Venous thromboembolism in cancer patients: a population-based cohort study.

The incidence of venous thromboembolism (VTE) in cancer patients may have changed in the past decade, possibly due to novel cancer therapies, improved survival, and high-resolution imaging. Danish medical registries were used to identify 499 092 patients with a first-time cancer diagnosis between 1997 and 2017, who were matched to 1 497 276 comparison individuals without cancer from the general population. We computed cumulative incidences of VTE 6 and 12 months after the diagnosis/index date. Hazard ratios (HRs) were calculated using Cox regression. Risk factors were examined by computing subdistribution hazard ratios (SHRs) in a competing-risk analysis. Cumulative incidence of VTE 12 months after the cancer diagnosis/index date was 2.3% (95% confidence interval [CI], 2.2% to 2.3%) in the cancer cohort and 0.35% (95% CI, 0.34% to 0.36%) in the comparison cohort (HR, 8.5; 95% CI, 8.2-8.8). Important risk factors for cancer patients were prior VTE (SHR, 7.6; 95% CI, 7.2-8.0), distant metastasis (SHR, 3.2; 95% CI, 2.9-3.4), and use of chemotherapy (SHR, 3.4; 95% CI, 3.1-3.7), protein kinase inhibitors (SHR, 4.1; 95% CI, 3.4-4.9), antiangiogenic therapy (SHR, 4.4; 95% CI, 3.8-5.2), and immunotherapy (SHR, 3.6; 2.8-4.6). Twelve-month incidence in the cancer cohort increased from 1.0% (95% CI, 0.9% to 1.2%) in 1997 to 3.4% (95% CI, 2.9% to 4.0%) in 2017, which was paralleled by improved 12-month survival and increased use of computed tomography scans, chemotherapy, and targeted therapies. In conclusion, the risk of VTE in cancer patients is increasing steadily and is ninefold higher than in the general population.

Increased maternal new-onset psychiatric disorders after delivering a child with a major anomaly: a cohort study.

BACKGROUND: The birth of a child with a major congenital anomaly may create chronic caregiving stress for mothers, yet little is known about their psychiatric outcomes. AIMS: To evaluate the association of the birth of a child with a major congenital anomaly with subsequent maternal psychiatric risk. METHODS: This Danish nationwide cohort study included mothers who gave birth to an infant with a major congenital anomaly (n = 19 220) between 1997 and 2015. Comparators were randomly selected mothers, matched on maternal age, year of delivery and parity (n = 195 399). The primary outcome was any new-onset psychiatric diagnosis. Secondary outcomes included specific psychiatric diagnoses, psychiatric in-patient admissions and redeemed psychoactive medicines. Cox models were used to estimate hazard ratios (HRs), adjusted for socioeconomic and medical variables. RESULTS: Mothers of affected infants had an elevated risk for a new-onset psychiatric disorder vs. the comparison group (adjusted HR, 1.16, 95% CI 1.11-1.22). The adjusted HR was particularly elevated during the first postpartum year (1.65, 95% CI 1.42-1.90), but remained high for years, especially among mothers of children with multiorgan anomalies (1.37, 95% CI 1.18-1.57). The risk was also elevated for most specific psychiatric diagnoses, admissions and medicines. CONCLUSIONS: Mothers who give birth to a child with a major congenital anomaly are at increased risk of new-onset psychiatric disorders, especially shortly after birth and for mothers of children with more severe anomalies. Our study highlights the need to screen for mental illness in this high-risk population, as well as to integrate adult mental health services and paediatric care.

Preadmission use of glucocorticoids and risk of cardiovascular events in patients with ischemic stroke.

Essentials The risk of thrombosis among ischemic stroke patients using glucocorticoids is unknown. We examined the risk of thrombosis in 98 487 ischemic stroke patients, by glucocorticoid use. Myocardial infarction and venous thromboembolism risk was increased in glucocorticoid users. Hemorrhagic stroke risk was lower and recurrent ischemic stroke the same in glucocorticoid users. SUMMARY: Background Glucocorticoid users have a high mortality rate following stroke, but the underlying clinical pathways are poorly understood. Objectives To examine the risk of cardiovascular events among ischemic stroke patients using glucocorticoids. Methods We conducted a nationwide population-based cohort study by using medical registries in Denmark. We identified all patients hospitalized with a first-time ischemic stroke (2004-2013). We categorized glucocorticoid use into current use (last prescription redemption ≤ 90 days before admission), former use, and non-use. With non-users as reference, we studied the risks of recurrent ischemic stroke, hemorrhagic stroke, myocardial infarction and venous thromboembolism associated with glucocorticoid use. Comorbidity and comedication-adjusted 1-year hazard ratios (aHRs) with 95% confidence intervals (CIs) were computed on the basis of Cox regression analysis. Results We identified 98 487 patients with a first-time (index) ischemic stroke. After the index stroke, the 1-year cumulative incidence of recurrent ischemic stroke was 16.4% among current glucocorticoid users, whereas risks were lower for hemorrhagic stroke (0.46%), myocardial infarction (1.35%), and venous thromboembolism (0.98%). Among current glucocorticoid users, aHRs were increased for myocardial infarction (1.32, 95% CI 0.98-1.76) and venous thromboembolism (1.39, 95% CI 0.99-1.94), whereas the risk of hemorrhagic stroke was reduced (aHR 0.60, 95% CI 0.38-0.93). There was no association with recurrent ischemic stroke (aHR 1.01, 95% CI 0.94-1.09). Conclusions During the first year after ischemic stroke, current glucocorticoid use was associated with moderately increased risks of myocardial infarction and venous thromboembolism, and a lower risk of hemorrhagic stroke, whereas the risk of recurrent ischemic stroke was not affected.

Comorbidity and the increased mortality after hospitalization for stroke: a population-based cohort study.

Essentials Comorbidity is prevalent in the stroke population and affects post-stroke survival. A stroke patient cohort (n = 201 691) and a general population cohort were followed for survival. Cancer and advanced renal/liver disease substantially increased one-year stroke mortality. Tailoring stroke interventions according to comorbidity may reduce excess mortality. SUMMARY: Background Comorbidity is prevalent among stroke patients, affecting post-stroke survival. It remains unknown whether comorbidity impacts post-stroke mortality beyond the combined individual effects of stroke and comorbidity. Methods Using nationwide Danish databases, we performed a cohort study of 201 691 patients ≥ 18 years old with incident ischemic stroke, intracerebral or subarachnoid hemorrhage, or unspecified stroke during 1995-2012, and 992 942 adults from the general population, matched to stroke patients by birth year, sex and individual comorbidities in the Charlson Comorbidity Index. During up to 5 years of follow-up, we computed standardized mortality rates (SMRs) to assess interaction contrasts as a measure of excess mortality not explained by the additive effects of stroke and comorbidity acting alone. Results Five-year post-stroke mortality was 48%, corresponding to an SMR of 187 deaths per 1000 person-years. During the 30-day peak post-stroke mortality (SMR, 180 per 1000 person-months), interaction with comorbidity represented 23%, 34% and 51% of post-stroke mortality rates among patients with low (score = 1), moderate (score = 2-3) and high (score = 4+) comorbidity based on Charlson Comorbidity Index scores. The interaction accounted for 5% to 32% of subsequent 31-365-day post-stroke mortality rates, depending on comorbidity level. The interaction contrasts were most notable among comorbid patients with cancer, particularly with hematological or metastatic disease, followed by patients with moderate-to-severe liver or renal disease. Conclusion Comorbidity, notably cancer and advanced renal or liver disease, increased 1-year mortality after stroke beyond the combined effects expected from either disease acting alone.

Venous thromboembolism and risk of cancer in patients with rheumatoid arthritis.

Essentials Can venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients be marker of cancer? RA patients with VTE and comparison cohorts from population-based registries were compared. Increased risk of cancer in RA patients with VTE during the first year of VTE was observed. Risk of cancer in RA patients was increased also during the longer period following VTE. SUMMARY: Background It is unknown whether venous thromboembolism (VTE) in rheumatoid arthritis (RA) patients can be a marker of occult cancer. Objectives To examine risk of cancer subsequent to VTE among RA patients compared with risk of cancer in an RA cohort without VTE and in a general population without RA and without VTE. Patients/Methods All RA patients with a first-time diagnosis of VTE (index date) during 1978-2013 and comparison cohorts were identified from population-based registries in Denmark. Results We identified three cohorts: 2497 RA patients with VTE, 11 672 RA patients without VTE and 12 730 persons from the general population. The cumulative incidence of cancer within the first year of the index date was 3.2% among RA with VTE, 2.2% among RA without VTE, and 2.0% in the general population cohort. Incidence rate ratios (IRRs) were 1.79 (95% confidence interval [CI], 1.37-2.33) for RA patients with VTE vs. RA patients without VTE and 2.12 (95% CI, 1.63-2.76) for RA patients with VTE vs. the general population. The IRR of cancer at > 1 to 36 years from the index date among RA patients with VTE was 1.16 (95% CI, 1.00-1.34) compared with the RA patients without VTE and 1.33 (95% CI, 1.15-1.53) compared with the general population. Conclusions We found an increased risk of cancer in RA patients with VTE during the first year following VTE and also during the longer follow-up period. Thus, VTE may not only be a result of inflammation and immunological dysfunctions associated with RA, but may also be a marker for occult cancer.

Corticosteroid use and mortality risk in patients with perforated colonic diverticular disease: a population-based cohort study.

BACKGROUND: Corticosteroids are a potential risk factor for mortality in patients with perforated diverticular disease, due to blinding of disease severity, hampered wound healing or adrenal insufficiency. We examined mortality in corticosteroid users and non-users among patients with perforated diverticular disease. METHODS: A cohort study based on medical databases including all patients ≥18 years in Denmark (source population 5 289 261 inhabitants) admitted to a hospital with incident perforated diverticular disease between 2005 and 2013. 7-day, 1-month, 3-month and 1-year mortality risks in corticosteroid users and non-users were calculated using the Kaplan-Meier method, and compared with Cox proportional hazard regression adjusted for age, sex and comorbidities. RESULTS: The study included 4640 patients with perforated diverticular disease. Of these, 3743 (80.7%) had not used corticosteroids in the year before admission and 725 (15.6%) had been exposed to systemic corticosteroid treatment. The remaining 172 patients had been exposed to either inhaled or intestinal acting corticosteroid therapy. Mortality risk in non-users was 4.4% after 7 days and 15.6% after 1 year. This risk was doubled for corticosteroid users who filled their last prescription during the 90 days before admission, with mortality risks ranging from 14.2% after 7 days to 47.6% after 1 year. 1-year mortality risk was even higher for corticosteroid users with a first filled prescription ≤90 days before admission: 52.5%. CONCLUSIONS: Corticosteroid use was associated with clearly increased mortality risk after perforated diverticular disease. Thus, use of corticosteroids should be regarded as an important clinical prognostic factor for mortality in patients with this condition.

Mortality and cardiovascular diseases risk in patients with Barrett's oesophagus: a population-based nationwide cohort study.

BACKGROUND: Patients with Barrett's oesophagus may be at increased risk of mortality overall, and cardiovascular disease has been suggested as the main underlying cause of death. AIM: To examine cause-specific mortality and risk of cardiovascular events among patients with Barrett's oesophagus. METHODS: Utilising existing Danish data sources (1997-2011), we identified all patients with histologically verified Barrett's oesophagus (n = 13 435) and 123 526 members of the general population matched by age, sex and individual comorbidities. We calculated cause-specific mortality rates and incidence rates of cardiovascular diseases. We then compared rates between patients with Barrett's oesophagus and the general population comparison cohort, using stratified Cox proportional hazard regression. RESULTS: Patients with Barrett's oesophagus had a 71% increased risk of overall mortality. The cause-specific mortality rate per 1000 person-years for patients with Barrett's oesophagus was 8.5 for cardiovascular diseases, 14.7 for non-oesophageal cancers, and 5.4 for oesophageal cancer. Compared to the general population cohort, corresponding hazard ratios were 1.26 (95% confidence interval (CI): 1.15-1.38), 1.77 (95% CI: 1.65-1.90), and 19.4 (95% CI: 16.1-23.4), respectively. The incidence rates of cardiovascular diseases per 1000 person-years for Barrett's oesophagus patients and for persons from the general population cohort, respectively, varied from 0.4 and 0.2 for subarachnoid bleeding (hazard ratio 1.10, 95% CI: 0.87-1.39) to 8.1 and 5.9 for congestive heart failure (hazard ratio 1.33, 95% CI: 1.21-1.46). CONCLUSION: Prophylactic measures targeted at cardiovascular diseases and non-oesophageal cancers potentially could be more important than measures against oesophageal cancer, for improving prognosis among patients with Barrett's oesophagus.

Inflammatory bowel disease and venous thromboembolism during pregnancy and the postpartum period.

Essentials Risk of pregnancy-related venous thromboembolism may be increased in inflammatory bowel disease. We performed a study on inflammatory bowel disease and pregnancy-related venous thromboembolism. Inflammatory bowel disease is a risk factor for pregnancy-related venous thromboembolism. Proper disease control before conception is pivotal to avoid venous thromboembolism. SUMMARY: Background The incidence of inflammatory bowel disease (IBD) increases, and thus is more common, in pregnant women. IBD is a risk factor for venous thromboembolism (VTE) but it is not clear whether IBD predisposes women to an excess risk of VTE during pregnancy and the postpartum period. Methods This was a nationwide population-based cohort study of all deliveries during 1980-2013 in Denmark, using data from two nationwide health registries: the Danish National Patient Registry and the Medical Birth Registry. We computed incidence rates (IRs) per 1000 person-years, and crude and adjusted relative risks (RRs) with 95% confidence intervals (CIs) for VTE during pregnancy and the first 12 postpartum weeks in women with and without IBD. Results We included 1 046 754 women with 1 978 701 deliveries. We identified 3465 VTE events during pregnancy and 1302 VTE events postpartum. The IR for VTE during pregnancy was 4.20 (95% CI, 2.83-5.58) in IBD patients and 2.41 (95% CI, 2.33-2.50) in women without IBD, corresponding to an RR of 1.72 (95% CI, 1.22-2.43). Adjustment for maternal age and smoking (pregnancies during 1991-2013) yielded an adjusted RR of 1.67 (95% CI, 1.15-2.41). IBD flare was associated with an RR of 2.64 (95% CI, 1.69-4.14) for VTE during pregnancy. The IR for postpartum VTE was 7.03 (95% CI, 3.87-10.20) among IBD patients and 2.88 (95% CI, 2.72-3.04) in women without IBD, corresponding to an adjusted RR of 2.10 (95% CI, 1.33-3.30). Conclusions IBD is a risk factor for VTE during pregnancy and postpartum.

Preadmission use of selective serotonin reuptake inhibitors and short-term mortality in diabetic patients hospitalized due to stroke.

BACKGROUND: Patients with diabetes have an increased risk of stroke with a poor prognosis. Moreover, diabetic patients are at increased risk of depression and therefore likely to use selective serotonin reuptake inhibitors (SSRIs). We examined whether preadmission SSRI use was associated with increased mortality in diabetic patients hospitalized due to stroke. METHODS: Population-based medical databases were used to identify all first-time stroke-related hospitalizations and subsequent mortality in diabetic patients in Denmark between 2004 and 2012 (n = 12 620). Based on redeemed prescriptions, SSRI use was categorized as current (new or long term), former or nonuse, and absolute 30-day mortality and mortality rate ratios (MRRs) were computed using Cox regression controlling for confounding factors. RESULTS: Amongst SSRI nonusers, 30-day stroke mortality was 15.8% (10.4% for ischaemic stroke, 41.8% for intracerebral haemorrhage and 27.3% for subarachnoid haemorrhage). Amongst current SSRI users, 30-day stroke mortality was 23.3% (17.1% for ischaemic stroke, 50.7% for intracerebral haemorrhage and 28.6% for subarachnoid haemorrhage). Current SSRI use was associated with increased 30-day stroke mortality compared with nonuse [adjusted MRR 1.3, 95% confidence interval (CI) 1.1-1.5], with the highest risk observed amongst new users (MRR 1.5, 95% CI 1.2-1.8). Overall stroke mortality was driven by increased mortality due to ischaemic stroke, with adjusted MRRs of 1.3 (95% CI 1.1-1.7) for current users and 1.7 (95% CI 1.2-2.4) for new users. Propensity score-matched results were similar and robust across subgroups. CONCLUSION: In patients with diabetes, preadmission SSRI use was associated with increased mortality following ischaemic stroke, compared with nonuse.

Preconception venous thromboembolism and placenta-mediated pregnancy complications.

BACKGROUND: Placenta-mediated complications are leading causes of maternal and fetal morbidity and mortality. We hypothesized that a preconception history of venous thromboembolism (VTE) is associated with increased risk of placenta-mediated pregnancy complications. METHODS: A nationwide population-based cohort study of all singleton pregnancies leading to delivery from 1997 to 2012 (n = 964 967). We obtained data on placenta-mediated pregnancy complications from the Danish Medical Birth Registry and data on VTE before pregnancy from the Danish National Patient Registry. We computed absolute risks, crude and adjusted risk differences (RDs) using a binomial regression model, and crude and adjusted risk ratios (RRs) from a modified Poisson regression model. RESULTS: Overall, 1419 women had a preconception history of VTE, while 578 112 did not. Preeclampsia occurred in 4.2% of pregnancies in the VTE group and in 2.7% of pregnancies in a comparison cohort (adjusted RD = 1.3%, 95% confidence interval (CI) 0.6-2.0%; adjusted RR = 1.5, 95% CI 1.3-1.8). Stillbirth occurred in 0.7% of pregnancies in the VTE group and in 0.4% of pregnancies in the comparison cohort (adjusted RD = 0.3%, 95% CI 0.02-0.6%; adjusted RR = 1.8, 95% CI 1.1-3.0). Placental abruption occurred in 0.8% of pregnancies in the VTE group and in 0.5% of pregnancies in the comparison cohort (adjusted RD = 0.3%, 95% CI - 0.05-0.6%; adjusted RR = 1.6, 95% CI 1.1-2.4). Small-for-gestational-age infants accounted for 10.9% of live births in the VTE group and 9.8% of live births in the comparison cohort (adjusted RD = 0.6%, 95% CI - 0.5-1.7%; adjusted RR = 1.1, 95% CI 0.9-1.3). CONCLUSION: Women with a history of VTE were at increased risk of placenta-mediated complications.

Mortality in cancer patients previously diagnosed with herpes zoster in the hospital setting: a nationwide cohort study.

BACKGROUND: Herpes zoster (HZ) is associated with underlying immunodeficiency and may thereby predict mortality of subsequent cancer. METHODS: By using Danish nationwide medical databases, we identified all cancer patients with a prior hospital-based HZ diagnosis during 1982-2011 (n=2754) and a matched cancer cohort without prior HZ (n=26 243). We computed adjusted mortality rate ratios (aMRRs) associating prior HZ with mortality following cancer. RESULTS: Prior HZ was associated with decreased mortality within the year after cancer diagnosis (aMRR 0.87; 95% confidence interval (CI): 0.81-0.93), but not thereafter (aMRR 1.07; 95% CI: 0.99-1.15). However, prior HZ predicted increased mortality throughout the entire follow-up among patients aged <60 years (aMRR 1.39; 95% CI: 1.15-1.68) and those with disseminated HZ (aMRR 1.18; 95% CI: 1.01-1.37). The increased mortality rates were observed primarily for haematological and immune-related cancers. CONCLUSIONS: Overall, HZ was not a predictor of increased mortality following subsequent cancer.

Preadmission use of ACE inhibitors or angiotensin receptor blockers and short-term mortality after stroke.

BACKGROUND AND AIM: The prognostic impact of ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) on stroke mortality remains unclear. We aimed to examine whether prestroke use of ACE-Is or ARBs was associated with improved short-term mortality following ischaemic stroke, intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH). METHODS: We conducted a nationwide population-based cohort study using medical registries in Denmark. We identified all first-time stroke patients during 2004-2012 and their comorbidities. We defined ACE-I/ARB use as current use (last prescription redemption <90 days before admission for stroke), former use and non-use. Current use was further classified as new or long-term use. We used Cox regression modelling to compute 30-day mortality rate ratios (MRRs) with 95% CIs, controlling for potential confounders. RESULTS: We identified 100 043 patients with a first-time stroke. Of these, 83 736 patients had ischaemic stroke, 11 779 had ICH, and 4528 had SAH. For ischaemic stroke, the adjusted 30-day MRR was reduced in current users compared with non-users (0.85, 95% CI 0.81 to 0.89). There was no reduction in the adjusted 30-day MRR for ICH (0.95, 95% CI 0.87 to 1.03) or SAH (1.01, 95% CI 0.84 to 1.21), comparing current users with non-users. No association with mortality was found among former users compared with non-users. No notable modification of the association was observed within sex or age strata. CONCLUSIONS: Current use of ACE-Is/ARBs was associated with reduced 30-day mortality among patients with ischaemic stroke. We found no association among patients with ICH or SAH.

Kidney disease and risk of venous thromboembolism: a nationwide population-based case-control study.

BACKGROUND: Chronic kidney disease is associated with hemostatic derangements, including both procoagulant activity and platelet dysfunction, which may influence the risk of venous thromboembolism. However, data associating kidney disease with risk of venous thromboembolism are sparse. OBJECTIVES: We examined whether kidney disease is associated with increased risk of venous thromboembolism. METHODS: We conducted this nationwide case-control study using data from medical databases. We included 128,096 patients with a hospital diagnosis of VTE in Denmark between 1980 and 2010 (54,473 had pulmonary embolism and 73,623 had deep venous thrombosis only) and 642,426 age- and gender-matched population controls based on risk-set sampling. We identified all previous hospital diagnoses of kidney disease, including nephrotic syndrome, glomerulonephritis without nephrotic syndrome, hypertensive nephropathy, chronic pyelonephritis/interstitial nephritis, polycystic kidney disease, diabetic nephropathy, or other kidney diseases. We used conditional logistic regression models to compute odds ratios (ORs) for venous thromboembolism with adjustment for potential confounders. RESULTS: Kidney disease was associated with an adjusted OR for venous thromboembolism ranging from 1.41 (95% CI, 1.22-1.63) for hypertensive nephropathy to 2.89 (95% CI, 2.26-3.69) for patients with nephrotic syndrome. The association was strongest within the first 3 months after a diagnosis of chronic kidney disease (adjusted OR for nephrotic syndrome = 23.23; 95% CI, 8.58-62.89), gradually declining thereafter. The risk, however, remained elevated for more than 5 years, especially in patients with nephrotic syndrome and glomerulonephritis. CONCLUSIONS: Kidney diseases, in particular nephrotic syndrome and glomerulonephritis, were associated with an increased risk of venous thromboembolism.

Statin use and venous thromboembolism recurrence: a combined nationwide cohort and nested case-control study.

BACKGROUND: Data on statins' effect on venous thromboembolism (VTE) recurrence are conflicting. OBJECTIVES: We examined whether statin use was associated with reduced risk of recurrent VTE in a nationwide population-based setting. PATIENTS/METHODS: Using the Danish National Patient Registry, we identified first-time and recurrent VTEs between 1 July 2004 and 31 December 2012 (n = 27,862). VTE diagnoses were validated by medical record review of a subsample of patients. We ascertained nationwide prescription data and categorized statin use as current (further divided into new and long-term use), former and no use. We identified statin use at baseline (mimicking an intention-to-treat analysis) and in a time-varying manner during follow-up (mimicking per-protocol analysis) and computed hazard ratios (HRs) for recurrent VTE using Cox regression. In a supplementary nested case-control study, we identified statin use at time of VTE recurrence and computed odds ratios as unbiased estimates of the incidence rate ratios (IRRs) using conditional logistic regression. We adjusted for age, sex, year of diagnosis, provoking factors, co-morbidities and co-medications, including time-varying use of aspirin and anticoagulant drugs. RESULTS: The adjusted HR comparing current use with no use was 0.72 (95% confidence interval [CI], 0.59-0.88) for recurrent VTE, with a stronger effect of high (0.40; 95% CI, 0.21-0.78) vs. low potency statins (0.77; 95% CI, 0.63-0.94). Consistently, the recurrence rate was reduced in both the time-varying analysis (HR=0.64; 95% CI, 0.54-0.77) and nested case-control analysis (IRR=0.55; 95% CI, 0.45-0.67). The effect was largest for recurrent deep venous thrombosis. CONCLUSIONS: Statin use was associated with reduced VTE recurrence.

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=56963), and five times as many persons from the general population (n=271670) 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.

Autoimmune skin and connective tissue diseases and risk of venous thromboembolism: a population-based case-control study.

BACKGROUND: Systemic inflammation is associated with vessel wall damage, upregulation of procoagulants, downregulation of anticoagulants, and suppression of fibrinolysis. Autoimmune diseases may therefore increase the risk of venous thromboembolism (VTE). OBJECTIVES: To examine whether autoimmune skin and connective tissue diseases are associated with increased VTE risk. METHODS: We conducted this population-based case-control study in northern Denmark, using administrative databases. From 1999 to 2009, we identified 14,721 VTE cases and 147,210 birth year-matched, sex-matched and county-matched population controls. The date of diagnosis/matching was considered to be the index date for cases and controls. For all study subjects, we identified hospital diagnoses of autoimmune skin or connective tissue diseases between 1977 and the index date. We used conditional logistic regression with adjustment for VTE risk factors to calculate odds ratios and 95% confidence intervals (CIs) for patients with vs. without autoimmune disease. Given the risk-set sampling design, odds ratios estimate incidence rate ratios (IRRs). RESULTS: Autoimmune skin disease was not associated with VTE (IRR 1.0; 95% CI 0.9-1.2). Patients with connective tissue disease had an increased VTE risk within 90 days (IRR 2.3; 95% CI 1.5-3.7) and 91-365 days (IRR 2.0; 95% CI 1.5-2.8) after diagnosis, but not thereafter (IRR 1.1; 95% CI 1.0-1.2). Among connective tissue diseases, the greatest overall risk increases were found for juvenile rheumatoid arthritis (IRR 3.0; 95% CI 1.4-6.4) and systemic lupus erythematosus (IRR 2.8; 95% CI 1.7-4.7). CONCLUSIONS: Autoimmune connective tissue disease was associated with an increased risk of VTE within 1 year after diagnosis, whereas skin diseases were not.

Acute infections and venous thromboembolism.

BACKGROUND: Data on the association between acute infections and venous thromboembolism (VTE) are sparse. We examined whether various hospital-diagnosed infections or infections treated in the community increase the risk of VTE. METHODS: We conducted this population-based case-control study in Northern Denmark (population 1.8 million) using medical databases. We identified all patients with a first hospital-diagnosed VTE during the period 1999-2009 (n = 15 009). For each case, we selected 10 controls from the general population matched for age, gender and county of residence (n = 150 074). We identified all hospital-diagnosed infections and community prescriptions for antibiotics 1 year predating VTE. We used odds ratios from a conditional logistic regression model to estimate incidence rate ratios (IRRs) of VTE within different time intervals of the first year after infection, controlling for confounding. RESULTS: Respiratory tract, urinary tract, skin, intra-abdominal and bacteraemic infections diagnosed in hospital or treated in the community were associated with a greater than equal to twofold increased VTE risk. The association was strongest within the first 2 weeks after infection onset, gradually declining thereafter. Compared with individuals without infection during the year before VTE, the IRR for VTE within the first 3 months after infection was 12.5 (95% confidence interval (CI): 11.3-13.9) for patients with hospital-diagnosed infection and 4.0 (95% CI: 3.8-4.1) for patients treated with antibiotics in the community. Adjustment for VTE risk factors reduced these IRRs to 3.3 (95% CI: 2.9-3.8) and 2.6 (95% CI: 2.5-2.8), respectively. Similar associations were found for unprovoked VTE and for deep venous thrombosis and pulmonary embolism individually. CONCLUSIONS: Infections are a risk factor for VTE.

Non-steroidal anti-inflammatory drug use and risk of venous thromboembolism.

BACKGROUND: The association between the use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase-2-selective inhibitors (COX2Is) and the risk of venous thromboembolism (VTE) remains unclear. OBJECTIVES: To examine this association. PATIENTS/METHODS: We conducted a population-based case-control study in northern Denmark (population of 1.7 million). Using the National Patient Registry, we identified patients with a first hospital VTE diagnosis during 1999-2006 (n = 8368) and their comorbidities. For each case, we selected 10 controls (n = 82, 218) matched by age and sex. From the prescription database, we ascertained the use of NSAIDs at the time of diagnosis (current use) or before (recent use), and comedications. Current use was further classified as new use (first-ever prescription redemption within 60 days before diagnosis date) or long-term use. We used odds ratios from a logistic regression model to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: As compared with no use, the adjusted IRR associating current non-selective NSAID use with VTE was 2.51 (95% CI 2.29-2.76), and that for current COX2I use was 2.19 (95% CI 1.99-2.41). Recent users had substantially smaller increases than current users. The adjusted IRRs among long-term users were 2.06 for non-selective NSAIDs (95% CI 1.85-2.29) and 1.92 for COX2Is (95% CI 1.72-2.15). Similarly increased risks were found for unprovoked VTE (occurrence in the absence of pregnancy, cancer, major trauma, fracture or surgery within 3 months preceding the VTE), deep vein thrombosis, pulmonary embolism, and individual NSAIDs. CONCLUSIONS: The use of non-selective NSAIDs or COX2Is was associated with a two-fold or more increased risk of VTE.

Venous thromboembolism and subsequent diagnosis of subarachnoid hemorrhage: a 20-year cohort study.

BACKGROUND: Venous thromboembolism is a predictor of subsequent risk of ischemic stroke and intracerebral hemorrhage, but no data are available regarding its association with risk of subarachnoid hemorrhage. OBJECTIVES: To examine this issue, we conducted a nationwide cohort study in Denmark. PATIENTS AND METHODS: Between 1977 and 2007, we identified 97,558 patients with a hospital diagnosis of venous thromboembolism and obtained information on risk of subsequent subarachnoid hemorrhage during follow-up in the Danish Registry of Patients. The incidence of subarachnoid hemorrhage in the venous thromboembolism cohort was compared with that of 453,406 population control cohort members. RESULTS: For patients with pulmonary embolism (PE), there was clearly an increased risk of subarachnoid hemorrhage, both during the first year of follow-up [relative risk 2.69; 95% confidence interval (CI), 1.32-5.48] and during later follow-up of 2-20 years (relative risk 1.40; 95% CI, 1.05-1.87). For patients with deep venous thrombosis (DVT) the risk was likewise clearly increased during the first year of follow-up (relative risk 1.91; 95% CI, 1.13-3.22), but not during later follow-up (relative risk 1.04; 95% CI, 0.81-1.32). CONCLUSIONS: We found evidence that PE is associated with an increased long-term risk of subarachnoid hemorrhage. The two diseases might share etiologic pathways affecting the vessel wall or share unknown risk factors.

Use of oral bisphosphonates and risk of venous thromboembolism: a population-based case-control study.

UNLABELLED: Oral bisphosphonates are widely used for fracture prevention, but there is a concern regarding potential adverse cardiovascular effects of bisphosphonates. In this large, population-based case-control study, we found no evidence of an association between bisphosphonate use and risk of venous thromboembolism (VTE). INTRODUCTION: We examined the relation between the use of oral bisphosphonates for osteoporosis and the risk of VTE. METHODS: We conducted a population-based case-control study in Northern Denmark (population, 1.7 million). Using the Danish National Registry of Patients, we identified all women with a first-time hospital diagnosis of VTE between 1999 and 2006. For each case, we selected up to ten female population controls, matched on date of the index VTE event and age. Data on use of oral bisphosphonates, other medications, and comorbidity were obtained from medical databases. We used logistic regression to estimate odds ratios (OR) for VTE associated with bisphosphonate users while adjusting for potential confounding factors. RESULTS: Four thousand one hundred ninety-three cases and 41,197 controls were included in the study. One hundred forty-nine cases (3.6%) and 1,078 controls (2.6%) were current bisphosphonate users. The adjusted OR for VTE among the current bisphosphonate users compared with nonusers was 1.03 (95% confidence interval (CI): 0.84-1.26), and when restricted to cases of unprovoked thromboembolism, the adjusted OR was 1.08 (95% CI: 0.82-1.42). There was no association either for pulmonary embolism or for deep venous thrombosis. CONCLUSION: We found no evidence of an association of oral bisphosphonate use with the risk of VTE.