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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
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
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
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 decreases pulmonary neutrophilic activity 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 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’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
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