What are Important Endpoints in Anaesthesia Research?

Paul Myles, MB.BS, MPH, MD, FCARCSI, FANZCA, FRCA

Alfred Hospital & Monash University, Melbourne, Australia

A recent publication

RCT, inguinal hernia repair (n=273), 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, P=0.04), at 12 h (20 vs 30, P=0.0014), and at 24 h (29 vs 33, P=0.013).

Conclusions

“Ultrasound-guided TAP block provided better pain control than 'blind' IHN block after inguinal hernia repair”

A recent publication

RCT, inguinal hernia repair (n=273), 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, P=0.04), at 12 h (20 vs 30, P=0.0014), and at 24 h (29 vs 33, P=0.013).

Conclusions

“Ultrasound-guided TAP block provided better pain control than 'blind' IHN block after inguinal hernia repair”

What is a Meaningful Change in a VAS Score?

The VAS score has a measurement error of about 20 mm1. Campbell W, et al. Quantifying meaningful changes in pain. Anaesthesia 1998

2. DeLoach L, et al. The visual analogue scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale. Anesth Analg 1998

3. Cepeda MS, et al. What decline in pain intensity is meaningful to patients with acute pain? Pain 2003

A clinically important reduction in pain:1. VAS score ≥20 mm

2. 50% change (see: Moore A, et al. Pain 1996)

ECG ischaemia, cardiac output, urine output, cerebral oximetry, ICP, TCD, POCD, PaO2, PEFR, lactate, CRP, IL-10, TNF …

Uncertain clinical importance, transientUnconvincing relationship with outcome

Surrogate endpoints: are they meaningful? Fisher DM. Anesthesiology 1994

Decompressive craniectomy in diffuse traumatic brain injury

Cooper DJ, et al. N Engl J Med 2011

P=0.03

P<0.001

What Are Important Endpoints?

(for patients)

Serious disability or death– major sepsis (2-8%) – myocardial infarction (2-4%)– renal failure (<2%)– stroke (<2%)– mortality (<2%)

How Many Patients?

type I error = 0.05 (false conclusion of effect)type II error = 0.2 (false conclusion of no effect)

Baseline incidence 25% improvement

No. of patients

required

2%

4%

8%

1.5%

3%

6%

30,000

14,000

7,000

Large Studies (for adequate power)

1. Observational studies

2. Meta-analysis of small trials

3. 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

The Primary Endpoint

What are Important Endpoints in Anaesthesia Research?

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

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 patientsPrimary endpoint = a composite of cardiovascular death,

non-fatal MI and non-fatal cardiac arrest 5.8% vs. 6.9%, p=0.04 (MI: 4.2% vs. 5.7%, p=0.0017)

But: more deaths (3.1% vs. 2.3%, p=0.032) more strokes (1.0% vs. 0.5%, p=0.005)

Hospital length of stay – adjusted HR 1.1 (logrank P=0.06)

ICU length of stay– adjusted HR 1.4 (logrank P=0.02)

Recovery After Surgery

1. Comfort pain nausea and vomiting, thirst, hunger dyspnoea, cough headache, backache anxiety, depression, confusion

2. Avoid complications

3. Physical functioning and independence

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 22. Had support from others (especially doctors & nurses) 0 1 23. Been able to understand instructions and advice. Not being confused 0 1 24. Been able to look after personal toilet and hygiene unaided 0 1 25. Been able to pass urine ("waterworks") and having no trouble with bowel function 0 1 26. Been able to breathe easily 0 1 27. Been free from headache, backache or muscle pains 0 1 28. Been free from nausea, dry-retching or vomiting 0 1 29. Been free from experiencing severe pain, or constant moderate pain 0 1 2

•

•

•

• • • • •

• • • • • • ••

••

•

••

• • ••

• • • • •

10

11

12

13

14

15

16

17

18

Postoperative time period

• Minor, n=30

• Major, n=30

**

**

** *

Development and psychometric testing of a quality of recovery score after general anesthesia and surgery in adults Myles PS, et al. Anesth Analg 1999

1. 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

2. 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

3. 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

4. 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

5. Leslie K, Troedel S, Irwin K, et al. Quality of recovery from anesthesia in neurosurgical patients. Anesthesiology 2003

6. Herrera FJ, Wong J, Chung F. A systematic review of postoperative recovery outcomes measurements after ambulatory surgery. Anesth Analg 2007

7. Kluivers K, Riphagen I, Vierhout M, et al. Systematic review on recovery specific quality-of-life instruments. Surgery 2008

8. 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

9. 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

10. 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

Health Status: quality of recovery, quality of life

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

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

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”

What Do Our Patients Want?

A return or maintenance of health, functional capacity and emotional well-being after surgery

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%, p=0.04

• But: – more deaths: 3.1% vs. 2.3%, p=0.032

– more strokes: 1.0% vs. 0.5%, p=0.005

What aboutDisability-free Survival?

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

ENIGMA-II and ATACAS

Current long-term outcome data, n>2500 (>30 sites, <1% missing data)

1. For cardiac surgery, ATACAS (n=718): 31 deaths, 48 new disability– combined death/disability 11%

2. For noncardiac surgery, ENIGMA-II (n=1800): 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

How Many Patients?

type I error = 0.05 (false conclusion of effect)type II error = 0.2 (false conclusion of no effect)

Baseline incidence 25% improvement

No. of patients

required

2%

20%

40%

1.5%

15%

30%

30,000

2,500

920

A Sample Size Calculation

1. Serious complications; baseline incidence 20%– ≥25% difference, α error 0.05, β error 0.2 (80% power)

– need 2,400 patients

2. Disability-free survival; if median 3 years– ≥25% difference (hazard ratio ≥1.25)

– 93% power

Conclusions

Study true outcomes– Serious complications– Comfort and health status

> quality of recovery, quality of life

– Death and disability, using disability-free survival