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What are Important Endpoints in Anaesthesia Research?

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What are Important Endpoints in Anaesthesia Research? Paul Myles, MB.BS, MPH, MD, FCARCSI, FANZCA, FRCA Alfred Hospital & Monash University, Melbourne, Australia – PowerPoint PPT presentation

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Title: What are Important Endpoints in Anaesthesia Research?


1
What are Important Endpoints in Anaesthesia
Research?
  • Paul Myles, MB.BS, MPH, MD, FCARCSI, FANZCA, FRCA
  • Alfred Hospital Monash University, Melbourne,
    Australia

2
A recent publication
  • RCT, inguinal hernia repair (n273), TAP block
    vs. IHN block
  • Results
  • Median VAS pain scores at rest were lower in the
    ultrasound-guided TAP group at 4 h (11 vs 15,
    P0.04), at 12 h (20 vs 30, P0.0014), and at 24
    h (29 vs 33, P0.013).
  • Conclusions
  • Ultrasound-guided TAP block provided better pain
    control than 'blind' IHN block after inguinal
    hernia repair

3
A recent publication
  • RCT, inguinal hernia repair (n273), TAP block
    vs. IHN block
  • Results
  • Median VAS pain scores at rest were lower in the
    ultrasound-guided TAP group at 4 h (11 vs 15,
    P0.04), at 12 h (20 vs 30, P0.0014), and at 24
    h (29 vs 33, P0.013).
  • Conclusions
  • Ultrasound-guided TAP block provided better pain
    control than 'blind' IHN block after inguinal
    hernia repair

4
What is a Meaningful Change in a VAS Score?
  • The VAS score has a measurement error of about 20
    mm
  • Campbell W, et al. Quantifying meaningful
    changes in pain. Anaesthesia 1998
  • DeLoach L, et al. The visual analogue scale in
    the immediate postoperative period intrasubject
    variability and correlation with a numeric scale.
    Anesth Analg 1998
  • Cepeda MS, et al. What decline in pain intensity
    is meaningful to patients with acute pain? Pain
    2003
  • A clinically important reduction in pain
  • VAS score 20 mm
  • 50 change (see Moore A, et al. Pain 1996)

5
Surrogate endpoints are they meaningful?

Fisher DM. Anesthesiology 1994
  • ECG ischaemia, cardiac output, urine output,
    cerebral oximetry, ICP, TCD, POCD, PaO2, PEFR,
    lactate, CRP, IL-10, TNF
  • Uncertain clinical importance, transient
  • Unconvincing relationship with outcome

6
Decompressive craniectomy in diffuse traumatic
brain injury Cooper DJ, et al. N Engl J
Med 2011
P0.03
Plt0.001
7
What Are Important Endpoints? (for patients)
  • Serious disability or death
  • major sepsis (2-8)
  • myocardial infarction (2-4)
  • renal failure (lt2)
  • stroke (lt2)
  • mortality (lt2)

8
How Many Patients?
Baseline incidence 25 improvement No. of patients required
2 4 8 1.5 3 6 30,000 14,000 7,000
type I error 0.05 (false conclusion of
effect) type II error 0.2 (false conclusion of
no effect)
9
Large Studies (for adequate power)
  • Observational studies
  • Meta-analysis of small trials
  • If RCT
  • study high-risk patients
  • use a composite endpoint

Baseline incidence 25 improvement No. of patients required
4 20 40 3 15 30 14,000 2,400 920
10
The Primary Endpoint
What are Important Endpoints in Anaesthesia
Research?
11
Composite Endpoints
  • Increases incidence (event rate) lowers sample
    size
  • Major complications
  • major adverse cardiac events (MACE)
  • death, non-fatal MI, non-fatal stroke, chronic
    heart failure, and revascularization
  • but no standard definition
  • Assume that each component of the endpoint has a
    similar burden on health
  • beware single dominant event
  • beware large variations between components

Myles PS, Devereaux PJ. Pros and cons of
composite endpoints in anesthesia trials.
Anesthesiology 2010
12
Effects of extended-release metoprolol succinate
in patients undergoing non-cardiac surgery (POISE
trial) a randomised controlled trial
Devereaux PJ, et al. Lancet 2008
  • RCT, 8351 patients
  • Primary endpoint a composite of cardiovascular
    death, non-fatal MI and non-fatal cardiac arrest
  • 5.8 vs. 6.9, p0.04 (MI 4.2 vs. 5.7,
    p0.0017)
  • But
  • more deaths (3.1 vs. 2.3, p0.032)
  • more strokes (1.0 vs. 0.5, p0.005)

13
  • Hospital length of stay
  • adjusted HR 1.1 (logrank P0.06)
  • ICU length of stay
  • adjusted HR 1.4 (logrank P0.02)

14
Recovery After Surgery
  • Comfort
  • pain
  • nausea and vomiting, thirst, hunger
  • dyspnoea, cough
  • headache, backache
  • anxiety, depression, confusion
  • Avoid complications
  • Physical functioning and independence

15
Development and psychometric testing of a quality
of recovery score after general anesthesia and
surgery in adults
Myles PS, et al. Anesth Analg 1999
  • Not at Some of Most of
  • The QoR Score all
    the time the time
  • 1. Had a feeling of general well-being
    0 1 2
  • 2. Had support from others
  • (especially doctors nurses)
    0 1 2
  • 3. Been able to understand instructions and
  • advice. Not being confused 0
    1 2
  • 4. Been able to look after personal toilet and
  • hygiene unaided 0
    1 2
  • 5. Been able to pass urine ("waterworks") and
  • having no trouble with bowel function
    0 1 2
  • 6. Been able to breathe easily 0
    1 2
  • 7. Been free from headache, backache or
  • muscle pains 0
    1 2
  • 8. Been free from nausea, dry-retching or
  • vomiting 0
    1 2
  • 9. Been free from experiencing severe pain, or
  • constant moderate pain 0
    1 2

16
Development and psychometric testing of a quality
of recovery score after general anesthesia and
surgery in adults
Myles PS, et al. Anesth Analg 1999
17
Health Status quality of recovery, quality of
life
  • Myles PS, Hunt JO, Fletcher H, et al.
    Relationship between quality of recovery in
    hospital, and quality of life at three months
    after cardiac surgery. Anesthesiology 2001
  • Myles PS, Viira D, Hunt JO. Quality of life at
    three years after cardiac surgery relationship
    with preoperative status and quality of recovery.
    Anaesth Intensive Care 2006
  • Gower ST, Quigg CA, Hunt JO, Wallace SK, Myles
    PS. A comparison of patient self-administered
    and investigator-assisted measurement of quality
    of recovery using the QoR-40. Anaesth Intensive
    Care 2006
  • Hansdottir V, Philip J, Olsen M, et al. Thoracic
    epidural versus intravenous patient-controlled
    analgesia after cardiac surgery a randomized
    controlled trial on length of hospital stay and
    patient-perceived quality of recovery.
    Anesthesiology 2006
  • Leslie K, Troedel S, Irwin K, et al. Quality of
    recovery from anesthesia in neurosurgical
    patients. Anesthesiology 2003
  • Herrera FJ, Wong J, Chung F. A systematic review
    of postoperative recovery outcomes measurements
    after ambulatory surgery. Anesth Analg 2007
  • Kluivers K, Riphagen I, Vierhout M, et al.
    Systematic review on recovery specific
    quality-of-life instruments. Surgery 2008
  • Lena P, Balarac N, Lena D, et al. Fast-track
    anesthesia with remifentanil and spinal analgesia
    for cardiac surgery the effect on pain control
    and quality of recovery. J Cardiothorac Vasc
    Anesth 2008
  • Murphy G, Szokol J, Marymont J, et al.
    Morphine-based cardiac anesthesia provides
    superior early recovery compared with fentanyl in
    elective cardiac surgery patients. Anesth Analg
    2009
  • Murphy G, Szokol J, Greenberg S, et al.
    Preoperative dexamethasone enhances quality of
    recovery after laparoscopic cholecystectomy
    effect on in-hospital and postdischarge recovery
    outcomes. Anesthesiology 2011

18
Preoperative dexamethasone enhances quality of
recovery after laparoscopic cholecystectomy
effect on in-hospital and post-discharge recovery
outcomes Murphy GS, et al.
Anesthesiology 2011
120 patients, laparoscopic cholecystectomy RCT
dexamethasone 8 mg vs. placebo
19
Health-related quality of life after elective
surgery measurement of longitudinal changes
Mangione CM, et al. J Gen Intern Med 1997
  • Prospective cohort study, 528 patients (AAA,
    thoracotomy, THR)
  • SF-36 to measure QoL at 1, 6, and 12 mths

But no measure or definition of disability was
used
20
Quality of Recovery and Quality of Life
  • Quality of recovery not directly related to
    longer-term disability (and not designed for
    this)
  • Quality of life measures not responsive to
    change, and no clear cut-off value that defines
    disability

21
What Do Our Patients Want?
  • A return or maintenance of health, functional
    capacity and emotional well-being after surgery

22
Effects of extended-release metoprolol succinate
in patients undergoing non-cardiac surgery (POISE
trial) a randomised controlled trial
Devereaux PJ, et al. Lancet 2008
  • RCT, 8351 patients
  • Primary endpoint a composite of cardiovascular
    death, non-fatal MI and non-fatal cardiac arrest
  • 5.8 vs. 6.9, p0.04
  • But
  • more deaths 3.1 vs. 2.3, p0.032
  • more strokes 1.0 vs. 0.5, p0.005

23
What aboutDisability-free Survival?
24
What is Disability?
Katz S, et al. Studies of illness in the aged.
The index of ADL a standardized measure of
biological and psychosocial function. JAMA 1963
25
ENIGMA-II and ATACAS
  • Current long-term outcome data, ngt2500 (gt30
    sites, lt1 missing data)
  • For cardiac surgery, ATACAS (n718) 31 deaths,
    48 new disability
  • combined death/disability 11
  • For noncardiac surgery, ENIGMA-II (n1800) 242
    deaths, 286 new disability
  • combined death/disability 31
  • Disability should not be ignored in perioperative
    outcome trials
  • can enhance study power
  • But the concept and definition of disability
    required validation
  • onset time, pattern, and longevity
  • relationship with quality of recovery and
    postoperative complications

26
How Many Patients?
Baseline incidence 25 improvement No. of patients required
2 20 40 1.5 15 30 30,000 2,500 920
type I error 0.05 (false conclusion of
effect) type II error 0.2 (false conclusion of
no effect)
27
A Sample Size Calculation
  • Serious complications baseline incidence 20
  • 25 difference, a error 0.05, ß error 0.2 (80
    power)
  • need 2,400 patients
  • Disability-free survival if median 3 years
  • 25 difference (hazard ratio 1.25)
  • 93 power

28
Conclusions
  • Study true outcomes
  • Serious complications
  • Comfort and health status
  • quality of recovery, quality of life
  • Death and disability, using disability-free
    survival
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