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Oral Anticoagulants in the ICU:
A summary of the evidence for efficacy in atrial fibrillation, venous thromboembolism, and unique clinical cases
Direct oral anticoagulants (DOACs) are recommended as the preferred treatment for venous thromboembolism (VTE) and as a first-line option for stroke prevention in nonvalvular atrial fibrillation (NVAF), but warfarin may be preferred in certain situations.1-4 These medications may be initiated or continued in the intensive care setting when not acutely contraindicated. This summary provides an overview of the evidence regarding efficacy in clinical and real-world trials of oral anticoagulants (OACs). Clinicians should be familiar with relative benefits and patient-specific factors to guide optimal treatment choice.
Acutely, OACs may be contraindicated for critically ill patients. Short-acting parenteral therapy may be preferred initially, particularly for patients with anticipated procedures or neuraxial interventions. Once the patient is stable and can receive an OAC, ongoing indication and dosing should be assessed. Drug interactions, change in organ function, or assessment of risks may have implications for dosing. Beyond the acute treatment phase of VTE, dose reduction of apixaban and rivaroxaban may be indicated. Alternatively, changing to aspirin may be appropriate in some cases.
For patients initiated on OACs, decision-making is complex. Considerations include:
- All DOACs are reasonable choices for NVAF and VTE, though real-world data for VTE has been predominantly published with rivaroxaban (Table 1 and 2).5-19
- Achieving the efficacy observed in clinical trials depends on appropriately selecting patients and correctly dosing the DOAC.
- Patients with poor adherence or lack of medical follow up are poor candidates for any anticoagulant, and this should not serve as rationale to select a DOAC over warfarin.
Once these barriers are addressed, patient-specific factors and drug characteristics should be considered (Table 3).20-30
- Those with frequent dietary changes or logistical challenges to frequent monitoring may benefit from a DOAC over warfarin.
- On the other hand, patients who are predisposed to developing acute kidney injury or have moderate to severe liver disease may be more appropriately treated with warfarin.
- Patients who miss taking a few doses a week would be better candidates to receive warfarin due to the longer pharmacodynamic effect.
- In the intensive care unit (ICU) setting, patients who cannot take dabigatran due to inability to swallow the capsule or who have inconsistent enteral intake imposing concerns for reduced absorption of rivaroxaban 15 and 20 mg doses could be treated with apixaban.
- Patients with at-home medication assistance only once a day would likely benefit from a once-daily agent such as rivaroxaban.
- OAC bioavailability may also be impacted by gastrointestinal surgery. Rivaroxaban should be avoided in patients with a total gastrectomy, while Roux-en-Y gastric bypass or distal resections have been reported to reduce dabigatran bioavailability.31
If a DOAC is the best treatment option for a patient, correctly dosing the medication is imperative. Each agent has unique dosing specific to the indication, and each requires adjustment for different patient-specific factors.
Up to 60% of patients receiving DOACs have medication errors, and about half of those are related to dosing.32 These errors can occur in the inpatient setting even with active monitoring, and patients with contraindications may also receive DOACs.33
Dose adjustments can impact outcomes, particularly when dosing is not concordant with those recommended in the package labeling.12,34
Notably, dosing and creatinine clearance used for exclusion from clinical trials was based on the Cockcroft-Gault equation using total body weight.
Medications often used in ICUs that may interact include cyclosporine, rifampin, conivaptan, amiodarone, verapamil, diltiazem, phenytoin, phenobarbital, carbamazepine, erythromycin, and dexamethasone, though this list is not all-inclusive.
In general, a reassessment for potential drug interactions should be performed for those taking OACs who experience the removal/addition of any medication known to be a strong inhibitor/inducer of cytochrome P450 3A4, P-glycoprotein, or breast cancer resistance protein.
Pharmacodynamic interactions, particularly increased bleeding risks when DOACs are combined with NSAIDs and antiplatelet therapy, must be considered. Although NSAIDs are often avoidable, patients may have compelling indications for concomitant antiplatelet therapy. The challenge lies in the uniqueness of each clinical situation and the often uncertain risk-to-benefit ratios of prescribing dual antiplatelet therapy (DAPT) vs dual therapy (OAC+ single antiplatelet) vs triple therapy (OAC + DAPT).
The landmark DOAC studies for stroke prevention in NVAF allowed for concomitant aspirin use, with 30-40% of patients being on dual therapy. With the exception of dabigatran, efficacy endpoints were similar in those that received each DOAC irrespective of the addition of antiplatelet therapy. Moreover, concomitant use of aspirin with apixaban or edoxaban resulted in a significant decrease in stroke or systemic embolism when compared with warfarin.35-38 In a real-world analysis, ischemic events were low in both groups.39 A large proportion of patients in the aforementioned studies did not appear to have an indication for aspirin therapy.
Other studies have investigated DOACs combined with different antiplatelet regimens in patients requiring a coronary stent or for secondary prevention of unstable coronary artery disease (CAD). The thrombotic benefit of increasing intensity (double vs triple therapy) remains inconclusive given the limitations of many of these studies.
- The PIONEER AF-PCI study used low-dose rivaroxaban (15 mg daily) as part of dual therapy or very low-dose rivaroxaban (2.5 mg twice daily) as part of triple therapy.40 Both rivaroxaban regimens had a lower bleeding risk than warfarin triple therapy; however, it was not powered to evaluate prevention of ischemic events.
- The RE-DUAL PCI study used dabigatran (110 mg or 150 mg twice daily) as part of dual therapy with clopidogrel or ticagrelor. The dabigatran regimen had a lower bleeding risk and similar rate of efficacy to the warfarin triple therapy regimen.41
- The APPRAISE-2 study used apixaban (2.5 mg or 5 mg twice daily) as part of triple therapy with clopidogrel or ticagrelor for secondary prevention following acute coronary syndrome.42 The rate of bleeding was higher than standard antiplatelet therapy and it did not improve ischemic efficacy.
Given the increased bleeding risk and inconclusive effectiveness, it is imperative to conduct a patient-specific risk-to-benefit assessment including anticoagulation/antiplatelet indications, comorbidities, end-organ function, drug-drug interactions, validated risk-based scoring systems, and procedure/device specifics when designing a treatment regimen. In many cases, dual therapy with dabigatran or rivaroxaban combined with a P2Y12 inhibitor rather than triple therapy may suffice. There is less data supporting apixaban or edoxaban, however the AUGUSTUS (apixaban) and ENTRUST-PCI (edoxaban) studies are ongoing.43 In a patient with a very high thrombotic risk, it is reasonable to consider triple therapy targeting the shortest possible exposure (1 to 6 months based on case-by-case specifics).
When anticoagulation is being initiated, transition of care needs should be considered. The prescriber should work with the case manager, pharmacist, or other resources to ensure the preferred OAC is financially viable for the patient. For uninsured or underinsured (commercial plan) patients who meet program criteria, prescription assistance will often defray patient costs for DOACs for at least 1 year and may be extended in some situations. For patients with state or federal government-based coverage, identifying the preferred DOAC is critical to ensure appropriate care transitions and avoid extending hospitalization to make treatment changes.
Regardless of anticoagulant choice, the patient will require close follow up with a primary care provider (PCP). If the patient regularly sees a provider already, he or she must be willing and able to assume monitoring as needed. If the patient does not have a PCP, this will need to be resolved prior to discharge. Generally, patients receiving warfarin will need an INR check scheduled within a week after discharge, and those initiated on a DOAC should have routine post-discharge follow up.
Critically ill patients often have multiple comorbid conditions that are often excluded from clinical trials. This section provides a brief overview of data for DOACs in several conditions of interest. Other than cancer-related VTE, it is possible that publication bias has contributed to the absence of cases with negative outcomes.
Cancer-associated Thrombosis (CAT)
Low molecular weight heparins (LMWHs) are currently recommended over DOACs for the treatment of VTE in patients with cancer.2,44-46 However, daily to twice-daily subcutaneous injections and high costs make LMWH therapy challenging for patients. Many practitioners are incorporating DOACs as a treatment option for CAT based on subgroup analyses of patients with cancer in phase III randomized controlled trials for VTE.47-50 Extrapolating these results should be done with caution. Small percentages of included patients had a diagnosis of cancer (~2 to 9%). Patients with thrombocytopenia or hematologic malignancies with an increased risk for thrombocytopenia were often excluded. Definitions of active cancer and history of cancer varied among the studies. Higher annualized risk of recurrent VTE and major bleeding among patients in LMWH trials suggests that the cancer patient populations studied in the DOAC VTE trials were at lower risk. Several systematic reviews and meta-analyses of the phase III randomized controlled trials for VTE have attempted to resolve the issue of power. These studies found no difference in recurrent VTE or major bleeding.51-53 To address inadequacies in using a VKA comparator group, a network meta-analysis conducted an indirect network comparison between DOACs and LMWH and found no difference in efficacy or safety.54
Randomized controlled trials supporting the use of DOACs in CAT have been published. In the Hokusai VTE Cancer trial, edoxaban was found to be noninferior to dalteparin in the composite outcome of recurrent VTE or major bleeding.55 Although not statistically significant, the percentage of patients with recurrent VTE was lower but major bleeding was higher in the edoxaban group compared with the dalteparin group. The difference in bleeding was mainly driven by a higher rate of upper gastrointestinal bleeding in patients with gastrointestinal cancer. Although a smaller number of patients were included and the study duration was shorter, another randomized controlled trial (SELECT-D) observed similar outcomes when comparing rivaroxaban with dalteparin.56
Other considerations for patients with cancer include changes in drug absorption during episodes of vomiting or mucositis, and the lack of data regarding drug interactions. Of note, a prospective cohort study implemented a clinical pathway to account for situations specific to the oncology setting to evaluate use of rivaroxaban in patients with CAT.57 Rates of new or recurrent VTE and major bleeding were comparable to the subgroup analysis of patients with active cancer in the EINSTEIN trials. Ongoing trials (CARAVAGGIO trial, ClinicalTrials.gov number NCT03045406; CANVAS trial, ClinicalTrials.gov number, NCT02744092) should provide additional guidance on the role of DOACs in the treatment of CAT.
Outcomes examining the use of DOACs in patients with cancer and atrial fibrillation are even more limited. A study utilizing MarketScan databases found that in patients with cancer and atrial fibrillation, rates of bleeding and stroke were lower or similar in those receiving DOACs compared with warfarin.58
End Stage Renal Disease (ESRD)
Warfarin is commonly used in patients with ESRD, but may confer unique risks such as calcific uremic arteriolopathy in this population. Further, the benefits observed with warfarin in patients with normal renal function may be greater, and the risks lower, than in patients with ESRD. Several small pharmacokinetic studies have been conducted in patients with ESRD with apixaban and rivaroxaban, the two DOACs with the least renal elimination. Based on a single-dose study, apixaban is approved for patients with VTE and ESRD on hemodialysis without dose adjustment.20 Multi-dose studies indicate that accumulation may occur and adjusted doses may yield serum drug concentrations similar to full doses in patients with normal renal function.79 Clinical outcomes data is sparse and lacks robustness, but recent retrospective data suggests apixaban may be safe.80 The ongoing studies RENAL-AF and ADAXIA AF-NET(ClinicalTrials.gov number NCT02942407 and NCT02933697 will provide more guidance on the use of apixaban in hemodialysis patients.
Extreme Obesity or Underweight
Apixaban has specific recommendations for dose adjustment in patients with NVAF and weight 60 kg or less when another risk factor is present (creatinine greater than or equal to 1.5 mg/dL or age greater than or equal to 80 years).20 Otherwise, standard cutoffs delineating extremes of body weight have not been established. The International Society on Thrombosis and Haemostasis recommends that DOACs should not be used in patients with a body mass index (BMI) greater than 40 kg/m2 or a weight greater than 120 kg.81 In healthy subjects, no difference in overall DOAC exposure in patients at extremes of body weight (less than 50 to 60 kg or greater than 120 kg) has been found when compared with patients with normal weight.21,82-85 However, phase III clinical trials either included a limited number of patients with extremes of body weight or excluded them altogether.86 Taking into account some variation in weight divisions, the percentage of patients with low body weight (generally less than 50 to 70 kg) ranged from 1% to 13% in landmark VTE trials and 2% to 28% in landmark NVAF trials. The percentage of patients with high body weight (generally greater than 100 kg) ranged from 14% to 19% in landmark VTE trials and 17% to 39% in landmark NVAF trials. Outcomes from subgroup analyses for both efficacy and safety were generally not significantly different than warfarin.86,87
Interestingly, observations from several DOAC studies in patients with NVAF have supported the “BMI paradox” concept in which patients with high body weight demonstrate lower risks for efficacy outcomes than patients with low or normal body weight.88-92 In the RE-LY trial, patients receiving dabigatran 150 mg twice daily with low body weight or BMI appeared to have better outcomes than patients with a high body weight or BMI.7,93 In the RE-COVER trial, patients weighing greater than 100 kg and receiving dabigatran had higher incidences of stroke or systemic embolism compared with the those receiving VKA.15 A subgroup analysis of the ARISTOLE trial based on patients with high or low body weight showed significantly less stroke or systemic embolism and major bleeding in the apixaban group compared with the VKA group.6 A meta-analysis of 6 randomized controlled VTE trials found no difference in efficacy between different weight categories when compared with VKA therapy, but the reduced risk of major and clinically relevant non-major bleeding (CRNMB) in patients with normal weight compared with VKA therapy was not evident in patients with low or high body weight.94 Bleeding outcomes were found to be comparable for all body weights. Overall, real-world data is lacking, and not enough evidence exists to guide dosing in patients with extremes of body weight.
Heparin-Induced Thrombocytopenia (HIT)
Several centers have published data in small cohorts of patients with HIT.77,78 Most patients were initially treated with a parenteral direct thrombin inhibitor. The DOAC with the most reported use is rivaroxaban, followed by apixaban. Overall, outcomes have been good with 2 possible thrombotic events: 1 patient with ischemia requiring amputation and 1 patient with catheter-associated thrombosis extension that may have occurred prior to DOAC initiation.78 No patient has experienced major bleeding attributed to DOAC treatment.77,78 The data thus far indicate DOACs offer an attractive alternative for the treatment of HIT.
Splanchnic Vein Thrombosis (SVT)
Patients with splanchnic vein thrombosis (SVT) were excluded in phase III clinical trials of DOACs.
Most studies examining the use of a DOAC for SVT have utilized rivaroxaban with varied doses and durations.59 In general, treatment with DOACs for SVT has been successful or no differences have been found in efficacy or safety outcomes between comparator groups.60-66 If DOACs are used in this patient population, certain issues must be taken into consideration. Reduced mesenteric perfusion in patients with mesenteric vein thrombosis may impair drug absorption.66 Approximately 25% to 30% of individuals with SVT have concomitant cirrhosis, and most DOACs are not recommended or are contraindicated in patients with Child-Pugh scores of B or C.20-23,67,68 The degree of liver impairment must be assessed prior to initiation and periodically during treatment. Additionally, these patients commonly have comorbid conditions that increase bleeding risks (e.g, intestinal infarction, portal vein hypertension, thrombocytopenia). Some studies appear to support the need to decrease doses of DOACs in patients with cirrhosis69,70 while others have used standard doses successfully.63-65 For those with portal vein thrombosis, local anticoagulant effects have been proposed, potentially supporting the use of low doses of DOACs.63 Conversely, one study reports decreased in vitro anticoagulant potency of apixaban and rivaroxaban in patients with cirrhosis.71 Depending on laboratory availability, monitoring of factor X levels or factor II levels may be helpful to ensure therapeutic efficacy.59
Cerebral Sinus Thrombosis (CSVT)
There are several published case series with small cohorts of patients utilizing a DOAC for the treatment of CSVT. The majority of cases involve rivaroxaban, but cases of edoxaban and dabigatran success have also been reported.72-76 In almost all cases, the DOAC was initiated after 1-2 weeks of acute treatment with heparin or LMWH. Few patients receiving a DOAC had a CSVT associated intracranial hemorrhage (ICH) and the degree and location of thrombosis was not well characterized. In the acute setting, particularly in patients with an associated ICH or those that may require surgical intervention, it is best to consider heparin or LMWH until the patient is clinically stable. Ongoing studies (ClinicalTrials.gov number NCT03178864 and NCT02913326) should clarify the potential role of DOACs in the treatment of CSVT.
For critically ill patients who are candidates for OACs, treatment choice should be individualized by considering patient-specific factors, drug characteristics, and likely outpatient limitations in the context of landmark studies and real-world data. Continued research is warranted in disease states such as ESRD, significant under- or over-weight, HIT, antiphospholipid antibody syndrome (APS), and thrombosis in sites other than pulmonary or peripheral deep veins. Overall, DOACs provide an attractive option for most patients, but dosing should be carefully evaluated.
Nicole M. Bohm1
Ron R. Neyens2
1Medical University of South Carolina College of Pharmacy
2Medical University of South Carolina Department of Pharmacy
NVAF landmark studies
PROTECT + PREVAIL10
1.27 vs 1.6
NNT = 303
|1.11 vs 1.71
NNT = 167
|1.57 vs 1.8||2.1 vs 2.4||
1.8 vs 1.7
|Ischemic||0.97 vs 1.05||0.9 vs 1.2
NNT = 303
|1.25 vs 1.25||
|0.95 vs 1.6|
3.52 vs 3.94
NNT = 238
3.64 vs 4.13
3.99 vs 4.35
1.9 vs 2.2
4.9 vs 3.6
NNH = 77
NVAF real world data- event hazard ratio compared to VKA11
|Ischemic Stroke/systemic embolism||
Odds ratio for event with apixaban regular or any dose vs control (compared to apixaban reduced dose vs control) 12
|Any TE event||
All characteristics and outcomes presented as percent unless otherwise indicated
n/a not applicable
NR not reported
|AMPLIFY13||RE-COVER14||RE-COVER II15||HOKUSAI-VTE16||EINSTEIN DVT17||EINTEIN-PE18||LITE (proximal VTE/PE)19|
|Up to 12||
|Recurrent VTE (%)||2.3 vs 2.7
|2.4 vs 2.1||2.3 vs 2.2||3.2 vs 3.5||2.1 vs 3.0
NNT = 111
|2.1 vs 1.8
NNT = 333
|3.3 vs 3.3|
|Mortality (%)||1.5 vs 1.9||1.6 vs 1.7||2.0 vs 1.9||3.2 vs 3.1||2.2 vs 2.9||2.4 vs 2.1||3.8 vs 3.8|
|Long-term dosing frequency||
|Parenteral bridge indicated for VTE||
2C9, 3A, 1A2
|ABCa transport (Pgp or BRCP)25,26||
|Swallow whole with water||Can crush||Can crush;
15-20 mg with meal
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016; 149(2):315-352.
- Kirchhof P, Benussi S, Kotecha D, et al. ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016; 37(38):2893-2962.
- January CT, Wann LS, Alpert JS, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-76.
- Beyer-Westendorf J. What have we learned from real-world NOAC studies in venous thromboembolism treatment? Thromb Res. 2018;163:83-91.
- Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365(11):981-92.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361(12):1139-51.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369(22):2093-104.
- Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365(10):883-91.
- Reddy VY, Doshi SK, Kar S, et al. 5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials. J Am Coll Cardiol. 2017;70(24):2964-2975
- Ntaios G, Papavasileiou V, Makaritsis K, et al. Real-World Setting Comparison of Nonvitamin-K Antagonist Oral Anticoagulants Versus Vitamin-K Antagonists for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis. Stroke. 2017; 48(9):2494-2503.
12. Proietti M, Romanazzi I, Romiti GF, et al. Real-World Use of Apixaban for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis. Stroke. 2018;49(1):98-106.
- Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013; 369(9):799-808.
- Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009; 361(24):2342-52.
- Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72.
- Büller HR, Décousus H, Grosso MA et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013; 369(15):1406-15.
- Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010; 363(26):2499-510.
- Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012; 366(14):1287-97
- Hull RD, Pineo GF, Brant R, et al. Home therapy of venous thrombosis with long-term LMWH versus usual care: patient satisfaction and post-thrombotic syndrome. Am J Med. 2009; 122(8):762-769.e3.
- Apixaban (Eliquis®) [product information]. Princeton, NJ: Bristol-Myers Squibb Company; June 2018.
- Dabigatran (Pradaxa®) [product information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; March 2018.
- Edoxaban (Savaysa®) [product information]. Parisippany, NJ: Daiichi Sankyo, Inc; November 2017.
- Rivaroxaban (Xarelto®) [product information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; October 2017.
- Warfarin (Coumadin®) tablets, for oral use [product information]. Princeton, NJ: Bristol-Myers Squibb Company; 2017.
- Hodin S, Basset T, Jacqueroux E, et al. In Vitro Comparison of the Role of P-Glycoprotein and Breast Cancer Resistance Protein on Direct Oral Anticoagulants Disposition. Eur J Drug Metab Pharmacokinet. 2018; 43(2):183-191.
- Gschwind L, Rollason V, Daali Y, et al. Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model. Basic Clin Pharmacol Toxicol. 2013; 113(4):259-65.
- Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis. Am J Nephrol. 2016; 43(4):229-36.
- Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016; 56(5):628-36
- Ifudu O, Dulin AL. Pharmacokinetics and dialysability of warfarin in end-stage renal disease. Nephron. 1993; 65(1):150-1.
- Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost. 2015; 113(4):719-27.
- Hakeam HA, Al-Sanea N. Effect of major gastrointestinal tract surgery on the absorption and efficacy of direct acting oral anticoagulants (DOACs). J Thromb Thrombolysis. 2017; 43(3):343-351
- Whitworth MM, Haase KK, Fike DS, et al. Utilization and prescribing patterns of direct oral anticoagulants. Int J Gen Med. 2017; 10:87-94.
- Tran E, Duckett A, Fisher S, Bohm N. Appropriateness of direct oral anticoagulant dosing for venous thromboembolism treatment. J Thromb Thrombolysis. 2017; 43(4):505-513.
- Chopard R, Serzian G, Humbert S, et al. Non-recommended dosing of direct oral anticoagulants in the treatment of acute pulmonary embolism is related to an increased rate of adverse events. J Thromb Thrombolysis. 2018; 46(3):283-291
- Alexander JH, Lopes RD, Thomas L, et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2014;35(4):224-32.
- Xu H, Ruff CT, Giugliano RP, et al. Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF-TIMI48 Trial. J Am Heart Assoc. 2016;5(2).
- Shah R, Hellkamp A, Lokhnygina Y, et al. Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial. Am Heart J. 2016; 179:77-86.
- Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127(5):634-640.
- Steinberg BA, Kim S, Piccini JP, et al. Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation 2013; 128(7):721-728.
- Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med 2016; 375(25):2423-2434.
- Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med 2017; 377(16):1513-1524.
- Hess CN, James S, Lopes RD, et al. Apixaban Plus Mono Versus Dual Antiplatelet Therapy in Acute Coronary Syndromes: Insights From the APPRAISE-2 Trial. J Am Coll Cardiol 201; 66(7):777-787.
- Duerschmied D, Brachmann J, Darius H, et al. Antithrombotic therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention: should we change our practice after the PIONEER AF-PCI and RE-DUAL PCI trials? Clin Res Cardiol 2018; 107(7):533-538.
- Lyman GH, Khorana AA, Kuderer NM et al. American Society of Clinical Oncology Clinical Practice. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013; 31(17):2189-204.
- Streiff MB, Bockenstedt PL, Cataland SR, et al. National comprehensive cancer network. Venous thromboembolic disease. J Natl Compr Canc Netw. 2013; 11(11):1402-29.
- Soff GA. Use of Direct Oral Anticoagulants for Treating Venous Thromboembolism in Patients With Cancer. J Natl Compr Canc Netw. 2018; 16(5S):670-673.
- Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost. 2015; 13(12):2187-91.
- Schulman, S., Eriksson, H., Goldhaber, et al. Influence of active cancer on the efficacy and safety of dabigatran versus warfarin for the treatment of acute venous thromboembolism: a pooled analysis form RE-Cover and RE-Cover II. Blood. 2018; 122(21), 582.
- Raskob GE, van Es N, Segers A, et al. Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016;3(8):e379-87.
- Prins MH, Lensing AW, Brighton TA, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomized controlled trials. Lancet Haematol. 2014;1(1):e37-46.
- Carrier M, Cameron C, Delluc A, et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res. 201; 134(6):1214-9.
- van der Hulle T, den Exter PL, Kooiman J, et al. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost. 2014; 12(7):1116-20.
- Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest. 2015; 147(2):475-483.
- Posch F, Königsbrügge O, Zielinski C, et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res. 2015; 136(3):582-9.
- Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018; 378(7):615-624.
- Young AM, Marshall A, Thirlwall J, et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 2018:JCO2018788034.
- Mantha S, Laube E, Miao Y, et al. Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study. J Thromb Thrombolysis. 2017; 43(2):166-171.
- Shah S, Norby FL, Datta YH, et al. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation. Blood Adv. 2018;2(3):200-209.
- Priyanka P, Kupec JT, Krafft M, et al. Newer Oral Anticoagulants in the Treatment of Acute Portal Vein Thrombosis in Patients with and without Cirrhosis. Int J Hepatol. 2018 eCollection: 8432781.
- Pannach S, Babatz J, Beyer-Westendorf J. Successful treatment of acute portal vein thrombosis with rivaroxaban. Thromb Haemost. 2013; 110(4):626-7.
- Martinez M, Tandra A, Vuppalanchi R. Treatment of acute portal vein thrombosis by nontraditional anticoagulation. Hepatology. 2014; 60(1):425-6.
- Nery F, Valadares D, Morais S, et al. Efficacy and Safety of Direct-Acting Oral Anticoagulants Use in Acute Portal Vein Thrombosis Unrelated to Cirrhosis. Gastroenterology Res. 2017; 10(2):141-143.
- Lenz K, Dieplinger B, Buder R, et al. Successful treatment of partial portal vein thrombosis (PVT) with low dose rivaroxaban. Z Gastroenterol. 2014; 52(10):1175-7.
- Yang H, Kim SR, Song MJ. Recurrent acute portal vein thrombosis in liver cirrhosis treated by rivaroxaban. Clin Mol Hepatol. 2016; 22(4):499-502.
- Hum J, Shatzel JJ, Jou JH, Deloughery TG. The efficacy and safety of direct oral anticoagulants vs traditional anticoagulants in cirrhosis. Eur J Haematol. 2017; 98(4):393-397.
- Janczak DT, Mimier MK, McBane RD, et al. Rivaroxaban and Apixaban for Initial Treatment of Acute Venous Thromboembolism of Atypical Location. Mayo Clin Proc. 2018; 93(1):40-47.
- Thatipelli MR, McBane RD, Hodge DO, Wysokinski WE. Survival and recurrence in patients with splanchnic vein thromboses. Clin Gastroenterol Hepatol. 2010; 8(2):200-5.
- Ageno W, Riva N, Schulman S, Bang SM, et al. Antithrombotic treatment of splanchnic vein thrombosis: results of an international registry. Semin Thromb Hemost. 2014; 40(1):99-105.
- De Gottardi A, Trebicka J, Klinger C, et al. Antithrombotic treatment with direct-acting oral anticoagulants in patients with splanchnic vein thrombosis and cirrhosis. Liver Int. 2017; 37(5):694-699.
- Intagliata NM, Henry ZH, Maitland H et al. Direct Oral Anticoagulants in Cirrhosis Patients Pose Similar Risks of Bleeding When Compared to Traditional Anticoagulation. Dig Dis Sci. 2016; 61(6):1721-7.
- Potze W, Adelmeijer J, Lisman T. Decreased in vitro anticoagulant potency of Rivaroxaban and Apixaban in plasma from patients with cirrhosis. Hepatology. 2015; 61(4):1435-6.
- Sui J, Zhang Y, Yang L, et al. Successful treatment with rivaroxaban of cerebral venous thrombosis and bone marrow necrosis induced by pegaspargase: A case report and literature review. Medicine (Baltimore). 2017; 96(46):e8715.
- Cho YH, Chae MK, Cha JM, et al. Cerebral venous thrombosis in a patient with Crohn's disease. Intest Res. 2016; 14(1):96-101.
- Geisbüsch C, Richter D, Herweh C, et al. Novel factor xa inhibitor for the treatment of cerebral venous and sinus thrombosis: first experience in 7 patients. Stroke. 2014; 45(8):2469-71.
- Hon SF, Li HL, Cheng PW. Use of direct thrombin inhibitor for treatment of cerebral venous thrombosis. J Stroke Cerebrovasc Dis. 2012; 21(8):915.e11-5.
- Amemiya T, Uesaka T, Kameda K et al. Usefulness of Edoxaban for Deep Cerebral Venous Sinus Thrombosis with Hemorrhagic Infarction :A Case Report. No Shinkei Geka. 2017; 45(7):607-613.
- Davis KA, Davis DO. Direct acting oral anticoagulants for the treatment of suspected heparin-induced thrombocytopenia. Eur J Haematol. 2017; 99(4):332-335.
- Tran PN, Tran MH. Emerging Role of Direct Oral Anticoagulants in the Management of Heparin-Induced Thrombocytopenia. Clin Appl Thromb Hemost. 2018;24(2):201-209
- Mavrakanas TA, Samer CF, Nessim SJ, et al. Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients. J Am Soc Nephrol. 2017; 28(7):2241-2248.
- Siontis KC, Zhang X, Eckard A et al. Outcomes Associated with Apixaban Use in End-Stage Kidney Disease Patients with Atrial Fibrillation in the United States. Circulation. 2018 [Epub ahead of print]
- Upreti VV, Wang J, Barrett YC, et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013; 76(6):908-16.
- Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007; 47(2):218-26.
- Barsam SJ, Patel JP, Roberts LN, et al. The impact of body weight on rivaroxaban pharmacokinetics. Res Pract Thromb Haemost. 2017;1:180–187.
- Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J. 2014; 35(28):1844-55.
- McCaughan GJB, Favaloro EJ, Pasalic L, Curnow J. Anticoagulation at the extremes of body weight: choices and dosing. Expert Rev Hematol. 2018. [Epub ahead of print]
- Di Nisio M, Vedovati MC, Riera-Mestre A, et al. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost. 2016; 116(4):739-46.
- Sandhu RK, Ezekowitz J, Andersson U, et al: The 'obesity paradox' in atrial fibrillation: observations from the ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) trial. Eur. Heart J. 2016; 37:2869-2878.
- Boriani G, Ruff C, Kuder J, et al: Relationship between body mass index and outcomes in 21,028 patients with atrial fibrillation treated with edoxaban or warfarin in ENGAGE AF-TIMI 48 trial. Eur. Heart J. 2016; 37:1199.
- Balla SR, Cyr DD, Lokhnygina Y, et al: Relation of risk of stroke in patients with atrial fibrillation to body mass index (from patients treated with rivaroxaban and warfarin in the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation trial). Am. J. Cardiol. 2017; 119:1989-1996.
- Proietti M, Guiducci E, Cheli P, Lip GY. Is There an Obesity Paradox for Outcomes in Atrial Fibrillation? A Systematic Review and Meta-Analysis of Non-Vitamin K Antagonist Oral Anticoagulant Trials. Stroke. 2017 Apr;48(4):857-866.
- Tittl L, Endig S, Marten S, Reitter A, et al. J. Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119). Int J Cardiol. 2018;262:85-91.
- Ezekowitz ME, Parise H, Connolly SJ, et al. The use of dabigatran according to body mass index: the RE-LY experience. Eur Heart J 2014;35:1111.
- Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials. Ann Med. 2015;47(1):61-8.