The Problem of Subgroup Analyses: An Example from a Trial on Ruptured Intracranial Aneurysms

Naggara, Olivier; Raymond, Jean; Guilbert, F; Altman, Doug

doi:10.3174/ajnr.a2442

Cited by 34 publications

(22 citation statements)

References 28 publications

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“…The 6 trials included in this patient‐level pooled analysis were not originally planned to investigate outcomes in women. Female patients represent a subgroup and our study therefore has intrinsic limitations of subgroup analyses . Subgroup analyses are fundamentally underpowered and should be considered hypothesis generating only.…”

Section: Discussionmentioning

confidence: 98%

Short‐versus long‐term Dual Antiplatelet therapy after drug‐eluting stent implantation in women versus men: A sex‐specific patient‐level pooled‐analysis of six randomized trials

Sawaya

Morice

Spaziano

et al. 2016

Cathet Cardio Intervent

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Section: Discussionmentioning

confidence: 98%

Short‐versus long‐term Dual Antiplatelet therapy after drug‐eluting stent implantation in women versus men: A sex‐specific patient‐level pooled‐analysis of six randomized trials

Sawaya

Morice

Spaziano

et al. 2016

Cathet Cardio Intervent

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“…However, given that only 292 of the 814 strains assayed were BI/NAP1/PCR ribotype 027, even the combined dataset is underpowered to conclude that fidaxomicin has no beneficial effect for treating BI/NAP1/PCR ribotype 027 strains, which was suggested in the previously reported mITT and per-protocol analyses [17]. The perils of concluding lack of benefit in underpowered subgroups of patients are well recognized in the medical literature [25, 26]. …”

Section: Discussionmentioning

confidence: 99%

Fidaxomicin Versus Vancomycin for Clostridium difficile Infection: Meta-analysis of Pivotal Randomized Controlled Trials

Crook

Walker

Kean

et al. 2012

Clinical Infectious Diseases

232

176

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Two recently completed phase 3 trials (003 and 004) showed fidaxomicin to be noninferior to vancomycin for curing Clostridium difficile infection (CDI) and superior for reducing CDI recurrences. In both studies, adults with active CDI were randomized to receive blinded fidaxomicin 200 mg twice daily or vancomycin 125 mg 4 times a day for 10 days. Post hoc exploratory intent-to-treat (ITT) time-to-event analyses were undertaken on the combined study 003 and 004 data, using fixed-effects meta-analysis and Cox regression models. ITT analysis of the combined 003/004 data for 1164 patients showed that fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval [CI], 26%–51%; P < .0001) compared with vancomycin through day 40. A 37% (95% CI, 2%–60%; P = .037) reduction in persistent diarrhea or death was evident through day 12 (heterogeneity P = .50 vs 13–40 days), driven by 7 (1.2%) fidaxomicin versus 17 (2.9%) vancomycin deaths at <12 days. Low albumin level, low eosinophil count, and CDI treatment preenrollment were risk factors for persistent diarrhea or death at 12 days, and CDI in the previous 3 months was a risk factor for recurrence (all P < .01). Fidaxomicin has the potential to substantially improve outcomes from CDI.

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“…Subgroup analyses are notoriously potentially misleading [32], however, they can be used to help formulate hypotheses for a new trial, especially when there are a priori reasons to suspect that results in certain subgroups may differ from the overall results.…”

Section: Discussionmentioning

confidence: 99%

International subarachnoid aneurysm trial – ISAT Part II: Study protocol for a randomized controlled trial

Darsaut

Jack

Kerr

et al. 2013

Trials

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BackgroundThe International Subarachnoid Aneurysm Trial (ISAT) demonstrated improved one-year clinical outcomes for patients with ruptured intracranial aneurysms treated with endovascular coiling compared to surgical clipping. Patients included in ISAT were mostly good grade subarachnoid hemorrhage (SAH) patients with small anterior circulation aneurysms. The purported superiority of coiling is commonly extrapolated to patients not studied in the original trial or to those treated using new devices not available at the time. Conversely, many patients are treated by clipping despite ISAT, because they are thought either to be better candidates for surgery, or to offer more durable protection from aneurysm recurrences. These practices have never been formally validated. Thus, for many ruptured aneurysm patients the question of which treatment modality leads to a superior clinical outcome remains unclear.Methods/trial designISAT II is a pragmatic, multicenter, randomized trial comparing clinical outcomes for non-ISAT patients with subarachnoid hemorrhage allocated to coiling or clipping. Inclusion criteria are broad. The primary end-point is the incidence of poor clinical outcome (defined as mRS >2) at one year, just as in ISAT. Secondary end-points include measures of treatment safety for a number of pre-specified subgroups, with efficacy end-points including the presence of a major recurrence at one year; 1,896 patients (862 each arm plus 10% losses) are required to demonstrate a significant difference between coiling and clipping, hypothesizing 23% and 30% poor clinical outcome rates, for coiling and clipping, respectively. The trial should involve at least 50 international centers, and will take approximately 12 years to complete. Analysis will be by intention-to-treat.Trial registrationISAT II is registered at clinicaltrials.gov: NCT01668563.

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The Problem of Subgroup Analyses: An Example from a Trial on Ruptured Intracranial Aneurysms

Cited by 34 publications

References 28 publications

Short‐versus long‐term Dual Antiplatelet therapy after drug‐eluting stent implantation in women versus men: A sex‐specific patient‐level pooled‐analysis of six randomized trials

Short‐versus long‐term Dual Antiplatelet therapy after drug‐eluting stent implantation in women versus men: A sex‐specific patient‐level pooled‐analysis of six randomized trials

Fidaxomicin Versus Vancomycin for Clostridium difficile Infection: Meta-analysis of Pivotal Randomized Controlled Trials

International subarachnoid aneurysm trial – ISAT Part II: Study protocol for a randomized controlled trial

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