1. Recombinant Activated Protein C in Scotland SICSAG Trainee Sprint Audit How we use it What we think about it (not going to get into should we use it!) Alex Puxty SpR

3. OUTLINE Background ▫The PROWESS trial ▫Controversies The audit- ▫Objectives ▫Methods ▫Results ▫Conclusions

4. BACKGROUND PROWESS study published in 2001 FDA approval in early 2002 European licence six months later Adopted into both Surviving sepsis and NICE guidelines (2004)

5. PROWESS Randomized, double blind trial 164 centres (none in UK) 1690 patients Severe sepsis of less than 24hrs duration

6. PROWESS-HEADLINE RESULTS 19.4% RRR of death (6.1% ARR); p=0.005 Trend towards more bleeding (3.5% Vs 2%; p=0.06)

7. PROWESS-CONTROVERSIES Post Hoc sub-group analysis Protocol changes- ▫Co-morbidites ▫Cell line production Mortality reduction greater after the change FDA and Eli Lily tested both cell lines

8. GUIDELINES NICE 2004- The intervention is a cost-effective option for use in severe sepsis whose risk of death was increased due to multiple organ failure SURVIVING SEPSIS 2004 rhAPC is recommended in patients at high risk of death (APACHE II ≥ 25, sepsis-induced multiple organ failure, septic shock, or sepsis-induced acute respiratory distress syndrome [ARDS]) and with no absolute contraindication related to bleeding risk or relative contraindication that outweighs the potential benefit of rhAPC

9. GUIDELINES SURVIVING SEPSIS 2008 Consider rhAPC in adult patients with sepsis induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II ≥25 or multiple organ failure) if there are no contra-indications

10. RESOLVE AND ADDRESS RESOLVE  Not a mortality study  Stopped early as little chance of reaching efficacy endpoint ADDRESS  Stopped after 2 nd interim analysis  <5% chance of reaching endpoint of significant mortality reduction

11. COCHRANE 2008 This review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC seems to be associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.

12. The Audit Itself What is the trainee Sprint audit again?

13. SICSAG TRAINEE SPRINT AUDIT 3 RD audit carried out Previously audit of thromboprophylaxis R+R audit

16. GETTING STARTED Proposal to SICSAG committee Three regional coordinators Further recruitment to total 24 data collectors Protocol written Database formed Pilot

17. OBJECTIVES To determine the pattern of usage of rAPC in Scottish ICU’s Compare this to published guidelines Determine consultants attitudes towards rAPC

19. METHODS Two parts:  2 week data collection  Questionnaire to all consultants with ICU sessions

20. METHODS Two parts:  2 week data collection  Questionnaire to all consultants with ICU sessions

21. DATA COLLECTION All patients admitted with severe sepsis 2 weeks beginning second week of January 2008 Followed up for 72hrs split into 4 time periods

22. DATA COLLECTION Demographics Source sepsis Organ failures APACHE II score Contra-indications Reasons recorded for not prescribing (if needed) Inotropes (converted to mcg/kg/min) INR

23. DATA COLLECTION SICSAG provided:  Unit and hospital LOS  Predicted mortality  Mortality

24. RESULTS 97 patients 49 (51.5%) male Mean age 59.8yrs Median APACHE II -25

25. RESULTS Overall 66 of 97 had outcome data In these, mean predicted mortality was 45.9% Actual mortality was 36.3% (SMR 0.79)

26. APACHE II SCORES RECORDED

27. DIVIDING THE PATIENTS Stratified-split into 3 categories Excluded all with contra-indications Split into NICE and SSC guidelines

28. ORGAN FAILURE CRITERIA 97 patients 81 patients with 2 or more organ failures 9 patients received rAPC 41 patients “missed” 31contra- indications 16 patients never “triggered”

29. ORGAN FAILURE CRITERIA 41 patients 4 discharged in the 72hrs 15 improved but still met criteria 8 improved and no longer met criteria 2 died 12 had no improvement

30. PERCENTAGE OF PRESCRIPTIONS “MISSED”-ORGAN CRITERIA

31. APACHE II CRITERIA 97 PATIENTS 48 met criteria 20 patients “missed” 20 patients had contra- indications 8 patients received rAPC 49 patients never “triggered”

32. APACHE II CRITERIA 20 patients 8 had no improvement 8 improved but still qualified 2 died 2 improved and no longer qualified

33. PERCENTAGE OF PRESCRIPTIONS “MISSED”-APACHE II CRITERIA

34. CONTRA-INDICATIONS

35. WHO DID GET rAPC? Median APACHE II-33 All on inotropes No age difference Median organ failures -4

38. THOSE WHO GOT rAPC 8 of 9 survived to discharge from hospital 2 of these had the drug discontinued before completion ▫1 for bleeding ▫1 as improved Mean unit LOS 17 days (range 6-26) Mean hospital LOS 39 days (range 18-65)

39. CONCLUSIONS OF DATA COLLECTION No one got rAPC who did not qualify by either criteria Contra-indications were common (33%) rAPC seemed to be used only in some of the sicker patients

40. CONCLUSIONS OF DATA COLLECTION Using organ failure criteria: Between 61% and 79% “missed” prescription of rAPC Using APACHE II criteria: Between 50% and 71% “missed” prescription of rAPC

41. THE QUESTIONNAIRE DONT WORRY, WE’RE MORE THAN HALF WAY!

42. METHODS Direct contact! All consultants with daytime ICU sessions After data collection complete 125/162 returns=77% response rate

45. DO YOU BELIEVE THE EVIDENCE IN SUPPORT OF rAPC

47. Organ/System FailureMedian Score CVS1 Respiratory3 Renal3 Metabolic4 Haematological5

48. SCENARIO You have a patient with chest sepsis with a reduced blood pressure and acute kidney injury. You use all standard therapies over the first day of treatment. The inotrope requirement reduces and the ventilation improves slightly. THEY STILL MEET CRITERIA FOR rAPC.

49. CLINICAL SCENARIO-WOULD YOU PRESCRIBE?

50. CONCLUSIONS FROM QUESTIONNAIRE In no unit did all consultants say they did not use rAPC Despite this, there remains significant concern regarding the current evidence Cardiovascular failure is generally felt to be the most important “system” Most consultants would use discretion in prescription

51. RECOMMENDATIONS Be aware that more patients are qualifying for treatment than are currently being considered Record decisions in notes Ideally single guideline

52. ACKNOWLEDGEMENTS SICSAG (in particular Angela Kellacher, Catriona Haddow, Sarah Ramsay and Brian Cook) Paul McConnell, Simon Crawley, Simon McAree Lia PatonJane WilkinsonLaura Robertson Tim GearyCatriona ChalmersEwan McMillan Dave GriffithsClaire TordoffRichard Appleton Craig BeattieKirankumar SachaneAndrew Goddard Jonathan AntrobusGordon HoustonAndrew Clarkin Fahmi FarazMegan DaleRaj Najeurs Euan McGregorPrit Anand SinghMyra McAdam Bhushan JoshiJohn Glen