Recombinant Activated Protein C in Scotland SICSAG Trainee Sprint Audit

1. Recombinant Activated Protein C in ScotlandSICSAG 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 2nd 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 • 3RD 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. DATACOLLECTION 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

29. ORGAN FAILURE CRITERIA

30. PERCENTAGE OF PRESCRIPTIONS “MISSED”-ORGAN CRITERIA

31. APACHE II CRITERIA

32. APACHE II CRITERIA

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

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