- Email: [email protected]
Thrombolytic therapy in the elderly
COMMENTARY
seems to have an effect on adult BMI that is independent of the time of rebound.6 However, the correlations between BMI at age 7 and adult BMI and between age at rebound and adult BMI are much the same. BMI at age 7 may thus be a more practical criterion for the determination of risk.7 Because BMI is weight (kg) divided by height (m2), an increased BMI can reflect either increased weight or decreased height, and it is not known whether children or adults with early increases in BMI are heavier or have a reduced height velocity compared with children with later increases in BMI. Even if the differences in BMI in childhood can be attributed to increased weight, whether the increase is in body fat rather than bone or muscle mass remains unclear. A similar argument applies to adults. The factors that predispose to early BMI rebound also remain uncertain. Television viewing by American children has been linked to obesity,9 but there is no evidence that children with early rebound are more sedentary than children with later rebound. Two small studies have suggested that early protein intake predicts an increase in BMI10,11 or subscapular skinfold thickness10 at the time of adiposity rebound11 or at age 8 years.10 In a larger sample of children for whom 3-day prospective household measures were collected at ages 8 and 18 months, no significant association was found between protein, fat, or carbohydrate intake and the timing of BMI rebound.12 Furthermore, how would increased protein intake lead to early rebound? Nor do children always eat what their parents urge them to. For example, encouragement to eat certain foods may reduce intake of that food13 whereas restrictions on a food item may lead to increased consumption of it when the restriction is removed.14 In a cross-sectional study, increased parental control over food intake was associated with an impaired capacity of children to regulate their own intake15 but this study cannot tell whether this finding indicated cause and effect or effect and cause. Adiposity rebound has been based on population measures. In an individual this rebound may be difficult to judge. Measurement error will probably confound assessment of early BMI rebound in young children. For example, a measurement error of 2 cm in a child who weighs 20 kg and is 115 cm tall will account for an error of 0·5 of a BMI unit. Furthermore, few children are likely to be seen frequently enough for the period of rebound to be identified—and because the period of rebound can be identified only retrospectively, early rebound may not be preventable. William H Dietz Division of Nutrition and Physical Activity, Centers for Disease Control and Prevention, Atlanta, GA 30341,USA
1
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Rolland-Cachera M-F, Deheeger M, Bellisle F, Sempe M, GuilloudBataille M, Patois E. Adiposity rebound in children: a simple indicator for predicting adiposity. Am J Clin Nutr 1984; 39: 129–35. Rolland-Cachera MF, Avons P, Patois E, Sempe M. Tracking the development of adiposity from one month of age to adulthood. Ann Human Biol 1987; 14: 219–29. Rolland-Cachwera M-F, Bellisle F, Deheeger M, Guilloud-Bataille M, Pequignot F, Sempe, M. Adiposity development and prediction during growth in humans: a two decade follow-up study. In: Bjorntorp P, Rossner S, eds. Obesity in Europe 88. London: John Libbey, 1988. Siervogel RM, Roche AF, Guo S, Mukherjee D, Chumlea WC. Patterns of change in weight/stature2 from 2 to 18 years: findings from long-term serial data for children in the Fels longitudinal growth study. Int J Obesity 1991; 15: 479–85. Prokopec M, Bellisle F. Adiposity in Czech children followed from 1 month of age to adulthood: analysis of individual BMI
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7
8 9
10
11
12
13
14
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patterns. Ann Human Biol 1993; 20: 517–25. Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics 1998; 101(electronic pages)/3/e5. Williams S, Davie G, Lam F. Predicting BMI in young adults from childhood data using two approaches to modeling adiposity rebound. Int J Obes Relat Metab Disord 1999; 23: 348–54. Dietz WH. Critical periods in childhood for the development of obesity. Am J Clin Nutr 1994; 59: 995–99. Dietz WH, Gortmaker SL. Do we fatten our children at the TV set? obesity and television viewing in children and adolescents. Pediatrics 1985; 75: 807–12. Rolland-Cachera MF, Deheeger M, Akrout M, Bellisle F. Influence of macronutrients on adiposity development. Int J Obesity 1995; 19: 573–78. Scaglioni S, Agostini C, De Notarus R, et al. Early macronutrient intake and overweight at five years of age. Int J Obesity 2000; 24: 777–81. Dorosty AR, Emmett PM, Cowin IS, Reilly JJ, ALSPAC Study Team. Factors associated with early adiposity rebound. Pediatrics 2000; 105: 1115–18. Birch LL, Marlin DW, Rotter J. Eating as the “means” activity in a contingency: effects on young children’s food preference. Child Dev 1985; 55: 431–39. Fisher JO, Birch LL. Restricting access to palatable foods affects children’s behavioral response, food selection and intake. Am J Clin Nutr 1999; 69: 1264–72. Johnson SL, Birch LL. Parents’ and children’s adiposity and eating style. Pediatrics 1994; 94: 653–61.
Thrombolytic therapy in the elderly A recent observational study by Thiemann et al1 of 7864 Medicare patients treated for acute myocardial infarction in the USA has been widely interpreted as meaning that the use of thrombolytic therapy in patients over 75 may do more harm than good.2 30-day mortality in patients aged 76-86 was significantly higher in those who received thrombolytic therapy within 4 h of admission than in those who did not (18·0% vs 13·6%, p=0·003). These results appear to contradict the Fibrinolytic Therapy Trialists’ (FTT) overview3 of 58 600 patients randomised into thrombolytic trials, which concluded that the 35-day mortality rate in the 5788 patients aged over 75 was lower in those who received thrombolytic therapy than in those who did not (24·3% vs 25·3%). The difference was not significant and the 95% CI was -16% to +36%). However, the absolute mortality reduction in patients over 75 (10 potential lives saved per 1000 treated) was similar to that of patients under 55 (11 per 1000). What can the clinician conclude from such disparate reports, and how much credence can be given to observational studies? In the Thiemann study, there were significant imbalances between the groups in terms of prognostic factors, and the analysis was adjusted for these. However, even with such adjustment, selection of treatments based on physicians’ preferences can affect outcomes that are not due to the treatment itself. The only way to ensure that unknown factors are balanced between treatment groups is by randomised treatment assignment.4 The fact that only 34% of electrocardiographically eligible patients were included in the Thiemann study suggests that there was indeed a selection bias. Another confounding factor is that a large proportion of the patients aged 76–86 who did receive thrombolytic therapy had relative contraindications; for example, 12% had a systolic blood pressure of over 180 mm Hg and 18·0% had a history of trauma, peptic ulceration, or internal bleeding—all of which would have increased the risk of intracranial and systemic bleeding.
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
THE LANCET • Vol 356 • December 16, 2000
Rates of mortality, total stroke, and non-fatal disabling stroke according to age* 25 20 15
Mortality Stroke Non-fatal disabling stroke
%
Two recent reports have claimed that observational studies may generally produce valid results.5,6 However, there are numerous instances in which observational findings have not been confirmed in clinical trials. Various registry studies reported that women taking hormonereplacement therapy had fewer cardiovascular events, but when a randomised trial was done, hormone replacement was found to have no effect.7 Registries are a useful way to audit whether treatments are given appropriately, but they cannot establish the superiority of one treatment over another. The most rigorous way to assess the benefits of therapy is the randomised trial. An important point to remember when interpreting clinical trials is that the overall results (a 21% reduction in 30-day mortality in the FTT overview for patients presenting within 12 h with ST-segment elevation or bundle-branch block)3 should be applied to all subgroups unless there is an a priori reason why a particular subgroup might differ. Subgroup analyses often exaggerate differences between treatments, and these differences (showing greater or lesser benefit, or even harm) may simply be due to chance. For instance, although the ISIS-2 trial results were very strongly positive overall,8 analysis of the patients' birth dates revealed that there were non-significantly worse outcomes in those born under the astrological signs of Gemini or Libra. There is good evidence that thrombolytic therapy lyses coronary thrombi just as well in the elderly as it does in younger patients.9 GUSTO-I reported that age was not a multivariate predictor of the degree of reperfusion at 90 min and that normal coronary flow was achieved in similar proportions of patients above and below the age of 75.10 It is therefore mechanistically unlikely that thrombolytic therapy would be beneficial in the young and harmful in the elderly, unless the elderly had an overwhelmingly high rate of intracranial haemorrhage. Thrombolytic therapy does carry a greater risk of intracranial haemorrhage in the elderly, but because most patients with an intracranial haemorrhage die (60% in GUSTO-I) rather than survive with disability (20%),11 the benefit/risk ratio of thrombolytic therapy is largely already accounted for in the mortality statistics (figure). Although most of the patients in the FTT overview received streptokinase, tissue plasminogen activator was shown in GUSTO-I to be superior to streptokinase for the combined endpoint of death or non-fatal disabling stroke up to age 84. In another recent publication involving US Medicare patients aged over 65, there was no difference in 30-day mortality between those who received thrombolytic therapy and those who did not.12 At 1 year, however, the mortality rate was significantly lower in those given thrombolytic therapy (odds ratio 0·84 [95% CI 0·790·89]), and similar to that of patients treated by primary angioplasty (0·71 [0·61–0·83]). Interestingly, another publication13 from the same database showed that primary angioplasty had no significant impact on 1-year mortality in patients classified as ideal for reperfusion therapy (ie, presenting within 6 h with ST-segment elevation or bundle-branch block). Few randomised trials have compared primary angioplasty with thrombolytic therapy in patients over 75. In GUSTO-IIb, the largest randomised trial comparing angioplasty and thrombolysis, 1138 patients received either an accelerated infusion of tissue plasminogen activator or primary angioplasty. Those treated with primary angioplasty were slightly less likely to die or suffer reinfarction within the first 30 days, but the difference was
10 5 0 8 4 8 1 9 4 5 71 –76 <4 5–4 0–5 5–5 9–6 2–6 5–6 9– 6 6 72 5 5 5 4 6
6
>7
Age *In GUSTO-I trial16 Figure from Straznicky IT, White HD. Thrombolysis in elderly patients. In: Califf RM, ed. Thrombolytic therapy: new standards of AMI care. Belle Mead: American Journal of Cardiology, 1998: 23-28
no longer apparent at 6 months. Primary angioplasty was no more beneficial in older than in younger patients.14 Although the numbers were small (n=90), there was no significant difference in mortality for patients over 80 (27·3% with primary angioplasty vs 26·7% with tissue plasminogen activator). Features that may limit the potential benefits of primary angioplasty in elderly patients include more severe coronary artery stenosis, impairment of TIMI flow at baseline,14 and delayed presentation to hospital, which narrows the window of opportunity for myocardial salvage. The published FTT overview did not specifically report outcomes for elderly patients meeting the current eligibility criteria for reperfusion15 (ie, presenting within 12 h with only ST-segment elevation or bundle-branch block), but did include data on patients who were randomised 12-24 h after symptom onset and also those with normal electrocardiograms, T-wave inversion, or ST-segment depression. Thrombolytic therapy does not benefit individuals with these features, and can even be harmful to patients with ST-segment depression.15 The FTT Secretariat have recently analysed their data on patients presenting within 12 h of symptom onset with either ST-segment elevation or bundle-branch block. About 3300 patients were over the age of 75, and their mortality rate was significantly reduced by thrombolytic therapy from 29·4% to 26·0%, p=0·03; a proportional reduction of 15%) (personal communication from the FTT Secretariat). The proportional reduction in younger patients was 25–30%. The absolute mortality reduction in patients over 75 was 34 lives saved per 1000 patients treated—over three times greater than previously reported, and similar to the reduction seen in patients aged 65–74 (40 per 1000). In comparison, the absolute mortality reduction in patients under 55 was only 16 per 1000. With the new FTT data, there is now clear clinical trial evidence that thrombolytic therapy is beneficial in elderly patients who present within 12 h of symptom onset and fulfil the electrocardiographic eligibility criteria. Their event rates remain high even with the best new thrombolytic regimens available and irrespective of the reperfusion strategy used. But rather than being excluded from treatment, the elderly should be the focus of more intensive research so that better treatments can be developed. Considering all of the information currently 2029
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
available, it is vital that elderly patients without contraindications15 are not denied the benefits of thrombolytic therapy. Harvey D White Cardiovascular Research Unit, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand 1
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Thiemann DR, Coresh J, Schulman SP, Gerstenblith G, Oetgen WJ, Powe NR. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 2000; 101: 2239–46. Ayanian JZ, Braunwald E. Thrombolytic therapy for patients with myocardial infarction who are older than 75 years: do the risks outweigh the benefits? Circulation 2000; 101: 2224–26. 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. Pocock SJ, Elbourne DR. Randomized trials or observational tribulations? N Engl J Med 2000; 342: 1907–09. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000; 342: 1878–86. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342: 1887–92. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280: 605–13. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349–60. Lundergan CF, Reiner JS, McCarthy WF, et al. Clinical predictors of early infarct-related artery patency following thrombolytic therapy: importance of body weight, smoking history, infarct-related artery and choice of thrombolytic regimen: the GUSTO-I experience. J Am Coll Cardiol 1998; 32: 641–47. Lesnefsky EJ, Lundergan CF, Hodgson JM, et al. Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: the GUSTO-I angiographic experience. J Am Coll Cardiol 1996; 28: 331–37. White HD, Barbash GI, Califf RM, et al. Age and outcome with contemporary thrombolytic therapy: results from the GUSTO-I Trial. Circulation 1996; 94: 1826–33. Berger AK, Radford MJ, Wang Y, Krumholz HM. Thrombolytic therapy in older patients. J Am Coll Cardiol 2000; 36: 366–74. Berger AK, Schulman KA, Gersh BJ, et al. Primary coronary angioplasty vs thrombolysis for the management of acute myocardial infarction in elderly patients. JAMA 1999; 282: 341–48. Holmes DR Jr, White HD, Pieper KS, Ellis SG, Califf RM, Topol EJ. Effect of age on outcome with primary angioplasty versus thrombolysis. J Am Coll Cardiol 1999; 33: 412–19. White HD, Van de Werf FJJ. Clinical cardiology: new frontiers: thrombolysis for acute myocardial infarction. Circulation 1998; 97: 1632–46. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673–82.
UK’s failure to act on research misconduct More than a year ago the good and the great of British medicine assembled in Edinburgh and agreed that the time had come to act decisively on research misconduct.1–3 Unfortunately, nothing visible has happened. Yet the so far largely submerged problem of research misconduct is surfacing like a decomposing corpse.4 If the leaders of medicine do not act, they risk the loss of public confidence in medical research. Fraud in research has a long and dishonourable history, but the problem came firmly on to the agenda in the UK in the early 1980s.5 One consequence was a report from the Royal College of Physicians of London in 1991.6 2030
Unfortunately the report was shelved. The excuses are familiar—fraud doesn’t really matter because science is self-correcting; patients have not been harmed; fraud is very rare; existing local systems can handle the problem; action needs to be taken on all of scientific research, not just medical research; the Committee on Publication Ethics (COPE) does not have the legal standing to act. At last year’s Edinburgh conference the excuses were abandoned. A consensus statement said that there was a problem and that a national body was needed to respond.3 The presidents of several colleges and of the General Medical Council (GMC) were there, and they accepted the challenge to act. They have been busy, not least with modernising the National Health Service and the GMC, and they have talked. But they have not acted. Stephen Lock, immediate past editor of the BMJ, spoke prophetically at the Edinburgh meeting, denouncing the slowness of the British medical establishment in acting on research misconduct.7 He drew a parallel with the UK’s slowness in creating ethics committees. It was in the 1960s that Henry Beecher in the USA and Maurice Pappworth in the UK exposed medical research that harmed patients.8,9 The British, however, took 20 years longer than the Americans to create ethics committees.10 The same delay is occurring with a response to research misconduct. Indeed the 20 years are almost up. While the leaders of the medical profession are fiddling, the research enterprise may be starting to burn. Last week saw an academic found guilty by the GMC of serious professional misconduct over research published in 1990.4 The medical school had tried to bury the misconduct, and the doctor’s supervisor will appear before the council in the new year. Many more cases of research misconduct are due to appear before the GMC, and COPE’s report published this week describes another 53 cases of research misconduct, some of them extremely serious.11 The Edinburgh agreement must be implemented. It suggested that a broad definition of research misconduct be adopted, that a national body be set up to lead the response to the problem, and that emphasis be put on promoting good behaviour. Please, men and women in gowns, do something. A version of this commentary appears in the current issue of Gut and the BMJ.
Michael Farthing, Richard Horton, Richard Smith, Committee on Publication Ethics; Gut; Lancet; BMJ 1
Christie B. Panel needed to combat research fraud. BMJ 1999; 318: 1222. 2 Horton R. Scientific misconduct: exaggerated fear but still real and requiring a proportionate response. Lancet 1999; 354: 7–8. 3 Misconduct in biomedical research: final consensus statement. In: Nimmo WS, ed. Joint consensus conference on misconduct in biomedical research. Proc R Coll Physicians Edinb 2000; 3 (suppl 7); 2. 4 Ferriman A. Consultant suspended for research fraud. BMJ 2000; 321: 1429. 5 Lock S. Research misconduct: a resume of recent events. In: Lock S, Wells F. Fraud and misconduct in medical research. London: BMJ Publishing, 1996. 6 Royal College of Physicians of London. Fraud and misconduct in medical research. London: RCP, 1991. 7 Lock S. Misconduct in biomedical research: when did it start? In: Nimmo WS, ed. Joint consensus conference on misconduct in biomedical research. Proc R Coll Physicians Edinb 2000; 3 (suppl 7); 23. 8 Beecher H. Ethics and clinical research. N Engl J Med 1966; 274: 1354–60. 9 Pappworth M. Human guinea pigs. London: Routledge and Kegan Paul, 1967. 10 Doyal L, Tobias JS, eds. Informed consent in medical research. London: BMJ Publishing, 2000. 11 Committee on Publication Ethics. Annual report 2000. London: BMJ Books, 2000.
THE LANCET • Vol 356 • December 16 2000
For personal use only. Not to be reproduced without permission of The Lancet.
seems to have an effect on adult BMI that is independent of the time of rebound.6 However, the correlations between BMI at age 7 and adult BMI and between age at rebound and adult BMI are much the same. BMI at age 7 may thus be a more practical criterion for the determination of risk.7 Because BMI is weight (kg) divided by height (m2), an increased BMI can reflect either increased weight or decreased height, and it is not known whether children or adults with early increases in BMI are heavier or have a reduced height velocity compared with children with later increases in BMI. Even if the differences in BMI in childhood can be attributed to increased weight, whether the increase is in body fat rather than bone or muscle mass remains unclear. A similar argument applies to adults. The factors that predispose to early BMI rebound also remain uncertain. Television viewing by American children has been linked to obesity,9 but there is no evidence that children with early rebound are more sedentary than children with later rebound. Two small studies have suggested that early protein intake predicts an increase in BMI10,11 or subscapular skinfold thickness10 at the time of adiposity rebound11 or at age 8 years.10 In a larger sample of children for whom 3-day prospective household measures were collected at ages 8 and 18 months, no significant association was found between protein, fat, or carbohydrate intake and the timing of BMI rebound.12 Furthermore, how would increased protein intake lead to early rebound? Nor do children always eat what their parents urge them to. For example, encouragement to eat certain foods may reduce intake of that food13 whereas restrictions on a food item may lead to increased consumption of it when the restriction is removed.14 In a cross-sectional study, increased parental control over food intake was associated with an impaired capacity of children to regulate their own intake15 but this study cannot tell whether this finding indicated cause and effect or effect and cause. Adiposity rebound has been based on population measures. In an individual this rebound may be difficult to judge. Measurement error will probably confound assessment of early BMI rebound in young children. For example, a measurement error of 2 cm in a child who weighs 20 kg and is 115 cm tall will account for an error of 0·5 of a BMI unit. Furthermore, few children are likely to be seen frequently enough for the period of rebound to be identified—and because the period of rebound can be identified only retrospectively, early rebound may not be preventable. William H Dietz Division of Nutrition and Physical Activity, Centers for Disease Control and Prevention, Atlanta, GA 30341,USA
1
2
3
4
5
Rolland-Cachera M-F, Deheeger M, Bellisle F, Sempe M, GuilloudBataille M, Patois E. Adiposity rebound in children: a simple indicator for predicting adiposity. Am J Clin Nutr 1984; 39: 129–35. Rolland-Cachera MF, Avons P, Patois E, Sempe M. Tracking the development of adiposity from one month of age to adulthood. Ann Human Biol 1987; 14: 219–29. Rolland-Cachwera M-F, Bellisle F, Deheeger M, Guilloud-Bataille M, Pequignot F, Sempe, M. Adiposity development and prediction during growth in humans: a two decade follow-up study. In: Bjorntorp P, Rossner S, eds. Obesity in Europe 88. London: John Libbey, 1988. Siervogel RM, Roche AF, Guo S, Mukherjee D, Chumlea WC. Patterns of change in weight/stature2 from 2 to 18 years: findings from long-term serial data for children in the Fels longitudinal growth study. Int J Obesity 1991; 15: 479–85. Prokopec M, Bellisle F. Adiposity in Czech children followed from 1 month of age to adulthood: analysis of individual BMI
2028
6
7
8 9
10
11
12
13
14
15
patterns. Ann Human Biol 1993; 20: 517–25. Whitaker RC, Pepe MS, Wright JA, Seidel KD, Dietz WH. Early adiposity rebound and the risk of adult obesity. Pediatrics 1998; 101(electronic pages)/3/e5. Williams S, Davie G, Lam F. Predicting BMI in young adults from childhood data using two approaches to modeling adiposity rebound. Int J Obes Relat Metab Disord 1999; 23: 348–54. Dietz WH. Critical periods in childhood for the development of obesity. Am J Clin Nutr 1994; 59: 995–99. Dietz WH, Gortmaker SL. Do we fatten our children at the TV set? obesity and television viewing in children and adolescents. Pediatrics 1985; 75: 807–12. Rolland-Cachera MF, Deheeger M, Akrout M, Bellisle F. Influence of macronutrients on adiposity development. Int J Obesity 1995; 19: 573–78. Scaglioni S, Agostini C, De Notarus R, et al. Early macronutrient intake and overweight at five years of age. Int J Obesity 2000; 24: 777–81. Dorosty AR, Emmett PM, Cowin IS, Reilly JJ, ALSPAC Study Team. Factors associated with early adiposity rebound. Pediatrics 2000; 105: 1115–18. Birch LL, Marlin DW, Rotter J. Eating as the “means” activity in a contingency: effects on young children’s food preference. Child Dev 1985; 55: 431–39. Fisher JO, Birch LL. Restricting access to palatable foods affects children’s behavioral response, food selection and intake. Am J Clin Nutr 1999; 69: 1264–72. Johnson SL, Birch LL. Parents’ and children’s adiposity and eating style. Pediatrics 1994; 94: 653–61.
Thrombolytic therapy in the elderly A recent observational study by Thiemann et al1 of 7864 Medicare patients treated for acute myocardial infarction in the USA has been widely interpreted as meaning that the use of thrombolytic therapy in patients over 75 may do more harm than good.2 30-day mortality in patients aged 76-86 was significantly higher in those who received thrombolytic therapy within 4 h of admission than in those who did not (18·0% vs 13·6%, p=0·003). These results appear to contradict the Fibrinolytic Therapy Trialists’ (FTT) overview3 of 58 600 patients randomised into thrombolytic trials, which concluded that the 35-day mortality rate in the 5788 patients aged over 75 was lower in those who received thrombolytic therapy than in those who did not (24·3% vs 25·3%). The difference was not significant and the 95% CI was -16% to +36%). However, the absolute mortality reduction in patients over 75 (10 potential lives saved per 1000 treated) was similar to that of patients under 55 (11 per 1000). What can the clinician conclude from such disparate reports, and how much credence can be given to observational studies? In the Thiemann study, there were significant imbalances between the groups in terms of prognostic factors, and the analysis was adjusted for these. However, even with such adjustment, selection of treatments based on physicians’ preferences can affect outcomes that are not due to the treatment itself. The only way to ensure that unknown factors are balanced between treatment groups is by randomised treatment assignment.4 The fact that only 34% of electrocardiographically eligible patients were included in the Thiemann study suggests that there was indeed a selection bias. Another confounding factor is that a large proportion of the patients aged 76–86 who did receive thrombolytic therapy had relative contraindications; for example, 12% had a systolic blood pressure of over 180 mm Hg and 18·0% had a history of trauma, peptic ulceration, or internal bleeding—all of which would have increased the risk of intracranial and systemic bleeding.
THE LANCET • Vol 356 • December 16, 2000
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
THE LANCET • Vol 356 • December 16, 2000
Rates of mortality, total stroke, and non-fatal disabling stroke according to age* 25 20 15
Mortality Stroke Non-fatal disabling stroke
%
Two recent reports have claimed that observational studies may generally produce valid results.5,6 However, there are numerous instances in which observational findings have not been confirmed in clinical trials. Various registry studies reported that women taking hormonereplacement therapy had fewer cardiovascular events, but when a randomised trial was done, hormone replacement was found to have no effect.7 Registries are a useful way to audit whether treatments are given appropriately, but they cannot establish the superiority of one treatment over another. The most rigorous way to assess the benefits of therapy is the randomised trial. An important point to remember when interpreting clinical trials is that the overall results (a 21% reduction in 30-day mortality in the FTT overview for patients presenting within 12 h with ST-segment elevation or bundle-branch block)3 should be applied to all subgroups unless there is an a priori reason why a particular subgroup might differ. Subgroup analyses often exaggerate differences between treatments, and these differences (showing greater or lesser benefit, or even harm) may simply be due to chance. For instance, although the ISIS-2 trial results were very strongly positive overall,8 analysis of the patients' birth dates revealed that there were non-significantly worse outcomes in those born under the astrological signs of Gemini or Libra. There is good evidence that thrombolytic therapy lyses coronary thrombi just as well in the elderly as it does in younger patients.9 GUSTO-I reported that age was not a multivariate predictor of the degree of reperfusion at 90 min and that normal coronary flow was achieved in similar proportions of patients above and below the age of 75.10 It is therefore mechanistically unlikely that thrombolytic therapy would be beneficial in the young and harmful in the elderly, unless the elderly had an overwhelmingly high rate of intracranial haemorrhage. Thrombolytic therapy does carry a greater risk of intracranial haemorrhage in the elderly, but because most patients with an intracranial haemorrhage die (60% in GUSTO-I) rather than survive with disability (20%),11 the benefit/risk ratio of thrombolytic therapy is largely already accounted for in the mortality statistics (figure). Although most of the patients in the FTT overview received streptokinase, tissue plasminogen activator was shown in GUSTO-I to be superior to streptokinase for the combined endpoint of death or non-fatal disabling stroke up to age 84. In another recent publication involving US Medicare patients aged over 65, there was no difference in 30-day mortality between those who received thrombolytic therapy and those who did not.12 At 1 year, however, the mortality rate was significantly lower in those given thrombolytic therapy (odds ratio 0·84 [95% CI 0·790·89]), and similar to that of patients treated by primary angioplasty (0·71 [0·61–0·83]). Interestingly, another publication13 from the same database showed that primary angioplasty had no significant impact on 1-year mortality in patients classified as ideal for reperfusion therapy (ie, presenting within 6 h with ST-segment elevation or bundle-branch block). Few randomised trials have compared primary angioplasty with thrombolytic therapy in patients over 75. In GUSTO-IIb, the largest randomised trial comparing angioplasty and thrombolysis, 1138 patients received either an accelerated infusion of tissue plasminogen activator or primary angioplasty. Those treated with primary angioplasty were slightly less likely to die or suffer reinfarction within the first 30 days, but the difference was
10 5 0 8 4 8 1 9 4 5 71 –76 <4 5–4 0–5 5–5 9–6 2–6 5–6 9– 6 6 72 5 5 5 4 6
6
>7
Age *In GUSTO-I trial16 Figure from Straznicky IT, White HD. Thrombolysis in elderly patients. In: Califf RM, ed. Thrombolytic therapy: new standards of AMI care. Belle Mead: American Journal of Cardiology, 1998: 23-28
no longer apparent at 6 months. Primary angioplasty was no more beneficial in older than in younger patients.14 Although the numbers were small (n=90), there was no significant difference in mortality for patients over 80 (27·3% with primary angioplasty vs 26·7% with tissue plasminogen activator). Features that may limit the potential benefits of primary angioplasty in elderly patients include more severe coronary artery stenosis, impairment of TIMI flow at baseline,14 and delayed presentation to hospital, which narrows the window of opportunity for myocardial salvage. The published FTT overview did not specifically report outcomes for elderly patients meeting the current eligibility criteria for reperfusion15 (ie, presenting within 12 h with only ST-segment elevation or bundle-branch block), but did include data on patients who were randomised 12-24 h after symptom onset and also those with normal electrocardiograms, T-wave inversion, or ST-segment depression. Thrombolytic therapy does not benefit individuals with these features, and can even be harmful to patients with ST-segment depression.15 The FTT Secretariat have recently analysed their data on patients presenting within 12 h of symptom onset with either ST-segment elevation or bundle-branch block. About 3300 patients were over the age of 75, and their mortality rate was significantly reduced by thrombolytic therapy from 29·4% to 26·0%, p=0·03; a proportional reduction of 15%) (personal communication from the FTT Secretariat). The proportional reduction in younger patients was 25–30%. The absolute mortality reduction in patients over 75 was 34 lives saved per 1000 patients treated—over three times greater than previously reported, and similar to the reduction seen in patients aged 65–74 (40 per 1000). In comparison, the absolute mortality reduction in patients under 55 was only 16 per 1000. With the new FTT data, there is now clear clinical trial evidence that thrombolytic therapy is beneficial in elderly patients who present within 12 h of symptom onset and fulfil the electrocardiographic eligibility criteria. Their event rates remain high even with the best new thrombolytic regimens available and irrespective of the reperfusion strategy used. But rather than being excluded from treatment, the elderly should be the focus of more intensive research so that better treatments can be developed. Considering all of the information currently 2029
For personal use only. Not to be reproduced without permission of The Lancet.
COMMENTARY
available, it is vital that elderly patients without contraindications15 are not denied the benefits of thrombolytic therapy. Harvey D White Cardiovascular Research Unit, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand 1
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4 5 6
7
8
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12 13
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Thiemann DR, Coresh J, Schulman SP, Gerstenblith G, Oetgen WJ, Powe NR. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation 2000; 101: 2239–46. Ayanian JZ, Braunwald E. Thrombolytic therapy for patients with myocardial infarction who are older than 75 years: do the risks outweigh the benefits? Circulation 2000; 101: 2224–26. 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. Pocock SJ, Elbourne DR. Randomized trials or observational tribulations? N Engl J Med 2000; 342: 1907–09. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000; 342: 1878–86. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342: 1887–92. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280: 605–13. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349–60. Lundergan CF, Reiner JS, McCarthy WF, et al. Clinical predictors of early infarct-related artery patency following thrombolytic therapy: importance of body weight, smoking history, infarct-related artery and choice of thrombolytic regimen: the GUSTO-I experience. J Am Coll Cardiol 1998; 32: 641–47. Lesnefsky EJ, Lundergan CF, Hodgson JM, et al. Increased left ventricular dysfunction in elderly patients despite successful thrombolysis: the GUSTO-I angiographic experience. J Am Coll Cardiol 1996; 28: 331–37. White HD, Barbash GI, Califf RM, et al. Age and outcome with contemporary thrombolytic therapy: results from the GUSTO-I Trial. Circulation 1996; 94: 1826–33. Berger AK, Radford MJ, Wang Y, Krumholz HM. Thrombolytic therapy in older patients. J Am Coll Cardiol 2000; 36: 366–74. Berger AK, Schulman KA, Gersh BJ, et al. Primary coronary angioplasty vs thrombolysis for the management of acute myocardial infarction in elderly patients. JAMA 1999; 282: 341–48. Holmes DR Jr, White HD, Pieper KS, Ellis SG, Califf RM, Topol EJ. Effect of age on outcome with primary angioplasty versus thrombolysis. J Am Coll Cardiol 1999; 33: 412–19. White HD, Van de Werf FJJ. Clinical cardiology: new frontiers: thrombolysis for acute myocardial infarction. Circulation 1998; 97: 1632–46. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673–82.
UK’s failure to act on research misconduct More than a year ago the good and the great of British medicine assembled in Edinburgh and agreed that the time had come to act decisively on research misconduct.1–3 Unfortunately, nothing visible has happened. Yet the so far largely submerged problem of research misconduct is surfacing like a decomposing corpse.4 If the leaders of medicine do not act, they risk the loss of public confidence in medical research. Fraud in research has a long and dishonourable history, but the problem came firmly on to the agenda in the UK in the early 1980s.5 One consequence was a report from the Royal College of Physicians of London in 1991.6 2030
Unfortunately the report was shelved. The excuses are familiar—fraud doesn’t really matter because science is self-correcting; patients have not been harmed; fraud is very rare; existing local systems can handle the problem; action needs to be taken on all of scientific research, not just medical research; the Committee on Publication Ethics (COPE) does not have the legal standing to act. At last year’s Edinburgh conference the excuses were abandoned. A consensus statement said that there was a problem and that a national body was needed to respond.3 The presidents of several colleges and of the General Medical Council (GMC) were there, and they accepted the challenge to act. They have been busy, not least with modernising the National Health Service and the GMC, and they have talked. But they have not acted. Stephen Lock, immediate past editor of the BMJ, spoke prophetically at the Edinburgh meeting, denouncing the slowness of the British medical establishment in acting on research misconduct.7 He drew a parallel with the UK’s slowness in creating ethics committees. It was in the 1960s that Henry Beecher in the USA and Maurice Pappworth in the UK exposed medical research that harmed patients.8,9 The British, however, took 20 years longer than the Americans to create ethics committees.10 The same delay is occurring with a response to research misconduct. Indeed the 20 years are almost up. While the leaders of the medical profession are fiddling, the research enterprise may be starting to burn. Last week saw an academic found guilty by the GMC of serious professional misconduct over research published in 1990.4 The medical school had tried to bury the misconduct, and the doctor’s supervisor will appear before the council in the new year. Many more cases of research misconduct are due to appear before the GMC, and COPE’s report published this week describes another 53 cases of research misconduct, some of them extremely serious.11 The Edinburgh agreement must be implemented. It suggested that a broad definition of research misconduct be adopted, that a national body be set up to lead the response to the problem, and that emphasis be put on promoting good behaviour. Please, men and women in gowns, do something. A version of this commentary appears in the current issue of Gut and the BMJ.
Michael Farthing, Richard Horton, Richard Smith, Committee on Publication Ethics; Gut; Lancet; BMJ 1
Christie B. Panel needed to combat research fraud. BMJ 1999; 318: 1222. 2 Horton R. Scientific misconduct: exaggerated fear but still real and requiring a proportionate response. Lancet 1999; 354: 7–8. 3 Misconduct in biomedical research: final consensus statement. In: Nimmo WS, ed. Joint consensus conference on misconduct in biomedical research. Proc R Coll Physicians Edinb 2000; 3 (suppl 7); 2. 4 Ferriman A. Consultant suspended for research fraud. BMJ 2000; 321: 1429. 5 Lock S. Research misconduct: a resume of recent events. In: Lock S, Wells F. Fraud and misconduct in medical research. London: BMJ Publishing, 1996. 6 Royal College of Physicians of London. Fraud and misconduct in medical research. London: RCP, 1991. 7 Lock S. Misconduct in biomedical research: when did it start? In: Nimmo WS, ed. Joint consensus conference on misconduct in biomedical research. Proc R Coll Physicians Edinb 2000; 3 (suppl 7); 23. 8 Beecher H. Ethics and clinical research. N Engl J Med 1966; 274: 1354–60. 9 Pappworth M. Human guinea pigs. London: Routledge and Kegan Paul, 1967. 10 Doyal L, Tobias JS, eds. Informed consent in medical research. London: BMJ Publishing, 2000. 11 Committee on Publication Ethics. Annual report 2000. London: BMJ Books, 2000.
THE LANCET • Vol 356 • December 16 2000
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