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Randomized Controlled Trials
What do they have to do with you?
Joseph H Piatt, Jr, MD, FAAP
Neurological Surgery and Pediatrics
Doernbecher Children’s Hospital
Oregon Health Sciences University
Portland, Oregon, USA
RCTs - Hydrocephalus 2000 / Sydney
EXPERIMENTAL
EXPERIMENTAL
STANDARD
STANDARD
TREATMENT
OUTCOMES
PATIENTS
RCTs - Hydrocephalus 2000 / Sydney
The patients in the RCT must be like
your patient.
� Similar
with respect to
known prognostic factors
� Successfully randomized
(or stratified before
randomization)
� Enrolled in the trial
without bias
RCTs - Hydrocephalus 2000 / Sydney
Medulloblastoma
�
Evans AE, Jenkin RD, Sposto R, et al.: The treatment of
medulloblastoma. Results of a prospective randomized trial of
radiation therapy with and without CCNU, vincristine, and
prednisone. J Neurosurg 72:572-582, 1990
�
Krischer JP, Ragab AH, Kun L, et al.: Nitrogen mustard,
vincristine, procarbazine, and prednisone as adjuvant
chemotherapy in the treatment of medulloblastoma. A Pediatric
Oncology Group study. J Neurosurg 74:905-909, 1991
�
Mulhern RK, Kepner JL, Thomas PR, et al.: Neuropsychologic
functioning of survivors of childhood medulloblastoma
randomized to receive conventional or reduced-dose craniospinal
irradiation: a Pediatric Oncology Group study. J Clin Oncol
16:1723-1728, 1998
RCTs - Hydrocephalus 2000 / Sydney
EC / IC Bypass
�
Failure of extracranial-intracranial arterial bypass to reduce
the risk of ischemic stroke. Results of an international
randomized trial. The EC/IC Bypass Study Group. N Engl J
Med 313:1191-1200, 1985
�
Medicare program; withdrawal of coverage of extracranialintracranial arterial bypass surgery for the treatment or
prevention of stroke-- HCFA. Final notice. Fed Regist
56:8206-8208, 1991
�
Grubb RL Jr, Derdeyn CP, Fritsch SM, et al.: Importance of
hemodynamic factors in the prognosis of symptomatic
carotid occlusion. Jama 280:1055-1060, 1998
RCTs - Hydrocephalus 2000 / Sydney
Nimodipine for Head Injury
�
Teasdale G, Bailey I, Bell A, et al.: A randomized trial of
nimodipine in severe head injury: HIT I. British/Finnish Cooperative Head Injury Trial Group. J Neurotrauma 9 Suppl
2:S545-550, 1992
�
Murray GD, Teasdale GM, Schmitz H: Nimodipine in
traumatic subarachnoid haemorrhage: a re-analysis of the
HIT I and HIT II trials. Acta Neurochir (Wien) 138:1163-1167,
1996
�
Harders A, Kakarieka A, Braakman R: Traumatic
subarachnoid hemorrhage and its treatment with
nimodipine. German tSAH Study Group. J Neurosurg
85:82-89, 1996
RCTs - Hydrocephalus 2000 / Sydney
Other treatment measures must be
similar to your practice.
� Institutional
practice variation
surgical technique
operating room practices
medications
nursing policies
� New
technology
RCTs - Hydrocephalus 2000 / Sydney
Antifibrinolytics
� Fodstad
H, Liliequist B, Schannong
M, et al.: Tranexamic acid in the
preoperative management of
ruptured intracranial aneurysms.
Surg Neurol 10:9-15, 1978
RCTs - Hydrocephalus 2000 / Sydney
The experimental treatment must
be relevant to your practice.
� Institutional
practice variation
surgical technique
operating room practices
medications
nursing policies
� New
technology
� “Efficacy” vs “effectiveness”
RCTs - Hydrocephalus 2000 / Sydney
Barbiturate Coma
�
Ward JD, Becker DP, Miller JD, et al.: Failure of
prophylactic barbiturate coma in the treatment of severe
head injury. J Neurosurg 62:383-388, 1985
�
Eisenberg HM, Frankowski RF, Contant CF, et al.: Highdose barbiturate control of elevated intracranial pressure in
patients with severe head injury. J Neurosurg 69:15-23,
1988
�
Schwartz ML, Tator CH, Rowed DW, et al.: The University of
Toronto head injury treatment study: a prospective,
randomized comparison of pentobarbital and mannitol.
Can J Neurol Sci 11:434-440, 1984
RCTs - Hydrocephalus 2000 / Sydney
The outcomes reported for the
standard treatment must make sense.
� Institutional
practice variation
surgical technique
operating room practices
medications
nursing policies
RCTs - Hydrocephalus 2000 / Sydney
Antibiotic prophylaxis
�
Walters BC, Goumnerova L, Hoffman HJ, et al.: A
randomized controlled trial of perioperative
rifampin/trimethoprim in cerebrospinal fluid shunt surgery
[see comments]. Childs Nerv Syst 8:253-257, 1992
�
Zentner J, Gilsbach J, Felder T: Antibiotic prophylaxis in
cerebrospinal fluid shunting: a prospective randomized trial
in 129 patients. Neurosurg Rev 18:169-172, 1995
�
Djindjian M, Fevrier MJ, Otterbein G, et al.: Oxacillin
prophylaxis in cerebrospinal fluid shunt procedures:
results of a randomized open study in 60 hydrocephalic
patients. Surg Neurol 25:178-180, 1986
RCTs - Hydrocephalus 2000 / Sydney
The outcomes measured must
be important clinically.
�
Patient-centered end-points
functional measures
QALYs
�
Hard end-points
death
device failure
�
“Surrogate“ outcomes
biochemical data
physiological data
RCTs - Hydrocephalus 2000 / Sydney
Hyperbaric Oxygen
� Rockswold
GL, Ford SE, Anderson
DC, et al.: Results of a prospective
randomized trial for treatment of
severely brain-injured patients with
hyperbaric oxygen. J Neurosurg
76:929-934, 1992
RCTs - Hydrocephalus 2000 / Sydney
“Surrogate” End-points - examples
�
�
�
�
van Ek B, Dijkmans BA, van Dulken H, et al.: Effect of
cloxacillin prophylaxis on the bacterial flora of craniotomy
wounds. Scand J Infect Dis 22:345-352, 1990
Niemi T, Tanskanen P, Taxell C, et al.: Effects of
nonsteroidal anti-inflammatory drugs on hemostasis in
patients with aneurysmal subarachnoid hemorrhage. J
Neurosurg Anesthesiol 11:188-194, 1999
Simma B, Burger R, Falk M, et al.: A prospective,
randomized, and controlled study of fluid management in
children with severe head injury: lactated Ringer's solution
versus hypertonic saline. Crit Care Med 26:1265-1270, 1998
Eisenberg HM, Frankowski RF, Contant CF, et al.: Highdose barbiturate control of elevated intracranial pressure in
patients with severe head injury. J Neurosurg 69:15-23,
1988
RCTs - Hydrocephalus 2000 / Sydney
Surrogate End-points
�
Because
that’s
where
the light
is!
RCTs - Hydrocephalus 2000 / Sydney