Agreement Between Mega-Trials and Smaller Trials: A Systematic Review and Meta-Research Analysis

Overview

Journal JAMA Netw Open

Publisher American Medical Association

Specialty General Medicine

Date 2024 Sep 6

PMID 39240561

Authors

Lum Kastrati

Hamidreza Raeisi-Dehkordi

Erand Llanaj

Hugo G Quezada-Pinedo

Farnaz Khatami

Noushin Sadat Ahanchi

Adea Llane

Renald Mecani

Taulant Muka

John P A Ioannidis

Affiliations

Soon will be listed here.

Abstract

Importance: Mega-trials can provide large-scale evidence on important questions.

Objective: To explore how the results of mega-trials compare with the meta-analysis results of trials with smaller sample sizes.

Data Sources: ClinicalTrials.gov was searched for mega-trials until January 2023. PubMed was searched until June 2023 for meta-analyses incorporating the results of the eligible mega-trials.

Study Selection: Mega-trials were eligible if they were noncluster nonvaccine randomized clinical trials, had a sample size over 10 000, and had a peer-reviewed meta-analysis publication presenting results for the primary outcome of the mega-trials and/or all-cause mortality.

Data Extraction And Synthesis: For each selected meta-analysis, we extracted results of smaller trials and mega-trials included in the summary effect estimate and combined them separately using random effects. These estimates were used to calculate the ratio of odds ratios (ROR) between mega-trials and smaller trials in each meta-analysis. Next, the RORs were combined using random effects. Risk of bias was extracted for each trial included in our analyses (or when not available, assessed only for mega-trials). Data analysis was conducted from January to June 2024.

Main Outcomes And Measures: The main outcomes were the summary ROR for the primary outcome and all-cause mortality between mega-trials and smaller trials. Sensitivity analyses were performed with respect to the year of publication, masking, weight, type of intervention, and specialty.

Results: Of 120 mega-trials identified, 41 showed a significant result for the primary outcome and 22 showed a significant result for all-cause mortality. In 35 comparisons of primary outcomes (including 85 point estimates from 69 unique mega-trials and 272 point estimates from smaller trials) and 26 comparisons of all-cause mortality (including 70 point estimates from 65 unique mega-trials and 267 point estimates from smaller trials), no difference existed between the outcomes of the mega-trials and smaller trials for primary outcome (ROR, 1.00; 95% CI, 0.97-1.04) nor for all-cause mortality (ROR, 1.00; 95% CI, 0.97-1.04). For the primary outcomes, smaller trials published before the mega-trials had more favorable results than the mega-trials (ROR, 1.05; 95% CI, 1.01-1.10) and subsequent smaller trials published after the mega-trials (ROR, 1.10; 95% CI, 1.04-1.18).

Conclusions And Relevance: In this meta-research analysis, meta-analyses of smaller studies showed overall comparable results with mega-trials, but smaller trials published before the mega-trials gave more favorable results than mega-trials. These findings suggest that mega-trials need to be performed more often given the relative low number of mega-trials found, their low significant rates, and the fact that smaller trials published prior to mega-trial report more beneficial results than mega-trials and subsequent smaller trials.

References

Dahlof B, Sever P, Poulter N, Wedel H, Beevers D, Caulfield M . Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm.... Lancet. 2005; 366(9489):895-906. DOI: 10.1016/S0140-6736(05)67185-1. View

Riaz H, Khan S, Rahman H, Shah N, Kaluski E, Lincoff A . Effects of high-density lipoprotein targeting treatments on cardiovascular outcomes: A systematic review and meta-analysis. Eur J Prev Cardiol. 2019; 26(5):533-543. PMC: 7879587. DOI: 10.1177/2047487318816495. View

Cummings S, Rosen C . VITAL Findings - A Decisive Verdict on Vitamin D Supplementation. N Engl J Med. 2022; 387(4):368-370. DOI: 10.1056/NEJMe2205993. View

Duncan D, Sankar A, Beattie W, Wijeysundera D . Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery. Cochrane Database Syst Rev. 2018; 3:CD004126. PMC: 6494272. DOI: 10.1002/14651858.CD004126.pub3. View

DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177-88. DOI: 10.1016/0197-2456(86)90046-2. View

Landray M, Haynes R, Hopewell J, Parish S, Aung T, Tomson J . Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014; 371(3):203-12. DOI: 10.1056/NEJMoa1300955. View

Aberle D, Adams A, Berg C, Black W, Clapp J, Fagerstrom R . Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011; 365(5):395-409. PMC: 4356534. DOI: 10.1056/NEJMoa1102873. View

Dong W, Yan W, Song X, Zhou W, Chen Z . Fluid resuscitation with balanced crystalloids versus normal saline in critically ill patients: a systematic review and meta-analysis. Scand J Trauma Resusc Emerg Med. 2022; 30(1):28. PMC: 9013977. DOI: 10.1186/s13049-022-01015-3. View

Leppala J, Virtamo J, Fogelholm R, HUTTUNEN J, Albanes D, Taylor P . Controlled trial of alpha-tocopherol and beta-carotene supplements on stroke incidence and mortality in male smokers. Arterioscler Thromb Vasc Biol. 2000; 20(1):230-5. DOI: 10.1161/01.atv.20.1.230. View

10.

Gencer B, Djousse L, Al-Ramady O, Cook N, Manson J, Albert C . Effect of Long-Term Marine ɷ-3 Fatty Acids Supplementation on the Risk of Atrial Fibrillation in Randomized Controlled Trials of Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. Circulation. 2021; 144(25):1981-1990. PMC: 9109217. DOI: 10.1161/CIRCULATIONAHA.121.055654. View

11.

Hasebe M, Yoshiji S, Keidai Y, Minamino H, Murakami T, Tanaka D . Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials. Cardiovasc Diabetol. 2023; 22(1):62. PMC: 10024854. DOI: 10.1186/s12933-023-01773-z. View

12.

Singh S, Bahekar A, Molnar J, Khosla S, Arora R . Adjunctive low molecular weight heparin during fibrinolytic therapy in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized control trials. Clin Cardiol. 2009; 32(7):358-64. PMC: 6653358. DOI: 10.1002/clc.20432. View

13.

Cappelleri J, Ioannidis J, Schmid C, de Ferranti S, Aubert M, CHALMERS T . Large trials vs meta-analysis of smaller trials: how do their results compare?. JAMA. 1996; 276(16):1332-8. View

14.

Ennezat P, Guerbaai R, Marechaux S, Le Jemtel T, Francois P . Extent of Low-density Lipoprotein Cholesterol Reduction and All-cause and Cardiovascular Mortality Benefit: A Systematic Review and Meta-analysis. J Cardiovasc Pharmacol. 2022; 81(1):35-44. PMC: 9812424. DOI: 10.1097/FJC.0000000000001345. View

15.

Roncaglioni M, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P . n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013; 368(19):1800-8. DOI: 10.1056/NEJMoa1205409. View

16.

Tsigkas G, Apostolos A, Trigka A, Chlorogiannis D, Katsanos K, Toutouzas K . Very Short Versus Longer Dual Antiplatelet Treatment After Coronary Interventions: A Systematic Review and Meta-analysis. Am J Cardiovasc Drugs. 2022; 23(1):35-46. PMC: 9845152. DOI: 10.1007/s40256-022-00559-0. View

17.

Bhatt D, Fox K, Hacke W, Berger P, Black H, Boden W . Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354(16):1706-17. DOI: 10.1056/NEJMoa060989. View

18.

Wactawski-Wende J, Kotchen J, Anderson G, Assaf A, Brunner R, OSullivan M . Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006; 354(7):684-96. DOI: 10.1056/NEJMoa055222. View

19.

Hansson L, Lindholm L, Niskanen L, Lanke J, Hedner T, Niklason A . Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999; 353(9153):611-6. DOI: 10.1016/s0140-6736(98)05012-0. View

20.

Wiviott S, Raz I, Bonaca M, Mosenzon O, Kato E, Cahn A . Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2018; 380(4):347-357. DOI: 10.1056/NEJMoa1812389. View