1. Risk of colorectal cancer in patients taking statins and NSAIDS Dr Yana Vinogradova, Prof Julia Hippisley-Cox, Dr Carol Coupland and Prof Richard Logan Divisions of Primary Care, and Epidemiology & Public Health, University of Nottingham, UK UEGW Plenary session Berlin 23 rd October 2006

2. Background to CRC statin analysis Evidence from animal models and other lab data that statins might prevent cancer Evidence from animal models and other lab data that statins might prevent cancer A meta-analysis of 26 large statin trials found no difference in incidence of CRC but limited power as only 4 reported CRC data A meta-analysis of 26 large statin trials found no difference in incidence of CRC but limited power as only 4 reported CRC data Recent case control study found a 47% reduction in CRC risk Recent case control study (Poynter NEJM 2005) found a 47% reduction in CRC risk

3. Meanwhile Mass of observational and experimental evidence that aspirin and traditional NSAIDs lower CRC risk Mass of observational and experimental evidence that aspirin and traditional NSAIDs lower CRC risk Trials of Colorectal adenoma prevention with COX2 show a 40-50% reduction in recurrence Trials of Colorectal adenoma prevention with COX2 show a 40-50% reduction in recurrence (Bertagnolli, Arber NEJM August 2006) Little observational data available on risk of colorectal cancer in COX2 users Little observational data available on risk of colorectal cancer in COX2 users

4. Study population: QRESEARCH database Currently largest primary care database in the UK Currently largest primary care database in the UK 537 general practices across the UK 537 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

5. General Practice data collection:

6. 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

7. Study design & setting Nested case control study Nested case control study Study period Jan 1995-July 2005 Study period Jan 1995-July 2005 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

8. Exposure assessment : Exposure assessment : statins, NSAIDs, Cox2 Inhibitors and aspirin prescriptions statins, NSAIDs, Cox2 Inhibitors and aspirin prescriptions analysis restricted to subjects with +4yrs analysis restricted to subjects with +4yrs of prescribing data of prescribing data any use: any use: at least 1 script in 13-48 months prior to the index date (date of diagnosis in the case) at least 1 script in 13-48 months prior to the index date (date of diagnosis in the case) number of prescriptions: number of prescriptions: 1 script only 1 script only 2-12 scripts 2-12 scripts 13-24 scripts 13-24 scripts 25 or more scripts 25 or more scripts

9. Statistical analysis Conditional logistic regression Conditional logistic regression Odds ratios + 95% CI Odds ratios + 95% CI Unadjusted & adjusted Unadjusted & adjusted

10. Study Sample: Study Sample: 9,694 incident cases of colorectal cancer 1995/2005 5,686 cases with 4 years of medical records 2,425 cases with 8 years of medical records 24,982 controls with 4 years of medical records 12,131 controls with 8 years of medical records

11. Comorbidity in CRC cases and controls:

12. Confounding factors : Body mass index Body mass index Less than 25 kg/m2 Less than 25 kg/m2 25 to 29.9 kg/m2 25 to 29.9 kg/m2 30 kg/m2 or more 30 kg/m2 or more BMI not recorded BMI not recorded Smoking status Smoking status Non-smoker Non-smoker Smoker Smoker not recorded not recorded Socio-economic status (Townsend score for post code) Socio-economic status (Townsend score for post code) quintiles Morbidities Morbidities IHD (±MI) Diabetes High BP Osteoarthritis Colitis Rheumatoid arthritis Stroke

13. Any use in 13-48 months prior to the index date

16. Risks with prolonged prescribing in 13-48 months prior to index date 25 or more statin scripts: 25 or more statin scripts: adj. OR 1.13 (0.91 - 1.41) adj. OR 1.13 (0.91 - 1.41) 25 or more COX-2 scripts: 25 or more COX-2 scripts: adj. OR 0.34 (0.14 - 0.85) adj. OR 0.34 (0.14 - 0.85) 25 or more NSAID scripts: 25 or more NSAID scripts: adj. OR 0.76 (0.60 – 0.95) adj. OR 0.76 (0.60 – 0.95) 25 or more Aspirin scripts: 25 or more Aspirin scripts: adj. OR 0.88 (0.74 – 1.05) adj. OR 0.88 (0.74 – 1.05)

17. Conclusions Prolonged statin use is not associated with reduced risk of colorectal cancer Prolonged statin use is not associated with reduced risk of colorectal cancer Prolonged NSAID and Cox2 inhibitor use is associated with reduced risk of colorectal cancer Prolonged NSAID and Cox2 inhibitor use is associated with reduced risk of colorectal cancer

18. Implications No increase in risk of colorectal cancer with cholesterol lowering No increase in risk of colorectal cancer with cholesterol lowering Supports role for COX 2 inhibitors in secondary / tertiary prevention of colorectal cancer Supports role for COX 2 inhibitors in secondary / tertiary prevention of colorectal cancer

20. 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

21. Use of individual statins Cases no. (%) Controls no. (%) Unadjusted odds ratio (95%CI) Adjusted † odds ratio (95%CI) Atorvastatin 250 (4.4)954 (3.8)1.19(1.02-1.38)1.11(0.95 - 1.30) Simvastatin 287 (5.0)1420 (5.7)0.88(0.77-1.01)0.83(0.72 - 0.96) Pravastatin27 (0.5)136 (0.5)0.90(0.59-1.37)0.84(0.55 - 1.28) Fluvastatin44 (0.8)150 (0.6)1.35(0.95-1.91)1.21(0.85 - 1.74) Cerivastatin56 (1.0)179 (0.7)1.40(1.03-1.91)1.34(0.97 - 1.86)

23. Baseline characteristics: Casesn=5,686Controlsn=24,982 Males (number, percent) 3,181 (55.9) 14,014 (56.1) Age in years (median, IQR) 72 (64 to 79) Months of records (median, IQR) 88 (66 to 117) Deprivation Townsend score -1.26 (-3.05 to 1.57) -1.43 (-3.16 to 1.46) Body mass index (median, IQR) 26.0 (23.5 to 29.0) 26.1 (23.6 to 29.0) Smokers (number, percent) 985 (17.3) 4,060 (16.3)

24. Study sample: Study sample: 9,694 incident cases of colorectal cancer 1995/2005 5,686 cases with 4 years of medical records 3,460 cases with colon cancer 2,226 cases with rectal cancer 24,982 controls with 4 years of medical records

25. Rel Risk of CRC with aspirin use by recency, duration and dose in UK GPRD (Garcia Rodriguez Epidemiology 2001) in UK GPRD (Garcia Rodriguez Epidemiology 2001)