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The prevalence of heart failure (HF) and co-morbidities are increasing. The prognostic impact of interaction between co-morbidity and HF remains unknown. The purpose of the present study was to examine if HF interacts with co-morbidity burden to increase mortality. We conducted a cohort study of all adult Danish patients (aged ≥18 years) with a hospital inpatient or outpatient clinic diagnosis of HF (n = 252,726) between 1995 and 2016. We matched each patient with up to 3 members of the general population without a history of HF (n = 744,372). Noncardiac co-morbidities were assessed using the Charlson co-morbidity index and were defined by 4 categories of co-morbidity: 0 (none), 1 (low), 2 to 3 (moderate), and ≥4 (severe). Cardiac co-morbidities were assessed individually. Among patients with HF with severe co-morbidity, 42% of the mortality rate during 30 days of follow-up was explained by the interaction with co-morbidity. The interaction effect was also substantial in patients with moderate (31%) and low co-morbidity burden (16%). During 31 to 365 days of follow-up, interaction effects were 1% for low co-morbidity, 8% for moderate co-morbidity, and 22% for severe co-morbidity. Beyond 1 year of follow-up, no interaction effect was observed. With the exception of cardiomyopathy, cardiac co-morbidities did not interact substantially with HF during the first year of follow-up. During longer follow-up, pulmonary hypertension, cardiomyopathy, and endocarditis showed interaction. In conclusion, noncardiac co-morbidities had biological interaction with HF that increased short-term mortality substantially beyond the individual effects of HF and co-morbidity.

BACKGROUND: Survival after heart transplantation has increased due to continuously refined and effective care management. Knowledge is sparse on the influence of multimorbidity and social vulnerability on management. We assessed the long-term influence of multimorbidity and socioeconomic factors on cross-sectional health care service utilization in heart transplant recipients.METHODS: First-time heart transplant recipients, from the Transplant Center at Aarhus University Hospital, were followed from transplant until December 31, 2018. We linked individual-level data from the Scandiatransplant Database to Danish national registers. We followed recipients for 15 years using descriptive statistic.RESULTS: We identified 325 recipients; 79% were male and 60% were between 41 and 60 years of age. The median (IQR) number of chronic conditions at baseline was 1.0 (1.0-2.0). The prevalence of recipients with ≥3 chronic conditions in the follow-up period 0 to 1 year was 10% and 65% within 10 to 15 years. The median use of cross-sectional health care services was higher in recipients with ≥3 chronic conditions compared to CONCLUSIONS: The use of cross-sectional health care services was higher in heart transplant recipients with increased incidence of comorbidities during follow-up intervals. A socioeconomic influence was observed in the utilization of services.

Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients. Background: Outcome after colorectal liver metastases (CRLM) resection has improved over time, despite increased resection rates. Hence, it's crucial to identify all patients possible to treat with curative intent. The objectives of this study were to map recurrence pattern, treatment strategy and survival depending on treatment and follow-up strategy.Methods: In the COLOFOL-trial, patients with radically resected stage II-III colorectal cancer were randomized to high-frequency (6, 12, 18, 24 and 36 months; HF) or low-frequency (12 and 36 months; LF) follow-up. In this study, all CRLM within 5 years were identified and medical files scrutinized. Overall survival (OS) was analysed in uni- and multivariable analyses. Primary endpoint was 5-year OS.Results: Of 2442 patients, 235 (9.6%) developed metachronous CRLM of which 123 (52.3%) underwent treatment with curative intent, resulting in 5-year OS of 58%. Five-year OS for patients with CRLM was 43% after HF versus 24% after LF. The survival benefit was confirmed for HF 8 years from resection of the primary tumour, HR 0.63 (CI 0.46-0.85).Conclusion: A high proportion of metachronous CRLM was possible to treat with curative intent, yielding high survival rates. More intense follow-up after colorectal cancer resection might be of value in high-risk patients.

Objectives: Sarcoidosis may have an infectious trigger, including Mycobacterium spp. The Bacille Calmette-Guérin (BCG) vaccine provides partial protection against tuberculosis and induces trained immunity. We examined the incidence rate (IR) of sarcoidosis in Danish individuals born during high BCG vaccine uptake (born before 1976) compared with individuals born during low BCG vaccine uptake (born in or after 1976). Methods: We performed a quasi-randomized registry-based incidence study using data from the Danish Civil Registration System and the Danish National Patient Registry between 1995 and 2016. We included individuals aged 25–35 years old and born between 1970 and 1981. Using Poisson regression models, we calculated the incidence rate ratio (IRR) of sarcoidosis in individuals born during low BCG vaccine uptake versus high BCG vaccine uptake, adjusting for age and calendar year (separately for men and women). Results: The IR of sarcoidosis was increased for individuals born during low BCG vaccine uptake compared with individuals born during high BCG vaccine uptake, which was largely attributed to men. The IRR of sarcoidosis for men born during low BCG vaccine uptake versus high BCG vaccine uptake was 1.22 (95% confidence interval [CI] 1.02–1.45). In women, the IRR was 1.08 (95% CI 0.88–1.31). Conclusion: In this quasi-experimental study that minimizes confounding, the time period with high BCG vaccine uptake was associated with a lower incidence rate of sarcoidosis in men, with a similar effect seen in women that did not reach significance. Our findings support a potential protective effect of BCG vaccination against the development of sarcoidosis. Future interventional studies for high-risk individuals could be considered.

BACKGROUND: The effects of statins in prevention of venous thromboembolism (VTE) is not well established.OBJECTIVES: To examine the risks of first-time VTE in a cohort of patients initiating statin treatment and in a matched general population comparison cohort.METHODS: We conducted a nationwide, population-based, matched cohort study based on data from Danish health registries. The study period was 1 January 2005-31 December 2015. We identified statin initiators (without VTE, myocardial infarction, or ischemic stroke) and sex-, age-, and calendar year-matched (1,3) individuals from the general population (without statin use, VTE, myocardial infarction, or ischemic stroke). We computed cumulative risks and comorbidity-adjusted hazard ratios (HRs) of VTE, myocardial infarction, and ischemic stroke.RESULTS: Among 601,011 statin initiators and 1,803,033 matched population cohort members during 2005-2015, the cumulative risk after 11 years was 2.8% for VTE (both cohorts), 4.7% vs. 2.9% for myocardial infarction, and 7.1% vs. 5.2 for ischemic stroke. After adjustment, statin use was associated with a slightly decreased risk of VTE (adjusted HR: 0.95 [95% CI: 0.92-0.97]), driven by a reduced risk of unprovoked VTE (adjusted HR: 0.92 [95% CI: 0.89-0.95]). The reduced risks of VTE were more pronounced among patients who had an imaging examination performed. The adjusted HRs were elevated for myocardial infarction and ischemic stroke.CONCLUSION: Statin initiation was associated with a reduced risk of VTE, with no indication of a healthy-user effect. Based on available evidence, statins have weak thromboprophylactic effects.

The CHA2DS2-VASc score is used to predict stroke risk among patients with atrial fibrillation (AF). We examined whether a CHA2DS2-VASc score predicts stroke risk among individuals without hospital-diagnosed AF and quantified the magnitude of the association in comparison to AF patients. We used data from population-based medical registries (1995 to 2005) covering all Danish hospitals to identify patients diagnosed with AF (n = 122,980). We matched ≤5 non-AF individuals (n = 612,723) to each AF patient on the individual risk factors included in the CHA2DS2-VASc score. We calculated 10-year absolute risk of ischemic and all-cause stroke in AF and non-AF individuals and compared the stroke risk between cohorts within strata of CHA2DS2-VASc scores using Cox regression. The 10-year risk of ischemic/all-cause stroke was 4.4%/8.8% among non-AF individuals and 6.2%/12% in AF patients, corresponding to a risk difference of 1.8% for ischemic stroke and 3.3% for all-cause stroke. In both cohorts, the stroke risk correlated with increasing CHA2DS2-VASc scores. However, in individuals with CHA2DS2-VASc scores ≥5 who were 2DS2-VASc score was associated with 10-year stroke risk also among individuals without hospital-diagnosed AF. In conclusion, primary prophylactic anticoagulation therapy may be relevant in male and younger non-AF individuals with CHA2DS2-VASc scores ≥5. These findings should be confirmed in clinical trials.

PURPOSE: The etiology of pericarditis, myocarditis, and endocarditis is predominantly infectious, and infections often show seasonal variation. Little is known, however, about seasonal patterns in these cardiopathies.METHODS: Using Danish health care registries, we identified all patients with a first-time hospital-based diagnosis of pericarditis, myocarditis, or endocarditis between 1994 and 2016. We estimated peak-to-trough ratios from fitted sine curves to measure the intensity of seasonal variation in occurrence during the study period. Because randomness will lead to small apparent seasonal patterns, we also conducted a plasmode simulation to assess the degree of seasonality that randomness would produce.RESULTS: Crude peak-to-trough ratios of monthly frequencies summarized over a year were small. We estimated a peak-to-trough ratio of 1.10 (95% confidence interval [CI], 1.05-1.14) for pericarditis, 1.11 (95% CI, 1.02-1.21) for myocarditis, and 1.01 (95% CI, 1.00-1.07) for endocarditis. The simulated mean peak-to-trough ratios found after randomly reassigning the monthly frequencies within each year were 1.04 (95% CI, 1.00-1.09) for pericarditis, 1.04 (95% CI, 1.00-1.13) for myocarditis, and 1.04 (95% CI, 1.00-1.10), for endocarditis.CONCLUSION: The data indicate no important seasonal variation in the occurrence of pericarditis, myocarditis, and endocarditis in Denmark between 1994 and 2016.

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.

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. SummaryBackground 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.

OBJECTIVES: To examine long-term associations between constipation and Parkinson's disease (PD) in men and women, we conducted a population-based cohort study using prospectively collected registry data on hospital contacts for constipation and PD, stratified by follow-up time and sex.METHODS: We linked Danish registries to construct a cohort of all patients in Denmark with an outpatient hospital diagnosis of constipation 1995-2012 and a matched general population comparison cohort. Using Cox regression, we computed hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders, stratified by sex and follow-up time.RESULTS: The 31,905 patients with constipation had a higher risk of PD than 159,092 comparison cohort members (adjusted (a) HR = 3.03, 95% CI 2.50-3.66), which was sustained to 11-15 years follow-up (aHR = 3.65, 95% CI 1.67-7.95). Increased risk was apparent in both sexes but stronger in men [aHR = 3.52 (2.67-4.64] than women [aHR = 2.64 (95% CI 2.02-3.44].CONCLUSION: In this large population-based cohort study, constipation was associated with sustained increased risk of a PD diagnosis, and the relative risk was higher for men than for women.

OBJECTIVES: To examine the association between vagotomy and multiple sclerosis.METHODS: We conducted a matched cohort study of all patients who underwent truncal or super-selective vagotomy and a comparison cohort, by linking Danish population-based medical registries (1977-1995). Hazard ratios (HRs) for multiple sclerosis, adjusting for potential confounders were computed by means of Cox regression analysis.RESULTS: Median age of multiple sclerosis onset corresponded to late onset multiple sclerosis. No association with multiple sclerosis was observed for truncal vagotomy (0-37 year adjusted HR=0.91, 95% confidence interval [CI]: 0.48-1.74) or super-selective vagotomy (0-37 year adjusted HR=1.28, 95% CI: 0.79-2.09) compared with the general population.INTERPRETATION: We found no association between vagotomy and later risk of late onset multiple sclerosis.

Summary 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.

Purpose Venous thromboembolism (VTE) is associated with renal cell carcinoma (RCC), but data on the effect of comorbidities are limited. Therefore, our purpose was to determine the effect of comorbidity on VTE risk among patients with RCC.

INTRODUCTION: The association between lower-extremity venous thrombosis and cancer is well-established. However, the extent to which upper-extremity deep venous thrombosis (U-DVT) is a marker of cancer and a prognostic factor for all-cause mortality remains poorly understood. We examined the risk of cancer after a diagnosis of U-DVT compared with cancer risk in the general population.MATERIALS AND METHODS: Using Danish nationwide population-based medical registries, we identified all patients with first-time U-DVT during 1980-1993 and 2000-2013. Cancer incidence was ascertained using data from the Danish Cancer Registry. We computed standardized incidence ratios (SIRs) calculated as the observed number of cancers relative to the expected number based on national incidence rates by sex, age, and calendar year. We created a matched comparison cohort of cancer patients without U-DVT, to assess the impact of U-DVT on all-cause mortality.RESULTS: Among 1087 patients with U-DVT, 232 patients subsequently were diagnosed with cancer, corresponding to an overall SIR of 1.69 (95% confidence interval, 1.48-1.92). During the first 6months following U-DVT, the absolute risk of any cancer was 5.4%, corresponding to a 13-fold elevated SIR. During the subsequent 6-12months and >12months, the SIR remained 2-fold and 1.3-fold elevated, respectively. U-DVT was a prognostic factor for all-cause mortality in patients with lung, prostate, and colorectal cancer during the first 6months of follow-up.CONCLUSION: U-DVT was a marker of cancer. The clinical utility of searching for occult cancer in patients with U-DVT remains unknown.

Background: Venous thromboembolism can be a presenting symptom of cancer, but the association between lower limb arterial thrombosis and cancer is unknown. We therefore examined cancer risk and prognosis of cancer in patients with lower limb arterial thrombosis. Methods: Using nationwide population-based Danish medical registries, we identified all patients diagnosed with first-time lower limb arterial thrombosis (1994−2013) and followed them until the occurrence of any subsequent cancer diagnosis, emigration, death, or November 30, 2013, whichever came first. We computed standardized incidence ratios with 95% confidence intervals as the observed number of cancers relative to the expected number based on national incidence rates by sex, age, and calendar year. To examine the prognostic impact of lower limb arterial thrombosis on all-cause mortality after cancer, we constructed a matched comparison cohort of patients who had cancer without lower limb arterial thrombosis. Results: Among 6600 patients with lower limb arterial thrombosis, we observed 772 subsequent cancers. The risk of any cancer was 2.5% after 6 months of follow-up, increasing to 17.9% after 20 years. During the first 6 months of follow-up, the standardized incidence ratio of any cancer was 3.28 (95% confidence interval, 2.79–3.82). The standardized incidence ratio remained elevated during 7 to 12 months (1.42; 95% confidence interval, 1.09–1.83) and beyond 12 months (1.14; 95% confidence interval, 1.05–1.24). The strongest associations were found for lung cancer and other smoking-related cancers. Lower limb arterial thrombosis also was associated with increased all-cause mortality after colon, lung, urinary bladder, and breast cancer, but not after prostate cancer. Conclusions: Lower limb arterial thrombosis was a marker of occult cancer, especially lung cancer, and was an adverse prognostic factor for mortality in common cancers.

Udgivelsesdato: 2009 Summary Background: Atherosclerotic disease has been associated with the risk of venous thromboembolism, but the available data are conflicting. There are similar confusions regarding the association of use of aspirin and statins with venous thromboembolism. Objectives: To determine whether arterial cardiovascular events, use of statins and low dose aspirin were associated with the risk of venous thromboembolism. Patients and methods: In this population-based case-control study we identified 5824 patients with venous thromboembolism and 58 240 population controls with complete hospital and prescription history. We used logistic regression to estimate the relative risk of venous thromboembolism, adjusted for potentially confounding factors. Results: Patients with a history of arterial cardiovascular events had a clearly increased relative risk. An event within three months before the index date conferred large increases in risk, [relative risk 4.22 (95% confidence interval (CI), 2.33-7.64) after myocardial infarction, 4.41 (95% CI, 2.92-6.65) after stroke]. Myocardial infarction more than three months before the index date was not significantly associated with risk, though there was a relative risk of 1.29 (95% CI, 1.05-1.57) for myocardial infarction more than 60 months previously. A history of stroke was associated with small increases in risk after three months. Current use of statins was associated with a reduced risk of venous thromboembolism (relative risk = 0.74 (95% CI, 0.63-0.85). Aspirin use was not associated with risk. Conclusions: Patients with cardiovascular events are at short term increased risk of venous thromboembolism. Statins might prevent venous thromboembolism but aspirin does not. However, since the study is non-randomized residual confounding cannot be excluded.

Background: Self-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 CRC recurrence and long-term mortality, but data regarding these risks are sparse. Several attempts to compare SEMS with acute surgery in randomized settings have failed and the existing evidence from observational studies is based primarily on singlecenter studies conducted in highly specialized settings with little or no information on potential confounding factors.Methods:We conducted a nationwide population-based cohort study using Danish medical registries (2005-2010) by comparing overall mortality and recurrence after CRC resection in patients with preoperative stenting (n=581) to patients undergoing urgent (n=3,333) or elective resection (n=13,722). For patients surviving the first 30 days after CRC resection, we used the Kaplan Meier method to compute absolute survival. For CRC patients with localized and regional disease, the risk of CRC recurrence was estimated treating death as a competing risk. We computed mortality rate ratios (MRRs) and cause specific hazard ratios of recurrence within 5 years, using Cox regression with adjustment for important covariates. Results: Crude 5-year survival was 49% (95% CI: 43%55%) among patients with preoperative SEMS, 40% (95% CI: 38%-43%) among patients undergoing urgent resection, and 65% (95% CI: 64%-66%) among patients with elective resection. For SEMS vs. urgent resection, the adjusted MRR was 0.99 (95% CI: 0.91-1.07) and for SEMS vs. elective resection, the adjusted MRR was 1.39 (95% CI: 1.19-1.62). The 5-year recurrence risk was 39% (95% CI: 31%-46%) after preoperative SEMS, 30% (95% CI: 27%-32%) after urgent resection, and 22% (95% CI: 21%-24%) after elective surgery. The adjusted cause-specific hazard ratios for recurrence were 1.13 (95% CI: 0.99-1.28) for SEMS vs. urgent resection and 1.81 (95% CI: 1.44-2.28) for SEMS vs. elective resection. Conclusions: Long-term mortality associated with use of SEMS as a bridge to surgery was comparable to that of urgent resection, but higher than that observed following elective resection. SEMS use may be associated with an increased risk of CRC recurrence.