Epidemiological evidence for a protective role for statins in

Community Acquired Pneumonia

British Thoracic Society Winter Meeting 2012 , London

Yana Vinogradova

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

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.

From: Does Statin Use Improve Pneumonia Outcomes?

Chopra, Flanders, CHEST. 2009;136(5):1381-1388. doi:10.1378/chest.09-0941

Pharmacoepidemiology

and Prescription Kwok et al. Eur J Clin Pharmacol (2012) 68, 747-755

Fig. 3 Meta-analysis of adjusted risk of pneumonia with statin therapy

From: Statins and associated risk of pneumonia: a systematic review and meta-

analysis of observational studies

• QResearch– 660 GP practices

• 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

• 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 pravastatin cerivastatinsimvastatin fluvastatin rosuvastatin

• time before the index date: 28 days29-89 days90-365 days

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 co-morbidities 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

2231 cases (12.6%) statin users

80,484 controls with 2 years of

medical records

8759 controls (10.9%) statin

users

0

5

10

15

20

25

%

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005Index year

any statin simvastatin atorvastatin pravastatin fluvastatin rosuvastatin

controls cases

©RESEARCH 2006 version 11

Proportion of cases and controls exposed to statins by index year

0

200

400

600

800

1000

1200

1400

1600

rate

per

100

.000

pop

ulat

ion/

yea

r

45- 50- 55- 60- 65- 70- 75- 80- 85- 90+Age groups

Men Women©QRESEARCH 2006 version 11

Pneumonia episode rates by age and gender in 2005

0

5

10

15

20

25

45 50 55 60 65 70 75 80 85 90 95 45 50 55 60 65 70 75 80 85 90 95

Women Men

cases controls

%

Age at index date

©RESEARCH 2006 version 11

Proportion of cases and controls exposed to statinsby age and sex

Crude OR, 95%CI 1.23, 1.13 – 1.33 Crude OR, 95%CI 1.25, 1.16 – 1.34

0

5

10

15

20

45 50 55 60 65 70 75 80 85 90 95 45 50 55 60 65 70 75 80 85 90 95

cases controls

3 to 12 months1 to 3 monthsup to 28 days

%

Age at index date

©QRESEARCH 2006 version 11

Last use of statin before the index date

Crude OR, 95%CI

1.27, 1.20 – 1.34

1.14, 1.08 – 1.20

1.03, 0.98 – 1.09

13%

55%

11%

9%

37%30%

62%

7%

0

1

2

3

4

5

6

7

8

%

cases controls

28days29-89days

90-365days28days

29-89days90-365days

©QRESEARCH 2006 version 11

Proportion of cases and controls and number of prescriptionsby the last prescription time

2-67-1212+

Number ofprescriptions

69%

63%

48%

70%

60%

38%

0

10

20

30

40

50

60

45 50 55 60 65 70 75 80 85 90 95 45 50 55 60 65 70 75 80 85 90 95

cases controls

not on statinon statin

%

Age at index date

©QRESEARCH 2006 version 11

Proportion of cases and controls with heart disease and strokeand their use of statin

CHD and stroke

Crude OR, 95%CI

2.18, 2.10 – 2.27

Statin use, OR, 95%CI

Crude 1.24, 1.18 – 1.31

Adjusted 0.81, 0.77 – 0.86

37%23%

26% 31%

3 months ago (190) 0.89 (0.75 to 1.06)

1 to 3 months (819) 0.97 (0.88 to 1.06)

in 28 days (1222) 0.68 (0.63 to 0.73)

by time of use

overall use (2231) 0.78 (0.74 to 0.83)

Last year use (N of cases) OR (95%CI)

.5 .75 1 1.25Odds ratios are adjusted for co-morbidities, deprivation, smoking status,acid lowering drugs and influenza and pneumococcal vaccinations©QRESEARCH 2006 version 11

OR and 95%CIRisk of pneumonia and use of statin in the last year

rosuvastatin (26) 0.93 (0.58 to 1.48)

fluvastatin (79) 0.82 (0.63 to 1.07)

pravastatin (210) 0.80 (0.68 to 0.94)

atorvastatin (823) 0.79 (0.72 to 0.86)

simvastatin (1222) 0.82 (0.76 to 0.88)

Types (N of cases) OR (95%CI)

.5 .75 1 1.25 1.5Odds ratios are adjusted for co-morbidities, deprivation, smoking status,acid lowering drugs and influenza and pneumococcal vaccinations©QRESEARCH 2006 version 11

OR and 95%CIRisk of pneumonia and use of different types of statins

3 months ago (37) 0.88 (0.60 to 1.30)1 to 3 months (70) 1.06 (0.79 to 1.41)in 28 days (103) 0.65 (0.52 to 0.82)

pravastatin3 months ago (99) 0.98 (0.78 to 1.25)

1 to 3 months (292) 0.89 (0.77 to 1.02)in 28 days (432) 0.70 (0.62 to 0.78)

atorvastatin3 months ago (131) 0.86 (0.70 to 1.06)1 to 3 months (442) 1.02 (0.91 to 1.15)

in 28 days (649) 0.70 (0.63 to 0.77)simvastatin

Last use (N of cases) OR (95%CI)

.5 .75 1 1.25 1.5Odds ratios are adjusted for co-morbidities, deprivation, smoking status,acid lowering drugs and influenza and pneumococcal vaccinations©QRESEARCH 2006 version 11

OR and 95%CIRisk of pneumonia and use of most common types of statin

Limitations

• Residual confounding as no information – on X-ray– on microbiological tests– on severity of pneumonia

• Information on prescriptions only

• Over-the-counter statin use

• Missing data

Strengths

• 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

Further research

• 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

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.

HR (95%CI) 1st

CAP 0.81 (0.67 – 1.97)

Further research

• 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?