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Venous thromboembolism (VTE) is a serious medical condition associated with significant morbidity and mortality, and an incidence that is expected to double in the next forty years. The advent of direct oral anticoagulants (DOACs) has catalyzed significant changes in the therapeutic landscape of VTE treatment. As such, it is imperative that clinicians become familiar with and appropriately implement new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for VTE treatment with the DOACs. When possible, guidance statements are supported by existing published evidence and guidelines. In instances where evidence or guidelines are lacking, guidance statements represent the consensus opinion of all authors of this manuscript and are endorsed by the Board of Directors of the Anticoagulation Forum.
The authors of this manuscript first developed a list of pivotal practical questions related to real-world clinical scenarios involving the use of DOACs for VTE treatment. We then performed a PubMed search for topics and key words including, but not limited to, apixaban, antidote, bridging, cancer, care transitions, dabigatran, direct oral anticoagulant, deep vein thrombosis, edoxaban, interactions, measurement, perioperative, pregnancy, pulmonary embolism, reversal, rivaroxaban, switching, \thrombophilia, venous thromboembolism, and warfarin to answer these questions. Non- English publications and publications > 10 years old were excluded. In an effort to provide practical information about the use of DOACs for VTE treatment, answers to each question are provided in the form of guidance statements, with the intent of high utility and applicability for frontline clinicians across a multitude of care settings.
Keywords: DOACs, NOACs, Direct thrombin inhibitors, Factor Xa inhibitors, Antidotes, Care transitions, Bridging anticoagulation, Drug interactions
The availability of the new direct oral anticoagulants (DOACs) has significantly changed the therapeutic landscape of anticoagulation and these agents may eventually displace conventional VTE treatment with a rapid-acting parenteral anticoagulant overlapped with a vitamin K antagonist (e.g. warfarin) in appropriately selected patients. As a class, the DOACs exhibit comparable efficacy and a significantly lower bleeding risk compared to warfarin among patients with acute symptomatic VTE [1, 2]. For patients who need extended anticoagulation for secondary VTE prevention, the safety record of the DOACs is strong [3–5].
In this paper we will examine key questions pertaining to the practical management of DOACs for VTE treatment, summarize the evidence (where it exists) pertaining to those questions, and finally, provide guidance that may be applied to real-world practice by frontline clinicians.
To provide guidance on the practical management of the DOACs, we first developed a number of pivotal practical questions that apply to DOACs as they might be used in the treatment of VTE. (Table 1 ). Questions were developed by consensus of the authors. The medical literature was reviewed using PubMed for topics and key words including, but not limited to, adherence, anticoagulant, apixaban, appropriate patient selection, bleed, bridging, care transitions, adherence, CYP, dabigatran, deep venous thrombosis (DVT), direct, edoxaban, education, follow-up, hemorrhage, initiation, interaction, measurement, monitoring, novel, oral, peri-operative, p-glycoprotein, practical management, prothrombin complex concentrate (PCC) pulmonary embolism (PE), reversal, rivaroxaban, safety, switching, target-specific, temporary interruption (TI), and venous thromboembolism (VTE). Non-English language publications and publications >10 years old were excluded. Guidance provided in this document is, whenever possible, based on the best available evidence. For some issues, however, published evidence is lacking. In all instances, guidance statements represent the consensus opinion(s) of all authors and are endorsed by the Anticoagulation Forum’s Board of Directors.
Guidance questions to be considered
| 1. Which VTE patients are (and are not) good candidates for DOAC therapy? |
| 2. How should DOACs be initiated for VTE treatment? |
| 3. How should the anticoagulant activity of DOACs be measured? |
| 4. How should VTE patients who require temporary interruption of DOAC therapy be managed? |
| 5. How should patients with DOAC drug–drug interactions be managed? |
| 6. How should patients transition between anticoagulants? |
| 7. How should DOAC-associated bleeding be managed? |
| 8. What is an appropriate care transitions and follow-up strategy for VTE patients on DOAC therapy? |
| 9. How can patients enhance safety and efficacy of their DOAC therapy? |
The DOACs have been studied extensively in clinical trials and the results demonstrate they are at least as safe and effective as conventional treatment in the majority of typical VTE patients. However, many specific subgroups were excluded or underrepresented in these studies and the safety and efficacy of DOACs within these subgroups has yet to be established. The inclusion criteria for the VTE treatment trials included patients age ≥18 (no pediatric studies have been published) with an acute symptomatic proximal DVT and/or PE. Exclusion criteria varied slightly among the trials, but in general, patients were excluded if they had any of the following: need for thrombolytic therapy, another indication for anticoagulation, high risk of bleeding, clinically significant liver disease (acute or chronic hepatitis, cirrhosis, or alanine aminotransferase level greater than three times the upper limit of normal), creatinine clearance (CrCl) 100 mg/day, using interacting medications, uncontrolled hypertension, breastfeeding or pregnant or of childbearing potential without appropriate contraceptive measures [3–10]. Table 2 represents potential advantages and disadvantages of DOACs in comparison to conventional therapy that should be considered by both clinicians and patients before deciding on an anticoagulant regimen. Table 3 provides selection criteria for patients suitable for DOAC therapy. Table 4 provides further considerations regarding patient-controlled aspects, such as adherence, values and preferences as each of these will have a direct impact on outcomes with DOAC therapy.
Potential advantages and disadvantages of DOACs compared to VKAs [119]
| Advantages | Disadvantages |
|---|---|
| No routine monitoring | No reliable, readily available measurement assay |
| Improved safety profile | Dose reduction or avoidance in renal impairment and avoidance in moderate or severe hepatic impairment |
| Rapid onset (may preclude the need for induction or bridging therapy) | No specific antidote |
| Short half-life (advantageous for invasive procedures or in the setting of active bleed) | Short half-life (mandates strict adherence) |
| Fixed dosing | Less flexibility in dosing |
| Greater convenience, patient satisfaction and quality of life | Fewer studies and approved indications (e.g., contraindicated in mechanical valve replacement) |
| Potentially more cost-effective from health system perspective | Potentially higher drug acquisition costs for patients |
| Fewer drug, disease and diet interactions | DOAC drug interactions do exist that may preclude use |
DOAC patient selection criteria
| Criteria for DOAC use | Comment(s) |
|---|---|
| Patient preference for and willingness to take DOAC | Patients should be presented will all therapeutic options and their respective perceived advantages and disadvantages (See Table 2 ) |
| No contraindication to DOAC therapy | E.g. pregnancy, breastfeeding, mechanical heart valve |
| Adequate organ function | Clinicians should regularly monitor renal function, particularly for DOACs with greater reliance on renal elimination (see Tables 5 , 6 and and12) 12 ) and, if there are other factors that may increase DOAC exposure (e.g. age, unavoidable use of concomitant p-gp/CYP3A4 inhibitors). Avoid in moderate or severe hepatic dysfunction |
| No significant drug–drug interactions | See Tables 13 and and14 14 for detailed guidance Patients taking any anticoagulant with antiplatelet agents or NSAIDs have a significantly higher risk of bleeding. To minimize bleeding, avoid these drug combinations when possible |
| No significant disease state interactions | VTE patients with a history of GI bleeding or at risk for GI bleeding may be better candidates for warfarin, apixaban, or edoxaban, as there may be a higher risk of bleeding or GI adverse effects with dabigatran and rivaroxaban |
| Highly likely to be adherent with DOAC therapy and follow-up plan | See Table 4 for further details |
| Confirmed ability to obtain DOAC on a longitudinal basis from a financial, insurance coverage and retail availability standpoint | The drug costs of DOACs may be prohibitive for some patients, as compared with generic warfarin plus laboratory monitoring There are patient assistance programs available via the pharmaceutical companies, and this should be arranged prior to prescribing |
Patient adherence assessments when choosing anticoagulant therapies [118–123]
| Taking medications | How often does the patient miss or forget to take doses of their medication(s)? • If a warfarin patient frequently misses doses, switching to a shorter half-life DOAC may more rapidly predispose the patient to risk of thrombosis • Often, a subtherapeutic INR is a reliable indicator to the clinician and patient that warfarin doses have been missed • Without the requirement for laboratory monitoring with the DOACs, there is no such alert to indicate opportunities to improve adherence |
| Is a once-daily or a twice-daily medication dosing frequency preferred? • If patient is adherent with other twice daily medications, any of the DOACs may be appropriate • Conversely, if patient prefers once daily medications, rivaroxaban or edoxaban may be preferred | |
| Laboratory monitoring | Is laboratory access difficult? • Patients with transportation challenges, difficult venous access, inflexible work or school schedules or other reasons for difficulty complying with INR monitoring may significantly benefit from DOAC therapy • Clinicians should remind DOAC patients that renal function and a complete blood count should be monitored at least annually or more frequently as the clinical situation dictates |
| Health care responsibility | Is the patient reliable to notify health care providers about changes to health and pertinent medical issues? • It is important for the patient to make all health care providers aware he or she is taking an anticoagulant medication, as this information will aid in: – design of peri-procedural anticoagulation plans – addressing medication interactions – consideration of other health status changes • Patients who may be unreliable to report pertinent issues to the clinician may be better suited to warfarin so that at least some of these may be uncovered during INR follow-up • DOAC patients and their clinicians may elect to interact via clinic visit, phone, or electronic media at a regular interval |
INR International normalized ratio, DOAC direct oral anticoagulant
Pregnancy and breastfeeding
Animal studies of dabigatran and rivaroxaban demonstrated pregnancy loss and fetal harm [11, 12], and one study demonstrated that dabigatran does cross the human placenta [13]. A case report of maternal rivaroxaban use during weeks 1–19 of pregnancy (when pregnancy discovered at week 19, the patient was switched to enoxaparin) resulted in a full-term, low growth percentile, otherwise healthy infant [14]. Apixaban has no human data in pregnancy, but showed no maternal or fetal harm in animal studies [15]. Edoxaban animal studies demonstrated no fetal harm. The edoxaban VTE treatment trial reported 10 pregnancies, with edoxaban exposure during the first 6 weeks of gestation (4 full-term births, 2 pre-term births, 1 first-trimester spontaneous abortion, and 3 elective pregnancy terminations) [16]. It is unknown whether any of the DOACs are excreted in breast milk. Because of the potential for infant harm, a decision should be made to either avoid breastfeeding or use an alternative anticoagulant, such as warfarin, in these women.
Body weight extremes
Patients at extremes of weight represented a very small proportion of subjects in DOAC VTE treatment trials. [3–10]. The mean weight was around 84 kg, with the majority of patients weighing between 60 and 100 kg. Underweight patients (100 kg. Approximately 30 % of patients in the EINSTEIN, AMPLIFY and RE-COVER studies had a BMI ≥ 30 kg/m 2 , and in the AMPLIFY and RE-COVER studies, only 12 % of subjects had a BMI ≥ 35 kg/m 2 . Based on very limited data, extremes of weight do not appear to affect peak concentrations or bioavailability of dabigatran [17]. The pharmacokinetics and pharmacodynamics of factor Xa inhibitors may be affected by weight [10, 15, 18–20], but the clinical impact of these effects remains unknown. Pending further evidence in patients at extremes of weight (e.g., 120 kg or BMI ≥ 35 kg/m 2 ) it is advisable to limit DOAC use to situations where vitamin K antagonists cannot be used.
Patients with thrombophilias represented 2–18 % of DOAC VTE clinical trial populations [3–9]. A posthoc subgroup analysis of thrombophilia patients within the RE-MEDY trial was recently presented [21]. Results showed that the frequencies of VTE-related death and PE did not differ between dabigatran and warfarin patients. The authors concluded that dabigatran’s efficacy in preventing recurrent VTE is not influenced by the presence of thrombophilia. Conversely, six cases citing possible failure of rivaroxaban or dabigatran to prevent thrombosis in patients with antiphospholipid antibody syndrome were recently published [22, 23]. While it is possible the DOACs may be a viable option for VTE treatment in patients with weaker underlying thrombophilias (e.g., heterozygous Factor V Leiden), caution or avoidance, especially in highly pro-thrombotic states such as antiphospholipid antibody syndrome or heparin-induced thrombocytopenia, is suggested until further evidence becomes available.
Four meta-analyses of DOAC VTE clinical trials including approximately 1000 cancer patients (patients with a history of cancer or some with active cancer) demonstrated similar efficacy and safety for the DOACs compared to conventional therapy of a vitamin K antagonist overlapped with LMWH [24–27]. Previous trials, which included approximately 2000 patients with active cancer (many in advanced stages), indicate that vitamin K antagonists are inferior to long-term LMWH monotherapy for treatment of cancer-related VTE [28–31]. While most evidence to date is with dalteparin, the recent CATCH study [32] showing a trend (p = 0.07) towards superiority of tinzaparin over warfarin for prevention of recurrent symptomatic DVT and reduction in clinically relevant non-major bleeding suggests this may be a class effect of the LMWHs. Whether DOACs convey similar benefit as LMWH monotherapy for VTE treatment in cancer patients remains unknown. Data from head-to-head randomized controlled trials or robust comparative effectiveness studies is needed and future research in this area is encouraged. Until then, among patients with cancer-associated VTE, long-term LMWH is the preferred first-line therapy for anticoagulant treatment (see chapter by Khorana et al.). However, for those patients who cannot (or will not) use long term LMWH, either a DOAC or VKA could be prescribed as a second-line option. Given their improved safety profile compared to warfarin, DOACs may well be preferred in these instances, particularly among patients with a perceived increased risk for bleeding. However, it is important to emphasize the lack of experience with DOACs compared to warfarin in cancer patients who may have profound thrombocytopenia and other clinical challenges pertaining to anticoagulation. The lack of readily available measurement assays for DOACs may be particularly problematic in the setting of drug interactions, nephrotoxic chemotherapy, and potential disruption in absorption due to short gut or malnutrition, common issues in a cancer population.
Much of the available data on DOACs and gastrointestinal (GI) bleeding is from atrial fibrillation trials, which generally consisted of older patients with more comorbidities than the VTE treatment populations. In a real- world study of Medicare claims data among new users of dabigatran or warfarin for non-valvular atrial fibrillation [33], there was a 28 % overall increased risk for gastrointestinal bleeding among dabigatran patients compared to warfarin patients. This was most pronounced in women ≥75 years of age (HR 1.5; 95 % CI 1.2–1.88), men ≥85 years of age (HR 1.55; 95 % CI 1.04–2.32) and in patients receiving the higher dose of 150 mg twice daily (HR 1.51; 95 % CI 1.32–1.73). A meta-analysis of 4 dabigatran trials of both NVAF and VTE treatment reported a 41 % increase in the risk of GI bleeding with dabigatran [34]. In the individual DOAC VTE treatment trials [3–10], GI bleeding event rates were too low to draw definite conclusions (dabigatran and rivaroxaban numerically higher rates of GI bleeding, apixaban and edoxaban numerically lower rate of GI bleeding) compared to conventional anticoagulation therapy. A meta-analysis of data from 11 phase-3 DOAC NVAF or VTE treatment trials found no significant difference in major gastrointestinal bleeding between DOACs and warfarin (2.09 vs. 1.7 %; RR 0.94; 95 % CI 0.75–1.99; p = 0.62, I 2 71 %) [35]. Even so, careful consideration should be exercised in regards to DOAC use in patients with a history of gastrointestinal bleeding.
Intracranial hemorrhage (ICH) is the most feared complication of anticoagulant therapy. A significant advance with DOAC therapy over warfarin has been a reduction in the rates of ICH in atrial fibrillation. Numerically lower rates of both ICH and fatal bleeding were seen in all DOAC arms of the VTE trials [3–10], with the exception of intracranial hemorrhage in the EINSTEIN-DVT trial (2 events in the rivaroxaban arm vs. none in the warfarin arm) [4]. A systematic review and meta-analysis of 12 randomized controlled trials including over 100,000 patients with either NVAF or VTE showed that DOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant non-major bleeding, and total bleeding compared to warfarin [35]. This provides a compelling argument to favor these agents over conventional therapy for VTE treatment whenever possible.
DOACs are suggested as an alternative to conventional therapy for VTE treatment in patients who meet appropriate patient selection criteria. For all other patients, we suggest VTE treatment with conventional therapy. Until further data are available, we suggest avoiding DOACs for VTE in patients with antiphospholipid antibody syndrome and patients at extremes of weight. LMWH monotherapy remains first line for patients with cancer-related VTE, but DOACs may be considered in select patients unwilling or unable to receive subcutaneous injections.
How should DOACs be initiated for VTE treatment?Before prescribing a DOAC, a thorough evaluation should be conducted to ensure the patient is a good candidate for DOAC therapy, as detailed in Tables 3 and and4. 4 . Baseline labs should be performed, including serum creatinine, liver function tests, complete blood count, and coagulation assays such as aPTT and PT to ensure adequate organ function and rule out coagulopathy. In general, DOAC therapy should not be initiated in patients presenting with extensive VTE if there is potential need for an invasive procedure, such as thrombolysis or thrombectomy. Instead, preference should be given to a shorter-acting, reversible agent such as unfractionated heparin until no further immediate procedures are needed. Clinicians should consider characteristics of the individual agents when selecting which DOAC to initiate (detailed in Table 5 ). In addition, concomitant drug therapies and comorbidities should also be accounted for in DOAC dose management as detailed in Table 6 . In clinical trials of edoxaban and dabigatran [6, 10] initial treatment consisted of open-label parenteral anticoagulation (median of 9 and 7 days in the dabigatran and edoxaban trials, respectively) overlapped with warfarin titrated to an INR of 2–3 in the control arm or overlapped with warfarin-placebo titrated to a sham INR in the intervention arms. Concomitant administration of a parenteral anticoagulant and a DOAC was not employed in either of these trials, as that would likely lead to excessive anticoagulation based on the rapid onset of the DOACs. Dabigatran was initiated at 150 mg BID. Edoxaban was initiated at 60 mg once daily, with a dose reduction to 30 mg once daily in patients with a creatinine clearance of 30–50 mL/min or a body weight of 60 kg or less or in patients who were receiving concomitant treatment with potent P-glycoprotein inhibitors. Package labelling for dabigatran and edoxaban also indicates the required 5–10 days of parenteral anticoagulation prior to their initiation for acute VTE, which closely approximates the conventional approach to VTE treatment.
Drug characteristics to consider when deciding which DOAC to prescribe for VTE [3–12, 15, 16]
| DOAC | Parenteral lead-in | Single-drug approach | Switch or dose de-escalation | Dosing frequency | Renal elimination | Potential for increased adverse effects |
|---|---|---|---|---|---|---|
| Dabigatran | √ | √ | BID | ++++ | MI, GIB, dyspepsia | |
| Rivaroxaban | √ | √ | BID × 21 days, then once daily | ++ | GIB | |
| Apixaban | √ | √ | BID | + | N/A | |
| Edoxaban | √ | √ | Once daily | ++ | N/A |