Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses

Brok, Jesper; Thorlund, Kristian; Gluud, Christian; Wetterslev, Jørn

doi:10.1016/j.jclinepi.2007.10.007

Cited by 889 publications

(523 citation statements)

References 35 publications

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“…Because no reason exists why the standards for a meta-analysis should be less rigorous than those for a single trial, analogous trial sequential monitoring boundaries can be used. 15,16 The underlying assumption for this analysis is that significance testing is done each time a new trial is published. Trial sequential analysis depends on the quantification of the required information size.…”

Section: Trial Sequential Analysismentioning

confidence: 99%

Perioperative β blockers in patients having non-cardiac surgery: a meta-analysis

Bangalore¹,

Wetterslev²,

Pranesh³

et al. 2008

The Lancet

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328

173

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Section: Trial Sequential Analysismentioning

confidence: 99%

Perioperative β blockers in patients having non-cardiac surgery: a meta-analysis

Bangalore¹,

Wetterslev²,

Pranesh³

et al. 2008

The Lancet

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328

173

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“…The cumulative Z ‐curve crosses the monitoring boundary (red dashed line) before reaching the required information size ( RIS , red vertical line), providing evidence for the superiority of PFO closure over antithrombotic therapy to prevent recurrent stroke 26. CLOSE indicates Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence; CLOSURE I, STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale; DEFENSE‐PFO, Device Closure Versus Medical Therapy for Cryptogenic Stroke Patients With High‐Risk Patent Foramen Ovale; Gore REDUCE, Gore Helex septal occluder and antiplatelet medical management for reduction of recurrent stroke or imaging‐confirmed transient ischemic attack in patients with patent foramen ovale; PC trial, Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism; PFO, patent foramen ovale; RESPECT, Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment.…”

Section: Resultsmentioning

confidence: 98%

“…In the trial sequential analysis (Figure 2), the cumulative Z score curve crossed the monitoring boundary, suggesting a “true‐positive” result regarding the superiority of PFO closure over medical therapy (Figure S1). 26 The HR for stroke recurrence was provided in 5 out of 6 RCTs (pooled HR 0.40, 95% CI, 0.20–0.82, P =0.01; I 2 =54%; Figure 1B) 7, 8, 10, 11, 12. The random‐effects pooled incidence of stroke recurrence per 100 person‐years was 0.29 (95% CI, 0.02–0.76; I 2 =83%) in the PFO closure group (Figure S4) and 1.27 (95% CI, 0.84–1.78; I 2 =53%) in the antithrombotic therapy group (Figure S5).…”

Section: Resultsmentioning

confidence: 99%

“…Briefly, in TSA, a cumulative meta‐analysis of RCTs is similar to several interim analyses of a single RCT, with the construction of specific trial sequential monitoring boundaries by using the Lan–DeMets α spending function approach 15, 16. In the present TSA, the low‐bias heterogeneity‐adjusted information size method was used to determine the required information size 26. A description of the interpretation of the TSA plot to determine whether a given meta‐analysis would correspond to a false‐positive, true‐positive, false‐negative, or true‐positive result is provided in Figure S1.…”

Section: Methodsmentioning

confidence: 99%

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Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta‐Analysis, and New Insights From the CLOSE Study

Turc

Calvet

Guérin

et al. 2018

JAHA

119

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BackgroundWe conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) comparing patent foramen ovale (PFO) closure, anticoagulation, and antiplatelet therapy to prevent stroke recurrence in patients with PFO‐associated cryptogenic stroke.Methods and ResultsWe searched Medline, Cochrane Library, and EMBASE through March 2018. The primary outcome was stroke recurrence. Pooled incidences, hazard ratios, and risk ratios (RRs) were calculated in random‐effects meta‐analyses. PFO closure was associated with a lower risk of recurrent stroke compared with antithrombotic therapy (antiplatelet therapy or anticoagulation: 3560 patients from 6 RCTs; RR=0.36, 95% CI: 0.17–0.79; I2=59%). The effect of PFO closure on stroke recurrence was larger in patients with atrial septal aneurysm or large shunt (RR=0.27, 95% CI, 0.11–0.70; I2=42%) compared with patients without these anatomical features (RR=0.80, 95% CI, 0.43–1.47; I2=12%). Major complications occurred in 2.40% (95% CI, 1.03–4.25; I2=77%) of procedures. New‐onset atrial fibrillation was more frequent in patients randomized to PFO closure versus antithrombotic therapy (RR=4.33, 95% CI, 2.37–7.89; I2=14%). One RCT compared PFO closure versus anticoagulation (353 patients; hazard ratio=0.14, 95% CI, 0.00–1.45) and 2 RCTs compared PFO closure versus antiplatelet therapy (1137 patients; hazard ratio=0.18, 95% CI, 0.05–0.63; I2=12%). Three RCTs compared anticoagulation versus antiplatelet therapy, with none showing a significant difference.Conclusions PFO closure is superior to antithrombotic therapy to prevent stroke recurrence after cryptogenic stroke. The annual absolute risk reduction of stroke was low, but it has to be tempered by a substantial time at risk (at least 5 years) in young and middle‐aged patients. PFO closure was associated with an increased risk of atrial fibrillation.

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“…When the mean response is not measured on the same scale, the standardized mean difference (SMD) was calculated allowing for pooling across trials on the same scale. 18 The average effects for the outcomes across trials was estimated using a random effects model, as described by DerSimonian. 19 We chose the random effects method as primary analysis because of its conservative summary estimate and incorporation of between-and within-study variance.…”

Section: Discussionmentioning

confidence: 99%

SSRIs for Hot Flashes: A Systematic Review and Meta-Analysis of Randomized Trials

et al. 2013

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BACKGROUND: Hot flashes are the most commonly reported vasomotor symptom during the peri-and early post-menopausal period. OBJECTIVES: To systematically review, appraise and summarize the evidence of the impact of different SSRIs on peri-menopausal hot flashes in healthy women in randomized, controlled trials. METHODS: A comprehensive literature search was conducted of MEDLINE™, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and Scopus through March 2013. Two independent reviewers selected studies and extracted data. Random effects meta-analysis was used to pool outcomes across studies, and Bayesian mixed treatment methods were used to rank SSRIs in terms of effectiveness. RESULTS: We included a total of 11 randomized controlled trials with good methodological quality enrolling 2,069 menopausal and post-menopausal women (follow-up 1-9 months, mean age 36-76 years, mean time since menopause 2.3-6.6 years). Compared with placebo, SSRIs were associated with a statistically significant decrease in hot flash frequency (difference in means −0.93; 95 % CI −1.46 to −0.37; I 2 = 21 %) and severity assessed by various scales (standardized difference in means −0.34; 95 % CI −0.59 to −0.10; I 2 = 47 %). Adverse events did not differ from placebo. Mixed treatment comparison analysis demonstrated the superiority of escitalopram compared to other SSRIs in terms of efficacy. CONCLUSION: SSRI use is associated with modest improvement in the severity and frequency of hot flashes but can also be associated with the typical profile of SSRI adverse effects.

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Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses

Cited by 889 publications

References 35 publications

Perioperative β blockers in patients having non-cardiac surgery: a meta-analysis

Perioperative β blockers in patients having non-cardiac surgery: a meta-analysis

Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta‐Analysis, and New Insights From the CLOSE Study

SSRIs for Hot Flashes: A Systematic Review and Meta-Analysis of Randomized Trials

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