ß-Blockers for Secondary Prophylaxis of Bleeding Esophageal Varices

Clinical Question

Does B-blocker therapy reduce the risk of subsequent bleeding episodes in patients with known esophageal varices and cirrhosis who've had one or more previous episodes of variceal bleeding?

Clinical Bottom Lines

  1. ß-Blocker therapy results in a reduction in rebleeding episodes.
  2. Mortality is not significantly reduced with the use of these agents.

See comments below

The Evidence

Pagliaro, et al.

Study No. patients Re-bleeding Mortality
RR(95%CI) ARR RR(95%CI) ARR
Lebrec 74 0.1(.05-.3) 0.48 0.3(.09-1.2) 0.14
Burroughs 48 0.8(.3-2.5) 0.05 0.6(.1-2.6) 0.07
Villanueve 79 0.7(.3-2.2) 0.05 1.3(.5-3.3) NA
Queuniet 99 0.7(.3-2.6) 0.08 1.2(.4-3.0) NA
Gatta 24 0.2(.04-.95) 0.42 0.3(.04-2.6) 0.17
Colombo 62 0.4(.1-1.1) 0.22 0.5(.1-1.7) 0.11
Colombo 62 0.5(.2-1.4) 0.15 0.4(.09-1.4) 0.14
Sheen 36 0.3(.09-1.2) 0.28 0.1(.01-2.1) 0.11
Garden 81 0.3(.1-.7) 0.29 0.7(.3-1.8) 0.07
Cerbelaud 100 0.3(.1-.6) 0.32 NR NR
667 PRR PRD PRR PRD
0.4(0.3-0.5) 0.22 0.7(.5-1.04) 0.08


Hayes, et al.

Studies Number of Patients Re-bleeding RRR Death from re-bleeding RRR Mortality RRR
11 of 19 * 880 0.46(.33-.57) 0.51(.27-.68) 0.34(.16-.48)
p value p < 0.0001 p = 0.0004 p = 0.0007
heterogeneity (chi-square) p 0.073 0.696 0.447

Comments

  1. Both of these studies were Meta-Analyses that employed common statistical maneuvers to combine data. However, several flaws need to be addressed.
  2. In the Pagliaro paper, although only RCT's were included in the analyses, no weight-ranking was given to the individual studies (for validity, results, and applicability). This was also true of the Hayes paper, however an attempt was made to address this by removing some studies by applying "stricter criteria", which in effect reduced the heterogeneity among these studies.
  3. Neither of the studies reveals the methodology for finding relevant studies; therefore, it is unkown if all relevant studies were included.
  4. Neither paper addressed reproducibility of study assessments, and no mention is made about individual study validity.
  5. There was significant heterogeneity among studies in both the Pagliaro and Hayes papers with regard to secondary prophylaxis.
  6. Patients with Child's C liver disease were included with all others, and subset analysis suggests no positive effect on any outcomes for decompensated liver disease.
  7. Only 4 of the 10 trials included in the Pagliaro paper were able to exclude a relative risk of 1.0, although the pooled RR confidence interval did. This is one of the benefits of doing meta-analyses of smaller studies which show conflicting results or have too small numbers to have significant statistical power.

These meta-analyses, although they both show statistically significant results, are not terribly valid according to the JAMA guidelines and the above mentioned flaws. However, because generic ß-blockers are inexpensive and relatively safe, and have not demonstrated significant harm in these patients, it is not unreasonable to continue their use until well-conducted meta-analyses are done.

APPRAISED BY: Patrick Sousa, MD

DATE: April 16, 1996

Pagliaro L, et al. Prevention of Upper Gastrointestinal Bleeding from Portal Hypertension in Cirrhosis: Rationale for Medical Treatment. Dig Dis 1992;10(suppl):56-64.

Hayes PC, et al. Meta-analysis of value of propanolol in prevention of variceal hemorrhage. Lancet 1990:336:153-156.

Burroughs AK and Panagou E. Pharmacological Therapy for Portal Hypertension: Rationale and Results. Seminar Gastroint Dis 1995;6:148-164.