- Email: [email protected]
HEAT-PPCI sheds light on consent in pragmatic trials
Comment
radial access in 81% of patients. Radial access decreases bleeding complications,7 and might have reduced a potential advantage of bivalirudin in terms of bleeding. In conclusion, HEAT-PPCI was an exciting, well done trial, for which the trial team should be congratulated. Most of the criticism has been based on inappropriate comparisons with trials that required use of a GP IIb/IIIa inhibitor with heparin, or that administered much larger doses of heparin. HEAT-PPCI provides strong evidence that bivalirudin alone compared with 70 U/kg of heparin alone (with infrequent bailout use of GP IIb/IIIA inhibitors in both arms), with radial access for STEMI percutaneous coronary intervention, seems to be inferior to heparin as administered in this trial. Even if heparin alone had produced statistically similar outcomes to bivalirudin, it would have been a win for heparin. A drug that costs less than a 400th of another that has similar efficacy and safety ought be used preferentially.
PBB has received grants from Janssen, The Medicines Company, AstraZeneca, Eli Lilly and Company, Sanofi, DRDI Holdings, and Genenews, and personal fees from Janssen and Medicure. JCB is the primary investigator at Geisinger Medical Center for multicentre trials sponsored by Abbott Vascular, Hamilton Health Sciences, Tryton Medical, Boston Scientific, Stentys, Regado Biosciences, Volcano Corp, AstraZeneca, and The Medicines Company. JCB receives no direct compensation from these sources.
*Peter B Berger, James C Blankenship
8
Department of Cardiology, Geisinger Health System, Danville, PA 17822-2775, USA [email protected]
1
2 3 4 5
6
7
9
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S0140-6736(14)60924-7. Wood S. HEAT-PPCI: heparin bests bivalirudin in STEMI, amid heated debate. http://www.medscape.com/viewarticle/822927 (accessed June 30, 2014). Shaw D. HEAT-PPCI sheds light on consent in pragmatic trials. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S0140-6736(14)61040-0. Stone GE, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Fung AY, Saw J, Starovoytov A, et al. Abbreviated infusion of eptifibatide after successful coronary intervention: the BRIEF-PCI (Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention) randomized trial. J Am Coll Cardiol 2009; 53: 837–45. Schulz S, Mehilli J, Neumann FJ, et al. ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention. Eur Heart J 2010; 31: 2482–91. Karrowni W, Vyas A, Giacomino B, et al. Radial versus femoral access for primary percutaneous interventions in ST-segment elevation myocardial infarction patients. A meta-analysis of randomized controlled trials. JACC Cardiovasc Interv 2013; 6: 814–23. Steg PG, Van’t Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013; 369: 2207–17. Kastrati A, Neumann FJ, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359: 688–96.
HEAT-PPCI sheds light on consent in pragmatic trials Published Online July 5, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61040-0 See Comment page 1824 See Articles page 1849
1826
In The Lancet, Adeel Shahzad and colleagues report the results of their groundbreaking How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) trial.1 In 1829 patients with suspected ST segment elevation myocardial infarction, percutaneous coronary intervention was attempted in 1491 (82%), and the trial’s primary efficacy outcome (a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation) occurred in 79 (9%) of 905 patients randomised to receive bivalirudin as compared with 52 (6%) of 907 receiving heparin (relative risk 1·52, 95% CI 1·09–2·13). This study has attracted some criticism because of its use of delayed consent.2 In fact, HEAT-PPCI is not only an impressive achievement in medical research, but also in ethical study design. Far from being unethical, the study sets a high standard for consent in pragmatic trials. HEAT-PPCI’s use of delayed consent was entirely ethical. Shahzad and colleagues randomly allocated patients
undergoing percutaneous coronary intervention to heparin or bilvalirudin without first gaining consent; patients provided consent after the operation. In this context, this strategy was preferable to attempting to obtain consent from potentially incompetent patients needing extremely urgent cardiac treatment. Delayed consent is recognised as an acceptable method of respecting patients’ autonomy in emergency research in the Declaration of Helsinki.3 The use of delayed consent is particularly appropriate in pragmatic comparative effectiveness trials where the two drugs under investigation are both used for licensed indications in conditions of equipoise. In routine clinical care, it would be perfectly normal for a doctor to choose either heparin or bilvalirudin without involvement of the patient in the decision. As Shahzad and colleagues note in their study protocol, informed consent for percutaneous coronary intervention is frequently not sought at all; why patients should be asked to consent in advance to formal randomisation of a drug used in the intervention is thus unclear. www.thelancet.com Vol 384 November 22, 2014
It would have been unethical to have done the study differently. Attempting to get consent from patients would have increased the risk of harming them4 by delaying treatment, and could also have affected recruitment. Although it is easier to enrol patients to a study if consent is not sought, the high retention rate at the point of delayed consent suggests that this method met with patients’ approval. In this sense, HEAT-PPCI also provides insight into participants’ views on delayed consent. If patients had objected to the consent mechanism, they could have withdrawn—but of the patients who were asked to consent to inclusion in the trial, only four refused. The extremely high recruitment rate made possible by delayed consent provides another reason to favour this design over lengthy consent procedures. It would also have been unethical to prevent this trial from being done because of misplaced concerns about consent. Had HEAT-PPCI not been done, doctors around the world would have carried on giving patients inferior treatment. As Ben Goldacre said regarding the CRASH head injury trial,5 which also used delayed consent, “nobody was losing out by being in the trial, but the patients of the future were being harmed with every day this trial was delayed”.6 In addition, the results of HEAT-PPCI mean that resources will not be wasted on bivalirudin, a more expensive and less effective treatment than heparin.1 These findings are why this type of head-to-head research is so important, and also why it has many opponents. When US President Barack Obama promised US$ 1 billion for comparative effectiveness research,7 he was accused of being anti-industry.8 Unsurprisingly, much of the opposition to HEAT-PPCI has come from doctors with close industry ties.2 Ultimately, HEAT-PPCI’s use of delayed consent might have been too conservative. Consent might not be necessary in some pragmatic comparative effectiveness trials.9 Despite the tradition of obtaining informed consent for almost all research, some debate surrounds whether patient consent should be sought when both treatments are licensed, consensus is present regarding equipoise, and randomisation does not pose any added risk. Outcome data can be used without consent in normal clinical care and audit, and randomisation alone does not make consent necessary. In view of traditional consent paradigms, the HEAT-PPCI researchers understandably did use delayed consent, but their www.thelancet.com Vol 384 November 22, 2014
Corbis
Comment
trial raises important questions about the relevance of informed consent in this context. The contribution of HEAT-PPCI to ethical trial design should not be underestimated. The use of delayed consent respected patients’ autonomy, while also increasing recruitment to an essential trial that has the potential to improve future patient care. Traditional lengthy consent procedures are entirely inappropriate for pragmatic comparative effectiveness trials where equipoise exists, and HEAT-PPCI has blazed a trail for future research of this type. David Shaw Institute for Biomedical Ethics, University of Basel, 4056 Basel, Switzerland [email protected] I declare no competing interests. 1
2 3 4
5
6 7
8
9
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S0140-6736(14)60924-7. Wood S. HEAT-PPCI: heparin bests bivalirudin in STEMI, amid heated debate. http://www.medscape.com/viewarticle/822927 (accessed June 4, 2014). WMA. Declaration of Helsinki, 2013 revision. http://www.wma.net/ en/30publications/10policies/b3/ (accessed June 4, 2014). Rathore SS, Curtis JP, Chen J, et al. Association of door-to-balloon time and mortality in patients admitted to hospital with ST elevation myocardial infarction: national cohort study. BMJ 2009; 338: b1807. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury—outcomes at 6 months. Lancet 2005; 365: 1957–59. Goldacre B. Bad Pharma. Fourth Estate: London, 2013: 231. Pear R. US to compare medical treatments. New York Times Feb 15, 2009. http://www.nytimes.com/2009/02/16/health/policy/16health.html?_r=0 (accessed June 4, 2014). Mundy A. Drug makers fight stimulus provision. Wall Street Journal Feb 10, 2009. http://online.wsj.com/news/articles/SB1234230242039 66081?mg=reno64-wsj&url=http%3A%2F%2Fonline.wsj.com%2Farticle% 2FSB123423024203966081.html (accessed June 4, 2014). Faden RR, Beauchamp TL, Kass NE. Informed consent, comparative effectiveness, and learning health care. N Engl J Med 2014; 370: 766–68.
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radial access in 81% of patients. Radial access decreases bleeding complications,7 and might have reduced a potential advantage of bivalirudin in terms of bleeding. In conclusion, HEAT-PPCI was an exciting, well done trial, for which the trial team should be congratulated. Most of the criticism has been based on inappropriate comparisons with trials that required use of a GP IIb/IIIa inhibitor with heparin, or that administered much larger doses of heparin. HEAT-PPCI provides strong evidence that bivalirudin alone compared with 70 U/kg of heparin alone (with infrequent bailout use of GP IIb/IIIA inhibitors in both arms), with radial access for STEMI percutaneous coronary intervention, seems to be inferior to heparin as administered in this trial. Even if heparin alone had produced statistically similar outcomes to bivalirudin, it would have been a win for heparin. A drug that costs less than a 400th of another that has similar efficacy and safety ought be used preferentially.
PBB has received grants from Janssen, The Medicines Company, AstraZeneca, Eli Lilly and Company, Sanofi, DRDI Holdings, and Genenews, and personal fees from Janssen and Medicure. JCB is the primary investigator at Geisinger Medical Center for multicentre trials sponsored by Abbott Vascular, Hamilton Health Sciences, Tryton Medical, Boston Scientific, Stentys, Regado Biosciences, Volcano Corp, AstraZeneca, and The Medicines Company. JCB receives no direct compensation from these sources.
*Peter B Berger, James C Blankenship
8
Department of Cardiology, Geisinger Health System, Danville, PA 17822-2775, USA [email protected]
1
2 3 4 5
6
7
9
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S0140-6736(14)60924-7. Wood S. HEAT-PPCI: heparin bests bivalirudin in STEMI, amid heated debate. http://www.medscape.com/viewarticle/822927 (accessed June 30, 2014). Shaw D. HEAT-PPCI sheds light on consent in pragmatic trials. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S0140-6736(14)61040-0. Stone GE, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–30. Fung AY, Saw J, Starovoytov A, et al. Abbreviated infusion of eptifibatide after successful coronary intervention: the BRIEF-PCI (Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention) randomized trial. J Am Coll Cardiol 2009; 53: 837–45. Schulz S, Mehilli J, Neumann FJ, et al. ISAR-REACT 3A: a study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention. Eur Heart J 2010; 31: 2482–91. Karrowni W, Vyas A, Giacomino B, et al. Radial versus femoral access for primary percutaneous interventions in ST-segment elevation myocardial infarction patients. A meta-analysis of randomized controlled trials. JACC Cardiovasc Interv 2013; 6: 814–23. Steg PG, Van’t Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013; 369: 2207–17. Kastrati A, Neumann FJ, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359: 688–96.
HEAT-PPCI sheds light on consent in pragmatic trials Published Online July 5, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61040-0 See Comment page 1824 See Articles page 1849
1826
In The Lancet, Adeel Shahzad and colleagues report the results of their groundbreaking How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) trial.1 In 1829 patients with suspected ST segment elevation myocardial infarction, percutaneous coronary intervention was attempted in 1491 (82%), and the trial’s primary efficacy outcome (a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation) occurred in 79 (9%) of 905 patients randomised to receive bivalirudin as compared with 52 (6%) of 907 receiving heparin (relative risk 1·52, 95% CI 1·09–2·13). This study has attracted some criticism because of its use of delayed consent.2 In fact, HEAT-PPCI is not only an impressive achievement in medical research, but also in ethical study design. Far from being unethical, the study sets a high standard for consent in pragmatic trials. HEAT-PPCI’s use of delayed consent was entirely ethical. Shahzad and colleagues randomly allocated patients
undergoing percutaneous coronary intervention to heparin or bilvalirudin without first gaining consent; patients provided consent after the operation. In this context, this strategy was preferable to attempting to obtain consent from potentially incompetent patients needing extremely urgent cardiac treatment. Delayed consent is recognised as an acceptable method of respecting patients’ autonomy in emergency research in the Declaration of Helsinki.3 The use of delayed consent is particularly appropriate in pragmatic comparative effectiveness trials where the two drugs under investigation are both used for licensed indications in conditions of equipoise. In routine clinical care, it would be perfectly normal for a doctor to choose either heparin or bilvalirudin without involvement of the patient in the decision. As Shahzad and colleagues note in their study protocol, informed consent for percutaneous coronary intervention is frequently not sought at all; why patients should be asked to consent in advance to formal randomisation of a drug used in the intervention is thus unclear. www.thelancet.com Vol 384 November 22, 2014
It would have been unethical to have done the study differently. Attempting to get consent from patients would have increased the risk of harming them4 by delaying treatment, and could also have affected recruitment. Although it is easier to enrol patients to a study if consent is not sought, the high retention rate at the point of delayed consent suggests that this method met with patients’ approval. In this sense, HEAT-PPCI also provides insight into participants’ views on delayed consent. If patients had objected to the consent mechanism, they could have withdrawn—but of the patients who were asked to consent to inclusion in the trial, only four refused. The extremely high recruitment rate made possible by delayed consent provides another reason to favour this design over lengthy consent procedures. It would also have been unethical to prevent this trial from being done because of misplaced concerns about consent. Had HEAT-PPCI not been done, doctors around the world would have carried on giving patients inferior treatment. As Ben Goldacre said regarding the CRASH head injury trial,5 which also used delayed consent, “nobody was losing out by being in the trial, but the patients of the future were being harmed with every day this trial was delayed”.6 In addition, the results of HEAT-PPCI mean that resources will not be wasted on bivalirudin, a more expensive and less effective treatment than heparin.1 These findings are why this type of head-to-head research is so important, and also why it has many opponents. When US President Barack Obama promised US$ 1 billion for comparative effectiveness research,7 he was accused of being anti-industry.8 Unsurprisingly, much of the opposition to HEAT-PPCI has come from doctors with close industry ties.2 Ultimately, HEAT-PPCI’s use of delayed consent might have been too conservative. Consent might not be necessary in some pragmatic comparative effectiveness trials.9 Despite the tradition of obtaining informed consent for almost all research, some debate surrounds whether patient consent should be sought when both treatments are licensed, consensus is present regarding equipoise, and randomisation does not pose any added risk. Outcome data can be used without consent in normal clinical care and audit, and randomisation alone does not make consent necessary. In view of traditional consent paradigms, the HEAT-PPCI researchers understandably did use delayed consent, but their www.thelancet.com Vol 384 November 22, 2014
Corbis
Comment
trial raises important questions about the relevance of informed consent in this context. The contribution of HEAT-PPCI to ethical trial design should not be underestimated. The use of delayed consent respected patients’ autonomy, while also increasing recruitment to an essential trial that has the potential to improve future patient care. Traditional lengthy consent procedures are entirely inappropriate for pragmatic comparative effectiveness trials where equipoise exists, and HEAT-PPCI has blazed a trail for future research of this type. David Shaw Institute for Biomedical Ethics, University of Basel, 4056 Basel, Switzerland [email protected] I declare no competing interests. 1
2 3 4
5
6 7
8
9
Shahzad A, Kemp I, Mars C, et al, for the HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; published online July 5. http://dx.doi.org/10.1016/S0140-6736(14)60924-7. Wood S. HEAT-PPCI: heparin bests bivalirudin in STEMI, amid heated debate. http://www.medscape.com/viewarticle/822927 (accessed June 4, 2014). WMA. Declaration of Helsinki, 2013 revision. http://www.wma.net/ en/30publications/10policies/b3/ (accessed June 4, 2014). Rathore SS, Curtis JP, Chen J, et al. Association of door-to-balloon time and mortality in patients admitted to hospital with ST elevation myocardial infarction: national cohort study. BMJ 2009; 338: b1807. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury—outcomes at 6 months. Lancet 2005; 365: 1957–59. Goldacre B. Bad Pharma. Fourth Estate: London, 2013: 231. Pear R. US to compare medical treatments. New York Times Feb 15, 2009. http://www.nytimes.com/2009/02/16/health/policy/16health.html?_r=0 (accessed June 4, 2014). Mundy A. Drug makers fight stimulus provision. Wall Street Journal Feb 10, 2009. http://online.wsj.com/news/articles/SB1234230242039 66081?mg=reno64-wsj&url=http%3A%2F%2Fonline.wsj.com%2Farticle% 2FSB123423024203966081.html (accessed June 4, 2014). Faden RR, Beauchamp TL, Kass NE. Informed consent, comparative effectiveness, and learning health care. N Engl J Med 2014; 370: 766–68.
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