Pathophysiological Sex Differences in Heart Failure Progression After Acute Coronary Syndrome: Insights From the EXAMINE Trial.

Background: Therapies can reduce the risk of heart failure (HF) development and progression in type 2 diabetes; nevertheless, the risk of these outcomes is greater in females than in males.

Methods And Results: To investigate sex differences in HF development and progression, we compared baseline circulating proteins (Olink Cardiovascular II panel) in males and females with type 2 diabetes and recent acute coronary syndrome for the outcome of HF hospitalization. Data were from the placebo-controlled Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care (EXAMINE) trial.

External validation and extension of the TIMI risk score for heart failure in diabetes for patients with recent acute coronary syndrome: An analysis of the EXAMINE trial.

Aims: The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure (HF) in Diabetes (TRS-HF ) prognosticates HF hospitalization in people with type 2 diabetes (T2D). This study aimed to externally validate and extend its use for those with recent acute coronary syndrome (ACS).

Materials And Methods: The TRS-HF was externally validated in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial (n = 5380) and extended with natriuretic biomarkers.

Fasiglifam-Induced Liver Injury in Patients With Type 2 Diabetes: Results of a Randomized Controlled Cardiovascular Outcomes Safety Trial.

Objective: To evaluate the cardiovascular (CV) safety of fasiglifam, a first-in-man G-protein-coupled receptor 40 (GPR40) agonist, in patients with type 2 diabetes.

Research Design And Methods: A phase 3 multicenter randomized double-blind placebo-controlled two-arm trial was intended to randomize 5,000 participants with type 2 diabetes at high CV risk to fasiglifam or placebo. The primary objective of the trial was to rule out an upper noninferiority bound >1.

Optimal promising zone designs.

Clinical trials with adaptive sample size reassessment based on an unblinded analysis of interim results are perhaps the most popular class of adaptive designs (see Elsäßer et al., 2007). Such trials are typically designed by prespecifying a zone for the interim test statistic, termed the promising zone, along with a decision rule for increasing the sample size within that zone.

Extensile lateral versus sinus tarsi approach for displaced, intra-articular calcaneal fractures: a meta-analysis.

Background: Operative management of displaced, intra-articular calcaneal fractures is associated with improved functional outcomes but associated with frequent complications due to poor soft tissue healing. The use of a minimally invasive sinus tarsi approach to the fixation of these fractures may be associated with a lower rate of complications and therefore provide superior outcomes without the associated morbidity of operative intervention.

Methods: We reviewed four prospective and seven retrospective trials that compared the outcomes from the operative fixation of displaced intra-articular calcaneal fractures via either an extensile lateral approach or minimally invasive fixation via a sinus tarsi approach.

The distance of the femoral neurovascular bundle from the hip joint: an intraoperative guide to reduce iatrogenic injury.

Background: Iatrogenic injury to the femoral neurovascular bundle is not uncommon during primary and revision total hip replacement (THR) and can result in permanent weakness, pain and poor function. Prevention of injury to these structures relies on a sound knowledge of their relationships to the hip joint.

Methods: We studied 115 consecutive hip magnetic resonance imaging (MRI) results in order to identify objective relationships between these structures and the hip joint that can be used intraoperatively.

Total cardiovascular events analysis of the EXAMINE trial in patients with type 2 diabetes and recent acute coronary syndrome.

Alogliptin, a dipeptidyl peptidase-4 inhibitor, is approved for the treatment of patients with type 2 diabetes (T2DM). EXAMINE was a randomized controlled clinical trial designed to demonstrate the cardiovascular (CV) safety of alogliptin. In the trial, 5380 patients with established T2DM who had a recent acute coronary syndrome event (between 15 and 90 days) were randomized to treatment with either alogliptin or placebo.

The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors.

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes.

A gatekeeping procedure to test a primary and a secondary endpoint in a group sequential design with multiple interim looks.

Glimm et al. (2010) and Tamhane et al. (2010) studied the problem of testing a primary and a secondary endpoint, subject to a gatekeeping constraint, using a group sequential design (GSD) with K=2 looks.

Serial Measurement of High-Sensitivity Troponin I and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus in the EXAMINE Trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care).

Background: We aimed to describe the relationship between changes in high-sensitivity cardiac troponin I (hsTnI) and cardiovascular outcomes.

Methods: The EXAMINE trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) was a phase IIIb clinical outcomes trial designed to evaluate the cardiovascular safety of alogliptin, a nonselective dipeptidyl peptidase 4 inhibitor. Patients with type 2 diabetes mellitus, glycohemoglobin between 6.

Relationship of glycated haemoglobin and reported hypoglycaemia to cardiovascular outcomes in patients with type 2 diabetes and recent acute coronary syndrome events: The EXAMINE trial.

Aims: To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE).

Methods: The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events.

Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.

Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies.

Cardiovascular Mortality in Patients With Type 2 Diabetes and Recent Acute Coronary Syndromes From the EXAMINE Trial.

Objective: We evaluated the risk of cardiovascular (CV) death in all Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study participants and in those who experienced an on-study, major nonfatal CV event.

Research Design And Methods: The study randomly assigned 5,380 patients with type 2 diabetes to alogliptin or placebo within 15 to 90 days of an acute coronary syndrome (ACS). Deaths and nonfatal CV events (myocardial infarction [MI], stroke, hospitalized heart failure [HHF], and hospitalization for unstable angina [UA]) were adjudicated.

Ischemic cardiac outcomes and hospitalizations according to prior macrovascular disease status in patients with type 2 diabetes and recent acute coronary syndrome from the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care trial.

Background: Concerns raised regarding adverse cardiovascular (CV) outcomes with new therapies for type 2 diabetes mellitus (T2DM) have led to several large-scale CV outcome trials. The EXAMINE trial confirmed noninferiority of the dipeptidyl dipeptidase 4 inhibitor alogliptin to placebo on major adverse cardiac event rates in a post-acute coronary syndrome (ACS) T2DM population. We present data on additional ischemic cardiac events and CV hospitalizations in EXAMINE.

Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial.

Background: The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event (MACE) rates in patients with type 2 diabetes and recent acute coronary syndromes. Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported. We therefore assessed hospital admission for heart failure in the EXAMINE trial.

A randomized, controlled trial of oral propranolol in infantile hemangioma.

Background: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited.

Methods: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months).

Alogliptin after acute coronary syndrome in patients with type 2 diabetes.

Background: To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.

Methods: We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy.

Adaptive extensions of a two-stage group sequential procedure for testing primary and secondary endpoints (II): sample size re-estimation.

In this part II of the paper on adaptive extensions of a two-stage group sequential procedure (GSP) for testing primary and secondary endpoints, we focus on the second stage sample size re-estimation based on the first stage data. First, we show that if we use the Cui-Huang-Wang statistics at the second stage, then we can use the same primary and secondary boundaries as for the original procedure (without sample size re-estimation) and still control the type I familywise error rate. This extends their result for the single endpoint case.

Adaptive extensions of a two-stage group sequential procedure for testing primary and secondary endpoints (I): unknown correlation between the endpoints.

In a previous paper we studied a two-stage group sequential procedure (GSP) for testing primary and secondary endpoints where the primary endpoint serves as a gatekeeper for the secondary endpoint. We assumed a simple setup of a bivariate normal distribution for the two endpoints with the correlation coefficient ρ between them being either an unknown nuisance parameter or a known constant. Under the former assumption, we used the least favorable value of ρ = 1 to compute the critical boundaries of a conservative GSP.

Adaptive increase in sample size when interim results are promising: a practical guide with examples.

This paper discusses the benefits and limitations of adaptive sample size re-estimation for phase 3 confirmatory clinical trials. Comparisons are made with more traditional fixed sample and group sequential designs. It is seen that the real benefit of the adaptive approach arises through the ability to invest sample size resources into the trial in stages.

Population enrichment designs: case study of a large multinational trial.

A method is proposed for modifying a group-sequential clinical trial by restricting future enrollment to a subgroup and possibly altering the sample size of the subgroup, based on an interim analysis of the data already obtained. The method provides strong control of type 1 error without requiring prespecification of the list of possible subgroups or of the decision rule for selecting among them. Nevertheless, for regulatory submissions it is recommended that the subgroups and decision rule be prespecified.

Testing a primary and a secondary endpoint in a group sequential design.

We consider a clinical trial with a primary and a secondary endpoint where the secondary endpoint is tested only if the primary endpoint is significant. The trial uses a group sequential procedure with two stages. The familywise error rate (FWER) of falsely concluding significance on either endpoint is to be controlled at a nominal level α.

Exact confidence bounds following adaptive group sequential tests.

We provide a method for obtaining confidence intervals, point estimates, and p-values for the primary effect size parameter at the end of a two-arm group sequential clinical trial in which adaptive changes have been implemented along the way. The method is based on applying the adaptive hypothesis testing procedure of Müller and Schäfer (2001, Biometrics 57, 886-891) to a sequence of dual tests derived from the stage-wise adjusted confidence interval of Tsiatis, Rosner, and Mehta (1984, Biometrics 40, 797-803). In the nonadaptive setting this confidence interval is known to provide exact coverage.