Familywise error for multiple time-to-event endpoints in a group sequential design.

We investigate the familywise error rate (FWER) for time-to-event endpoints evaluated using a group sequential design with a hierarchical testing procedure for secondary endpoints. We show that, in this setup, the correlation between the log-rank test statistics at interim and at end of study is not congruent with the canonical correlation derived for normal-distributed endpoints. We show, both theoretically and by simulation, that the correlation also depends on the level of censoring, the hazard rates of the endpoints, and the hazard ratio. To optimize operating characteristics in this complex scenario, we propose a simulation-based method to assess the FWER which, better than the alpha-spending approach, can inform the choice of critical values for testing secondary endpoints.

Glucose-lowering effect of insulin degludec is independent of subcutaneous injection region.

BACKGROUND AND OBJECTIVES: Patients with diabetes mellitus inject insulin in different regions of the body. This study investigated the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a new-generation once-daily basal insulin with an ultra-long duration of action, after subcutaneous (SC) administration in different injection regions. METHODS: In this study, 20 healthy subjects received single SC doses of IDeg (0.4 U/kg; separated by 13-21 days) in the thigh, abdomen and deltoid in a randomised, open-label, single-centre, single-dose, complete crossover trial. Each dose was followed by a 24-h euglycaemic clamp and 120-h pharmacokinetic blood sampling. The obtained pharmacokinetic/pharmacodynamic profiles were extrapolated to steady state by simulation using a pharmacokinetic/pharmacodynamic model. RESULTS: Total IDeg exposure [area under the IDeg serum concentration-time curve 0-120 h after a single dose (AUCIDeg,0-120h,SD)] and maximum serum concentration [maximum IDeg serum concentration after a single dose (C max,IDeg,SD)] were higher (6-7 and 23-27 %, respectively) following a single SC dose in the deltoid or abdomen, compared with the thigh, as also observed with other insulin preparations. No statistical difference was observed in these measures between deltoid and abdominal administration. No pronounced differences were observed in the glucose-lowering effect of IDeg [area under the glucose infusion rate (GIR) curve 0-24 h after a single dose (AUCGIR,0-24h,SD) and maximum GIR after a single dose (GIRmax,SD)] when injected in the thigh, abdomen or deltoid (AUCGIR,0-24h,SD 2,572, 2,833 and 2,960 mg/kg, respectively). Simulated mean steady-state pharmacokinetic and pharmacodynamic profiles supported a flat and stable IDeg exposure and effect regardless of injection region, with comparable total glucose-lowering effects [area under the GIR curve at steady state (AUCGIR,τ,SS)] between the thigh, abdomen and deltoid. CONCLUSIONS: These findings support administering IDeg SC in the thigh, upper arm or abdominal wall without affecting IDeg absorption or effect at steady state.

Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: insights from a patient-level pooled analysis of six randomized clinical trials.

AIMS: To quantify the effect of liraglutide on systolic blood pressure (SBP) and pulse in patients with type 2 diabetes (T2D), and assess the influence of covariates on observed SBP reductions. METHODS: A patient-level pooled analysis of six phase 3, randomized trials was conducted. RESULTS: The analysis included 2792 randomized patients. In the intention-to-treat population (n=2783), mean [±SE] SBP reductions from baseline with liraglutide 1.2 mg (2.7 [0.8] mmHg) and 1.8 mg (2.9 [0.7] mmHg) once daily were significantly greater than with placebo (0.5 [0.9] mmHg; P=0.0029 and P=0.0004, respectively) after 26 weeks, and were evident after 2 weeks. Liraglutide was also associated with significantly greater SBP reductions than glimepiride and, at a dose of 1.8 mg, insulin glargine and rosiglitazone. SBP reductions with liraglutide weakly correlated with weight loss (Pearson's correlation coefficient: 0.08-0.12; P≤0.0148). No dependence of these reductions on concomitant antihypertensive medications was detected (P=0.1304). Liraglutide 1.2 and 1.8 mg were associated with mean increases in pulse of 3 beats per minute (bpm), versus a 1 bpm increase with placebo (P<0.0001 for each dose versus placebo). CONCLUSIONS: Liraglutide reduces SBP in patients with T2D, including those receiving concomitant antihypertensive medication.

Pharmacokinetic and pharmacodynamic responses of insulin degludec in African American, white, and Hispanic/Latino patients with type 2 diabetes mellitus.

BACKGROUND: Pharmacokinetic and pharmacodynamic profiles of exogenous insulin may be affected by intrinsic factors, such as age, ethnicity/race, and hepatic and renal function. Insulin degludec (IDeg) is a basal insulin with an ultralong duration of action and a flat and stable glucose-lowering effect profile. OBJECTIVE: The purpose of this study was to investigate whether the pharmacokinetic and pharmacodynamic responses to IDeg at steady state vary according to patient race/ethnicity. METHODS: This randomized, single-center, double-blind, 2-period crossover trial investigated responses to IDeg in 59 patients with type 2 diabetes mellitus from 3 groups: African American, Hispanic/Latino, and white. Patients were allocated randomly to a sequence of 2 treatment periods, separated by a 7- to 21-day washout period, with once-daily IDeg or insulin detemir dosing for 6 days at a predefined fixed dose level (0.6 U/kg). Differences in pharmacokinetic and pharmacodynamic variables among groups were analyzed using an ANOVA with treatment period, an interaction between race/ethnicity, and treatment as fixed factors, subject as a random effect, and residual variance, depending on treatment. RESULTS: Total exposure to IDeg during one dosing interval at steady state (AUCIDeg,τ,SS) was similar among the racial/ethnic groups (ratio [95% CI]: African American vs white, 1.10 [0.91-1.31]; African American vs Hispanic/Latino, 1.13 [0.95-1.34]; and Hispanic/Latino vs white, 0.97 [0.82-1.16]). The total glucose-lowering effect of IDeg (AUCGIR,τ,SS) was also similar among the groups, with no statistically significant difference in pairwise comparisons (1940, 1735, and 2286 mg/kg in African American, white, and Hispanic/Latino patients, respectively). Steady state was reached in all groups after 2 to 3 days of dosing. In all groups, both exposure and glucose-lowering effect for IDeg were evenly distributed between the first and second 12 hours of the 24-hour dosing interval at steady state (mean AUCIDeg,0-12h,SS/AUCIDeg,τ,SS = 53%-54%; AUCGIR,0--12h,SS/AUCGIR,τ,SS = 47%-52%). CONCLUSION: The similar pharmacokinetic and pharmacodynamic responses to IDeg in 3 racial/ethnic groups of patients with type 2 diabetes mellitus suggest that the flat, stable, and ultralong pharmacokinetic and pharmacodynamic profiles of IDeg are preserved irrespective of race/ethnicity. Although insulin doses must be adjusted on an individual basis, similar pharmacokinetic and pharmacodynamic responses to IDeg are observed in patients with differing race/ethnicity.

Once-daily initiation with biphasic insulin aspart 30 versus insulin glargine in patients with type 2 diabetes inadequately controlled with oral drugs: an open-label, multinational RCT.

OBJECTIVES: To assess the efficacy and safety of biphasic insulin aspart 70/30 (BIAsp 30) and insulin glargine, administered once daily in subjects with type 2 diabetes inadequately controlled with oral anti-diabetic drugs. RESEARCH DESIGN AND METHODS: In this 26-week, open-labeled, randomized, parallel-group, multinational, treat-to-target trial, 480 insulin-naïve subjects were randomized to receive either BIAsp 30 before dinner or insulin glargine at bedtime, both in combination with metformin and glimepiride. TRIAL REGISTRATION: NCT00469092, ClinicalTrials.gov. RESULTS: A total of 433 subjects completed the trial. Estimated mean reduction in HbA(1c) from baseline to end of treatment was -1.41% with BIAsp 30 and -1.25% with insulin glargine (BIAsp 30 - insulin glargine = -0.16%, 95% CI [-0.30; -0.02], p = 0.029). At the end of treatment, mean HbA(1c) was 7.1% and 7.3% for BIAsp 30 and insulin glargine, respectively. Significantly lower plasma glucose levels were observed with BIAsp 30 post-dinner (BIAsp 30 - insulin glargine = -0.52 mmol/L, 95% CI [-1.02; -0.03], p = 0.04) and at bedtime (BIAsp 30 - insulin glargine = -0.78 mmol/L, 95% CI [-1.25; -0.31], p < 0.01). The relative risk (RR) of experiencing a nocturnal hypoglycemic episode (00:00-06.00 a.m.) was significantly higher with BIAsp 30 than with insulin glargine (1.1 versus 0.5 episodes/year, RR = 2.41, 95% CI [1.34; 4.34], p = 0.003), but overall hypoglycemia rates were low. There were three major hypoglycemic episodes in each group. CONCLUSIONS: With respect to HbA(1c), BIAsp 30 fulfilled the statistical criteria for non-inferiority and superiority to insulin glargine and, according to pre-defined criteria, the improvements in HbA(1c) are considered clinically equivalent. Subjects had an increased risk of minor nocturnal hypoglycemia with BIAsp 30. There were no differences in treatment satisfaction between the two groups.

Risk of cholecystitis in patients with cancer: a population-based cohort study in Denmark.

BACKGROUND: To the authors' knowledge, little information is available regarding the incidence of cholecystitis among patients with cancer. METHODS: The authors conducted a population-based historical cohort study of 51,228 patients with incident cancer, identified in medical databases of western Denmark between 1995 and 2003. A general population comparison cohort of 512,280 persons was assembled using the Danish Civil Registration System. The occurrence of cholecystitis in the 2 groups was determined by linkage to the regional Hospital Discharge Registry. RESULTS: In all, 230 incident diagnoses of cholecystitis were identified in the cancer cohort during 130,185 person-years (median follow-up time: 1.6 years), corresponding to an incidence rate of 1.8 of 1000 person-years. After adjustment for confounders, the relative risk (RR) for cholecystitis among cancer patients compared with the general population cohort was 1.38 (95% confidence interval [95% CI], 1.20-1.58). Overall, the RR for cholecystitis was doubled during the first 6 months after cancer diagnosis (RR = 1.95; 95% CI, 1.50-2.54), after which the RR declined but remained greater than 1 throughout the rest of the follow-up period (RR = 1.23; 95% CI, 1.05-1.45). Cancer patients between the ages of 51 and 70 years had the highest risk increase for cholecystitis compared with other age groups. During the first 6 months after a cancer diagnosis, pancreatic cancers (12 cholecystitis events; RR = 9.44 [95% CI, 5.18-17.18]) and colorectal cancers (10 cholecystitis events; RR = 4.98 [95% CI, 2.65-9.34]) were found to be associated with the greatest cholecystitis risk increase compared with other tumor types. After 6 months, most cancers were associated with a relatively small increased risk, although there was an RR of 4.72 (95% CI, 1.99-11.21) based on 5 cholecystitis events among thyroid cancer patients. CONCLUSIONS: The results of the current study indicate that cholecystitis occurs more frequently among cancer patients than in the general population, particularly within the first 6 months after a cancer diagnosis. Clinicians who treat cancer patients should remain vigilant about this type of infection.

Low-dose aspirin may prevent growth and later surgical repair of medium-sized abdominal aortic aneurysms.

Experimental data suggest that aspirin-induced platelet inhibition may retard growth of abdominal aortic aneurysms. In this article, whether low-dose aspirin use is associated with reduced aneurysm progression and subsequent need for surgery is examined. In this observational cohort study within a screening trial, 148 patients with small aneurysms (maximum diameter 30-48 mm) annually are followed. Patients were referred for surgery when the aneurysmal diameter exceeded 50 mm. Median follow-up time was 6.6 years. Among patients whose abdominal aortic aneurysms were initially 40 to 49 mm in size, the abdominal aortic aneurysm expansion rate for low-dose aspirin users compared with nonusers was 2.92 mm/y versus 5.18 mm/y (difference 2.27 mm/y, 95% CI, 0.42-4.11). No difference in expansion rates and risk ratios for operative repair was found for patients with abdominal aortic aneurysms <40 mm. For medium-sized abdominal aortic aneurysms, low-dose aspirin may prevent abdominal aortic aneurysm growth and need for subsequent repair, but residual confounding cannot be excluded.

Amiodarone protects diabetics and non-diabetics undergoing coronary artery bypass grafting equally.

OBJECTIVE: To evaluate amiodarone prophylaxis in diabetics and non-diabetics. Further to clarify whether the risk of developing atrial fibrillation is higher for diabetics than non-diabetic patients, and to evaluate whether the diabetic status has any influence on the length of in-hospital stay. DESIGN: Subgroup analysis within a randomized, controlled, double-blinded trial. RESULTS: At 30 days of follow-up atrial fibrillation was equally frequent among diabetics (22%) and non-diabetics (17%) (p =0.41). The length of in-hospital stay for diabetics was prolonged with 25% (9%; 45%). The prophylactic amiodarone was found equally efficient in diabetics and non-diabetics, as the relative risk ratios were 1.2 (0.4-5.4) and 2.0 (0.3-12.5), respectively. CONCLUSIONS: Diabetics and non-diabetics had the same effect of the amiodarone prophylaxis regime. Atrial fibrillation developed equally among diabetics and non-diabetics, but the length of stay was prolonged for diabetics.

Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study.

BACKGROUND: There are concerns about highly active antiretroviral therapy (HAART) causing a progressive increase in the risk of ischemic heart disease. We examined this issue in a nationwide cohort study of patients with human immunodeficiency virus (HIV) infection and a population-based control group. METHODS: We determined the rate of first hospitalization for ischemic heart disease in all Danish patients with HIV infection (3953 patients) from 1 January 1995 through 31 December 2004 and compared this rate with that for 373,856 subjects in a population-based control group. Data on first hospitalization for ischemic heart disease and comorbidity were obtained from the Danish National Hospital Registry for all study participants. We used Cox's regression to compute the hospitalization rate ratio as an estimate of relative risk, adjusting for comorbidity. RESULTS: Although the difference was not statistically significant, patients with HIV infection who had not initiated HAART were slightly more likely to be hospitalized for the first time with ischemic heart disease than were control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.81-2.33). After HAART initiation, the risk increase became substantially higher (adjusted relative risk, 2.12; 95% confidence interval, 1.62-2.76), but the relative risk did not further increase in the initial 8 years of HAART. CONCLUSIONS: Compared with the general population, HIV-infected patients receiving HAART have an increased risk of ischemic heart disease, but the relative risk is stable up to 8 years after treatment initiation.

Practical regimen for amiodarone use in preventing postoperative atrial fibrillation.

BACKGROUND: Postoperative atrial fibrillation occurs in 5% to 65% of patients undergoing cardiac surgery. Although postoperative atrial fibrillation is often regarded as a temporary, benign, operation-related problem, it is associated with a twofold to threefold increase in risk of adverse events, including permanent or transient stroke, acute myocardial infarction, and death. METHODS: This randomized, controlled, double-blinded trial included 250 eligible consecutively enrolled patients undergoing coronary artery bypass grafting (CABG). They received 300 mg of amiodarone/placebo administered intravenously over 20 minutes on the first postoperative day and an oral dose of 600 mg of amiodarone or placebo twice daily for the first 5 postoperative days. RESULTS: The patients in amiodarone prophylaxis experienced a reduction in risk of atrial fibrillation of 14% (95% confidence interval [CI], 5.0% to 24%), with the number needed to treat at 6.9 (95% CI, 4.2 to 20), and the results for symptomatic atrial fibrillation showed a risk reduction of 18% (95% CI, 9.4% to 26), with the number needed to treat at 5.7 (95% CI, 3.9 to 11). Of the patients who developed atrial fibrillation in the placebo group, 84% experienced a symptomatic attack versus only 43% in the amiodarone group. CONCLUSIONS: Postoperative prophylaxis with a high dose of oral amiodarone after an intravenous bolus infusion is a safe, practical, feasible, and effective regimen for CABG patients. It significantly diminishes the occurrence of postoperative atrial fibrillation.

Overnight versus 24 hours of continuous subcutaneous insulin infusion as supplement to oral antidiabetic drugs in type 2 diabetes.

BACKGROUND: Basal continuous subcutaneous insulin infusion (CSII) therapy at a fixed rate may effectively improve glycemic control in patients with type 2 diabetes when oral antidiabetic treatment fails. Regimens of simple constant subcutaneous delivery of insulin may provide theoretical advantages in type 2 diabetes. METHODS: Ten subjects with type 2 diabetes who obtained insufficient glycemic control on oral antidiabetic drugs were included. Following an initial control day, two periods of 3 days with CSII of a rapid-acting insulin analogue, 1.5 IU/h (dose obtained from a preceding study), for 8 hours overnight and for 24 hours, respectively, were carried out in random order. Profiles of serum insulin aspart, serum endogenous insulin, and plasma glucose were recorded. RESULTS: Compared to the control day, an 8-hour overnight insulin infusion during a 3-day period improved fasting plasma glucose (FPG) (mean differences +/- SEM; Delta59.0 +/- 10.1 mg/dl; p < 0.01) and 2-hour postprandial plasma glucose (PPPG) (Delta57.8 +/- 10.6 mg/dl; p < 0.01) after breakfast. Compared to an 8-hour overnight infusion, a 24-hour infusion further improved all three PPPG values after breakfast, lunch, and dinner (Delta28.8 +/- 8.1 mg/dl, Delta30.6 +/- 8.1 mg/dl, and Delta35.1 +/- 7.9 mg/dl; p < 0.01). During insulin infusion, only one hypoglycemic episode with PG <55.8 mg/dl and mild symptoms was recorded. CONCLUSION: Continuous subcutaneous insulin infusion with a rapid-acting insulin analogue at a fixed rate of 1.5 IU/h, either overnight or for 24 hours, improved glycemic control without safety concerns in patients with type 2 diabetes who had secondary failure to oral antidiabetic drugs. The effect on FPG was similar for both treatments, whereas the effect on PPPG was superior when insulin was infused during the entire 24 hours.