Statin use does not prevent recurrent adenomatous polyp formation in a VA population

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1 Indian J Gastroenterol (2010) 29: DOI /s ORIGINAL ARTICLE Statin use does not prevent recurrent adenomatous polyp formation in a VA population Nikki Parker-Ray & Jehad Barakat & Praveen K. Roy & Robert E. White & Ronald M. Schrader & Richard M. Hoffman Received: 9 September 2009 /Accepted: 25 May 2010 /Published online: 25 July 2010 # Indian Society of Gastroenterology 2010 Abstract Purpose To evaluate whether statin use was associated with recurrent adenomatous polyps. Methods We conducted a retrospective cohort study. We used electronic health records to evaluate veterans who underwent polypectomy between January 1, 1999 and December 31, 2001 and surveillance colonoscopy by December We obtained data on pathology, demographics, body mass index, comorbidity, habits, family history, and medications. We used multivariate proportional hazards regression models to analyze data. Results We evaluated 197 eligible patients from among 821 who underwent colonoscopy during this period; their mean (SD) age was 63.1 (8.8) years, 192 (98%) were men, and 80 (41%) non-hispanic white. Surveillance colonoscopy was performed after a mean (SD) 1207 (452) days and 108 (55%) patients had recurrent adenomas. During follow-up, N. Parker-Ray Southwest Gastroenterology, J. Barakat : R. M. Schrader : R. M. Hoffman University of New Mexico School of Medicine, J. Barakat : R. M. Hoffman (*) New Mexico VA Health Care System, Mailstop 111, 1501 San Pedro Drive SE, Albuquerque, NM 87108, USA rhoffman@unm.edu P. K. Roy Albuquerque Health Partners, R. E. White Lovelace Clinic Foundation, 88 (47%) of patients received statins, but use was not protective against recurrent adenomas (hazard ratio=1.36, 95% CI ). Only number of polyps at initial colonoscopy predicted recurrent adenomas (1.98, 95% CI ). Conclusions The use of statins was not protective against the recurrence of adenomatous polyps. Keywords Antineoplastic agents. Colorectal neoplasms. Hydroxymethylglutaryl-CoA. Reductase inhibitors. Retrospective study Introduction Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer in the United States and the second leading cause of death following lung cancer with approximately 56,600 deaths per year [1]. Primary chemoprevention has been evaluated as a strategy for reducing the burden of colorectal cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin, possibly by inducing apoptosis and inhibiting cyclooxygenase, reduce the occurrence of adenomatous polyps in patients with hereditary polyposis syndromes, previous adenomatous polyps, and colorectal cancer [2, 3]. Studies of human cancer cell lines and animal tumor models suggest that hydroxy-3-methylglutaryl (HMG) Co A reductase inhibitors (statins) may also be chemoprotective against colorectal cancer [4 7]. Results from the clinical literature, though, have been mixed. Secondary analyses of randomized controlled trials targeting cardiovascular endpoints or recurrent adenomatous polyp formation did not show reduced risk of all-site cancers [8] orof recurrent polyps [9]. However, a recent meta-analysis of

2 Indian J Gastroenterol (2010) 29: statins and colorectal cancer incidence involving 18 studies and 1.5 million patients found no effect in randomized controlled trials or cohort studies, but a modest incidence reduction in case-control studies [10]. These studies had important potential methodological limitations, including recall and selection biases in the case-control studies, lack of systematic efforts to detect prevalent and incident cancers in the cardiovascular trials, limited characterization of statin use in the recurrent polyp prevention trials, and a failure to adjust for colorectal cancer screening in most of the cohort studies. The cardiovascular studies did not systematically evaluate for prevalent or incident colorectal cancers and the average study duration was relatively short. The studies evaluating recurrence of polyps did not characterize statin use in detail [9]. To overcome some of these limitations, we used the Department of Veterans Affairs (VA) electronic health record, which provides extensive pharmacy, procedure and pathology data, to characterize statin use in a cohort of veterans who had undergone an index colonoscopy and polypectomy, and a surveillance colonoscopy. The objective of our study was to evaluate the association between statin use and the surrogate endpoint of recurrent adenomatous polyps. Methods We conducted a retrospective cohort study. We extracted procedure and pathology files from the VA Computerized Patient Record System (CPRS) to identify patients who underwent colonoscopy with removal of adenomatous polyps at the Albuquerque VA Medical Center during the calendar years 1999 through The study cohort was comprised of patients who were followed in the primary care clinic and subsequently underwent a surveillance colonoscopy at least 1 year after the index procedure, and before December 31, We extracted CPRS pharmacy files to obtain data on the type of statin (lovastatin, simvastatin, atorvastatin were the only statin medications prescribed at the Albuquerque VA), dose, pills dispensed, and date of prescription fills; we counted the number of pills of each type of statin at each dose for each patient beginning with the date of the initial colonoscopy exam through the time of the surveillance colonoscopy. We recorded the total number of days of statin prescription for each subject during the study period. We also documented prescriptions for other medications that may affect polyp formation, including hormone replacement therapy, calcium, folate, aspirin, and other NSAIDs. We conducted a medical record review with a standardized abstraction form to collect data from CPRS on the index and surveillance colonoscopy procedures (date, number of polyps removed, histopathology, and whether the colon was cleared of polyps), demographics (age, gender), body mass index (BMI), habits (current tobacco and/or alcohol use), medical history including cardiovascular disease, diabetes, inflammatory bowel disease, and previous adenomatous polyps, and family history of colorectal cancer. We re-abstracted medical records from a randomly selected 10% sample of subjects for quality control. We excluded patients with a history of a previous colorectal cancer and those who were found to have a colorectal cancer, and those who could not be cleared of polyps on the index colonoscopy. The local institutional review board study approved the study protocol in April 2006 with waiver of the need for informed consent because this was a database study. Statistical analysis We used descriptive statistics to describe baseline and follow-up characteristics. We used the Kolmogorov- Smirnov statistic to determine whether variables were normally distributed and used non-parametric statistics when appropriate. In order to model statin use, we determined the total number of each type and strength of statin pills that was dispensed between the index and surveillance colonoscopy. We converted statin doses to a lovastatin dose equivalent based on atorvastatin and simvastatin being two- and four-fold stronger than lovastatin, respectively [11]. We calculated the cumulative grams of statin prescribed by multiplying the daily doses (in lovastatin equivalents) by the number of pills dispensed. We used multivariate models to evaluate the association between statin use and recurrent polyps. Analyses were adjusted for age at the index colonoscopy; gender, race/ ethnicity; BMI; current smoking and alcohol at the time of the index colonoscopy; hormone replacement therapy, folate, calcium, ASA, or other NSAID use during the interval between colonoscopies; comorbidities; family history of colorectal cancer; statin use at baseline; previous adenomatous polyps; and the number of adenomatous polyps removed at the index colonoscopy. We used a multivariate proportional hazards model to determine whether statin use, based on the cumulative lovastatin dose equivalent, predicted recurrence of any polyps. We used the log of the cumulative statin dose in milligrams (if the dose was >0) and the square root of the number of polyps removed at the index colonoscopy because the distribution of these variables was skewed. The time variable was days between first and second colonoscopy. Lack of adenomatous polyps at the second colonoscopy was treated as a censored value. Time until development of additional adenomatous polyps was modeled as a function of statin use.

3 108 Indian J Gastroenterol (2010) 29: We also used multivariate Poisson regression to determine whether statin use predicted the number of recurrent polyps. We entered the log of statin dose equivalent and the square root of the number of adenomatous polyps at first screening to account for distributional problems. Statistical analyses were performed with SAS using proc PHREG and with Stata using the poisson command, respectively. P- values less than 0.05 were considered significant for all multivariate analyses. Results The initial cohort was comprised of 821 patients who had an index colonoscopy with removal of adenomatous polyps. Subsequently, 240 of these patients underwent an additional endoscopy during the study period. Nearly all of the patients who did not undergo a surveillance endoscopy had disenrolled from VA care, while the rest failed to keep appointments, underwent colonoscopy after the study period, or died. We also excluded 43 of those undergoing additional colonoscopy from further analyses because they were not eligible for the study, including 19 with colorectal cancer with the index procedure, 22 who did not undergo a complete index and surveillance colonoscopy, and 2 who were not enrolled in primary care clinics. Table 1 shows the baseline characteristics of the 197 eligible subjects; most were middle-aged, overweight men who were either of non- Hispanic white or Hispanic ethnicity. Approximately 20% of the subjects had a family history of colorectal cancer, 33% were diabetic, and 42% had a history of previous polypectomy. At the time of the index colonoscopy, 28% were using statins and 32% were using aspirin. The median (interquartile range) for the number of polyps was 2 (1 4). The mean (SD) in days between colonoscopies was 1208 (452) (Table 2); 108 (55%) subjects had at least one adenomatous polyp removed on the second colonoscopy and one had an adenocarcinoma. The median (interquartile range) number of polyps removed was 2 (0 3). Nearly half of the subjects received at least one statin prescription and 45% received aspirin during the interval between their two exams. Among statin users, the mean (SD) number of days of statin use was 809 (516) with a mean (SD) dose in grams of 35.3 (39.6) grams. We found no association between either the use of statins or the log of the cumulative statin dose and the recurrence of adenomatous polyps on bivariate proportional hazards analyses (hazard ratio [95% CI] for statin use=1.36 [ ] and for statin dose=1.04 [ ]) or on multivariate proportional hazards analyses (Table 3). The only predictor on multivariate analysis was the square root of the number of adenomatous polyps found at the index colonoscopy (hazard ratio 1.98 [95% CI ]). We Table 1 Baseline characteristics (n=197) Variable Demographics Age (years) (mean [SD]) 63.1 (8.8) Sex: male 192 (97.5) Race/ethnicity Non-Hispanic white 80 (45.0) Hispanic 67 (34.0) African American 5 (2.5) Other/Unknown 45 (22.8) Clinical Body mass index (kg/m 2 ) (mean [SD]) 28.9 (5.4) Smoker (current) 66 (33.5) Alcohol (current) 83 (42.1) Diabetes 65 (33.0) Inflammatory bowel disease 3 (1.5) Cardiovascular disease 71 (36.0) Family history of colorectal cancer 39 (19.8) Previous polypectomy 82 (41.6) Number of adenomatous polyps removed at index 2(1 4) colonoscopy (median, interquartile range) Medications Statins 56 (28.4) Aspirin 63 (32.0) Other non-steroidal anti-inflammatory drugs 82 (41.6) Calcium 4 (2.0) Folate 6 (3.0) Hormone replacement therapy 3 (1.5) Data are as n (%); except when reporting mean (SD) or median (interquartile range) found no association between statin use (vs. no use) during the follow-up period and recurrence of adenomatous polyps when restricting analyses to 127 subjects without previous adenomas (before the index colonoscopy) (33/56 [59%] vs. 35/71 [49%], P=0.28), the 141 subjects who were not on statins at baseline (20/37 [54%] vs. 55/104 [53%], P=0.95), and the 163 subjects with at least a 2-year interval between procedures, respectively (44/74 [59%] vs. 48/89 [51%], P=0.26). On multivariate Poisson regression analysis, the log of cumulative statin use was not associated with the number of adenomatous polyps detected at follow-up colonoscopy (coefficient 0.07, standard error 0.06, P=0.20). The square root of the number of adenomatous polyps found on index colonoscopy was a significant predictor (coefficient 0.53, standard error 0.12, P=<0.001) of the number of adenomatous polyps detected at follow-up colonoscopy. Increasing age at index colonoscopy (P<0.001) and higher BMI (P=0.005) were also associated with the number of polyps detected at follow-up colonoscopy, while diabetes (P=0.01)

4 Indian J Gastroenterol (2010) 29: Table 2 Cohort follow-up Data are as n (%); except when mean (SD) or median (interquartile range) are reported Variable Interval between colonoscopies in days (mean [SD]) 1208 (452) Adenomatous polyps at 2nd colonoscopy 108 (55) Number of adenomatous polyps (median [interquartile range]) 1 (0 2) Interval statin use 88 (47) Cumulative statin days among users (mean [SD]) 809 (516) Cumulative grams of statins among users (median [interquartile range]) 35.3 (39.6) Interval aspirin use 89 (45.2) Interval other NSAID use 107 (54.3) Interval calcium use 15 (7.6) Interval folate use 11 (5.6) Interval hormone replacement therapy 3 (1.5) and non-hispanic white race (P<0.02) were inversely associated. Discussion We found that statin use did not decrease the risk for or number of adenomatous polyps in a cohort of male veterans undergoing surveillance colonoscopy. The only factor associated with adenoma recurrence was the number of polyps that were found on the index colonoscopy. Factors positively associated with the number of polyps detected at follow-up colonoscopy included the number of polyps found at the index colonoscopy, age, and BMI, while diabetes and non-hispanic white race were inversely associated. Wei and colleagues found no association between statin use and any recurrence of colorectal adenomas (risk ratio= 1.03, 95% CI ) in a secondary analysis of data from 3 large randomized colorectal adenoma chemoprevention trials evaluating antioxidants, calcium, and aspirin [9]. Statin use was also not associated with advanced neoplasia (polyp >1 cm) or multiple adenomas. However, exposure was defined only according to self-reported statin use on follow-up questionnaires. Meta-analyses of randomized statin trials targeting cardiovascular endpoints have found no protective effect against colorectal cancer [8, 10]. However, the cardiovas- Table 3 Multivariate model of factors associated with recurrent polyps ASA aspirin, NSAID nonsteroidal anti-inflammatory drugs, HRT hormone replacement therapy Variable Hazard ratio (95% CI) P-value Statin use 1.24 ( ) 0.84 Log cumulative statin use (mgs) 0.90 ( ) 0.68 Statin use at baseline 1.37 ( ) 0.33 Age at time of first colonoscopy 1.02 ( ) 0.28 Gender (male vs. female) (0.00 ) 0.99 Race (non-hispanic white vs. other) 1.04 ( ) 0.87 Body mass index (kg/m 2 ) 1.00 ( ) 0.91 Smoker during follow up 1.48 ( ) 0.09 Alcohol use during follow up 1.21 ( ) 0.76 Diabetes 0.88 ( ) 0.60 Inflammatory bowel disease 1.70 ( ) 0.61 Cardiovascular disease 0.87 ( ) 0.61 Family history of colorectal cancer 1.06 ( ) 0.83 History of previous polypectomy 1.44 ( ) 0.12 Number of polyps removed at initial colonoscopy 1.98 ( ) ASA or NSAID use during follow-up 0.87 ( ) 0.53 Calcium use during follow-up 1.12 ( ) 0.76 HRT during follow-up 1.27 (0.00 ) 1.00 Folate use during follow-up 1.08 ( ) 0.86

5 110 Indian J Gastroenterol (2010) 29: cular trials did not systematically identify either prevalent or incident colorectal cancers. This could confound the temporal association between statin exposure and cancer incidence and underestimate cancer incidence. Furthermore, the average study duration was just under 4 years an important potential limitation because the malignant transformation of adenomatous polyps is estimated to occur over approximately 10 to 15 years [12]. A number of cohort studies found no association between statin use and colorectal cancer [13 15]. However, these studies did not adjust for colorectal cancer screening, an important potential confounder. In contrast, Farwell and colleagues found a significant protective effect for statin users against colorectal cancer, adjusted hazard ratio of 0.65 (95% CI ) [16]. Statin users were compared against patients using antihypertensive medications but no cholesterol-lowering medications and analyses were adjusted for numerous demographic and clinical factors, including age, weight, comorbidities, habits, and diagnostic testing with sigmoidoscopy or colonoscopy. Investigators also found a dose-response relationship, with an hazard ratio of 0.59 (95% CI ) for the highest statin dose. We found that increasing age is associated with the number of recurrent adenomatous polyps, consistent with epidemiologic data showing age to be a risk for colorectal cancer [17]. Non-Hispanic race and diabetes were inversely associated with the number of recurrent polyps. Although the race/ethnicity was unknown for 22% of the subjects, the finding is consistent with recent data from the New Mexico Tumor Registry showing colorectal cancer incidence increasing in Hispanic men and decreasing in non-hispanic white men [18]. Our findings contrast with literature identifying diabetes as a risk factor for colorectal cancer [19] and metabolic syndrome as a risk for adenomatous polyps [20]; however, we did find that high body mass index, another risk factor particularly for men was associated with recurrent polyps [21]. Our study had a number of limitations. Although the hazard ratio for recurrent polyps associated with statin use actually exceeded 1, the sample size was small and the confidence intervals large. However, it seems unlikely that we would have missed an effect size comparable to the 50% cancer risk reduction reported in the case-control study from Israel [22]. We were unable to extract data on diet or exercise, which are both associated with colorectal cancer [23]. Although we collected data on family history of colorectal cancer, this information was not consistently ascertained or recorded in the medical record. We may have underestimated the true prevalence of family history, though this is unlikely to confound the association between statin use and colorectal cancer. We also likely underestimated ASA, NSAID, calcium, and folate use; VA-dispensed prescriptions for these medications are well documented, but we could not reliably obtain data on the use of over-thecounter medications. However, by using the electronic medical record we obtained comprehensive and accurate data on statin prescriptions. We also had comprehensive and accurate data on the recurrence of adenomatous polyps; however, this is only a surrogate endpoint. Farwell and colleagues found that statin use was associated with a lower risk for colorectal cancer [16]. Possibly, the role of statins might be in inhibiting the progression of adenomatous polyps to carcinoma. Finally, our study population was comprised largely of older male veterans with a substantial prevalence of cardiovascular disease and diabetes; results may not be generalizable to women, younger patients, or those receiving statins for primary prevention. We found that statin use was not associated with a decreased recurrence of adenomatous polyps among a population of older veterans. Our findings are consistent with results from most observational studies and with the secondary analyses of randomized trials. A phase II trial evaluating the efficacy of statins for preventing adenomatous polyp formation in high-risk patients is underway [24]. Currently, however, there is no convincing evidence to support prescribing statins for the chemoprevention of colorectal neoplasia. Acknowledgments This work was supported by the Medicine Service, Albuquerque VA Medical Center. Conflicts of Interest References None of the authors have any conflicts to declare. 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin. 2008;58: Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA. 2005;294: Chan AT, Giovannucci EL, Schernhammer ES, et al. A prospective study of aspirin use and the risk for colorectal adenoma. Ann Intern Med. 2004;140: Agarwal B, Rao CV, Bhendwal S, et al. Lovastatin augments sulindacinduced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. Gastroenterology. 1999;117: Buchwald H. Cholesterol inhibition, cancer, and chemotherapy. Lancet. 1992;339: Narisawa T, Morotomi M, Fukaura Y, Hasebe M, Ito M, Aizawa R. Chemoprevention by pravastatin, a 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor, of N-methyl-N-nitrosoureainduced colon carcinogenesis in F344 rats. Jpn J Cancer Res. 1996;87: Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002;16: Dale KM, Coleman CI, Henyan NN, Kluger J, White CM. Statins and cancer risk: a meta-analysis. JAMA. 2006;295:74 80.

6 Indian J Gastroenterol (2010) 29: Wei JT, Mott LA, Baron JA, Sandler RS. Reported use of 3- hydroxy-3-methylglutaryl coenzyme A reductase inhibitors was not associated with reduced recurrence of colorectal adenomas. Cancer Epidemiol Biomarkers Prev. 2005;14: Bonovas S, Filioussi K, Flordellis CS, Sitaras NM. Statins and the risk of colorectal cancer: a meta-analysis of 18 studies involving more than 1.5 million patients. J Clin Oncol. 2007;25: Wenig TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010;35: Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology. 1997;112: Friis S, Poulsen AH, Johnsen SP, et al. Cancer risk among statin users: a population-based cohort study. Int J Cancer. 2005;114: Setoguchi S, Glynn RJ, Avorn J, Mogun H, Schneeweiss S. Statins and the risk of lung, breast, and colorectal cancer in the elderly. Circulation. 2007;115: Jacobs EJ, Rodriguez C, Brady KA, Connell CJ, Thun MJ, Calle EE. Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort. J Natl Cancer Inst. 2006;98: Farwell WR, Scranton RE, Lawler EV, et al. The association between statins and cancer incidence in a veterans population. J Natl Cancer Inst. 2008;100: Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, National Cancer Institute, Hoffman RM, Stone SN, Viera RL, New Mexico Cancer Facts and Figures. New Mexico Department of Health, 2007 [monograph online]. Available from URL: cancercouncil/facts_figures.htm [Accessed May 22, 2010]. 19. Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97: Kim JH, Lim YJ, Kim YH, et al. Is metabolic syndrome a risk factor for colorectal adenoma? Cancer Epidemiol Biomarkers Prev. 2007;16: Giovannucci E, Michaud D. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas. Gastroenterology. 2007;132: Poynter JN, Gruber SB, Higgins PD, et al. Statins and the risk of colorectal cancer. N Engl J Med. 2005;352: World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective, 2007 [monograph online]. Available from URL: [accessed March 17, 2009]. 24. Zielinski SL. Following positive epidemiologic studies, statins to enter clinical trials for cancer prevention. J Natl Cancer Inst. 2005;97: