Need for expertise based randomised controlled trials
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《英国医生杂志》
1 Department of Clinical Epidemiology and Biostatistics, McMaster University, 1200 Main Street, West Hamilton ON, Canada L8N 3Z5, 2 Department of Surgery, McMaster University, 3 UK Cochrane Centre, Oxford, 4 Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, United States, 5 Population Health Research Institute, McMaster University, 6 Trout Research and Education Centre of Irish Lake, Markdale, Ontario, Canada, 7 Departments of Medicine and Social and Preventive Medicine, University at Buffalo, Buffalo, New York, United States
Correspondence to: P J Devereaux, philipj@mcmaster.ca
Surgical procedures are less likely to be rigorously evidence based than drug treatments because of difficulties with randomisation. Expertise based trials could be the way forward
Introduction
Investigators have used the expertise based design when conventional randomised controlled trials were impossible because different specialty groups provided the interventions under evaluation—for example, percutaneous transluminal coronary angioplasty versus coronary artery bypass graft surgery.7-9 In 1980, Van der Linden suggested randomising participants to clinicians committed to performing different interventions in an area in which a conventional randomised controlled trial was possible.10 Since that time, however, the expertise based design has been little used, even in areas where it has high potential (such as, surgery, physiotherapy, and chiropractic).
Problems with validity of conventional randomised controlled trials
In the surgical expertise based randomised controlled trial, patients are randomised to different surgeons with expertise in the relevant intervention. The first advantage of the expertise based randomised controlled trial is that surgeons will perform only the procedure in which they have expertise, avoiding the problem of differential expertise.
As in the conventional randomised controlled trial, surgeons in the expertise based randomised controlled trial will be unblinded. However, in the expertise based randomised controlled trial surgeons are likely to be subconsciously biased toward the procedure in which they have expertise. Consequently, the likelihood of differential procedural performance, cointerventions, data collection, and outcome assessment decreases. A third advantage of the expertise based randomised controlled trial is that procedural crossovers are less likely to occur because surgeons are doing the procedures with which they are most comfortable.16-18
Applicability of expertise based randomised controlled trials
Randomised controlled trials done in the past few decades show that conventional surgical randomised controlled trials are feasible. However, surgical research is still dominated by observational studies,19 21 and general surgery interventions are half as likely to be based on the results of randomised controlled trials as medical interventions.22 23 To investigate the feasibility of the expertise based randomised controlled trial in areas in which both designs are an option we searched three electronic bibliographic databases: MEDLINE (1966 to September Week 2 2003), EBM Reviews—Cochrane Central Register of Controlled Trials (issue 2, 2003), and EMBASE (1980 to 2003 Week 38). Complete listings of search strategies are available from the authors.
This search identified 162 citations, and two researchers independently reviewed each citation to determine if the report was a surgical expertise based randomised controlled trial. We contacted one of the trial authors in cases of disagreements. We identified five surgical expertise based randomised controlled trials that were conducted in an area in which both designs were a potential option.24-27 Table 3 summaries the characteristics of these expertise based randomised controlled trials, showing that such trials are feasible in both emergency and elective surgery.
Table 3 Surgical expertise based randomised controlled trials
Surgical expertise based randomised controlled trials may be more feasible than conventional randomised controlled trials. Surgeons may be more willing to participate in an expertise based randomised controlled trial because they have to perform only the procedure for which they have developed expertise. Furthermore, surgeons do not have to do a minimum number of operations with the unfamiliar intervention before participating in the trial. This is likely to appeal to both surgeons and investigators and could prevent delays in starting trials.
The feasibility of expertise based randomised controlled trials will be enhanced when an intermediary physician randomises patients before they are seen by the participating surgeon. For example, in trials of patients admitted to accident and emergency, a surgical resident or an emergency physician could randomise the patient. Expertise based randomised controlled trials may also work well in group practices. Some cardiac surgeons, for instance, have group practices and accept patients for surgery without assignment to a specific surgeon. Patients at such practices could be randomised into an expertise based randomised controlled trial when they are accepted for surgery. Greater practical experience with the expertise based design is needed to evaluate the effectiveness of these approaches to recruitment.
Enrolling patients into an expertise based randomised controlled trial may be more challenging after a patient has seen a specific surgeon because randomising such a patient to another surgeon may be awkward. Even under these circumstances, an expertise based randomised controlled trial may prove feasible. For instance, in the largest randomised trial of treatment for subarachnoid haemorrhage, in which 2143 patients were randomised to neurosurgical clipping versus endovascular coiling,29 patients were seen first by neurosurgeons, who then randomised them to neurosurgery or endovascular coiling by an interventional radiologist.
A potential challenge to undertaking an expertise based randomised controlled trial is that it is highly desirable to have surgeons from both treatment groups at all participating hospitals. This avoids the possible negative impact on recruitment resulting from patients having to travel to other hospitals and the potential confounding related to variations in non-surgical care in the different hospitals. If, in an expertise based randomised controlled trial, it is not possible to have surgeons from both treatment groups at all participating hospitals, the effect of centre is likely to vary depending on the nature of the procedure. The centre may not have an important effect for outpatient procedures, but the effect may be large for major inpatient procedures. For trials of major procedures, trialists will have to weigh the potential influence of differential expertise bias, surgeon unblinding, and differential crossover versus centre effect when deciding on the optimal trial design. The need to have two groups of surgeons on call presents a further challenge to undertaking expertise based randomised controlled trials of 24 hour acute surgical care.
A surgical expertise based randomised controlled trial must ensure satisfactory competence among the surgeons doing each procedure. Strategies to achieve this goal will include selecting qualified surgeons who have attained a specified level of post training experience, who fulfil requirements established by professional guidelines, or who have documented their expertise is at the plateau of the learning curve.
Ethics
The issues of validity, applicability, feasibility, and the ethics of expertise based randomised controlled trials relative to conventional randomised controlled trials are also relevant to the evaluation of interventions in many other fields including rehabilitation, behaviour modification, physiotherapy, chiropractic, radiation oncology, occupational therapy, and education. The issues are relevant to any area in which the skill set that a clinician requires to perform the experimental and control interventions varies importantly. The issues become increasingly germane when clinicians administering the interventions cannot be blinded.
Summary points
Questions remain about the use of randomised controlled trials to evaluate non-pharmacological interventions such as surgery
An alternative is to use expertise based randomised controlled trials, in which participants are randomised to clinicians with expertise in intervention A or intervention B
Interventions are performed only by clinicians with expertise in the procedure, which reduces both bias and ethical concerns
Expertise based randomised controlled trials may have greater applicability and feasibility than conventional trials
We thank the study to prospectively evaluate reamed intramedullary nails in tibial shaft fractures (SPRINT) investigators for completing our survey and providing data related to their trial. We also thank D Altman, I Boutron, M Gent, C Meinert, K Schulz, and W Van der Linden for helpful comments and Neera Bhatnagar for the electronic database search.
Contributors and sources: PJD originated the idea for this paper and brought together all the authors to formulate and debate the points included in the text. PJD, MB, SDW, and GHG conducted the survey presented in this paper, PJD undertook the data analysis, and all authors contributed to the data interpretation. PJD wrote the first draft of the paper and all authors provided critical revisions to the manuscript. All authors have expertise in randomised controlled trial methodology and most haveled large international randomised controlled trials, including surgical randomised controlled trials. PJD will act as the guarantor.
Funding: PJD is supported by a Canadian Institutes of Health Research senior research fellowship award, MB holds a Canada research chair in surgical outcomes, DJC holds a Canada research chair, SY holds an endowed chair of the Heart and Stroke Foundation of Ontario and is a senior scientist of the Canadian Institues of Health Research, GRN holds a Canadian research chair from the Social Sciences and Humanities Research Council. VMM is a Mayo Foundation scholar.
Competing interests: None declared.
References
Chalmers I. Unbiased, relevant, and reliable assessments in health care: important progress during the past century, but plenty of scope for doing better. BMJ 1998;317: 1167-8.
Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134: 663-94.
Russell R. Surgical research. Lancet 1996;347: 1480.
Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996;312: 1215-8.
Wehbe MA. The prospective, randomized, double-blind clinical trial in orthopaedic surgery. J Bone Joint Surg Am 1998;80: 1395.
Black N. Evidence-based surgery: A passing fad? World J Surg 1999;23: 789-93.
Coronary angioplasty versus coronary artery bypass surgery: the Randomized Intervention Treatment of Angina (RITA) trial. Lancet 1993;341: 573-80.
CABRI Trial Participants. First-year results of CABRI (coronary angioplasty versus bypass revascularisation investigation). Lancet 1995;346: 1179-84.
Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335: 217-25.
Van der Linden W. Pitfalls in randomized surgical trials. Surgery 1980;87: 258-62.
Rudicel S, Esdaile J. The randomized clinical trial in orthopaedics: obligation or option? J Bone Joint Surg Am 1985;67: 1284-93.
Devereaux PJ, Bhandari M, Walter S, Sprague S, Guyatt G. Participating surgeons' experience with and beliefs in the procedures evaluated in a randomized controlled trial. Clin Trials 2004;1: 225.
Prystowsky JB, Bordage G, Feinglass JM. Patient outcomes for segmental colon resection according to surgeon's training, certification, and experience. Surgery 2002;132: 663-70 (discussion pp670-2).
Bridgewater B, Grayson AD, Au J, Hassan R, Dihmis WC, Munsch C, et al. Improving mortality of coronary surgery over first four years of independent practice: retrospective examination of prospectively collected data from 15 surgeons. BMJ 2004;329: 421.
Devereaux PJ, Bhandari M, Montori VM, Manns BJ, Ghali WA, Guyatt GH. Double blind, you are the weakest link—good-bye! ACP J Club 2002;136: A11.
DeTurris SV, Cacchione RN, Mungara A, Pecoraro A, Ferzli GS. Laparoscopic herniorrhaphy: beyond the learning curve. J Am Coll Surg 2002;194: 65-73.
Menon VS, Manson JM, Baxter JN. Laparoscopic fundoplication: learning curve and patient satisfaction. Ann R Coll Surg Engl 2003;85: 10-3.
Lobato AC, Rodriguez-Lopez J, Diethrich EB. Learning curve for endovascular abdominal aortic aneurysm repair: evaluation of a 277-patient single-center experience. J Endovasc Ther 2002;9: 262-8.
Bhandari M, Richards RR, Sprague S, Schemitsch EH. The quality of reporting of randomized trials in the Journal of Bone and Joint Surgery from 1988 through 2000. J Bone Joint Surg Am 2002;84A: 388-96.
Solomon MJ, McLeod RS. Clinical studies in surgical journals—have we improved? Dis Colon Rectum 1993;36: 43-8.
Pollock AV. Surgical evaluation at the crossroads. Br J Surg 1993;80: 964-6.
Howes N, Chagla L, Thorpe M, McCulloch P. Surgical practice is evidence based. Br J Surg 1997;84: 1220-3.
Ellis J, Mulligan I, Rowe J, Sackett DL. Inpatient general medicine is evidence based. A-Team, Nuffield Department of Clinical Medicine. Lancet 1995;346: 407-10.
Finkemeier CG, Schmidt AH, Kyle RF, Templeman DC, Varecka TF. A prospective, randomized study of intramedullary nails inserted with and without reaming for the treatment of open and closed fractures of the tibial shaft. J Orthop Trauma 2000;14: 187-93.
Machler HE, Bergmann P, Anelli-Monti M, Dacar D, Rehak P, Knez I, et al. Minimally invasive versus conventional aortic valve operations: a prospective study in 120 patients. Ann Thorac Surg 1999;67: 1001-5.
Wyrsch B, McFerran MA, McAndrew M, Limbird TJ, Harper MC, Johnson KD, et al. Operative treatment of fractures of the tibial plafond. A randomized, prospective study. J Bone Joint Surg Am 1996;78: 1646-57.
Wihlborg O. Fixation of femoral neck fractures. A four-flanged nail versus threaded pins in 200 cases. Acta Orthop Scand 1990;61: 415-8.
Phillips WA, Schwartz HS, Keller CS, Woodward HR, Rudd WS, Spiegel PG, et al. A prospective, randomized study of the management of severe ankle fractures. J Bone Joint Surg Am 1985;67: 67-78.
Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360: 1267-74.(P J Devereaux, assistant professor1, Moh)
Correspondence to: P J Devereaux, philipj@mcmaster.ca
Surgical procedures are less likely to be rigorously evidence based than drug treatments because of difficulties with randomisation. Expertise based trials could be the way forward
Introduction
Investigators have used the expertise based design when conventional randomised controlled trials were impossible because different specialty groups provided the interventions under evaluation—for example, percutaneous transluminal coronary angioplasty versus coronary artery bypass graft surgery.7-9 In 1980, Van der Linden suggested randomising participants to clinicians committed to performing different interventions in an area in which a conventional randomised controlled trial was possible.10 Since that time, however, the expertise based design has been little used, even in areas where it has high potential (such as, surgery, physiotherapy, and chiropractic).
Problems with validity of conventional randomised controlled trials
In the surgical expertise based randomised controlled trial, patients are randomised to different surgeons with expertise in the relevant intervention. The first advantage of the expertise based randomised controlled trial is that surgeons will perform only the procedure in which they have expertise, avoiding the problem of differential expertise.
As in the conventional randomised controlled trial, surgeons in the expertise based randomised controlled trial will be unblinded. However, in the expertise based randomised controlled trial surgeons are likely to be subconsciously biased toward the procedure in which they have expertise. Consequently, the likelihood of differential procedural performance, cointerventions, data collection, and outcome assessment decreases. A third advantage of the expertise based randomised controlled trial is that procedural crossovers are less likely to occur because surgeons are doing the procedures with which they are most comfortable.16-18
Applicability of expertise based randomised controlled trials
Randomised controlled trials done in the past few decades show that conventional surgical randomised controlled trials are feasible. However, surgical research is still dominated by observational studies,19 21 and general surgery interventions are half as likely to be based on the results of randomised controlled trials as medical interventions.22 23 To investigate the feasibility of the expertise based randomised controlled trial in areas in which both designs are an option we searched three electronic bibliographic databases: MEDLINE (1966 to September Week 2 2003), EBM Reviews—Cochrane Central Register of Controlled Trials (issue 2, 2003), and EMBASE (1980 to 2003 Week 38). Complete listings of search strategies are available from the authors.
This search identified 162 citations, and two researchers independently reviewed each citation to determine if the report was a surgical expertise based randomised controlled trial. We contacted one of the trial authors in cases of disagreements. We identified five surgical expertise based randomised controlled trials that were conducted in an area in which both designs were a potential option.24-27 Table 3 summaries the characteristics of these expertise based randomised controlled trials, showing that such trials are feasible in both emergency and elective surgery.
Table 3 Surgical expertise based randomised controlled trials
Surgical expertise based randomised controlled trials may be more feasible than conventional randomised controlled trials. Surgeons may be more willing to participate in an expertise based randomised controlled trial because they have to perform only the procedure for which they have developed expertise. Furthermore, surgeons do not have to do a minimum number of operations with the unfamiliar intervention before participating in the trial. This is likely to appeal to both surgeons and investigators and could prevent delays in starting trials.
The feasibility of expertise based randomised controlled trials will be enhanced when an intermediary physician randomises patients before they are seen by the participating surgeon. For example, in trials of patients admitted to accident and emergency, a surgical resident or an emergency physician could randomise the patient. Expertise based randomised controlled trials may also work well in group practices. Some cardiac surgeons, for instance, have group practices and accept patients for surgery without assignment to a specific surgeon. Patients at such practices could be randomised into an expertise based randomised controlled trial when they are accepted for surgery. Greater practical experience with the expertise based design is needed to evaluate the effectiveness of these approaches to recruitment.
Enrolling patients into an expertise based randomised controlled trial may be more challenging after a patient has seen a specific surgeon because randomising such a patient to another surgeon may be awkward. Even under these circumstances, an expertise based randomised controlled trial may prove feasible. For instance, in the largest randomised trial of treatment for subarachnoid haemorrhage, in which 2143 patients were randomised to neurosurgical clipping versus endovascular coiling,29 patients were seen first by neurosurgeons, who then randomised them to neurosurgery or endovascular coiling by an interventional radiologist.
A potential challenge to undertaking an expertise based randomised controlled trial is that it is highly desirable to have surgeons from both treatment groups at all participating hospitals. This avoids the possible negative impact on recruitment resulting from patients having to travel to other hospitals and the potential confounding related to variations in non-surgical care in the different hospitals. If, in an expertise based randomised controlled trial, it is not possible to have surgeons from both treatment groups at all participating hospitals, the effect of centre is likely to vary depending on the nature of the procedure. The centre may not have an important effect for outpatient procedures, but the effect may be large for major inpatient procedures. For trials of major procedures, trialists will have to weigh the potential influence of differential expertise bias, surgeon unblinding, and differential crossover versus centre effect when deciding on the optimal trial design. The need to have two groups of surgeons on call presents a further challenge to undertaking expertise based randomised controlled trials of 24 hour acute surgical care.
A surgical expertise based randomised controlled trial must ensure satisfactory competence among the surgeons doing each procedure. Strategies to achieve this goal will include selecting qualified surgeons who have attained a specified level of post training experience, who fulfil requirements established by professional guidelines, or who have documented their expertise is at the plateau of the learning curve.
Ethics
The issues of validity, applicability, feasibility, and the ethics of expertise based randomised controlled trials relative to conventional randomised controlled trials are also relevant to the evaluation of interventions in many other fields including rehabilitation, behaviour modification, physiotherapy, chiropractic, radiation oncology, occupational therapy, and education. The issues are relevant to any area in which the skill set that a clinician requires to perform the experimental and control interventions varies importantly. The issues become increasingly germane when clinicians administering the interventions cannot be blinded.
Summary points
Questions remain about the use of randomised controlled trials to evaluate non-pharmacological interventions such as surgery
An alternative is to use expertise based randomised controlled trials, in which participants are randomised to clinicians with expertise in intervention A or intervention B
Interventions are performed only by clinicians with expertise in the procedure, which reduces both bias and ethical concerns
Expertise based randomised controlled trials may have greater applicability and feasibility than conventional trials
We thank the study to prospectively evaluate reamed intramedullary nails in tibial shaft fractures (SPRINT) investigators for completing our survey and providing data related to their trial. We also thank D Altman, I Boutron, M Gent, C Meinert, K Schulz, and W Van der Linden for helpful comments and Neera Bhatnagar for the electronic database search.
Contributors and sources: PJD originated the idea for this paper and brought together all the authors to formulate and debate the points included in the text. PJD, MB, SDW, and GHG conducted the survey presented in this paper, PJD undertook the data analysis, and all authors contributed to the data interpretation. PJD wrote the first draft of the paper and all authors provided critical revisions to the manuscript. All authors have expertise in randomised controlled trial methodology and most haveled large international randomised controlled trials, including surgical randomised controlled trials. PJD will act as the guarantor.
Funding: PJD is supported by a Canadian Institutes of Health Research senior research fellowship award, MB holds a Canada research chair in surgical outcomes, DJC holds a Canada research chair, SY holds an endowed chair of the Heart and Stroke Foundation of Ontario and is a senior scientist of the Canadian Institues of Health Research, GRN holds a Canadian research chair from the Social Sciences and Humanities Research Council. VMM is a Mayo Foundation scholar.
Competing interests: None declared.
References
Chalmers I. Unbiased, relevant, and reliable assessments in health care: important progress during the past century, but plenty of scope for doing better. BMJ 1998;317: 1167-8.
Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134: 663-94.
Russell R. Surgical research. Lancet 1996;347: 1480.
Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ 1996;312: 1215-8.
Wehbe MA. The prospective, randomized, double-blind clinical trial in orthopaedic surgery. J Bone Joint Surg Am 1998;80: 1395.
Black N. Evidence-based surgery: A passing fad? World J Surg 1999;23: 789-93.
Coronary angioplasty versus coronary artery bypass surgery: the Randomized Intervention Treatment of Angina (RITA) trial. Lancet 1993;341: 573-80.
CABRI Trial Participants. First-year results of CABRI (coronary angioplasty versus bypass revascularisation investigation). Lancet 1995;346: 1179-84.
Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996;335: 217-25.
Van der Linden W. Pitfalls in randomized surgical trials. Surgery 1980;87: 258-62.
Rudicel S, Esdaile J. The randomized clinical trial in orthopaedics: obligation or option? J Bone Joint Surg Am 1985;67: 1284-93.
Devereaux PJ, Bhandari M, Walter S, Sprague S, Guyatt G. Participating surgeons' experience with and beliefs in the procedures evaluated in a randomized controlled trial. Clin Trials 2004;1: 225.
Prystowsky JB, Bordage G, Feinglass JM. Patient outcomes for segmental colon resection according to surgeon's training, certification, and experience. Surgery 2002;132: 663-70 (discussion pp670-2).
Bridgewater B, Grayson AD, Au J, Hassan R, Dihmis WC, Munsch C, et al. Improving mortality of coronary surgery over first four years of independent practice: retrospective examination of prospectively collected data from 15 surgeons. BMJ 2004;329: 421.
Devereaux PJ, Bhandari M, Montori VM, Manns BJ, Ghali WA, Guyatt GH. Double blind, you are the weakest link—good-bye! ACP J Club 2002;136: A11.
DeTurris SV, Cacchione RN, Mungara A, Pecoraro A, Ferzli GS. Laparoscopic herniorrhaphy: beyond the learning curve. J Am Coll Surg 2002;194: 65-73.
Menon VS, Manson JM, Baxter JN. Laparoscopic fundoplication: learning curve and patient satisfaction. Ann R Coll Surg Engl 2003;85: 10-3.
Lobato AC, Rodriguez-Lopez J, Diethrich EB. Learning curve for endovascular abdominal aortic aneurysm repair: evaluation of a 277-patient single-center experience. J Endovasc Ther 2002;9: 262-8.
Bhandari M, Richards RR, Sprague S, Schemitsch EH. The quality of reporting of randomized trials in the Journal of Bone and Joint Surgery from 1988 through 2000. J Bone Joint Surg Am 2002;84A: 388-96.
Solomon MJ, McLeod RS. Clinical studies in surgical journals—have we improved? Dis Colon Rectum 1993;36: 43-8.
Pollock AV. Surgical evaluation at the crossroads. Br J Surg 1993;80: 964-6.
Howes N, Chagla L, Thorpe M, McCulloch P. Surgical practice is evidence based. Br J Surg 1997;84: 1220-3.
Ellis J, Mulligan I, Rowe J, Sackett DL. Inpatient general medicine is evidence based. A-Team, Nuffield Department of Clinical Medicine. Lancet 1995;346: 407-10.
Finkemeier CG, Schmidt AH, Kyle RF, Templeman DC, Varecka TF. A prospective, randomized study of intramedullary nails inserted with and without reaming for the treatment of open and closed fractures of the tibial shaft. J Orthop Trauma 2000;14: 187-93.
Machler HE, Bergmann P, Anelli-Monti M, Dacar D, Rehak P, Knez I, et al. Minimally invasive versus conventional aortic valve operations: a prospective study in 120 patients. Ann Thorac Surg 1999;67: 1001-5.
Wyrsch B, McFerran MA, McAndrew M, Limbird TJ, Harper MC, Johnson KD, et al. Operative treatment of fractures of the tibial plafond. A randomized, prospective study. J Bone Joint Surg Am 1996;78: 1646-57.
Wihlborg O. Fixation of femoral neck fractures. A four-flanged nail versus threaded pins in 200 cases. Acta Orthop Scand 1990;61: 415-8.
Phillips WA, Schwartz HS, Keller CS, Woodward HR, Rudd WS, Spiegel PG, et al. A prospective, randomized study of the management of severe ankle fractures. J Bone Joint Surg Am 1985;67: 67-78.
Molyneux A, Kerr R, Stratton I, Sandercock P, Clarke M, Shrimpton J, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002;360: 1267-74.(P J Devereaux, assistant professor1, Moh)