- Email: [email protected]
ASPECT-2 study
CORRESPONDENCE
ASPECT-2 study
Authors’ reply
Sir—The study by R van Es and colleagues (July 13, p 109)1 assessed the effect of antithrombotic treatment compared with antiplatelet treatment on composite outcome in patients recovering from acute coronary events. The study was randomised and partly masked. The allocated treatments were known to the investigators and other care providers. We disagree with the authors’ statement that the unmasked treatment phases were unlikely to have introduced bias. This unmasked portion of the study is a potential source of unrecognised systematic bias that could have been introduced into the study in the form of preferential management for patients allocated to either treatment. We feel that this situation could have contributed to the noted outcomes despite the masking of outcome assessors to treatment allocation. This potential source of bias could have been minimised or eliminated altogether with appropriate masking of the treatments and the concomitant use of inactive alternative treatment.2,3 Although, as noted by the authors, this would have introduced some logistical problems into the execution of the study, it would have contributed the soundness of the study findings. The use of  blockers and angiotensin-converting-enzyme (ACE) inhibitors was strongly encouraged and similar proportions of patients received these drugs, but conventional medical therapy was not characterised. Details of dosage and treatment compliance should be provided throughout the study. This is an important issue since treatment with ACE inhibitors and  blockers has been associated with improved clinical outcomes. Although analyses were stated to have been done on an intention-totreat basis, were all patients included in the final analyses?
Sir—The ASPECT-2 study was indeed, and purposely, only partly masked.1 Masking in a trial has two objectives, one of which is to reduce observer bias in the outcome assessment. In ASPECT-2, the primary endpoints (death, myocardial infarction, or stroke) were unlikely to be affected by biased assessment. A second objective of masking in randomised trials is to remove extraneous effects. These effects may be inherent to the intervention, placebo effects, or effects induced by knowledge of the intervention including lifestyle changes and differences in concomitant medication. Such extraneous effects can either be accepted as part of the contrasting treatment regimens or be excluded by masking. When extraneous effects are excluded, the estimates of benefit in a trial exclusively reflect the effects of the pharmacological properties of the drug. Although important from a causal perspective, these effects are likely to be smaller than the effects that are eventually achieved in practice. There is an increasing appreciation of the importance of trials that compare strategies, including all extraneous effects, rather than compounds. For example, in ASPECT-2, the randomised groups differed with regard to the need to monitor international normalised ratio (INR). Moreover, although baseline concomitant drug use was similar in the groups, during the trial, differences might have occurred that were not monitored. However, in real life, INR monitoring is necessary only for oral anticoagulants and not for aspirin, and knowledge of the type of antithrombotic treatment may or may not affect the choice of other treatments. If anything, differences in concomitant medication in ASPECT-2 are likely to be small. We do not have further information on dosing during the trial, and do not think that such information is needed to interpret the findings. The difference in approach between studies that compare compounds and studies that compare strategies became known as a difference between explanatory and pragmatic trials after publication of a paper by Schwarz and Lellouch.2 Whereas an explanatory trial may be essential early in phase III to show unequivocally the unique pharmacological properties of a drug, pragmatic trials will generally provide results with a greater practical relevance. Masking in a trial is an option and not a prerequisite for better or more valid studies. The ASPECT-2 trial was a
Katherine A Lewis, *Enrique V Carbajal VA Central California Health Care System, Fresno, CA 93703, USA (e-mail: [email protected]) 1
2 3
Es R van, Jonker JJC, Verheugt FWA, Deckers JW, Grobbee DE, for the Antithrombotics in the Secondary Prevention of Coronary Thrombosis (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002; 360: 109–13. Day S, Altman D. Blinding in clinical trial and other studies. BMJ 2000; 321: 504. Schulz K, Chalmers I, Altman D. The landscape and lexicon of blinding in randomized trials. Ann Intern Med 2002; 136: 254–59.
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pragmatic randomised trial by design. Apart from this aspect of the interventions, a pragmatic trial such as ASPECT-2 should be equally well controlled and methodologically strict as any other, explanatory, trial.3 In ASPECT-2, complete follow-up information was available for virtually all patients, as indicated by the numbers analysed in figure 1 of the report. *Diederick E Grobbee, Jan J C Jonker, Freek W Verheught Julius Centrum, 3584 CX Utrecht, Netherlands (e-mail: [email protected]) 1
2
3
Es R van, Jonker JJC, Verheugt FWA, Deckers JW, Grobbee DE, for the Antithrombotics in the Secondary Prevention of Coronary Thrombosis (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002; 360: 109–13. Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutic trials. J Chron Dis 1967; 20: 637–48. Armitage P. Attitudes in clinical trials. Stat Med 1998; 17: 2675–83.
Obstructive sleep apnoea Sir—In their otherwise informative Seminar on obstructive sleep apnoea (July 20, p 237),1 Atul Malhotra and David P White do not mention the perioperative management of these patients either for operations specifically for obstructive sleep apnoea (eg, uvulopalatopharyngoplasty) or for unrelated procedures. Clinicians involved in the care of patients with obstructive sleep apnoea must be aware of the importance of the disorder and its appropriate management during the perioperative period. Patients with obstructive sleep apnoea have increased sensitivity to anaesthetic agents, sedative drugs, and opiates. The result is reduced pharyngeal tone and reduced ventilatory and arousal responses to hypercapnia and hypoxia.2 These patients’ tracheas are often difficult to intubate, and in serious obstructive sleep apnoea, intubation is often done while the patient is awake. Patients are at increased risk of perioperative hypoxaemia, hypercarbia, and secretion retention, and are consequently best recovered in a high dependency or intensive care setting; in severe cases, they might need an elective preoperative tracheostomy. They are also at increased risk of gastrooesophageal reflux and consequently of aspiration of gastric contents. Where possible, a regional anaesthetic technique can be used, which avoids the potential problems of general anaesthesia.3 Day-case operations are contraindicated because of patients’ airway
THE LANCET • Vol 360 • December 21/28, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
ASPECT-2 study
Authors’ reply
Sir—The study by R van Es and colleagues (July 13, p 109)1 assessed the effect of antithrombotic treatment compared with antiplatelet treatment on composite outcome in patients recovering from acute coronary events. The study was randomised and partly masked. The allocated treatments were known to the investigators and other care providers. We disagree with the authors’ statement that the unmasked treatment phases were unlikely to have introduced bias. This unmasked portion of the study is a potential source of unrecognised systematic bias that could have been introduced into the study in the form of preferential management for patients allocated to either treatment. We feel that this situation could have contributed to the noted outcomes despite the masking of outcome assessors to treatment allocation. This potential source of bias could have been minimised or eliminated altogether with appropriate masking of the treatments and the concomitant use of inactive alternative treatment.2,3 Although, as noted by the authors, this would have introduced some logistical problems into the execution of the study, it would have contributed the soundness of the study findings. The use of  blockers and angiotensin-converting-enzyme (ACE) inhibitors was strongly encouraged and similar proportions of patients received these drugs, but conventional medical therapy was not characterised. Details of dosage and treatment compliance should be provided throughout the study. This is an important issue since treatment with ACE inhibitors and  blockers has been associated with improved clinical outcomes. Although analyses were stated to have been done on an intention-totreat basis, were all patients included in the final analyses?
Sir—The ASPECT-2 study was indeed, and purposely, only partly masked.1 Masking in a trial has two objectives, one of which is to reduce observer bias in the outcome assessment. In ASPECT-2, the primary endpoints (death, myocardial infarction, or stroke) were unlikely to be affected by biased assessment. A second objective of masking in randomised trials is to remove extraneous effects. These effects may be inherent to the intervention, placebo effects, or effects induced by knowledge of the intervention including lifestyle changes and differences in concomitant medication. Such extraneous effects can either be accepted as part of the contrasting treatment regimens or be excluded by masking. When extraneous effects are excluded, the estimates of benefit in a trial exclusively reflect the effects of the pharmacological properties of the drug. Although important from a causal perspective, these effects are likely to be smaller than the effects that are eventually achieved in practice. There is an increasing appreciation of the importance of trials that compare strategies, including all extraneous effects, rather than compounds. For example, in ASPECT-2, the randomised groups differed with regard to the need to monitor international normalised ratio (INR). Moreover, although baseline concomitant drug use was similar in the groups, during the trial, differences might have occurred that were not monitored. However, in real life, INR monitoring is necessary only for oral anticoagulants and not for aspirin, and knowledge of the type of antithrombotic treatment may or may not affect the choice of other treatments. If anything, differences in concomitant medication in ASPECT-2 are likely to be small. We do not have further information on dosing during the trial, and do not think that such information is needed to interpret the findings. The difference in approach between studies that compare compounds and studies that compare strategies became known as a difference between explanatory and pragmatic trials after publication of a paper by Schwarz and Lellouch.2 Whereas an explanatory trial may be essential early in phase III to show unequivocally the unique pharmacological properties of a drug, pragmatic trials will generally provide results with a greater practical relevance. Masking in a trial is an option and not a prerequisite for better or more valid studies. The ASPECT-2 trial was a
Katherine A Lewis, *Enrique V Carbajal VA Central California Health Care System, Fresno, CA 93703, USA (e-mail: [email protected]) 1
2 3
Es R van, Jonker JJC, Verheugt FWA, Deckers JW, Grobbee DE, for the Antithrombotics in the Secondary Prevention of Coronary Thrombosis (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002; 360: 109–13. Day S, Altman D. Blinding in clinical trial and other studies. BMJ 2000; 321: 504. Schulz K, Chalmers I, Altman D. The landscape and lexicon of blinding in randomized trials. Ann Intern Med 2002; 136: 254–59.
2078
pragmatic randomised trial by design. Apart from this aspect of the interventions, a pragmatic trial such as ASPECT-2 should be equally well controlled and methodologically strict as any other, explanatory, trial.3 In ASPECT-2, complete follow-up information was available for virtually all patients, as indicated by the numbers analysed in figure 1 of the report. *Diederick E Grobbee, Jan J C Jonker, Freek W Verheught Julius Centrum, 3584 CX Utrecht, Netherlands (e-mail: [email protected]) 1
2
3
Es R van, Jonker JJC, Verheugt FWA, Deckers JW, Grobbee DE, for the Antithrombotics in the Secondary Prevention of Coronary Thrombosis (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002; 360: 109–13. Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutic trials. J Chron Dis 1967; 20: 637–48. Armitage P. Attitudes in clinical trials. Stat Med 1998; 17: 2675–83.
Obstructive sleep apnoea Sir—In their otherwise informative Seminar on obstructive sleep apnoea (July 20, p 237),1 Atul Malhotra and David P White do not mention the perioperative management of these patients either for operations specifically for obstructive sleep apnoea (eg, uvulopalatopharyngoplasty) or for unrelated procedures. Clinicians involved in the care of patients with obstructive sleep apnoea must be aware of the importance of the disorder and its appropriate management during the perioperative period. Patients with obstructive sleep apnoea have increased sensitivity to anaesthetic agents, sedative drugs, and opiates. The result is reduced pharyngeal tone and reduced ventilatory and arousal responses to hypercapnia and hypoxia.2 These patients’ tracheas are often difficult to intubate, and in serious obstructive sleep apnoea, intubation is often done while the patient is awake. Patients are at increased risk of perioperative hypoxaemia, hypercarbia, and secretion retention, and are consequently best recovered in a high dependency or intensive care setting; in severe cases, they might need an elective preoperative tracheostomy. They are also at increased risk of gastrooesophageal reflux and consequently of aspiration of gastric contents. Where possible, a regional anaesthetic technique can be used, which avoids the potential problems of general anaesthesia.3 Day-case operations are contraindicated because of patients’ airway
THE LANCET • Vol 360 • December 21/28, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.