Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis

1471-2407-3-28 1471-2407 Research article Effects of non-steroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis González-Pérez Antonio agonzalez@ceife.es García Rodríguez A Luis lagarcia@ceife.es López-Ridaura Ruy rlopez@hsph.harvard.edu

Centro Español de Investigación Farmacoepidemiológica, Madrid, Spain

Department of Epidemiology. Harvard School of Public Health, Boston, MA, USA

Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

BMC Cancer 1471-2407 2003 3 1 28 http://www.biomedcentral.com/1471-2407/3/28 14588079 10.1186/1471-2407-3-28 31 7 2003 31 10 2003 31 10 2003 2003 González-Pérez et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

Abstract

Background

Observational studies have consistently shown that aspirin and non-steroidal anti-inflammatory drug (NSAID) use is associated with a close to 50% reduced risk of colorectal cancer. Studies assessing the effects of NSAIDs on other cancers have shown conflicting results. Therefore, we conducted a meta-analysis to evaluate the relationship between NSAID use and cancer other than colorectal.

Methods

We performed a search in Medline (from 1966 to 2002) and identified a total of 47 articles (13 cohort and 34 case-control studies). Overall estimates of the relative risk (RR) were calculated for each cancer site using random effects models.

Results

Aspirin use was associated with a reduced risk of cancer of the esophagus and the stomach (RR, 0.51; 95%CI (0.38–0.69), and 0.73; 95%CI (0.63–0.84)). Use of NSAIDs was similarly associated with a lower risk of esophageal and gastric cancers (RR,0.65; 95% CI(0.46–0.92) and RR,0.54; 95%CI (0.39–0.75)). Among other cancers, only the results obtained for breast cancer were fairly consistent in showing a slight reduced risk among NSAID and aspirin users (RR, 0.77; 95%CI (0.66–0.88), and RR, 0.77; 95%CI (0.69–0.86) respectively)).

Conclusions

The results of this meta-analysis show that the potential chemopreventive role of NSAIDs in colorectal cancer might be extended to other gastrointestinal cancers such as esophagus and stomach. Further research is required to evaluate the role of NSAIDs at other cancers sites.

Background

People who have regularly taken aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) are at a reduced risk of developing or dying from colorectal cancer 123. The association with other types of cancer remains unclear. Animal studies have shown a protective effect of these drugs in colon 4, esophagus 5, stomach 67, pancreas 8, breast 910, prostate 11, lung 12, and bladder cancer 13, suggesting a common mechanistic effect of NSAIDs in all these different cancers.

NSAIDs could reduce the risk of cancer through the inhibition of cyclooxygenase-2 (COX-2) 14, the enzyme that is responsible for the production of various prostaglandins. Prostaglandins play a key role on the accelerated proliferation of tumor tissue. Furthermore there is mounting evidence that NSAIDs may have the ability to restore apoptosis and inhibit angiogenesis 15.

If this proposed protective mechanism of NSAIDs is valid, the preventive effect of NSAIDs could extend to other human cancers. To date, epidemiological studies in cancer other than colorectal are scarce and offer inconsistent results.

The primary aim of our analysis is the use of meta-analytical techniques to evaluate the effect of aspirin and non-aspirin NSAIDs (NA-NSAIDs) on cancer sites other than the colon and rectum. We present summary estimates for the effect of these drugs in cancer sites where at least two epidemiological studies could be found.

Methods

Our search included original articles indexed in Medline from January 1966 to December 2002. We searched for different common terms used to refer to non-steroidal anti-inflammatory drugs ("NSAIDs", "anti-inflammatory drugs") or specific drug names such as "aspirin". Similarly we used different terms referring to cancer ("neoplasm", "malignancies", and the prefix "carcino-"). Additionally we included references cited in original or review articles that were not included in our original list. We restricted our search to studies performed in humans and published in English or Spanish. We individually reviewed all the abstracts and obtained those articles that satisfied our inclusion criteria: cohort or case-control studies studying the association between NSAIDs and cancer other than colorectal, and reporting an estimate of association such as relative risk (RR) with confidence intervals or enough information to compute it. Forty-nine articles were considered to meet our inclusion criteria. After review by two of the authors, two of these articles were excluded. The reasons for exclusion were absence of a control group 16, invalid exposure and outcome ascertainment 17. A total of forty-seven eligible studies were finally identified.

Two of the authors participated in the data extraction process using a standardized form. Data regarding study design, analyses and results were entered into a database. The fields extracted included study design, year of publication, country, matching used, percentage of response, exposure assessment, exposure definition, lag time between exposure and outcome, prevalence of exposure, outcome assessment, and RR with 95% confidence intervals (CI). We assumed that the odds ratio (OR) from case-control studies provided a valid estimate for the RR. The exposures of interest consisted of aspirin, and non-aspirin NSAIDs (NA-NSAIDs). In this study, the term NSAIDs refers to either aspirin and/or NA-NSAIDs. Some studies included paracetamol in the NSAID and/or NA-NSAID groups. Most studies reported a definition of regular use (n = 34) and whenever available the estimate for this exposure was the one extracted. When no clear definition of regular use was provided (n = 13), we extracted the most mechanistically meaningful estimate after reaching consensus between authors in all instances. A total of nine studies reporting estimates for multiple endpoints contributed to more than one cancer site. We explored all nine cancer sites for which two or more eligible studies were found. In the case of cancer of the esophagus we focused on adenocarcinoma when more than one histological type was studied.

We fit a DerSimonian and Laird random effects model 18 to obtain overall estimates for the effects of aspirin, NA-NSAIDs and NSAIDs in each specific cancer site using STATA software. This model is more robust than the fixed effects model and incorporates into the weighting scheme both the within-study and among-study variance. Heterogeneity was explored using Q test statistic 18 in sets where three or more studies were available. When the result from this test reached statistical significance we further assessed to what extent different study characteristics could explain the heterogeneity with meta-regression. We explored potential publication bias qualitatively and quantitatively using funnel plots and kendall's tau rank correlation tests 19.

Results

Studies characteristics

Among the 47 studies analyzed 2021222324252627282930313233343536373839404142434445464748495051525354555657585960616263646566, 13 were cohort and 34 were case-control studies. Seventeen of the case-control studies were population based (either nested in a cohort or using methods like random digit dialing to ensure that controls are a sample of the underlying cohort that gave rise to the cases)2122242728303639445459606163646566 whereas the other seventeen were hospital based (using non-cancer hospital controls) 232632333435373842454748495153555662. Regarding exposure assessment, most studies (n = 22) used personal interview typically performed by trained personnel 22242526283031323334384142434547515660636566. Thirteen studies used mailed questionnaires 21232729394046505254565864 and six used in-hospital questionnaires 353748495355. The rest used either automated databases (n = 4)20364461 or medical records (n = 2) 5962. Exposure definition was very heterogeneous across the different studies and attempts to categorize it in a few groups for further analysis were unsuccessful. It ranged from more than 6 tablets per day to ever use of NSAIDs in the 30 days prior to start date. Prevalence of exposure among controls or cohort members ranged from 4 to 42 percent for NSAIDs (median, 8 percent), from 2 to 64 percent for aspirin (median, 16 percent), and from 3 to 46 percent for NA-NSAIDs (median, 12 percent).

Some studies incorporated the concept of lag time into their exposure definition (time period before the index date that was discounted for assessing the exposure status). This is mainly motivated by the belief that early symptoms of the disease (cancer in this case) in the sub-clinical phase (latent period) might induce or contra-indicate the use of NSAIDs (protopathic bias) 4467. Nine studies used a lag time of 1 year, one study used 1 year and a half, and two studies used 2 years.

All but ten case-control studies used matched designs (frequency matched (n = 12) or individually matched (n = 12)). Among the individually matched seven studies considered the matching in the analysis and five did not. All studies used newly diagnosed cancer as the primary endpoint except for studies by Thun et al and Suleiman et al that used fatal cancer as outcome.

Most studies were published after 1997 (n = 33). The rest were published in 1996 (n = 3), 1995 (n = 4), 1994 (n = 1), 1993 (n = 2), 1989 (n = 1), 1988 (n = 1), 1985 (n = 1) and 1980 (n = 1). The majority of the studies were conducted in North America (USA (n = 32) or Canada (n = 2)). Ten studies were conducted in Europe (U.K. (n = 4), Greece (n = 2), France (n = 1), Italy (n = 1), Russia (n = 1), and Sweden (n = 1)), one study in Australia and one study in New Zealand. Additionally, there was one multicentered international study.

Tables 1 through 9 show the exposure definition, exposure assessment, study type, and the estimates of association for each individual study according to the cancer site. Table 10 summarizes the results by type of drug and cancer site. The pooled RR estimates for esophagus and stomach showed a significant protective effect of NSAIDs in the range of a 40 percent reduction. Aspirin but not NA-NSAIDs appeared to be associated with a reduced pancreas cancer incidence around 30 percent (although this result was not significant). Breast cancer was the only other site where results were rather consistent in showing a protection ranging around a 20 percent reduction. Results obtained for other studied cancer sites, i.e. ovary, prostate, bladder, and lung were compatible with no effect or a possibly slight reduced risk. The result for kidney cancer is compatible with no effect or possibly a slight increased risk.

Table 1

Esophagus

Author

Cases n

Controls_a/Cohort_b

Source population

Exposure definition

Exposure assessment

Drug

95% CI

Coogan et al. 26

207

5,833_a

Hospital based

>4 days/week for >3 months. Continuing use during 1 year of lag time

Personal Interview

NSAIDs (7%)

0.8

0.5–1.4

Farrow et al. 30

277

687_a

Population based

>1 tablet/week during >6 months. 1 year lag time

Personal Interview

Aspirin (31%)

0.48^†

0.32–0.70

279

NA-NSAIDs (13%)

0.81^†

0.51–1.30

Langman et al. 36

550

1,650_a

Population based

>7 prescriptions during months 13–36 before index date

Automated Database

NSAIDs (8%)

0.64

0.41–0.98

Garidou et al. 32

200_a

Hospital based

Chronic intake

Personal Interview

NSAIDs (14%)

0.52^†

0.17–1.62

Suleiman et al. 59

56_a

Population based

Ever use for >1 year

Medical records

NSAIDs (38%)

0.16

0.03–0.93

Cheng et al. 60

74_a

Population based

Ever daily use for >1 month

Personal Interview

Aspirin (21%)

0.67

0.27–1.63

Funkhouser et al.³¹

13,179_b

Cohort

Use 30 days before baseline (ocasional)

Personal Interview

Aspirin (51%)

0.10

0.01–0.76

Thun et al. 46

157

635,031_b

Cohort

More than 16 times per month for at least one year

Mailed questionnaire

Aspirin (11%)

0.59

0.34–1.03

Prevalence of exposure among controls/cohort; ^†Adenocarcinoma.

Table 2

Stomach

Author

Cases n

Controls_a/Cohort_b

Source population

Exposure definition

Exposure assessment

Drug

95% CI

Farrow et al. 30

612

687_a

Population based

>1 tablet/week during >6 months. 1 year lag time

Personal Interview

Aspirin (31%)

0.76

0.60–0.97

610

NA-NSAIDs (13%)

0.79

0.56–1.10

Akre et al. 22

480

1,055_a

Population based

>30 tablets/month. 2 years lag time

Personal Interview

Aspirin (3%)

0.8

0.7–1.1

NA-NSAIDs^†

1.1

0.6–1.4

Zaridze et al. 48

448

610_a

Hospital based

>2 days/week for >6 months

In-hospital Questionnaire

Aspirin (14%)

0.60

0.41–0.90

NSAIDs (17%)

0.65

0.45–0.93

Langman et al. 36

613

1,837_a

Population based

>7 prescriptions during months 13–36 before index date

Automated Database

NSAIDs (8%)

0.51

0.33–0.79

Coogan et al. 26

250

5,883_a

Hospital based

>4 days/week for >3 months. Continuing use during 1 year of lag time

Personal Interview

NSAIDs (7%)

0.3

0.1–0.6

Thun et al. 46

266

635,031_b

Cohort

More than 16 times per month for at least one year

Mailed Questionnaire

Aspirin (11%)

0.53

0.34–0.81

Schreinemachers et al. 43

12,668_b

Cohort

Ever use of aspirin in the 30 days prior to start date

Personal Interview

Aspirin (59%)

0.93

0.49–1.74

Prevalence of exposure among controls/cohort; ^†Exposure definition not provided.

Table 3

Pancreas

Author

Cases n

Cotrols_a/Cohort_b

Source population

Exposure definition

Exposure assessment

Drug

95% CI

Coogan et al. 26

491

5,833_a

Hospital based

>4 days/week for >3 months. Continuing use during 1 year of lag time

Personal Interview

NSAIDs (7%)

0.8

0.5–1.1

Langman et al. 36

513

1,535_a

Population based

>7 prescriptions during months 13–36 before index date

Automated Database

NSAIDs (7%)

1.49

1.02–2.18

Menezes et al. 49

194

582_a

Hospital based

>1 tablet/week for at least 6 months

In-hospital Questionnaire

Aspirin (44%)

1.00

0.72–1.39

Schreinemachers et al. 43

12,668_b

Cohort

Ever use of aspirin in the 30 days prior to start date

Mailed Questionnaire

Aspirin (59%)

0.67

0.33–1.36

Anderson et al. 23

28,283_b

Cohort

>6 times/week at baseline

Mailed Questionnaire

Aspirin (21%)

0.40

0.20–0.82

NA-NSAIDs (NR)

1.28

0.68–2.43

Prevalence of exposure among controls/cohort

Table 4

Breast

Author

Cases n

Controls_a/Cohort_b

Source population

Exposure definition

Exposure assessment

Drug

95% CI

Sharpe et al. 44

5,882

23,517_a

Population based

>2 tablets/week during years 2 – 5 before index date

Automated Database

NSAIDs (4%)

0.76

0.63–0.92

Harris et al. 33

744

767_a

Hospital based

>3 tablets/week during more than 5 years

Personal Interview

NSAIDs (16%)

0.6

0.4–0.8

Harris et al. 34

511

1,534_a

Hospital based

>3 tablets/week for at least 1 year

Personal Interview

Aspirin (12%)

0.69

0.46–0.99

NSAIDs (28%)

0.66

0.52–0.83

Coogan et al. 25

6,558

2,925_a

Hospital based

>4 days/week for >3 months.

Personal Interview

Aspirin (N.R.)

0.7

0.5–0.8

Continuing use during 1 year of lag time

NA-NSAIDs (N.R.)

0.8

0.6–1.1

NSAIDs (7%)

0.7

0.6–0.8

Langman et al. 36

3,105

9,772_a

Population based

>7 prescriptions during months 13–36 before index date

Automated Database

NSAIDs (6%)

1.10

0.92–1.30

Cotterchio et al. 27

3,133

3,062_a

Population based

Daily use for more than two months. 1 year before start date excluded

Mailed Questionnaire

Aspirin (14%)

0.73

0.61–0.87

NA-NSAIDs (11%)

0.79

0.66–0.96

NSAIDs (26%)

0.76

0.66–0.88

Meier et al. 61

3,706

14,155_a

Population based

≥30 prescriptions

Automated Database

NSAIDs (8%)

1.0

0.8–1.1

Rosenberg et al. 56

4,485

4,906_a

Hospital based

>3 days/week for >3 months 1.5 years of lag timev

Personal Interview

NSAIDs (6%)

0.8

0.6–1.0

Neugut et al. 62

252

176_a

Hospital based

Chronic aspirin use

Medical Records

Aspirin (9%)

0.80

0.35–1.80

Friedman et al. 20

143,574_b

Cohort

ever use

Medical Records

Aspirin^‡(2%)

0.20

0.05–0.80

NA-NSAIDs^»(3%)

0.50

0.28–0.88

Johnson et al. 58

938

27,616_b

Cohort

>5 times per week

Mailed questionnaire

Aspirin (21%)

0.71

0.58–0.87

NA-NSAID (13%)

1.01

0.83–1.25

Egan et al. 29

2,414

89,528_b

Cohort

>2 tablets/week reported in 4 consecutive questionnaires

Mailed Questionnaire

Aspirin (15%)

1.01

0.80–1.27

NA-NSAIDs (4%)

0.95

0.78–1.17^†

Harris et al. 35

393

32,505_b

Cohort

>4 tablest/week at start date

In-hospital Questionnaire

Aspirin (13%)

0.64

0.45–0.90

NSAIDs (25%)

0.57

0.44–0.74

Paganini-Hill et al. 40

214

8,881_b

Cohort

Daily use of aspirin for an undefined time

Mailed Questionnaire

Aspirin (15%)

1.05^§

0.73–1.50

Thun et al. 46

NR.

344,350_b

Cohort

More than 16 times per month for at least one year

Mailed Questionnaire

Aspirin (11%)

0.88

0.62–1.24

Schreinemachers et al. 43

147

7,489_b

Cohort

Ever use of aspirin in the 30 days prior to start date

Personal Interview

Aspirin (64%)

0.70

0.50–0.96

Prevalence of exposure among controls/cohort; ^§Crude estimate calculated from data provided in the original manuscript; ^†For NA – NSAIDs only the baseline questionnaire was considered; ^‡includes only Fiorinal (aspirin, phenacetin, caffeine and butalbital combination); ^»indomethacin only.

Table 5

Ovary

Author

Cases n

Controls_a/Cohort_b

Source population

Exposure definition

Exposure assessment

Drug

95% CI

Tzonou et al. 47

189

200_a

Hospital based

>2 tablets/week

Personal Interview

NSAIDs (26%)

0.51

0.26–1.02

Cramer et al. 28

563

523_a

Population based

>1 tablet/week for >6 months. 1 year lag time.

Personal Interview

Aspirin^†(14%)

0.75

0.52–1.10

NSAIDs^‡(7%)

0.91

0.53–1.54

Tavani et al. 45

749

898_a

Hospital based

>1 tablet/week for >6 months. (current and/or former)

Personal Interview

Aspirin (6%)

0.93

0.53–1.62

Rosenberg56

448

4,906_a

Hospital based

>3 days/week for >3 months 1.5 years of lag time

Personal Interview

NSAIDs (6%)

0.8

0.5–1.3

Rosenberg et al. 42

780

2,570_a

Hospital based

>4 days/week for at least 6 months.1 year lag time

Personal Interview

Aspirin (5%)

0.8

0.5–1.2

NA-NSAIDs (3%)

0.5

0.3–1.0

NSAIDs (8%)

0.7

0.5–1.0

Moysich et al. 37

547

1,094_a

Hospital based

>1 day/week for 6 consecutive months

In-hospital Questionnaire

Aspirin (12%)

1.00

0.73–1.39

Akhmedkhanov et al. 21

680_a

Population based

Ever use of >3 tablet/week for >6 months. 1 year lag time

Mailed Questionnaire

Aspirin (16%)

0.60

0.26–1.38

Meier et al. 61

483

1,877_a

Population based

≥30 prescriptions. 1 year lag time

Automated Database

NSAIDs (5%)

1.1

0.6–1.8

Fairfield et al. 50

333

76,821_b

Cohort

>1 tablet/week

Mailed

Aspirin (46%)

1.00

0.80–1.25

NSAIDs (N.R.)

0.60

0.38–0.95

Prevalence of exposure among controls/cohort; ^†Over-the-counter only; ^‡Prescription only.

Table 6

Prostate

Author

Cases n

Controls_a/Cohort_b

Source population

Exposure definition

Exposure assessment

Drug

95% CI

Nelson et al. 38

417

420_a

Hospital based

>1 tablet/day in the year prior to admission

Personal Interview

NSAIDs (15%)

0.34

0.20–0.58

Langman et al. 36

1,813

5,354_a

Population based

>7 prescriptions during months 13–36 before index date

Automated Database

NSAIDs (7%)

1.33

1.07–1.64

Norish et al. 39

317

480_a

Population based

>1 tablet/week

Mailed Questionnaire

Aspirin (29%)

0.85

0.61–1.19

NA-NSAIDs (7%)

0.87

0.49–1.55

NSAIDs (36%)

0.88

0.64–1.20

Irani et al. 53

639

659_a

Hospital based

Ever use

In-hospital Questionnaire

NA-NSAIDs (46%)

0.80

0.66–1.07

Neugut et al. 62

319

189_a

Hospital based

Chronic aspirin use

Medical records

Aspirin (7%)

1.60

0.82–3.11

Roberts et al. 41

1,362_b

Cohort

Daily use

Mailed Questionnaire

NSAIDs (42%)

0.37

0.22–0.62

Paganini-Hill et al. 40

149

5,106_b

Cohort

Daily use of aspirin for an undefined time

Mailed Questionnaire

Aspirin (17%)

0.94^§

0.61–1.44

Thun et al. 46^†

N.R.

290,681_b

Cohort

More than 16 times per month for at least one year

Mailed Questionnaire

Aspirin (11%)

0.82

0.56–1.19

Schreinemachers et al. 43

123

5,179_b

Cohort

Ever use of aspirin in the 30 days prior to start date

Personal Interview

Aspirin (51%)

0.95

0.66–1.35

Leitzmann et al. 52

2,479

47,882_b

Cohort

≥2 tablets per week reported in 4 consecutive questionnaires

Mailed Questionnaire

Aspirin (N.R.)

1.04

0.86–1.26

Habel et al. 57

2,574

90,100_b

Cohort

>6 tablets almost ever day

In hospital Questionnaire

Aspirin (2.7%)

0.76

0.60–0.98

Prevalence of exposure among controls/cohort; ^§Crude estimate calculated from data provided in the original manuscript; ^†Genital (includes prostate and testis).

Table 7

Lung

Author

Cases N

Controls_a/Cohort_b

Source Population

Exposure definition

Exposure assessment

Drug

95% CI

Langman et al. 36

2,560

7,643_a

Population based

>7 prescriptions during months 13–36 before index date

Automated Database

NSAIDs (7%)

0.84

0.69–1.02

Harris et al. 51

489

978_a

Hospital based

>7 tablets per week during more than 2 years

Personal Interview

NSAIDs(26%)

0.32

0.23–0.44

Akhmedkhanov et al54

808_a

Population based^‡

>2 tablets per week during at least 6 months. 1 year lag time

Mailed Questionnaire

Aspirin (19%)

0.66

0.34–1.28

Moysich et al. 55

868

935_a

Hospital based

>1 tablet per week for at least 1 year

In hospital Questionnaire

Aspirin (18%)

0.57

0.41–0.78

Rosenberg56

1,110

4,906_a

Hospital based

>3 days/week for >3 months 1.5 years of lag time

Personal Interview

NSAIDs (6%)

1.0

0.7–1.4

Paganini-Hill et al. 40

111

13,987_b

Cohort

Daily use of aspirin for an undefined time

Mailed Questionnaire

Aspirin (16%)

0.92^§

0.54–1.55

Thun et al. 46^†

NR men

290,681_b

Cohort

More than 16 times per month for at least one year

Mailed Questionnaire

Aspirin (11%)

1.11

0.98–1.25

NR women

344,350_b

1.07

0.88–1.30

Schreinemachers et al. 43^†

163

12,668_b

Cohort

Ever use of aspirin in the 30 days prior to start date

Personal Interview

Aspirin (59%)

0.68

0.49–0.94

Prevalence of exposure among controls/cohort; ^†Respiratory (includes others); ^§Crude estimate calculated from data provided in the original manuscript; ^‡Female population.

Table 8

Bladder

Author

Cases N

Controls_a/Cohort_b

Source Population

Exposure definition

Exposure assessment

Drug

95% CI

Castelao et al. 25

1,514

1,514_a

Population based

>2 days/week for >1 month

Personal Interview

Aspirin (12%)^†

0.85

0.66–1.09

NSAIDs (39%)

0.81

0.68–0.96

Langman et al. 36

1,041

3,122_a

Population based

>7 prescriptions during months 13–36 before index date

Automated Database

NSAIDs (7%)

1.14

0.85–1.53

Rosenberg56

1,110

4,906_a

Hospital based

>3 days/week for >3 months 1.5 years of lag time

Personal Interview

NSAIDs (6%)

0.8

0.4–1.6

Paganini-Hill et al. 40

13,987_b

Cohort

Daily use of aspirin for an undefined time

Mailed questionnaire

Aspirin (16%)

1.10^§

0.65–1.85

Schreinemachers et al. 43

12,668_b

Cohort

Ever use of aspirin in the 30 days prior to start date

Personal Interview

Aspirin (59%)

1.06

0.54–2.09

Prevalence of exposure among controls/cohort; ^†Exclusive users of aspirin.

Table 9

Kidney

Author

Cases N

Controls_a/Cohort_b

Source Population

Exposure definition

Exposure assessment

Drug

95% CI

McLaughlin et al. 63

495*

697_a

Population based

More than 14 times per month for >36 months

Personal Inter