All 3 cohort studies combined yielded 508,842 individuals (262,680 men and 246,162 women). A total of 3,582,284 person-years were accrued, during which 2,489 incident cases of bladder cancer were identified.
The baseline median age (NIH-AARP: 63.5 years; PLCO: 62.5 years) and prevalence of regular aspirin use (NIH-AARP: 34.8%; PLCO: 34.5%) and nonaspirin NSAID use (NIH-AARP: 16.3%; PLCO: 15.2%) were comparable among PLCO and NIH-AARP participants (). The prevalence of regular aspirin use among USRT participants was lower (aspirin: 11.2%) compared with the other cohorts, although the prevalence of regular use in USRT for the same age range as PLCO and NIH-AARP (55–75 years) was similar (data not shown).
Characteristics of the Cohort Studies Included in the Multicohort Analysis of Aspirin and Nonaspirin NSAID Use and Risk of Bladder Cancer Among Men and Women, NIH-AARP, PLCO, USRT
Regular aspirin users were more likely to be older, be male, be white, and have a higher body mass index than individuals who reported no use of aspirin (). Former smokers were more likely to be regular aspirin users compared with never and current smokers. Regular nonaspirin NSAID users were more likely to be female, be white, and have a higher body mass index than individuals who reported no use of nonaspirin NSAIDs.
Selected Characteristics of Participants by Aspirin and Nonaspirin NSAID Use in a Pooled Analysis, NIH-AARP, PLCO, USRT
A reduction in risk was observed for regular use of nonaspirin NSAIDs in the fixed-effects meta-analysis (hazard ratio (HR) = 0.90, 95% confidence interval (CI): 0.80, 1.02; P = 0.10) (). No significant heterogeneity was observed between the study-specific hazard ratios for nonaspirin NSAID use overall (χ2 = 1.41, Pheterogeneity = 0.50) or when stratified by age (≤75 years: χ2 = 2.16, Pheterogeneity = 0.34; >75 years: χ2 = 2.57, Pheterogeneity = 0.28). When we stratified by age 75 years, a significant inverse association was observed for regular nonaspirin NSAID users compared with nonusers in the age ≤75 years group (HR = 0.87, 95% CI: 0.77, 0.99), but no association was observed in the age >75 years group (HR = 1.13, 95% CI: 0.80, 1.59; Pinteraction = 0.21) (). Results from the aggregated analysis were similar to those from the meta-analysis (). We observed no significant trend in risk with increasing frequency of nonaspirin NSAID use (P = 0.30). The protective association between regular nonaspirin NSAID use and bladder cancer was stronger for women (HR = 0.78, 95% CI: 0.59, 1.03) than for men (HR = 0.96, 95% CI: 0.84, 1.10), although this difference was not significant (Pinteraction = 0.14) (). Adjustment for history of cardiovascular disease as a proxy for low-dose aspirin use had no impact on our results.
Bladder Cancer Risk and Use of Nonaspirin NSAIDs Stratified by Age 75 Years in a Pooled Analysis, NIH-AARP, PLCO, USRT
Bladder Cancer Risk and Use of Nonaspirin NSAIDs or Aspirin Among Men and Women in a Pooled Analysis, NIH-AARP, PLCO, USRT
No association was observed between aspirin use and risk of bladder cancer in the fixed-effects meta-analytic model (HR = 1.04, 95% CI: 0.94, 1.14) or the aggregate data (HR = 1.04, 95% CI: 0.94, 1.15) (). In addition, no significant differences were found by gender or smoking status.
Since smoking is an important risk factor for bladder cancer and constituents of tobacco smoke increase cyclooxygenase-2 expression (31
), we stratified our pooled data by smoking status. A significant 40% reduction in risk of bladder cancer was found for nonsmokers who reported regular use of nonaspirin NSAIDs (HR = 0.58, 95% CI: 0.41, 0.83; Ptrend
= 0.008); no association was observed for former smokers (HR = 0.98, 95% CI: 0.85, 1.14) or current smokers (HR = 0.98, 95% CI: 0.74, 1.29) (Pinteraction
= 0.02) (). Similar inverse associations for nonsmokers were found for regular nonaspirin NSAID users by gender (HR for males = 0.58, 95% CI: 0.38, 0.89; HR for females = 0.61, 95% CI: 0.33, 1.15). Former smokers were further stratified by recency of quitting smoking. No reduction in risk was observed for individuals who reported regular use of nonaspirin NSAIDs and quit smoking more than 10 years ago (HR = 0.96, 95% CI: 0.80, 1.15) or quit in the last 10 years (HR = 1.01, 95% CI: 0.78, 1.32).
Bladder Cancer Risk and Use of Nonaspirin NSAIDs or Aspirin Among Men and Women by Smoking Status in a Pooled Analysis, NIH-AARP, PLCO, USRT
Because use of aspirin and nonaspirin NSAIDs was positively correlated in our data set (ρ = 0.028), we compared those individuals who exclusively reported use of nonaspirin NSAIDs with those who had not used either aspirin or nonaspirin NSAIDs. No significant association was observed for exclusive users (HR = 0.98, 95% CI: 0.79, 1.21), but power was low because of the smaller number of cases who were exclusive users (n = 106). Exclusive regular aspirin users had a higher risk (HR = 1.12, 95% CI: 0.99, 1.27), but there was no association for users of both aspirin and nonaspirin NSAIDs (HR = 1.03, 95% CI: 0.91, 1.16).
The magnitude of the association between regular nonaspirin NSAID use and bladder cancer did not change when we excluded the first year of follow-up (HR = 0.91, 95% CI: 0.80, 1.04), although, for the second year of follow-up, it was closer to the null (HR = 0.96, 95% CI: 0.84, 1.11) compared with the nonlagged analysis (HR = 0.92, 95% CI: 0.81, 1.04). The null associations between regular aspirin use and risk of bladder cancer were unaffected by the lagged time analysis (data not shown).
When we restricted the analysis to urothelial carcinoma, we observed associations similar to the overall findings (HR = 0.92, 95% CI: 0.81, 1.04). Although no association between regular use of nonaspirin NSAIDs and low-grade in situ tumors was observed (HR = 1.03, 95% CI: 0.73, 1.45), suggestive inverse associations were observed with intermediate (HR = 0.83, 95% CI: 0.68, 1.01) and high-grade (HR = 0.92, 95% CI: 0.75, 1.13) bladder cancers.