Use of Aspirin or Nonsteroidal Anti-inflammatory Drugs Increases Risk for Diverticulitis and Diverticular Bleeding

  • Lisa L. Strate
    Correspondence
    Reprint requests Address requests for reprints to: Lisa L. Strate, MD, MPH, Harborview Medical Center, 325 Ninth Avenue, Box 359773, Seattle, Washington 98104. fax: (206) 744-8698
    Affiliations
    University of Washington School of Medicine, Seattle, Washington

    Division of Gastroenterology, Department of Medicine, Harborview Medical Center, Seattle, Washington
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  • Yan L. Liu
    Affiliations
    Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
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  • Edward S. Huang
    Affiliations
    Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
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  • Edward L. Giovannucci
    Affiliations
    Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts

    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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  • Andrew T. Chan
    Affiliations
    Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Published:February 14, 2011DOI:https://doi.org/10.1053/j.gastro.2011.02.004

      Background & Aims

      Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have been implicated in diverticular complications. We examined the influence of aspirin and NSAID use on risk of diverticulitis and diverticular bleeding in a large prospective cohort.

      Methods

      We studied 47,210 US men in the Health Professionals Follow-up Study cohort who were 40–75 years old at baseline in 1986. We assessed use of aspirin, nonaspirin NSAIDs, and other risk factors biennially. We identified men with diverticulitis or diverticular bleeding based on responses to biennial and supplementary questionnaires.

      Results

      We documented 939 cases of diverticulitis and 256 cases of diverticular bleeding during a 22-year period of follow-up evaluation. After adjustment for risk factors, men who used aspirin regularly (≥2 times/wk) had a multivariable hazard ratio (HR) of 1.25 (95% confidence interval [CI], 1.05–1.47) for diverticulitis and a HR of 1.70 (95% CI, 1.21–2.39) for diverticular bleeding, compared with nonusers of aspirin and NSAIDs. Use of aspirin at intermediate doses (2–5.9 standard, 325-mg tablets/wk) and frequency (4–6 days/wk) were associated with the highest risk of bleeding (multivariable HR, 2.32; 95% CI, 1.34–4.02, and multivariable HR, 3.13; 95% CI, 1.82–5.38, respectively). Regular users of nonaspirin NSAIDs also had an increased risk of diverticulitis (multivariable HR, 1.72; 95% CI, 1.40–2.11) and diverticular bleeding (multivariable HR, 1.74; 95% CI, 1.15–2.64), compared with men who denied use of these medications.

      Conclusions

      Regular use of aspirin or NSAIDs is associated with an increased risk of diverticulitis and diverticular bleeding. Patients at risk of diverticular complications should carefully consider the potential risks and benefits of using these medications.

      Keywords

      Abbreviations used in this paper:

      CI (confidence interval), COX (cyclooxygenase), HR (hazard ratio), NSAID (nonsteroidal anti-inflammatory drug)
      Podcast interview: www.gastro.org/gastropodcast.
      Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, are a well-known cause of upper gastrointestinal tract complications. These medications also are implicated in lower gastrointestinal injury.
      • Lanas A.
      • Sekar M.C.
      • Hirschowitz B.I.
      Objective evidence of aspirin use in both ulcer and nonulcer upper and lower gastrointestinal bleeding.
      • Lanas A.
      • Serrano P.
      • Bajador E.
      • et al.
      Evidence of aspirin use in both upper and lower gastrointestinal perforation.
      • Langman M.J.
      • Morgan L.
      • Worrall A.
      Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage.
      In randomized trials of patients with rheumatoid or osteoarthritis, 30%–50% of all serious gastrointestinal events associated with NSAIDs were localized to the lower gastrointestinal tract,
      • Chan F.K.
      • Hung L.C.
      • Suen B.Y.
      • et al.
      Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.
      • Laine L.
      • Connors L.G.
      • Reicin A.
      • et al.
      Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use.
      • Laine L.
      • Curtis S.P.
      • Langman M.
      • et al.
      Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac.
      with diverticulitis and diverticular bleeding as the most common etiologies.
      • Laine L.
      • Connors L.G.
      • Reicin A.
      • et al.
      Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use.
      • Laine L.
      • Curtis S.P.
      • Langman M.
      • et al.
      Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac.
      Although a number of case-control studies have shown a significantly higher prevalence of NSAID use among cases with complications of diverticular disease (diverticulitis and bleeding) compared with controls, risk estimates vary widely, with odds ratios ranging from 1.8 to 16.
      • Campbell K.
      • Steele R.J.
      Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a case-control study.
      • Goh H.
      • Bourne R.
      Non-steroidal anti-inflammatory drugs and perforated diverticular disease: a case-control study.
      • Morris C.R.
      • Harvey I.M.
      • Stebbings W.S.
      • et al.
      Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease.
      • Mpofu S.
      • Mpofu C.M.
      • Hutchinson D.
      • et al.
      Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions.
      • Wilson R.G.
      • Smith A.N.
      • Macintyre I.M.
      Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study.
      • Yamada A.
      • Sugimoto T.
      • Kondo S.
      • et al.
      Assessment of the risk factors for colonic diverticular hemorrhage.
      In addition to the inherent biases in selection of controls and ascertainment of medication exposure associated with the case-control study design, these analyses also had limited data regarding medication type (NSAID vs aspirin), dose, timing, and duration of use.
      Thus, to address these limitations, we prospectively examined the influence of aspirin and NSAIDs on risk of diverticular complications in a large cohort of men enrolled in the Health Professionals Follow-up Study, which provided long-term, detailed, and updated information on aspirin and NSAID use. In an earlier study of this cohort, we found that regular NSAID use, but not aspirin use, was associated positively with symptomatic diverticular disease
      • Aldoori W.H.
      • Giovannucci E.L.
      • Rimm E.B.
      • et al.
      Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men.
      ; however, that analysis was limited by the number of overall cases (n = 310), the short follow-up period (4 y), and the inability to evaluate medication dose and frequency or to differentiate diverticulitis or diverticular bleeding from gastrointestinal symptoms that arose in the setting of diverticulosis. In the present study, we offer results that include detailed data on aspirin and NSAID dose and frequency, encompassing 22 years of follow-up evaluation with 939 cases of diverticulitis and 256 cases of diverticular bleeding.

      Materials and Methods

       Study Population

      The Health Professionals Follow-up Study is a prospective cohort of 51,529 male dentists, veterinarians, pharmacists, optometrists, osteopathic physicians, and podiatrists, age 40–75 years at baseline in 1986, who returned a detailed medical and dietary questionnaire. Medical information has been updated biennially and dietary information has been updated every 4 years via self-administered questionnaires.

       Assessment of Diverticulitis and Diverticular Bleeding

      The primary study end points were diverticulitis and diverticular bleeding. Beginning in 1990, men reporting newly diagnosed diverticulosis or diverticulitis on the biennial main study questionnaire were sent supplementary questionnaires to assess the date of diagnosis, procedures performed to confirm the diagnosis, symptoms or tests leading to the detection of diverticular disease, and treatment received. We defined cases of complicated diverticulitis as a report of a fistula, abscess, perforation, or obstruction. We defined cases of uncomplicated diverticulitis as reports of abdominal pain attributed to diverticular disease requiring antibiotics, hospitalization, or surgery; pain categorized as severe or acute; or abdominal pain presenting with fever, requiring medication, or evaluated with computed tomography. Diverticular bleeding was defined as rectal bleeding attributed to diverticulosis that required hospitalization, blood transfusions, intravenous fluids, surgery, angiography, tagged red blood cell scanning, or endoscopic hemostasis. We previously used these case definitions and have reported our methods for validation in detail.
      • Strate L.L.
      • Liu Y.L.
      • Aldoori W.H.
      • et al.
      Physical activity decreases diverticular complications.
      • Strate L.L.
      • Liu Y.L.
      • Aldoori W.H.
      • et al.
      Obesity increases the risks of diverticulitis and diverticular bleeding.
      • Strate L.L.
      • Liu Y.L.
      • Syngal S.
      • et al.
      Nut, corn, and popcorn consumption and the incidence of diverticular disease.
      In addition, beginning in 2006, we updated the supplementary questionnaire to include a checklist of diverticular complications with definitions (diverticular bleeding; uncomplicated diverticulitis; and diverticular abscess, obstruction, perforation, and fistula) in addition to questions regarding diagnosis and treatment. In 2006, among all participants, we also inquired about gastrointestinal bleeding requiring hospitalization or blood transfusion, the location of the bleeding, and the date of onset. In a review of 239 cases, the self-reported date of diagnosis correlated with the medical record (correlation coefficient, 0.87; P < .001), and self-reported location of bleeding (upper vs lower) was correct in 93%. Therefore, patients who reported diverticular disease and gastrointestinal bleeding from the colon requiring hospitalization or blood transfusion in corresponding study periods were classified as having diverticular bleeding, and cases in addition to those documented via the supplementary questionnaire were included.

       Assessment of Medication Use

      We previously detailed our assessment of aspirin and NSAID use.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Aspirin dose and duration of use and risk of colorectal cancer in men.
      Briefly, since 1986, the biennial study questionnaire assessed regular use (defined as ≥2 times/wk) of aspirin (“eg, Anacin, Bufferin, Alka-Seltzer”) and other anti-inflammatory drugs (“eg, Motrin, Indocin, Naprosyn, Dolobid”). In 1992, additional questions were added to assess the average number of aspirin tablets used per week and the frequency of aspirin use. Because of secular trends in the use of baby or low-dose aspirin, beginning in 1994 participants were instructed to convert baby aspirin to standard tablets (4 baby aspirin = 1 tablet). Indications for aspirin use were assessed on a 1993 supplementary questionnaire sent to 221 men who reported aspirin use since 1986. Indications for aspirin use included cardiovascular disease (25.4%), to decrease the risk of cardiovascular disease (58.4%), headaches (25.4%), joint or musculoskeletal pain (33%), and other (7%).
      • Giovannucci E.
      • Rimm E.B.
      • Stampfer M.J.
      • et al.
      Aspirin use and the risk for colorectal cancer and adenoma in male health professionals.
      No participant reported taking aspirin for the relief of abdominal pain.

       Assessment of Other Potential Risk Factors

      We also assessed dietary fiber, fat, red meat, corn, popcorn, and nut intake; physical activity; and obesity as potential confounders.
      • Strate L.L.
      • Liu Y.L.
      • Aldoori W.H.
      • et al.
      Physical activity decreases diverticular complications.
      • Strate L.L.
      • Liu Y.L.
      • Aldoori W.H.
      • et al.
      Obesity increases the risks of diverticulitis and diverticular bleeding.
      • Strate L.L.
      • Liu Y.L.
      • Syngal S.
      • et al.
      Nut, corn, and popcorn consumption and the incidence of diverticular disease.
      • Aldoori W.H.
      • Giovannucci E.L.
      • Rimm E.B.
      • et al.
      A prospective study of diet and the risk of symptomatic diverticular disease in men.
      • Aldoori W.H.
      • Giovannucci E.L.
      • Rockett H.R.
      • et al.
      A prospective study of dietary fiber types and symptomatic diverticular disease in men.
      • Dobbins C.
      • Defontgalland D.
      • Duthie G.
      • et al.
      The relationship of obesity to the complications of diverticular disease.
      • Manousos O.
      • Day N.E.
      • Tzonou A.
      • et al.
      Diet and other factors in the aetiology of diverticulosis: an epidemiological study in Greece.
      • Rosemar A.
      • Angeras U.
      • Rosengren A.
      Body mass index and diverticular disease: a 28-year follow-up study in men.
      Nutritional information was assessed every 4 years using a food-frequency questionnaire. Physical activity was assessed on biennial questionnaires, and expressed in metabolic equivalent hours per week. Body mass index (kg/m2) was calculated from self-reported body weight that was updated biennially, and height, which was reported at baseline in 1986. The validity and reproducibility of the dietary questionnaires, body measurements, and physical activity assessment have been shown previously.
      • Chasan-Taber S.
      • Rimm E.B.
      • Stampfer M.J.
      • et al.
      Reproducibility and validity of a self-administered physical activity questionnaire for male health professionals.
      • Rimm E.B.
      • Giovannucci E.L.
      • Stampfer M.J.
      • et al.
      Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals.
      • Rimm E.B.
      • Stampfer M.J.
      • Colditz G.A.
      • et al.
      Validity of self-reported waist and hip circumferences in men and women.

       Statistical Analysis

      We excluded from the analysis men who reported a diagnosis of diverticulosis, diverticulitis or diverticular bleeding, cancer (except nonmelanoma skin cancer), or inflammatory bowel disease on the baseline questionnaire. In addition, we excluded men who did not return the baseline food-frequency questionnaire or provided implausible dietary data (men with average daily intakes outside the range of 800–4300 kcal). The remaining baseline population included 47,210 men. Men contributed person-time from the date of return of the baseline questionnaire in 1986 to the date of the first diagnosis of diverticular complications, the date of death, or December 31, 2008, whichever came first. Men who reported a new diagnosis of gastrointestinal cancer, diverticulosis, diverticulitis, diverticular bleeding, or inflammatory bowel disease were censored at the date of diagnosis.
      We examined the association between regular use of aspirin and NSAIDs and the incidence of diverticulitis and diverticular bleeding using simple updating (the medication use reported on the questionnaire immediately preceding the follow-up interval of interest). Consistent with prior analyses, regular use was defined as 2 or more times per week, and nonregular use was defined as less than 2 times per week.
      • Chan A.T.
      • Giovannucci E.L.
      • Meyerhardt J.A.
      • et al.
      Aspirin dose and duration of use and risk of colorectal cancer in men.
      • Giovannucci E.
      • Rimm E.B.
      • Stampfer M.J.
      • et al.
      Aspirin use and the risk for colorectal cancer and adenoma in male health professionals.
      For this analysis, regular users of aspirin only, NSAIDs only, and both aspirin and NSAIDs were compared separately with nonusers of both aspirin and NSAIDs. Frequency of aspirin use also was evaluated according to the average number of days aspirin was used per week in categories. In addition, we assessed the relationship between aspirin dose and the risk of diverticular complications. Dose was estimated and categorized according to the number of standard dose (325 mg) tablets used per week. We evaluated the cumulative updated dose to account for variation in dose over the study period using time-varying covariates. In this analysis, each participant contributed person-time according to data they provided on each biennial questionnaire. Last, we examined the risk of diverticular complications according to the duration of aspirin and NSAID use. Duration was calculated in years of regular use beginning in 1986 with updating every 2 years and accounting for interruptions in use.
      We divided the number of new cases of diverticulitis and diverticular bleeding by the number of person-years in each use category to calculate incidence rates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for each end point using a Cox proportional hazards model. Men in each category of use were compared with men in the reference category (nonregular users).
      • Cox D.R.
      Regression models and life tables.
      Age-adjusted models were stratified by age in 1-year intervals and study period in 2-year intervals. Multivariable models adjusted for age and study period as well as body mass index (6 categories); dietary intake (quintiles) of fat; fiber, red meat, nut, corn, and popcorn consumption; total caloric intake; and physical activity (quintiles). We used the most recent information available for each covariate. We excluded NSAID users from the analyses of aspirin use, and aspirin users from the analyses of NSAID use to better isolate the effect of each drug individually. We assessed statistical interaction of aspirin and NSAID use by including cross-product terms in our models and assessing their significance using the Wald test.
      All analyses were performed using SAS software, version 9.1.3 (SAS Institute Inc, Cary, NC). Tests for linear trend were performed by treating the median value of each of the measurement categories as a continuous variable.
      • Ascherio A.
      • Rimm E.B.
      • Hernan M.A.
      • et al.
      Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States.
      All tests were 2-sided and a P value of less than .05 was considered statistically significant. Return of the self-administered study questionnaire was regarded as informed consent. The institutional review boards of the Harvard School of Public Health approved the study protocol.

      Results

      During 859,164 person-years of follow-up evaluation, we documented 939 incident cases of diverticulitis, and 256 incident cases of diverticular bleeding. Baseline characteristics of the cohort are summarized in Table 1 according to regular use of aspirin and NSAIDs and standardized for age. Approximately 29% of participants reported regular aspirin use (≥2 times/wk) and 5% reported regular NSAID use. On average, regular users of aspirin were more likely to have a history of coronary heart disease than nonusers, and users of aspirin and NSAIDs were more likely to have osteoarthritis and to consume more alcohol than nonusers.
      Table 1Baseline Characteristics of the Study Cohort in 1986 According to Regular Use of Aspirin and NSAIDs
      AspirinNSAIDs
      Nonregular users (n = 33,336)Regular users (n = 13,874)Nonregular users (n = 44,633)Regular users (n = 2577)
      Age, mean (SD), y53 (9.7)56 (9.7)54 (9.7)55 (9.9)
      Body mass index, mean (SD), kg/m224.9 (5.0)25.1 (5.2)24.9 (5.0)25.5 (5.6)
      Physical activity, mean (SD), MET, h/wk21 (29.5)21 (28.8)21 (29.3)21 (29.5)
      Coronary heart disease, %41266
      Osteoarthritis, %711736
      Current smoking, %9101010
      Dietary intake, mean (SD)
       Calories, kcal/day1973 (617)2018 (623)1984 (619)2017 (623)
       Fiber, g/day21 (7.0)21 (7.0)21 (7.1)21 (6.7)
       Fat, g/day72 (14.0)71 (14.1)71 (14.1)72 (13.7)
       Red meat, servings/day4.3 (3.2)4.3 (3.1)4.3 (3.2)4.5 (3.2)
       Alcohol, g/day, mean11 (15.0)13 (16.3)11 (15.4)13 (16.7)
      Current NSAID use, %57
      Current aspirin use, %2939
      NOTE. All variables except for age are age-standardized. Regular use was defined as at least 2 times per week. Nonregular use was defined as less than 2 times per week.
      MET, metabolic equivalent.
      After controlling for other potential risk factors for diverticular complications, we observed a significantly higher risk of diverticulitis among regular users of NSAIDs (multivariable HR, 1.72; 95% CI, 1.40–2.11), and to a lesser degree among regular users of aspirin (multivariable HR, 1.25; 95% CI, 1.05–1.47) when compared with men who denied use of either drug (Table 2). In analyses according to subtypes of diverticulitis, we observed that regular NSAID use appeared to be associated more strongly with risk of complicated diverticulitis (multivariable HR, 2.55; 95% CI, 1.32–4.95) than uncomplicated diverticulitis (multivariable HR, 1.65; 95% CI, 1.32–2.05) compared with nonuse of either NSAIDs or aspirin. For both subtypes, we found comparable risk estimates for regular aspirin use, with a multivariable HR of 1.13 (95% CI, 0.61–2.10) for complicated diverticulitis and 1.24 (95% CI, 1.04–1.47) for uncomplicated diverticulitis.
      Table 2Aspirin and NSAID Use and Risk of Diverticulitis and Diverticular Bleeding
      Nonusers of aspirin and NSAIDsRegular use of aspirin onlyRegular use of NSAIDs onlyRegular use of aspirin and NSAIDs
      Person-years367,223273,23396,726120,609
      Diverticulitis
       Incident cases288313148190
       Age-adjusted HR (95% CI)
      Age-adjusted HRs adjusted for age (in years) and study period in 2-year intervals.
      1.01.32 (1.12–1.55)1.87 (1.52–2.29)1.85 (1.53–2.42)
       Multivariate HR (95% CI)
      Multivariate HR adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      1.01.25 (1.05–1.47)1.72 (1.40–2.11)1.65 (1.36–2.01)
      Diverticular bleeding
       Incident cases58934065
       Age-adjusted HR (95% CI)
      Age-adjusted HRs adjusted for age (in years) and study period in 2-year intervals.
      1.01.90 (1.36–2.65)1.92 (1.27–2.91)2.45 (1.69–3.53)
       Multivariate HR (95% CI)
      Multivariate HR adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      1.01.70 (1.21–2.39)1.74 (1.15–2.64)2.02 (1.38–2.96)
      NOTE. Regular use was defined as at least 2 times per week. Nonregular use was defined as less than 2 times per week.
      a Age-adjusted HRs adjusted for age (in years) and study period in 2-year intervals.
      b Multivariate HR adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      For diverticular bleeding, the associations of regular use of NSAIDs and aspirin were similar (multivariable HR, 1.74; 95% CI, 1.15–2.64; and multivariable HR, 1.70; 95% CI, 1.21–2.39, respectively). Combined use of aspirin and NSAIDs was associated with a multivariable HR for diverticulitis of 1.65 (95% CI, 1.36–2.01) and for bleeding of 2.02 (95% CI, 1.38–2.96). A formal test of whether the concurrent use of aspirin and NSAIDs was associated with a greater risk than use of each drug alone was not statistically significant for diverticulitis (P = .06) or for bleeding (P = .145).
      The association between aspirin use and diverticular complications did not display a linear dose-relationship in the multivariable analyses excluding NSAID users (P = .28 for trend for diverticulitis and P = .10 for trend for diverticular bleeding) (Table 3). However, we observed that men who took intermediate doses of aspirin (2–5.9 standard [325-mg] tablets/wk) had the highest risk of diverticular bleeding (multivariable HR, 2.32; 95% CI, 1.34–4.02) when compared with men who reported no aspirin use.
      Table 3Dose of Aspirin and Risk of Diverticulitis and Diverticular Bleeding
      Tablets/wk, 325 mg
      None0.1–1.92–5.9≥6P for trend
      Person-years127,213107,53598,50547,467
      Diverticulitis
       Incident cases12411012858
       Age-adjusted HR (95% CI)
      Age-adjusted HRs adjusted for age (in years) and study period in 2-year intervals.
      1.01.09 (0.83–1.41)1.35 (1.05–1.73)1.21 (0.88–1.66).09
       Multivariate HR (95% CI)
      Multivariate HRs adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      1.01.02 (0.78–1.33)1.26 (0.97–1.62)1.11 (0.81–1.52).28
      Diverticular bleeding
       Incident cases19344716
       Age-adjusted HR (95% CI)
      Age-adjusted HRs adjusted for age (in years) and study period in 2-year intervals.
      1.01.81 (1.02–3.21)2.75 (1.60–4.71)2.02 (1.04–3.95).02
       Multivariate HR (95% CI)
      Multivariate HRs adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      1.01.58 (0.88–2.82)2.32 (1.34–4.02)1.65 (0.84–3.26).10
      NOTE. Analyses limited to non-NSAID users. Regular use was defined as at least 2 times per week. Nonregular use was defined as less than 2 times per week. Dose was analyzed using cumulative updating.
      a Age-adjusted HRs adjusted for age (in years) and study period in 2-year intervals.
      b Multivariate HRs adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      To better assess the effect of consistency of use on the risk of diverticular complications, we also examined frequency of regular aspirin use in non-NSAID users (Table 4). Compared with nonregular users, men who used aspirin daily had a significantly higher risk of diverticulitis (multivariable HR, 1.46; 95% CI, 1.13–1.88; P = .002 for trend). Similar to the findings for aspirin dose, we found that moderately frequent use of aspirin was associated strongly with the risk of diverticular bleeding. Men who reported aspirin use 4–6 days per week had a multivariable HR of 3.13 (95% CI, 1.82–5.38) when compared with men who denied aspirin use.
      Table 4Frequency of Aspirin Use and Risk of Diverticulitis and Diverticular Bleeding
      Days per week
      None<22–3.94–6DailyP for trend
      Person-years220,30350,67421,78740,15371,418
      Diverticulitis
       Incident cases194502454102
       Age-adjusted HR (95% CI)
      Age-adjusted HRs adjusted for age in 1-year intervals and study period in 2-year intervals.
      1.00.94 (0.68–1.31)1.05 (0.69–1.61)1.30 (0.94–1.78)1.52 (1.18–1.95)<.001
       Multivariate HR (95% CI)
      Multivariate HRs adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      1.00.88 (0.64–1.23)0.99 (0.65–1.53)1.24 (0.90–1.71)1.46 (1.13–1.88).002
      Diverticular bleeding
       Incident cases43952436
       Age-adjusted HR (95% CI)
      Age-adjusted HRs adjusted for age in 1-year intervals and study period in 2-year intervals.
      1.01.20 (0.57–2.55)1.35 (0.53–3.46)3.49 (2.05–5.96)1.87 (1.19–2.95)<.001
       Multivariate HR (95% CI)
      Multivariate HRs adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      1.01.08 (0.51–2.30)1.21 (0.47–3.11)3.13 (1.82–5.38)1.57 (0.98–2.51).003
      NOTE. Analyses limited to non-NSAID users. Regular use was defined as at least 2 times per week. Nonregular use was defined as less than 2 times per week.
      a Age-adjusted HRs adjusted for age in 1-year intervals and study period in 2-year intervals.
      b Multivariate HRs adjusted for age; study period; body mass index; dietary fat, fiber, red meat, nut, corn, and total caloric intake; and physical activity.
      In addition, we found that increasing duration of regular aspirin and NSAID use was associated with greater risk of diverticular complications among nonusers of NSAIDs and aspirin, respectively. Ten years or more of aspirin use was associated with a multivariable HR of 1.51 (95% CI, 1.13–2.03; P = .01 for trend) for diverticulitis, and 2.53 (95% CI, 1.43-4.46; P = .003 for trend) for bleeding compared with nonregular use. Likewise, after 10 years of NSAID use the HR of diverticulitis was 1.80 (95% CI, 1.30–2.51; P < .001 for trend), and of diverticular bleeding was 2.17 (95% CI, 1.23–2.85; P = .006 for trend).
      To address the possibility of confounding by comorbid illness, we additionally adjusted our analyses for cardiovascular disease and osteoarthritis, the 2 most common indications for aspirin use in this cohort. In this analysis, the relationships between aspirin and NSAID use and diverticulitis remained largely unchanged (multivariable HR, 1.20; 95% CI, 1.01–1.42 for aspirin; multivariable HR, 1.64; 95% CI, 1.33–2.02 for NSAIDs). For diverticular bleeding, the association with aspirin use was not materially altered (multivariable HR, 1.66; 95% CI, 1.18–2.33), but the association with NSAIDs was somewhat attenuated (multivariable HR, 1.42; 95% CI, 0.92–2.18).

      Discussion

      In this large prospective study of men, we observed that regular use of aspirin or NSAIDs was associated with an increased risk of diverticulitis and diverticular bleeding. The magnitude of the increased risk of bleeding was similar for regular aspirin and NSAID users. The highest risk of diverticular bleeding was observed in men who used aspirin with moderately high frequency (4–6 days/wk) and in moderately high doses (2–5.9 standard [325-mg] tablets/wk). For diverticulitis, the risk appeared somewhat greater for regular NSAID users than for regular aspirin users, and the risk increased with frequency of aspirin use but not with higher doses.
      Several previous case-control studies and one prospective cohort study have observed similar associations between aspirin and/or NSAID use and diverticular complications.
      • Campbell K.
      • Steele R.J.
      Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a case-control study.
      • Goh H.
      • Bourne R.
      Non-steroidal anti-inflammatory drugs and perforated diverticular disease: a case-control study.
      • Morris C.R.
      • Harvey I.M.
      • Stebbings W.S.
      • et al.
      Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease.
      • Mpofu S.
      • Mpofu C.M.
      • Hutchinson D.
      • et al.
      Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions.
      • Wilson R.G.
      • Smith A.N.
      • Macintyre I.M.
      Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study.
      • Yamada A.
      • Sugimoto T.
      • Kondo S.
      • et al.
      Assessment of the risk factors for colonic diverticular hemorrhage.
      • Aldoori W.H.
      • Giovannucci E.L.
      • Rimm E.B.
      • et al.
      Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men.
      Our study expanded on these findings in several notable ways. First, we distinguished diverticulitis from diverticular bleeding and studied a spectrum of complications. In contrast, aside from one small study of diverticular bleeding,
      • Yamada A.
      • Sugimoto T.
      • Kondo S.
      • et al.
      Assessment of the risk factors for colonic diverticular hemorrhage.
      prior studies have focused on perforated diverticulitis,
      • Goh H.
      • Bourne R.
      Non-steroidal anti-inflammatory drugs and perforated diverticular disease: a case-control study.
      • Morris C.R.
      • Harvey I.M.
      • Stebbings W.S.
      • et al.
      Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease.
      • Mpofu S.
      • Mpofu C.M.
      • Hutchinson D.
      • et al.
      Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions.
      a severe manifestation, or combined diverticulitis and diverticular bleeding.
      • Campbell K.
      • Steele R.J.
      Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a case-control study.
      • Wilson R.G.
      • Smith A.N.
      • Macintyre I.M.
      Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study.
      • Aldoori W.H.
      • Giovannucci E.L.
      • Rimm E.B.
      • et al.
      Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men.
      This differentiation is important because diverticulitis and diverticular bleeding likely have distinct biologic mechanisms, and it is not known whether aspirin or NSAIDs serve to initiate or promulgate complications. Second, we were able to examine separately the effects of aspirin and NSAID use, whereas most prior studies used a combined exposure measure.
      • Campbell K.
      • Steele R.J.
      Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a case-control study.
      • Goh H.
      • Bourne R.
      Non-steroidal anti-inflammatory drugs and perforated diverticular disease: a case-control study.
      • Mpofu S.
      • Mpofu C.M.
      • Hutchinson D.
      • et al.
      Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions.
      • Wilson R.G.
      • Smith A.N.
      • Macintyre I.M.
      Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study.
      Third, we collected detailed data on aspirin use during 22 years of prospective follow-up evaluation, which enabled us to disentangle the specific effects of dose, frequency, duration, and timing of medication use in relation to diverticular complications. Last, we were able to adjust for many important known potential confounders of diverticular complications including diet, body mass index, and physical activity.
      There are several potential mechanisms by which aspirin and NSAIDs may promote diverticular complications. NSAIDs, including aspirin, are thought to damage the colon via direct topical injury and/or impaired prostaglandin synthesis, which compromise mucosal integrity, increase permeability, and enable the influx of bacteria and other toxins.
      • Lanas A.
      • Sopena F.
      Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications.
      Diverticulitis is defined by the presence of microperforation or macroperforation leading to abscess formation, and is believed to be the result of an impaired mucosal barrier and increased intracolonic pressure.
      • Morris C.R.
      • Harvey I.M.
      • Stebbings W.S.
      • et al.
      Epidemiology of perforated colonic diverticular disease.
      Diverticular bleeding occurs when a nutrient artery ruptures into the colon lumen, and commonly involves local mucosal ulceration in the absence of inflammation.
      • Foutch P.G.
      Diverticular bleeding: are nonsteroidal anti-inflammatory drugs risk factors for hemorrhage and can colonoscopy predict outcome for patients?.
      • Meyers M.A.
      • Alonso D.R.
      • Baer J.W.
      Pathogenesis of massively bleeding colonic diverticulosis: new observations.
      In addition, NSAIDs, including aspirin, likely promote blood loss from existing lesions via inhibition of platelet aggregation.
      Our results indicate that NSAID use is associated more strongly with diverticulitis than aspirin use. In fact, the HR of combined NSAID and aspirin use was similar to the risk of NSAID use alone. This result is supported by several other studies in which aspirin and NSAID use were evaluated independently. In an earlier analysis of the Health Professionals Follow-up cohort, NSAID use was associated significantly with symptomatic diverticular disease whereas aspirin use was not.
      • Aldoori W.H.
      • Giovannucci E.L.
      • Rimm E.B.
      • et al.
      Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men.
      In a case-control study, Morris et al
      • Morris C.R.
      • Harvey I.M.
      • Stebbings W.S.
      • et al.
      Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease.
      found that NSAID use, but not aspirin use, was associated with perforated diverticulitis. We also found a stronger association between NSAIDs and complicated diverticulitis. Although the association with NSAIDs remained significant when excluding individuals with complicated disease, the study questionnaires did not explicitly denote complications before 2006, and it is possible that the observed associations are largely owing to complicated diverticulitis. The greater effect of NSAIDs vs aspirin in diverticulitis may be owing in part to the fact that low-dose aspirin is absorbed primarily in the stomach and duodenum, limiting topical injury to the colon.
      • Lanas A.
      • Sopena F.
      Nonsteroidal anti-inflammatory drugs and lower gastrointestinal complications.
      We found that men in the moderately high-dose and frequency categories of aspirin use were at a somewhat higher risk of diverticular bleeding than men in the highest categories. The antiplatelet effects of aspirin may account for these findings. At low and moderate doses of aspirin the predominant effect is on the cyclooxygenase (COX)-1 isoenzyme leading to thromboxane A2–mediated platelet inhibition.
      • Patrono C.
      • Garcia Rodriguez L.A.
      • Landolfi R.
      • et al.
      Low-dose aspirin for the prevention of atherothrombosis.
      However, at higher doses aspirin preferentially may inhibit the COX-2 isoenzyme, which promotes thrombosis and vasoconstriction rather than bleeding.
      • Patrono C.
      • Garcia Rodriguez L.A.
      • Landolfi R.
      • et al.
      Low-dose aspirin for the prevention of atherothrombosis.
      Indeed, several studies have suggested that higher aspirin doses are associated with somewhat greater risk of thrombotic cardiovascular events.
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.
      • Taylor D.W.
      • Barnett H.J.
      • Haynes R.B.
      • et al.
      Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial ASA and Carotid Endarterectomy (ACE) Trial Collaborators.
      • Chan A.T.
      • Manson J.E.
      • Albert C.M.
      • et al.
      Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events.
      Our study had several limitations. Diverticular complications and medication use were self-reported. However, study participants were well-educated health care professionals who likely accurately report their diagnoses and medication use. Moreover, we confirmed self-reported outcomes via chart review in a subset of individuals and self-reported aspirin and NSAID use in this cohort previously have been associated with several disease outcomes that have been validated separately.
      • Strate L.L.
      • Liu Y.L.
      • Syngal S.
      • et al.
      Nut, corn, and popcorn consumption and the incidence of diverticular disease.
      • Rimm E.B.
      • Stampfer M.J.
      • Colditz G.A.
      • et al.
      Validity of self-reported waist and hip circumferences in men and women.
      Any misclassification bias is likely to be nondifferential, resulting in an underestimate of any true association between NSAID and aspirin use and diverticular complications. Given the observational nature of our study, we cannot exclude the possibility of residual confounding. Nonetheless, controlling for purported risk factors for diverticular complications including diet and lifestyle did not appreciably alter our results. In addition, our results are consistent with previous investigations and have clear biologic plausibility. We were unable to examine the impact of NSAID dose and frequency or COX-2 selective inhibitor use because of the limited follow-up evaluation (NSAID dose and duration were assessed since 2000 and COX-2 selective use was assessed since 2004). Finally, our study cohort consisted of male health professionals, which may limit the generalizability of our results to other populations. However, we would not expect the association of aspirin with bleeding to differ by occupation.
      In conclusion, we observed significantly increased risks of diverticulitis and diverticular bleeding among users of aspirin and NSAIDs. These findings have important clinical and public health implications given the prevalence of diverticular disease and NSAID use particularly in the elderly.
      • Shaheen N.J.
      • Hansen R.A.
      • Morgan D.R.
      • et al.
      The burden of gastrointestinal and liver diseases, 2006.
      • Talley N.J.
      • Evans J.M.
      • Fleming K.C.
      • et al.
      Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly.
      Analgesia should be selected carefully in individuals with diverticulosis, especially those with prior complications. Future studies are needed to better identify individuals at risk of diverticular complications, and to develop strategies to mitigate the lower gastrointestinal toxicity of NSAIDs.

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