Transcript NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND …

NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS AND PANCREATIC CANCER RISK: A
NESTED CASE-CONTROL STUDY
Marie Bradley, Carmel Hughes, Marie
Cantwell and Liam Murray
Cancer Epidemiology and Prevention
Research Group, & School of Pharmacy,
Queen’s University Belfast
Overview
• Pancreatic cancer
• Chemoprevention of cancer with NSAIDs
• GPRD
• Nested case-control study examining the effect
of NSAIDs on pancreatic cancer risk using
GPRD
Pancreatic Cancer
• In the United Kingdom (UK) in 2006 there were around
7,600 cases of pancreatic cancer diagnosed.
• Rapidly fatal
• Presents at an advanced stage
• 5th leading cause of cancer mortality, in the western
world
• Five year survival rate of 1%.
• As incidence and mortality increase with age, the
pancreatic cancer burden will rise in the future, due to
population ageing and increased life expectancy.
Known risk factors for
pancreatic cancer
1. Smoking
4. Age
2. Genetic factors/
Family history
5. Obesity
3. Chronic pancreatitis
Important to identify other aetiological factors for pancreatic
cancer in order to improve prospects for primary
prevention.
Chemoprevention of cancer
using cyclooxygenase (COX)
inhibitors
• Large body of epidemiological and experimental
evidence suggesting that exposure to aspirin and
NSAIDs is associated with a reduced risk of colorectal
cancer through inhibition of COX-2.
• COX-2 expression is increased in inflammation and
carcinogenesis.
• COX- 2 blockade has been shown in experimental
studies to induce apoptosis, inhibit endothelial cell
migration, neovascularisation and the invasive potential
of pancreatic cancer cells.
• However evidence is limited.
Aims
• Primary Aim:
“Investigation of the role of NSAIDs and aspirin in
the aetiology/prevention of pancreatic cancer
using the General Practice Research Database
(GPRD)”
The general practice
research database
(GPRD)
• GPRD is the world’s largest computerised database of
anonymised longitudinal patient records from primary
care.
• Started up in 1987.
• 3.7 million (up to standard) UTS patients.
• 434 UTS practices across the UK.
• 5.5% of the UK population.
• Representative of UK population in terms of age, sex,
and geographic distribution.
Methods
• Case-control study.
• Source population from (GPRD).
• Patients <85years old and had ≥5 years of follow-up, prior
to the diagnosis date.
• Cases had a diagnosis of primary malignant neoplasia of
the exocrine pancreas between 01/1995 and 06/2006.
• Up to 7 controls matched with each case on general
practice site, sex and year of birth.
• Primary exposure of interest was exposure to
NSAIDs/aspirin in the five years prior to the diagnosis date
• One year lag time.
Methods
• Total dose of NSAIDS per patient
(the average daily dose in units of Defined Daily Dose [DDD]).
• Total duration of NSAID use per patient.
• The dose (DDDs) and duration (days) of NSAID use per
patient were divided into quartiles.
• The effect of dose (DDDs) and duration (years) combined.
• Effect of different NSAID groups.
Analyses
• Conditional logistic regression analyses were used to
generate odds ratios (OR) and 95% confidence intervals
(95% CI) associated with NSAID use compared to nonuse.
• All estimates of OR were adjusted for smoking status,
Body Mass Index (BMI), alcohol use, and history of
chronic pancreatitis, prior cancer, diabetes. Also
adjusted for use of steroids, PPIs, H2RAs and hormone
replacement therapy (HRT).
Results
• 1141 cases and 7954 controls were identified.
• Analysis examined:
– Effect of any use
– Effect of dose
– Effect of duration of use
– Effect of dose and duration
– Effect of different groups of NSAIDs
1.Dose of NSAIDs used
Period of NSAID use
Five years before index date, excluding the year
before index date
NSAID Dose
(DDDs)
Cases
(n)
Controls
(n)
Adjusted OR
(95% CI)*
Entry into GPRD until one year before index date
NSAID Dose
(DDDs)
Cases
(n)
Controls
(n)
Adjusted OR
(95% CI)*
OR per 200
DDDs increase
607
4178
0.99
(0.94-1.04)
OR per 200
DDDs increase
796
5389
0.99
(0.97-1.01)
Category 1:
No use:
534
3776
1.0
Category 1:
No use
345
2565
1.0
Category2:
0-9.2
156
1058
0.98
(0.80-1.20)
Category 2:
0-31.5
192
1354
1.01
(0.83-1.23)
Category 3:
9.25-26.5
145
1059
0.91
(0.74-1.11)
Category 3:
31.55-90.5
217
1357
1.11
(0.91-1.34)
Category 4:
26.55-100.5
160
1020
1.04
(0.85-1.26)
Category 4:
90.55-298
198
1333
1.03
(0.84-1.26)
Category 5:
>100.5
146
1041
0.93
(0.76-1.14)
Category 5:
>298
189
1345
0.96
(0.78-1.17)
P for trend
0.62
0.87
2.Duration of NSAID use
Period of NSAID use
Five years before index date, excluding the year
before index date
NSAID Duration
(days)
Cases
(n)
Entry into GPRD until one year before index date
Controls
(n)
Adjusted OR
(95% CI)*
NSAID Duration
(days)
Cases
(n)
Controls
(n)
Adjusted OR
(95% CI)*
OR per 200 days
increase
607
4178
0.95
(0.91-1.00)
OR per 200 days
increase
796
5389
0.97
(0.95-0.99)
Category1:
No use
Category 2:
0 - 33.5
534
3776
1.0
345
2565
1.0
155
1078
0.97
(0.80-1.19)
Category 1:No
use
Category 2:
0 - 40.5
204
1377
1.06
(0.87-1.28)
Category 3:
33.55 - 156.5
152
1013
1.01
(0.83-1.24)
Category 3:
40.55 - 156.5
204
1320
1.09
(0.90-1.33)
Category 4:
156.55 – 773
171
1044
1.09
(0.90-1.33)
Category 4:
156.55 - 834
214
1346
1.08
(0.88-1.31)
Category 5:
>773
129
1043
0.79
(0.64-0.99)
Category 4:
>834
174
1346
0.85
(0.69-1.06)
P for trend
0.24
0.41
3.Dose and Duration of
NSAID use combined since
entry into GPRD
Dose of NSAID
Duration
of NSAID use
High dose (≥1.0 DDD/day)
Low dose (<1.0 DDD/day)
Cases
(n)
Controls
(n)
Adjusted OR
(95%CI)*
Cases
(n)
Controls
(n)
Adjusted OR
(95%CI)*
Nonuser and
504
use for 0-1 years
3560
1.0
705
4976
1.0
0-2.99 years
87
518
1.17 (0.88 1.56)
52
332
1.02 (0.73-1.42)
3-4.99 years
48
355
0.95 (0.66-1.34)
18
180
0.66 (0.39-1.11)
5 years or more 48
421
0.70 (0.49-0.99)
24
177
0.83 (0.52-1.34)
P for trend
0.11
0.20
4.NSAID groups
Period of NSAID use
Subgroups of
NSAIDs
Five years before index date, excluding the year
before index date
Cases
Controls
OR
Adjusted
(n)
(n)
(95%CI)
OR
(95%CI)
Entry into GPRD until one year before index date
Cases
(n)
Controls
(n)
OR
(95%C)
Adjusted
OR
(95%CI)
Aspirin and
derivatives
267
1813
1.04 (0.891.21)
0.95 (0.811.12)
236
1747
1.03
(0.881.22)
0.95 (0.811.13)
Acetic Acid
derivatives
249
1747
0.99 (0.851.16)
0.96 (0.821.13)
409
2762
1.06
(0.921.21)
0.99 (0.861.14)
Coxibs
45
353
0.87 (0.631.22)
0.80 (0.561.11)
47
356
0.91
(0.661.26)
0.82 (0.581.16)
Fenamates
14
93
1.06 (0.591.89)
1.02 (0.561.86)
43
267
1.14
(0.811.60)
1.09 (0.771.55)
Other NSAIDs
19
86
1.57 (0.952.60)
1.43 (0.852.43)
44
219
1.44
(1.032.01)
1.41 (1.01.99)
Oxicams
24
234
0.71 (0.461.08)
0.67 (0.431.03)
62
480
0.89
(0.681.18)
0.83(0.621.10)
Propionic Acid
Derivatives
307
2023
1.08 (0.941.25)
1.06 (0.921.23)
574
3715
1.17
(1.031.32)
1.12 (0.981.28)
High dose aspirin
30
208
1.0
(0.67 –1.48
0.91 (0.611.35)
53
314
1.19
(0.881.61)
1.10 (0.811.50)
Results
•No significant reductions in risk of pancreatic cancer for ever
use compared with never use of a NSAID.
•No overall association between pancreatic cancer risk and the
total dose of NSAIDs prescribed and no risk reduction was seen
among subjects who used the highest doses of NSAIDs.
•A 20% reduction in risk was seen among subjects who had
been prescribed a NSAID for approximately 2 years or longer in
the 5 years before diagnosis.
•A 30% reduction in pancreatic cancer risk was also seen in
subjects who had used lower than average doses of NSAIDs for
5 years or more since entry into the GPRD.
Results
•Ever use versus never use of COX-2 inhibitors and
oxicams in the five years before the index date, was
associated with modest reductions in pancreatic cancer risk
(20% and 30% respectively) but statistical significance was
not achieved and too few subjects were exposed to these
preparations to allow a more detailed analysis of use of
these drugs.
Discussion
•
Study strengths:
– NSAID exposure was determined by prospectively
collected prescription data, avoiding self-reported
exposure and its associated disadvantages
– Study size
– Representative sample
Conclusion
• It therefore appears that long-term use (>2 years) of
NSAIDs may protect against pancreatic cancer and that
duration of use may be more important than dose.
• As there was no further reduction in risk with use of more
than one DDD per day, which represents a standard
anti-inflammatory dose, it does not appear that doses
which exceed those that are routinely used for the main
indications of these drugs are required for prevention.