CORRESPONDENCE

June 1992

3. Christie ML, Sack DM, Pomposelli J, Horst D. Enriched branched-chain amino acid formula versus a casein-based supplement in the treatment of cirrhosis. JPEN 1985;9:671678. 4. Eriksson LS, Conn HO. Branched-chain amino acids in the management of hepatic encephalopathy: an analysis of variants. Hepatology 1989;10:228-246. 5. Naylor CD, O’Rourke K, Detsky AS, Baker JP. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. Gastroenterology 1989;97:1033-1042. 6. Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2:1276-1278. 7. Diehl AM, Boitnott JK, Herlong HF, Potter JJ, Van Duyn MA, Chandler E, Mezey E. Effect of parenteral amino acid supplementation in alcoholic hepatitis. Hepatology 1985;5:57-63. 8. Naveau S, Pelletier G, Poynard T, Attali P, Poitrine A, Buffet C, Etienne J-P, Chaput J-C. A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients. Hepatology 1986;6:270-274. 9. Alchord J. A prospective randomized clinical trial of peripheral amino acid-glucose supplementation in acute alcoholic hepatitis. Am J Gastroenterol 1987;82:871-875. 10. Simon D, Galambos JT. A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis. J Hepatol 1988;7:200-207. 11. Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:1200-1208. 12. Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. Effect of parenteral amino acid supplementation on short-term and long-term outcome in severe alcoholic hepatitis: a randomized controlled trial. Hepatology 1991;14:10901096. 13. Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol 1985;1:141-151. 14.Koretz RL. Branched-chain amino acids in hepatic encephalopathy (letter). Gastroenterology 1990;99:287-288. Reply. Dr. Koretz notes differences between control and treated patients in our study’ but challenges the conclusions. A critical feature to emphasize is the acceleration in improvement of encephalopathy and biochemical outcomes. Analyzing the means leads Dr. Koretz to conclude that even though improved, most patients did not have clinically apparent encephalopathy. This would make the therapy of questionable value. We found the disturbance in day-night cycle distressing to patients and clinically apparent. In addition, analyzing means hides the fact that 6 of 15 controls had a deterioration in mental status during the first 2 weeks, whereas no treated patient increased the degree of encephalopathy. One control increased to grade 4 and three others increased to grade 2. Dr. Koretz bases his challenge on parenteral and/or enteral nutrition studies. We hesitate to compare studies of fundamentally different therapies. Restricting oneself to enteral studies listed, one study showed improved survival, encephalopathy and biochemical markers in treated patients.’ Our study showed accelerated improvement in encephalopathy and biochemical indices.’ The third enteral study cited includes parenteral as well as enteral supplement? and failed to achieve different nitrogen intakes in control and treated arms. Failure to observe differences in outcome when nitrogen intake was similar lends credibility to our conclusion. Even the studies of Diehl et al,* Naveau,’ and Bonkovsky’ show at least one outcome improved at a faster rate in

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supplemented patients. Nasrallah7 and Mezey’ found an overall improvement in biochemical, nutritional, and metabolic or survival outcomes. A majority of studies listed show benefit with nutritional supplements. We remain convinced that aggressive nutritional supplementation should serve as control therapy for future studies. PATRICK J. KEARNS, M.D. Nutritional Support Services Santa Clara Valley Medical Center Fourth Floor 751 South Bascom Avenue San Jose, California 95128 Kearns PJ, Young H, Garcia G, et al. Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102:200-205. 2. Cabre E, Gonzalez-Huix F, Abad-Lacruz A, et al. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: a randomized controlled trial. Gastroenterology 1990;98:715-720. 3. Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol 1985;1:141-151. 4. Diehl AM, Boitnott JK, Herlong HF, et al. Effect of parenteral amino acid supplementation in alcoholic hepatitis. Hepatology 1985;5:57-63. 5. Naveau S, Pelletier G, Poynard T, et al. A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients. Hepatology 1986;6:270-274. 6. Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT. ,4 randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrilion and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:1200-1208. 7. Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2:1276-1278. 8. Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. Effect of parenteral amino acid supplementation on short-term and long-term outcome in severe alcoholic hepatitis: an randomized controlled trial. Hepatology 1991;14:10901096. 1.

Prophylactic Sclerotherapy: Versus ‘Aggregate’ Analysis

Meta-analysis

Dear Sir: Van Ruiswyk and Byrd’s meta-analysis’ of prophylactic sclerotherapy (PS) for primary prevention of variceal hemorrhage dealt with an important clinical question. While we commend the authors for attempting a much-needed synthesis of the randomized trials, we agree with Blei’ that for this topic “the significant heterogeneity amongst studies does not allow the satisfactory use of meta-analysis.” Clinical heterogeneity [dissimilarity] is present among the individual trials in the populations randomized (for etiology and severity of both varices and liver disease); in the method of sclerotherapy (sclerosant, injection site, number of injections, volume used, and interval between treatments); in the accompanying therapies (frequency of follow-up visits); and for outcomes, with varying lengths of follow-up for the combined tabular data. Using meta-analysis to “pool” such clinically heterogeneous data may “drown out” any effect of PS in clinically distinct patient subgroups. In addition, though only eight trials were pooled, the authors’ statistical test of homogeneity showed significant heterogeneity for the outcomes of first variceal bleed and death due to variceal bleed. Such heterogeneity would indicate that the studies are not combinable from a statistical standpoint.

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The incomplete subgroup analyses underscore another problem with using meta-analysis for these trials: the richness of the results of meta-analysis depends on the detail and uniformity of reporting of the individual trials. Because only two trials reported separate results of PS for different Child’s classes, the subgroup analyses for severity of disease contain just two of the eight pooled trials, an inadequate number for a proper analysis. Furthermore, there are additional variables whose effect on outcome from PS could not be determined because these data were not reported in any trials: compliance with follow-up visits and, more important, whether variceal obliteration with treatment (the intermediate effect) affects outcome. Rather than use meta-analysis for this topic, we believe that it would be more appropriate to pool the raw data from the trials, as was done by Poynard et al. for some of the trials of B-adrenergic blockade for esophageal vaTices This strategy of combining the original, individual-level data provides opportunities to adjust for clinically important differences among study populations using multivariate analysis, and to investigate a treatment effect in a greater number of subgroups than is possible with “classical” meta-analysis4 Several months ago, on offering to coordinate a collaborative effort to conduct this type of analysis for the PS trials, we received cooperative responses from eight PIs. When this aggregate analysis is completed, it will be interesting to compare the results with those of the meta-analysis, particularly for the subgroup analyses. We believe that this aggregate analysis will clarify the value of PS and will serve as a model for collaboration among investigators who share common interests and goals. THOMAS F. IMPERIALE, M.D. ARTHUR J. MCCULLOUGH, M.D.

Case Western Reserve University at MetroHealth Medical Center Cleveland, Ohio 44109 Van Ruiswyk J, Byrd JC. Efficacy of prophylactic sclerotherapy for prevention of a first variceal hemorrhage. Gastroenterology 1992;102:587-597. Blei AT. Prevention of the complications of cirrhosis. Postgraduate Course of the American Association for the Study of Liver Disease. 1990:104-117. Poynard T, Cal& P, Pasta L, et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. N Engl J Med 1991;324:1532-1538. Imperiale TF, McCullough AJ. Prophylactic B-blocker therapy: clinical implications of an aggregate analysis. Hepatology 1992;15:354-356. Reply. We agree that there were many differences in study populations and study protocols among the trials included in our metaanalysis.’ Despite the differences between the patients enrolled in each study, the mortality rates of patients in each trial’s control group were similar. This suggests that the study populations had similar prognoses with respect to the meta-analysis’ primary outcome of mortality. To the extent that any differences between studies reduce the likelihood of a significant treatment effect, this would only strengthen our finding of a significant pooled mortality reduction. Although the tabulated reductions in the rates of the secondary outcomes of first variceal bleed and death due to variceal bleeding were heterogeneous, the mortality rate reductions (which were the primary outcome analyzed) obtained from the survival curves were homogeneous. Analysis of aggregate data should help determine how much differing lengths of follow-up contributed to the heterogeneity of the secondary outcomes. As Drs. Imperiale and McCullough point out, our subgroup analyses were incomplete because very few of the trials reported sub-

GASTROENTEROLOGY

Vol. 102, No. 6

group analyses. Therefore, our comparisons of the efficacy of prophylactic sclerotherapy across patient subgroups should be considered hypothesis-generating, rather than hypothesis-testing, analyses. The primary purpose of the subgroup analyses was to try to determine which study factors may have confounded measurement of the efficacy of prophylactic sclerotherapy. We were hoping to generate initial data that might support hypotheses for the conflicting results of the Veterans Affairs Cooperative Study (VACS).’ When different clinical trials have yielded conflicting results, the sensitivity analyses and subgroup analyses that are performed as part of a meta-analysis can provide a method for examining how study differences affected the study results. The use of aggregate data should avoid many of the weaknesses of our meta-analysis. For example, it should allow much more powerful subgroup analyses. However, it may not be possible to adequately adjust for all clinical differences between the trials. Because three different methods were used to define high-risk varices, it will be difficult to adjust for patient’s risk of variceal bleeding. In addition, it will not be possible to adjust for data not collected during the initial trial. Unfortunately, during the period we were performing our meta-analysis, we were not able to obtain additional data about the VACS because that study was being reviewed for publication. Therefore, we look forward to the results of the aggregate analysis planned by Drs. Imperiale and McCullough. It should provide an interesting example of the strengths and weaknesses of these two methods of summarizing the data obtained from different clinical trials. JEROME VAN RUISWYK, JAMES C. BYRD, M.D.

M.D.

Department of Internal Medicine Medical College of Wisconsin 8700 West Wisconsin Avenue Milwaukee, Wisconsin 53226 1. Van Ruiswyk J, Byrd J. Efficacy of prophylactic sclerotherapy for prevention of first variceal hemorrhage. Gastroenterology 1992;102:587-597. Sclerotherapy Group. Pro2. The Veterans Affairs Cooperative phylactic sclerotherapy for esophageal varices in men with alcoholic liver disease. A randomized, single-blind, multicenter clinical trial. N Engl J Med 1991;324:1779-1784.

Microlithiasis and Cholesterolosis ‘Idiopathic’ Acute Pancreatitis

in

Dear Sir: We have read with great interest the article by Ros et al.’ dealing with the diagnosis of occult cholelithiasis in patients with acute pancreatitis (AP) by the microscopic examination of stimulated duodenal bile. Because gallstone disease has a very high prevalence in our country, it is not surprising that most of our AP are also gallstone related, but we still have about 25% of the cases in which usual imaging procedures do not demonstrate gallbladder disease. In the absence of another identifiable associated clinical condition (i.e., excessive alcohol ingestion or hypertriglyceridemia), these patients are thought to have idiopathic pancreatitis and, as Ros stated, they are exposed to an unduly high risk of relapse. In a prospective study we have approached this problem using a methodology similar to that of Ros et al., and even though we have obtained similar results, we would like to comment on some differences. From January 1990 to June 1991 there were 61 patients hospitalized because of AP at our hospital in Santiago, Chile. In 14 of these patients (25%) repeated ultrasonography (US), and in some of

Prophylactic sclerotherapy: meta-analysis versus 'aggregate' analysis.

CORRESPONDENCE June 1992 3. Christie ML, Sack DM, Pomposelli J, Horst D. Enriched branched-chain amino acid formula versus a casein-based supplement...
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