Prevalence of Colorectal Neoplasms and Mortality in New Users of Low-Dose Aspirin With Lower Gastrointestinal Bleeding.

BACKGROUND: Aspirin inhibits platelet function and may therefore accelerate early lower gastrointestinal bleeding (LGIB) from colorectal cancer (CRC) precursor polyps. The bleeding may increase endoscopic polyp detection. STUDY QUESTION: To estimate the prevalence of polyps and CRC comparing new users of low-dose aspirin with nonusers who all received a diagnosis of LGIB and to investigate the mortality among these patients. STUDY DESIGN: Using Danish nationwide health registries, we conducted a cohort study (2006-2013) of all new aspirin users who also received a diagnosis of LGIB (n = 40,578). Each new user was matched with 5 nonusers with LGIB by gender and age at the LGIB diagnosis date. MEASURES AND OUTCOMES: We computed the prevalence and prevalence ratios (PRs) of colorectal polyps and CRCs, and the mortality ratios within 6 months after the LGIB, comparing new users with nonusers. RESULTS: We identified 1038 new aspirin users and 5190 nonusers with LGIB. We observed 220 new users and 950 nonusers recorded with endoscopically detected polyps. New aspirin users had a higher prevalence of conventional {PR = 1.28 [95% confidence interval (CI): 1.06-1.55]} and serrated [PR = 1.31 (95% CI: 0.95-1.80)] polyps. New users and nonusers had a similar prevalence of CRC [PR = 1.04 (95% CI: 0.77-1.39)]. However, after stratifying by location of CRC, the prevalence of proximal tumors was lower [PR = 0.71 (95% CI: 0.35-1.43)] in new users than in nonusers. No difference in mortality was observed. CONCLUSIONS: These findings indicate that new use of low-dose aspirin is associated with an increased detection of colorectal polyps compared with nonuse.

Cancer and risk of Alzheimer's disease: Small association in a nationwide cohort study.

INTRODUCTION: Small observational studies with short-term follow-up suggest that cancer patients are at reduced risk of Alzheimer's disease (AD) compared to the general population. METHODS: A nationwide cohort study using Danish population-based health registries (1980-2013) with cancer patients (n = 949,309) to identify incident diagnoses of AD. We computed absolute reductions in risk attributed to cancer and standardized incidence rate ratios (SIRs) accounting for survival time, comparing the observed to expected number of AD cases. RESULTS: During up to 34 years of follow-up of cancer survivors, the attributable risk reduction was 1.3 per 10,000 person-years, SIR = 0.94 (95% confidence interval 0.92-0.96). SIRs were similar after stratification by sex, age, and cancer stage, and approached that of the general population for those surviving >10 years. DISCUSSION: Inverse associations between cancer and AD were small and diminished over time. Incidence rates in cancer survivors approached those of the general population, suggesting limited association between cancer and AD risk.

Risk of cancer in patients with epistaxis and haemoptysis.

This corrects the article DOI: 10.1038/bjc.2017.85.

Long-Term Risk of Dementia Among Survivors of Ischemic or Hemorrhagic Stroke.

BACKGROUND AND PURPOSE: Stroke is a risk factor for dementia, but the risk of dementia after different stroke types is poorly understood. We examined the long-term risk of dementia among survivors of any first-time stroke and of first-time ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. METHODS: We conducted a 30-year nationwide population-based cohort study using data from Danish medical databases (1982-2013) covering all Danish hospitals. We identified 84 220 ischemic stroke survivors, 16 723 intracerebral hemorrhage survivors, 9872 subarachnoid hemorrhage survivors, and 104 303 survivors of unspecified stroke types. Patients were aged ≥18 years and survived for at least 3 months after diagnosis. We formed a comparison cohort from the general population (1 075 588 patients without stroke, matched to stroke patients by age and sex). We computed absolute risks and hazard ratios of dementia up to 30 years after stroke. RESULTS: The 30-year absolute risk of dementia among stroke survivors was 11.5% (95% confidence interval, 11.2%-11.7%). Compared with the general population, the hazard ratio (95% confidence interval) for dementia among stroke survivors was 1.80 (1.77-1.84) after any stroke, 1.72 (1.66-1.77) after ischemic stroke, 2.70 (2.53-2.89) after intracerebral hemorrhage, and 2.74 (2.45-3.06) after subarachnoid hemorrhage. Younger patients regardless of stroke type faced higher risks of poststroke dementia than older patients. The pattern of hazard ratios by stroke type did not change during follow-up and was not altered appreciably by age, sex, or preexisting diagnoses of vascular conditions. CONCLUSIONS: Stroke increases dementia risk. Survivors of intracerebral hemorrhage and subarachnoid hemorrhage are at particularly high long-term risk of poststroke dementia.

Conisation as a marker of persistent human papilloma virus infection and risk of breast cancer.

BACKGROUND: Human papillomavirus (HPV) infection may increase breast cancer (BC) risk. METHODS: To examine this, we used nationwide medical registries to identify all Danish women who underwent conisation to remove HPV-associated cervical precancerous lesions (n=87 782) from 1978 to 2013. We computed the absolute risk of BC and standardised incidence ratios (SIRs) and 95% confidence intervals (95% CIs) for breast cancer, based on national breast cancer incidence rates. RESULTS: Conisation was associated with slightly increased BC incidence (SIR=1.1, 95% CI=1.0-1.1), and an absolute BC risk of 7.7% (95% CI=7.3-8.1%) in 35.9 years of follow-up. BC risk was elevated throughout follow-up, especially in the first 5 years (<1 year: SIR=1.2, 95% CI=0.92-1.5; 1-5 years: SIR=1.2, 95% CI=1.1-1.3; ⩾5 years: SIR=1.1, 95% CI=1.0-1.1). Women who underwent conisation and had autoimmune disease had elevated BC risk after 5 years of follow-up (SIR=1.4, 95% CI=1.0-1.8). CONCLUSIONS: BC risk is slightly elevated in women with persistent HPV infection, possibly due to detection bias.

Colorectal cancer, comorbidity, and risk of venous thromboembolism: assessment of biological interactions in a Danish nationwide cohort.

BACKGROUND: Venous thromboembolism (VTE) is a major source of morbidity and mortality in cancer patients. Incident colorectal cancer (CRC) and comorbidity both predict VTE, but potential synergy between these factors has not been explored. METHODS: Danish nationwide cohort study of CRC cases diagnosed in 1995-2010 and a matched general population reference cohort of subjects without CRC who matched cases on age, sex, and comorbidities. We calculated the Charlson Comorbidity Index using diagnoses recorded in the Danish National Patient Registry. We calculated standardised incidence rates (SIRs) and interaction contrasts (IC) to measure additive interaction between comorbidity and CRC status with respect to 5-year VTE incidence. RESULTS: Among 56 189 CRC patients, 1372 VTE cases were diagnosed over 145 211 person-years (SIR=9.5 cases per 1000 person-years). Among 271 670 reference subjects, 2867 VTE cases were diagnosed over 1 068 860 person-years (SIR=2.8 cases per 1000 person-years). CRC and comorbidity were positively and independently associated with VTE, but there was no evidence for biological interaction between these factors (e.g., comparing the 'severe comorbidity' stratum with the 'no comorbidity' stratum, IC=0.8, 95% CI: -3.3, 4.8). CONCLUSIONS: There is neither a deficit nor a surplus of VTE cases among patients with both comorbidity and CRC, compared with rates expected from these risk factors in isolation.

Prostate cancer, comorbidity, and the risk of venous thromboembolism: A cohort study of 44,035 Danish prostate cancer patients, 1995-2011.

BACKGROUND: Venous thromboembolism (VTE) is a serious complication of cancer. It is unknown whether comorbidity interacts clinically with prostate cancer (PC) to increase the VTE rate beyond that explained by PC and comorbidity alone, for example, by delaying diagnosis or precluding treatment. METHODS: A nationwide, registry-based cohort study of all 44,035 Danish patients diagnosed with PC from 1995 to 2011 and 213,810 men from the general population matched 5:1 on age, calendar time, and comorbidities. The authors calculated VTE rate ratios and the interaction contrast as a measure on the additive scale of the excess VTE rate explained by synergy between PC and comorbidity. RESULTS: In total, 849 patients in the PC cohort and 2360 men from the general population had VTE during 5 years of follow-up, and their risk of VTE was 2.2% and 1.3%, respectively. The 1-year VTE standardized rate among PC patients who had high comorbidity levels was 15 per 1000 person-years (PYs) (95% confidence interval, 6.8-24 per 1000 PYs), and 29% of that rate was explained by an interaction between PC and comorbidity. The VTE risk was increased among older patients, those with metastases, those with high Gleason scores, those in the D'Amico high-risk group, and those who underwent surgery. CONCLUSIONS: PC interacted clinically with high comorbidity levels and increased the VTE rate. Because of the large PC burden, reducing VTEs associated with comorbidities may have an impact on VTE risk and the potential to improve prognosis. Clinical interactions between high levels of comorbidity and PC on the risk of VTE were observed. Almost 30% of all episodes of VTE occurred among patients who had high levels of comorbidity.

Comparative effectiveness and safety of edoxaban versus warfarin in patients with atrial fibrillation: A nationwide cohort study.

BACKGROUND AND PURPOSE: The effectiveness and safety of edoxaban 60 mg and 30 mg for stroke prevention compared with warfarin in patients with atrial fibrillation have not been well-described in a nationwide cohort of Caucasian patients treated in standard clinical practice. METHODS: We used Danish nationwide registries to identify patients with atrial fibrillation during June 2016 and November 2018 who were treated with edoxaban or warfarin and computed rates per 100 person-years of thromboembolic, all-cause mortality, and bleeding events using an inverse probability of treatment weighting approach to account for baseline confounding. We used weighted pooled logistic regression to compute hazard ratios with 95% confidence intervals comparing events between edoxaban 60 mg and warfarin users; edoxaban 30 mg was not included in formal comparisons. RESULTS: We identified 6451 atrial fibrillation patients, mean age was 72 years and 40% were females. A total of 1772 patients were treated with edoxaban 60 mg, 537 with edoxaban 30 mg, and 4142 with warfarin. The median CHA2DS2-VASc score was similar between warfarin and edoxaban 60 mg with a score of 3 (interquartile range (IQR) 2-4). In the inverse probability of treatment-weighted pseudo-population, the thromboembolic event rate for edoxaban 60 mg was 0.95 and 1.0 for warfarin, corresponding weighted hazard ratio of 1.00 (95% confidence intervals (CI) 0.59, 1.71). Edoxaban 60 mg users were associated with lower rates of all-cause mortality (3.93) compared to warfarin (6.04), with a hazard ratio of 0.64 (95% CI 0.47 to 0.88). The event rates for bleeding were 3.36 and 3.14, respectively; hazard ratio 1.09 (95% CI 0.77, 1.57). CONCLUSION: Edoxaban 60 mg is a safe and effective treatment compared with warfarin for stroke prevention in routine clinical care for Danish (mainly Caucasian) patients with AF, with non-significantly different risks for stroke and clinically relevant bleeding, but lower all-cause mortality.

The Khorana score and venous and arterial thrombosis in patients with cancer treated with immune checkpoint inhibitors: A Danish cohort study.

BACKGROUND: Thrombosis is common among patients with cancer. Primary thromboprophylaxis guided by the Khorana score is endorsed by guidelines but recommendations rely mainly on data from patients treated with chemotherapy. OBJECTIVES: To explore if the Khorana score could risk stratify patients with cancer treated with immune checkpoint inhibitors according to risk of venous and arterial thrombosis. PATIENTS/METHODS: The study population and Khorana score were defined using administrative Danish health registries. The primary outcome was 6-month risk of venous thromboembolism after initiation of checkpoint inhibitor treatment. Secondary outcomes were arterial thrombosis and any thromboembolic event. Death was considered a competing risk event. RESULTS: Among 3946 patients with cancer initiating checkpoint inhibitor treatment without other indications for anticoagulation, the overall 6-month incidence of venous thromboembolism was 2.6% (95% confidence interval [CI]: 2.1-3.1). Risks were 2.1% (95% CI: 1.5-3.0), 2.6% (95% CI: 2.0-3.4), and 3.7% (95% CI: 2.1-5.9) in low (score 0), intermediate (score 1-2), and high risk (score ≥3) Khorana categories, respectively. Among patients eligible for primary thromboprophylaxis according to guidelines (Khorana score ≥2), risk of venous thromboembolism was 4.1% (95% CI: 3.1-5.4). Higher Khorana risk category was also associated with higher 6-month risk of both arterial thrombosis and any thromboembolic events. CONCLUSIONS: The Khorana score was able to risk stratify patients with cancer treated with immune checkpoint inhibitors according to 6-month risk of thromboembolic events. Risks of venous thromboembolism were lower than in randomized thromboprophylaxis trials, thus questioning the absolute benefit of routine primary thromboprophylaxis in an unselected population of patients treated with immune checkpoint inhibitors.

Alzheimer's and Parkinson's Diseases and the Risk of Cancer: A Cohort Study.

Observational studies have shown inverse associations between neurological diseases, particularly dementia, and subsequent cancer risk, but is unknown whether this association is valid or arises from bias. We conducted a Danish nationwide cohort study using population-based health registries (1980-2012). The study included patients with dementia (n = 173,434) and with Parkinson's disease (n = 28,835). We followed patients for 10 years to assess subsequent cancer diagnoses. We computed absolute reduction in cancer risk attributable to dementia or Parkinson's disease (expected minus the observed number of cancer cases divided by the person time) and standardized incidence rate ratios (SIRs) as the observed to expected number of cancers, based on sex-, age-, and calendar year-standardized national incidence rates. During 10 years, the reduction in cancer cases were 79.9 per 10,000 person-years for Alzheimer's disease [SIR = 0.68 (95% CI: 0.66, 0.70)], 74.4 per 10,000 person-years for vascular dementia [SIR = 0.71 (95% CI: 0.67, 0.74)], 55.8 per 10,000 person-years [SIR = 0.77 (95% CI: 0.75, 0.78)] for all-cause dementia, and 4.0 per 10,000 person-years [SIR = 0.98 (95% CI: 0.95, 1.02) for Parkinson's disease. Associations were nearly similar for solid tumors diagnosed at localized, regional, or distant stages. We found an inverse association between dementia and cancer risk, with similar associations when considering only cancers diagnosed at distant stage. The cancer risk varied by type of dementia, with a gradient toward a stronger protective effect associated with Alzheimer's disease and vascular dementia, which may favor a biological explanation. Overall results do not show an inverse association between Parkinson's disease and cancer.

In utero exposure to the 1918 pandemic influenza in Denmark and risk of dementia.

BACKGROUND: Substantial but inconclusive evidence suggests in utero exposure to influenza infection may be linked with Alzheimer's disease. OBJECTIVES: We examined whether individuals exposed in utero to the 1918 influenza pandemic are at increased risk of dementia. PATIENTS/METHODS: In this cohort study, surveillance data were used to identify months when influenza activity was at its peak during the pandemic. Using birth dates, exposed and unexposed individuals were identified based on whether they were in utero during ≥1 of the peak months. The outcome, any type of dementia, was identified in population-based medical registries. Time and age at risk were restricted so exposed and unexposed had equal time at risk; diagnoses for dementia were assessed between ages 62 and 92, with a maximum of 30 years at risk. Poisson regression was used to estimate sex-adjusted incidence rate ratios (IRRs). RESULTS: We identified 106 479 exposed and 177 918 unexposed persons. Using the cumulative risk function, there were similar proportions of exposed and unexposed with a dementia diagnosis at 11.9% and 11.7%, respectively. Across all ages, the IRR for the association between in utero influenza exposure and any dementia was 1.01 (95% CI 0.99-1.04); for Alzheimer's disease, it was 0.97 (0.93-1.01). When stratified by age and sex, and when dementia type was examined, estimates of association were also null or close to null. CONCLUSIONS: Our study suggests there is likely not an association between in utero exposure to the 1918 influenza pandemic and dementia among those 62 and older.

Risk of cancer in patients with thyroid disease and venous thromboembolism.

OBJECTIVE: Risk of venous thromboembolism (VTE) is increased in patients with hypo/hyperthyroidism. It is unknown whether VTE may be a presenting symptom of occult cancer in these patients. DESIGN: Nationwide population-based cohort study based on Danish medical registry data. METHODS: We identified all patients diagnosed with VTE during 1978-2013 who had a previous or concurrent diagnosis of hypothyroidism (N=1481) or hyperthyroidism (N=1788). We followed them until a first-time cancer diagnosis, death, emigration, or study end, whichever came first. We calculated 1-year absolute cancer risk and standardized incidence ratios (SIRs) for cancer incidence in the study population compared with national cancer incidence in the general population. RESULTS: During the first year after a VTE diagnosis, the 1-year absolute cancer risk was 3.0% among patients with hypothyroidism and 3.9% among those with hyperthyroidism. During the first year of follow-up, SIRs for cancer in the study population compared with the general population were 1.96 (95% CI: 1.42-2.64) among patients with hypothyroidism and 2.67 (95% CI: 2.07-3.39) among those with hyperthyroidism. SIRs declined substantially after 1 year but remained increased during the remainder of the follow-up period (up to 36 years) (SIR for hypothyroidism=1.16 [95% CI: 0.97-1.39]; SIR for hyperthyroidism=1.26 [95% CI: 1.08-1.46]). CONCLUSION: VTE may be a marker of underlying occult cancer in patients with hypothyroidism or hyperthyroidism.

Non-melanoma skin cancer and risk of Alzheimer's disease and all-cause dementia.

Cancer patients may be at decreased risk of Alzheimer's disease. This hypothesis is best developed for non-melanoma skin cancer (NMSC), but supportive epidemiological data are sparse. We therefore conducted a nationwide cohort study of the association between NMSC and Alzheimer's disease (main outcome) and all-cause dementia. Using Danish medical databases, we identified adults diagnosed with NMSC between 1 January 1980 and 30 November 2013 (n = 216,221) and a comparison cohort of five individuals matched to each NMSC patient by sex and birth year (n = 1,081,097). We followed individuals from the time of diagnosis, or corresponding date for matched comparators, until a dementia diagnosis, death, emigration, or 30 November 2013, whichever came first. We used stratified Cox regression adjusted for comorbidities to compute hazard ratios (HRs) associating NMSC with dementia. We computed cumulative risks of dementia, treating death as a competing risk. NMSC was associated with a HR of 0.95 (95% confidence interval [CI]: 0.92-0.98) for Alzheimer's disease and 0.92 (95% CI: 0.90-0.94) for all-cause dementia. HRs were similar for basal cell and squamous cell carcinoma, the two most common forms of NMSC. Estimates of risk reduction were more pronounced in the beginning of follow-up, reaching null after 5-10 years. At the end of follow-up (34 years), cumulative risk of Alzheimer's disease was 4.6% (95% CI: 4.4%-4.8%) among patients with NMSC vs. 4.7% (95% CI: 4.6%-4.9%) in the comparison cohort. In conclusion, NMSC was associated with 2%-10% reductions in relative risks of Alzheimer's disease and all-cause dementia. However, these small inverse associations may have been caused by ascertainment bias due to decreased awareness of NMSC tumors in persons with undiagnosed early cognitive impairment or by confounding from a more neuroprotective lifestyle among persons with NMSC.

Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study.

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA2 DS2 VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs.

Venous thromboembolism and effect of comorbidity in bladder cancer: A danish nationwide cohort study of 13,809 patients diagnosed between 1995 and 2011.

OBJECTIVES: Bladder cancer (BC) is associated with venous thromboembolism (VTE), but data on the effect of comorbidities are scarce. MATERIALS AND METHODS: Population-based cohort study with 13,809 patients with BC diagnosed in Denmark (1995-2011) and a general population comparison cohort matched on age, sex, and comorbidities (n = 132,421). Risk of VTE, pulmonary embolism and deep venous thrombosis was computed for the first month, 3 months, 1 year, and 5 years following cancer diagnosis and stratified by Charlson Comorbidity Index (CCI) scores, cystectomy, and metastases. RESULTS: VTE risk was higher among the patients with BC than in the comparison cohort during five years of follow-up (risk difference = 20 per 1,000 persons [95% CI: 16-23]). Excess risk was relatively stable with increasing comorbidity score. In the first year, the risk difference was 17 per 1,000 persons (95% CI: 14-21) and 16 (95% CI: 4.8-27) for CCI score = 0 and CCI score = 4, respectively, and similar results were observed by stratification on pulmonary embolism and deep venous thrombosis. For patients with BC undergoing cystectomy, VTE risk was 70-fold higher than in the general population cohort within 3 months after diagnosis. CONCLUSIONS: BC is associated with increased risk of VTE, compared with the general Danish population. Risks are particularly high for VTE after cystectomy. Risk did not increase with higher comorbidity burden, as the relative risk of VTE was greatest among patients without comorbidity. Clinical attention to VTE risk, particularly cystectomy-related VTE, in patients with BC is appropriate irrespective of comorbidities.

Five-year mortality in colorectal cancer patients with ulcerative colitis or Crohn's disease: a nationwide population-based cohort study.

BACKGROUND: The impact of inflammatory bowel disease (IBD) on colorectal cancer (CRC) prognosis, taking into account other comorbidities, is not clear. We studied the overall mortality in CRC patients with a history of ulcerative colitis (UC) or Crohn's disease (CD) compared with non-IBD-CRC patients. METHODS: Data on all CRC and IBD patients diagnosed with CRC between 1977 and 2009 were retrieved from Danish medical registries. One-year and 5-year overall mortality were evaluated with the Kaplan-Meier method and with Cox regression, adjusting for year of CRC diagnosis, sex, Duke's stage, age at CRC diagnosis, and Charlson Comorbidity Index score. RESULTS: We identified 653 CRC patients diagnosed with UC, 238 patients with CD, and 107,024 CRC patients without IBD. The patients with IBD were younger at diagnosis than patients without IBD. The Duke's stage distribution was similar for UC-CRC patients and non-IBD-CRC patients. The CD-CRC patients had a lower frequency of Duke's A and B stage tumors (36% versus 42%), a higher frequency of Duke's C stage tumors (31% versus 27%) and Duke's D-stage tumors (23% versus 21%), and a similar frequency of unknown stage tumors (10%) compared with non-IBD-CRC patients. After 5-years of follow-up, 59% of the UC and the non-UC-CRC patients had died compared with 62% of the patients with CD and 56% of the non-CD-CRC patients. The 5-year adjusted mortality rate ratios for patients with UC or CD were 1.14 (95% confidence interval, 1.03-1.27) and 1.26 (95% confidence interval, 1.07-1.49), respectively, compared with patients without IBD. CONCLUSION: A history of IBD in patients with CRC may be associated with increased mortality.