Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

AIMS: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer. METHODS AND RESULTS: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively. CONCLUSION: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Small-Area Analysis of Treatment and Clinical Outcomes in Patients with Venous Thromboembolism in Denmark: A Nationwide Cohort Study.

OBJECTIVES: To investigate geographical variation in initiation and extended treatment with anticoagulants and clinical outcomes among patients hospitalized with first-time venous thromboembolism (VTE) in Denmark between 2007 and 2018. METHODS: Using nationwide health care registries, we identified all patients with a first-time VTE hospital diagnosis supported by imaging data from 2007 to 2018. Patients were grouped according to residential region (5) and municipality (98) at the time of VTE diagnosis. Cumulative incidence of initiation of and extended (beyond 365 days) anticoagulation treatment as well as clinical outcomes, including recurrent VTE, major bleeding, and all-cause death, were assessed. Sex- and age-adjusted relative risks (RRs) of the outcomes were computed when comparing across individual regions and municipalities. Overall geographic variation was quantified by computing the median RR. RESULTS: We identified 66,840 patients with a first-time VTE hospitalization. A difference in initiation of anticoagulation treatment of more than 20 percentage points between regions was observed (range: 51.9-72.4%, median RR: 1.09, 95% confidence interval [CI]: 1.04-1.13). Variation was also observed for extended treatment (range: 34.2-46.9%, median RR: 1.08, 95% CI: 1.02-1.14). The cumulative incidence of recurrent VTE ranged from 3.6 to 5.3% at 1 year (median RR: 1.08, 95% CI: 1.01-1.15). The difference remained after 5 years, and variation was also observed for major bleeding (median RR: 1.09, 95% CI: 1.03-1.15), whereas it appeared smaller for all-cause mortality (median RR: 1.03, 95% CI: 1.01-1.05). CONCLUSION: Substantial geographical variation in anticoagulation treatment and clinical outcomes occurs in Denmark. These findings indicate a need for initiatives to ensure uniform high-quality care for all VTE patients.

Effectiveness and safety of oral anticoagulation treatment beyond 1 year after venous thromboembolism in patients at intermediate recurrence risk.

Effectiveness and safety of long-term anticoagulation treatment are uncertain in venous thromboembolism (VTE) patients at intermediate risk of recurrence. We examined the association between treatment beyond 1 year and outcomes in a Danish nationwide register-based study. VTE patients at intermediate risk of recurrence, that is, non-cancer patients with a first-time unprovoked VTE, who started oral anticoagulation treatment within 30 days and were alive 365 days after the index VTE were included and followed between 2007 and 2015. Exposure was extended (>365 days) or intermediate (91-365 days) treatment. Analyses were done using Cox regression on a propensity score weighted population. We included 18 609 patients with 7232 (38.9%) receiving extended treatment. Mean duration of follow-up was 2.6 years. Compared with intermediate treatment, treatment beyond 365 days was associated with a lower weighted risk of recurrent VTE (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.49-0.65) and all-cause mortality (HR 0.81, 95% CI 0.72-0.90) and an increased risk of major bleeding (HR 1.87, 95% CI 1.58-2.22). In conclusion, extended anticoagulation treatment (predominantly warfarin) beyond 1 year was in real-life settings associated with a lower risk of recurrent VTE and all-cause mortality among VTE patients with an intermediate risk of recurrence. However, an increased bleeding risk should be considered.

Setting priorities in the health care sector - the case of oral anticoagulants in nonvalvular atrial fibrillation in Denmark.

AIM: Resources devoted to health care are limited, therefore setting priorities is required. It differs between countries whether decision-making concerning health care technologies focus on broad economic perspectives or whether focus is narrow on single budgets ("silo mentality"). The cost perspective as one part of the full health economic analysis is important for decision-making. With the case of oral anticoagulants in patients with nonvalvular atrial fibrillation (NVAF), the aim is to discuss the implication of the use of different cost perspectives for decision-making and priority setting. METHODS: In a cost analysis, the annual average total costs of five oral anticoagulants (warfarin and non-vitamin K oral anticoagulants [NOACs; dabigatran, rivaroxaban, apixaban, and edoxaban]) used in daily clinical practice in Denmark for the prevention of stroke in NVAF patients are analyzed. This is done in pairwise comparisons between warfarin and each NOAC based on five potential cost perspectives, from a "drug cost only" perspective up to a "societal" perspective. RESULTS: All comparisons of warfarin and NOACs show that the cost perspective based on all relevant costs, ie, total costs perspective, is essential for the choice of therapy. Focusing on the reimbursement costs of the drugs only, warfarin is the least costly option. However, with the aim of therapy to prevent strokes and limit bleedings, including the economic impact of this, all NOACs, except rivaroxaban, result in slightly lower health care costs compared with warfarin. The same picture was found applying the societal perspective. CONCLUSION: Many broad cost-effectiveness analyses of NOACs exist. However, in countries with budget focus in decision-making this information does not apply. The present study's case of oral anticoagulants has shown that decision-making should be based on health care or societal cost perspectives for optimal use of limited resources. Otherwise, the risk is that suboptimal decisions will be likely.

Major Bleeding Complications and Persistence With Oral Anticoagulation in Non-Valvular Atrial Fibrillation: Contemporary Findings in Real-Life Danish Patients.

BACKGROUND: The nonvitamin K antagonist oral anticoagulants have recently become available as an alternative to warfarin as stroke prophylaxis in atrial fibrillation, but data on real-life patient experience, including bleeding risk, are lacking. Our objective was to compare major bleeding events and nonpersistence between the nonvitamin K antagonist oral anticoagulant apixaban and other nonvitamin K antagonist oral anticoagulants (dabigatran and rivaroxaban) and warfarin in a contemporary, nation-wide cohort of patients with nonvalvular atrial fibrillation. METHODS AND RESULTS: Of 54 321 patients (median age, 73 years; 56% male; mean CHA2DS2-VASc score, 2.9), 7963, 6715, 15 413, and 24 230 patients initiated apixaban, rivaroxaban, dabigatran, and warfarin, respectively. Apixaban and rivaroxaban initiators were older, less often male, with higher HAS-BLED and CHA2DS2-VASc scores compared with dabigatran and warfarin initiators. A total of 2418 patients (4.5%) experienced a major bleeding event over all available follow-up. In this period, rivaroxaban (hazard ratio [HR] [95% CI], 1.49 [1.27-1.77]), dabigatran (HR, 1.17 [1.00-1.38]), and warfarin (HR, 1.23 [1.05-1.43]) users were significantly more likely to bleed than apixaban users. Findings were similar when restricted to the first 30 days after OAC initiation. Risk of nonpersistence was higher for dabigatran (HR, 1.45 [1.33-1.59]) and warfarin initiators (HR, 1.22 [1.12-1.33]), but not for rivaroxaban initiators (HR, 1.07 [0.96-1.20]) compared with apixaban initiators. CONCLUSIONS: In a real-world cohort of nonvalvular atrial fibrillation patients, apixaban had a lower adjusted major bleeding risk compared with rivaroxaban, dabigatran, and warfarin. Apixaban had a lower risk of nonpersistence compared with dabigatran and warfarin and similar risk compared with rivaroxaban.