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Anticoagulant therapy in acute myocardial infarction: Demonstration of a selection bias in a retrospective study
THROMBOSIS RESEARCH 18; 753-757, 1980 0049-3848/80/120753-05$02.00/O Printed in the USA. All rights reserved. Copyright (c) 1980 Pergamon Press Ltd
ANTICOAGULANT THERAPY IN ACUTE MYOCARDIAL INFARCTION: DEMONSTRATION OF A SELECTION BIAS IN A RETROSPECTIVE STUDY
M. Ravid, N. Kleinmu, J. Shapira, M. Lischner and D. Feigl Department of Medlcine, Meir and Jsffa Hospitals and the Heller Institute of Medical Research, Sackler School of Medicine, Tel Aviv University, Israel (Received 7.3.1980. Accepted by Editor D. Danon. Received by Executive Editorial Office 17.4.1980)
ABSTRACT
Records of 851 paticats with first acute myocardial iufarctim were BLJBlyzed in order to identify the effect of anticosgulsnt therapy 011hospW mortality. A coronary prognostic index was applied snd the patients .were allocated into subgrms with similar predicted prognosis. When the mortality rates of treated versus mm-treated pat&&s were cmpared within each subgratp, no effect of snticoagulants m mortality could be demmstrated. However, when the patseats were divided arly according to snticoagulant therapy, a significantly lower mortality rate was found $n the treated gratp: 12.3% versus 22.3% @< 0.001). Tbe disparity of results obtained via Werent methods of patient allocation may be expla&ed by the existence of a selectim bias expressed by the choice of better risk patients for anticoagulant treatment. Indeed, analysis of the reoerds showed that the ratio of treated versus nm-treated patients decreased in parallel with the worsening of prognosis.
INTRODUCTION The dispute over the merits of anticoagulant therapy in acute myocardial infarction was reopened by a series of epidemiological surveys (l-3) which showed a significant decrease in case fatality rate among treated patients. The methodology of these retrospective studies was criticized (4, 5). Itwas pointed outthata case selection bias could not have been eliminated. Furthermore, analysis of the data suggested that the decisim to s&coagulate acted as a prognostic screening test with better risk patients being chosen for treatment (5). Key words: Myocardial infarctim,
snticoagulsnts, prognostic index, selectim bias. 753
754
ONACUTEMYOCARDIAL INFARCTION
Vo1.18,No.6
These assumptions of the critics were put to the test in the present analysis of the effect of anticoagulants on mortality in 851 cases of acute myocardial infarction. Admission prognostic criteria were employed in order to eliminate the case selection bias. The effect of patient allocation on the results and on the conclusions is demonstrated. MATERIALS AND METHODS The records of all patients admitted to the Jaffa Hospital with a diagnosis of acute myocardial infarction, acute coronary insufficiemy and other related diagnostic entities during Sur consecutive years starting January 1, 1966 were reviewed. The original electrocardiograms were examined according to World Health Organization criteria (6). The diagnosis of acute myocardial infarctian was made if two of the following three criteria were met: a conclusive electrocardiographic pattern, a typical history and abnormally high levels of serum enzymes. Altogether close to 2000 records were reviewed. The present report includes 851 cases of definite first acute myocardial infarction. Since the vast majority of the patients were discharged on the twentieth day or later it was possible to establish the patients’ vital status through the hospital records. The only information extracted regarding anticoagulants was whether or not they were given. An admission coronary prognostic index (7) was calculated for each patient based on the following parameters: age, electrocardiographic assessment of the site and extent of infarction, systolic blood pressure co admission, heart size and degree of lung congestian assessed from a chest X-ray and history of previous ischemia. In order to test the value of the index for the purpose of this study the patients were allocated into five groups according to the sum of points scored by each patient. The correlation coefficient between the logarithm of mortality rate of each group and the prognostic index was computed (8). The patients in each index group were then subdivided according to whether they had or had not received anticoagulant therapy. The difference in mortality between the anticoagulant and non-anticoagulant subgroups within each index group was tested by the chi-square test. During the study period there was no coronary care unit in the hospital, and there was no standard policy of anticoagulant therapy. RESULTS There were 151 deaths among 851 patients with first acute myocardial infarction (17.7%). The difference in mortality rates between anticoagulant treated and non-treated groups was highly significant (p< 0.001) in favor of the anticoagulant group. The risk ratio did not change when patients who died within the first 48 hours were excluded. When the patients were subdivided according to the coronary prognostic index, the lowest mortality rate (6.3%) was found among patients with the lowest index while the group with the highest index showed the highest mortality rate (74.6%). There was a logarithmic rise of mortality rates in the consecutive index groups, as demonstrated in Figure 1. A highly significant correlation was found between the coronary prognostic index and the logarithm of mortality rate (r= 0.86, p< 0.005).
ONACUTEMYOCARDIAL INFARCTION
Vo1.18,No.6
7.55
hog. lndtx 12 11 10 9 8 7 6 5
loJ aorlality FIG, 1 Logarithmic correlation between mortality from acute myocardial infarction and the coronary prognostic index.
TABLE 1 Mortality according to the coronary prognostic index groups and anticoagulant therapy in 851 patients. ACT Prognostic Index
(A)
No. of Mortality cases $
<5
No ACT
(B)
No. of Mortaljty cases %
105
6. ‘7
68
5.1- 7 7.1- 9 9.1- 11 > 11.1
168 ‘76 28 12
7.1 13.2 35. 7 75. 0
All cases
389
Exe luding 48 h. death
379
All
p Value Avs. B
cases
Mortality Given ACT s9&
158 104 81 51
5.9 8.2 17. 2 37.0 74.5
NS* NS NS NS NS
6.3 7. 7 15.6 36.6 74.6
60. 7 51.5 42.2 25.6 19.0
12.3
462
22.3
< 0.001
17.7
45.7
10.0
433
17.1
< 0.001
13.8
46.7
ACT - Anticoagulants;
NS - Non-significant
756
ON ACUTE M-YOCARDIALINFARCTION
Vo1.18,No.6
The comparison between the mortality rates among patients who received anticoagulant therapy and the ccatrol patients within each index group showed that the differences were small and insignificant in either direction. Thus the subdivision into anticoagulant and non-anticoagulant groups did not affect the basic correlation between mortality rates and the prognostic index without any apparent influence of anticoagulant therapy on mortality. Table 1 also reveals that while among patients with a good prognosis (index c 7) there was a prepcnderance of those who received anticoagulant therapy, their relative and absolute number gradually decreased in the subsequent groups with a worsening prognosis: from over 60% among the low risk patients to only 19% of the highest risk patients. DISCUSSION The present study highlights the impact of patient allocation on the results, and demonstrates that a selection bias, inherent to many retrospective studies (9, 10) may be omitted if a proper method of stratification for prognosis is applied to retrospective data. When the total group of patients was divided according to anticoagulant therapy, a lower mortality rate was found in the treated group. However, when the patients were reallocated into subgroups with similar predicted prognosis and the comparison between treated and non-treated patients was carried out within each subgroup, the effect of anticoagulants on mortality could no longer be demonstrated. The behavior of both the treated and the non-treated subgroups did not differ from the behavior of the whole group and showed a highly significant correlation with the coronary prognostic index. This discrepancy between the results obtained via the two methods may be explained by the assumption raised by Feinstein (5) that better risk patients were selected for treatment. Indeed, in our material the better the prognosis the larger was the percentage of patients who received anticoagulant therapy. We analyzed our data separately for each of the four years included in the study and found that the same pattern persisted: the majority of the good risk patients received anticoagulant therapy while most of the bad risk patients did not. One would have to recruit psychological considerations in order to try and explain this phenomenon of the “anticoagulant prognostic screening” but it seems to be outside the scope of this report. significantly
Since it is retrospective, this report may not constitute an unequivocal proof 03 the inefficacy of anticoagulant therapy in myocardial infarction. It may, however, shed some light on the causes of the disparities between the results of some retrospective studies (1, 2) and those of prospective control trials (11-13).
REFERENCES 1. MODAN, B., SHANI, M., SCHOR, S. and MODAN, M. Reduction of hospital mortality from acute myocardial infarction by anticoagulant therapy. N. Engl. J. Med. 292, 1359-1362. 1975. 2. TONASCIA, J., GORDIS, L, and SCHMERLER, H. Retrospective evidence favoring use of anticoagulants for myocardial infarction. N. Engl. J. Med. 292, 1362-1366, 1975.
Vo1.18,No.6
3.
ONACUTEMYOCARDIAL INFARCTION
757
CHALMERS, T. C., MATTA, R. J. , SMITH, H., et al. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N. En&. J. Med. 297, 1091-1096, 1977.
4. ROGEL, S. and BASSAN, M.M. Anticoagulants in ischemic heart disease. Intern. Med. 136, 1229-1230, 1976.
Arch.
5.
FEINSTEIN, A. R. More blood for the anticoagulant battle. 1400-1402, 1975.
N. Engl. J. Med. 292,
6.
SLQMAN, G. and BROWN, R. Hospital registration in patients with acute myocardial infarction. Am.HeartJ. 79, 761-768, 1970.
7. NORRIS, R. M., BRANDT, F. W. T., CAUGHEY, D. E., et al. A new coronary prognostic index. Lancet & 274-278, 1969. 8.
ENGLAND, J. M. Medical Research. A Statistical and Epidemiological Approach. Edinburgh: Churchill & Livingston, 1975, pp. 147-154.
9.
FEINSTEIN, A. R. Clinical Biostatistics, X. Sources of “Transition Bias” in cohort statistics. Clin. Pharmacol. Ther. 12, 704-721, 1971.
10. GIFFORD, R. H. and FEINSTEIN, A. R. A critique of methodology in studies of anticoagulant therapy for acute myocardial infarction. N. Engl. J. Med. 208, 351-357, 1969. 11. Assessment of short term anticoagulant administration after cardiac infarcticus: Report of the Working Party c11Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Br. Med. J. 1, 335-342, 1969. 12. Anticoagulants in acute myocardial infarction: trial. J.A.M.A. 225, 724-729, 1973.
results of a cooperative clinical
13. HILDEN, T., IVERSON, K., RAASCHOU, F., et al. Anticoagulants in acute myocardial infarction. Lancet 2, 327-331, 1961.
ANTICOAGULANT THERAPY IN ACUTE MYOCARDIAL INFARCTION: DEMONSTRATION OF A SELECTION BIAS IN A RETROSPECTIVE STUDY
M. Ravid, N. Kleinmu, J. Shapira, M. Lischner and D. Feigl Department of Medlcine, Meir and Jsffa Hospitals and the Heller Institute of Medical Research, Sackler School of Medicine, Tel Aviv University, Israel (Received 7.3.1980. Accepted by Editor D. Danon. Received by Executive Editorial Office 17.4.1980)
ABSTRACT
Records of 851 paticats with first acute myocardial iufarctim were BLJBlyzed in order to identify the effect of anticosgulsnt therapy 011hospW mortality. A coronary prognostic index was applied snd the patients .were allocated into subgrms with similar predicted prognosis. When the mortality rates of treated versus mm-treated pat&&s were cmpared within each subgratp, no effect of snticoagulants m mortality could be demmstrated. However, when the patseats were divided arly according to snticoagulant therapy, a significantly lower mortality rate was found $n the treated gratp: 12.3% versus 22.3% @< 0.001). Tbe disparity of results obtained via Werent methods of patient allocation may be expla&ed by the existence of a selectim bias expressed by the choice of better risk patients for anticoagulant treatment. Indeed, analysis of the reoerds showed that the ratio of treated versus nm-treated patients decreased in parallel with the worsening of prognosis.
INTRODUCTION The dispute over the merits of anticoagulant therapy in acute myocardial infarction was reopened by a series of epidemiological surveys (l-3) which showed a significant decrease in case fatality rate among treated patients. The methodology of these retrospective studies was criticized (4, 5). Itwas pointed outthata case selection bias could not have been eliminated. Furthermore, analysis of the data suggested that the decisim to s&coagulate acted as a prognostic screening test with better risk patients being chosen for treatment (5). Key words: Myocardial infarctim,
snticoagulsnts, prognostic index, selectim bias. 753
754
ONACUTEMYOCARDIAL INFARCTION
Vo1.18,No.6
These assumptions of the critics were put to the test in the present analysis of the effect of anticoagulants on mortality in 851 cases of acute myocardial infarction. Admission prognostic criteria were employed in order to eliminate the case selection bias. The effect of patient allocation on the results and on the conclusions is demonstrated. MATERIALS AND METHODS The records of all patients admitted to the Jaffa Hospital with a diagnosis of acute myocardial infarction, acute coronary insufficiemy and other related diagnostic entities during Sur consecutive years starting January 1, 1966 were reviewed. The original electrocardiograms were examined according to World Health Organization criteria (6). The diagnosis of acute myocardial infarctian was made if two of the following three criteria were met: a conclusive electrocardiographic pattern, a typical history and abnormally high levels of serum enzymes. Altogether close to 2000 records were reviewed. The present report includes 851 cases of definite first acute myocardial infarction. Since the vast majority of the patients were discharged on the twentieth day or later it was possible to establish the patients’ vital status through the hospital records. The only information extracted regarding anticoagulants was whether or not they were given. An admission coronary prognostic index (7) was calculated for each patient based on the following parameters: age, electrocardiographic assessment of the site and extent of infarction, systolic blood pressure co admission, heart size and degree of lung congestian assessed from a chest X-ray and history of previous ischemia. In order to test the value of the index for the purpose of this study the patients were allocated into five groups according to the sum of points scored by each patient. The correlation coefficient between the logarithm of mortality rate of each group and the prognostic index was computed (8). The patients in each index group were then subdivided according to whether they had or had not received anticoagulant therapy. The difference in mortality between the anticoagulant and non-anticoagulant subgroups within each index group was tested by the chi-square test. During the study period there was no coronary care unit in the hospital, and there was no standard policy of anticoagulant therapy. RESULTS There were 151 deaths among 851 patients with first acute myocardial infarction (17.7%). The difference in mortality rates between anticoagulant treated and non-treated groups was highly significant (p< 0.001) in favor of the anticoagulant group. The risk ratio did not change when patients who died within the first 48 hours were excluded. When the patients were subdivided according to the coronary prognostic index, the lowest mortality rate (6.3%) was found among patients with the lowest index while the group with the highest index showed the highest mortality rate (74.6%). There was a logarithmic rise of mortality rates in the consecutive index groups, as demonstrated in Figure 1. A highly significant correlation was found between the coronary prognostic index and the logarithm of mortality rate (r= 0.86, p< 0.005).
ONACUTEMYOCARDIAL INFARCTION
Vo1.18,No.6
7.55
hog. lndtx 12 11 10 9 8 7 6 5
loJ aorlality FIG, 1 Logarithmic correlation between mortality from acute myocardial infarction and the coronary prognostic index.
TABLE 1 Mortality according to the coronary prognostic index groups and anticoagulant therapy in 851 patients. ACT Prognostic Index
(A)
No. of Mortality cases $
<5
No ACT
(B)
No. of Mortaljty cases %
105
6. ‘7
68
5.1- 7 7.1- 9 9.1- 11 > 11.1
168 ‘76 28 12
7.1 13.2 35. 7 75. 0
All cases
389
Exe luding 48 h. death
379
All
p Value Avs. B
cases
Mortality Given ACT s9&
158 104 81 51
5.9 8.2 17. 2 37.0 74.5
NS* NS NS NS NS
6.3 7. 7 15.6 36.6 74.6
60. 7 51.5 42.2 25.6 19.0
12.3
462
22.3
< 0.001
17.7
45.7
10.0
433
17.1
< 0.001
13.8
46.7
ACT - Anticoagulants;
NS - Non-significant
756
ON ACUTE M-YOCARDIALINFARCTION
Vo1.18,No.6
The comparison between the mortality rates among patients who received anticoagulant therapy and the ccatrol patients within each index group showed that the differences were small and insignificant in either direction. Thus the subdivision into anticoagulant and non-anticoagulant groups did not affect the basic correlation between mortality rates and the prognostic index without any apparent influence of anticoagulant therapy on mortality. Table 1 also reveals that while among patients with a good prognosis (index c 7) there was a prepcnderance of those who received anticoagulant therapy, their relative and absolute number gradually decreased in the subsequent groups with a worsening prognosis: from over 60% among the low risk patients to only 19% of the highest risk patients. DISCUSSION The present study highlights the impact of patient allocation on the results, and demonstrates that a selection bias, inherent to many retrospective studies (9, 10) may be omitted if a proper method of stratification for prognosis is applied to retrospective data. When the total group of patients was divided according to anticoagulant therapy, a lower mortality rate was found in the treated group. However, when the patients were reallocated into subgroups with similar predicted prognosis and the comparison between treated and non-treated patients was carried out within each subgroup, the effect of anticoagulants on mortality could no longer be demonstrated. The behavior of both the treated and the non-treated subgroups did not differ from the behavior of the whole group and showed a highly significant correlation with the coronary prognostic index. This discrepancy between the results obtained via the two methods may be explained by the assumption raised by Feinstein (5) that better risk patients were selected for treatment. Indeed, in our material the better the prognosis the larger was the percentage of patients who received anticoagulant therapy. We analyzed our data separately for each of the four years included in the study and found that the same pattern persisted: the majority of the good risk patients received anticoagulant therapy while most of the bad risk patients did not. One would have to recruit psychological considerations in order to try and explain this phenomenon of the “anticoagulant prognostic screening” but it seems to be outside the scope of this report. significantly
Since it is retrospective, this report may not constitute an unequivocal proof 03 the inefficacy of anticoagulant therapy in myocardial infarction. It may, however, shed some light on the causes of the disparities between the results of some retrospective studies (1, 2) and those of prospective control trials (11-13).
REFERENCES 1. MODAN, B., SHANI, M., SCHOR, S. and MODAN, M. Reduction of hospital mortality from acute myocardial infarction by anticoagulant therapy. N. Engl. J. Med. 292, 1359-1362. 1975. 2. TONASCIA, J., GORDIS, L, and SCHMERLER, H. Retrospective evidence favoring use of anticoagulants for myocardial infarction. N. Engl. J. Med. 292, 1362-1366, 1975.
Vo1.18,No.6
3.
ONACUTEMYOCARDIAL INFARCTION
757
CHALMERS, T. C., MATTA, R. J. , SMITH, H., et al. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N. En&. J. Med. 297, 1091-1096, 1977.
4. ROGEL, S. and BASSAN, M.M. Anticoagulants in ischemic heart disease. Intern. Med. 136, 1229-1230, 1976.
Arch.
5.
FEINSTEIN, A. R. More blood for the anticoagulant battle. 1400-1402, 1975.
N. Engl. J. Med. 292,
6.
SLQMAN, G. and BROWN, R. Hospital registration in patients with acute myocardial infarction. Am.HeartJ. 79, 761-768, 1970.
7. NORRIS, R. M., BRANDT, F. W. T., CAUGHEY, D. E., et al. A new coronary prognostic index. Lancet & 274-278, 1969. 8.
ENGLAND, J. M. Medical Research. A Statistical and Epidemiological Approach. Edinburgh: Churchill & Livingston, 1975, pp. 147-154.
9.
FEINSTEIN, A. R. Clinical Biostatistics, X. Sources of “Transition Bias” in cohort statistics. Clin. Pharmacol. Ther. 12, 704-721, 1971.
10. GIFFORD, R. H. and FEINSTEIN, A. R. A critique of methodology in studies of anticoagulant therapy for acute myocardial infarction. N. Engl. J. Med. 208, 351-357, 1969. 11. Assessment of short term anticoagulant administration after cardiac infarcticus: Report of the Working Party c11Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Br. Med. J. 1, 335-342, 1969. 12. Anticoagulants in acute myocardial infarction: trial. J.A.M.A. 225, 724-729, 1973.
results of a cooperative clinical
13. HILDEN, T., IVERSON, K., RAASCHOU, F., et al. Anticoagulants in acute myocardial infarction. Lancet 2, 327-331, 1961.