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Meta-analysis: Combination Endoscopic and Drug Therapy to Prevent Variceal Rebleeding in Cirrhosis

Rosario Gonzalez, MD; Javier Zamora, MD, PhD; Judith Gomez-Camarero, MD; Luis-Miguel Molinero, PhD; Rafael Bañares, MD, PhD; and Agustín Albillos, MD, PhD
[+] Article and Author Information

From Hospital Universitario Ramón y Cajal, Hospital General Universitario Gregorio Marañón, Alce Ingeniería, Unidad I+D Asociada al Centro Nacional de Biotecnología (CSIC), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (Ciberehd), Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública (Ciberesp), Universidad Complutense, Universidad de Alcalá, Madrid, Spain.


Acknowledgment: The authors thank Ana Burton and Kimiyo Nishimura for their assistance with English and Japanese translations, respectively.

Grant Support: From the Spanish Ministry of Health, Instituto de Salud Carlos III, CM04/00132 (Dr. González) and PI051871, Ciberehd (Drs. Bañares and Albillos); Fundación para la Investigación Biomédica, Hospital General Universitario Gregorio Marañón (Dr. Gomez-Camarero); the Fundación Mutua Madrileña (Drs. Bañares and Albillos [FundacionMM-2006-001 for Dr. Albillos]); and the Spanish Ministry of Education, BFU 2006-09280/BFI (Dr. Albillos). Ciberesp and Ciberehd are funded by the Instituto de Salud Carlos III.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Agustín Albillos, MD, PhD, Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Carretera de Colmenar km 9.100, 28034 Madrid, Spain; e-mail, aalbillosm@meditex.es.

Current Author Addresses: Drs. González and Albillos: Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, Carretera De Colmenar km 9.100, 28034 Madrid, Spain.

Dr. Zamora: Servicio de Bioestadística, Hospital Universitario Ramón y Cajal, Carretera de Colmenar km 9.100, 28034 Madrid, Spain.

Drs. Gomez-Camarero and Bañares: Servicio de Gastroenterología, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo 46, 28007 Madrid, Spain.

Dr. Molinero: Alce Ingeniería, Calle Fray Luis de León, Bajo D, 28230 Madrid, Spain.


Ann Intern Med. 2008;149(2):109-122. doi:10.7326/0003-4819-149-2-200807150-00007
Text Size: A A A

Background: Combining endoscopic therapy and β-blockers may improve outcomes in patients with cirrhosis and bleeding esophageal varices.

Purpose: To assess whether a combination of endoscopic and drug therapy prevents overall and variceal rebleeding and improves survival better than either therapy alone.

Data Sources: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and conference proceedings through 30 December 2007.

Study Selection: Randomized trials comparing endoscopic plus β-blocker therapy with either therapy alone, without language restrictions.

Data Extraction: Two reviewers independently extracted data on interventions and the primary study outcomes of overall rebleeding and mortality. Metaregression and stratified analysis were used to explore heterogeneity.

Data Synthesis: 23 trials (1860 patients) met inclusion criteria. Combination therapy reduced overall rebleeding more than endoscopic therapy alone (pooled relative risk, 0.68 [95% CI, 0.52 to 0.89]; I2 = 61%) or β-blocker therapy alone (pooled relative risk, 0.71 [CI, 0.59 to 0.86]; I2 = 0%). Combination therapy also reduced variceal rebleeding and variceal recurrence. Reduction in mortality from combination therapy did not statistically significantly differ from that from endoscopic (Peto odds ratio, 0.78 [CI, 0.58 to 1.07) or drug therapy (Peto odds ratio, 0.70 [CI, 0.46 to 1.06]). Effects were independent of the endoscopic procedure (injection sclerotherapy or banding). No trial-level variable associated with the effect was identified through metaregression or stratified analysis.

Limitation: Statistically significant heterogeneity in trial quality and evidence for selective reporting and publication bias were found.

Conclusion: A combination of endoscopic and drug therapy reduces overall and variceal rebleeding in cirrhosis more than either therapy alone.

Figures

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Figure 1.
Study flow diagram.

RCT = randomized, controlled trial.

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Figure 2.
Forest plots of rebleeding events (top) and mortality (bottom) in trials comparing combination therapy with endoscopic therapy.

The size of the squares is proportional to the weight of the studies. Horizontal lines indicate the 95% CIs. Top. Rebleeding events and risk ratios. Squares represent the relative risk for rebleeding events. Bottom. Mortality and Peto odds ratios. Squares represent the Peto odds ratio for mortality.

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Appendix Figure 1.
Forest plot of risk for rebleeding events.

Trials shown are the same as in Figure 2,top, stratified by length of follow-up. Horizontal lines indicate 95% CIs.

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Appendix Figure 2.
Forest plot of Peto odds ratio for mortality.

Trials shown are the same as in Figure 2,bottom, stratified by length of follow-up. Horizontal lines indicate 95% CIs.

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Figure 3.
Forest plots of rebleeding events (top) and mortality (bottom) in trials comparing combination therapy with drug therapy.

The size of the squares is proportional to the weight of the studies. Horizontal lines indicate 95% CIs. Top. Rebleeding events and risk ratios. Squares represent the relative risk for rebleeding events. Bottom. Mortality and Peto odds ratios. Squares represent the Peto odds ratio for mortality.

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