Lesson learnt from big trials. Sung Phil Chung, MD Gangnam Severance Hospital, Yonsei Univ.

Transcription

1 Lesson learnt from big trials Sung Phil Chung, MD Gangnam Severance Hospital, Yonsei Univ.

2 Trend of cardiac arrest research Prospective Registry Cohort Animal Simulation

3 RCTs for cardiac arrest (92 papers during 1995~2014) NUMBER OF PAPERS Only 11 trials N>1,000 Witness arrest 74% Bystander CPR 41% Industry sponsored 52% Positive outcome 25% Quality of life outcomes 15% 81 LOCATION TOPIC PERIOD OHCA IHCA Both drug device process during both post-arrest Circ Cardiovasc Qual Outcomes 2016;9:

4

5

6 Epinephrine for OHCA: 1 st RCT N=601 Failed to show better survival, possibly due to inadequate sample size. Intended 5,000 pts à refused to participate (standard of care issue) Resuscitation 2011;82:

7 Epinephrine for OHCA: paramedic-2 N=8, day survival (Epi 3.2% vs placebo 2.4%)* NNTs Epinephrine: 112 Early defibrillation: 5 Early recognition: 11 Bystander CPR: 15 NEJM 2018 July

8 Paramedic 2 trial N=8,014 Favorable neurologic outcome (mrs 0-3: Epi 2.2% vs 1.9%) Severe neurologic impairment was more frequent in the epinephrine group (mrs 4-5: Epi 31% vs 17.8%) NEJM 2018 July

9 Current Guideline?

10 Next research questions Optimal timing of epinephrine? Median of 21 minutes after call (IV access time?) Would different dosing regimes alter outcomes? Lower doses would be superior to higher doses Different approach on the basis of cardiac rhythm? Epinephrine increased 30-day survival in patients with non-shockable rhythms (adjusted OR, 2.15; 95% CI, 1.13 to 4.09) Unclear benefit in those with shockable rhythms (adjusted OR, 1.33; 95% CI, 0.95 to 1.86) Some subgroups causes benefit more than others from epinephrine?

11 N=4,471 Intention to treat LUCAS-2 was actually used NS NS Only 60% patients in mechanical group actually received the LUCAS Time delays in initiating mechanical CPR? Pragmatic = Effectiveness trials: evaluate interventions in real-life settings and focus on longer-term outcomes Lancet 2015; 385:

12 N=1,697 non-inferiority safety study More risk of manual CPR More risk of mechanical CPR Eur Heart J 2017;38:

13 Current Guideline?

14 ROC-ALPS N=3,026 NS NS Neither amiodarone nor lidocaine resulted in a significantly higher rate of survival to hospital discharge or favorable neurologic outcome among patients with OHCA due to initial shock-refractory VF or pulseless VT. N Engl J Med 2016;374:

15 N Engl J Med 2016;374: :Supple

16 Should we exclude asystole? Calculation: 80% power for an increase 25% of survival 10% à 12.5%: require 2,507 patients in each group 30% à 37.5%: require 623 patients in each group Survival discharge (%) Resuscitation 2009;80:723 5 Sample size Rate of asystole patients (%) Rate of asystole patients (%)

17 N=1,063 initial non-shockable à shockable rhythms Circulation 2017;136:

18 Current Guideline?

19 N= 108,079, AHA-GWTGR registry, propensity matched cohort No intubation is better than tracheal intubation during first 15 minutes of resuscitation JAMA 2017;317:

20 N=2,043 CPC 1-2 at 28 day: 4.3% in BMV and 4.2% in ETI Secondary outcome Different prehospital setting: France and Belgium CI: 1.64% to (p=0.11), non-inferiority margin: >-1% JAMA 2018;319(8):

21 Current Guideline?

22 N=120 Exenatide - glucagon-like peptide-1 (GLP-1) analogs - drug for type 2 DM Primary outcome - feasibility - area under the NSE curve 24~72 hours Feasible: drug was initiated within 4h of ROSC in 96% No significant differences in the area under the NSE curve Circulation 2016;134:

23 N=476 Erythropoietin analog 40,000U, bid for 48h CPC 1 at 60 day Epo: 32.4% = Control: 32.1% OR: 1.01 (95% CI: 0.68~1.48) Survival at 60 day (NS) Serious adverse events Epo: 22.6% > Control: 14.9% (p=0.03) Thrombotic complications J Am Coll Cardiol 2016 Jul 5;68(1):40-9

24 N=794 Cyclosporine, 2.5 mg/kg IV vs None Prevent the opening of mitochondrial permeability transition pore JAMA Cardiol 2016;1(5):557-65

25 N=110 inhaled xenon + hypothermia (33 C) vs Hypothermia alone Primary outcome cerebral white matter damage measured by fractional anisotropy (diffusion tensor MRI) 36~52 hours after cardiac arrest xenon group resulted in less cerebral white matter damage Secondary outcome No difference in mrs or 6-month mortality rate JAMA 2016;315:1120-8

26 N=978 in 50 hospitals in China Shenfu Contains ginseng and aconite 100 ml twice daily for 14 days or until hospital discharge Primary outcome: 28 days survival Significantly higher in Shenfu group: 42.7% vs. 30.1%, p=0.02 Absolute risk reduction = 12.6% (NNT = 8) Crit Care Med 2017;45:

27 Limitations Lack of blinding (yellowish) Sample size calculation: 500 patients were needed à 978 randomized Crit Care Med 2017;45:

28 THAPCA-OH trial N=295 Blanketrol III, 33.0 C/48h vs 36.8 C/120h 72% respiratory condition, 8% shockable rhythm Previous studies: did not prevent fever in control group N Engl J Med 2015;372:

29 THAPCA-IH trial N=329 Blanketrol III, 33.0 C/48h vs 36.8 C/120h Target sample size: 558 à stopped after interim analysis N Engl J Med 2017;376:318-29

30 TTH48 trial N=355, TTM(33±1 C) for 48 h (n=176) vs 24 h (n=179) N=355 à powered to detect 15% absolute difference JAMA 2017;318(4):

31 Current Guideline?

32 RINSE trial N=1,198 Planned sample size 2,512 à 1,198 (Study stopped earlier) Many hospitals changed their temperature target from 33 C to 36 C after TTM trial Circulation 2016;134:

33 Rapid infusion of large-volume IV cold saline during CPR may cause harm in the subset of OHCA patients who present with shockable rhythm. Circulation 2016;134:

34 N=585 ice packs + cold saline, 5 min after ROSC Successful TTM rate prehospital cooling 30% vs control 25%, p=0.22 mrs Resuscitation 2017;121:187 94

35 Current Guideline?

36 HUI3 (8 items) SF-36v2 (36 items) EQ-5D-5L (5 items) Circulation 2018;137:e783 e801

37 Ongoing trials Intensive Care Med 2017;43:

38 RCT + Korea + cardiac arrest

39 Thanks for your attention