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Thrombolytic therapy and mortality
CORRESPONDENCE
Thrombolytic therapy and mortality Sir—Harvey White’s Dec 6 commentary1 about our observational study in which we showed an association between thrombolytic therapy and excess 30-day mortality for US patients with myocardial infarction aged older than 75 years2 contains curious factual elisions. Despite White’s concern that our results contradict those of the original Fibrinolytic Therapy Trialists’ (FTT) meta-analysis,3 recognition that the relative benefit of thrombolytic therapy diminishes with age is not new. The FTT study showed an odds ratio of 0·74 for 35 day mortality in patients younger than 55 years, with a significant increase to 0·96 among patients older than 75 years. The same trend holds in White’s unpublished analysis of FTT patients meeting current thrombolytic criteria, albeit with greater benefit. Such continuous interactions inherently meet a higher standard than the arbitrary, dichotomous, posthoc subgroup analyses criticised in the commentary. Responsible arguments for thrombolysis in elderly people have always been couched in terms of diminished relative benefit but the expectation of persistent absolute benefit. The commentary ascribes our findings to selection bias, although we used the same selection criteria as randomised trials of thrombolysis. In actuality bias strongly favoured thrombolytic patients, who had lower comorbidity, illness severity, and predicted mortality than did patients who did not receive thrombolytic therapy. The survival disadvantage for older thrombolytic patients persisted after excluding patients with thrombolytic contraindications and those who had had transfusion or stroke, so attribution of our findings to contraindications and bleeding complications is unsupportable. In the commentary, White cites an observational study4 that suggests thrombolytic benefit in 1 year mortality, irrespective of age, without mentioning that the same study replicated our 30 day findings, with benefit among patients younger than 75 years and an adjusted survival disadvantage among thrombolytic patients aged 75–84 years. Since workers in randomised trials have shown no additive benefit beyond 30 days,5 there is every reason to suspect that long-term survival in
THE LANCET • Vol 357 • April 28, 2001
observational studies is determined by underlying selection bias favouring thrombolytic patients rather than by thrombolytic effectiveness. Although White advocates reliance on randomised trials, we believe that trials and observational studies are complementary. Trials can assess therapeutic efficacy in selected populations but frequently have limited generalisability and do not guarantee effectiveness in community practice. The skewed age distribution of patients in existing thrombolytic trials, in which the disproportionately small subgroup of patients older than 75 years consists mostly of patients in their mid-70s, provides little management guidance for octogenarians. The question raised by our findings is therefore, whether in the real world thrombolysis is harmful for elderly patients generally or for subgroups identified by sex, electrocardiography, or time from symptoms to treatment. This issue cannot be resolved by the commentary’s description of results from an unpublished FTT metaanalysis, in which many control patients did not receive aspirin or heparin. Inclusive randomised and observational studies of contemporary reperfusion therapy focused specifically on elderly patients with myocardial infarction are urgently needed. *David R Thiemann, Josef Coresh, Steven P Schulman, Gary Gerstenblith, Neil R Powe Departments of *Medicine, Epidemiology, Biostatistics, and Health Policy and Management, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, MD 21287, USA 1 2
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White HD. Thrombolytic therapy in the elderly. Lancet 2001; 356: 2028–30. Thiemann DR, Coresh J, Schulman SP, et al. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 2000; 101: 2239–46. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343: 311–22. Berger AK, Radford MJ, Wang Y, Krumholz HM. Thrombolytic therapy in older patients. J Am Coll Cardiol 2000; 36: 366–74. Franzosi MG, Santoro E, De Vita C, et al, for the GISSI investigators. Ten-year followup of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-1 Study. Circulation 1998; 98: 2659–65.
Author’s reply Sir—I agree with David Thiemann and colleagues that absolute benefit is the most appropriate measure of thrombolytic benefit in elderly people. However, they again present old data from the FTT overview, which included all patients randomised within 24 h of symptom onset irrespective of electrocardiographic features. As I stated in my commentary, the new FTT data show that the absolute mortality reduction in patients older than 75 years presenting within 12 h with ST elevation or left bundle branch block (around 1800 of whom were octogenarians) was 34 patients per 1000 randomised (vs 16 per 1000 in those <55 years). The 35 day mortality reduction (from 29·4% to 26·0%) was significant in patients older than 75 years, and thrombolytic therapy is, therefore, beneficial in these patients. Contrary to Dr Thiemann’s assertion, there was no significant heterogeneity of proportional effects between the different age-groups. There is therefore good evidence of thrombolytic benefit overall, and none of any lack of benefit in elderly people. Registry studies can raise important issues about usage rates of various treatments, and can help to assess how representative trial populations are of patients encountered in clinical practice. Such studies cannot, however, prove whether treatments with moderate effects do or do not work.1 The most rigorous way to assess the benefits of thrombolytic therapy in elderly people is to use randomised trial data. Registries cannot correct for unknown differences between groups. Thiemann and colleagues acknowledged in their observational study that the value of direct comparisons between thrombolytictreated and non-thrombolytic-treated populations in their registry was limited by selection bias. Only 34% of eligible patients in the 76–86 years age-group who met Thiemann and colleagues’ electrocardiographic criteria for thrombolysis were included in the study. Only 60% of those patients received thrombolytic therapy, which equates to a thrombolysis rate of 21% of patients judged eligible for the study and only 6% of all patients with a discharge diagnosis of infarction. In a concurrent study from Auckland,2 75% of patients in the same age-group who fulfilled electrocardiographic
1367
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Thrombolytic therapy and mortality Sir—Harvey White’s Dec 6 commentary1 about our observational study in which we showed an association between thrombolytic therapy and excess 30-day mortality for US patients with myocardial infarction aged older than 75 years2 contains curious factual elisions. Despite White’s concern that our results contradict those of the original Fibrinolytic Therapy Trialists’ (FTT) meta-analysis,3 recognition that the relative benefit of thrombolytic therapy diminishes with age is not new. The FTT study showed an odds ratio of 0·74 for 35 day mortality in patients younger than 55 years, with a significant increase to 0·96 among patients older than 75 years. The same trend holds in White’s unpublished analysis of FTT patients meeting current thrombolytic criteria, albeit with greater benefit. Such continuous interactions inherently meet a higher standard than the arbitrary, dichotomous, posthoc subgroup analyses criticised in the commentary. Responsible arguments for thrombolysis in elderly people have always been couched in terms of diminished relative benefit but the expectation of persistent absolute benefit. The commentary ascribes our findings to selection bias, although we used the same selection criteria as randomised trials of thrombolysis. In actuality bias strongly favoured thrombolytic patients, who had lower comorbidity, illness severity, and predicted mortality than did patients who did not receive thrombolytic therapy. The survival disadvantage for older thrombolytic patients persisted after excluding patients with thrombolytic contraindications and those who had had transfusion or stroke, so attribution of our findings to contraindications and bleeding complications is unsupportable. In the commentary, White cites an observational study4 that suggests thrombolytic benefit in 1 year mortality, irrespective of age, without mentioning that the same study replicated our 30 day findings, with benefit among patients younger than 75 years and an adjusted survival disadvantage among thrombolytic patients aged 75–84 years. Since workers in randomised trials have shown no additive benefit beyond 30 days,5 there is every reason to suspect that long-term survival in
THE LANCET • Vol 357 • April 28, 2001
observational studies is determined by underlying selection bias favouring thrombolytic patients rather than by thrombolytic effectiveness. Although White advocates reliance on randomised trials, we believe that trials and observational studies are complementary. Trials can assess therapeutic efficacy in selected populations but frequently have limited generalisability and do not guarantee effectiveness in community practice. The skewed age distribution of patients in existing thrombolytic trials, in which the disproportionately small subgroup of patients older than 75 years consists mostly of patients in their mid-70s, provides little management guidance for octogenarians. The question raised by our findings is therefore, whether in the real world thrombolysis is harmful for elderly patients generally or for subgroups identified by sex, electrocardiography, or time from symptoms to treatment. This issue cannot be resolved by the commentary’s description of results from an unpublished FTT metaanalysis, in which many control patients did not receive aspirin or heparin. Inclusive randomised and observational studies of contemporary reperfusion therapy focused specifically on elderly patients with myocardial infarction are urgently needed. *David R Thiemann, Josef Coresh, Steven P Schulman, Gary Gerstenblith, Neil R Powe Departments of *Medicine, Epidemiology, Biostatistics, and Health Policy and Management, and Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, MD 21287, USA 1 2
3
4
5
White HD. Thrombolytic therapy in the elderly. Lancet 2001; 356: 2028–30. Thiemann DR, Coresh J, Schulman SP, et al. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 2000; 101: 2239–46. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994; 343: 311–22. Berger AK, Radford MJ, Wang Y, Krumholz HM. Thrombolytic therapy in older patients. J Am Coll Cardiol 2000; 36: 366–74. Franzosi MG, Santoro E, De Vita C, et al, for the GISSI investigators. Ten-year followup of the first megatrial testing thrombolytic therapy in patients with acute myocardial infarction: results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto-1 Study. Circulation 1998; 98: 2659–65.
Author’s reply Sir—I agree with David Thiemann and colleagues that absolute benefit is the most appropriate measure of thrombolytic benefit in elderly people. However, they again present old data from the FTT overview, which included all patients randomised within 24 h of symptom onset irrespective of electrocardiographic features. As I stated in my commentary, the new FTT data show that the absolute mortality reduction in patients older than 75 years presenting within 12 h with ST elevation or left bundle branch block (around 1800 of whom were octogenarians) was 34 patients per 1000 randomised (vs 16 per 1000 in those <55 years). The 35 day mortality reduction (from 29·4% to 26·0%) was significant in patients older than 75 years, and thrombolytic therapy is, therefore, beneficial in these patients. Contrary to Dr Thiemann’s assertion, there was no significant heterogeneity of proportional effects between the different age-groups. There is therefore good evidence of thrombolytic benefit overall, and none of any lack of benefit in elderly people. Registry studies can raise important issues about usage rates of various treatments, and can help to assess how representative trial populations are of patients encountered in clinical practice. Such studies cannot, however, prove whether treatments with moderate effects do or do not work.1 The most rigorous way to assess the benefits of thrombolytic therapy in elderly people is to use randomised trial data. Registries cannot correct for unknown differences between groups. Thiemann and colleagues acknowledged in their observational study that the value of direct comparisons between thrombolytictreated and non-thrombolytic-treated populations in their registry was limited by selection bias. Only 34% of eligible patients in the 76–86 years age-group who met Thiemann and colleagues’ electrocardiographic criteria for thrombolysis were included in the study. Only 60% of those patients received thrombolytic therapy, which equates to a thrombolysis rate of 21% of patients judged eligible for the study and only 6% of all patients with a discharge diagnosis of infarction. In a concurrent study from Auckland,2 75% of patients in the same age-group who fulfilled electrocardiographic
1367
For personal use. Only reproduce with permission from The Lancet Publishing Group.