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What have we learned from real-world NOAC studies in venous thromboembolism treatment?
Beyer-Westendorf, J
Thrombosis research. 2018;:83-91
Abstract
Venous thromboembolism (VTE) remains a substantial clinical and health-economic burden worldwide and effective anticoagulant treatment is necessary immediately after VTE is suspected to reduce short- and long-term VTE related morbidity and mortality. For decades, low molecular weight heparin (LMWH), fondaparinux and Vitamin K antagonists (VKAs) have been the standard of anticoagulant therapy for VTE patients but these treatment options had clinically relevant drawbacks and limitations. The introduction of non-VKA oral anticoagulants (NOACs) that specifically inhibit either thrombin or factor Xa have resolved many of these drawbacks because these new compounds exhibit a rapid onset and offset of action, fewer food and drug interactions and a predictable anticoagulant effect. All NOACs have successfully completed their respective phase-III trial programs consisting of many large randomized controlled trials, leading to approval for acute VTE treatment around the world. Nevertheless, their introduction into daily care practice is challenging and a careful evaluation of the effectiveness and safety of NOACs in less selected cohorts outside carefully monitored clinical trials is essential. This review introduces the different types of real-world evidence (RWE) and explores the available data for VTE treatment with NOACs, based on a literature search using the key words "venous thromboembolism" or "VTE" in combination with "NOAC", "DOAC", "apixaban", "dabigatran", "edoxaban" and "rivaroxaban" on June 30; 2017, followed by data extraction from studies that reported real-world outcome data for VTE treatment with NOACs, although available evidence is almost exclusively limited to rivaroxaban.
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Novel oral anticoagulants in chronic kidney disease: ready for prime time?
Ashley, J, Sood, MM
Current opinion in nephrology and hypertension. 2018;(3):201-208
Abstract
PURPOSE OF REVIEW Patients with chronic kidney disease (CKD) are at increased risk of atrial fibrillation, stroke, and bleeding posing unique clinical challenges. Novel oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have become recognized as alternative therapy to Vitamin K Antagonists (VKA) regarding the prevention of venous thromboembolism (VTE) and reduce the risk of stroke in atrial fibrillation. However, the understanding of NOACs in CKD is still underdeveloped. This review summarizes recent literature on the efficacy and safety of NOACs in patients with CKD. RECENT FINDINGS Studies focusing on patients with moderate kidney disease were drawn from post hoc analyses from three major NOAC trials, meta-analyses, and postmarketing surveillance studies. Cumulatively, these studies continue to demonstrate NOACs as equivalent if not superior therapies to VKAs in regards to both efficacy and safety. These studies are limited by small sample sizes as well as a lack of direct comparison between NOACs. SUMMARY The role of NOACs in managing VTE and atrial fibrillation is increasing. Current research suggests that NOACs are at least as efficacious and well tolerated as VKAs. More research is required to elucidate which NOAC is preferable in the clinical setting.
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Trends in direct oral anticoagulant (DOAC) use: health benefits and patient preference.
de Jong, LA, Koops, M, Gout-Zwart, JJ, Beinema, MJ, Hemels, MEW, Postma, MJ, Brouwers, JRBJ
The Netherlands journal of medicine. 2018;(10):426-430
Abstract
In 2012, the Dutch Health Council published a report addressing barriers for an early and broad introduction of direct oral anticoagulants (DOACs). The report raised concerns about the lack of an antidote, adherence, lack of monitoring in the case of overdose and the increased budget impact at DOAC introduction. In the past decade, international studies have shown that DOACs can provide healthcare benefits for a large number of patients. This has led to an increase in the prescription of DOACs, as they are an effective and user-friendly alternative to vitamin K antagonists (VKAs). Unlike VKAs, DOACs do not need monitoring of the international normalized ratio due to more predictable pharmacokinetics. However, the number of prescriptions of DOACs in the Netherlands is still lagging, compared to other European countries. This article highlights the potential health gains in the Netherlands if the use of DOACs were to increase, based on current international experience.
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Plasma hepcidin is associated with future risk of venous thromboembolism.
Ellingsen, TS, Lappegård, J, Ueland, T, Aukrust, P, Brækkan, SK, Hansen, JB
Blood advances. 2018;(11):1191-1197
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Abstract
Red cell distribution width (RDW) is associated with venous thromboembolism (VTE), but the underlying mechanism(s) is unclear. Iron deficiency is associated with high RDW, and studies suggest an association between iron deficiency and VTE. To assess whether iron deficiency is a risk factor for VTE that explains the association between RDW and VTE, we conducted a nested case-control study of 390 patients with VTE and 802 age- and sex-matched controls selected from the population-based cohort of the Tromsø Study. Physical measurements and blood samples were collected from 1994 to 1995. Logistic regression models were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE by RDW, hepcidin, and ferritin light chain (FtL). RDW was inversely associated with hepcidin, FtL, and hemoglobin. The risk of VTE increased linearly across categories of higher plasma hepcidin levels. Participants with hepcidin in the highest quartile had an OR for VTE of 1.32 (95% CI, 1.00-2.42), and those in the >90% percentile had an OR for VTE of 1.66 (95% CI, 1.14-2.42) compared with the reference group (quartiles 2 and 3). The risk estimates remained similar after adjustment for C-reactive protein. The risk of VTE increased by categories of higher RDW and was strengthened after inclusion of hepcidin and FtL in the multivariable model. Our findings reject the hypothesis that iron deficiency explains the association between RDW and VTE and suggest, in contrast, that high body iron levels might increase the risk of VTE.
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To What Extent Does Posthospital Discharge Chemoprophylaxis Prevent Venous Thromboembolism After Bariatric Surgery?: Results From a Nationwide Cohort of More Than 110,000 Patients.
Thereaux, J, Lesuffleur, T, Czernichow, S, Basdevant, A, Msika, S, Nocca, D, Millat, B, Fagot-Campagna, A
Annals of surgery. 2018;(4):727-733
Abstract
OBJECTIVE The aim of the present study was to assess the incidence, risk factors, and the impact of posthospital discharge (PHD) chemoprophylaxis on venous thromboembolism (VTE) in patients undergoing bariatric surgery (BS). BACKGROUND VTE is a major concern after BS, especially during the PHD period. No large-scale study has previously focused on the clinical value of PHD chemoprophylaxis. METHODS In this nationwide observational population-based cohort study, all data from patients undergoing BS were extracted from the French National Health Insurance database (SNIIRAM) from 1st January 2012 to 31st September 2014. Logistic regression models were used to compute odds ratios for potential risk factors for VTE occurring within 90 postoperative days (PODs). The association between use of PHD chemoprophylaxis (heparin) and VTE was also assessed. RESULTS The majority (56%) of the 110,824 patients had sleeve gastrectomy. VTE rates during the first 30 and 90 PODs were 0.34% and 0.51%, respectively. On multivariate analyses, the major risk factors for VTE during the first 90 PODs were history of VTE [odds ratio = 6.33 95% confidence interval (4.44-9.00)], postoperative complications [9.23 (7.30-11.70)], heart failure [2.45 (1.48-4.06)], and open surgery [2.38 (1.59-3.45)]. PHD chemoprophylaxis was delivered to 75% of patients. No use of PHD chemoprophylaxis [1.27 (1.01-1.61)] was an independent predictive factor of VTE during the first 90 PODs [in the gastric bypass group: 1.51 (1.01-2.29)). CONCLUSIONS In the modern era of BS, this nationwide study shows a non-negligible rate of VTE especially after sleeve gastrectomy, depending on the individual risk level. Use of PHD chemoprophylaxis may decrease the risk of PHD VTE.
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Management of venous thromboembolism with non-vitamin K oral anticoagulants: A review for nurse practitioners and pharmacists.
Schmerge, M, Earl, S, Kline, C
Journal of the American Association of Nurse Practitioners. 2018;(4):185-192
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Abstract
BACKGROUND AND PURPOSE Venous thromboembolism (VTE), comprising deep-vein thrombosis and pulmonary embolism, is associated with significant morbidity and mortality. Non-vitamin K oral anticoagulants (NOACs), including apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban, are as effective and safe as vitamin K antagonists (VKAs) for primary prophylaxis, treatment, and/or secondary prevention of VTE and present significant advantages in convenience of use. This review provides guidance to nurse practitioners (NPs) and pharmacists on NOAC usage for the management of VTE and examines how traditional anticoagulation clinics can adapt to cater to patients on NOACs. METHODS A review of the scientific literature pertaining to treatment guideline recommendations, large randomized clinical trials, and real-world evidence studies related to VTE management was conducted. CONCLUSIONS With current data suggesting that NOACs may present as better alternatives over VKAs for the management of VTE, comprehensively educating NPs and pharmacists can help incorporate these agents in their clinical practice. IMPLICATIONS FOR PRACTICE Repurposing anticoagulation clinics, led by well-informed NPs and pharmacists, will allow effective integration and optimal management of patients with VTE taking NOACs as well as those taking VKAs.
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Risk of intracranial hemorrhage associated with therapeutic anticoagulation for venous thromboembolism in cancer patients: a systematic review and meta-analysis.
Rojas-Hernandez, CM, Oo, TH, García-Perdomo, HA
Journal of thrombosis and thrombolysis. 2017;(2):233-240
Abstract
Intracranial hemorrhage (ICH) in cancer patients can result from tumor bleeding and from antitumor and anticoagulation therapy. The effect of anticoagulation on the incidence of ICH in cancer patients has not been quantified. Our objective was to determine the risk of intracranial hemorrhage associated with anticoagulation therapy for cancer-associated venous thromboembolism (VTE). Systematic review and meta-analysis of studies assessing the safety of anticoagulation therapy in patients with cancer-associated VTE. The primary endpoint of interest was the incidence of ICH and secondary outcomes included all major bleeding, and the time to ICH and major bleeding. After identifying 595 studies, five studies and 2089 patients were included in the analyses. We found that the relative risk (RR) for ICH was 0.494, 95 % CI (0.105-2.331) when low molecular weight heparin (LMWH) with vitamin K antagonist (VKA) anticoagulants were compared. No statistically significant differences in risk were measured. The risk of major bleeding using any type of anticoagulation therapy in patients with cancer-associated VTE was RR 0.853, 95 % CI (0.549, 1.327). After meta-analytic review of data published through August 2015, we conclude that therapeutic anticoagulation with LMWH given ≤6 months does not increase the risk of ICH in cancer patients compared to VKA. The risk of ICH in cancer patients is also similar to that of non-cancer patients. Available data were insufficient to determine if the ICH risk increase changes when the duration of anticoagulation is >6 months.
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Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation and Venous Thromboembolism: A Systematic Review and Meta-analyses.
Almutairi, AR, Zhou, L, Gellad, WF, Lee, JK, Slack, MK, Martin, JR, Lo-Ciganic, WH
Clinical therapeutics. 2017;(7):1456-1478.e36
Abstract
PURPOSE The findings from the observational studies comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) for atrial fibrillation (AF) and venous thromboembolism (VTE) are inconsistent. We conducted separate meta-analyses examining the efficacy/effectiveness and safety of NOACs versus VKAs by disease (AF vs VTE), study design (randomized controlled trials [RCTs] vs observational studies), and NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban). METHODS The main data sources included PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, and Scopus from January 1, 2005, to February 15, 2016. We searched for Phase III RCTs and observational studies comparing NOACs versus VKAs. The primary outcomes were stroke/systemic embolism (SE) for AF; recurrent VTE/fatal pulmonary embolism (PE) for VTE; and major bleeding for both conditions. Secondary outcomes included stroke and myocardial infarction (MI) for AF, recurrent deep vein thrombosis (DVT)/PE for VTE, and mortality, intracranial hemorrhage (ICH), and gastrointestinal bleeding for both conditions. Pooled hazard ratios (HRs) were reported by using inverse variance-weighted random effects models. FINDINGS A total of 13 RCTs and 27 observational studies (AF, n = 32; VTE, n = 8) were included. For AF, dabigatran and VKAs were comparable for stroke/SE risk in 1 RCT (HR, 0.77 [95% CI, 0.57-1.03]) and 6 observational studies (HR, 1.03 [95% CI, 0.83-1.27]). Rivaroxaban had a 20% decreased risk of stroke/SE in 3 RCTs (HR, 0.80 [95% CI, 0.67-0.95]) compared with VKA, but the effect was nonsignificant in 3 observational studies (HR, 0.78 [95% CI, 0.59-1.04]). Apixaban decreased stroke/systemic embolism risk (HR, 0.79 [95% CI, 0.66-0.95]) compared with VKA in 1 RCT, but edoxaban was comparable to VKA (HR, 0.99 [95% CI, 0.77-1.28]) in 1 RCT (no observational studies available for apixaban/edoxaban). Dabigatran, apixaban, and edoxaban decreased the risk of hemorrhagic stroke, mortality, major bleeding, and ICH by 10% to 71% compared with VKAs but not rivaroxaban. For VTE, NOACs and VKAs were comparable for recurrent VTE/fatal PE/DVT/PE risk in 7 RCTs and 1 observational study. The 7 RCTs demonstrated a 32% to 69% decreased risk of major bleeding for dabigatran, rivaroxaban, and apixaban compared with VKAs. No difference was shown in 1 rivaroxaban observational study (HR, 0.77 [95% CI, 0.40-1.49]) and 1 edoxaban RCT (HR, 0.84 [95% CI, 0.59-1.20]). Except for dabigatran, the NOACs had a 61% to 86% decreased risk of ICH and gastrointestinal bleeding. IMPLICATIONS Overall, NOACs were comparable or superior to VKAs. Although no observational studies are currently available for apixaban/edoxaban, a few notable inconsistencies exist for dabigatran (ischemic stroke, MI) and rivaroxaban (stroke/SE, major bleeding in VTE) between RCTs and observational studies. Individualizing NOAC/VKA therapy based on benefit/safety profiles and patient characteristics is suggested.
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In-Hospital Management and Follow-Up Treatment of Venous Thromboembolism: Focus on New and Emerging Treatments.
Lenchus, JD, Biehl, M, Cabrera, J, Moraes, AG, Dezfulian, C
Journal of intensive care medicine. 2017;(5):299-311
Abstract
Venous thromboembolism (VTE), encompassing pulmonary embolism (PE) and deep venous thrombosis (DVT), is a major cause of morbidity and mortality of particular relevance for intensivists and hospitalists. Acute VTE is usually managed with parenteral unfractionated heparin or low-molecular-weight heparin, followed by an oral vitamin K antagonist. Data are lacking for optimal treatment of less common occurrences, such as upper extremity DVT, and for approaches such as thrombolysis for PE associated with early signs of hemodynamic compromise or inferior vena cava filters when anticoagulation is contraindicated. Direct oral anticoagulants (DOACs) including apixaban, dabigatran, edoxaban, and rivaroxaban are now added to the armamentarium of agents available for acute management of VTE and/or reducing the risk of recurrence. This review outlines an algorithmic approach to acute VTE treatment: from aggressive therapies when anticoagulation may be inadequate, to alternative choices when anticoagulation is contraindicated, to anticoagulant options in the majority of patients in whom anticoagulation is appropriate. Evidence-based guidelines and the most recent DOAC clinical trial data are discussed in the context of the standard of care. Situations and treatment approaches for which data are unavailable or insufficient are identified. VTE therapy in care transitions is discussed, as are choices for secondary prevention.
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Safety of warfarin in "high-risk" populations: A meta-analysis of randomized and controlled trials.
Di Minno, MN, Ambrosino, P, Dentali, F
Thrombosis research. 2017;:1-7
Abstract
INTRODUCTION Few data are available about safety of vitamin K antagonists (VKAs) in patients with clinical/demographic characteristics predisposing to an increased risk of bleeding. We performed a meta-analysis to evaluate the safety of VKAs in patients with atrial fibrillation (AF) or venous thromboembolism (VTE) in the following subgroups of "high-risk" patients: elderly patients, patients with low body weight and patients with impaired renal function. MATERIALS AND METHODS Major electronic databases were systematically searched to identify randomized controlled trials (RCTs) addressing this issue. Pooled Risk Ratios (RR) and 95% Confidence Intervals (CI) were calculated for each outcome using a random effects model. RESULTS Eleven RCTs for a total of 41,015 patients treated with VKAs (25,901 with AF and 15,114 with VTE) were included. We found a significant association between age>75years and bleeding in patients receiving VKAs (RR: 1.62, 95%CI: 1.28-2.05; P<0.0001). Moreover, the prevalence of bleeding events under VKAs was significantly higher in patients with low body weight (RR: 1.20, 95%CI: 1.03-1.40; P=0.02) and in those with impaired renal function (RR: 1.59, 95%CI: 1.30-1.94; P<0.00001). Results were confirmed when separately analyzing data on AF and VTE. Regression models showed that treatment duration did not impact on the differences found in the safety profile of VKAs in different settings analyzed. CONCLUSIONS Results of our meta-analysis suggest an increased risk of bleeding complications in "high-risk" patients. Although all results are significant, other studies focused on this issue are warranted to further validate these results.