Is low-dose Aspirin use associated with a reduced risk of colorectal cancer ? a QResearch primary care database analysis

Prof Richard Logan, Dr Yana Vinogradova, Dr Carol Coupland, Prof Julia Hippisley-Cox,Divisions of Primary Care, and Epidemiology & Public Health, University of Nottingham, UK

BSG Annual Meeting, Birmingham15th March 2011

Cohort studies of Colorectal Cancer in NSAID users

Low-Dose Aspirin in the Primary Prevention of Cancer

(Cook et al. JAMA 2005)

Aspirin 50mg/day Placebo Rel Risk

Colon 103 / 111 0.92

Rectum 30 / 25 1.20

Colorectal 133 / 136 0.97 (0.77-1.24)

Average of 10 years of treatment

Incidence of colorectal cancer in aspirin trials(from Cuzick et al Lancet Oncol 2009)

1

0

.25

.5

.75

1

1.25

1.5

1.75

1 2- 13-25-37-49+ 1 2- 13-25-37-49+ 1 2- 13-25-37-49+ 1 2- 13-25-37-49+

Statins COX-2 Inhibitors Traditional NSAIDs Aspirin

odds ratio compared to no prescriptions for a drug grouplower/upper limits of 95 percent confidence interval

Adj

uste

d O

dds

Rat

io

Number of scripts

© QRESEARCH 2005

Number of scripts in 13-96 months prior to the index date

Vinogradova et al. Gastroenterology 2007

1

0

.25

.5

.75

1

1.25

1.5

1.75

1 2-12 13-24 25+ 1 2-12 13-24 25+ 1 2-12 13-24 25+ 1 2-12 13-24 25+

Statins COX-2 Inhibitors Traditional NSAIDs Aspirin

odds ratio compared to no prescriptions for a drug grouplower/upper limits of 95 percent confidence interval

Adj

uste

d O

dds

Rat

io

Number of scripts

© QRESEARCH 2005

Number of scripts in 13-48 months prior to the index date

Vinogradova et al. Gastroenterology 2007

Lancet Oct 22 2010

5yr 10yr 15yr 20yr 5yr 10yr 15yr 20yr

(n=391)

5yr 10yr 15yr 20yr

Lancet Dec 7 2010

Risk of death from CRC

Study population: QRESEARCH database

• Currently largest primary care database in the UK

• 574 general practices across the UK

• > 9 million patients including those who have died or left, as well as patients still registered

• > 30 million person-years of observation

Data source: QRESEARCH database

• Derived from GP clinical records

• Patient level consolidated database

• Anonymised data

• Longitudinal data for 15+ years

• Validated against external and internal measures

Study design & setting• Nested case control study• Study period Jan 1998-July 2008 • Cases were incident colorectal

cancer patients• 5 controls matched by

• Age• Sex• Practice• Calendar year

Exposure assessment :• Aspirin exposure analysis restricted to subjects with +10 and

+15yrs of prescribing data • any use:

• at least 1 script in 13-120 months and 13 to 180 months prior to the index date (date of diagnosis in the case)

• Years of exposure: • up to 1 years• 1 to 2 years• 3 to 5 years• 6 to 9 years• 10 to 14 years

Statistical analysis• Multiple imputations

• ICE procedure in STATA• 5 imputed datasets• Rubin’s rule’s to combine estimates

• Conditional logistic regression• Odds ratios + 95% CI ( unadjusted & adjusted)• 1% significance level

Study Sample:14,948 incident cases of colorectal cancer

1998/2008

9534 cases with 10 years of medical records

6643 cases with 15 years of medical records

35,013 controlswith 10 years ofmedical records

20,652 controls with 15 years of medical records

Confounding factors :

• Body mass index• in kg/m2

• Smoking status• Non-smoker• Ex-smoker• Smoker

• Socio-economic status (Townsend score for post code)• quintiles

• Morbidities• CVD • Diabetes• High BP• Osteoarthritis• Colitis• Crohn’s disease• Rheumatoid arthritis

Aspirin – median dose prescribed

10 year cohort 15 year cohortTablet dose (n = 10,073) (n = 6,506)

≥ 75 mg 77% 78%

76 – 150 mg 16% 15%

151 – 300 mg 5% 5%

>300 mg 2% 2%

Aspirin – frequency of use recommended

Daily 65%

Twice daily 15%

Alternate days 5%

Cases (%) Controls (%)

Unadjusted odds ratio

Adjusted odds ratio

P-value

(n=6643) (n=20652) (95% CI) (95% CI)

Any use 1572 (23.7) 4934 (23.9) 1.03 (0.96 to 1.11) 0.98 (0.91 to 1.07) 0.709

No use 5071 (76.3) 15718 (76.1) 1.0 reference 1.0 reference

Up to 365days 464 (7.0) 1369 (6.6) 1.07 (0.96 to 1.20) 1.04 (0.92 to 1.17) 0.522

1 to 3 years 453 (6.8) 1304 (6.3) 1.10 (0.98 to 1.24) 1.05 (0.93 to 1.19) 0.418

4 to 6 years 373 (5.6) 1253 (6.1) 0.97 (0.86 to 1.10) 0.91 (0.79 to 1.04) 0.160

7 to 9 years 196 (3.0) 655 (3.2) 0.99 (0.84 to 1.17) 0.90 (0.75 to 1.09) 0.279

10 to 14 years 86 (1.3) 353 (1.7) 0.83 (0.65 to 1.06) 0.73 (0.56 to 0.94) 0.017

Cumulative exposure to aspirin in 1 to 15 yr period prior to CRC diagnosis / index date

10 to 14 years (164) 0.81 (0.66 to 0.98)

7 to 9 years (233) 0.87 (0.73 to 1.02)

4 to 6 years (378) 0.96 (0.84 to 1.10)

1 to 3 years (380) 0.97 (0.85 to 1.11)

Up to 1 year (417) 1.12 (0.99 to 1.26)

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

.6 .8 1 1.2 1.4

Odds ratios and 95%CI are adjusted for deprivation, smoking, BMI, comorbidities, use of medicationReference group: No use of aspirin in 2 to 15 years prior the index date© QRESEARCH 2008 version 20

Adjusted odds ratios and 95% confidence intervals

Risk of colorectal cancer in patients using aspirinin 2 to 15 years prior to the index date

Risk of Colorectal cancer in patients using aspirin in 1-15 yr period prior to CRC diagnosis / index date

Cases (%) Controls (%)

Unadjusted odds ratio

Adjusted odds ratio

P-value

(n=9534) (n=35013) (95% CI) (95% CI)

Any use 2147 (22.5) 7926 (22.6) 1.03 (0.97 to 1.09) 0.98 (0.91 to 1.04) 0.472Years of use

No use 7387 (77.5) 27087 (77.4) 1.0 reference 1.0 referenceUp to 365 days 614 (6.4) 2281 (6.5) 1.01 (0.92 to 1.11) 0.98 (0.88 to 1.08) 0.6352 to 4 years 842 (8.8) 2944 (8.4) 1.08 (1.00 to 1.18) 1.03 (0.94 to 1.13) 0.5245 to 6 years 329 (3.5) 1194 (3.4) 1.04 (0.91 to 1.18) 0.96 (0.83 to 1.10) 0.5227 to 10 years 362 (3.8) 1507 (4.3) 0.93 (0.82 to 1.05) 0.85 (0.74 to 0.97) 0.017

Cumulative exposure to aspirin in 1 to 10 yr period prior to CRC diagnosis / index date

CRC cases Controls unadj OR adj OR

No use

7387 (77.5)

27087 (77.4) 1.0 reference 1.0 reference

P

value

Up to 1 year 547 (5.7) 1946 (5.6) 1.06 (0.96- 1.17) 1.02 (0.92- 1.13) 0.712

1 to 3 yrs 742 (7.8) 2621 (7.5) 1.07 (0.98- 1.17) 1.02 (0.93- 1.12) 0.703

4 to 6 yrs 359 (3.8) 1254 (3.6) 1.08 (0.95- 1.22) 1.00 (0.88 -1.14) 0.972

7 to 10 yrs 499 (5.2) 2105 (6.0) 0.91 (0.82- 1.01) 0.82 (0.73 -0.93) 0.001

Exposure to aspirin in 1 to 10 yr period prior to CRC diagnosis / index date

7 to 9 years (499) 0.82 (0.73 to 0.93)

5 to 6 years (359) 1.00 (0.88 to 1.14)

1 to 4 years (742) 1.02 (0.93 to 1.12)

Up to 1 year (547) 1.02 (0.92 to 1.13)

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

.6 .8 1 1.2 1.4

Odds ratios and 95%CI are adjusted for deprivation, smoking, BMI, comorbidities, use of medicationReference group: No use of aspirin in 2 to 10 years prior the index date© QRESEARCH 2008 version 20

Adjusted odds ratios and 95% confidence intervals

Risk of colorectal cancer in patients using aspirinin 2 to 10 years prior to the index date

Risk of Colorectal cancer in patients using aspirin in 1-10 yr period prior to CRC diagnosis / index date

Conclusions• Patients taking low dose aspirin have a

reduced risk of Colorectal cancer• An 18% reduction in risk is evident after

more than 7yrs of aspirin use • Effect not consistent with being COX-2

mediated

Methodological strengths• Large sample size and representative

population• Data electronically collected – unlikely

misclassification bias • Data collected before the diagnosis – no

recall bias• Excluded prescriptions 12 months prior to

cancer diagnosis

Baseline characteristics (15 years of data):Cases

n=9,534 Controls

n=35,013 Males (number, percent) 5,447 (57.1) 19,980 (57.1) Age in years (median, IQR) 71 (63 to 78) 72 (64 to 78) Months of records (median, IQR) 243 (173 to 417) 248 (176 to 1422) Body mass index (median, IQR) 26.2 (23.7 to 29.2) 26.1 (23.7 to 29.0) Smokers (number, percent) 1,325 (13.9) 4,941 (14.1)

18.2 17.9

9.58.1

34.1 33.8

1.3 1.5

15.3 15.9

1.1 0.7 0.2 0.20

5

10

15

20

25

30

35

Pro

porti

on o

f pat

ient

s (%

)

CVD DM HBP RA OA Col Crohns© QRESEARCH 2008 version 20

Proportion of patients with morbidities

cases controls

Comorbidity in CRC cases and controls: