Direct-Acting Oral Anticoagulants in Critically Ill Patients

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Direct-Acting Oral Anticoagulants in Critically Ill Patients

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Parth Rali, MD; Andrew Gangemi, MD; Aimee Moores, MD; Kerry Mohrien, PharmD; and Lisa Moores, MD

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The direct-acting oral anticoagulants (DOACs) have been increasingly used over vitamin K

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antagonists in recent years because they do not require monitoring and have an immediate

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anticoagulation effect. In general, DOACs have exhibited a better safety proﬁle and non-

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inferiority for prophylaxis and treatment of venous thromboembolism (VTE) and stroke pre-

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vention in patients with atrial ﬁbrillation compared with vitamin K antagonists in the non-ICU

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population; whether this ﬁnding holds true in patients who are critically ill remains unknown.

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The current review addresses the role of DOACs in special ICU populations, use of these agents

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for VTE prophylaxis, perioperative management of DOACs, drug monitoring, and potential drug

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interactions of DOACs in critically ill patients. Adverse events and available reversal agents for

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DOACs are also discussed.

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KEY WORDS:

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antithrombotic therapy; critical care; drugs

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Increasing utilization of direct-acting oral anticoagulants (DOACs) for therapeutic and prophylactic indications warrants familiarity of these agents among critical care physicians. Despite perceived concerns regarding increased hemorrhagic risk, particularly GI bleeding (GIB), DOACs have an overall better safety proﬁle and are noninferior to vitamin K antagonists (VKAs) for prophylaxis and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial ﬁbrillation (AF). Few trials have examined the use of DOACs in patients in the ICU, and most of the phase III trials examining their efﬁcacy in the aforementioned

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conditions excluded patients in the ICU. Given the availability of multiple agents, the ease of use, and availability of speciﬁc reversal agents, it is important for critical care physicians to understand the optimal management of patients receiving a DOAC. Managing anticoagulation in the perioperative period remains a signiﬁcant challenge as well. The current review addresses the role of DOACs in special ICU populations, use of these agents for VTE prophylaxis, perioperative management of DOACs, appropriate drug monitoring, and potential drug interaction of DOACs in critically ill

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101 ABBREVIATIONS:

ACS = acute coronary syndromes; AF = atrial ﬁbrillation; aPTT = activated partial thromboplastin time; DOAC = direct-acting oral anticoagulant; FDA = US Food and Drug Administration; GIB = GI bleeding; HIT = heparin-induced thrombocytopenia; LMWH = low-molecular-weight heparin; NVAF = nonvalvular atrial ﬁbrillation; PT = prothrombin time; TAVR = transcatheter aortic valve replacement; UFH = unfractionated heparin; VKA = vitamin K antagonist Q2 Q3 AFFILIATIONS: From the Division of Thoracic Medicine and Surgery (Drs Rali and Gangemi) and Department of Pharmacy (Dr Mohrien), Temple University Hospital, Philadelphia, PA; Department of Medicine (Dr A. Moores), Madigan Army Medical Center, Joint Base Lewis-

McChord, WA; and the Department of Medicine (Dr L. Moores), The Uniformed Services University of the Health Sciences, Bethesda, MD. The opinions are those of the authors and are not ofﬁcial statements of the Uniformed Services University or the Department of the Army. CORRESPONDENCE TO: Lisa Moores, MD, F. Edward Hebert School of Medicine, The Uniformed Services University of the Health Sciences, Bethesda, MD 20814; e-mail: [email protected] Q4 Copyright Ó 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2019.05.025

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patients. Adverse events and available reversal agents for DOACs are also covered.

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Pharmacokinetic and Dynamic Interactions of DOACs in Critically Ill Patients

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Q6

In contrast to VKA therapy, DOACs result in predictable pharmacokinetic and dynamic interactions in nonacutely ill patients. Key physiologic changes that are common in patients in the ICU which may lead to unpredictable anticoagulant effects of DOACs include impaired gastric perfusion and motility, increased volume of distribution, impaired hepatic clearance due to inhibition of enzymatic metabolism, and changes in renal function.1 Both apixaban and rivaroxaban undergo clinically signiﬁcant biotransformation within the hepatic system.2 In patients with moderate hepatic function (Child-Turcotte-Pugh class B), a single 10-mg dose of rivaroxaban resulted in a 1.27-fold increase in maximum drug concentration and a 2.27-fold increase in area under the plasma concentration-time curve; there was no change in the maximum drug concentration and only a 1.09-fold increase in the area under the plasma concentration-time curve of apixaban.3,4 Despite recent in vitro studies reporting altered pharmacokinetic variables of the DOACs (mainly rivaroxaban and apixaban) in patients with cirrhosis, multiple small retrospective analyses from real-world patients with cirrhosis have reported safe and effective use of DOACs.5-9 In contrast to apixaban and rivaroxaban, the remaining DOACs have limited (edoxaban and betrixaban) or no (dabigatran) hepatic metabolism, and pharmacokinetic properties are minimally changed in the setting of liver dysfunction.10-12 However, DOACs should be avoided in the setting of severe liver dysfunction (Child-TurcottePugh class C) and acute liver failure. Renal impairment (acute and chronic) signiﬁcantly alters the pharmacokinetic properties of all available DOACs. All DOACs require dose adjustment in the setting of renal failure, particularly dabigatran and rivaroxaban.2,13-16 US Food and Drug Administration (FDA) labeling recommends no change in apixaban dosing in patients undergoing hemodialysis based on an initial single-dose study.17 However, literature examining the effect of multidose pharmacokinetic changes revealed signiﬁcant accumulation following 8 days of apixaban 5 mg bid.18 A reduction to 2.5 mg bid resulted in drug exposure comparable to standard dosing in patients with preserved renal function. In patients with acute kidney injury, the anticoagulant

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effect of DOACs reportedly lasts for 4 days following the last dose.19 There is no literature evaluating the impact of acute injury on renal clearance of DOACs; such use is therefore not recommended.2 Drug exposure of DOACs increases in a stepwise manner as renal function worsens.13-16 Dabigatran can be signiﬁcantly removed from plasma following hemodialysis.13 Due to their comparatively large volume of distribution and/or high plasma protein-binding, rivaroxaban, apixaban, and edoxaban are minimally removed following hemodialysis. Table 1 highlights the standard DOAC dosing for various clinical indications and adjusted dosing for patients with renal and liver impairment. Extremes of weight are also of concern. Current FDA labeling offers no recommendations for dose adjustments for either an abnormally high or low BMI. The impact of obesity (BMI > 30 kg/m2) on treatment with DOACs is variable and conﬂicting. Peak apixaban concentrations and total drug exposure were found to be 31% and 23% lower, respectively, in healthy patients weighing > 120 kg with a BMI $ 30 kg/m2 compared with those in a reference body weight group.20 In a pharmacokinetic analysis of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran plasma concentrations were found to be 21% lower when total body weight was > 100 kg.21 The impact of obesity on the pharmacokinetic properties of rivaroxaban is minimal, likely due to a reduced lipophilicity compared with apixaban and dabigatran. Based on a subgroup analysis of the published literature, Martin et al22 observed that weight < 120 kg or BMI < 40 kg/m2 does not signiﬁcantly alter the plasma concentrations, distribution, or elimination half-life of DOACs.

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Emerging Role of DOACs in Special Clinical Scenarios in the ICU

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Given the safety proﬁle, ease of use, and reduction in drug interactions of DOACs compared with VKAs, it is likely that increasing numbers of patients admitted to the critical care setting will be receiving therapy with one of these agents. In addition, there will be situations in which the initiation of a DOAC in the ICU is considered. Speciﬁc patient populations discussed here include those with new-onset valvular or nonvalvular AF (NVAF); patients undergoing valve replacement; patients with acute coronary syndromes (ACS), stroke, or heparin-induced thrombocytopenia (HIT); and postoperative cardiac surgery patients. We also brieﬂy discuss VTE treatment and prevention with DOACs in the ICU setting. We do not discuss critically ill patients

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TABLE 1

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] Standard DOAC Dosing for Different Clinical Indications and Recommended Adjusted Dosing for Renal and Liver Impairment

222 Variable

Recommended dosing

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Apixaban

Betrixaban

Dabigatran

Edoxaban

NVAF: 5 mg bid VTE treatment: 10 mg bid 7 days, then 5 mg bid Prevention of VTE: 2.5 mg bid (following 6 mo standard therapy) VTE prophylaxis post-hip/knee surgery: 2.5 mg bid

VTE prophylaxis: 160 mg 1, then 80 mg once daily

NVAF: 150 mg bid VTE treatment: initial LMWH/ heparin, then 150 mg BID Prevention of VTE: 150 mg bid (following 6 mo standard therapy) VTE prophylaxis post-hip/knee surgery: 110 mg 1 dose, then 220 mg once daily

NVAF: 60 mg once daily Initial LMWH/ heparin, then 60 mg once daily

237 238 239 240 241 242

Recommended renal dose adjustments

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Recommended hepatic dose adjustments

254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271

If 2 of the following: SCr $ 1.5 mg/ dL, age $ 80 y, weight # 60 kg: reduce dose to 2.5 mg bid CrCl < 15 mL/min or ESRD: use with caution; consider dose reduction to 2.5 mg bid

CrCl 1530 mL/min: reduce dose to 80 mg 1, then 40 mg once daily CrCl < 15 mL/ min or ESRD: avoid use

CTP class A: no adjustments necessary CTP class B: use with caution CTP class C: avoid use

No available data

CrCl 15-30 mL/min: reduce dose to 75 mg bida CrCl < 15 mL/min or ESRD: avoid use

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Rivaroxaban

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NVAF: 20 mg once daily VTE treatment: 15 mg BID 21 d, then 20 mg once daily Prevention of VTE: 10 mg once daily (following 6 mo standard therapy) VTE prophylaxis post-hip/knee surgery: 10 mg once daily

CrCl 15-50 mL/ min: reduce dose to 30 mg once daily CrCl < 15 mL/min or ESRD: avoid use CrCl > 95 mL/ min: avoid use (reduced efﬁcacy in atrial ﬁbrillation)

CrCl 15-50 mL/ min: reduce dose to 15 mg once dailyb CrCl < 15 mL/ min or ESRD: avoid use

CTP class A: no adjustments necessary CTP class B: avoid use CTP class C: avoid use

CTP class A: no adjustments CTP class B: avoid use CTP class C: avoid use

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CTP class A: no adjustments necessary CTP class B: use with caution CTP class C: avoid use

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CrCl ¼ creatinine clearance; CTP ¼ Child-Turcotte-Pugh; DOAC ¼ direct-acting oral anticoagulant; ESRD ¼ end-stage renal disease; LMWH ¼ lowmolecular-weight heparin; NVAF ¼ nonvalvular atrial ﬁbrillation; SCr ¼ serum creatinine; VTE ¼ venous thromboembolism. a US Food and Drug Administration (FDA)-labeled dose reduction speciﬁc for NVAF. FDA labeling recommends avoiding the use of dabigatran if CrCl < 30 mL/min when used for the treatment of VTE or postorthopedic surgery. b FDA-labeled dose reduction speciﬁc for NVAF. FDA labeling recommends avoiding use of rivaroxaban if CrCl < 30 mL/min when used for the treatment/ prophylaxis of VTE or postorthopedic surgery.

admitted with sepsis or acute kidney injury. In our opinion, DOACs should be avoided in these conditions given the unpredictable pharmacokinetic proﬁle and potential need for invasive procedures. For patients who are admitted to the ICU with sepsis or acute kidney injury and who are already receiving DOACs, a switch to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is warranted.

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Atrial Fibrillation

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Valvular AF is commonly referred to as AF that occurs in the setting of mechanical heart valves or moderate to

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severe mitral stenosis. VKAs remain the agent of choice in this setting given the exclusion of such patients in major DOAC trials and evidence suggesting excessive thrombotic and bleeding risks with DOACs in this population.23-27 The term NVAF has been used when AF occurs outside of the aforementioned clinical scenarios. DOACs are noninferior to VKAs in stroke prevention in patients with NVAF.28 In patients with new-onset AF > 48 h, in which cardioversion is urgently needed, DOACs can be given 4 h prior to transesophageal echocardiogram and cardioversion.29 Local institutional protocols should be followed in terms

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of anticoagulation and need for transesophageal echocardiogram before cardioversion. In patients with AF > 48 h, in which cardioversion can be delayed, DOACs can be initiated in the ICU and cardioversion performed electively as an outpatient. Valve Replacement and ACS

In patients undergoing transcatheter aortic valve placement (TAVR), the incidence of radiographically apparent postvalve thrombosis ranges from 7% to 40%.28 Larger size valves and lack of postprocedure antithrombotic treatment seem to be associated with valvular thrombosis.30 It is unknown at this stage which regimen is ideal in patients with TAVR (dual antiplatelet therapy þ VKA vs VKA only vs dual antiplatelet therapy þ DOACs). The European Society of Cardiology allows the use of DOACs beginning 3 months’ post-TAVR, whereas the American Heart Association 2017 guidelines do not recommend the same given the lack of dedicated studies in this population.28,31 For bioprosthetic mitral valve and mitral valvuloplasty, a VKA remains the agent of choice over DOACs.28 For patients already taking DOACs who present with ACS, DOACs should be stopped on admission. At the time of the discharge following ACS or elective percutaneous coronary intervention, DOACs should be resumed, at least in the immediate period.29 When added to single platelet therapy following ACS, DOACs were well tolerated but did not lead to a reduction in major adverse cardiovascular events. When added to dual platelet therapy following ACS, DOACs resulted in a reduction in major adverse cardiovascular events but were associated with an increased risk of major bleeding.32

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Patients With Stroke

In patients with acute ischemic stroke, American Heart Association/American Stroke Association 2018 expert guidelines caution against the use of IV thrombolytic therapy in patients who are receiving DOAC therapies at the time of presentation.33 If coagulation study results are completely normal and the last dose of DOAC was > 48 h prior to presentation (presuming normal renal function), thrombolysis may then be considered. A recent meta-analysis suggested that IV thrombolysis, along with pharmacomechanical neurologic intervention, is safe in patients presenting with acute stroke who are taking DOACs at presentation.34,35 There is uncertainty regarding the timing and safety of DOACs

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in acute ischemic stroke postthrombolysis. Fortunately, Q7 several clinical trials are ongoing that will address whether thrombolysis is safe in patients who are on DOACs at presentation and the role of DOAC initiation for secondary prevention following acute ischemic stroke.36-40

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Heparin-Induced Thrombocytopenia

HIT is traditionally treated with parenteral thrombin inhibitors until platelet recovery, after which patients are transitioned to VKAs. There is growing interest in the role of DOACs in treating patients with HIT both as an alternative to VKAs or as a ﬁrst-line agent.41-45 Current data are limited to small retrospective and in vitro studies only. Of note, rivaroxaban did not cause platelet activation or aggregation in the presence of HIT antibodies in one in vitro study.46 A large prospective trial evaluating the role of rivaroxaban in HIT was stopped due to poor enrollment.47 Currently, DOACs are not approved for use in HIT. There is an ongoing trial in the enrollment phase assessing the use of apixaban in HIT.48

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Patients With VTE

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DOACs are the anticoagulation agents of choice for the long-term treatment of most patients with acute VTE. The use of DOACs for acute treatment of VTE in the ICU setting, however, has not been adequately studied. Patients presenting with submassive or massive pulmonary embolism and patients who are at high risk of decompensation should receive UFH over DOACs. Traditionally, patients are started on anticoagulation following thrombolysis when the activated partial thromboplastin time (aPTT) is less than one and onehalf times the normal limit. In a small retrospective study, DOAC use compared with warfarin following catheter-directed thrombolysis seemed safe and was associated with a reduced length of stay (4.0 vs 6.1 days; P ¼ .002).49 DOACs may be considered in patients with pulmonary embolism when they are stable for transfer out of the ICU, after taking into consideration bleeding risk, comorbid organ dysfunction, and potential drug interactions.

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The incidence of VTE in critically ill patients who do not receive prophylaxis varies but has been reported to be as high as 40%.50 None of the current DOACs has been studied for the prevention of VTE events in patients in the ICU. Four phase III trials have examined the DOACs Q8 in VTE prevention in hospitalized medical patients:

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Role of DOACs in VTE Prevention

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Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT), Venous Thromboembolic Event (VTE) Prophylaxis in Medically Ill Patients (MAGELLAN), Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX), and Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk (MARINER).51-54 Some of the information gathered may be used to inform care or to answer research questions in critically ill patients. Study design, outcomes, and patient characteristics from these trials are summarized in eTables 1 and 2. Importantly, only one trial (MARINER)54 speciﬁed the number of patients who were cared for in the ICU (54%), further limiting the extrapolation of results. Assessing the admission diagnoses of the patients in the other trials suggests that a proportion may have been cared for in the ICU. Importantly, all of these trials were designed to investigate extended vs short-term duration of chemical prophylaxis and were not designed to determine the best agent for chemical prophylaxis, particularly in the critically ill.

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Al Yami et al55-57 published the most recent of three meta-analyses that have combined ADOPT, MAGELLAN, and APEX (all were published prior to the publication of the MARINER trial).51-53 Among other ﬁndings, this study advanced our understanding by reporting a quantitative approach to risk-beneﬁt analysis. The authors reported that the trials failed to establish clear efﬁcacy/safety signals for any of the DOACs. Although, as a class, DOACs extend a beneﬁt against select efﬁcacy outcomes (symptomatic VTE, all VTE), this achievement comes at the expense of a marked increase in the risk of bleeding events. Interestingly, when the authors examined the risk/ beneﬁt ratio, there was a class effect in favor of prophylaxis with DOACs for all VTE events compared with major bleeding events. It should be noted, however, that the authors assumed that all DOACs have the same risk proﬁle, whereas emerging evidence suggests that apixaban likely has a superior safety proﬁle. Overall, there are few data regarding the use of DOACs in VTE prevention in the ICU. Currently, betrixaban is the only FDA-approved agent for VTE prevention in acutely ill medical patients, based on a favorable safety proﬁle.58 Clinical trials in this patient population are warranted, especially because the characteristics of these oral agents may increase adherence to thromboprophylaxis guidelines. Clinicians need further guidance not on whether to provide prophylaxis but on which agent and

the nuances that identify the highest risk patients most likely to beneﬁt.

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Management of anticoagulation in the perioperative period has become more challenging since the introduction of DOACs. Current guidance largely comprises expert opinion, based on known pharmacologic properties of the drugs, and information derived from retrospective subgroup analysis of existing trials.59 For minor procedures (ophthalmologic, dermatologic, and dental) in which minimal blood loss is expected, it is considered safe to continue anticoagulation throughout the perioperative period as long as procedures are performed at trough drug concentration (usually at 24 h since the last dose), as local hemostasis can be easily achieved.60-63 The recently published Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial 2 (BRUISE CONTROL 2) reported no increase in clinically signiﬁcant pocket hematoma with uninterrupted DOAC therapy during cardiac device implantation.64 However, interruption is generally recommended for all other interventions, with speciﬁc timing for preprocedural cessation based on the risk of bleeding and the clearance rate of the DOAC in question.60-63 Procedures deemed to be low risk of bleeding are those in which adequate hemostasis can be achieved and bleeding would not lead to signiﬁcant morbidity or require a transfusion. Moderate bleeding risk procedures include ones in which it may be difﬁcult to obtain hemostasis or might require a transfusion or lead to reoperation. High bleeding risk procedures include those in which bleeding would place the patient’s life at risk or affect the outcome of the procedure.65 DOACs should typically be withheld for 48 h in higher risk procedures; this window can be extended in cases of renal impairment to account for changes in drug clearance.66 Time to restart anticoagulation should be based on individual risk factors for bleeding, as well as bleeding risk inherent to the procedure itself. A simple rule is to withhold the anticoagulant for an identical number of days postprocedure as preprocedure.67 It is advisable to withhold anticoagulation at least 24 to 48 h for procedures with a high risk of bleeding. In instances in which anticoagulation is to be withheld for a prolonged period of time, one can consider using a prophylactic dose of LMWH or a DOAC. Unlike warfarin, the rapid onset of action and short half-lives of the DOACs largely negate the need for bridging anticoagulation regardless

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Management of DOACs in the Perioperative Period

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Q10

of the duration of cessation.60-63,68 Routine use of bridging with LMWH is not recommended prior to procedures, as observational studies suggest a higher risk of bleeding in patients who undergo bridging.67 Dubois et al62 suggest considering a bridge in patients with high thromboembolic risk (CHA2DS2-VASc [congestive heart failure, hypertension, age $ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category] score > 5 in AF, VTE within 3 months, or VTE with severe thrombophilia) and prolonged interruption, such as in neuraxial anesthesia. This approach is based on the observation that in most trials showing no increased VTE risk in perioperative DOAC cessation, the cessation period was generally short (# 3 days), and patients at high risk of VTE were underrepresented. In 2015, Schulman et al69 conducted a multicenter, prospective cohort trial in 541 patients that reported the safety of their perioperative protocol for dabigatran, based on creatinine clearance and surgical bleeding risk; their ﬁndings subsequently inﬂuenced expert recommendations. To date, there are no completed trials pertaining to the remaining DOACs. However, the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) trial70 is an ongoing randomized cohort study with an enrollment goal of 3,300 patients; the primary aim of the study is to show the safety of a standardized but patient-speciﬁc protocol for the perioperative management of apixaban, rivaroxaban, and dabigatran.62,71 Table 2 summarizes current expert opinion regarding stopping and re-starting DOACs in the perioperative period.65,67

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Monitoring of DOACs in the ICU Although DOACs do not require routine laboratory monitoring, there may be select clinical scenarios, including obesity, renal failure, and potential drug interactions, in which monitoring is useful. Measuring plasma concentrations may also beneﬁt those admitted to the ICU, especially in the setting of emergent procedures, potential therapeutic failure, or reversal of life-threatening bleeding. In studies examining the relationship between plasma drug concentrations and clinical outcomes, there seems to be a consistent predictable response among all agents.72 Having the ability to tailor plasma drug concentrations in patients prone to bleeding may allow clinicians to maximize the beneﬁts, while minimizing the risk, associated with DOACs. Although no expert consensus exists regarding the optimal way to measure the anticoagulant effect of DOACs, various coagulation tests are affected during treatment. Prothrombin time (PT) and/or aPTT are prolonged in the setting of most DOACs. The relation to plasma drug concentration, however, is unpredictable and not suitable for quantitative monitoring.72-74 Elevations in PT are sensitive to rivaroxaban, but this association varies widely according to the reagent used. Prolongation of the PT during apixaban therapy is unpredictable and insensitive and should not be used either qualitatively or quantitatively. The direct thrombin inhibitor dabigatran preferentially prolongs aPTT; however, the relation is nonlinear and insensitive.73 More accurate representations of the level of factor Xa anticoagulants may be obtained by using calibrated chromogenic anti-Xa assays. Although highperformance liquid chromatography/tandem mass

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TABLE 2

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High or moderate

593

All DOACs Hold for 2 d preprocedure

595 Low

All DOACs Hold for 1 d preprocedure

598

30-50 mL/min

603 604 605

615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641

646 647

Dabigatrana Hold for 4 d preprocedure All oral Xa inhibitors Hold for 2 d preprocedureb

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Dabigatran Hold for 2 d preprocedure All oral Xa inhibitors Hold for 1 d preprocedure

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649 650 651 653

599

602

613 614

645

$ 50 mL/min

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601

611 612

644

CrCl

591

600

610

643

] Perioperative Management of DOACs65,67

Procedure-Related Bleeding Risk

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609

642

590

596

607 608

654 See Table 1 legend for expansion of abbreviations. a Spanish Guidelines (Vivas et al65) recommend a three-tiered approach to withholding dabigatran. In moderate or high bleeding risk procedures, guidelines recommend holding 3 days preprocedure for CrCl $ 80 mL/min, 4 days for CrCl 50 to 79 mL/min, and 5 days for CrCl < 50 mL/min. For low bleeding risk procedures, guidelines recommend holding for 2 days preprocedure for CrCl $ 80 mL/min, 3 days for CrCl 50 to 79 mL/min, and 4 days for CrCl < 50 mL/ min. b Spanish Guidelines (Vivas et al65) recommend a more conservative approach with the oral Xa inhibitors. For medium or high bleeding risk procedures, hold for 3 days preprocedure for CrCl > 30 mL/min and 4 days for CrCl 15 to 30 mL/min. For low bleeding risk procedures, hold for 2 days preprocedure for CrCl > 30 mL/min and 3 days for CrCl 15 to 30 mL/min.

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spectroscopy is considered the most accurate method, chromogenic anti-Xa assays have shown good correlation.74,75 The availability of speciﬁc anti-Xa assays has increased in recent years, but it is still limited and can be associated with impractical turnaround times, particularly in patients admitted to the ICU. Accurate approximations of dabigatran can be achieved by using a dilute thrombin time or ecarin clotting time. Both laboratory tests have shown strong linear relationships at concentrations > 50 ng/mL, making them useful monitoring tools for dabigatran-treated patients.25,74,75 Table 3 summarizes the effect of DOACs on various nonspeciﬁc and drug-speciﬁc coagulation parameters. Although DOACs have fewer drug-to-drug interactions, in general, compared with VKAs, as their use becomes more prevalent in the ICU setting, clinicians should familiarize themselves with potential interactions with some of the most commonly used drugs in this situation (Table 4).29

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716

Evolving real-world data are adding to our knowledge obtained from the pivotal phase III trials of DOACs. A large registry involving > 9,900 patients with AF reported similar major bleeding events, fewer intracranial hemorrhage events, and more GIB with DOACs compared with VKAs. Mortality, all-cause hospitalization, and recurrent major bleeding rates at 30 days did not differ compared with warfarin.89 The ﬁndings of higher GIB (mainly dabigatran) and fewer intracranial hemorrhage events with DOACs compared with VKAs are consistent across other multicenter retrospective studies.90 A more recent study of 146,871 Medicare patients, when stratiﬁed according to comorbidity burden, showed improved overall safety of dabigatran and rivaroxaban compared with VKAs. Rivaroxaban loses the advantage of reduced bleeding (particularly GIB) when comorbid scores are high.91 A summary of the major bleeding rates among main trials is provided in e-Table 3.24,51,53,77-88,92-108 It should be noted, however, that many of these trials excluded patients with preexisting renal or hepatic impairment, recent major bleeds, and thrombocytopenia, as well as patients receiving dual antiplatelet therapy or high-dose aspirin.

Adverse Side Effects of DOACs Major bleeding is the most concerning adverse effect of DOACs. Major bleeding is deﬁned by the International Society on Thrombosis and Haemostasis as bleeding that is fatal, involves a critical organ (ie, intraspinal, intracerebral, intraocular, retroperitoneal, intramuscular), causes a 2 g/dL drop in hemoglobin level, requires transfusion of $ 2 units of blood, or leads to therapy cessation.76 Orthopedic literature also includes the criterion of bleeding that requires reoperation.77-88

717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742

Additional adverse effects of DOACs include transient transaminitis (1%-4%), GI intolerance (nausea, vomiting, dyspepsia, diarrhea, and constipation [up to 17%]), peripheral edema (2%-8% with apixaban), gross hematuria (12%-15%, particularly with edoxaban), and headaches and/or dizziness (2%-11%). Pyrexia has been reported in 6% to 12% of patients.52,77-88,92-96,100,101,103,105,106,109,110 Thrombocytopenia was only rarely reported with apixaban (< 2%) and would be low in the differential for

743 744 745 746 747 748 749 750 751 752

698

753

699

754

700

TABLE 3

] Effect of DOACs on Drug-Speciﬁc and Nonspeciﬁc Coagulation Parameters

701

Parameter

702

Approximate on-therapy peak concentrations

703

Dilute thrombin time/ecarin clotting assay, ng/mL

704

Chromogenic anti-factor-Xa, ng/mL

705 706 707 708 709

755

Apixaban

Dabigatran

Edoxaban

Rivaroxaban

NA

50-400

NA

NA

60-300

NA

100-300

180-350

756 757 Q17

759 760

Approximate on-therapy trough concentrations Dilute thrombin time/ecarin clotting assay, ng/mL Chromogenic anti-factor-Xa, ng/mL

758

NA

30-225

NA

NA

25-200

NA

10-40

10-140

761 762 763

Effect on routine coagulation testsa

764

710

Activated partial thromboplastin time

þ

þþþþ

þ

þ

765

711

Prothrombin time

þ

þ

þþ

þþþ

766

712

Thrombin time

NA

þþþþþ

NA

NA

767

713 714 715

768 See Table 1 legend for expansion of abbreviation. a The effect of DOACs on routine coagulation tests can be signiﬁcantly inﬂuenced by variability in laboratory assays and reagents. Anti-Xa values can vary widely based on agent, indication, and dosing regimen. Values presented in this table are approximate values based on published trial data.

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769 770

771 772

TABLE 4

] Major Drug Interaction Between DOACs and Commonly Used Drugs in the ICU Setting

773

Medication (Mechanism of Interaction)

774

Antiepileptic agents

775 776 777 778 779 780 781 782 783 784

Phenytoin (strong CYP450 3A4 inducer/ P-glycoprotein inducer)

791 792 793

Dabigatran

Avoid use; signiﬁcant reduction in AUC predicted

800

Ketoconazole, itraconazole, and voriconazole (strong CYP450 3A4 inhibitor/ P-glycoprotein inhibitor)

Use with caution; theoretical increase in concentrations; consider alternative agent if additional interactions and/or risk factors presenta

No available data

Avoid use; 100% increase in AUC

Avoid use; 150% increase in AUC

Posaconazole (strong CYP450 3A4 inhibitor/ P-glycoprotein inhibitor)

Avoid use; signiﬁcant increase in AUC predicted

Avoid use; signiﬁcant increase in AUC predicted

802 804 805 806 807 808 809

Cardiovascular agent

815 816 817 818 819 820 821

Use with caution; 42% increase in AUC; consider alternative agent if additional interactions and/or risk factors presenta

Consider dose reduction or alternative agent; 95% increase in AUC; consider alternative agent if additional interactions and/or risk factors presenta

Avoid use; 160% increase in AUC

Use with caution; theoretical increase in concentrations; consider alternative agent if additional interactions and/or risk factors presenta

Avoid use; signiﬁcant increase in AUC predicted

Avoid use; 35% reduction in AUC; increase in active metabolite

Avoid use; 50% reduction in AUC

837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858

Avoid use; 54% reduction in AUC

Avoid use; 66% reduction in AUC

860 861 862 863

Antiretroviral agent

814

812

No available data

859

Rifampin (strong CYP 3A4 inducer/ P-glycoprotein inducer)

813

811

833

Anti-infective agents

Ritonavir (strong CYP450 3A4 inhibitor/Pglycoprotein inhibitor)

810

831 832

Fluconazole (moderate CYP450 3A4 inhibitor)

801 803

Avoid use; signiﬁcant reduction in AUC predicted

835

796

799

Avoid use; signiﬁcant reduction in AUC predicted

830

836

795

798

Rivaroxaban

Antifungal agents

794

797

Edoxaban

834

787

790

Apixaban

Avoid use; signiﬁcant reduction in AUC predicted

786

789

827 828 829

785

788

826

Amiodarone (P-glycoprotein inhibitor)

Avoid use; signiﬁcant increase in AUC predicted

Avoid use; signiﬁcant increase in AUC predicted

Avoid use; signiﬁcant increase in AUC predicted

864

Avoid use; 153% increase in AUC

865 866 867 868 869

Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

Use with caution; 58% increase in AUC; consider alternative agent if additional interactions and/or risk factors presenta

Use with caution; 40% increase in AUC; consider alternative agent if additional interactions and/or risk factors presenta

870

Use with caution; 1.36-fold increase in AUC; consider alternative agent if additional interactions and/or risk factors presenta

822

871 872 873 874 875 876 877

(Continued)

823

878

824

879

825

880

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881 882 883 884 885 886 887 888 889

TABLE 4

936

] (Continued)

Medication (Mechanism of Interaction) Diltiazem (mild to moderate CYP450 3A4 inhibitor/Pglycoprotein inhibitor)

890

937 Apixaban

Dabigatran

Use with caution; 40% increase in AUC; consider alternative agent if additional interactions and/or risk factors presenta

Use with caution; theoretical increase in concentrations; consider alternative agent if additional interactions and/or risk factors presenta

Edoxaban No available data

891 892 893 894 895 896 897

Verapamil (moderate CYP450 3A4 inhibitor/Pglycoprotein inhibitor)

Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914

921

Avoid use; signiﬁcant reduction in AUC predicted

948

Avoid use; signiﬁcant reduction in AUC predicted

Avoid use; signiﬁcant reduction in AUC predicted

Avoid use; signiﬁcant reduction in AUC predicted

958

Avoid use; signiﬁcant increase in AUC predicted

Consider dose reduction or alternative agent; 73% increase in AUC

Tacrolimus (mild CYP450 3A4 inhibitor/Pglycoprotein inhibitor)

Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

Avoid use; signiﬁcant increase in AUC predicted

Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

926

931 932 933 934 935

949 950 951 952 953 954 955 956

959 960 961 963

925

930

947

Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

962 Use with caution; increase in AUC by 120%; consider alternative agents if additional interactions and/or risk factors presenta

Cyclosporine (moderate CYP450 3A4 inhibitor/Pglycoprotein inhibitor)

924

929

945 946

Immunosuppressant agents

923

928

943 944

957

Dexamethasone (strong CYP450 3A4 inducer/Pglycoprotein inducer)

922

927

941 942

Consider dose reduction or alternative agent; 40% to 53% increase in AUC; consider alternative agent if additional interactions and/or risk factors presenta

917

920

939 940

Consider dose reduction or alternative agent; variable increase in AUC (12% to 180%); consider alternative agent if additional interactions and/or risk factors presenta

916

919

Rivaroxaban Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

Systemic steroid

915

918

938

964

Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

965 966 967 968 969 970 971 972 973

Use with caution; theoretical increase in concentration; consider alternative agent if additional interactions and/or risk factors presenta

974 975 976 977 978 979 980 981

AUC ¼ area under the plasma concentration-time curve; CYP ¼ cytochrome P450. See Table 1 legend for expansion of other abbreviation. a Additional factors for consideration include renal/liver impairment, age $ 75 years, weight # 60 kg, or concomitant medications that increase bleeding risk such as antiplatelet agents and/or nonsteroidal antiinﬂammatory agents.

drug-induced cytopenias.84,85 In most trials except those using dabigatran, major adverse cardiovascular events occur in < 2% of cases.99,102 QTc prolongation has not been shown with rivaroxaban,111 apixaban,112 or edoxaban.113

986

Initial concerns with the use of DOACs stemmed from the inability to reverse their anticoagulant effects. Newer speciﬁc and nonspeciﬁc agents, however, are now available to mitigate this concern. Reversal agents can be

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983 984 985

Reversal Agents for DOACs

chestjournal.org

982

987 988 989 990

991

992

993

994

995

996

997

998

999

1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

] DOACs Reversal Agent Properties

Q18

Agent

Mechanism of Action

4-Factor PCCs (KCentra)

Replacement of coagulation factors II, VII, IX, and X, small amounts of proteins C and S

All

DOAC Target

25-50 U/kg Additional doses can be given as needed, 25 U/kg

Dosing

79% effective in controlling bleeding based on trials

7%, elevated risk when receiving other reversal agents within 4 h, undergoing surgery, or receiving massive transfusion protocol

Preferred over fresh frozen plasma according to CHEST and ASH guidelines Contraindicated with concomitant DIC and abnormal ﬁbrinolysis Risk of contraction of HIV, viral hepatitis, and parvovirus B19 (all PCCs)

3-Factor PCC (Proﬁlnine, Bebulin)

Replacement of coagulation factors II, IX, and X

All

25-50 U/kg

Reverses endogenous thrombin potentially within 3 h, PT normalization after 6 h

None reported

Data limited to phase I studies

Activated PCC (FEIBA)

Replacement of activated factor VII also inactivated II, IX, and X

All

25-50 U/kg Additional doses can be given as needed, 25 U/kg

Overall, 86% control of bleeding Control of ICH, 71% according to 2 small retrospective studies

4 per 100,000 (manufacturer safety data). 0%-12% (retrospective studies)

Contraindicated to use with DIC, acute thrombosis, or embolism (including myocardial infarction), and with history of anaphylactic or severe hypersensitivity reactions to FEIBA or any of its components

Idarucizumab (Praxbind)

Monoclonal antibody

Dabigatran

5 g dose (as two 2.5 g infusions 15 min apart)

68% control of bleeding 13.5% 30-day mortality 18% 90-day mortality

5% (0.4% thrombosisspeciﬁc 30-day mortality)

Rebound of dabigatran levels can occur

Andexanet alfa (Andexxa)

Inactivated factor Xa (decoy protein)

Rivaroxaban Apixaban

Low dose (for rivaroxaban # 10 mg, apixaban # 5 mg, or last conﬁrmed dose > 8 h): 400-mg bolus (30 mg/min) followed by 4 mg/min (480 mg total) High dose (for rivaroxaban > 10 mg or apixaban > 5 mg conﬁrmed within 8 h or unknown dose): 800mg bolus (30 mg/min) followed by 8 mg/min (960 mg total)

79% efﬁcacy at 12 h

18% (10 deaths from CVD)

Data based on ANNEXA4124

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TABLE 5

Efﬁcacy

Thrombosis Risk

Comments

(Continued)

] 1047

1046

1049

1048

1051

1050

1052

1053

1055

1054

1057

1056

1059

1058

1061

1060

1062

1063

1065

1064

1067

1066

1069

1068

1071

1070

1072

1073

1075

1074

1077

1076

1079

1078

1081

1080

1082

1083

1085

1084

1087

1086

1089

1088

1091

1090

1092

1093

1095

1094

1097

1096

1098

1100

1099

1103 Comments

1104 1105 1106 1107 1108 1109 1110 1111

Thrombosis Risk

1113 1114 1115 1116 1117

NA

1112

1118 1120 1121 Efﬁcacy

1122 1123 1124 1125 1126 1127

66% survival according to small case series

1119

1128 1130 1131 Dosing

1132 1133 1134 1135 1136 1137

Intermittent effective for rapid removal Continuous replacement methods may prevent rebound

1129

1143 1144 1145 1146

1149 1150 1151 1152 1153 1154 1155

TABLE 5

1148

] (Continued)

1147

Dabigatran

1142

Extracorporeal drug removal

1141

Hemodialysis

1140

Agent

1139

Mechanism of Action

DOAC Target

1138

ANNEXA-4 ¼ Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors; ASH ¼ American Society of Hematology; CHEST ¼ American College of Chest Physicians; CVD ¼ cardiovascular disease; DIC ¼ disseminated intravascular coagulation; FEIBA ¼ Factor Eight Inhibitor Bypassing Activity; ICH ¼ intracranial hemorrhage; PCC ¼ prothrombin protein complex; PT ¼ prothrombin time; PTT ¼ partial thromboplastin time. See Table 1 legend for expansion of other abbreviation.

Q19

1102

Variable normalization of PT and PTT seen

1101

considered when conservative measures have failed and the site of bleeding could be fatal, when there is organthreatening bleeding (eg, hemarthrosis, intraocular), or when there is an indication for urgent surgery. Nonmajor bleeds are less likely to require such aggressive measures in light of the short half-life of the DOACs, especially considering the high cost of reversal agents.114,115 Table 5 outlines the available agents, as well as their dosing, efﬁcacy, and side effect proﬁles.19,114-126 We found no literature regarding the efﬁcacy or safety of tranexamic acid, aminocaproic acid, or desmopressin in DOAC-related bleeding. Ciraparantag (PER977) is a synthetic molecule that binds heparinoids and DOACs and showed promise in phase I studies as a broad-spectrum reversal agent.126 A phase II clinical trial of ciraparantag is currently enrolling as of this publication.127

1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176

Conclusions It will be increasingly common for patients in the ICU to be receiving DOAC therapy or have an indication to begin such therapy during their hospital stay. Intensivists should be familiar with the properties, dosing adjustments, management of life-threatening bleeding, and common drug interactions related to DOACs. Following is a summary of the take-home points: VKAs remain the agent of choice for valvular AF. In NVAF, DOACs are noninferior to VKAs in stroke prevention. DOACs are not currently approved for the treatment of HIT. Current guidelines caution against the use of IV thrombolysis in patients presenting with acute ischemic stroke while taking DOACs. Several studies are underway to answer this speciﬁc question. Limited data exist regarding the use of DOACs postthrombolysis in patients with massive or submassive pulmonary embolism. DOACs are not the anticoagulant agents of choice for the treatment of acute VTE in the ICU setting. Given the potential for hemodynamic decompensation and the need for thrombolysis, UFH should be used in the majority of patients in the ICU. There are few data regarding the use of DOACs in VTE prevention in the ICU. Currently, betrixaban is the only FDA-approved agent for VTE prevention in acutely ill medical patients. Minor procedures (eg, ophthalmologic, dermatologic, dental) should be performed at trough drug

11

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1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210

1211 1212 1213 1214 1215

1216 1217

1218 1219 1220 1221 1222

1223 1224 1225 1226

1227 1228 1229 1230 1231 1232 1233 1234 1235 1236

Acknowledgments Q21

Q11

1238 1239

1. Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong J. Introduction to drug pharmacokinetics in the critically ill patient. Chest. 2012;141(5):1327-1336.

1241 1242 1243 1244 1245 1246 1247 1248 1249

1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265

Financial/nonﬁnancial disclosures: None declared.

References

1240

1251

Author contributions: All authors contributed equally to the drafting of the manuscript.

Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.

1237

1250

concentration (usually 24 h since last dose). For highrisk procedures, DOACs should be held, with the duration depending on agent, renal clearance, and surgical procedure. Bridging with LMWH/UFH is usually not recommended in the periprocedural period. Dose adjustment of DOACs is recommended in patients with renal and liver failure. Apixaban has the most evidence for safety in both acute and chronic kidney disease; rivaroxaban and dabigatran should be avoided. Compared with VKAs, DOACs have an overall lower bleeding rate, although the rates of GIB vary according to agent. Development of speciﬁc reversal agents such as idarucizumab (for dabigatran) and andexanet alfa (for the factor Xa inhibitors apixaban, rivaroxaban, edoxaban, and betrixaban) have lessened clinician concerns for major bleeding with DOACs.

Q12

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1304

24. Diener H, Eikelboom J, Connolly SJ, et al. Apixaban versus aspirin in patients with atrial ﬁbrillation and previous stroke or transient ischaemic attack: a predeﬁned subgroup analysis from AVERROES, a randomised trial. Lancet Neurol. 2012;11(3):225-231.

1308

5. 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. 6. 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. 7. Hoolwerf EW, Kraaijpoel N, Büller HR, van Es N. Direct oral anticoagulants in patients with liver cirrhosis: a systematic review. Thromb Res. 2018;170:102-108.

25. Breithardt G, Baumgartner H, Berkowitz SD, et al. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial ﬁbrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial. Eur Heart J. 2014;35(47):3377-3385.

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9. Potze W, Arshad F, Adelmeijer J, et al. Differential in vitro inhibition of thrombin generation by anticoagulant drugs in plasma from patients with cirrhosis. PLoS One. 2014;9(2):e88390. 10. Graff J, Harder S. Anticoagulant therapy with the oral direct factor xa inhibitors rivaroxaban, apixaban and edoxaban and the

12 Contemporary Reviews in Critical Care Medicine

27. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in comparison with warfarin in patients with atrial ﬁbrillation and valvular heart disease: ﬁndings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Circulation. 2015;132(8):624-632.

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1321

28. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2017;70(2): 252-289.

1322 1323 1324 1325

29. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of nonvitamin-K antagonist anticoagulants in patients with non-valvular atrial ﬁbrillation: executive summary. Eur Heart J. 2017;38(27): 2137-2149.

1326 1327 1328 1329

30. Hansson NC, Grove EL, Andersen HR, et al. Transcatheter aortic valve thrombosis: incidence, predisposing factors, and clinical implications. J Am Coll Cardiol. 2016;68(19):2059-2069.

1330 1331

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