Ambrisentan for treatment of inoperable chronic thromboembolic pulmonary hypertension (CTEPH).

This multicenter, randomized, double-blind, placebo-controlled study assessed ambrisentan or placebo in patients with inoperable chronic thromboembolic pulmonary hypertension. Futility of enrollment led to early termination. Trends of improvement in favor of ambrisentan versus placebo in the primary and some secondary endpoints were observed; adverse event profiles were similar between groups.

Cancer and bone fractures in observational follow-up of the RECORD study.

AIMS: The RECORD study evaluated the effects of rosiglitazone on cardiovascular outcomes. A 4-year observational follow-up was added to the study to monitor the occurrence of cancer and bone fractures. We present the cancer and bone fracture data aggregated across the main study and its observational follow-up. METHODS: RECORD was a multicentre, open-label trial in people with type 2 diabetes on metformin or sulfonylurea monotherapy randomly assigned to addition of rosiglitazone (n = 2,220) or to a combination of metformin and sulfonylurea (n = 2,227). At the end of the main study, patients stopped study drug and were invited to enter the observational follow-up during which glucose-lowering treatment was selected by the patient's physician. Serious adverse events of cancer and serious and non-serious events of bone fracture were recorded. The study is registered with ClinicalTrials.gov, number NCT00379769. RESULTS: Of the 4,447 patients comprising the intent-to-treat population, 2,546 entered the observational follow-up (1,288 rosiglitazone, 1,258 metformin/sulfonylurea) and added 9,336 patient-years experience to the main RECORD study, making an aggregate of 33,744 patient-years. Based on the totality of follow-up, malignancies were reported in 179 of 2,220 patients (8.1 %) in the group originally randomised to rosiglitazone and in 195 of 2,227 patients (8.8 %) in the group allocated metformin/sulfonylurea [relative risk, RR, 0.92 (95 % CI 0.76-1.12)]. More patients reported bone fractures in the rosiglitazone group (238, 10.7 %) than in the metformin/sulfonylurea control [151, 6.8 %; RR 1.58 (1.30-1.92)]. For women, the corresponding figures were rosiglitazone 156 (14.5 %), metformin/sulfonylurea 91 (8.5 %), RR 1.71 (1.34-2.18), and for men, the corresponding figures were rosiglitazone 82 (7.2 %), metformin/sulfonylurea 60 (5.2 %), RR 1.37 (0.99-1.90). Potentially high-morbidity fractures (hip, pelvis, femur, and spine) occurred in the same number of patients (31, 1.4 %) in the two treatment groups. CONCLUSIONS: We conclude that data from a 4-year observational follow-up, combined with the main RECORD study data, do not suggest an increased risk of cancer in patients randomised to rosiglitazone combination use compared with those randomised to metformin/sulfonylurea. Consistent with the main study, rosiglitazone is associated with an increased risk of peripheral bone fracture in women, and probably in men, but the combined data do not suggest an increase in potentially high-morbidity (hip, pelvis, femur, and spine) fractures.

Incidence and prevalence of unrecognized myocardial infarction in people with diabetes: a substudy of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study.

OBJECTIVE: To examine the prevalence and incidence of unrecognized myocardial infarction in a contemporary population with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a retrospective analysis of the electrocardiograms (ECGs) recorded at baseline and after 2 years for the first 1,004 type 2 diabetic individuals to be randomized in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study. RESULTS: ECGs suitable for analysis were obtained from 669 participants. The prevalence of unrecognized Q-wave myocardial infarction at baseline was 1.9% (n = 13). The incidence of unrecognized Q-wave myocardial infarction at the end of 2 years of follow-up was 1.5/1,000-person-years (n = 2). One-third (13 of 39) of prevalent and one-quarter (2 of 8) of incident myocardial infarctions were unrecognized. CONCLUSIONS: Although the prevalence and incidence of myocardial infarction was low, unrecognized Q-wave myocardial infarctions made up a substantial proportion of all events.

Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial.

AIMS: Thiazolidinediones are insulin sensitizers, and are associated with fluid retention and increased risk of heart failure (HF) in people with type 2 diabetes. We assessed fatal and non-fatal HF events and their outcome, and identified HF predictors in the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial population. METHODS AND RESULTS: In a multicentre, open-label study, we randomized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA(1c) of 7.9% to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227) and followed them over 5.5 years on average. Heart failure hospitalizations and deaths were adjudicated by a Clinical Endpoint Committee using pre-specified criteria. Independent predictors of HF events were identified out of a group of 30 pre-specified clinical, demographic, and biological variables. In the rosiglitazone group, the risk of HF death or hospitalization was doubled: HR = 2.10 (95% CI, 1.35-3.27): the excess HF event rate was 2.6 (1.1-4.1) per 1000 person-years. An excess in HF deaths was observed (10 vs. two), including four HF deaths as first HF events. By contrast, there was no increase in cardiovascular mortality or hospitalization (HR = 0.99, 95% CI, 0.85-1.16) or in cardiovascular deaths (60 vs. 71). Independent predictors of HF were rosiglitazone assignment, age, urinary albumin : creatinine ratio, body mass index, and systolic blood pressure at baseline. A history of previous cardiovascular disease was not predictive of HF. Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups. CONCLUSION: These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication. Close follow-up for the risk of HF should be offered to elderly people, people with markedly increased body mass index, people with microalbuminuria/proteinuria, and people with increased systolic blood pressure.

Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial.

BACKGROUND: Rosiglitazone is an insulin sensitiser used in combination with metformin, a sulfonylurea, or both, for lowering blood glucose in people with type 2 diabetes. We assessed cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea compared with the combination of the two over 5-7 years of follow-up. We also assessed comparative safety. METHODS: In a multicentre, open-label trial, 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy with mean haemoglobin A(1c) (HbA(1c)) of 7.9% were randomly assigned to addition of rosiglitazone (n=2220) or to a combination of metformin and sulfonylurea (active control group, n=2227). The primary endpoint was cardiovascular hospitalisation or cardiovascular death, with a hazard ratio (HR) non-inferiority margin of 1.20. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00379769. FINDINGS: 321 people in the rosiglitazone group and 323 in the active control group experienced the primary outcome during a mean 5.5-year follow-up, meeting the criterion of non-inferiority (HR 0.99, 95% CI 0.85-1.16). HR was 0.84 (0.59-1.18) for cardiovascular death, 1.14 (0.80-1.63) for myocardial infarction, and 0.72 (0.49-1.06) for stroke. Heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group (HR 2.10, 1.35-3.27, risk difference per 1000 person-years 2.6, 1.1-4.1). Upper and distal lower limb fracture rates were increased mainly in women randomly assigned to rosiglitazone. Mean HbA(1c) was lower in the rosiglitazone group than in the control group at 5 years. INTERPRETATION: Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures, mainly in women. Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs. FUNDING: GlaxoSmithKline plc, UK.