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 (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”

3. 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”

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 P=0.03 P<0.001

7. 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%)

8. How Many Patients? 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

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 trialDevereaux 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 (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)

13. Hospital length of stay • adjusted HR 1.1 (logrank P=0.06) • ICU length of stay • adjusted HR 1.4 (logrank P=0.02)

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 adultsMyles 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 adultsMyles 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 changesMangione 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 trialDevereaux 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

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, n>2500 (>30 sites, <1% missing data) • For cardiac surgery, ATACAS (n=718): 31 deaths, 48 new disability • combined death/disability 11% • 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

26. How Many Patients? 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, α error 0.05, β 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