Correspondence ISONIAZID PREVENTIVE THERAPY OF TUBERCUWSIS: DECISION ANALYSIS CONSIDERING ETHNICITY AND GENDER
To the Editor: The decision analysis by Jordan and coworkers (1), while valuable in presenting ethnic and gender differences in the benefit to risk ratio from taking isoniazid (INH), utilizes several questionable assumptions. (1) The authors had to use estimated case rates of developing tuberculosis (TB) 20 years after INH could have been given because of a lack of data. The authors, as well as others (2-4), took their estimated case rates from an editorial (5). It used cross-sectional data, which inflated these rates by including data for recent convertors as well as long standing reactors for all periods of an individual's life, as shown in the following example. In the editorial (5), case rates for all tuberculin reactors, ages 40 to 49, from two surveys were used to derive a case rate that was then applied to a markedly different group-reactors who had reached the age of 40 to 49 but wereknown to be tuberculin positive 20 years earlier. Reactors found in surveys include both recent convertors and long standing reactors, but reactors who were tuberculin positive 20 years earlier include only long standing reactors. Because recent convertors have markedly higher case rates than long standing reactors, the estimated case rates used by the authors were inflated severalfold. (2) The assumption of 680/0 life-timeprotection from INH is questionable. The study on which it is based was limited to 20 years and showed only 50% protection in the last four years (6). Furthermore, protection from the widely used 6 months of INH appears to be limited to five years in persons with fibrotic pulmonary lesions (7), and is probably much less than life-time protection in reactors with normal chest X-rays. (3)The overallTB case-fatality rate of 8.750/0 is too high for young persons. From national statistics a TB case fatality rate of 2.2% for women and 2.7% for men, ages 25 to 44 can be calculated (8). If one assumes that the protection from INH lasts no more than 20 years, these lower TB case fatality rates should be used for young adults. (4) The "health concern factor" is not considered. Evidence suggests that persons with enough concern about their health to voluntarily take preventive treatment have a reduced chance of dying of TB, even if preventive treatment is not prescribed, because, if TB develops, they are likely to present for treatment sufficiently early to be readily cured (9). (5) Finally, even if INH increases life expectancy, the relative importance of a near-term INH death is probably considerably greater than a later TB death for many if not most people. (6) On the other hand, the authors probably overestimated the INH toxicity case fatality rates in young adults, especially males, because there were no INH deaths in males despite seven deaths in females between the ages of 15and 40 in one published series (10). In conclusion, the authors could improve the value of their decision analysis by using revised assumptions. ThOMAS MOULDING M.D.
Associate Clinical Professor of Medicine Harbor-UCLA Medical Center Torrance, California
1. Jordan TJ, Lewit EM, Reichman LB. Isoniazid preventive treatment for tuberculosis: decision analysis considering ethnicity and gender. Am Rev Respir Dis 1991; 144:1357-60. 2. Rose DN, Schecter CB, Silver AL. The age threshold for isoniazid chemprophylaxis. lAMA 1986; 256:2709-13. 3. Fitzgerald JM, Gafni A. A cost effectiveness analysis of the routine use 1118
of isoniazid prophylaxis in patients with a positive mantoux skin test. Am Rev Respir Dis 1990; 142:848-53. 4. Rose DR, Schecter CB, Fahs MC, Silver AI. Tuberculosis prevention: cost-effectiveness analysis of isoniazid chemoprophylaxis. Am 1 of Preventive Medicine 1988; 4:102-9. 5. Comstock GW, Edwards PQ. The competing risk of tuberculosis and hepatitis for adult tuberculin reactors. Am Rev Respir Dis 1975; 111:573-7. 6. Comstock GW, Baum C, Snider DE. Isoniazid prophylaxis among Alaskan eskimos: a final report of the bethel isoniazid studies. Am Rev Respir Dis 1979; 119:827-30. 7. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow up in the IUAT trial. Bull WHO 1982; 60:555-64. 8. U.S. Department of Health and Human Services/Public Health Service/Centers for Disease Control: Tuberculosis in the United States: 1981-1984. pages 20 and 22 HHS Publication No. (CDC) 86-8322. 9. Moulding T, Barnes P. Isoniazid for the tuberculin reactor: take it or leave it. Am Rev Respir Dis 1988; 138:489. 10. Moulding TS, Redeker AG, Kanel GC. l\venty isoniazid-associated deaths in one state. Am Rev Respir Dis 1989; 140:700-5.
From the Authors: We are pleased that Dr. Moulding acknowledges the possible importance of ethnic and gender differences in decisions to prescribe or withhold isoniazid preventive therapy, as presented in our recent analysis (1).We would like to respond to his other points as follows. Cross-sectional data most certainly cannot be equated with longitudinal data. It is probably accurate to expect cross sectional estimates of case rates to be higher than rates derived longitudinally. Unfortunately, as researchers in this area recognize, there are no adequate, longitudinal studies to provide such estimates. (This is why Dr. Moulding cannot point to a superior data source to be used.) Consequently, we used sensitivity analyses to drop the estimated risks of tuberculosis and found that even at much lower estimates the decisions remained intact, as noted in our discussion. The 8.75% tuberculosis case fatality rate was suggested by Dixie Snider (2) to accommodate a broad range of patients. Again, we decreased this risk estimate in sensitivity procedures, which revealed that the decisions to prescribe isoniazid would hold at substantially lower mortality rates. Regarding the longevity of isoniazid benefits, Dr. Moulding has previously questioned the length of isoniazid protection. However, we know of no specific data available to confirm his speculations. In 1971, he stated his assumption that the protective effect of chemoprophylaxis is limited to 10years (3) for which he cited Ferebee's (4) conclusion that the protective effect of isoniazid had been shown to last for at least 10 years). A lO-yearlimit was never confirmed as far as we know. Now Dr. Moulding apparently has revised his estimate of isoniazid protection upwards to 20 years (similarly without empirical confirmation). The "health concern" factor is a double-edged sword. It is true that persons who are health conscious are less likely than others to die from tuberculosis because they will seek early treatment. It is also likely that these are the individuals who will comply with a preventive therapy regimen and, by taking their medicine as prescribed, be at higher risk of hepatotoxicity than non-compliant persons. Thus, it is inappropriate to examine the effect of this personality factor on only one variable in a highly complex scenario. Developing such fine tuned decisions is an important goal, but existing data leave us far from the point at which such finely tuned decision models are a reality. The relative importance of a near term isoniazid death versus a later tuberculosis death has been taken into account through the use of life expectancies as utility values, i.e.,approximately 15weeks of life for the one and an average of 20 years for the other.
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Finally, we have clearly and repeatedly stated that we have taken a "devil's advocate" position against isoniazid, for the expressed purpose of examining the robustness of the decision in light of a ten year history of arguments about the correctness of specific parameter estimates. Ergo, we explicitly chose to use an upper bound estimate of isoniazid toxicity. The intent of our analysis was not to establish precisely correct parameter estimates, but rather to illustrate that even under "devil's advocate" assumptions, the decision to prescribe isoniazid would be preferred for most groups of patients. In conclusion, wedo not believethat Dr. Moulding's suggestions for revision lead in the direction of improvement, but perhaps back into the morass of arguments over whose estimate is correct, in an arena where there is presently no scientific way to resolve the differences. ThERESA JORDAN, PH.D.
Assistant Professor of Medicine LEE B. REICHMAN, M.D., M.P.H. Professor of Medicine, Preventive Medicine, and Community Health Director of Pulmonary Division University of Medicine and Dentistry of New Jersey New Jersey Medical School University Hospital Newark, NJ
1. Jordan TJ, Lewit EM, Reichman LB. Isoniazid preventive therapy for tuberculosis: a decision analysis considering race and gender. Am Rev Respir Dis 1991; 144:1357-60. 2. Snider DE. Decision analysis for isoniazid preventive therapy: take it or leave it? Am Rev Respir Dis 1988; 137:2-3. 3. Moulding T. Chemoprophylaxis of tuberculosis: when is the benefit work the risk and cost? Ann Intern Med 1971; 74:761-70. 4. FerebeeSH. Controlled chemoprophylaxis trials in tuberculosis: a general review. Advances in tuberculosis research. New York: Basal and S. Karger, 1970; 17:28-106.
To the Editor: The decision analysis by Jordan and coworkers (1), while valuable in presenting ethnic and gender differences in the benefit to risk ratio from taking isoniazid (INH), utilizes several questionable assumptions. (1) The authors had to use estimated case rates of developing tuberculosis (TB) 20 years after INH could have been given because of a lack of data. The authors, as well as others (2-4), took their estimated case rates from an editorial (5). It used cross-sectional data, which inflated these rates by including data for recent convertors as well as long standing reactors for all periods of an individual's life, as shown in the following example. In the editorial (5), case rates for all tuberculin reactors, ages 40 to 49, from two surveys were used to derive a case rate that was then applied to a markedly different group-reactors who had reached the age of 40 to 49 but wereknown to be tuberculin positive 20 years earlier. Reactors found in surveys include both recent convertors and long standing reactors, but reactors who were tuberculin positive 20 years earlier include only long standing reactors. Because recent convertors have markedly higher case rates than long standing reactors, the estimated case rates used by the authors were inflated severalfold. (2) The assumption of 680/0 life-timeprotection from INH is questionable. The study on which it is based was limited to 20 years and showed only 50% protection in the last four years (6). Furthermore, protection from the widely used 6 months of INH appears to be limited to five years in persons with fibrotic pulmonary lesions (7), and is probably much less than life-time protection in reactors with normal chest X-rays. (3)The overallTB case-fatality rate of 8.750/0 is too high for young persons. From national statistics a TB case fatality rate of 2.2% for women and 2.7% for men, ages 25 to 44 can be calculated (8). If one assumes that the protection from INH lasts no more than 20 years, these lower TB case fatality rates should be used for young adults. (4) The "health concern factor" is not considered. Evidence suggests that persons with enough concern about their health to voluntarily take preventive treatment have a reduced chance of dying of TB, even if preventive treatment is not prescribed, because, if TB develops, they are likely to present for treatment sufficiently early to be readily cured (9). (5) Finally, even if INH increases life expectancy, the relative importance of a near-term INH death is probably considerably greater than a later TB death for many if not most people. (6) On the other hand, the authors probably overestimated the INH toxicity case fatality rates in young adults, especially males, because there were no INH deaths in males despite seven deaths in females between the ages of 15and 40 in one published series (10). In conclusion, the authors could improve the value of their decision analysis by using revised assumptions. ThOMAS MOULDING M.D.
Associate Clinical Professor of Medicine Harbor-UCLA Medical Center Torrance, California
1. Jordan TJ, Lewit EM, Reichman LB. Isoniazid preventive treatment for tuberculosis: decision analysis considering ethnicity and gender. Am Rev Respir Dis 1991; 144:1357-60. 2. Rose DN, Schecter CB, Silver AL. The age threshold for isoniazid chemprophylaxis. lAMA 1986; 256:2709-13. 3. Fitzgerald JM, Gafni A. A cost effectiveness analysis of the routine use 1118
of isoniazid prophylaxis in patients with a positive mantoux skin test. Am Rev Respir Dis 1990; 142:848-53. 4. Rose DR, Schecter CB, Fahs MC, Silver AI. Tuberculosis prevention: cost-effectiveness analysis of isoniazid chemoprophylaxis. Am 1 of Preventive Medicine 1988; 4:102-9. 5. Comstock GW, Edwards PQ. The competing risk of tuberculosis and hepatitis for adult tuberculin reactors. Am Rev Respir Dis 1975; 111:573-7. 6. Comstock GW, Baum C, Snider DE. Isoniazid prophylaxis among Alaskan eskimos: a final report of the bethel isoniazid studies. Am Rev Respir Dis 1979; 119:827-30. 7. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow up in the IUAT trial. Bull WHO 1982; 60:555-64. 8. U.S. Department of Health and Human Services/Public Health Service/Centers for Disease Control: Tuberculosis in the United States: 1981-1984. pages 20 and 22 HHS Publication No. (CDC) 86-8322. 9. Moulding T, Barnes P. Isoniazid for the tuberculin reactor: take it or leave it. Am Rev Respir Dis 1988; 138:489. 10. Moulding TS, Redeker AG, Kanel GC. l\venty isoniazid-associated deaths in one state. Am Rev Respir Dis 1989; 140:700-5.
From the Authors: We are pleased that Dr. Moulding acknowledges the possible importance of ethnic and gender differences in decisions to prescribe or withhold isoniazid preventive therapy, as presented in our recent analysis (1).We would like to respond to his other points as follows. Cross-sectional data most certainly cannot be equated with longitudinal data. It is probably accurate to expect cross sectional estimates of case rates to be higher than rates derived longitudinally. Unfortunately, as researchers in this area recognize, there are no adequate, longitudinal studies to provide such estimates. (This is why Dr. Moulding cannot point to a superior data source to be used.) Consequently, we used sensitivity analyses to drop the estimated risks of tuberculosis and found that even at much lower estimates the decisions remained intact, as noted in our discussion. The 8.75% tuberculosis case fatality rate was suggested by Dixie Snider (2) to accommodate a broad range of patients. Again, we decreased this risk estimate in sensitivity procedures, which revealed that the decisions to prescribe isoniazid would hold at substantially lower mortality rates. Regarding the longevity of isoniazid benefits, Dr. Moulding has previously questioned the length of isoniazid protection. However, we know of no specific data available to confirm his speculations. In 1971, he stated his assumption that the protective effect of chemoprophylaxis is limited to 10years (3) for which he cited Ferebee's (4) conclusion that the protective effect of isoniazid had been shown to last for at least 10 years). A lO-yearlimit was never confirmed as far as we know. Now Dr. Moulding apparently has revised his estimate of isoniazid protection upwards to 20 years (similarly without empirical confirmation). The "health concern" factor is a double-edged sword. It is true that persons who are health conscious are less likely than others to die from tuberculosis because they will seek early treatment. It is also likely that these are the individuals who will comply with a preventive therapy regimen and, by taking their medicine as prescribed, be at higher risk of hepatotoxicity than non-compliant persons. Thus, it is inappropriate to examine the effect of this personality factor on only one variable in a highly complex scenario. Developing such fine tuned decisions is an important goal, but existing data leave us far from the point at which such finely tuned decision models are a reality. The relative importance of a near term isoniazid death versus a later tuberculosis death has been taken into account through the use of life expectancies as utility values, i.e.,approximately 15weeks of life for the one and an average of 20 years for the other.
1119
Finally, we have clearly and repeatedly stated that we have taken a "devil's advocate" position against isoniazid, for the expressed purpose of examining the robustness of the decision in light of a ten year history of arguments about the correctness of specific parameter estimates. Ergo, we explicitly chose to use an upper bound estimate of isoniazid toxicity. The intent of our analysis was not to establish precisely correct parameter estimates, but rather to illustrate that even under "devil's advocate" assumptions, the decision to prescribe isoniazid would be preferred for most groups of patients. In conclusion, wedo not believethat Dr. Moulding's suggestions for revision lead in the direction of improvement, but perhaps back into the morass of arguments over whose estimate is correct, in an arena where there is presently no scientific way to resolve the differences. ThERESA JORDAN, PH.D.
Assistant Professor of Medicine LEE B. REICHMAN, M.D., M.P.H. Professor of Medicine, Preventive Medicine, and Community Health Director of Pulmonary Division University of Medicine and Dentistry of New Jersey New Jersey Medical School University Hospital Newark, NJ
1. Jordan TJ, Lewit EM, Reichman LB. Isoniazid preventive therapy for tuberculosis: a decision analysis considering race and gender. Am Rev Respir Dis 1991; 144:1357-60. 2. Snider DE. Decision analysis for isoniazid preventive therapy: take it or leave it? Am Rev Respir Dis 1988; 137:2-3. 3. Moulding T. Chemoprophylaxis of tuberculosis: when is the benefit work the risk and cost? Ann Intern Med 1971; 74:761-70. 4. FerebeeSH. Controlled chemoprophylaxis trials in tuberculosis: a general review. Advances in tuberculosis research. New York: Basal and S. Karger, 1970; 17:28-106.
