- Email: [email protected]
Consent in emergency care research
Correspondence
Ian Roberts and colleagues (March 26, p 1071)1 used a logistic regression model to show that delayed consent in the receipt of tranexamic acid in adults with trauma-related haemorrhage could increase mortality. However, in CRASH-2 itself,2 mortality was similar for patients who received tranexamic acid 1 h or less after injury and those who received it more than 1 h to 3 h after injury. On the basis of this finding, a patient arriving at hospital 2 h after injury who incurs a 1 h delay in tranexamic acid receipt (total 3 h after injury) has a similar risk of mortality to one who arrives immediately after injury, incurs no delay to consent, and receives tranexamic acid 1 h or less after injury. As such, a 1 h delay to consent is expected to impose an additional risk of death only after a delay of 2 h or more to arrival at hospital. Whether the regression model1 was adjusted for important baseline factors such as systolic blood pressure, Glasgow coma scale, and injury type, is unclear. Time-dependent mortality reduction could be affected by the interplay between baseline clinical condition, clinicians’ ambivalence and time delay to achieving equipoise threshold, and previous belief in tranexamic acid. A doubting clinician might consider tranexamic acid to be worthwhile as salvage treatment after non-response to optimum blood-product; the result would be higher mortality associated with selection of sicker patients for later enrolment. Conversely, enthusiastic clinicians might champion early use of tranexamic acid in conjunction with aggressive blood-product resuscitation. Without examining patient and clinician factors associated with delay to receipt of tranexamic acid, one cannot reliably conclude that delayed consent in emergency trials and its detrimental outcome3 is solely attributable to consent procedures. I declare that I have no conflicts of interest.
www.thelancet.com Vol 378 July 2, 2011
Joseph Y Ting [email protected] Careflight Medical Services Queensland, GPO Box 3184, Brisbane, QLD 4001, Australia 1
2
3
Roberts I, Prieto-Merino D, Shakur H, Chalmers I, Nicholl J. Effect of consent rituals on mortality in emergency care research. Lancet 2011; 377: 1071–72. CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376: 23–32. Morrison CA, Horwitz IB, Carrick MM. Ethical and legal issues in emergency research: barrier to conducting randomized trials in emergency setting. J Surg Res 2009; 157: 115–22.
and a post-hoc assertion that harm with late treatment with consent is unethical, ignoring the converse, benefit with late placebo with consent. We have the right to rapid treatment if we become seriously ill. We do not expect benefit in trials, or have the “right” to receive rapid investigational treatments (that may help or harm) without consent. There is no evidence that not acquiring patients’ consent confers net aggregate benefit. Posthoc counterfactual arguments should not influence ethical debate.
Science Photo Library
Consent in emergency care research
We declare that we have no conflicts of interest.
We disagree with Ian Roberts and colleagues’ argument for lower ethical standards in investigational treatment than in clinical care, as implied in the pejorative phrase “consent rituals”.1 Their statistical and counterfactual arguments are unconvincing. Roberts and colleagues present time as the sole important treatment variable, but the analysis is flawed; it asks us to believe that all other important predictive factors are adjusted for, which is impossible, because the data are not available. Early admissions have higher death rates; time causes attrition and confounding. Dismissing a key variable, injury severity (“value of a stratified analysis based on…injury severity is small”),2 Roberts and colleagues omit earlier injury data (mortalities of 2–66%).3 In fact, keeping other variables constant (and mildly abnormal), injury severity scores of 25 and 35 carry respective mortality rates of 8·6% and 19·9%.3 Roberts and colleagues argue that putative early benefit means that consent is unethical, although they could not know that the treatment would work early; under the uncertainty principle, they could not know that it would work at all. This logic relies on data mining (the analysis above), assertions that benefit is related to time—not injury severity—and that injury stratification is unnecessary,
J F Boylan, N P Conlon, *M J Jaigirdar [email protected] St Vincents University Hospital, Elm Park, Dublin 4, Ireland 1
2
3
Roberts I, Prieto-Merino D, Shakur H, Chalmers I, Nicholl J. Effect of consent rituals on mortality in emergency care research. Lancet 2011; 377: 1071–72. CRASH-2 Collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377: 1096–101. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003; 54: 1127–30.
Ian Roberts and colleagues1 characterise consent in emergency care research as an unethical ritual. They draw support for this position from the CRASH-2 trial data, which they estimate show that a 1 h delay in giving tranexamic acid to trauma patients with bleeds reduces the proportion of patients who benefit from the trial treatment from 63% to 49%. The concern is not a new one and arises from the very real difficulty of obtaining consent in a timely manner from patients who lack capacity in emergency situations. Glasziou and Chalmers,2 citing data from the ISIS-2 streptokinase and aspirin trial,3 similarly argued that the written consent process imposed by ethics committees in the USA led to thousands of deaths. However, as noted by Collins and colleagues,4 before trial completion there was
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
25
Ian Roberts and colleagues (March 26, p 1071)1 used a logistic regression model to show that delayed consent in the receipt of tranexamic acid in adults with trauma-related haemorrhage could increase mortality. However, in CRASH-2 itself,2 mortality was similar for patients who received tranexamic acid 1 h or less after injury and those who received it more than 1 h to 3 h after injury. On the basis of this finding, a patient arriving at hospital 2 h after injury who incurs a 1 h delay in tranexamic acid receipt (total 3 h after injury) has a similar risk of mortality to one who arrives immediately after injury, incurs no delay to consent, and receives tranexamic acid 1 h or less after injury. As such, a 1 h delay to consent is expected to impose an additional risk of death only after a delay of 2 h or more to arrival at hospital. Whether the regression model1 was adjusted for important baseline factors such as systolic blood pressure, Glasgow coma scale, and injury type, is unclear. Time-dependent mortality reduction could be affected by the interplay between baseline clinical condition, clinicians’ ambivalence and time delay to achieving equipoise threshold, and previous belief in tranexamic acid. A doubting clinician might consider tranexamic acid to be worthwhile as salvage treatment after non-response to optimum blood-product; the result would be higher mortality associated with selection of sicker patients for later enrolment. Conversely, enthusiastic clinicians might champion early use of tranexamic acid in conjunction with aggressive blood-product resuscitation. Without examining patient and clinician factors associated with delay to receipt of tranexamic acid, one cannot reliably conclude that delayed consent in emergency trials and its detrimental outcome3 is solely attributable to consent procedures. I declare that I have no conflicts of interest.
www.thelancet.com Vol 378 July 2, 2011
Joseph Y Ting [email protected] Careflight Medical Services Queensland, GPO Box 3184, Brisbane, QLD 4001, Australia 1
2
3
Roberts I, Prieto-Merino D, Shakur H, Chalmers I, Nicholl J. Effect of consent rituals on mortality in emergency care research. Lancet 2011; 377: 1071–72. CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376: 23–32. Morrison CA, Horwitz IB, Carrick MM. Ethical and legal issues in emergency research: barrier to conducting randomized trials in emergency setting. J Surg Res 2009; 157: 115–22.
and a post-hoc assertion that harm with late treatment with consent is unethical, ignoring the converse, benefit with late placebo with consent. We have the right to rapid treatment if we become seriously ill. We do not expect benefit in trials, or have the “right” to receive rapid investigational treatments (that may help or harm) without consent. There is no evidence that not acquiring patients’ consent confers net aggregate benefit. Posthoc counterfactual arguments should not influence ethical debate.
Science Photo Library
Consent in emergency care research
We declare that we have no conflicts of interest.
We disagree with Ian Roberts and colleagues’ argument for lower ethical standards in investigational treatment than in clinical care, as implied in the pejorative phrase “consent rituals”.1 Their statistical and counterfactual arguments are unconvincing. Roberts and colleagues present time as the sole important treatment variable, but the analysis is flawed; it asks us to believe that all other important predictive factors are adjusted for, which is impossible, because the data are not available. Early admissions have higher death rates; time causes attrition and confounding. Dismissing a key variable, injury severity (“value of a stratified analysis based on…injury severity is small”),2 Roberts and colleagues omit earlier injury data (mortalities of 2–66%).3 In fact, keeping other variables constant (and mildly abnormal), injury severity scores of 25 and 35 carry respective mortality rates of 8·6% and 19·9%.3 Roberts and colleagues argue that putative early benefit means that consent is unethical, although they could not know that the treatment would work early; under the uncertainty principle, they could not know that it would work at all. This logic relies on data mining (the analysis above), assertions that benefit is related to time—not injury severity—and that injury stratification is unnecessary,
J F Boylan, N P Conlon, *M J Jaigirdar [email protected] St Vincents University Hospital, Elm Park, Dublin 4, Ireland 1
2
3
Roberts I, Prieto-Merino D, Shakur H, Chalmers I, Nicholl J. Effect of consent rituals on mortality in emergency care research. Lancet 2011; 377: 1071–72. CRASH-2 Collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377: 1096–101. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003; 54: 1127–30.
Ian Roberts and colleagues1 characterise consent in emergency care research as an unethical ritual. They draw support for this position from the CRASH-2 trial data, which they estimate show that a 1 h delay in giving tranexamic acid to trauma patients with bleeds reduces the proportion of patients who benefit from the trial treatment from 63% to 49%. The concern is not a new one and arises from the very real difficulty of obtaining consent in a timely manner from patients who lack capacity in emergency situations. Glasziou and Chalmers,2 citing data from the ISIS-2 streptokinase and aspirin trial,3 similarly argued that the written consent process imposed by ethics committees in the USA led to thousands of deaths. However, as noted by Collins and colleagues,4 before trial completion there was
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
25