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Purpose: Comorbid disease in patients with renal cancer may affect renal cancer prognosis. We estimated the risk of 1 and 5-year mortality in patients with renal cancer in northern Denmark by comorbidity status. Materials and Methods: We performed a cohort study tracking mortality in all patients with an incident diagnosis of renal cancer between 1995 and 2006 in a population of 1.6 million residents in northern Denmark. Using hospital discharge data before cancer diagnosis we calculated Charlson comorbidity index scores (0, 1–2 or 3+) in patients with renal cancer as well as absolute survival and relative mortality estimates according to comorbidity level. Results: We identified 2,315 patients with renal cancer, of whom 950 (41%) had comorbidity. The prevalence of comorbidity tended to increase during the study period with the rate in patients with a score of 3+ increasing from 9% to 13%. The 5-year relative mortality rate was lower in patients with a positive Charlson index score with mortality almost twice as high in those with a score of 3+ and 1.2-fold higher in those with a score of 1–2 compared to mortality in those with no comorbidity. Generally similar patterns were observed for 1-year relative mortality. Conclusions: Comorbidity is common in patients with renal cancer and it is a negative prognostic factor. [Copyright &y& Elsevier]

Aims It is well-known that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of upper gastrointestinal bleeding (UGIB), but characteristics of the association and quantification of excess risk at the population level require clarification. Methods All users of nonaspirin prescription NSAIDs in North Jutland County, Denmark during 1991–95 were identified in the regional Pharmaco-Epidemiologic Database. Using the Hospital Discharge Register, all hospitalizations for UGIBs were identified among the 156 138 users of NSAIDs and compared with the number of expected based on the North Jutland population who did not receive NSAID prescriptions. Results During periods of NSAID use without use of other drugs associated with UGIB, we observed 365 UGIBs, a number 3.6 times higher than expected (95% CI = 3.3, 4.0). The excess risk varied by sex, type of NSAID and form and route of administration of the NSAID, but not by age at first NSAID prescription or number of prior prescriptions. Risk declined sharply following cessation of use. For ibuprofen and naproxen, there was a clear trend in rising risk by increasing dose, although the lowest doses were also associated with an excess of UGIB. Concurrent use of corticosteroids, anticoagulants and aspirin further increased the risk of UGIB. Conclusions All types and formulations of NSAIDs appear to increase the risk of UGIBs, but the effect appear not to be cumulative and diminish rapidly with discontinue of use. Up to 15% of the UGIBs in the entire population of the North Jutland County may be explained by use of this drug. [ABSTRACT FROM AUTHOR]

Examines the occurrence of connective tissue diseases (CTDs) as well as ill-defined and other rheumatic conditions among Danish women with cosmetic silicone breast implants. Association between silicone breast implants and definite CTD; Cause of unspecified rheumatism among women with breast implants; Influence of a potential link between silicone breast implants and CTD on hospitalization for rheumatic conditions among Danish women with breast implants.

Objective: We examined overall and cause-specific mortality in a population-based cohort of individuals prescribed paracetamol. We evaluated rates of death due to liver and renal disease, cancer, and other major causes of death.Method: Using the population-based pharmacoepidemiology prescription database of North Jutland County, Denmark, we identified nearly 50,000 persons receiving prescriptions for paracetamol from 1989 to 1995 and evaluated mortality through 1996. Standardized mortality ratios (SMRs) for 18 specific causes of death were computed for persons prescribed paracetamol compared with persons among the general population of the county.Results: SMRs were elevated regardless of cause of death, with a nearly doubled overall death rate among persons prescribed paracetamol. The mortality ratios were highest within 1 year of paracetamol prescription and tended to decline with increasing follow-up, especially for cancers. The magnitudes of the excess mortality risks for liver and renal diseases were not materially higher than for other causes of death.Conclusion: Paracetamol is a first-line analgesic for patients with a wide variety of chronic or serious illnesses and therefore is associated with increased rates of nearly all causes of death. The findings are an example of confounding by indication. Paracetamol may be a drug most prone to this form of bias in pharmacoepidemiologic studies. Future observational studies reporting adverse effects of paracetamol must thoroughly evaluate confounding by indication before making causal inferences. [Copyright &y& Elsevier]

Objective: The optimal duration and dose of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) in the potential prevention of colorectal cancer (CRC) have not been established. We examined this issue in the Danish Diet, Cancer, and Health Study., Methods: Self-reported NSAID use at entry (January 1995-May 1997) was updated through June 2006, using a nationwide prescription database. CRC incidence was ascertained from nationwide registers. Cox proportional hazards regression was used to compute confounder-adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs)., Results: From 51,053 cohort subjects, we identified 615 CRC cases during 1995-2006. Daily aspirin use at entry was associated with a decreased risk of CRC (RR, 0.73; 95% CI, 0.49-1.10). A similar risk reduction was seen among subjects with 10 or more prescriptions for aspirin or non-aspirin NSAIDs and five or more years of follow-up. Most aspirin prescriptions were for 75-150 mg aspirin tablets. Among non-aspirin NSAID users, only those with body mass index (BMI) above 25 showed risk reductions [RR, 0.69 (0.47-1.03) for 10 or more prescriptions]., Conclusions: Long-term consistent use of aspirin or non-aspirin NSAIDs appears necessary to achieve a protective effect against CRC. Further studies of the effective dose of aspirin and the potential interaction between NSAID use and BMI are warranted.

Epidemiologic studies investigating the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer have yielded conflicting results. We examined the association between use of aspirin and nonaspirin NSAIDs and breast cancer risk among 28 695 women in the Danish Diet, Cancer and Health cohort. Information on NSAID and paracetamol use was obtained from a self-administered questionnaire completed at baseline (1993-1997) and updated through 2003 using a nationwide prescription database. Detailed information on breast cancer incidence and tumour characteristics was obtained from nationwide health registers. Cox proportional hazards regression was used to compute incidence rate ratios (RRs) and 95% confidence intervals (CIs). We identified 847 breast cancer cases over an average follow-up period of 7.5 years. Any NSAID use at baseline was associated with an increased incidence of breast cancer compared with nonuse (RR, 1.27; 95% CI, 1.10-1.45). A similar result was observed for any NSAID use in a combined analysis of baseline and prescription data (1.34; 95% CI, 1.15-1.56). Aspirin-only users experienced a slightly higher breast cancer incidence (RR, 1.38; 95% CI, 1.12-1.69) than exclusive users of nonaspirin NSAIDs (RR, 1.25; 95% CI, 1.04-1.49). Introduction of a lag time of 1 year provided similar results. We found no clear differences in risk estimates with frequency, recency or duration of NSAID use, or by hormone receptor status of the breast tumours. Paracetamol use was unrelated to breast cancer incidence. The increased breast cancer incidence among NSAID users may reflect a noncausal association, but our study provides no evidence of a chemopreventive effect of NSAIDs against breast cancer over the durations studied.

Epidemiologic evidence is conflicting regarding the potential for nonsteroidal antiinflammatory drugs (NSAIDs) to lower the risk of lung cancer. We thus determined the incidence of lung cancer among a cohort of over 242,000 adults in Denmark who had been issued NSAID prescriptions during 1991-2002 and calculated the relative risks of this cancer according to the numbers of prescriptions received. Similar analyses were conducted among a subset with chronic obstructive pulmonary disease, of whom the large majority was assumed to have been smokers, as an indirect control for smoking. Utilization of Danish registries ensured essentially complete and unbiased ascertainment of prescriptions and cancer outcomes. The relative risks of lung cancer among NSAID users redeeming 10 or more prescriptions vs. nonusers in the general population and among chronic obstructive pulmonary disease patients were 1.51 (95% CI = 1.33-1.71) and 1.55 (95% CI = 0.93-2.60) and tended to decline with decreasing numbers of NSAIDs prescribed. Separate analyses for adenocarcinoma and squamous cell carcinoma also failed to show reduced risks among NSAID users. Confounding by indication may have contributed to the increased risks, but the study provides no evidence to suggest that recent NSAID intake may be protective for lung cancer., (Copyright 2005 Wiley-Liss, Inc)

Objective: We sought to evaluate rates of hospitalizations for neurodegenerative disorders in a cohort of Danish metal manufacturing employees., Methods: A retrospective cohort study was conducted from 1977 to 2002 among 27,839 male Danish metal-manufacturing employees, with 9,817 of those employed in departments engaged in mild or stainless-steel welding and 6,163 welders., Results: The standardized hospitalization ratio and 95% confidence intervals (CI) for Parkinson's disease were 0.9 (CI = 0.7-1.2) for men in steel-manufacturing companies, 1.0 (CI = 0.7-1.5) for men in welding departments, and 0.9 (CI = 0.4-1.5) for welders. Observed numbers for other neurological conditions were small and not above population expectations. Analyses for time period worked, age, and duration of welding were unremarkable., Conclusions: This relatively large cohort study with long-term follow-up provides no support for the hypothesis that rates of hospitalization for Parkinson's disease or other neurological conditions are elevated under the exposure circumstances of these Danish workers.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of upper gastrointestinal bleeding (UGIB). Whether the severity of outcome of UGIB associated with NSAIDs differs from non-NSAID-related UGIB is less clear., Method: Medical records of 228 patients hospitalized for UGIB in the Danish county of North Jutland were evaluated. Preadmission characteristics and clinical outcomes were compared between 112 patients who had been prescribed ibuprofen and 116 patients who had been prescribed paracetamol within 90 days of the hospitalization., Results: The baseline characteristics of UGIB patients prescribed ibuprofen tended to differ from those prescribed paracetamol. The ibuprofen group significantly less often had histories of ulcer (11% vs 36%) and dyspepsia (19% vs 44%), or had been prescribed medications for these or other conditions, and had lower co-morbidity indices. Ibuprofen users also were somewhat less likely (31% vs 37%) to report GI pain at admission, but among hospitalized patients with endoscopic examinations were more likely (75% vs 58%) to be diagnosed with ulcer or hematemesis vs normal or gastritis/dyspepsia/reflux. For the clinical outcomes, 30 days case fatality rates were 12% for both ibuprofen and paracetamol users. The ibuprofen-related cases of UGIB more often required surgery (11% vs 3%) or transfusions (66% vs 57%), and those prescribed ibuprofen averaged 11 days in hospital, 4 days longer than those prescribed paracetamol. Adjustment for baseline characteristics and underlying conditions, or analyses eliminating patients with unconfirmed diagnoses and prior ulcers or restricted to patients with current hospital diagnoses of ulcer or hematemesis, did not materially alter the ibuprofen vs paracetamol differences in outcome measures. Generally similar results were obtained when restricting the analyses to patients prescribed ibuprofen or paracetamol within 30 days of UGIB hospitalization, except for a reduction in the 30 days case fatality rate among those prescribed ibuprofen., Conclusions: UGIB patients with antecedent ibuprofen prescriptions experienced about the same case fatality rates, but more surgery and longer hospital stays, than patients prescribed paracetamol. The differences appear in part due to differing characteristics among those prescribed ibuprofen compared with those prescribed paracetamol, but also raise the possibility of drug-related effects.

Using the population-based Pharmacoepidemiologic Prescription Database of North Jutland County, Denmark, we identified 113,538 persons who filled prescriptions for ibuprofen during 1989 through 1995 and determined subsequent mortality through 1996. Standardized mortality ratios [SMRs] for 25 specific causes of death were computed compared with the general population. SMRs were elevated for most causes of death, with an overall SMR of 1.21 (95% confidence interval 1.19-1.24) among persons who filled prescriptions for ibuprofen. There was a nearly threefold increase in the number of deaths from gastrointestinal bleeding within 1 year of ibuprofen prescription but no concomitant increase in hemorrhagic stroke. Elevated SMRs were seen for several cancer types, although the mortality ratios were highest within 1 year of prescription and declined with longer follow-up. For colon cancer, SMRs were below 1.0 three or more years after ibuprofen prescription. For hypertensive disease, nonhemorrhagic stroke, and diabetes, we observed slight but significant elevations of the SMRs that persisted beyond the fifth year of follow-up. Our findings indicate a slight increase in overall mortality among persons receiving ibuprofen on prescription. This excess was greatest within the first year, due partially to ibuprofen-related gastrointestinal bleeding but mostly to elevated cancer mortality among ibuprofen users. This temporal pattern is characteristic of an effect of confounding by indication, with ibuprofen being used for pain relief by patients with imminent fatal illnesses such as cancer. The slight excess mortality that persisted beyond the first few years was largely due to elevated death from hypertensive disease and diabetes, which may be explained in part by increased prescription of ibuprofen to patients with long-standing medical problems.

Background and Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs) have effects on hemostasis and have been associated with an increased risk of bleeding. However, data relating the use of nonaspirin NSAIDs and risk of intracerebral hemorrhage (ICH) are sparse., Methods: Using data from the County Hospital Patient Register and the Civil Registration System of North Jutland County, Denmark, we identified 912 cases of first-time ICH and 9059 sex- and age-matched population-based controls in the period of 1991 to 1999. All prescriptions for nonaspirin NSAIDs before the date of admission for ICH were identified through a population-based prescription database. Conditional logistic regression was used to adjust for potential confounding factors, including previous discharge diagnoses of hypertension, chronic bronchitis and emphysema, alcoholism, liver cirrhosis, diabetes mellitus, and prescriptions for insulin or oral hypoglycemic agents, antihypertensive agents, lipid-lowering agents, low-dose aspirin, high-dose aspirin, and oral anticoagulants., Results: No overall association was found between prescription for nonaspirin NSAIDs in the preceding 30, 60, or 90 days and risk of ICH; ie, odds ratios ranged from 0.92 (95% CI, 0.70 to 1.21) to 1.13 (95% CI, 0.81 to 1.58). Furthermore, there was no increased risk of ICH associated with prescription for nonaspirin NSAIDs when the study population was stratified by age, sex, and a previous discharge diagnosis of hypertension., Conclusions: Patients prescribed nonaspirin NSAIDs were not at an overall increased risk of being hospitalized for ICH. This reassuring finding was seen in all examined subgroups, including the elderly and patients with a previous discharge diagnosis of hypertension.

To assess whether maternal breast implants are related to adverse health outcomes in offspring, the authors conducted a retrospective cohort study of esophageal disorders, rheumatic disease, and congenital malformations among 2,854 children born to women with breast implants and among 5,805 children born to a comparison group of women who underwent breast reduction or other plastic surgery. Rates were calculated using both hospitalization and outpatient data. Significantly higher rates of esophageal disorders were observed (O) than were expected (E) for children born before (O/E, 2.0; 95% CI, 1.3-2.8) but not after (O/E, 1.3; 95% CI, 0.5-2.9) maternal breast implant surgery. Risk of rheumatic disease was similar among children born before (O/E, 1.4; 95% CI, 0.7-2.6) and after (O/E, 1.4; 95% CI, 0.2-5.0) maternal breast implant surgery. A marginally significant excess of congenital malformations of the digestive organs was observed among children born after maternal implant surgery (O/E, 1.8; 95% CI, 1.0-3.1), with a similar finding among children born to women in the comparison group (O/E, 1.9; 95% CI, 1.4-2.4). The risk of malformations overall was not statistically significantly higher than expected among children born after maternal breast implant surgery. The elevated risks of adverse health outcomes appear unrelated to breast implants per se, because similar findings were observed among children born both before and after the mother's implant surgery, as well as among children born to mothers in the comparison cohort.

Aims: It is well-known that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of upper gastrointestinal bleeding (UGIB), but characteristics of the association and quantification of excess risk at the population level require clarification., Methods: All users of nonaspirin prescription NSAIDs in North Jutland County, Denmark during 1991-95 were identified in the regional Pharmaco-Epidemiologic Database. Using the Hospital Discharge Register, all hospitalizations for UGIBs were identified among the 156,138 users of NSAIDs and compared with the number of expected based on the North Jutland population who did not receive NSAID prescriptions., Results: During periods of NSAID use without use of other drugs associated with UGIB, we observed 365 UGIBs, a number 3.6 times higher than expected (95% CI = 3.3, 4.0). The excess risk varied by sex, type of NSAID and form and route of administration of the NSAID, but not by age at first NSAID prescription or number of prior prescriptions. Risk declined sharply following cessation of use. For ibuprofen and naproxen, there was a clear trend in rising risk by increasing dose, although the lowest doses were also associated with an excess of UGIB. Concurrent use of corticosteroids, anticoagulants and aspirin further increased the risk of UGIB., Conclusions: All types and formulations of NSAIDs appear to increase the risk of UGIBs, but the effect appear not to be cumulative and diminish rapidly with discontinue of use. Up to 15% of the UGIBs in the entire population of the North Jutland County may be explained by use of this drug.

The use of paracetamol has been associated with increased risks for urinary tract cancers and decreased risk for ovarian cancer, although results have been inconsistent. We conducted a population-based cohort study using data from the Prescription Database of North Jutland County and the Danish Cancer Registry. Cancer incidence among 39,946 individuals receiving prescriptions for paracetamol was compared with expected incidence based on the North Jutland population who did not receive paracetamol prescriptions, during a 9-year follow-up period. Standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (95% CIs) were calculated for cancers overall and at selected sites. Overall, 2,173 cancers were observed with 1,973 expected, yielding a SIR of 1.10 (95% CI, 1.06-1.15). Significantly elevated SIRs were found for cancers of the esophagus (1.9; 95% CI, 1.3-2.8) and lung (1.6; 95% CI, 1.4-1.7). Nonsignificantly increased SIRs were observed for cancers of the liver (1.5; 95% CI, 0.96-2.2), renal parenchyma (1.3; 95% CI, 0.9-1.7) and renal pelvis/ureter (1.6; 95% CI, 0.96-2.6), whereas the SIR for cancer of the urinary bladder was close to unity (1.1; 95% CI, 0.9-1.4). For ovarian cancer, the SIR was close to expectation (0.9; 95% CI, 0.6-1.2) with no evidence of trends with duration of follow-up or number of prescriptions. A similar risk pattern was observed after exclusion of person-time experience following prescription for aspirin or other nonsteroidal antiinflammatory drugs in the study cohort and reference population. Our results do not support a major role for paracetamol in the development of cancers of the urinary tract, and we found little evidence of a protective effect of paracetamol against ovarian cancer. The elevated risks for cancers of the esophagus, lung and liver are most likely a result of confounding variables, but may warrant further investigation., (Copyright 2002 Wiley-Liss, Inc.)