Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Controlled trial of dexamethasone in neonatal chronic lung disease: a 3-year follow-up.

OBJECTIVE: We compared the effects of a policy of neonatal steroid administration versus placebo for babies chronically dependent on supplemental oxygen in terms of long-term health and development, judged at 3 years of age. DESIGN: Double-blind randomized controlled trial. SETTING: Thirty-one centers in the United Kingdom, Ireland, Belgium, Germany, Canada, and the United States. PATIENTS: Babies who were chronically dependent on supplemental oxygen between 2 and 12 weeks of age were recruited to the trial between 1986 and 1989. Sixty-two children were known to have died, 23 before discharge from the hospital and 10 afterward in the active group, compared with 25 and 4, respectively, in the placebo group. Information was available for 209 of the 212 eligible for follow-up (99%). INTERVENTIONS: A 1-week course of active dexamethasone phosphate 0.6 mg/kg/d (dexamethasone base 0.5 mg/kg/d) or saline placebo was given intravenously (or orally, if no intravenous line). There was an option to give a second tapering 9-day course if relapse occurred after initial improvement. OUTCOME MEASURES: Information about respiratory problems, growth, neurodevelopment and disability, infection, and health service use when the children were 3 years old was ascertained from questionnaires to general practitioners, health visitors, and parents (and occasionally pediatricians). RESULTS: About half the children in both groups had been admitted to the hospital for respiratory problems, with more in the active than the placebo group having at least five outpatient consultations for these problems over the 3 years. Overall, the children were below average in height, weight, and head circumference. About one fifth had cerebral palsy, 8% some visual loss, and 16% hearing loss; 18% needed or were anticipated to need special schooling. There were no clear differences between the randomized groups. These overall conclusions were not altered by any of the prespecified secondary analyses. CONCLUSIONS: Despite early benefits, there were no clear effects at 3 years of age. As 40% of the placebo group eventually received open steroids, even a trial of this size has limited statistical power to detect a moderate effect of the policy. Regardless of random allocation, overall morbidity was high, confirming that babies with protracted dependence on supplemental oxygen are at high risk of childhood disability and poor health.