Материал: ТЭЛА
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TABLE 1 Characteristics of the NOACs
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Dabigatran (Pradaxa) |
Rivaroxaban (Xarelto) |
Apixaban (Eliquis) |
Mechanism of acton |
Direct thrombin inhibitor |
Direct factor Xa inhibitor |
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Pharmacokinetcs |
0.5-2 hrs |
2-4 hrs |
3-4 hrs |
tmax |
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T 1/2 |
12-14 hr |
7-11 hrs |
8.3 hrs |
Eliminaton |
Renal 80% |
Renal 33% (actve drug) |
Renal 27% |
Dosing for acute VTE |
Afer 5-10 days LMWH, dabigatran |
Rivaroxaban 15 mg BID x 3 weeks, |
Apixaban 10 mg BID for 7 days, then |
treatment |
150 mg BID (110 mg BID*) |
then rivaroxaban 20 mg daily |
apixaban 5 mg BID |
Administraton |
Do not chew, break or open |
Take with food (preferably main |
Take with or without food |
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capsules |
meals) |
Can be crushed, suspended in water |
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Swallow capsule whole with or |
Can be crushed and administered |
and administered by NG |
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without food |
by NG |
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Contraindications |
Active bleeding; lesions at risk of clinically signifcant bleeding (e.g., hemorrhagic or ischemic stroke within 6 |
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months [note: for apixaban—recent cerebral infarction], active peptic ulcer disease with recent bleeding) |
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Treatment with strong P-glycoprotein inhibitors or inducers (e.g., ketoconazole, rifampin)
Concomitant treatment with strong inhibitors of both CYP P450 3A4 and P-glycoprotein (e.g., ketoconazole, ritonavir); strong inducers should also be avoided
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CrCl <30mL/min |
Use in patients with |
Not recommended in patients with CrCl |
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CrCl <30mL/min is not |
<15 mL/min, clinical data are very limited |
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recommended |
in patients with CrCl 15-24 mL/min |
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Not recommended in patients |
Hepatic disease (including |
Not recommended in severe hepatic |
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with hepatic enzymes >3X |
Child-Pugh Class B and C) |
impairment or hepatic disease |
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upper limit of normal |
associated with coagulopathy |
associated with coagulopathy and |
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and with clinically relevant |
clinically relevant bleeding risk. |
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bleeding risk |
Use with caution in mild or moderate |
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Use with caution in moderate |
hepatic impairment |
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hepatic impairment |
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Contraindicated in patients |
Not recommended in patients with prosthetic heart valves |
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with prosthetic heart valves |
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requiring anticoagulation due |
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to valvular status |
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Dabigatran is contraindicated in nursing women. Use in pregnancy is not recommended for rivaroxaban and |
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apixaban. |
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Laboratory assessment |
Monitor CBC at baseline and with any change in health status that may impact hemoglobin, red blood cell |
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and anticoagulation |
count or platelets. |
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testing |
Monitor CrCl at baseline and with any change in health status that may impact renal function and |
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appropriateness of dose/continued use. |
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Routine anticoagulant monitoring is not required. The INR and aPTT do not quantitatively correlate with drug levels and should not be used for routine monitoring.
A calibrated TT* (Hemoclot assay) will provide dabigatran levels. In absence of Hemoclot assay availability, a normal TT rules out presence of clinically important dabigatran levels; aPTT may be used to refect presence of drug, although
a minority of patients (<2%) may have a normal aPTT just prior to their next dose while chronically taking dabigatran.
Rivaroxaban-calibrated anti-Xa levels refect the pharmacodynamic efect in a
dose-dependent fashion. In the absence of calibrated anti-Xa levels, PT (Neoplastin reagent) may be useful to refect presence of drug.
Rotachrome Heparin Anti-Xa assay refects the pharmacodyamic efect of apixaban in a linear, dose-related fashion. In the absence of calibrated anti-Xa levels, PT/INR is not efective for assessing apixaban.
Adverse efects |
Dyspepsia, bleeding |
Bleeding |
Bleeding |
(continued)
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TABLE 1 (continued) |
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Dabigatran (Pradaxa) |
Rivaroxaban (Xarelto) |
Apixaban (Eliquis) |
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Antidote |
For dabigatran only, idarucizumab (Praxbind) has conditional notice of compliance for life-threatening |
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or uncontrolled bleeding as well as emergency surgery/urgent procedures. Recommended dose is 5 g (administered as 2 consecutive boluses or infusions of the 2.5 g vials).
Andexanet alpha is currently under study for reversal of anti-Xa inhibitors. Despite limited data, options may include activated prothrombin complex concentrates (PCCs), inactivated PCCs or rFVIIa.
For dabigatran only, dialysis may be considered but may not be practical.
Drug-drug interactions |
Dabigatran etexilate is a substrate |
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for the efux P-gp transporter. |
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Plasma concentrations are |
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afected by strong P-gp |
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inducers and P-gp inhibitors. |
Elimination by CYP3A4 and P-glycoprotein (P-gp); concomitant strong inhibitors/inducers of both of these pathways will increase/decrease rivaroxaban and apixaban exposure, respectively.
*Although not studied in the acute treatment of VTE, the manufacturer suggests aligning with the atrial fbrillation dosing strategy of 110 mg BID for those over the age of 80 years or 75 years or older with a concomitant bleeding risk factor and to consider 110 mg BID in those with a CrCl between 30-50 mL/min.
LMWH, low molecular weight heparin; BID, twice daily; TT, thrombin time; NG, nasogastric.
daily and 2.5 mg twice daily) had very similar rates of VTE recurrence, while the lower dose demonstrated less major bleeding. Given this, the apixaban product monograph recommends only the lower dose for this extension phase.2 For rivaroxaban, the EINSTEIN-choice study is now under way, comparing rivaroxaban 20 mg daily, rivaroxaban 10 mg daily and acetyl - salicylic acid (ASA) 100 mg daily and will ofer important information about using the lower (prophylactic) dose of rivaroxaban.35 Last, 2 trials (WARFASA and ASPIRE) assessed the use of ASA for secondary VTE prevention and
reported an overall 30% reduction in recurrent VTE.36,37 While this appears good relative to
placebo, one must realize that NOACs report (on average) an 80% risk reduction in the same setting, and most experts suggest that the use of ASA for long-term prophylaxis should be considered only when the use of an anticoagulant has been ruled out.
Step 5: Pertinent information for your patient
Patient education is paramount when using anticoagulants and should encompass the benefts and risks of therapy, emphasis on the need for adherence and dosing specifc to the agent prescribed, as well as integration with ongoing monitoring and follow-up (e.g., therapy reassessment, renal function).38
Summary
Pharmacists are well positioned and very accessible to the general public. As such, our role in ensuring optimal use of high-risk therapies such as anticoagulants that are relatively new in the marketplace is critical. As clinicians, we should be empowered to access diagnostic testing to allow both confrmation of the diagnosis and an ability to gauge the location and extent of the individual patient’s clot burden (Step 1). Pharmacists must be informed of the varying pharmacologic regimens for the treatment of VTE, having frsthand knowledge of dosing to ensure patients are prescribed appropriate therapies as they transition through the 3 phases of therapy (Step 2). As patients return to the pharmacy for reflls, the pharmacist should be attuned to the anticipated duration of therapy (Step 3), ensuring that at least annual reassessment occurs and that patients transitioned to the extended phase are prescribed the appropriate agent/dose (Step 4). Educating our patients to be proactive in their health care will optimize outcomes and must include information on the disease itself, the risk of therapy (major bleeding), and importance of adherence, knowing that 1 missed dose of a NOAC leaves the patient unprotected (Step 5). As therapy choices evolve, the complexities broaden, and the frontline pharmacist is well situated to optimize care and ensure good patient outcomes. ■
From the Division of Cardiology (Bungard), Department of Medicine, University of Alberta, Edmonton, Alberta; and Clinical Pharmacy Services (Semchuk), Regina Qu’Appelle Health Region, Regina, Saskatchewan. Contact tammy.bungard@ualberta.ca.
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Author Contributions: Both authors drafted, revised and approved the final version of this article.
Declaration of Conflicting Interests: T.J. Bungard has received honoraria from Bayer and Bristol Myers Squibb-Pfizer within the past 2 years. She has also received unrestricted grants from Pfizer and Bayer. W. Semchuk has received honoraria from Bayer, Pfizer, Bristol Myers Squibb and Boehringer Ingelheim
within the past 2 years. He has served as a consultant or on an Advisory Board for Bayer and Pfizer/Bristol Myers Squibb in the past 2 years, and he has received a research grant from Pfizer in the past 2 years.
Funding: Te authors received no fnancial support for the research, authorship and/or publication of this article.
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