Download Statins and pisk of pneumonia

Epidemiological evidence for a
protective role for statins in
Community Acquired Pneumonia
Yana Vinogradova
British Thoracic Society Winter Meeting 2012 , London
Background
• Statins – common medications, 24% in 45+ age
group.
• CAP – common infection, 230 per 100,000
person-years, 670 for 60+ age group.
• Evidence from lab data that statins may benefit in
cases of infectious diseases
From: Does Statin Use Improve Pneumonia Outcomes?
Chopra, Flanders, CHEST. 2009;136(5):1381-1388. doi:10.1378/chest.09-0941
Figure Legend:
Pleiotropic effects of statins. eNOS = endothelial nitric oxide synthase; PAI-1 = plasminogen activator inhibitor-1; NADPH = nicotinamide adenine dinucleotide
phosphate hydrogen; MCP1 = monocytic chemoattractant protein 1; TNF = tumor necrosis factor; LFA-1 = lymphocyte function-associated antigen-1.
Pharmacoepidemiology
and Prescription
From: Statins and associated risk of pneumonia:
a systematic review and meta-analysis of
observational studies
Kwok et al. Eur J Clin Pharmacol (2012) 68, 747-755
Fig. 3 Meta-analysis of adjusted risk of pneumonia with statin therapy
• QResearch
– 660 GP practices
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Currently largest database in
the UK
537 UK practices
> 6 practices in every SHA
> 9 million patients including
those who died, left and still
registered
> 30 million person years of
observation
Patient level data
from GP clinical records
Anonymised
Longitudinal data for 20+ years
Validated externally and internally
Industry independent
Methods: Study design and analysis
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Nested case control study
Study period Jan 1996-Dec 2005
Cases were incident CAP patients
5 controls matched by age, sex, practice
analysis restricted to subjects with at least 2 years
of prescribing data
• Conditional logistic regression, odds ratios 95%CI
Methods: Assessment of Exposure
• use:
at least 2 scripts in 12 months prior to the index date
• different types of statins
atorvastatin
simvastatin
pravastatin
fluvastatin
• time before the index date:
28 days
29-89 days
90-365 days
cerivastatin
rosuvastatin
Methods: Confounding factors
•Socio-economic status
• Townsend quintiles
•Smoking status
• Non-smoker
• Smoker
• not recorded
•Vaccinations
• Influenza
• pneumococcal
•Morbidities
• List of co-morbidities
recommended for
pneumococcal
vaccination
• Additional comorbidities limiting
mobility or
suppressing immune
system
•Medications
• Acid-lowering drugs
Results: Sample and statin use in the last year
17,757 cases
with 2 years of
medical records
80,484 controls
with 2 years of
medical records
2231 cases
(12.6%) statin
users
8759 controls
(10.9%) statin
users
Proportion of cases and controls exposed to statins by index year
25
controls
any statin
simvastatin
atorvastatin
pravastatin
fluvastatin
rosuvastatin
20
%
15
cases
10
5
0
1996
1997
©RESEARCH 2006 version 11
1998
1999
2000 2001
Index year
2002
2003
2004
2005
Pneumonia episode rates by age and gender in 2005
1600
1400
1200
1000
800
600
400
200
0
45-
50-
55-
60-
6570Age groups
Men
©QRESEARCH 2006 version 11
75Women
80-
85-
90+
Proportion of cases and controls exposed to statins
by age and sex
Women
25
Men
Crude OR, 95%CI 1.23, 1.13 – 1.33
Crude OR, 95%CI 1.25, 1.16 – 1.34
20
%
15
10
5
0
45 50 55 60 65 70 75 80 85 90 95 45 50 55 60 65 70 75 80 85 90 95
Age at index date
cases
©RESEARCH 2006 version 11
controls
Last use of statin before the index date
cases
20
%
15
controls
9%
13%
11%
37%
7%
30%
10
5
55%
62%
0
45 50 55 60 65 70 75 80 85 90 95
45 50 55 60 65 70 75 80 85 90 95
Age at index date
3 to 12 months
1 to 3 months
up to 28 days
©QRESEARCH 2006 version 11
Crude OR, 95%CI
1.27, 1.20 – 1.34
1.14, 1.08 – 1.20
1.03, 0.98 – 1.09
Proportion of cases and controls and number of prescriptions
by the last prescription time
8
7
6
%
5
4
70%
69%
3
Number of
prescriptions
63%
2
60%
1
0
38%
48%
28days
90-365days
29-89days
cases
©QRESEARCH 2006 version 11
29-89days
28days
90-365days
controls
2-6
7-12
12+
Proportion of cases and controls with heart disease and stroke
and their use of statin
cases
controls
60
50
%
40
30
23%
37%
20
10
26%
31%
0
45 50 55 60 65 70 75 80 85 90 95
CHD and stroke
Crude OR, 95%CI
2.18, 2.10 – 2.27
©QRESEARCH 2006 version 11
45 50 55 60 65 70 75 80 85 90 95
Age at index date
not on statin
on statin
Statin use, OR, 95%CI
Crude
1.24, 1.18 – 1.31
Adjusted 0.81, 0.77 – 0.86
Risk of pneumonia and use of statin in the last year
OR and 95%CI
Last year use (N of cases)
OR (95%CI)
overall use (2231) 0.78 (0.74 to 0.83)
by time of use
in 28 days (1222) 0.68 (0.63 to 0.73)
1 to 3 months (819) 0.97 (0.88 to 1.06)
3 months ago (190) 0.89 (0.75 to 1.06)
.5
Odds ratios are adjusted for co-morbidities, deprivation, smoking status,
acid lowering drugs and influenza and pneumococcal vaccinations
©QRESEARCH 2006 version 11
.75
1
1.25
Risk of pneumonia and use of different types of statins
OR and 95%CI
Types
(N of cases)
OR (95%CI)
simvastatin (1222) 0.82 (0.76 to 0.88)
atorvastatin (823) 0.79 (0.72 to 0.86)
pravastatin (210) 0.80 (0.68 to 0.94)
fluvastatin (79) 0.82 (0.63 to 1.07)
rosuvastatin (26) 0.93 (0.58 to 1.48)
.5
.75
Odds ratios are adjusted for co-morbidities, deprivation, smoking status,
acid lowering drugs and influenza and pneumococcal vaccinations
©QRESEARCH 2006 version 11
1
1.25
1.5
Risk of pneumonia and use of most common types of statin
OR and 95%CI
Last use
(N of cases)
in 28 days (649)
1 to 3 months (442)
3 months ago (131)
in 28 days (432)
1 to 3 months (292)
3 months ago (99)
in 28 days (103)
1 to 3 months (70)
3 months ago (37)
OR (95%CI)
simvastatin
0.70 (0.63 to 0.77)
1.02 (0.91 to 1.15)
0.86 (0.70 to 1.06)
atorvastatin
0.70 (0.62 to 0.78)
0.89 (0.77 to 1.02)
0.98 (0.78 to 1.25)
pravastatin
0.65 (0.52 to 0.82)
1.06 (0.79 to 1.41)
0.88 (0.60 to 1.30)
.5
.75
Odds ratios are adjusted for co-morbidities, deprivation, smoking status,
acid lowering drugs and influenza and pneumococcal vaccinations
©QRESEARCH 2006 version 11
1
1.25
1.5
Limitations
Strengths
• Residual confounding as
no information
• Large sample size and
representative population
• Data electronically
collected – unlikely
misclassification bias
• Data collected before
diagnosis – no recall bias
• All cases used – no
selection bias
– on X-ray
– on microbiological tests
– on severity of pneumonia
• Information on
prescriptions only
• Over-the-counter statin
use
• Missing data
Further research
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RCT in 26 countries
Randomisation in 2003-2006, last visit in 2008
17802 participants with no history of CVD and diabetes
Rosuvastatin 20mg or placebo
Incidence of infections during the trial
HR (95%CI) 1st CAP
0.81 (0.67 – 1.97)
Figure 2:
Kaplan–Meier estimates from intention-to-treat analysis showing cumulative incidence of first
pneumonia adjusted for competing risk of cardiovascular events. Participants were censored at the
time of a cardiovascular event.
Further research
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Danish National Registry
1997-2009, additional analysis for 2001-2009
70,914 patients hospitalised with pneumonia
Matched to up to 10 controls
Current statin use: at least 1 prescription in last 125 days
Adjusted for co-morbidities, medications, smoking, demographics...
Conclusions
There is an association between use of statins and
decreased risk of pneumonia, more pronounced
for patients having recent statin use.
• It may be due to anti-inflammatory and
immunomodulatory properties of statins
• It may also be due to reduced rate of CVD
events and rates of associated complication
such as pneumonia
Thank you
Questions?