmacodynamics of argatroban in combination with a platelet glycoprotein IIB/IIIA receptor antagonist in patients undergoing percutaneous coronary intervention.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of argatroban, administered in combination with a platelet glycoprotein IIb/IIIa receptor antagonist, was characterized in patients undergoing percutaneous coronary intervention (PCI). Plasma argatroban and activated clotting times (ACTs) were assessed periprocedurally in 152 patients administered argatroban (250- or 300-microg/kg bolus, then 15-microg/kg/min infusion) in combination with abciximab or eptifibatide during PCI. The PK and PK-PD models were developed utilizing a sequential population approach in NONMEM. Population PK estimates for clearance, central volume, and peripheral volume were 22.0 L/h, 11.0 L, and 13.0 L, respectively (coefficients of variation [CVs]