Clinical Trialsmeasuring their impact on clinical practice

Paul Myles, MB.BS, MPH, MD, FCAI, FANZCA, FRCA, FAHMS

1. Professor/Director, Dept of Anaesthesia and Perioperative Medicine, Alfred Hospital & Monash University

2. NHMRC Practitioner Fellow

1. Rigg J, Jamrozik K, Myles PS, et al. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet 2002

2. Myles PS, Leslie K, Forbes A, et al. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004

3. POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing noncardiac surgery (POISE trial). Lancet 2008

4. Myles PS, Leslie K, Chan M, et al. The safety of the addition of nitrous oxide to general anaesthesia in at risk patients having noncardiac surgery. Lancet 2014

5. Devereaux PJ, et al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med 20146. Devereaux PJ, et al. Clonidine in patients undergoing noncardiac surgery. N Engl J Med 20147. Myles PS, Smith J, Forbes A, et al. Stopping vs. continuing aspirin before coronary artery surgery. N Engl J

Med 20168. Myles PS, Smith J, Forbes A, et al. Tranexamic acid in patients undergoing coronary artery surgery. N Engl J

Med 2016

9. RELIEF Trial: 3,000 major abdominal surgery patients10. BALANCED Trial: 6,500 major surgery patients11. PADDI Trial: 8,800 major surgery patients12. ITACS Trial: 1,000 cardiac surgery patients13. ROCKet Trial: 4,900 surgical patients

ANZCA Clinical Trials Network

Class I evidenceCurrently on b-blocker therapyCommence b-blocker therapy in patients undergoing vascular surgery

Class IIa evidenceCommence b-blocker therapy if: known coronary artery disease, or risk factors for coronary artery disease

ACC/AHA GuidelinesPerioperative cardiovascular evaluation for noncardiac surgery

Eagle K, et al. Anesth Analg 2002 (updated 2005, 2007)

Perioperative Beta-blockersMangano – NEJM 1996N=200, high-risk, major surgery, atenolol

– → reduced mortality at 2 years: 10% vs. 21%, P=0.019– But:

– males (veterans’ hospital) – 8% of placebo patients who were on a b-blocker had it stopped perioperatively– hospital deaths excluded!

Poldermans – NEJM 1999N=112, +ve stress echo., vascular surgery, bisoprolol

– → cardiac death/MI: 3% vs. 34%, P<0.001– But:

– unblinded, stopped early– few events (11 deaths, 9 MIs)– unexpectedly large treatment effect (90-100% risk reduction)

“we are of the strong belief that the evidence for the benefit of beta-blockade … is convincing. Hence, to randomize half our patients to not receive the benefits of beta-blockade would not be acceptable to members of the Unit”

Alfred Ethics Committee: Special Conditions (Nov 2002)

High risk vascular surgery patients who are to receive beta-blockers as part of their routine care are to be excluded from this study.

How strong is the evidence for the use of perioperative beta-blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials

Devereaux PJ, et al. BMJ 2005

“The evidence that perioperative beta-blockers reduce major cardiovascular events is encouraging but too unreliable to allow definitive conclusions to be drawn”

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

CIHR and NHMRC-funded

Patorno E, et al. Am Heart J 2015

USA499,752 patients undergoing elective surgery

The ATACAS Trial

2016

Lysine Analogues and Graft Thrombosistranexamic acid epsilon aminocaproic acid

1. Tsementzis SA, et al. Cerebral blood flow in patients with a subarachnoid haemorrhage during treatment with tranexamic acid. Neurochirurgia (Stuttg) 1992

2. Dentz ME, et al. Early thrombus formation on heparin-bonded pulmonary artery catheters in patients receiving epsilon aminocaproic acid. Anesthesiology 1995

3. Risch A, et al. The effect of aprotinin and tranexamic acid on fibrinolysis and thrombin generation during cardiopulmonary bypass. Anaesthetist 2000

4. Kluger R, et al. Epsilon-aminocaproic acid in coronary artery bypass graft surgery: preincision or postheparin? Anesthesiology 2003

5. Stief TW. Tranexamic acid triggers thrombin generation. Hemost Lab 20096. Baharoglu MI, et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev

20137. Garg J, et al. ST elevation myocardial infarction after tranexamic acid: first reported case in the United States. Am J

Ther 2014

2011

ConclusionsAnti-fibrinolytic drugs provide worthwhile reductions in blood loss and the receipt of allogeneic red cell transfusion. ..

The lysine analogues are effective in reducing blood loss during and after surgery, and appear to be free of serious adverse effects.

Outcome: safetyTxA

(N=2311)Placebo(N=2320)

Risk Ratio(95% CI) P value

Primaryendpoint– no.(%)Death,MI,stroke,renalfailure,pulmonaryembolism,orbowelinfarction

386(16.7) 420(18.1) 0.92(0.81-1.05) 0.22

Myocardial infarction: RR 0.84 (0.70-1.00), P=0.045(3rd Universal definition)

The ATACAS TrialNEJM 2016

Efficacy endpointsTxA

(N=2311)Placebo(N=2320)

Risk Ratio(95% CI) P value

Reoperation for haemorrhage 32 (1.4) 65 (2.8) 0.49 (0.32 – 0.75) 0.001

Median blood loss at 24 hr - ml 790 1070 - <0.001

Blood transfusion up to 24 hr after surgery 721 (31) 1130 (49) 0.64 (0.60 – 0.69) <0.001

No. of units – median (IQR) 3 (2-6) 4 (2-8) - <0.001

The ATACAS TrialNEJM 2016

Tranexamic Acid: blood-sparing

• Patients in the TxA group received 46% fewer units of blood than those in the placebo group

– saves approximately 57 units of blood products for every 100 patients treated

• Number needed to treat (NNT) – Blood transfusion = 6 patients– Reoperation = 71 patients

Current Practice in Cardiac Surgery

• Antifibrinolytic therapy >90% in Australia (less elsewhere)– less in off-pump surgery

• We now have evidence for safety (and greater than expected effectiveness)

• Dose of TxA• Other types of surgery?

– Trauma– Orthopaedics (hip & knee replacement, spine)– Burns

TxA in Cardiac Surgery: cost savings?

1. Blood transfusion ($700 per unit)2. Reduced complications (reoperations, MI, stroke, etc)3. Shorter ICU stay4. Shorter hospital stay

→ reduced costs, $1,000 per case (drug cost = $100)

Australia: >20,000 cardiac operations per year

Support Clinical Trials: search for new knowledge

“A doctor who contributes to randomised treatment trials should not be thought of as a research worker, but simply as a clinician with an ethical duty to his patients not to go on giving them treatments without doing everything possible to assess their true worth”

Rees G, ed. The friendly professional. Selected writings of Thurstan Brewin. Bognor Regis: Eurocommunica, 1996.