Adjusted inference for multiple testing procedure in group sequential designs

Adjustment of statistical significance levels for repeated analysis in group sequential trials has been understood for some time. Similarly, methods for adjustment accounting for testing multiple hypotheses are common. There is limited research on simultaneously adjusting for both multiple hypothesis testing and multiple analyses of one or more hypotheses. We address this gap by proposing adjusted-sequential p-values that reject an elementary hypothesis when its adjusted-sequential p-values are less than or equal to the family-wise Type I error rate (FWER) in a group sequential design. We also propose sequential p-values for intersection hypotheses as a tool to compute adjusted sequential p-values for elementary hypotheses. We demonstrate the application using weighted Bonferroni tests and weighted parametric tests, comparing adjusted sequential p-values to a desired FWER for inference on each elementary hypothesis tested

Evidence for Prevention of Death and Myocardial Infarction With Platelet Membrane Glycoprotein IIb/IIIa Receptor Blockade by Abciximab (c7E3 Fab) Among Patients With Unstable Angina Undergoing Percutaneous Coronary Revascularization fn1fn1This study was supported by Centocor, Inc., Malvern, Pennsylvania.

AbstractObjectives. We sought to evaluate whether patients with unstable angina undergoing coronary intervention derive particular clinical benefit from potent platelet inhibition.Background. Plaque rupture and platelet aggregation are pathogenetic processes common to unstable angina and ischemic complications of percutaneous coronary intervention.Methods. Of the 2,099 patients undergoing a coronary intervention in the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial, 489 were enrolled with the diagnosis of unstable angina and randomized to receive placebo, an abciximab (c7E3) bolus immediately before the intervention or an abciximab bolus followed by a 12-h infusion. The primary end point was a composite of death, myocardial infarction (MI) or urgent repeat revascularization within 30 days of randomization. The occurrence of death, MI or any revascularization within 6 months was also assessed.Results. Compared with placebo, the bolus and infusion of abciximab resulted in a 62% reduction in the rate of the primary end point (12.8% vs. 4.8%, p = 0.012) among patients with unstable angina, due primarily to a reduction in the incidences of death (3.2% vs. 1.2%, p = 0.164) and MI (9% vs. 1.8%, p = 0.004). By 6 months, cumulative death and MI were further reduced by abciximab (6.6% vs. 1.8%, p = 0.018 and 11.1% vs. 2.4%, p = 0.002, respectively). The magnitude of the risk reduction with abciximab was greater among the patients with unstable angina than among other patients in the EPIC trial without unstable angina for the end points of death (interaction: p = 0.008 at 30 days, p = 0.002 at 6 months) and MI (interaction: p = 0.004 at 30 days, p = 0.003 at 6 months).Conclusions. The syndrome of unstable angina identifies patients who will experience particularly marked reductions in the risk of death and MI with abciximab during coronary intervention.(J Am Coll Cardiol 1997;30:149–56

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Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease

AbstractThe prevalence of abnormalities of lipoprotein cholesterol and apolipoproteins A-I and B and lipoprotein (a) [Lp(a)] was determined in 321 men (mean age 50 ± 7 years) with angiographically documented coronary artery disease and compared with that in 901 control subjects from the Framingham Offspring Study (mean age 49 ± 6 years) who were clinically free of coronary artery disease. After correction for sampling in hospital, beta-adrenergic medication use and effects of diet, patients had significantly higher cholesterol levels (224 ± 53 vs. 214 ± 36 mg/dl), triglycerides (189 ± 95 vs. 141 +- 104 mg/dl), low density lipoprotein (LDL) cholesterol (156 ± 51 vs. 138 ± 33 mg/dl), apolipoprotein B (131 ± 37 vs. 108 ± 33 mg/dl) and Lp(a) levels (19.9 ± 19 vs. 14.9 ± 17.5 mg/dl). They also had significantly lower high density lipoprotein (HDL) cholesterol (36 ± 11 vs. 45 ± 12 mg/dl) and apolipoprotein A-I levels (114 ± 26 vs. 136 ± 32 mg/dl) (all p < 0.005).On the basis of Lipid Research Clinic 90th percentile values for triglycerides and LDL cholesterol and 10th percentile values for HDL cholesterol, the most frequent dyslipidemias were low HDL cholesterol alone (19.3% vs. 4.4%), elevated LDL cholesterol (12.1% vs. 9%), hypertriglyceridemia with low HDL cholesterol (9.7% vs. 4.2%), hypertriglyceridemia and elevated LDL cholesterol with low HDL cholesterol (3.4% vs. 0.2%) and Lp(a) excess (15.8% vs. 10%) in patients versus control subjects, respectively (p < 0.05). Stepwise discriminant analysis indicates that smoking, hypertension, decreased apolipoprotein A-I, increased apolipoprotein B, increased Lp(a) and diabetes are all significant (p < 0.05) factors in descending order of importance in distinguishing patients with coronary artery disease from normal control subjects.Not applying a correction for beta-adrenergic blocking agents, sampling bias and diet effects leads to a serious underestimation of the prevalence of LDL abnormalities and an overestimation of HDL abnormalities in patients with coronary artery disease. However, 35% of patients had a total cholesterol level <200 mg/dl after correction; of those patients, 73% had an HDL cholesterol level <35 mg/dl