Variation in the Association between Antineoplastic Therapies and Venous Thromboembolism in Patients with Active Cancer.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of death in cancer patients. Although patients with cancer have numerous risk factors for VTE, the relative contribution of cancer treatments is unclear. OBJECTIVE: The objective of this study is to evaluate the association between cancer therapies and the risk of VTE. METHODS: From UK Clinical Practice Research Datalink, data on patients with first cancer diagnosis between 2008 and 2016 were extracted along with information on hospitalization, treatments, and cause of death. Primary outcome was active cancer-associated VTE. To establish the independent effects of risk factors, adjusted subhazard ratios (adj-SHR) were calculated using Fine and Gray regression analysis accounting for death as competing risk. RESULTS: Among 67,801 patients with a first cancer diagnosis, active cancer-associated VTE occurred in 1,473 (2.2%). During a median observation time of 1.2 years, chemotherapy, surgery, hormonal therapy, radiation therapy, and immunotherapy were given to 71.1, 37.2, 17.2, 17.5, and 1.4% of patients with VTE, respectively. The active cancers associated with the highest risk of VTE-as assessed by incidence rates-included pancreatic cancer, brain cancer, and metastatic cancer. Chemotherapy was associated with an increased risk of VTE (adj-SHR: 3.17, 95% confidence interval [CI]: 2.76-3.65) while immunotherapy with a not significant reduced risk (adj-SHR: 0.67, 95% CI: 0.30-1.52). There was no association between VTE and radiation therapy (adj-SHR: 0.91, 95% CI: 0.65-1.27) and hormonal therapies. CONCLUSION: VTE risk varies with cancer type. Chemotherapy was associated with an increased VTE risk, whereas with radiation and immunotherapy therapy, an association was not confirmed.

Prediction of significant bleeding during vitamin K antagonist treatment for venous thromboembolism in outpatients.

Bleeding is the most concerning complication associated with anticoagulant therapy but poorly characterized and important for risk/benefit assessment. We developed a risk stratification score to predict vitamin K antagonist (VKA)-associated bleeding in venous thromboembolism (VTE) using the UK Clinical Practice Research Datalink. Significant bleeding events in outpatients consisted of major bleeding and clinically relevant non-major bleeding requiring hospitalisation (CRNMB-H) within 90 days of VKA initiation. A scoring scheme for predicting bleeding was developed from subhazard ratios, validated using cross-validation and expressed by the C-statistic. The study cohort consisted of 10,010 patients with first VTE receiving initial VKA treatment, mean age 62·2 years. Between 2008 and 2016, 167 significant bleeding events were recorded (1·7%), i.e. incidence rate was 7·4/100 person-years. Independent predictors for community-acquired significant bleeding included active cancer, trauma/surgical procedure, male gender, dementia, liver disease, anaemia, history of bleeding, cerebrovascular, renal and chronic pulmonary disease, VTE presenting as pulmonary embolism and age over 75. The overall C-statistic was 0·68 (95% CI, 0·60-0·76), 0·75 (0·60-0·88) for major bleeding and 0·65 (0·55-0·75) for CRNMB-H, and higher than in other risk schemes applied to our study population. The developed risk score may identify patients having a significant bleeding risk, in particular major bleeding events, in outpatients.

Incident Atrial Fibrillation, Dementia and the Role of Anticoagulation: A Population-Based Cohort Study.

INTRODUCTION: Atrial fibrillation (AF) is associated with dementia. Anticoagulation may modify this relationship, but it is unclear if this is due to stroke reduction alone. METHODS: Age- and sex-matched individuals from the U.K. Clinical Practice Research Datalink (2008-2016) with and without an incident diagnosis of AF were followed for a new dementia diagnosis. We estimated adjusted hazard ratios (aHRs) for incident dementia diagnosis in the AF cohort, overall and stratified by anticoagulation status, using the matched non-AF cohorts as reference. We performed a sensitivity analysis excluding individuals with stroke/transient ischaemic attack (TIA) before the observation period. RESULTS: Over 193,082 person-years (mean follow-up 25.7 ± 0.1 months), 347/15,276 AF (2.3%) and 1,085/76,096 non-AF (1.4%) were newly diagnosed with dementia (aHR, 1.31, 95% confidence interval, 1.15-1.49). The AF group had more co-morbidity and higher rates of dementia, both with and without anticoagulation, than non-AF. When those with history of stroke/ TIA before the observation period were excluded and those with incident stroke/TIA during the observation period were censored, AF individuals not on anticoagulation had significantly higher rates of dementia compared with non-AF, aHR 1.30 (1.06-1.58). CONCLUSION: Our findings support the hypothesis that AF is a distinct risk factor for dementia, independent of stroke/TIA and other vascular risk factors. In those without stroke/TIA, risk of dementia is increased only in those who are not on anticoagulation, suggesting anticoagulation is protective presumably through reduction of sub-clinical embolic events. Further prospective research is needed to better ascertain the role of anticoagulation amongst targeted therapeutic strategies to reduce cognitive decline in AF.

Thirteen-year trend in the persistence with vitamin K antagonists for venous thromboembolism in the UK: a cohort study.

BACKGROUND: Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE) and is associated with significant recurrence and mortality risk. Standard VTE treatment includes at least 3 months anticoagulation. The objective was to describe time trends in the duration of oral anticoagulation in patients initially treated with vitamin K antagonists (VKAs). METHODS: A retrospective cohort study was conducted on patients with first VTE and VKA treatment initiation within 30 days, identified from the UK Clinical Practice Research Datalink from 2001 to 2014. VKA users were followed for the duration of oral anticoagulation which included switching to non-VKA oral anticoagulants. The probability of remaining on anticoagulation treatment (persistence) was estimated using Kaplan-Meier survival functions. RESULTS: A total of 16,018 patients with VTE initiated VKA; 48.2% males, mean age 62.1 years, median VKA treatment duration 6.5 months. The 90-day persistence increased from 75.6% in 2001 to 91.2% in 2013 (p < .0001) and the 180-day persistence from 39.3% in 2001 to 61.1% in 2013 (p < .0001). This time trend was also shown for patients with DVT, PE, provoked VTE, unprovoked VTE, provoked DVT, unprovoked DVT, provoked PE and unprovoked PE. There were no major differences in persistence between patients with provoked and unprovoked VTE, but persistence was lower following DVT than PE (p < .0001). CONCLUSIONS: The increase in persistence was independent of the presentation of the first VTE (provoked or unprovoked), but higher for first PE. Whether the increasing persistence resulted in decreasing risk of recurrent VTE needs to be confirmed.

Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study.

Population studies on the incidence of venous thromboembolism (VTE) in patients with active cancer are limited. An observational cohort study was undertaken to estimate the incidence of first and recurrent VTE. The source population consisted of all patients in the UK Clinical Practice Research Datalink, with additional information on hospitalisation and cause of death, between 2001 and 2011. A cancer-related clinical diagnosis or therapy within the 90 days before or after a VTE constituted an active-cancer-associated VTE. Incidence rates of first VTE among patients with active cancer and incidence rates of recurrent VTE during the 10-year observational period after a first VTE event were estimated. Incidence rates of all-cause mortality and age- and gender-specific mortality were also calculated. There were 6,592 active-cancer-associated VTEs with a total of 112,738 cancer-associated person-years of observation. The incidence rate of first VTE in patients with active cancer was 5.8 (95 % confidence interval 5.7-6.0) per 100 person-years. A first VTE recurrence was observed in 591 patients. The overall incidence rate for recurrence was 9.6 (95 % confidence interval 8.8-10.4) per 100 person-years, with a peak at 22.1 in the first six months. Recurrence rates were similar after initial pulmonary embolism and after initial deep-vein thrombosis. The mortality risk after VTE was considerable, with 64.5 % mortality after one year and 88.1 % after 10 years. VTE in patients with active cancer is common and associated with high recurrence and mortality rates. Efforts are needed to prevent VTE and reduce recurrence, especially in the first year after VTE diagnosis.

Testosterone treatment and risk of venous thromboembolism: population based case-control study.

OBJECTIVE:  To determine the risk of venous thromboembolism associated with use of testosterone treatment in men, focusing particularly on the timing of the risk. DESIGN:  Population based case-control study SETTING:  370 general practices in UK primary care with linked hospital discharge diagnoses and in-hospital procedures and information on all cause mortality. PARTICIPANTS:  19 215 patients with confirmed venous thromboembolism (comprising deep venous thrombosis and pulmonary embolism) and 909 530 age matched controls from source population including more than 2.22 million men between January 2001 and May 2013. EXPOSURE OF INTEREST:  Three mutually exclusive testosterone exposure groups were identified: current treatment, recent (but not current) treatment, and no treatment in the previous two years. Current treatment was subdivided into duration of more or less than six months. MAIN OUTCOME MEASURE:  Rate ratios of venous thromboembolism in association with current testosterone treatment compared with no treatment were estimated using conditional logistic regression and adjusted for comorbidities and all matching factors. RESULTS:  The adjusted rate ratio of venous thromboembolism was 1.25 (95% confidence interval 0.94 to 1.66) for current versus no testosterone treatment. In the first six months of testosterone treatment, the rate ratio of venous thromboembolism was 1.63 (1.12 to 2.37), corresponding to 10.0 (1.9 to 21.6) additional venous thromboembolisms above the base rate of 15.8 per 10 000 person years. The rate ratio after more than six months' treatment was 1.00 (0.68 to 1.47), and after treatment cessation it was 0.68 (0.43 to 1.07). Increased rate ratios within the first six months of treatment were observed in all strata: the rate ratio was 1.52 (0.94 to 2.46) for patients with pathological hypogonadism and 1.88 (1.02 to 3.45) for those without it, and 1.41 (0.82 to 2.41) for those with a known risk factor for venous thromboembolism and 1.91 (1.13 to 3.23) for those without one. CONCLUSIONS:  Starting testosterone treatment was associated with an increased risk of venous thromboembolism, which peaked within six months and declined thereafter.

Therapy persistence in newly diagnosed non-valvular atrial fibrillation treated with warfarin or NOAC. A cohort study.

Efforts to reduce stroke in atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines, but high early vitamin K antagonist (VKA) discontinuation is a limitation. We compared persistence of non-VKA OAC (NOAC) with VKA treatment in the first year after OAC inception for incident AF in real-world practice. We studied 27,514 anticoagulant-naïve patients with incident non-valvular AF between January 2011 and May 2014 in the UK primary care Clinical Practice Research Datalink, with full medication use linkage: mean age 74.2 ± 12.4, 45.7% female, mean follow-up 1.9 ± 1.1 years. After treatment initiation and follow-up until 1/2015, the proportion remaining on OAC at one year (persistence) was estimated using competing risk survival analyses. OAC was commenced ≤ 90 days after incident AF in 13,221 patients (48.1%): 12,307 VKA and 914 NOAC (apixaban, dabigatran, rivaroxaban). Amongst those treated with OAC, the proportion commencing NOAC increased from zero in 1/2011 to 27.0% in 5/2014, and OAC prescriptions for CHA2DS2VASc score ≥ 2 (guideline adherence) increased from 41.2% to 65.5%. Persistence with OAC declined over 12 months to 63.6% for VKA and 79.2% for NOAC (p< 0.0001). Persistence for those with CHA2DS2VASc ≥ 2 was significantly greater for NOAC (83.0%) than VKA (65.3%, p< 0.0001) at one year and all earlier time points. Comparison of VKA and NOAC cohorts matched on individual CHA2DS2VASc components showed consistent results. In conclusion, persistence was significantly higher with NOAC than VKA, and could alone lead to fewer cardioembolic strokes. Increased guideline adherence following NOAC introduction could further decrease AF stroke burden.

Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013.

OBJECTIVE: To determine whether the incidence of atrial fibrillation (AF) is static or rising in the UK. DESIGN: Among the cohort of all individuals aged ≥45 years in the UK Clinical Practice Research Datalink (CPRD) (linked to hospital discharges) we identified incident non-valvular AF cases between 2001 and 2013. Overall and annual AF incidence rates were calculated and standardised to the UK population. RESULTS: The cohort of 2.23 million individuals included 91,707 patients with incident AF. The overall standardised AF incidence rate was 6.7 (95% CI 6.7 to 6.8) per 1000 person-years, increasing exponentially with age and higher in men of all ages. There was a small increase in the standardised incidence of AF in the last decade from 5.9 (5.8 to 6.1)/1000 person-years in 2001 to 6.9 (6.8 to 7.1)/1000 person-years in 2013, mostly attributable to subjects aged >80 years with a non-primary hospital discharge diagnosis of AF. Standardised incidence rates of AF among white patients was 8.1 (8.1 to 8.2)/1000 person-years, compared with 5.4 (4.6 to 6.3) for Asians and 4.6 (4.0 to 5.3) for black patients. AF diagnosis was first made in general practice in 39% of incident AF. CONCLUSIONS: The incidence of AF in the UK has increased gradually in the last decade, with more than 200 000 first-ever non-valvular AF cases expected in 2015. This increase is only partly due to population ageing, though the principal increase has been in the elderly hospitalised for a reason other than AF.