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Research and Reporting Methods |

Single-Center Trials Show Larger Treatment Effects Than Multicenter Trials: Evidence From a Meta-epidemiologic Study

Agnes Dechartres, MD; Isabelle Boutron, MD, PhD; Ludovic Trinquart, MSc; Pierre Charles, MD; and Philippe Ravaud, MD, PhD
[+] Article and Author Information

From U738 INSERM; Assistance Publique Hôpitaux de Paris (APHP), Hôpital Hôtel-Dieu; Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine; and French Cochrane Centre, Paris, France, and Hôpital Foch, Suresnes, France.


Acknowledgment: The authors thank Dominique Hervault (Hôpital Hôtel-Dieu, APHP, Paris, France), the Bibliothèque InterUniversitaire de Medicine (Université Paris Descartes, Paris, France), and especially Guillemette Utard-Wlerick and Jean Avril for help in retrieving full-text articles and Aida Bafeta, MSc (INSERM U738, Centre d'Epidemiologie Clinique, Hôpital Hôtel-Dieu, APHP, Paris, France), for initial independent data extraction.

Grant Support: By an academic grant, Recherche Sur la Recherche (RSR-07002), from the Délégation Interrégionale à la Recherche Clinique, Ile de France, Assistance Publique-Hôpitaux de Paris (APHP).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0074.

Requests for Single Reprints: Agnes Dechartres, MD, Centre d'Epidémiologie Clinique, INSERM U738, Hôpital Hôtel-Dieu, 1, place du parvis Notre Dame, 75004 Paris, France; e-mail, agnes.dechartres@htd.aphp.fr.

Current Author Addresses: Dr. Dechartres: Centre d'Epidémiologie Clinique; INSERM U 738; French Cochrane center; Université Paris Descartes Sorbonne Paris Cité; Hôpital Hôtel-Dieu (APHP), 1 place du parvis Notre Dame, 75004 Paris, France.

Dr. Boutron: Centre d'Epidémiologie Clinique; INSERM U 738; French Cochrane Center; Université Paris Descartes Sorbonne Paris Cité; Hôpital Hôtel-Dieu (APHP), 1 place du parvis Notre Dame, 75004 Paris, France.

Mr. Trinquart: Centre d'Epidémiologie Clinique, INSERM U 738, French Cochrane Center; Université Paris Descartes Sorbonne Paris Cité; Hôpital Hôtel-Dieu, (APHP), 1 place du parvis Notre Dame, 75004 Paris, France.

Dr. Charles: Service de médecine interne, Hôpital Cochin (APHP), 27 rue du Faubourg St Jacques, 75014 Paris, France.

Dr. Ravaud: Centre d'Epidémiologie Clinique, INSERM U 738, French Cochrane Center; Université Paris Descartes Sorbonne Paris Cité; Hôpital Hôtel, Dieu (APHP), 1 place du parvis Notre Dame 75004 Paris, France.

Author Contributions: Conception and design: A. Dechartres, I. Boutron, P. Ravaud.

Analysis and interpretation of the data: A. Dechartres, I. Boutron, L. Trinquart, P. Charles, P. Ravaud.

Drafting of the article: A. Dechartres, L. Trinquart.

Critical revision of the article for important intellectual content: A. Dechartres, I. Boutron, L. Trinquart, P. Charles, P. Ravaud.

Final approval of the article: A. Dechartres, I. Boutron, L. Trinquart, P. Charles, P. Ravaud.

Statistical expertise: I. Boutron, L. Trinquart.

Obtaining of funding: I. Boutron, P. Ravaud.

Administrative, technical, or logistic support: P. Ravaud.

Collection and assembly of data: A. Dechartres, P. Charles, P. Ravaud.


Ann Intern Med. 2011;155(1):39-51. doi:10.7326/0003-4819-155-1-201107050-00006
Text Size: A A A

Background: A recent study suggested that results of single-center trials are frequently contradicted when similar trials are performed in multicenter settings.

Purpose: To perform a meta-epidemiologic study to evaluate whether estimates of treatment effect differ between single-center and multicenter randomized, controlled trials (RCTs).

Data Sources: MEDLINE was searched via PubMed for meta-analyses of RCTs with binary outcomes that were published between August 2008 and January 2009 and in the first 6 months of 2010 in the 10 leading journals of each medical specialty. One issue of the Cochrane Database of Systematic Reviews was also searched.

Study Selection: All individual RCTs included in the meta-analyses were selected.

Data Extraction: Data were extracted and their quality was assessed by use of the risk of bias tool of the Cochrane Collaboration.

Data Synthesis: The primary outcome was the ratio of odds ratios (ROR), used to quantify the difference in estimated intervention effect between single-center and multicenter RCTs. An ROR less than 1 would indicate larger estimates of the intervention effect in single-center trials. Sensitivity analyses were performed with adjustment for sample size, risk of bias within RCTs, and variance of the log odds ratio to take publication bias into account. Forty-eight meta-analyses were selected, including 421 RCTs (223 were single-center and 198 were multicenter). Single-center RCTs showed a larger intervention effect than did multicenter RCTs (combined ROR, 0.73 [95% CI, 0.64 to 0.83]), with low heterogeneity across individual meta-analyses (I2 = 12.0%; P = 0.24). Adjustment for sample size yielded consistent results (ROR, 0.85 [CI, 0.74 to 0.97]), as did adjustment for risk of bias within RCTs, such as allocation concealment (ROR, 0.76 [CI, 0.67 to 0.86]), and variance of log odds ratio (ROR, 0.83 [CI, 0.72 to 0.96]).

Limitation: Despite sensitivity analyses, meta-confounding cannot be fully excluded.

Conclusion: Single-center RCTs showed larger treatment effects than did multicenter RCTs, a finding that was consistent in all sensitivity analyses. These results suggest that this item should be considered when the results of RCTs and meta-analyses are interpreted.

Primary Funding Source: Academic grant Recherche sur la Recherche from the Délégation Interrégionale à la Recherche Clinique (DIRC), Ile de France, Assistance Publique-Hôpitaux de Paris (APHP).

Figures

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Figure 1.
Summary of evidence search and selection.

RCT = randomized, controlled trial.

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Figure 2.
Difference in intervention effect estimates between 223 single-center and 198 multicenter RCTs.

An ROR <1 indicated that single-center trials yielded larger estimates of the intervention effect than did multicenter trials. RCT = randomized, controlled trial; ROR = ratio of odds ratios.

* Weights are from random-effects model.

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Figure 3.
Exploration of heterogeneity.

Each point on the scatterplot represents a meta-analysis. The x-axis represents the contribution of the meta-analysis to the overall heterogeneity across ratios of odds ratios (RORs). The y-axis represents the contribution of the meta-analysis to the overall combined ROR. Eight meta-analyses accounted for most of the heterogeneity (65% of the overall heterogeneity) and had a strong influence on the combined ROR (84% of the sum of the influences).

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Figure 4.
Unadjusted and adjusted sensitivity analyses showing difference in intervention effect estimates between single-center and multicenter randomized, controlled trials.
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