1. Danny McAuley Queen’s University of Belfast Scottish Combined Critical Care Conference September 2010 Statins in ARDS

2. Novel therapies for ARDS - What is on the horizon? Conclusions Beta agonists –Potential benefit in phase II study –Phase III multi-centre clinical trials awaited Potential therapeutic interventions in phase II trials –APC –Statins Novel potential future treatments –Modulation of renin-angiotensin system –Stem cell therapy Scottish Critical Care Trials Group June 2007

3. Statins in ARDS Mechanism of action Observational data Statins and pulmonary inflammation Phase 2 clinical trial (HARP) HARP-2

4. Cecilia O’Kane Ashbaugh et al. described using “a clinical trial of a variety of drugs, respirators and fluid regimens” with limited success No pharmacological treatment for ALI Ashbaugh et al. Lancet 1967

5. Step-wise approach to new therapies McAuley et al. CCM (in press)

6. Cellular effects of statins

7. Simvastatin reduces thrombin-induced endothelial injury Jacobson et al. AJRCMB 2004;30:662

8. Simvastatin attenuates LPS-induced experimental lung injury Jacobson et al. AJP Lung 2005;288:L1026

9. Statin n = 24 No statin n = 164 34% 21% 10% 20% 30% 40% Mortality (%) OR 0.27 (0.06-1.21) p=0.09 Observational data to support a role for novel therapies in ALI Irish Critical Care Trials Group. Critical Care 2008;12:R30

10. Steiner et al. Circulation 2005; 111:1841 Pre-treatment with simvastatin attenuates systemic inflammation following LPS challenge

11. Inhaled LPS as an in vivo model to study pulmonary inflammation in healthy subjects FEV1 Plasma 50 µg LPS inhalation E. Coli serotype O26:B6 (Sigma) Breath activated dosimeter 6 hr18 hr FEV1 BAL FEV1 Plasma

12. Cecilia O’Kane Inhaled LPS induces inflammatory cytokines in pulmonary compartment

13. Simvastatin in the inhaled LPS model of ALI Treatment with a clinically relevant dose of simvastatin will reduce pulmonary inflammation induced by LPS inhalation in humans Shyamsundar et al. AJRCCM 2009 179:1107-1114

14. Schedule for patient safety monitoring

15. Simvastatin decreases pulmonary neutrophilia following LPS inhalation Placebo (n=10) Simvastatin (n=20) P value Total cells (x 10 5 /ml) 15.2 (10.3-49.8) 10.7 (4.6-17.4) 0.2 Neutrophils 8.5 (4.4-16.2) 3.0 (1.8-8.1) 0.05 Macrophages 7.0 (3.1-19.1) 5.1 (2.1-13.0) 0.48 Lymphocytes 1.1 (0.6-3.2) 0.9 (0.2-1.6) 0.37

16. Simvastatin increases neutrophil apoptosis following LPS inhalation * p < 0.05 vs placebo

17. Simvastatin decreases pulmonary neutrophilic activity following LPS inhalation * p < 0.05 vs placebo

18. Simvastatin decreases pulmonary TNF following LPS inhalation * p < 0.05 vs placebo

19. Simvastatin pre-treatment reduces systemic inflammation following LPS inhalation * p < 0.05 vs placebo

20. Simvastatin decreases pulmonary MMP secretion following LPS inhalation * p < 0.05 vs placebo

21. Simvastatin pretreatment reduces nuclear NFκB translocation in monocyte-derived macrophages p = 0.0001 for control vs. placebo BALF; ** p=0.03 for placebo BALF vs. simvastatin BALF; # p=0.03 for placebo BALF vs. simvastatin + placebo BALF

22. Lovastatin decreases pulmonary inflammation measured by FDG PET following LPS instillation Chen et al. AJRCCM 2009 180:533-539

23. FDG PET can detect pulmonary inflammation in patients with ALI Bellani et al. Critical Care Medicine 2009 37:2216-2222

24. HMGCoA reductase inhibition in ALI to Reduce Pulmonary oedema (HARP) Proof of concept single centre trial Prospective double blind Within 48 hours of onset of ALI Randomised to simvastatin 80mg or placebo for up to 14 days Outcomes: –Extra-vascular lung water –Pulmonary function and systemic organ failure –Safety –Biological markers in plasma and BAL Craig et al. AJRCCM 2010 (in press)

25. Cecilia O’Kane Age < 18 years Pregnancy Drug interactions Declined consent Participation in a clinical trial within 30 days Current treatment with statins Creatinine kinase (CK) > 10 times upper limit Transaminases > 3 times upper limit Exclusion criteria

26. Patient demographics Simvastatin n=30 Placebo n=30 p value Age (years) 52.5 (17.1)52.8 (20.0)0.95 Gender (% male) 73 1.00 APACHE II 25.1 (6.5)23.3 (6.8)0.30 APACHE II predicted mortality (%) 45.6 (25.0)46.1 (24.7)0.93 SAPS II 53.4 (14.4)54.2 (14.3)0.83 SAPS II predicted mortality (%) 51.2 (25.2)53.6 (24.9)0.72 Sepsis n (%) 15 (50) 1.00

27. Cecilia O’Kane Simvastatin improves oxygenation index n =30 n=30 n=10 n=9

28. Cecilia O’Kane Simvastatin reduces plateau pressure n=30 n=30 n=10 n=9

29. Cecilia O’Kane Simvastatin improves sequential organ failure assessment (SOFA) score n=30 n=30 n=10 n=9

30. Cecilia O’Kane Safety profile SimvastatinPlacebo p value CK > 10 times ULN (%) 4.58.70.58 ALT > 3 times ULN (%) 4.480.60 AST > 3 times ULN (%) 8.316.70.34 Adverse events (%) 47430.79 Serious adverse events (%) 20230.75 No serious adverse events due to study drug occurred

31. Cecilia O’Kane SimvastatinPlacebop value Ventilator free days8.2 (8.1)9.1 (8.7)0.7 ICU free days 7.20(7.47)8.4 (8.4)0.6 ICU survival n (%) 21 (70%) 1.0 Hospital LOS (days) 51.2 (39.3)48.0 (37.4)0.8 Hospital survival (days) 19 (63%) 1.0 Outcome data

32. Cecilia O’Kane Simvastatin decreases bronchoalveolar lavage IL-8 p=0.89 n=17 n=10 n=23 n=17

33. Simvastatin decreases bronchoalveolar lavage IL-6 p=0.43 n=17 n=10 n=23 n=17

34. Cecilia O’Kane Simvastatin decreases systemic inflammation as measured by plasma CRP p=0.06 n=30 n=9 n=29 n=8

35. Conclusions In a human LPS model of ALI simvastatin reduces pulmonary and systemic inflammation In patients with ALI simvastatin –Improves pulmonary and non-pulmonary organ dysfunction –Well tolerated –Reduces inflammation Study now needed to determine if simvastatin improves clinical outcome in large clinical trials

36. Cecilia O’Kane HARP-2

37. Acknowledgements

38. HMGCoA reductase inhibition in prevention of ALI (HARP-prevention) (http://www.controlled-trials.com/ISRCTN56543987) Proof of concept, double blind, placebo controlled, single centre study Study population –Patients undergoing oesphagectomy –N=30 of planned sample size 36 Simvastatin 80mg or placebo Endpoints: –Pulmonary dead space –Respiratory compliance, oxygenation index –Biological markers in plasma and EBC