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, Birmingham 15 th 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 Aspirin 50mg/day Placebo Rel Risk Colon0.92 Colon103 / Rectum 1.20 Rectum 30 / Colorectal0.97 ( ) Colorectal133 / ( ) Average of 10 years of treatment

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

Vinogradova et al. Gastroenterology 2007

Lancet Oct yr10yr15yr20yr5yr10yr15yr20yr (n=391)

5yr 10yr15yr 20yr Lancet Dec Risk of death from CRC

Study population: QRESEARCH database Currently largest primary care database in the UK Currently largest primary care database in the UK 574 general practices across the UK 574 general practices across the UK > 9 million patients including those who have died or left, as well as patients still registered > 9 million patients including those who have died or left, as well as patients still registered > 30 million person-years of observation > 30 million person-years of observation

Data source: QRESEARCH database Derived from GP clinical records Derived from GP clinical records Patient level consolidated database Patient level consolidated database Anonymised data Anonymised data Longitudinal data for 15+ years Longitudinal data for 15+ years Validated against external and internal measures Validated against external and internal measures

Study design & setting Nested case control study Nested case control study Study period Jan 1998-July 2008 Study period Jan 1998-July 2008 Cases were incident colorectal cancer patients Cases were incident colorectal cancer patients 5 controls matched by 5 controls matched by Age Age Sex Sex Practice Practice Calendar year Calendar year

Exposure assessment : Exposure assessment : Aspirin exposure Aspirin exposure analysis restricted to subjects with +10 and +15yrs of prescribing data analysis restricted to subjects with +10 and +15yrs of prescribing data any use: any use: at least 1 script in months and 13 to 180 months prior to the index date (date of diagnosis in the case) at least 1 script in months and 13 to 180 months prior to the index date (date of diagnosis in the case) Years of exposure: Years of exposure: up to 1 years up to 1 years 1 to 2 years 1 to 2 years 3 to 5 years 3 to 5 years 6 to 9 years 6 to 9 years 10 to 14 years 10 to 14 years

Statistical analysis Multiple imputations Multiple imputations ICE procedure in STATA ICE procedure in STATA 5 imputed datasets 5 imputed datasets Rubin’s rule’s to combine estimates Rubin’s rule’s to combine estimates Conditional logistic regression Conditional logistic regression Odds ratios + 95% CI ( unadjusted & adjusted) Odds ratios + 95% CI ( unadjusted & adjusted) 1% significance level 1% significance level

Study Sample: Study Sample:

Confounding factors : Body mass index Body mass index in kg/m2 in kg/m2 Smoking status Smoking status Non-smoker Non-smoker Ex-smoker Ex-smoker Smoker Smoker Socio-economic status (Townsend score for post code) Socio-economic status (Townsend score for post code) quintiles Morbidities Morbidities CVD Diabetes High BP Osteoarthritis Colitis Crohn’s disease Rheumatoid arthritis

Aspirin – median dose prescribed 10 year cohort15 year cohort Tablet dose(n = 10,073)(n = 6,506) ≥ 75 mg77%78% 76 – 150 mg16%15% 151 – 300 mg5%5% >300 mg2%2%

Aspirin – frequency of use recommended Daily65% Twice daily15% Alternate days5%

Cases (%) Controls (%) Unadjusted odds ratio Adjusted odds ratio P-value(n=6643)(n=20652) (95% CI) Any use 1572 (23.7) 4934 (23.9) 1.03 (0.96 to 1.11) 0.98 (0.91 to 1.07) No use 5071 (76.3) (76.1) 1.0 reference reference1.0reference Up to 365days 464 (7.0) 1369 (6.6) 1.07 (0.96 to 1.20) 1.04 (0.92 to 1.17) to 3 years 453 (6.8) 1304 (6.3) 1.10 (0.98 to 1.24) 1.05 (0.93 to 1.19) to 6 years 373 (5.6) 1253 (6.1) 0.97 (0.86 to 1.10) 0.91 (0.79 to 1.04) to 9 years 196 (3.0) 655 (3.2) 0.99 (0.84 to 1.17) 0.90 (0.75 to 1.09) to 14 years 86 (1.3) 353 (1.7) 0.83 (0.65 to 1.06) 0.73 (0.56 to 0.94) Cumulative exposure to aspirin in 1 to 15 yr period prior to CRC diagnosis / 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) Any use2147 (22.5)7926 (22.6)1.03(0.97 to 1.09)0.98(0.91 to 1.04)0.472 Years of use No use7387 (77.5)27087 (77.4)1.0reference1.0 reference Up to 365 days614 (6.4)2281 (6.5)1.01(0.92 to 1.11)0.98(0.88 to 1.08) to 4 years842 (8.8)2944 (8.4)1.08(1.00 to 1.18)1.03(0.94 to 1.13) to 6 years329 (3.5)1194 (3.4)1.04(0.91 to 1.18)0.96(0.83 to 1.10) to 10 years362 (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 casesControlsunadj ORadj OR No use 7387 (77.5) (77.4) 1.0reference1.0reference P value Up to 1 year 547 (5.7)1946 (5.6)1.06( )1.02( ) to 3 yrs 742 (7.8)2621 (7.5)1.07( )1.02( ) to 6 yrs 359 (3.8)1254 (3.6)1.08( )1.00( ) to 10 yrs 499 (5.2)2105 (6.0)0.91( )0.82( )0.001 Exposure to aspirin in 1 to 10 yr period prior to CRC diagnosis / 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 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 An 18% reduction in risk is evident after more than 7yrs of aspirin use Effect not consistent with being COX-2 mediated Effect not consistent with being COX-2 mediated

Methodological strengths Large sample size and representative population Large sample size and representative population Data electronically collected – unlikely misclassification bias Data electronically collected – unlikely misclassification bias Data collected before the diagnosis – no recall bias Data collected before the diagnosis – no recall bias Excluded prescriptions 12 months prior to cancer diagnosis Excluded prescriptions 12 months prior to cancer diagnosis

Baseline characteristics (15 years of data): Casesn=9,534Controlsn=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)

Comorbidity in CRC cases and controls: