- Email: [email protected]
Risk factors for healing and relapse of esophagitis
2052
CORRESPONDENCE
clinically relevant, as the standard dose of 300 mg daily of ranitidine is frequently ineffective in achieving complete healing (even after 8-12 wk of treatment), thus leading to the need for testing more effective antisecretory drugs, for example omeprazole (2-4). We have conducted a single-center randomized clinical trial on the comparative effect of the above-mentioned dosages of ranitidine in the treatment of reflux esophagitis. Identical inclusion-exclusion criteria to those of Koelz et al. have been chosen, as wel1 as definition of healing. Fifty consecutive patients have been enrolled (28 were men, mean age 44 yr). Control endoscopies were repeated after 12-wk of treatment, and in the case of no healing, again after another 12-wk period. So far, results of 36 patients are available for statistical analysis. In the group treated with ranitidine 300 mg daily, 10 of 19 patients (53%) were healed after 3 mo, and 14 of 19 (74%) after 6 mo. The corresponding figure in the group treated with ranitidine 600 mg daily was 5 of 17 (29%) and 11 of 17 (65%), respectively. The differences are not statistically significant at both intervals (p > 0.05). As far as the effects of the drug on symptoms are concerned, the percentage of pain-free patients after 3 mo was 79% (15 of 19) in the 300-mg ranitidine group and 71% (12 of 17) in the 600-mg ranitidine group (p > 0.05) and after 6 mo, 100% (19 of 19) and 76% (13 of 17) (p < 0.05), respectively. One patient in the 600-mg ranitidine group was lost to follow-up. None of the patients complained of clinically relevant side effects. We, therefore conclude that the ranitidine dosage of 300 mg twice daily is not more effective than the standard dosage of 150 mg iwice daily in promoting mucosal healing and pain relief in reflux esophagitis. G. BIANCHIPORRO F. PACE M. LAZZARONI Gastrointestinal Unit “L. Sacco” Hospita1 Via G.B. Gmssi, 74 20157 Milano Italy Koelz HR, Birchler R, Bretholz A, et al. Healing and relapse of reflux esophagitis during treatment with ranitidine. Gastroenterology 1986;91:1198-205. Dammann HG, Blum AL, Lux G, et al. Unterschiedliche Heilungstendenz der Refluxösophagitis nach omeprazol und ranitidin. Dtsch Med Wochenschr 1986;111:123-8. Blum AL, Riecken EO, Dammann HG, et al. Comparison of omeprazole and ranitidine in the treatment of reflux esophagitis. N Eng1 J Med 1986;314:716. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, Menwissen SCM, Lamera CBHW. Omeprazole versus ranitidine in the treatment of reflux esophagitis: a double-blind multicentre trial (abstr). Gut 1986;27:A1253.
GASTROENTEROLOGY Vol. 92, No. 6
absent, as about one-half the patients were asymptomatic, slight and moderate symptoms were not clearly differentiated, and only 1 patient was severely symptomatic after 6 wk of treatment. Linear regression was the multivariate analytic technique used. However, linear regression is properly applied only with continuous or approximately continuous outcome variables such as blood pressure or serum biochemical measurements. An essential assumption of linear regression analysis is that for any value of an independent or predictor variable, the dependent variable is a random variable with a certain probability distribution. In addition, for any fixed value of the independent variable, the dependent variable has a normal distribution (2). If there are but two or three possible values for the dependent variable, it is impossible for these values to vary normally about an independent variable, which would be obvious in a plot of residual error after an attempted straight-line fit (3). Logistic regression using dichotomous outcome variables would be an appropriate technique for the multivariate analysis. For example, in the follow-up study, in the logistic model, the natura1 logarithm of the odds of recurrence of esophagitis (with possible range -m to +=J) would be estimated as a linear function of the independent variables (4). For a change in value of an independent variable such as smoking, the relative risk of esophagitis recurrence would then be determined while controlling for other variables such as age and sex. To impart the most information, the risk should be expressed as a point estimate with confidence intervals rather than with just a probability value (5). Because assumptions of the linear regression model were violated, the statistical analysis was inefficient, decreasing the likelihood of finding a relationship between predictor and outcome variables if such a relationship existed. As there was little relationship on univariate analysis between potential risk factors and healing or relapse of esophagitis, it is quite possible that multivariate logistic regression analysis wil1 reveal no further associations than those suggested by Koelz et al. Nevertheless, it would be best to reconduct the analysis using the appropriate technique. Several commonly used statistical packages have programs for logistic regression (6,7). JAMES EVERHART,M.D.,
Epidemiology and Data Systems Program Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases Bethesda, Maryland 20892 1. Koelz HR, Birchler R, Bretholz A, et al. Healing and relapse of
2.
Risk Factors for Healing and Relapse of Esophagitis Dear Sir: Koelz et al. have made an important contribution toward determining risk factors for healing and relapse of esophagitis (1). Unfortunately, the linear regression methods used in the multivariate analysis of healing and relapse were inappropriately applied. The dependent or outcome variables were reported as categorical measurements. Esophagitis was present or absent and severity of symptoms were none, slight, moderate, and severe. Severity of symptoms might also allow collapse to two categories, present or
M.P.H.
RICHARD JOHANNES, M.D., M.S.
3. 4.
5. 6.
7.
reflux esophagitis during treatment with ranitidine. Gastroenterology 1986;91:1198-205. Draper N, Smith H. Applied regression analysis. 2nd ed. New York: John Wiley & Sons, 1981:22-3. Kleinbaum DS, Kupper LL. Applied regression analysis and other multivariate methods. Boston: Duxbury, 1978:235-41. Kleinbaum DS, Kupper LL, Morgenstern H. Epidemiologic research. New York: Van Nostrand Reinhold Company, 1982:419-46. Rothman KJ. Significante questing. Ann Intern Med 1986; 105:445-7. Harrel1 FE. The LOGIST procedure. In: Joyner SP, ed. SUGI supplemental library user’s guide. 1983 edition. Cary, North Carolina: SAS Institute, Inc., 1983:181-202. Engelman L. Stepwise logistic regression. In: Dixon WJ, Brown MB, Engelman L, et al. eds. BMDP statistical software. Berkeley: University of California Press, 1983:331-44.
CORRESPONDENCE
clinically relevant, as the standard dose of 300 mg daily of ranitidine is frequently ineffective in achieving complete healing (even after 8-12 wk of treatment), thus leading to the need for testing more effective antisecretory drugs, for example omeprazole (2-4). We have conducted a single-center randomized clinical trial on the comparative effect of the above-mentioned dosages of ranitidine in the treatment of reflux esophagitis. Identical inclusion-exclusion criteria to those of Koelz et al. have been chosen, as wel1 as definition of healing. Fifty consecutive patients have been enrolled (28 were men, mean age 44 yr). Control endoscopies were repeated after 12-wk of treatment, and in the case of no healing, again after another 12-wk period. So far, results of 36 patients are available for statistical analysis. In the group treated with ranitidine 300 mg daily, 10 of 19 patients (53%) were healed after 3 mo, and 14 of 19 (74%) after 6 mo. The corresponding figure in the group treated with ranitidine 600 mg daily was 5 of 17 (29%) and 11 of 17 (65%), respectively. The differences are not statistically significant at both intervals (p > 0.05). As far as the effects of the drug on symptoms are concerned, the percentage of pain-free patients after 3 mo was 79% (15 of 19) in the 300-mg ranitidine group and 71% (12 of 17) in the 600-mg ranitidine group (p > 0.05) and after 6 mo, 100% (19 of 19) and 76% (13 of 17) (p < 0.05), respectively. One patient in the 600-mg ranitidine group was lost to follow-up. None of the patients complained of clinically relevant side effects. We, therefore conclude that the ranitidine dosage of 300 mg twice daily is not more effective than the standard dosage of 150 mg iwice daily in promoting mucosal healing and pain relief in reflux esophagitis. G. BIANCHIPORRO F. PACE M. LAZZARONI Gastrointestinal Unit “L. Sacco” Hospita1 Via G.B. Gmssi, 74 20157 Milano Italy Koelz HR, Birchler R, Bretholz A, et al. Healing and relapse of reflux esophagitis during treatment with ranitidine. Gastroenterology 1986;91:1198-205. Dammann HG, Blum AL, Lux G, et al. Unterschiedliche Heilungstendenz der Refluxösophagitis nach omeprazol und ranitidin. Dtsch Med Wochenschr 1986;111:123-8. Blum AL, Riecken EO, Dammann HG, et al. Comparison of omeprazole and ranitidine in the treatment of reflux esophagitis. N Eng1 J Med 1986;314:716. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, Menwissen SCM, Lamera CBHW. Omeprazole versus ranitidine in the treatment of reflux esophagitis: a double-blind multicentre trial (abstr). Gut 1986;27:A1253.
GASTROENTEROLOGY Vol. 92, No. 6
absent, as about one-half the patients were asymptomatic, slight and moderate symptoms were not clearly differentiated, and only 1 patient was severely symptomatic after 6 wk of treatment. Linear regression was the multivariate analytic technique used. However, linear regression is properly applied only with continuous or approximately continuous outcome variables such as blood pressure or serum biochemical measurements. An essential assumption of linear regression analysis is that for any value of an independent or predictor variable, the dependent variable is a random variable with a certain probability distribution. In addition, for any fixed value of the independent variable, the dependent variable has a normal distribution (2). If there are but two or three possible values for the dependent variable, it is impossible for these values to vary normally about an independent variable, which would be obvious in a plot of residual error after an attempted straight-line fit (3). Logistic regression using dichotomous outcome variables would be an appropriate technique for the multivariate analysis. For example, in the follow-up study, in the logistic model, the natura1 logarithm of the odds of recurrence of esophagitis (with possible range -m to +=J) would be estimated as a linear function of the independent variables (4). For a change in value of an independent variable such as smoking, the relative risk of esophagitis recurrence would then be determined while controlling for other variables such as age and sex. To impart the most information, the risk should be expressed as a point estimate with confidence intervals rather than with just a probability value (5). Because assumptions of the linear regression model were violated, the statistical analysis was inefficient, decreasing the likelihood of finding a relationship between predictor and outcome variables if such a relationship existed. As there was little relationship on univariate analysis between potential risk factors and healing or relapse of esophagitis, it is quite possible that multivariate logistic regression analysis wil1 reveal no further associations than those suggested by Koelz et al. Nevertheless, it would be best to reconduct the analysis using the appropriate technique. Several commonly used statistical packages have programs for logistic regression (6,7). JAMES EVERHART,M.D.,
Epidemiology and Data Systems Program Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive and Kidney Diseases Bethesda, Maryland 20892 1. Koelz HR, Birchler R, Bretholz A, et al. Healing and relapse of
2.
Risk Factors for Healing and Relapse of Esophagitis Dear Sir: Koelz et al. have made an important contribution toward determining risk factors for healing and relapse of esophagitis (1). Unfortunately, the linear regression methods used in the multivariate analysis of healing and relapse were inappropriately applied. The dependent or outcome variables were reported as categorical measurements. Esophagitis was present or absent and severity of symptoms were none, slight, moderate, and severe. Severity of symptoms might also allow collapse to two categories, present or
M.P.H.
RICHARD JOHANNES, M.D., M.S.
3. 4.
5. 6.
7.
reflux esophagitis during treatment with ranitidine. Gastroenterology 1986;91:1198-205. Draper N, Smith H. Applied regression analysis. 2nd ed. New York: John Wiley & Sons, 1981:22-3. Kleinbaum DS, Kupper LL. Applied regression analysis and other multivariate methods. Boston: Duxbury, 1978:235-41. Kleinbaum DS, Kupper LL, Morgenstern H. Epidemiologic research. New York: Van Nostrand Reinhold Company, 1982:419-46. Rothman KJ. Significante questing. Ann Intern Med 1986; 105:445-7. Harrel1 FE. The LOGIST procedure. In: Joyner SP, ed. SUGI supplemental library user’s guide. 1983 edition. Cary, North Carolina: SAS Institute, Inc., 1983:181-202. Engelman L. Stepwise logistic regression. In: Dixon WJ, Brown MB, Engelman L, et al. eds. BMDP statistical software. Berkeley: University of California Press, 1983:331-44.