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
15th 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)
Number of scripts in 13-96 months prior to the index date
Statins
COX-2 Inhibitors Traditional NSAIDs
Aspirin
1.75
1.5
1.25
1
1
.75
.5
.25
0
1 2- 13-25-37-49+
1 2- 13-25-37-49+
1 2- 13-25-37-49+
1 2- 13-25-37-49+
Number of scripts
odds ratio compared to no prescriptions for a drug group
lower/upper limits of 95 percent confidence interval
© QRESEARCH 2005
Vinogradova et al. Gastroenterology 2007
Number of scripts in 13-48 months prior to the index date
Statins
COX-2 Inhibitors Traditional NSAIDs
Aspirin
1.75
1.5
1.25
1
1
.75
.5
.25
0
1
2-12 13-24 25+
1
2-12 13-24 25+
1
2-12 13-24 25+
1
2-12 13-24 25+
Number of scripts
odds ratio compared to no prescriptions for a drug group
lower/upper limits of 95 percent confidence interval
© QRESEARCH 2005
Vinogradova et al. Gastroenterology 2007
Lancet Oct 22 2010
(n=391)
5yr
10yr
15yr
20yr
5yr
10yr
15yr
20yr
Lancet Dec 7 2010
Risk of death from CRC
5yr
10yr
15yr
20yr
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
35,013 controls
with 10 years of
medical records
6643 cases
with 15 years of
medical 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
(n = 10,073)
15 year cohort
(n = 6,506)
77%
78%
76 – 150 mg
16%
15%
151 – 300 mg
5%
5%
2%
2%
Tablet dose
≥ 75 mg
>300 mg
Aspirin – frequency of use recommended
Daily
65%
Twice daily
15%
Alternate days
5%
Cumulative exposure to aspirin in 1 to 15 yr
period prior to CRC diagnosis / index date
Cases (%)
Controls (%)
(n=6643)
(n=20652)
Any use
1572 (23.7)
4934 (23.9)
No use
5071 (76.3)
15718 (76.1)
Unadjusted
odds ratio
Adjusted
odds ratio
(95% CI)
(95% CI)
1.03 (0.96 to 1.11)
1.0 reference
0.98 (0.91 to 1.07)
P-value
0.709
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
Risk of Colorectal cancer in patients using aspirin
in 1-15 yr period
priorcancer
to CRC
diagnosis
Risk of colorectal
in patients
using aspirin/ index date
in 2 to 15 years prior to the index date
Adjusted odds ratios and 95% confidence intervals
Exposure
(N of cases)
OR (95%CI)
Up to 1 year
(417)
1.12 (0.99 to 1.26)
1 to 3 years
(380)
0.97 (0.85 to 1.11)
4 to 6 years
(378)
0.96 (0.84 to 1.10)
7 to 9 years
(233)
0.87 (0.73 to 1.02)
10 to 14 years
(164)
0.81 (0.66 to 0.98)
.6
.8
1
1.2
Odds ratios and 95%CI are adjusted for deprivation, smoking, BMI, comorbidities, use of medication
Reference group: No use of aspirin in 2 to 15 years prior the index date
© QRESEARCH 2008 version 20
1.4
Cumulative exposure to aspirin in 1 to 10 yr
period prior to CRC diagnosis / index date
Any use
Cases (%)
Controls (%)
(n=9534)
(n=35013)
2147 (22.5)
7926 (22.6)
7387 (77.5)
27087 (77.4)
Unadjusted
odds ratio
Adjusted
odds ratio
(95% CI)
(95% CI)
1.03 (0.97 to 1.09)
0.98 (0.91 to 1.04)
P-value
0.472
Years of use
No use
1.0 reference
1.0 reference
Up to 365 days 614 (6.4)
2281 (6.5)
1.01 (0.92 to 1.11)
0.98 (0.88 to 1.08)
0.635
2 to 4 years
842 (8.8)
2944 (8.4)
1.08 (1.00 to 1.18)
1.03 (0.94 to 1.13)
0.524
5 to 6 years
329 (3.5)
1194 (3.4)
1.04 (0.91 to 1.18)
0.96 (0.83 to 1.10)
0.522
7 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
Exposure to aspirin in 1 to 10 yr period prior
to CRC diagnosis / index date
No use
CRC cases
Controls
7387
(77.5)
27087
(77.4)
unadj OR
1.0
reference
adj OR
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
Risk of Colorectal cancer in patients using aspirin
Risk of colorectal
in patients
using aspirin/ index date
in 1-10 yr period
prior cancer
to CRC
diagnosis
in 2 to 10 years prior to the index date
Adjusted odds ratios and 95% confidence intervals
Exposure
(N of cases)
OR (95%CI)
Up to 1 year
(547)
1.02 (0.92 to 1.13)
1 to 4 years
(742)
1.02 (0.93 to 1.12)
5 to 6 years
(359)
1.00 (0.88 to 1.14)
7 to 9 years
(499)
0.82 (0.73 to 0.93)
.6
.8
1
1.2
Odds ratios and 95%CI are adjusted for deprivation, smoking, BMI, comorbidities, use of medication
Reference group: No use of aspirin in 2 to 10 years prior the index date
© QRESEARCH 2008 version 20
1.4
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)
Comorbidity in CRC cases and controls:
Proportion of patients with morbidities
34.1 33.8
35
cases
controls
30
25
20
18.2 17.9
15.3
15.9
15
9.5
10
8.1
5
1.3 1.5
1.1 0.7
0.2 0.2
Col
Crohns
0
CVD
© QRESEARCH 2008 version 20
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