Danny McAuleyQueen’s University of Belfast

Scottish Combined Critical Care ConferenceSeptember 2010

Statins in ARDS

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

Statins in ARDS

• Mechanism of action• Observational data• Statins and pulmonary inflammation• Phase 2 clinical trial (HARP)• HARP-2

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

Step-wise approach to new therapies

McAuley et al. CCM (in press)

Cellular effects of statins

Simvastatin reduces thrombin-induced endothelial injury

Jacobson et al. AJRCMB 2004;30:662

Simvastatin attenuates LPS-induced experimental lung injury

Jacobson et al. AJP Lung 2005;288:L1026

Statinn = 24

No statinn = 164

34%

21%

10%

20%

30%

40%

Mor

talit

y (%

)

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

Steiner et al. Circulation 2005; 111:1841

Pre-treatment with simvastatin attenuates systemic inflammation following LPS challenge

Inhaled LPS as an in vivo model to study pulmonary inflammation in healthy subjects

Cecilia O’Kane Inhaled LPS induces inflammatory

cytokines in pulmonary compartment

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

Schedule for patient safety monitoring

Simvastatin decreases pulmonary neutrophilia following LPS inhalation

Placebo(n=10)

Simvastatin(n=20)

P value

Total cells (x 105/ml)

15.2(10.3-49.8)

10.7(4.6-17.4)

0.2

Neutrophils8.5

(4.4-16.2)3.0

(1.8-8.1)0.05

Macrophages7.0

(3.1-19.1)5.1

(2.1-13.0)0.48

Lymphocytes1.1

(0.6-3.2)0.9

(0.2-1.6)0.37

Simvastatin increases neutrophil apoptosis following LPS inhalation

* p < 0.05 vs placebo

Simvastatin decreases pulmonary neutrophilic activity following LPS inhalation

* p < 0.05 vs placebo

Simvastatin decreases pulmonary TNF following LPS inhalation

* p < 0.05 vs placebo

Simvastatin pre-treatment reduces systemic inflammation following LPS inhalation

0

20

40

60

80

Plasma CRP(mg/L)

*

PlaceboSimvastatin

* p < 0.05 vs placebo

Simvastatin decreases pulmonary MMP secretion following LPS inhalation

* p < 0.05 vs placebo

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

Lovastatin decreases pulmonary inflammation measured by FDG PET following LPS instillation

Chen et al. AJRCCM 2009 180:533-539

FDG PET can detect pulmonary inflammation in patients with ALI

Bellani et al. Critical Care Medicine 2009 37:2216-2222

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)

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

Patient demographics

Simvastatinn=30

Placebon=30

p value

Age (years) 52.5 (17.1) 52.8 (20.0) 0.95

Gender (% male) 73 73 1.00

APACHE II 25.1 (6.5) 23.3 (6.8) 0.30

APACHE IIpredicted mortality (%) 45.6 (25.0) 46.1 (24.7) 0.93

SAPS II 53.4 (14.4) 54.2 (14.3) 0.83

SAPS IIpredicted mortality (%) 51.2 (25.2) 53.6 (24.9) 0.72

Sepsis n (%) 15 (50) 15 (50) 1.00

Cecilia O’KaneSimvastatin improves oxygenation index

n =30 n=30 n=10 n=9

Cecilia O’KaneSimvastatin reduces plateau pressure

n=30 n=30 n=10 n=9

Cecilia O’Kane

Simvastatin improves sequential organ failure assessment (SOFA) score

n=30 n=30 n=10 n=9

Cecilia O’KaneSafety profile

Simvastatin Placebop value

CK > 10 times ULN (%) 4.5 8.7 0.58

ALT > 3 times ULN (%) 4.4 8 0.60

AST > 3 times ULN (%) 8.3 16.7 0.34

Adverse events (%) 47 43 0.79

Serious adverseevents (%) 20 23 0.75

• No serious adverse events due to study drug occurred

Cecilia O’Kane

Simvastatin Placebo p value

Ventilator free days 8.2 (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%) 21 (70%) 1.0

Hospital LOS (days) 51.2 (39.3) 48.0 (37.4) 0.8

Hospital survival (days) 19 (63%) 19 (63%) 1.0

Outcome data

Cecilia O’Kane

Simvastatin decreasesbronchoalveolar lavage IL-8

0

2000

4000

6000

8000

10000PlaceboSimvastatin

p = NS *p = 0.05

IL-8(pg/ml)

D0 D3 D0 D3

p=0.89

n=17 n=10 n=23 n=17

0

1000

2000

3000

4000

5000PlaceboSimvastatin

p = NS p = 0.07

IL-6(pg/ml)

D0 D3 D0 D3

Simvastatin decreasesbronchoalveolar lavage IL-6

p=0.43

n=17 n=10 n=23 n=17

Cecilia O’Kane

Simvastatin decreases systemic inflammation as measured by plasma CRP

0

100

200

300

400PlaceboSimvastatin

p = NS *p = 0.0004CRP

(mg/L)

D0 D14 D0 D14

p=0.06

n=30 n=9 n=29 n=8

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

Cecilia O’KaneHARP-2

Acknowledgements

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