Oral Anticoagulants in the ICU: Clinical Review

[tabby title="Overview"]

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. [tabby title="Initiation/Continuation"] 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

[tabby title="Dosing"] 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. [tabby title="Interactions"] 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). [tabby title="Care Transitions"] 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. [tabby title="Limitations"] 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.   [tabby title="Conclusions"] 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.   [tabby title="Authors"] Nicole M. Bohm1 Emmeline Tran1 Ron R. Neyens2   1Medical University of South Carolina College of Pharmacy 2Medical University of South Carolina Department of Pharmacy   [tabby title="Tables"] Table 1. Efficacy and real world effectiveness of anticoagulants in NVAF  

Apixaban

Dabigatran

Edoxaban

Rivaroxaban

Warfarin

NVAF landmark studies

ARISTOTLE6

RE-LY7 ENGAGE8 ROCKET-AF9

PROTECT + PREVAIL10

Comparator

Warfarin

Warfarin Warfarin Warfarin

Watchman device

n

18,201

18,113 21,105 14,264 1,114 Age (years) 70 72 72 73 74 CHADS score 2.1 2.1 2.8 3.5 2.4 Prior stroke/TIA 20 20 28 55 24 Warfarin TTR 66 64 65 55 NR Aspirin

31

40 30 36

NR

Stroke/systemic embolism

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 Mortality

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

n

66,482

606,855

NR

136,221

N/A

Ischemic Stroke/systemic embolism

1.07 (0.87-1.31)

1.17 (0.92-1.50)

0.73 (0.52-1.04)

Ischemic Stroke

0.95 (0.75-1.19)

0.96 (0.8-1.16)

0.89 (0.76-1.04)

Mortality

0.65 (0.56-0.75)

0.63 (0.52-0.76)

0.67 (0.35-1.30)

Odds ratio for event with apixaban regular or any dose vs control (compared to apixaban reduced dose vs control) 12

Any TE event

n/a

1.04 (0.92-1.19)

0.86 (0.75-0.99)

NR

1.04 (0.92-1.19) 0.86 (0.75-0.99)

0.77 (0.64-0.93)

1.27 (1.12-1.43) Stroke

1.04 (0.90-1.20)

0.91 (0.78-1.05)

1.04 (0.90-1.20) 0.91 (0.78-1.05)

0.84 (0.69-1.01)

0.63 (0.14-2.81)

All characteristics and outcomes presented as percent unless otherwise indicated n/a not applicable NR not reported   Table 2. Efficacy of anticoagulants in VTE in landmark studies   Apixaban Dabigatran Edoxaban Rivaroxaban Warfarin AMPLIFY13 RE-COVER14 RE-COVER II15 HOKUSAI-VTE16 EINSTEIN DVT17 EINTEIN-PE18 LITE (proximal VTE/PE)19 Comparator Warfarin

Warfarin

Warfarin

Warfarin

Tinzaparin n 5,244 2,539 2,589 4,921 3,449 4,832 480 Duration (mo)

6

6

Up to 12

3-12

12 weeks Recurrent VTE (%) 2.3 vs 2.7 NNT=250 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   Table 3. Anticoagulant clinical practice considerations

Apxiaban20

Dabigatran21 Edoxaban22 Rivaroxaban23

Warfarin24

Long-term dosing frequency

BID

BID Daily Daily

Daily, variable

Parenteral bridge indicated for VTE

No

Yes Yes No

Yes

CYP metabolism

3A4

Minimal Minimal 3A4, 2J2

2C9, 3A, 1A2

ABCa transport (Pgp or BRCP)25,26

Yes

Yes Yes Yes

No

Administration

Can crush

Swallow whole with water Can crush Can crush; 15-20 mg with meal

Can crush

Renal elimination

27%

80% 50% 36%

Minimal

Dialyzable27-30

Minimal

Yes Somewhat Minimal

Somewhat

Storage requirements

-

Original container

-

-

-

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