Rune Erichsen

Low-Dose Aspirin or Nonsteroidal Anti-inflammatory Drug Use and Colorectal Cancer Risk: A Population-Based, Case–Control Study

Context The relationship between the use of aspirin or nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and colorectal cancer risk may depend on several factors. Contribution This study found that continuous, long-term use (5 years) of low-dose aspirin (75 to 150 mg) and long-term, high-intensity use (0.3 defined daily doses) of nonaspirin NSAIDs were associated with reduced risk for colorectal cancer. Nonaspirin NSAIDs with the highest cyclooxygenase-2 selectivity had the largest risk reductions. Caution There were no data on over-the-counter purchases of aspirin and low-dose ibuprofen. Implication Continuous use of low-dose aspirin for 5 years or longer may be associated with decreased colorectal cancer risk. Colorectal cancer, the third most common nonskin cancer in the world, accounts for an estimated 1.4 million new cases of cancer each year (1). Colorectal neoplasms generally have a long progression, starting as small adenomatous polyps or serrated lesions that may progress to invasive carcinomas (2). These characteristics make colorectal cancer an obvious target for preventive interventions (3, 4). Aspirin is a promising candidate to use for this purpose (57) in addition to its familiar role in the prevention of cardiovascular diseases (8). Several epidemiologic studies have found an inverse association between regular aspirin use and colorectal cancer risk (57). Although there is some heterogeneity in the results across studies (9, 10), most studies have shown that long-term, regular use of aspirin is associated with a substantial reduction in colorectal cancer risk (5, 6, 10). Additional evidence of chemopreventive effects of aspirin has been found in randomized trials of adenoma recurrence and in randomized cardiovascular trials with postintervention long-term follow-up for colorectal cancer (1115). A recent comprehensive analysis (7) concluded that regular aspirin use for at least 5 years at daily doses of 75 to 325 mg had a favorable riskbenefit profile and that longer use would likely yield greater benefits. However, the optimum regimen remains to be determined. Some studies have indicated that aspirin at daily doses of 75 to 100 mg was as effective at reducing colorectal cancer risk as higher doses (7, 9, 12, 1618), but the results were not consistent (1924). Laboratory experiments, clinical trial data, and observational studies have also shown a consistent protective effect of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) on the development of colorectal neoplasia (2529). However, data about the duration and intensity of nonaspirin NSAID use and its relationship to colorectal cancer risk are limited (28, 30). Although findings about the effects of aspirin and nonaspirin NSAID use on colorectal cancer risk are compelling, important issues remain, including the optimum dose and duration of use (5, 7). Observational studies will be needed to address these issues without the stringent selection criteria and the limited dose ranges and duration of treatment that are seen in randomized studies. Therefore, we did a population-based, casecontrol study in Denmark of NSAID use and risk for colorectal cancer using a large collection of high-quality registry data. Methods Setting and Data Sources Our study was designed as a nested casecontrol analysis of population-based registry data from northern Denmark, a region encompassing the former (before 2007) counties of North Jutland, Aarhus, Viborg, and Ringkoebing (1.8 million inhabitants as of 2010) (31). We used data from the Danish Cancer Registry, Aarhus University Prescription Database, Danish National Patient Registry, and Danish Civil Registration System (3135). The Appendix provides a detailed description of these registries with codes for drug exposure and covariates. All data sources were linked by means of the personal identification number assigned to all Danish residents (35, 36). Selection of Case Patients and Control Participants The assembly of the study population is depicted in the Figure . Eligible case patients were persons in northern Denmark with a histologically verified first diagnosis of colorectal cancer from 1994 to 2011 in North Jutland, 2001 to 2011 in Aarhus, or 2003 to 2011 in Viborg and Ringkoebing, ensuring at least 5 years of prescription coverage before possible colorectal cancer diagnosis. Each patient was required to be aged 30 to 85 years at colorectal cancer diagnosis and a resident of 1 of the 4 counties at their entry into the Prescription Database (that is, 1989 in North Jutland, 1996 in Aarhus, and 1998 in Viborg and Ringkoebing). We also required case patients to have no history of cancer (except nonmelanoma skin cancer), inflammatory bowel disease, or familial adenomatous polyposis before the index date (the date of diagnosis). Using risk set sampling (37) and applying the same selection criteria as for case patients, we matched 10 population control participants for each case according to birth year, sex, and area (county/region). The index dates used for control participants were identical to the dates of diagnosis (index dates) of the corresponding case patients. Persons were eligible as control participants before they became case patients. Figure. Study flow diagram. Case patients were selected from the Danish Cancer Registry, and control participants (n= 102800) were selected from the Danish Civil Registration System with the use of risk set sampling and application of the same selection criteria (I, II, IV, and V) that was used for case patients. FAP = familial adenomatous polyposis; IBD = inflammatory bowel disease. * Except nonmelanoma skin cancer. Linkage to Danish Civil Registration System. Linkage to the Aarhus University Prescription Database. Linkage to the Danish National Patient Registry. Assessment of Low-Dose Aspirin and Nonaspirin NSAID Use We identified prescriptions for low-dose aspirin (75, 100, or 150 mg per tablet) and nonaspirin NSAIDs. In Denmark, most (>90%) of the total sales of low-dose aspirin are prescriptions, whereas high-dose aspirin (500 mg tablets) is sold primarily over the counter (38). Of nonaspirin NSAIDs, only low-dose (200 mg) ibuprofen (approximately 15% of total Danish sales of nonaspirin NSAIDs) is available over the counter (38). We defined ever use of low-dose aspirin or nonaspirin NSAIDs as 2 or more prescriptions filled on separate dates and nonuse as fewer than 2 prescriptions. Prescriptions filled within 1 year before the index date were disregarded to avoid reverse causation (37, 39). Ever use was divided into recent use (2 prescriptions overall and 1 prescription during 1 to <3 years before the index date) and former use (no prescriptions during the recent use period). Among participants with recent use of low-dose aspirin, we defined the cumulative duration of use on the basis of the dates of aspirin prescriptions and the number of days covered by the individual prescriptions. We defined the coverage of each prescription as the number of tablets dispensed plus a grace period of up to 30 days, assuming that low-dose aspirin users took 1 tablet daily and allowing for some degree of nonadherence. A treatment period continued as long as consecutive prescriptions were filled within the period covered by the preceding prescription (number of tablets plus grace period). The grace period contributed to the exposure time only until a new prescription, if any, was filled. Continuous use was defined as overlapping treatment periods from the start of treatment until 1 year before the index date. For participants with more than 1 treatment period, durations of separate treatment periods were added. We categorized the cumulative duration of low-dose aspirin use into different strata (1 to <5, 5 to <10, or 10 years, and 5 or 10 years). The daily dose of low-dose aspirin was estimated as the tablet dose prescribed during the exposure period and categorized as 75 to 100 mg, 150 mg, or mixed strength. Duration of nonaspirin NSAID use was defined as the time between the first and last filled prescriptions (until 1 year before the index date) plus the number of tablets for the last prescription and categorized in the same manner as for aspirin. We calculated intensity of nonaspirin NSAID use as the cumulative number of defined daily doses (DDDs) (40) divided by the duration of nonaspirin NSAID use in days. The distribution among control participants was used to define cutoff values for the estimated average dose of nonaspirin NSAID per day (<0.1, 0.1 to <0.3, or 0.3 DDDs) in approximate tertiles. We defined consistent use of nonaspirin NSAIDs as consecutive fillings of at least 2 prescriptions per year. Statistical Analysis We used conditional logistic regression analysis to estimate age-, sex-, and area (county/region)matched and multivariable-adjusted odds ratios (ORs) and 95% CIs for colorectal cancer associated with use of low-dose aspirin or nonaspirin NSAIDs. With the nested casecontrol design and risk set sampling of control participants, the ORs provide unbiased estimates of the corresponding incidence rate ratios in the underlying source population, without distortion by competing risks (41). The multivariable-adjusted models included use of high-dose aspirin, hormone replacement therapy, antidepressants, or statins; history of diabetes mellitus, alcoholism, migraine, or chronic obstructive pulmonary disorder or asthma; history of rheumatic, soft tissue, or connective tissue disease; history of cholecystectomy or colonoscopy; and mutual adjustment for low-dose aspirin or nonaspirin NSAID use (Appendix Table 1). Because rheumatic, soft tissue, and connective tissue diseases are the main indications for long-term use of nonaspirin NSAIDs, history of these diseases was included only in the models for low-dose aspirin. Appendix Table 1. Registry Data Used in the Analyses We estimated adjusted ORs for colorectal cancer among ever-users, recent users, and form

Characteristics and Survival of Interval and Sporadic Colorectal Cancer Patients: A Nationwide Population-Based Cohort Study

OBJECTIVES:Colorectal cancers (CRCs) diagnosed relatively soon after a colonoscopy are referred to as interval CRCs. It is not clear whether interval CRCs arise from prevalent lesions missed at colonoscopy or represent specific aggressive biology leading to poor survival.METHODS:Using Danish population-based medical registries (2000–2009), we investigated patients with “interval” CRC diagnosed within 1–5 years of a colonoscopy, and compared them with cases with colonoscopy ≥10 years before diagnosis and to “sporadic” CRCs with no colonoscopy before diagnosis. Multivariate logistic regression was used to explore the association between clinical, demographic, and comorbidity characteristics and interval CRC. We assessed survival using Kaplan–Meier methods and mortality rate ratios (MRRs) using Cox regression, adjusting for covariates including the Charlson Comorbidity Index (CCI 0, 1–2, 3+).RESULTS:The comparison of the 982 interval CRCs to the 358 patients with CRC ≥10 years after colonoscopy revealed nearly similar characteristics and mortality. In the comparison with the 35,704 sporadic CRCs, interval cases were slightly older (74 vs. 71 years), more likely to be female (54 vs. 48%), have comorbidities (CCI3+: 28 vs. 15%), have proximal tumors (38 vs. 22%), and tumors with mucinous histology (9.1 vs. 7.0%), but stage was similar (metastatic 23 vs. 24%). In logistic regression analysis, female sex, localized stage at diagnosis, proximal tumor location, and high comorbidity burden were factors independently associated with interval CRC. The 1-year survival was 68% (95% confidence interval (CI): 65%, 71%) in interval and 71% (95% CI: 70%, 71%) in sporadic cases, with an adjusted MRR of 0.92 (95% CI 0.82, 1.0). After 5 years, survival was 41% (95% CI: 37%, 44%) in interval and 43% (95% CI: 42%, 43%) in sporadic cases, and the adjusted 2–5 year MRR was 1.0 (95% CI 0.88, 1.2).CONCLUSIONS:Clinical characteristics and survival among interval CRCs did not suggest aggressive biology, but rather that the majority represented missed lesions.

Irritable bowel syndrome and risk of colorectal cancer: a Danish nationwide cohort study.

Background:Little is known about the risk of colorectal cancer among patients with irritable bowel syndrome (IBS).Methods:We conducted a nationwide cohort study using data from the Danish National Registry of Patients and the Danish Cancer Registry from 1977 to 2008. We included patients with a first-time hospital contact for IBS and followed them for colorectal cancer. We estimated the expected number of cancers by applying national rates and we computed standardised incidence ratios (SIRs) by comparing the observed number of colorectal cancers with the expected number. We stratified the SIRs according to age, gender, and time of follow-up.Results:Among 57u2009851 IBS patients, we identified 407 cases of colon cancer during a combined follow-up of 506u2009930 years (SIR, 1.14 (95% confidence interval (CI): 1.03–1.25) and 115 cases of rectal cancer, corresponding to a SIR of 0.67 (95% CI: 0.52–0.85). In the first 3 months after an IBS diagnosis, the SIR was 8.42 (95% CI: 6.48–10.75) for colon cancer and 4.81 (95% CI: 2.85–7.60) for rectal cancer. Thereafter, the SIRs declined and 4–10 years after an IBS diagnosis, the SIRs for both colon and rectal cancer remained below 0.95.Conclusion:We found a decreased risk of colorectal cancer in the period 1–10 years after an IBS diagnosis. However, in the first 3 months after an IBS diagnosis, the risk of colon cancer was more than eight-fold increased and the risk of rectal cancer was five-fold increased. These increased risks are likely to be explained by diagnostic confusion because of overlapping symptomatology.

Does comorbidity interact with colorectal cancer to increase mortality? A nationwide population-based cohort study

Background:It is unknown whether comorbidity interacts with colorectal cancer (CRC) to increase the rate of mortality beyond that explained by the independent effects of CRC and comorbid conditions.Methods:We conducted a cohort study (1995–2010) of all Danish CRC patients (n=56u2009963), and five times as many persons from the general population (n=271u2009670) matched by age, gender, and specific comorbidities. To analyse comorbidity, we used the Charlson Comorbidity Index (CCI) scores. We estimated standardised mortality rates per 1000 person-years, and calculated interaction contrasts as a measure of the excess mortality rate not explained by the independent effects of CRC or comorbidities.Results:Among CRC patients with a CCI score=1, the 0–1 year mortality rate was 415 out of 1000 person-years (95% confidence interval (CI): 401, 430) and the interaction accounted for 9.3% of this rate (interaction contrast=39 out of 1000 person-years, 95% CI: 22, 55). For patients with a CCI score of 4 or more, the interaction accounted for 34% of the mortality (interaction contrast=262 out of 1000 person-years, 95% CI: 215, 310). The interaction between CRC and comorbidities had limited influence on mortality beyond 1 year after diagnosis.Conclusion:Successful treatment of the comorbidity is pivotal and may reduce the mortality attributable to comorbidity itself, and also the mortality attributable to the interaction.

Long-term mortality and recurrence after colorectal cancer surgery with preoperative stenting: A Danish nationwide cohort study

BACKGROUND AND STUDY AIMSnSelf-expanding metal stents (SEMS) used as a bridge to surgery for obstructive colorectal cancer (CRC) have fallen under suspicion for inducing tumor dissemination, and thereby increasing recurrence risk and long-term mortality. The aim of this study was to compare overall mortality and CRC recurrence in patients receiving preoperative SEMS vs. patients undergoing urgent resection.nnnPATIENTS AND METHODSnThis was a Danish, nationwide, population-based cohort study (2005u200a-u200a2010). For patients with CRC who survived the first 30 days after resection, the long-term survival in terms of mortality rate ratios was assessed using Cox regression with adjustment for important covariates. For patients with Dukes Au200a-u200aC disease only, recurrence risk was similarly assessed using incidence rate ratios.nnnRESULTSnThe 5-year survival was 49u200a% among 581 patients with preoperative SEMS and 40u200a% among 3333 patients undergoing urgent resection, corresponding to an adjusted mortality rate ratio of 0.98 (95u200a% confidence interval [CI] 0.90 to 1.07). For patients with Dukes stage Au200a-u200aC disease, the 5-year recurrence risk was 39u200a% among 286 patients after preoperative SEMS and 30u200a% among 1627 patients after urgent resection, corresponding to an adjusted incidence rate ratio of 1.12 (95u200a%CI 0.99 to 1.28).nnnCONCLUSIONSnLong-term mortality associated with the use of SEMS as a bridge to surgery was comparable to that of urgent resection. SEMS use may be associated with an increased CRC recurrence risk.

Positive predictive values of the International Classification of Disease, 10th edition diagnoses codes for diverticular disease in the Danish National Registry of Patients

Objective: To investigate the accuracy of diagnostic coding for diverticular disease in the Danish National Registry of Patients (NRP). Study design and setting: At Aalborg Hospital, Denmark, with a catchment area of 640,000 inhabitants, we identified 100 patients recorded in the NRP with a diagnosis of diverticular disease (International Classification of Disease codes, 10th revision [ICD-10] K572–K579) during the 1999–2008 period. We assessed the positive predictive value (PPV) as a measure of the accuracy of discharge codes for diverticular disease using information from discharge abstracts and outpatient notes as the reference standard. Results: Of the 100 patients coded with diverticular disease, 49 had complicated diverticular disease, whereas 51 had uncomplicated diverticulosis. For the overall diagnosis of diverticular disease (K57), the PPV was 0.98 (95% confidence intervals [CIs]: 0.93, 0.99). For the more detailed subgroups of diagnosis indicating the presence or absence of complications (K573–K579) the PPVs ranged from 0.67 (95% CI: 0.09, 0.99) to 0.92 (95% CI: 0.52, 1.00). The diagnosis codes did not allow accurate identification of uncomplicated disease or any specific complication. However, the combined ICD-10 codes K572, K574, and K578 had a PPV of 0.91 (95% CI: 0.71, 0.99) for any complication. Conclusion: The diagnosis codes in the NRP can be used to identify patients with diverticular disease in general; however, they do not accurately discern patients with uncomplicated diverticulosis or with specific diverticular complications.

Intravenous bisphosphonate therapy and atrial fibrillation/flutter risk in cancer patients: a nationwide cohort study.

Background:There is conflicting evidence regarding bisphosphonates and atrial fibrillation (AF) risk in osteoporosis patients. However, bisphosphonates are used in much higher doses in treatment of bone metastasis and hypercalcemia, but little is known about the AF risk in cancer patients.Methods:We conducted a nationwide population-based cohort study using Danish databases. All cancer patients exposed to intravenous bisphosphonates during 2000–2008 were matched with two non-exposed cancer patients by cancer type, distant metastasis presence at diagnosis, age, and gender. We used Cox proportional hazard regression to estimate hazards ratios (HRs) of AF/flutter adjusting for important confounding factors.Results:Of the 3981 cancer patients exposed to intravenous bisphosponates, 128 (3.2%) developed AF/flutter. This condition occurred in 192 (2.4%) of the 7906 non-exposed cancer patients, corresponding to an adjusted HR of 1.7 (95% CI: 1.2–2.4).Conclusion:Intravenous bisphosphonates may increase AF/flutter risk in cancer patients.

Pancreatic cancer survival in central and northern Denmark from 1998 through 2009: a population-based cohort study

Objectives Pancreatic cancer has a relatively low incidence but ranks fourth among cancer- related deaths in western countries. In Denmark, cancer survival generally is lower than in other countries with comparable health care systems. As a result, in 2000, a national strategy to improve cancer survival was introduced. Here we examine time trends in survival and relative mortality among pancreatic cancer patients, using Danish population and medical databases. Methods Using the Danish National Patient Registry (DNPR), we identified all incident pancreatic cancer patients (n = 2968) diagnosed between 1998 and 2009 in the Central and North Denmark Regions. We computed the 1-, 3-, and 5-year survival and relative mortality (MRR) and associated 95% confidence intervals (CI) adjusting for age and gender. Among surgical patients, we also computed 30-day mortality and 30-day MRR. Results Median age at diagnosis was approximately 71 years. The annual number of patients increased from 189 in 1998–2000 to 302 in 2007–2009. There was a slight improvement in 1-, 3-, and 5-year survival over time from 14.8% to 17.7%; 3.5% to a predicted 5.6%; and from 2.0% to a predicted 3.8%, from 1998–2000 to 2007–2009, respectively. Correspondingly, the adjusted relative mortality decreased from 1998–2000 to 2007–2009. Thirty-day post-operative mortality decreased from 12.2% in 1998–2000 to 5.8% in 2007–2009, corresponding to a 30-day MRR of 0.38, 95% CI = 0.09, 1.6 in 2007–2009. Conclusion There was a slight, albeit modest, improvement in survival and relative mortality in pancreatic cancer patients between 1998 and 2009. As we lacked staging information, it is not clear if this improvement is attributable to earlier stage at diagnosis. However, these improvements likely reflect the national cancer strategy which aimed to centralize cancer services and involved the introduction of palliative and adjuvant chemotherapy for pancreatic cancer in Denmark. The dismal prognosis of pancreatic cancer means that efforts to improve survival need to be intensified.

Clinical and Molecular Characteristics of Post-Colonoscopy Colorectal Cancer: A Population-based Study

BACKGROUND & AIMSnColonoscopy provides incomplete protection from colorectal cancer (CRC), but determinants of post-colonoscopy CRC are not well understood. We compared clinical features and molecular characteristics of CRCs diagnosed at different time intervals after a previous colonoscopy.nnnMETHODSnWe performed a population-based, cross-sectional study of incident CRC cases in Denmark (2007-2011), categorized as post-colonoscopy or detected during diagnostic colonoscopy (in patients with no prior colonoscopy). We compared prevalence of proximal location and DNA mismatch repair deficiency (dMMR) in CRC tumors, relative to time since previous colonoscopy, using logistic regression and cubic splines to assess temporal variation.nnnRESULTSnOf 10,365 incident CRCs, 725 occurred after colonoscopy examinations (7.0%). These were more often located in the proximal colon (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.90-2.89) and were more likely to have dMMR (OR, 1.26; 95% CI, 1.00-1.59), but were less likely to be metastatic at presentation (OR, 0.65; 95% CI, 0.48-0.89) compared with CRCs diagnosed in patients with no prior colonoscopy. The highest proportions of proximal and/or dMMR tumors were observed in CRCs diagnosed 3-6 years after colonoscopy, but these features were still more frequent among cancers diagnosed up to 10 years after colonoscopy. The relative excess of dMMR tumors was most pronounced in distal cancers. In an analysis of 85 cases detected after colonoscopy, we found BRAF mutations in 23% of tumors and that 7% of cases had features of Lynch syndrome. Colonoscopy exams were incomplete in a higher proportion of cases diagnosed within <1 year (in 38%) than in those diagnosed within 1-10 years after colonoscopy (16%).nnnCONCLUSIONSnIn a study of incident CRC cases in Denmark, we observed that tumors found in patients who have undergone colonoscopy are more often proximal and have dMMR compared to CRCs detected in patients without previous colonoscopies. The excess of right-sided tumors andxa0the modest independent effects of dMMR reinforce thexa0importance of proper colonoscopic examination of the proximal large bowel.

Diverticular Disease Is Associated With Increased Risk of Subsequent Arterial and Venous Thromboembolic Events

BACKGROUND & AIMSnDiverticular disease and cardiovascular disease share several risk factors. Inflammation associated with diverticular disease could predispose to cardiovascular disease. We assessed the association between a diagnosis of diverticular disease and subsequent arterial and venous thromboembolic events, adjusting for related comorbidities to explore a possible causal relationship.nnnMETHODSnWe identified 77,065 incident cases of diverticular disease from 1980-2011 from Danish nationwide medical registries; these were matched for age and sex with 302,572 population comparison cohort members. Individuals with a history of cardiovascular disease were excluded. We used Cox proportional hazards regression to compute incidence rate ratios, comparing the incidence of acute myocardial infarction, stroke, venous thromboembolism, and subarachnoid hemorrhage in patients with diverticular disease with those of the population cohort members, adjusting for age, sex, obesity, diabetes, hyperlipidemia, chronic obstructive pulmonary disease, connective tissue disease, renal disease, and treatments and medications.nnnRESULTSnThe adjusted incidence rate ratios for patients with diverticular disease, compared with population cohort members, were 1.11 (95% confidence interval [CI], 1.07-1.14) for acute myocardial infarction, 1.11 (95% CI, 1.08-1.15) for overall stroke, 1.36 (95% CI, 1.30-1.43) for overall venous thromboembolism, and 1.27 (95% CI, 1.09-1.48) for subarachnoid hemorrhage. The relative risk of each event remained increased after we adjusted for changes in aspirin use or for endoscopy or colorectal surgery after the diagnosis of diverticular disease. These findings also held after excluding the first year of follow-up and limiting the analysis to patients with diverticulitis.nnnCONCLUSIONSnOn the basis of an analysis of Danish medical registries, a diagnosis of diverticular disease is associated with a modest increase in risk of arterial and venous thromboembolic events after adjustment for related disorders.