Statins in ARDS
Danny McAuley
Queen’s University of Belfast
Scottish Combined Critical Care Conference
September 2010
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
No pharmacological
treatment for ALI
Cecilia O’Kane
Ashbaugh et al.
described using “a clinical
trial of a variety of drugs,
respirators and fluid
regimens” with limited
success
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
Observational data to support a role for
novel therapies in ALI
40%
Mortality (%)
34%
OR 0.27 (0.06-1.21)
p=0.09
30%
21%
20%
10%
No statin
n = 164
Irish Critical Care Trials Group. Critical Care 2008;12:R30
Statin
n = 24
Pre-treatment with simvastatin attenuates
systemic inflammation following LPS challenge
Steiner et al. Circulation 2005; 111:1841
Inhaled LPS as an in vivo model to study
pulmonary inflammation in healthy subjects
FEV1
BAL
6 hr
FEV1
Plasma
50 µg LPS inhalation
E. Coli serotype O26:B6 (Sigma)
Breath activated dosimeter
FEV1
Plasma
18 hr
Inhaled LPS induces inflammatory
O’Kanecompartment
cytokines in Cecilia
pulmonary
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
Total cells
(x 105/ml)
Neutrophils
Macrophages
Lymphocytes
P
Placebo
Simvastatin
value
(n=10)
(n=20)
15.2
10.7
0.2
(10.3-49.8) (4.6-17.4)
8.5
3.0
0.05
(4.4-16.2)
(1.8-8.1)
7.0
5.1
0.48
(3.1-19.1)
(2.1-13.0)
1.1
0.9
0.37
(0.6-3.2)
(0.2-1.6)
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
80
Plasma CRP
(mg/L)
Placebo
Simvastatin
60
*
40
20
0
* 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)
Exclusion criteria
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
Patient demographics
Simvastatin
n=30
Placebo
n=30
p value
52.5 (17.1)
52.8 (20.0)
0.95
73
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
15 (50)
15 (50)
1.00
Age (years)
Gender (% male)
Sepsis n (%)
Simvastatin improves oxygenation index
Cecilia O’Kane
n =30
n=30
n=10
n=9
Simvastatin reduces plateau pressure
Cecilia O’Kane
n=30
n=30
n=10
n=9
Simvastatin improves sequential organ
Cecilia O’Kane
failure assessment
(SOFA) score
n=30
n=30
n=10
n=9
Safety profile
Cecilia O’Kane
Simvastatin
Placebo
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 adverse
events (%)
20
23
0.75
p value
• No serious adverse events due to study drug occurred
Outcome data
Cecilia O’Kane
Simvastatin
Placebo
p value
ICU free days
8.2 (8.1)
7.20(7.47)
9.1 (8.7)
8.4 (8.4)
0.7
0.6
ICU survival n (%)
21 (70%)
21 (70%)
1.0
51.2 (39.3)
48.0 (37.4)
0.8
19 (63%)
19 (63%)
1.0
Ventilator free days
Hospital LOS (days)
Hospital survival (days)
Simvastatin decreases
bronchoalveolar
lavage IL-8
Cecilia O’Kane
pp=0.89
= NS
*p = 0.05
IL-8 10000
(pg/ml)
8000
Placebo
Simvastatin
6000
4000
2000
0
D0
n=17
D3
D0
D3
n=10
n=23
n=17
Simvastatin decreases
bronchoalveolar lavage IL-6
p=0.43
p = NS
p = 0.07
IL-6 5000
(pg/ml)
4000
Placebo
Simvastatin
3000
2000
1000
0
D0
D3
n=17
n=10
D0
n=23
D3
n=17
Simvastatin decreases systemic
inflammation asCecilia
measured
O’Kaneby plasma CRP
CRP
(mg/L)
400
pp=0.06
= NS
*p = 0.0004
Placebo
Simvastatin
300
200
100
0
D0
n=30
D14
n=9
D0
n=29
D14
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
HARP-2
Cecilia O’Kane
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