Landmark trials in neuro critical care.pptx

Land mark trials in neurocritical care

1. Dr. K. S warna Deepak Sr. Consultant, DEPT. CRITICAL CARE MEDICINE. APOLLO HEALTH CITY , JUBILEE HILLS

2. EUROTHERM TRIAL

3. Andrews et al. NEJM Published first on line Oct 2015 In patients with traumatic brain injury (TBI), does hypothermia (32- 35°C) and standard care compared to standard care alone reduce death and major disability at 6 months after injury? Therapeutic hypothermia (32- 35°C) for at least 48 hours and continued until ICP controlled + standard care. Cooling achieved by bolus of 20- 30mls/kg of refrigerated, intravenous 0.9% sodium chloride and then maintained using individuals departments usual practice Core temperature was reduced by the minimum required to maintain ICP of 20mmHg or less Stage 2 treatments were added if hypothermia failed to control ICP

4. 55 centres (although only 47 actually recruited) in 18 countries 53% patients recruited in UK Nov 2009 – Oct 2014 2498 patients were screened, 387 were randomised, 386 received intended treatment, 376 were evaluated in an intention to treat analysis Conclusions In patients with intracranial pressure of more than 20mmHg after TBI, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in better outcomes compared with standard care alone

5. POLAR TRIAL

6. JAMES COOPER et al dec 2018

7. RESUE- ICP

8. Hutchinson. Published on line 7th Sept; NEJM 2016 Design International, multicenter randomised controlled trial Parallel group superiority 1:1 randomiation with the use of permuted blocks of random sizes and with stratification according to trial sizes Modified (excluded patients lost to follow up or withdrew consent) intention to treat analysis Sample size of 400 patients was calculated to detect a 15% difference in favourable outcome rate between the two groups. A power of 80% allowed for a loss of follow- up of up to 15% The primary outcome measure was analysed with an ordinal analysis method based on the proportional odds model

9. Conclusions At 6 months, decompressive craniectomy in patients with TBI and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care

10. STITCH TRIAL

11. Mendelow. Journal of Neurotrauma 2015 In patients with traumatic intracerebral haemorrhage (TICH), does early surgery (haematoma evacuation within 12 h of randomisation) compared with initial conservative management reduce major disability and death at 6 months after injury? 170 patients randomised from 31 of 59 registered centres in 13 countries worldwide. December 2009 to September 2012

12. Conclusions A larger trial is needed to confirm this potentially very beneficial effect of earlier surgery In the interim, there is a strong case for operating on patients with TICH who have a GCS of 9–12 A strategy of early surgery is associated with a small, non-significant increase in health care cost

13. EPO TBI

14. Nichol A. The Lancet 2015 In patients with moderate or severe traumatic brain injury does the administration of erythropoietin compared with placebo improve neurological outcome at 6 months after injury Design- Randomisation 1:1 erythropoietin or placebo Sample size of 606 gave 90% power to detect a 28% RRR of 6 month GOS- E 1- 4 (death, vegetative state and severe disability) and allowed a 5% loss to follow- up At six months a trained blinded staff member did a structured telephone interview with patients or carer to assess GOS- E Patients received 40000 IU of erythropoietin subcutaneouslyThe first dose was given within 24 hours of the TBI and then weekly for a maximum of 3 doses if the patient remained in ICU, their haemoglobin was <120g/L and they did not meet withholding criteria

15. Outcome Primary outcome: No difference in 6 month neurological status dichotomized to GOS- E of 1-4 (death, vegetative state, and severe disability) or GOS- E 5- 8 (moderate disability and good recovery) between the erythropoietin group (134/302, 44%) and placebo group (132/294, 45%) Secondary outcomes: No difference in a proportional odds model of neurological outcome & mortality assessed at 6 months Conclusions Following moderate or severe TBI, erythropoietin did not reduce the number of patients with severe neurological dysfunction or increase the incidence of DVT or composite thrombotic outcomes

16. MRC CRASH TRIAL

17. Roberts et al for the CRASH trial collaborators. Lancet 2004 In adults with a head injury, do early corticosteroids compared to placebo reduce death and disability? Design- Randomised, controlled trial Powered at 90% to detect 2% difference in mortality from baseline of 15%, with accepted type I error of 0.01 (chance of false positive), if 20,000 patients were recruited 239 hospitals from 49 countries 10,008 patients randomised

18. Administration of methylprednisolone for 48 hours Loading dose of 2 g over 1 hour in 100 ml 0.9% NaCl Maintenance of 0.4 g per hour for 48 hours in 20 ml per hour 0.9% NaCl Outcome Primary outcome: unmasking of randomisation took place after 10,008 patients due to a clear difference favouring placebo for mortality at 2- weeks Corticosteroid group 21% mortality vs placebo group 18% mortality Secondary outcome: 6-month follow- up favoured placebo for mortality and severe disability

19. (CRASH-3):

20. This randomised, placebo- controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. Patients were randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo.

21. PRIMARY OUTCOME: 28 day in-hospital head injury associated mortality in patients assigned within 3 hours of injury -no significant difference TXA group 855/4613 (18.5%) vs. 892/4514 (19.8%) in placebo RR 0.94 (95% CI 0.86 – 1.02) ARR 1.23% (95% CI -0.39 – 2.84%) Pre- specified Subgroup Analysis of Primary Outcome Excluding those with GCS 3 or bilateral unreactive pupils- no significant difference 28 day in hospital TBI associated mortality in TXA group 485/3880 (12.5%) vs. 525/3757 (14.0%) in placebo RR 0.89 (95% CI 0.80 – 1.00) ARR 1.47% (95% CI -0.05 – 2.99%) Patients with Mild to Moderate TBI (GCS 9- 15) - significantly reduced in TXA group 28 day in hospital TBI associated mortality in TXA group 166/2846 (5.8%) vs. 207/2769 (7.5%) in placebo RR 0.78 (95% CI 0.64 – 0.95) ARR 1.64% (95% CI 0.34 – 2.95%)

22. SECONDARY OUTCOMES : Timing of TXA: < 1 hr RR 0.96 (95% CI 0.79 – 1.17) 1-3 hr RR 0.93 (0.85 – 1.02) Early treatment was more effective than later treatment in mild – moderate injury (p=0.005), but timing had no effect in severe injury No statistical difference noted in high income vs low and middle income countries Disability Measures: No difference between groups for patient derived disability measures Complications: No increased risk of vaso- occlusive events (1.6% in both groups) or seizures (3.2% in TXA group vs 3.0% in placebo)

23. This trial provides evidence that the administration of tranexamic acid to patients with TBI within 3 h of injury reduces head injury- related death, with no evidence of adverse effects or complications. Substantial reduction in head injury- related deaths with tranexamic acid in patients with mild and moderate head injuries. No apparent reduction in those with severe head injury.

24. BEST:TRIP:

25. Chestnut. NEJM 2012 In patients with severe traumatic brain injury does monitoring intracranial pressure improve mortality and improve neurological function? September 2008 – October 2011,RCT,324 pt Intervention Intracranial pressure monitoring Intra- parenchymal monitor placed as soon as possible Treated to maintain ICP <20mmHg according to standard guidelines Monitored for median 3.6 days Control Treatment based on clinical finding and CT scan results

26. Outcome Primary outcome: Composite of 21 components including survival time, duration of impaired consciousness and neuropsychological status, at 6 months – no significant difference secondary outcomes: - No significant difference in mortality or GOS- E Scale Conclusions Management guided by ICP monitoring is not superior to management guided by neurological examination and serial CT imaging in patients with severe traumatic brain injury

27. TICH 2 TRIAL

28. Sprigg, N et al. The Lancet 2018 In adults with acute, spontaneous intra- cerebral haemorrhage (ICH) does the administration of tranexamic acid (TXA) compared to a placebo improve functional status at 90 days? Early surgery (STICH- II) and intensive blood pressure lowering (INTERACT) were not shown to reduce risk of death or severe disability Double blind, randomised, placebo- controlled, phase III trial 2325 randomised: 1161 assigned TXA and 1164 assigned placebo Tranexamic Acid 1g IV TXA in 100ml 0.9% NaCl infused over 10 minutes Followed by another 1g in 250ml 0.9% NaCl infused over 8 hours

29. Primary Outcome: There was no difference in function status at day 90 Conclusions TXA does not affect functional status at day 90, although some potential benefits were noted with regards to reduction in haematoma expansion, early death and numbers of serious adverse events

30. Moretti. Neurocrit Care. 2010 Aug;13 In mechanically ventilated patients with subarachnoid hemorrhage (SAH) and a low cardiac index, does the distensibility of IVC on ultrasound, predict fluid responsiveness? enrolled 29 adult patients requiring advanced hemodynamic monitoring, sedation, and mechanical ventilation. Inferior vena cava diameter was measured during a single mechanical breath.

31. ROC curves to determine the best predictor of fluid responsiveness: Area under the curve (AUC) SVV: 0.779 (95% C.I. 0.587- 0.911) dIVC: 0.902 (95% C.I. 0.733- 0.979) CVP: 0.667 (95% C.I. 0.468- 0.829) Intra- and inter- observer variabilities in the measurement of IVCD were 4 ± 4% and 6 ± 4%, respectively. Conclusions IVC distensibility was a reliable measure for predicting fluid responsiveness in critically ill patients with SAH

32. (PATCH):

33. Baharoglu. Lancet 2016; In patients with acute intracerebral haemorrhage (ICH), associated with antiplatelet therapy, does platelet transfusion compared with standard care reduce death or dependence? RCT, Feb 2009 – Oct 2015,190 patients Intervention Platelet transfusion (leucocyte depleted) 5 units if on COX inhibitor, 10 units if on ADP receptor inhibitor Control- not defined

34. Primary outcome: difference in functional outcome at 3 months as assessed by mRSOdds of a shift towards death or dependence at 3 months significantly higher in the intervention group than in standard care Conclusions Platelet transfusions cannot be recommended for the treatment of acute ICH in people taking antiplatelets therapy

35. (EXTEND- IA TNK)

36. B.C.V. Campbell et al for the EXTEND- IA TNK study investigators; New England Journal of Medicine April 2018 In patients with anterior circulation strokes undergoing endovascular thrombectomy, is IV thrombolysis within 4.5 hours of stroke onset with tenecteplase non- inferior to alteplase at establishing reperfusion? A previous phase II study has shown that tenecteplase may improve cerebral reperfusion on CT at 24 hours and may result in better clinical and functional outcomes (Parsons et al; NEJM 2012) 12 centres in Australia and 1 centre in New Zealand. March 2015 to October 2017. 202 patients included in analysis

37. Outcome Primary outcome: Reperfusion of > 50% of the involved territory or an absence of retrievable thrombus at the time of initial angiographic assessment – the intervention was non- inferior 22% in tenecteplase groups vs. 10% in alteplase group Secondary outcomes:- Significantly better Median modified Rankin Scale Score at 90 days Conclusions Tenecteplase was noninferior to alteplase in restoring perfusion in the territory of a proximal cerebral- artery occlusion. Overall functional outcome was better with tenecteplase than with alteplase. There was no significant difference in the incidence of cerebral haemorrhage

38. ECASS- 4: EXTEND

39. The benefit of thrombolytic therapy up to 4.5 h from stroke onset has been initially confirmed by the European Cooperative Acute Stroke Study (ECASS) III trial. Despite the efficacy and effectiveness of rt- PA therapyonly about 5% to 20% of eligible patients receive therapy. Beside the diffidence of rt-PA inexperienced physicians, the extremely short approved time window for rt- PA administration is one main reason for this. Thus extension of the time window for therapy is the most logical way to increase the number of patients eligible to receive rt- PA MRI allows the identification of ischemic penumbra by depicting the mismatch between the hypoperfused perfusion weighted image (PWI) and the infarct core seen on the diffusion weighted image (DWI) and may be present in up to 50% of patients presenting within 24 h from stoke onset.

40. DESIGN ExTEND is an investigator driven, phase 3, randomized, multi- center, double-blind, placebocontrolled study. Ischemic stroke patients presenting within 4.5 and 9 h of stroke onset, who fulfill clinical requirements (National Institutes of Health Stroke Score (NIHSS) 4–26 and pre- stroke modified Rankin Scale (mRS) 0–1) will undergo MRI. Patients who meet imaging criteria (infarct core volume <100 ml, perfusion lesion: infarct core mismatch ratio >1.2 and perfusion lesion minimum volume of 20 ml) additionally will be randomized to either rt- PA or placebo.

41. INCLUSION CRITERIA EXCLUSION CRITERIA Patients presenting with acute ischemic stroke. Patient’s age is more than 18 years. Treatment onset within 4.5–9 h after stroke onset. Patients who wake with stroke may be included if neurological and other exclusion criteria are satisfied. NIHSS score of 4 to 26 with clinical signs of hemispheric infarction. Penumbral imaging with a perfusion volume (PWI) to infarct core (DWI) ratio of 1.2, and a perfusion lesion minimum volume of 20 ml. ICH NIHSS<4, pre stroke mRS >1 C.I to MRI Infarct core >1/3 MCA territory or >100ml quantitatively Life expectancy less than 3 months Previous stroke,SAH,ICH,Neoplasm Pregnancy Use of anticoagulants with in 48 hrs Uncontrolled HTN PLT<1Lakh

42. STUDY ENDPOINTS Primary endpoint Categorical shift in mRS at day 90. Secondary endpoints Disability at day 90, dichotomized as a favorable outcome (mRS) 0–1 vs. 2–6. Change in >11 NIHSS or reaching or 1 on this scale at day 1 and day 90; Reperfusion at 12–24 h after treatment; Recanalization at 12–24 h after treatment; Infarct growth measured by DWI within 12–24 hrs after treatment. NIHSS score at day 7; BI at day 90; Cognitive impairment: MoCA at day 90 Tertiary endpoints Depression: MADRS score at day 90.

43. SUMMARY AND CONCLUSIONS ECASS- 4: ExTEND is a randomized, multi- center, double- blinded, placebo- controlled phase 3 trial investigating the efficacy and safety of MRI- based intravenous thrombolytic therapy in a 4.5–9- h time window after stroke Furthermore, this study assesses the impact of thrombolytic therapy on post stroke depression. The advantages of extension of the therapeutic time window for thrombolysis would be of significant benefit to the global stroke community, given an estimated increase of 22% of patients, who could be considered for this therapy

44. DAWN TRIAL

45. Nogueira et al, N Engl J Med 2018 In patients who are 6-24 hours post acute stroke, and have a mismatch between clinical deficit and infarct, does thrombectomy plus standard medical care, compared to standard medical care alone, improve functional outcomes at 90 days? Design- Randomised clinical trial 26 centres who performed at least 40 thrombectomy cases annually in: USA, Canada, Europe and Australia,206 patients enrolled (107 intervention, 99 control),Sept 2014 to Feb 2017 Intervention- Mechanical thrombectomy with the Trevo device plus standard medical therapy

46. Conclusions In patients with intracranial internal carotid artery or proximal MCA strokes who had mismatch of clinical symptoms vs infarct volumes and who were last seen normal 6-24 hours prior, thrombectomy is superior with regard to functional independence and disability at 90 days

47. DEFUSE III

48. Albers et Al, N Engl J Med 2018 In patients with proximal internal carotid (ICA) or middle cerebral artery (MCA) occlusion with likely salvageable ischaemic brain tissue, does thrombectomy, at 6- 16 hours post ischaemic stroke, in addition to medical therapy, compared to medical therapy alone, improve functional outcome at 90 days? Design- Randomized, open- label multi- centre trial 38 hospitals in the US: May 2016- May2017 Mechanical thrombectomy v/s medical management

49. Conclusions Endovascular therapy plus medical therapy results in lower rates of disability and improved 90 day functional outcomes on the mRS in comparison to medical therapy alone in patients who have large vessel occlusion and favourable prognostic perfusion imaging

50. (ESETT)

51. Evidence supports the use of benzodiazepines as the initial treatment for status epilepticus, however, seizures do not respond to benzodiazepines in up to a third of patients. The treatment for this type of benzodiazepine- refractory status epilepticus has not been well studied. The Established Status Epilepticus Treatment Trial (ESETT) was an investigator-initiated, multicenter, randomized, double blinded, comparative- effectiveness trial of levetiracetam, fosphenytoin, and valproate for the treatment of patients with established status epilepticus in the emergency department

52. INCLUSION CRITERIA EXCLUSION CRITERIA Age ≥ 2 years Treated with minimally accepted cumulative dose of benzodiazepines Diazepam 10mg IV/PR, (0.3mg/kg if <32kg) Lorazepam 4mg IV (0.1mg/kg if <32kg) Midazolam 10mg IV/IM (0.3mg/kg if <32kg) Generalised convulsive seizure lasting >5 minutes Continued to have persistent or recurrent seizures at least 5 minutes after last dose of benzodiazepine, and no more then 30 minutes after last dose Precipitant to seizure: major trauma, hypoglygcaemia, hyperglycaemia, cardiac arrest, post- anoxia, pregnant, Intubated Known contraindications to any of trial drugs including inborn metabolic diseases, liver disease, severe renal impairments. Patients who were already taking anticonvulsants were NOT excluded, and randomly assigned to a treatment group without regard to their normal anticonvulsant regimen

53. Intervention Levetiracetam 60mg/kg (maximum 4500mg) 50mg/ml Valproate 33.33mg/ml 40mg/kg (maximum 3000mg ) Fosphenytoin 16.6mg phenytoin equivalents per ml (mgPE) 20mgPE per kg (maximum 1500mg) Management common to both groups Drugs given by infusion pump over 10 minutes. Rescue therapy given as clinically determined for persistent or recurrent seizures after 20 minutes from the the start of the trial drug infusion. Unmasking of the trial drug for purposes of patient care, after determination of the primary outcome at 60 minutes, was allowed. This occurred in 154 (39%) of patients. Unblinding prior to 60 minutes was considered a protocol deviation. This occurred in 46 (12%) of patients, but only after a criteria for failure with regard to the primary outcome had been met

54. In patients with benzodiazepine refractory status epilepticus, the use of levetiracetam (60mg/kg), valproate (40mg/kg) or fosphenytoin (20mg/kg phenytoin equivalent), each led to the absence of seizures and improved responsiveness at 60 minutes in nearly half of the patients.

55. Legriel S et al. N Engl J Med 2016; In patients with convulsive status epilepticus, does the addition of therapeutic hypothermia to standard care improve neurological outcomes? RCT 11 French ICUs,Data collected: March 2011 – January 2015 270 patints, 138 assigned to intervention group and 130 to control group Target core temperature of 32 to 34°C as rapidly as possible post randomisation Target temperature maintained for 24 hours Hypothermia induced with ice-cold IV fluids at 4°C, maintained with ice packs at the groin and neck and a cold- air tunnel around the patient’s body

56. For both intervention and control group Propofol as sedative agent Continuous EEG monitoring within 2 hours of randomisation Outcome Primary outcome: GOS score of 5 (indicating survival with no or minimal neurological deficit) No significant difference: 49% in intervention vs 43% in control (CI 0.75 – 1.99, p=0.43) Secondary outcomes: comparing intervention vs. control group No significant difference in: mortality, seizure duration,icu stay Conclusions In critically ill patients with convulsive status epilepticus receiving mechanical ventilation, the addition of therapeutic hypothermia to standard antiepileptic therapy showed no significant benefit with respect to good functional outcome

57. TRACMAN

58. Young et al. JAMA 2013 In mechanically ventilated adult patients with a high risk of prolonged ventilation, does early tracheostomy compared with late tracheostomy reduce mortality at 30 days?

59. Conclusions In mechanically ventilated adult patients, there is no mortality benefit from performing an early tracheostomy.

60. SID – GBS