Erythropoietin in moderate and severe traumatic brain injury. Alistair Nichol ANZIC- RC

Transcription

1 Erythropoietin in moderate and severe traumatic brain injury Alistair Nichol ANZIC- RC

2 Aims In patients with moderate or severe TBI, EPO therapy improves long-term neurological function assessed six months after injury

3 Background-severe TBI Traumatic brain injury (TBI) affects young healthy individuals moderate and severe TBI significant -mortality -morbidity -economic cost Treatment mainly supportive (Brain Trauma Foundation, 2007) Studies to date in TBI have been disappointing -Steroids -Dexabinolol

4 Erythropoietin (EPO) EPO is a glycoprotein hormone Erythropoeisis

5 Erythropoietin (EPO) EPO is a glycoprotein hormone Erythropoeisis pleiotropic cytokine-like effects

6 EPO-TBI Laboratory studies of EPO EPO anti-apoptotic activity protects cells from injury due to hypoxemia and ischemia EPO protects the acutely injured brain augmenting neurovascular repair reducing post-traumatic brain oedema reducing infarct size, attenuating inflammation EPO improves functional outcomes 24 hours after TBI

7 EPO-TBI Laboratory studies of EPO Clinical studies of EPO in non traumatic neurological conditions EPO improved functional neurological outcomes subarachnoid haemorrhage acute ischemic stroke reduced neurocognitive dysfunction in coronary artery bypass graft surgery

8 EPO-TBI Laboratory studies of EPO EPO studied for RBC sparing effects in the critically ill Clinical studies of EPO in non traumatic neurological conditions Clinical studies of EPO in traumatic conditions

9 EPO-TBI

10 EPO-TBI

11 EPO-TBI

12 EPO in the critically ill TBI patients Concerns regarding thrombosis

13 EPO in the critically ill TBI patients Concerns regarding thrombosis Concerns about the effects of EPO on the rates of thrombosis Hb>120g /L Risk

14 EPO in the critically ill TBI patients Concerns regarding thrombosis Concerns about the effects of EPO on the rates of thrombosis Techniques for detecting deep venous thrombosis Clinical assessment

15 EPO in the critically ill TBI patients Concerns regarding thrombosis Concerns about the effects of EPO on the rates of thrombosis Techniques for detecting deep venous thrombosis Compression doppler ultrasound

16 EPO in the critically ill TBI patients Concerns regarding thrombosis Concerns about the effects of EPO on the rates of thrombosis Techniques for detecting deep venous thrombosis The TRUE effect of EPO on the rate of thrombosis in critically ill patients is unknown

17 EPO in the critically ill TBI patients Concerns regarding thrombosis Concerns about the effects of EPO on the rates of thrombosis Techniques for detecting deep venous thrombosis The TRUE effect of EPO on the rate of thrombosis in critically ill patients is unknown Concerns regarding the use of VTE prophylaxis in TBI patients

18 Concerns- EPO in TBI Current trials of EPO in TBI are not objectively assessing risk of thrombosis PROTECT Change in clinical practice despite lack of necessary safety information

19 Concerns- EPO in TBI Current trials of EPO in TBI are not objectively assessing risk of thrombosis PROTECT Change in clinical practice despite lack of necessary safety information

20 EPO-TBI ErythroPOietin in Traumatic Brain Injury

21 Aims Efficacy Aim: The primary aim of the study is to determine the efficacy of EPO compared to placebo in improving neurological function in patients six months after moderate or severe TBI Safety Monitoring: W e plan to systematically monitor the effect of EPO on proximal DVT rates in ICU patients with moderate or severe TBI

22 Outcome measures- Primary outcomes: Proportion of unfavourable neurological outcomes Secondary outcomes: Proportion of i) unfavourable neurological outcomes in survivors at 6 months ii) quality of life assessment (SF-36) at 6 months iii) 6 month survival iv) rate of proximal deep venous thrombosis screened by compression doppler ultrasound v) composite thrombotic vascular events (DVT, PE, myocardial infarction, cardiovascular events and cardiac arrest)

23 Study Design Multi-centre, randomised, double blinded, placebo-controlled trial

24 ICU-Screening Screening in ICU Inclusion criteria Non penetrating moderate or severe TBI 18 years of age 24 hours since primary trauma expected to stay 48hr haemoglobin <120g/L

25 ICU-Screening Screening in ICU Exclude those at high risk of complication Exclude unsalvageable Exclude impractical Exclusion criteria history of DVT, PE or other thromboembolic event a chronic hypercoagulable disorder treatment with EPO in the last 30 days uncontrolled hypertension acute myocardial infarct GCS = 3 and fixed dilated pupils imminent death pregnancy or lactation inability to perform lower limb ultrasounds.

26 Study groups Randomisation Placebo group Subcut Placebo Day 1, 8 and 15 if Hb <120g/L EPO group (subcut EPO (epoetin alfa 40,000U) Day 1, 8 and 15 if Hb <120g/L

27 ICU- Mx and assessment Placebo group EPO group Co-interventions Mechanical and Pharmaceutical VTE prophylaxis Stepwise treatment protocol for raised ICP and reduced CPP Assessment of Deep Venous Thrombosis (DVT) Assessment of Pulmonary Embolism (PE)

28 Study issues Minimizing bias Blinding of drug Haemoglobin levels Consent Data and Safety Monitoring Committee (DSMC)

29 Sample size- Efficacy endpoint 50% Australian patients with moderate and severe TBI- unfavourable neurological outcomes (ATBIS, SAFE-TBI) 30% RRR (15% ARR) in unfavourable neurological outcomes at 6 months. Based on: The 47% reduction in mortality in trauma patients with EPO (Corwin, 2007) 68% increase in favourable neurological outcomes in patients after subarachnoid haemorrhage (Tseng,M 2007) 36% increase in good outcomes in acute ischemic stroke patients (Ehrenreich H, 2002) Study sample size: 574 patients (95% power, two sided alpha 0.05)

30 Power- Safety endpoint Study sample size 574 patients Proximal DVT rate: 18% in moderate or severe TBI A clinically relevant increase in proximal DVT rate 50% relative risk increase (RRI) (9% ARI) based on: 41% increase in thrombotic events (Corwin, 2007) A sub-group analysis of this study, which reported a 58% increased rate of thrombotic events in patients not receiving heparin VTE prophylaxis (Corwin, 2007) 80% power to detect a 9% Absolute Risk Increase (ARI) in proximal DVT rates at a one sided alpha of 0.05

31 Recruitment Moderate and Severe TBI Inclusion criteria In 2.5 years 606 with only 73% predicted recruitment No exclusion criteria N=167 Number randomised every 6 months POLAR eligible patients excluded

32 Summary large RCT in ANZ to answer the EPO question Efficacy in TBI Safety in critically ill patients ANZ uniquely positioned to conduct this trial ICU network Experience with TBI trials and USS screening

33 Questions? Comments?