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. Pathophysiological sex-differences were interpreted with network and pathway over-representation analyses. The EXAMINE trial enrolled 5380 participants (32.1% females) with biomarker data available for 95.4% of individuals. Analyses revealed 43 biomarkers were differentially expressed in HF hospitalization, of which 18 were sex specific. Among these 43 biomarkers, interleukin-6 was identified as a central node for the pathogenesis of HF hospitalization in both females and in males. Additional pathway over-representation analyses demonstrated that biomarkers associated with inflammatory pathways related to endothelial dysfunction and cardiac fibrosis were more up-regulated in females than males with HF hospitalization. Differential expression of 3 biomarkers (pentraxin-related protein 3, hydroxyacid oxidase 1, and carbonic anhydrase 5A) was independently associated with an increased risk of HF hospitalization in females but not in males (interaction P < .05). CONCLUSIONS: In males and females with type 2 diabetes and acute coronary syndrome, interleukin-6 seems to be central in the pathogenesis of HF. Females exhibit higher levels of circulating proteins related to immunological pathways, reflecting sex-specific differences underlying HF development and progression.

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-HFDM ) 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-HFDM was externally validated in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial (n = 5380) and extended with natriuretic biomarkers. Missing data were multiply imputed. Initial TRS-HFDM variables were previous HF (2 points), atrial fibrillation (1 point), coronary artery disease (1 point), estimated glomerular filtration rate <60 ml/min/1.73 m2 (1 point), and urine albumin-to-creatinine ratio 30-300 mg/g (1 point) and >300 mg/g (2 points). RESULTS: In total, HF hospitalization occurred in 193 (3.6%) patients. Based on the TRS-HFDM , 25% of patients were classified as intermediate risk (1 point), 30% were classified as high risk (2 points), 19% were classified as very-high risk (3 points) and 26% were classified as severe risk (≥4 points). Before model extension, discrimination (C-index 0.76, 95%·CI 0.73-0.80) and calibration (calibration slope 0.82, 95%·CI 0.65-1.0; calibration-in-the-large -0.15, 95%·CI -0.37-0.64) were moderate-to-good in individuals with T2D and recent ACS. The extension of TRS-HFDM with the addition of N-terminal pro-B-type natriuretic peptide (NT-ProBNP) improved discrimination (C-index 0.82, 95%·CI 0.79-0.85) and calibration (calibration slope 0.84, 95%·CI 0.66-1.02; calibration-in-the-large -0.12, 95%·CI -0.33-0.081) for this higher-risk population. CONCLUSION: The TRS-HFDM with the extension of NT-ProBNP improves risk stratification and generalizes the use of the risk score for patients with T2D and ACS. Future validation studies in ACS populations may be warranted.

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. Mehta and Pocock (2011) provided some examples of promising zone designs and discussed several procedures for controlling their type-1 error. They did not, however, address how to choose the promising zone or the corresponding sample size reassessment rule, and proposed instead that the operating characteristics of alternative promising zone designs could be compared by simulation. Jennison and Turnbull (2015) developed an approach based on maximizing expected utility whereby one could evaluate alternative promising zone designs relative to a gold-standard optimal design. In this paper, we show how, by eliciting a few preferences from the trial sponsor, one can construct promising zone designs that are both intuitive and achieve the Jennison and Turnbull (2015) gold-standard for optimality.

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 >1.3 for a one-sided 97.5% confidence limit of the hazard ratio (HR) for CV composite events during treatment with fasiglifam compared with placebo. The primary outcome was the time to first occurrence of any component of the major adverse CV event composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for unstable angina. RESULTS: The study enrolled 3,207 participants but was terminated because of liver safety concerns. Increased rates of liver enzyme elevation (AST/ALT ≥3-5 × upper limit of normal [ULN]) with fasiglifam were observed. The incidence of ALT or AST ≥3 × ULN with fasiglifam compared with placebo was 2.1% vs. 0.5%, P < 0.001, and the incidence for ≥10 × ULN was 0.31% vs. 0.06%, P < 0.001. A primary CV composite outcome occurred in 40 participants, 2.5% each in the fasiglifam and placebo arms at 12 months (HR 1.05; 95% CI 0.67, 1.63). CONCLUSIONS: Development of fasiglifam was terminated due to concerns of drug-induced liver injury. Performance of a U.S. Food and Drug Administration-mandated CV outcomes trial supported the termination of the fasiglifam clinical program.

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. RESULTS: We determined that the shortest mean distances of the femoral nerve, artery and vein from the hip joint are 23.62 (standard deviation, SD = 5.44), 19.62 (SD = 4.17) and 17.47 (SD = 4.41) mm, respectively. The femoral nerve was lateral to the hip joint in 30 (55.5%) left- and 37 (60.7%) right-sided hip joints. The femoral artery was located medial to the hip joint in 28 (51.9%) left- and 34 (55.7%) right-sided hips. The femoral vein was medial to the hip joint in 52 (96.3%) left- and 58 (95.1%) right-sided hips. CONCLUSION: We have identified objective relationships between the hip joint and femoral neurovascular bundle that can be used with ease intraoperatively during THR. Our data show that patients with a low body weight and the elderly may be at a higher risk of iatrogenic injury due to increased proximity of the neurovascular structures to the hip. Application of this knowledge may serve to reduce the risk of iatrogenic injury to these structures and thereby improve patient satisfaction and outcomes.

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. To better understand and describe the CV safety of alogliptin, we analyzed data from the EXAMINE trial to determine whether treatment with alogliptin affected recurrent and total CV events. Poisson regression analysis compared the total number of occurrences of CV death, MI, stroke, unstable angina, and coronary revascularization between all patients randomized to alogliptin vs placebo groups. Patients with recurrent CV events were older and more likely to have renal disease and history of heart failure. There were 1100 first CV events and an additional 666 recurrent events over a median of 18 months of follow-up. There were no significant differences with regard to total number of events in patients treated with alogliptin (n = 873) or placebo (n = 893; P = 0.52). Furthermore, there were no differences in the types of events seen in patients treated with alogliptin or placebo. Alogliptin did not increase the risk of either first or recurrent CV events when compared with placebo in patients with T2DM and recent acute coronary syndrome. These data support the CV safety of alogliptin in patients who are at increased risk of future CV events.

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. In this article, we greatly extend the previous results to multiple (K>2) looks. If the familywise error rate (FWER) is to be controlled at a preassigned α level then it is clear that the primary boundary must be of level α. We show under what conditions one α-level primary boundary is uniformly more powerful than another. Based on this result, we recommend the choice of the O'Brien and Fleming (1979) boundary over the Pocock (1977) boundary for the primary endpoint. For the secondary endpoint the choice of the boundary is more complicated since under certain conditions the secondary boundary can be refined to have a nominal level α'>α, while still controlling the FWER at level α, thus boosting the secondary power. We carry out secondary power comparisons via simulation between different choices of primary-secondary boundary combinations. The methodology is applied to the data from the RALES study (Pitt et al., 1999; Wittes et al., 2001). An R library package gsrsb to implement the proposed methodology is made available on CRAN.

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. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication: "32%" in the previous sentence was corrected to "38%"]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate.

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 6.5% and 11% (or between 7% and 11% if they were on insulin), and a recent acute coronary syndrome (between 15 and 90 days before randomization) were eligible for the trial. hsTnI was measured using the Abbott ARCHITECT assay at baseline and 6 months in patients randomized in the EXAMINE trial. This analysis was restricted to patients randomized ≥30 days after qualifying acute coronary syndrome to mitigate the potential for persistent hsTnI elevation after acute coronary syndrome (n=3808). The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. Cardiovascular death or heart failure was a prespecified, adjudicated secondary end point. RESULTS: At baseline, hsTnI was detectable (≥1.9 ng/L) in 93% of patients and >99th percentile upper reference limit in 16%. There was a strong relationship between increasing hsTnI, both at baseline and 6 months, and the incidence of cardiovascular events through 24 months (P<0.001 for each). Patients with undetectable hsTnI at baseline and 6 months were at the lowest risk of future cardiovascular events. Stable patients with hsTnI ≥99th percentile upper reference limit at 6 months were at increased risk of cardiovascular death, myocardial infarction, or stroke compared with patients with hsTnI <99 percentile upper reference limit irrespective of whether hsTnI was newly elevated (28.1% versus 8.8%; adjusted hazard ratio, 2.65; 95% confidence interval, 1.64-4.28; P<0.001) or persistently so (22.5% versus 8.8%; adjusted hazard ratio, 1.90; 95% confidence interval, 1.33-2.70; P<0.001). Alogliptin neither increased nor decreased the risk of cardiovascular events compared with placebo in patients with high baseline hsTnI (22.3% versus 23.0%; hazard ratio, 0.87; 95% confidence interval, 0.60-1.25; P=0.44). CONCLUSIONS: Serial assessment of hsTnI revealed a substantial proportion of patients with type 2 diabetes mellitus without clinically recognized events had dynamic or persistently elevated values and were at high risk of recurrent events. hsTnI may have a role in personalizing preventive strategies in patients with diabetes mellitus based on risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00968708.

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. RESULTS: Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (Pinteraction = 0.971) or HbA1c category at 1 month. Patients in the combined treatment groups (n = 5380) who experienced serious hypoglycaemia (n = 34) had higher MACE rates than those who did not (35.3% vs 11.4%, adjusted hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.27-4.60; P = .007), although the association was less strong when analysing only events after the hypoglycaemic event (adjusted HR 1.60, 95% CI 0.80, 3.20). CONCLUSIONS: There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

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. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors.

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. Patients were monitored until censoring or death, regardless of a prior postrandomized nonfatal CV event. Time-updated multivariable Cox models were used to estimate the risk of death in the absence of or after each nonfatal event. RESULTS: Rates of CV death were 4.1% for alogliptin and 4.9% for placebo (hazard ratio [HR] 0.85; 95% CI 0.66, 1.10). A total of 736 patients (13.7%) experienced a first nonfatal CV event (5.9% MI, 1.1% stroke, 3.0% HHF, and 3.8% UA). Compared with patients not experiencing a nonfatal event, the adjusted HR (95% CI) for death was 3.12 after MI (2.13, 4.58; P < 0.0001) 4.96 after HHF (3.29, 7.47; P < 0.0001), 3.08 after stroke (1.29, 7.37; P = 0.011), and 1.66 after UA (0.81, 3.37; P = 0.164). Mortality rates after a nonfatal event were comparable for alogliptin and placebo. CONCLUSIONS: In patients with type 2 diabetes and a recent ACS, the risk of CV death was higher after a postrandomization, nonfatal CV event, particularly heart failure, compared with those who did not experience a CV event. The risk of CV death was similar between alogliptin and placebo.

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. METHODS: Patients with T2DM and an ACS event in the previous 15 to 90 days were randomly assigned to alogliptin or placebo on a background of standard treatment for diabetes. The incident rates of a 5-component composite end point of CV death, stroke, myocardial infarction, unstable angina, and coronary revascularization as well as CV hospitalization were calculated in all participants and according to macrovascular disease at baseline. RESULTS: There were no significant differences between alogliptin (n = 2,701) and placebo (n = 2,679) in the event rate of the 5-component composite endpoint with median follow-up 533 days (21.0% vs 21.5%, hazard ratio [HR] 0.98 [0.87-1.10], P = .72). No differences were observed in terms of CV hospitalization (25.0% vs 25.4%, HR 0.98 [0.88-1.09], P = .70) or coronary revascularization (10.6% vs 10.2%, HR 1.05 [0.88-1.09], P = .60). No interactions were observed for treatment and prior macrovascular disease. CONCLUSIONS: EXAMINE demonstrates that there was no increase in the risk of cardiac ischemic events and CV hospitalizations with alogliptin in a high-risk post-ACS patient population. Because these are major driver of overall health care costs, these data suggest that there would be no adverse impact on health care resource utilization.

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. METHODS: Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15-90 days were randomly assigned alogliptin or placebo plus standard treatment for diabetes and cardiovascular disease prevention. The prespecified exploratory extended MACE endpoint was all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, urgent revascularisation due to unstable angina, and hospital admission for heart failure. The post-hoc analyses were of cardiovascular death and hospital admission for heart failure, assessed by history of heart failure and brain natriuretic peptide (BNP) concentration at baseline. We also assessed changes in N-terminal pro-BNP (NT-pro-BNP) from baseline to 6 months. This study is registered with ClinicalTrials.gov, number NCT00968708. FINDINGS: 5380 patients were assigned to alogliptin (n=2701) or placebo (n=2679) and followed up for a median of 533 days (IQR 280-751). The exploratory extended MACE endpoint was seen in 433 (16·0%) patients assigned to alogliptin and in 441 (16·5%) assigned to placebo (hazard ratio [HR] 0·98, 95% CI 0·86-1·12). Hospital admission for heart failure was the first event in 85 (3·1%) patients taking alogliptin compared with 79 (2·9%) taking placebo (HR 1·07, 95% CI 0·79-1·46). Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis (HR 1·00, 95% CI 0·82-1·21) and results did not differ by baseline BNP concentration. NT-pro-BNP concentrations decreased significantly and similarly in the two groups. INTERPRETATION: In patients with type 2 diabetes and recent acute coronary syndromes, alogliptin did not increase the risk of heart failure outcomes. FUNDING: Takeda Development Center Americas.

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). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

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. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo. CONCLUSIONS: Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).

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. We further show that the secondary boundary can be sharpened in this case by taking the unknown correlation coefficient ρ between the primary and secondary endpoints into account through the use of the confidence limit method proposed in part I of this paper. If we use the sufficient statistics instead of the CHW statistics, then we need to modify both the primary and secondary boundaries; otherwise, the error rate can get inflated. We show how to modify the boundaries of the original group sequential procedure to control the familywise error rate. We provide power comparisons between competing procedures. We illustrate the procedures with a clinical trial example.

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. Under the latter assumption, we computed the critical boundaries of an exact GSP. However, neither assumption is very practical. The ρ = 1 assumption is too conservative resulting in loss of power, whereas the known ρ assumption is never true in practice. In this part I of a two-part paper on adaptive extensions of this two-stage procedure (part II deals with sample size re-estimation), we propose an intermediate approach that uses the sample correlation coefficient r from the first-stage data to adaptively adjust the secondary boundary after accounting for the sampling error in r via an upper confidence limit on ρ by using a method due to Berger and Boos. We show via simulation that this approach achieves 5-11% absolute secondary power gain for ρ ≤0.5. The preferred boundary combination in terms of high primary as well as secondary power is that of O'Brien and Fleming for the primary and of Pocock for the secondary. The proposed approach using this boundary combination achieves 72-84% relative secondary power gain (with respect to the exact GSP that assumes known ρ). We give a clinical trial example to illustrate the proposed procedure.