Newer Anticoagulants in the Emergency Department
Author:
Jennifer C. Chen, MD, Section Chief of Emergency Medicine, Department of Medicine, West Los Angeles Veterans Affairs Medical Center, Los Angeles, CA.
Peer Reviewer:
David E. Slattery, MD, FACEP, FAAEM, Associate Professor and Research Director, Department of Emergency Medicine, University of Nevada School of Medicine, Las Vegas, NV.
My mother was on warfarin for a number of years and her degree of anticoagulation was difficult to manage. She had a number of complications, including bleeding episodes. So, I was enthusiastic about these new anticoagulants with their more predictable therapeutic effect. As with all new drugs, there are downsides; currently the lack of a readily available coagulation test to assess if there is a significant coagulopathy and an effective reversal agent. As these drugs are increasingly used, emergency physicians will see patients such as the three cases presented below.
— J. Stephan Stapczynski, MD, Editor
Cases
Case 1. An 80-year-old male is brought by ambulance to the emergency department (ED) after a ground-level fall at home. Two months ago, he was diagnosed with atrial fibrillation. His cardiologist started him on dabigatran 150 mg twice a day for stroke prophylaxis. His initial Glasgow Coma Scale (GCS) was 15 with a normal, nonfocal neurologic exam. A noncontrast head computed tomography scan (CT) shows a small right subdural hematoma (SDH). There was also a small amount of left frontal lobe and left parietal subarachnoid hemorrhage (SAH). Laboratory values at presentation include an international normalized ratio (INR) of 1.3, a prothrombin time (PT) of 15.2 seconds, and a partial thromboplastin time (PTT) of 57 seconds (normal range 24-35 seconds). The platelet count is normal, and the patient is not on antiplatelet agents. The patient is admitted to the neurosurgical intensive care unit for serial neurological examinations. About 3 hours after admission, the patient developes dysarthria and altered mental status, with a repeat CT showing interval progression of the left frontal hemorrhage and development of right intraparenchymal hemorrhage.
Case 2. A 55-year-old female is taking an off-label use of rivaroxaban 20 mg once a day for deep venous thrombosis (DVT) treatment due to living in a remote area where access to recurrent anticoagulation testing and clinic visits is difficult. She had an unprovoked DVT 2 months ago. She presents to your ED with a 2-day history of hematochezia, initially scant red blood mixed in with formed generally brown bowel movements, but now with intermittent frank bright red blood per rectum, with the last about an hour ago. She endorses mild lightheadedness, but no chest pain, dyspnea, other active bleeding. Her initial vital signs are HR 85, BP 140/78, RR 14, T 36.8, O2 sat 97% on room air. Her initial hemoglobin (Hgb) is 9.8, down from her baseline of 12.5. Her creatinine is 1.2.
Case 3. A 74-year-old male presents to your ED with chest tightness and palpitations, and is found to have new-onset atrial fibrillation with rapid ventricular response. He is rate-controlled with diltiazem IV and then PO, has no new evidence of ischemia on his EKG or serial troponin testing, and is hemodynamically stable and feeling well after his ED treatment. His TSH is normal and you've arranged for an urgent outpatient echocardiogram and outpatient cardiology clinic appointment for him. His CHADS2 score is 2, with one point for hypertension and another for age.1 (See Table 1.) He walks one to two miles daily and has had no recent falls.
Table 1: CHADS2 Score
Condition |
Points |
|
C |
Congestive heart failure |
1 |
H |
Hypertension |
1 |
A |
Age ≥ 75 years |
1 |
D |
Diabetes |
1 |
S2 |
Prior stroke or TIA |
2 |
CHADS2 Score |
Annual Stroke Risk (%) |
95% CI |
Anticoagulation Therapy |
0 |
1.9 |
1.2-3.0 |
None or aspirin daily |
1 |
2.8 |
2.0-3.8 |
Aspirin daily or warfarin (goal INR 2.0-3.0) |
2 |
4.0 |
3.0-5.1 |
Warfarin (goal INR 2.0-3.0) or new oral anticoagulant unless contraindicated |
3 |
5.9 |
4.6-7.3 |
Warfarin (goal INR 2.0-3.0) or new oral anticoagulant unless contraindicated |
4 |
8.5 |
6.3-11.1 |
Warfarin (goal INR 2.0-3.0) or new oral anticoagulant unless contraindicated |
5 |
12.5 |
8.2-17.5 |
Warfarin (goal INR 2.0-3.0) or new oral anticoagulant unless contraindicated |
6 |
18.2 |
10.5-27.4 |
Warfarin (goal INR 2.0-3.0) or new oral anticoagulant unless contraindicated |
Introduction
These three cases illustrate various challenges of patient care using newer oral anticoagulants. In October 2010, the U.S. Food and Drug Administration (FDA) approved dabigatran etexilate (Pradaxa®) for the prevention of stroke in patients with non-valvular atrial fibrillation. In 2011, the FDA approved rivaroxaban (Xarelto®) for DVT prophylaxis in patients undergoing knee or hip replacement surgery and for prevention of stroke in patients with non-valvular atrial fibrillation. Since approval in October 2010 through August 2011, approximately 1.1 million dabigatran prescriptions have been dispensed in the United States, and since FDA approval, approximately 350,000 rivaroxaban prescriptions have been written in the United States.2
Traditional anticoagulants such as heparin and warfarin are currently widely used but also are known to have major limitations, including narrow therapeutic windows of adequate anticoagulation without bleeding, slow onset and offset of action, and highly variable dose-response relationships that necessitate frequent laboratory testing for individual monitoring.3 The ideal medication for long-term anticoagulation therapy would be an orally active agent that can be given in fixed doses with predictable therapeutic effect and wide therapeutic range, without the need for routine coagulation monitoring, with no food or medication interactions, and that has an available effective antidote. (See Table 2.) Limitations of traditional anticoagulants lead to underutilization, high discontinuation rates, and long periods of subtherapeutic medication levels.4,5 A meta-analysis of warfarin therapy for stroke prophylaxis in atrial fibrillation showed that INR is in the therapeutic range of 2.0-3.0 only 58% of the time, which obviously limits effectiveness.6
Table 2: Attributes of an Ideal Anticoagulant
|
There are many indications for chronic anticoagulation. The most common indications include stroke prophylaxis in atrial fibrillation, prevention and treatment of venous thromboembolism (VTE), and secondary prophylaxis of high-risk patients with previous myocardial infarction or stroke. Atrial fibrillation is associated with an increase in risk of ischemic stroke by up to fivefold.8 Atrial fibrillation accounts for up to 15% of all strokes, and up to 30% in persons older than 80 years of age.9 Knee and hip joint replacement surgeries are among the most common surgeries performed in the United States, with more than one million performed in 2009.10 Both surgeries have a high risk of postoperative VTE. Emergency physicians will take care of patients taking both old and new anticoagulants, will need to manage anticoagulant-related complications, and will need to choose anticoagulant regimens for patients to be started on anticoagulation.
For emergency physicians, the most relevant downside of current anticoagulation therapy with heparins and warfarin is the risk of bleeding, with bleeding frequencies reported in the 10-16% range.11 Emergency physicians also diagnose and treat acute VTE and strokes in the setting of medication noncompliance or failure, as well as manage frequent drug interactions with warfarin. In an analysis of a large national emergency department dataset, warfarin was the number one medication most commonly implicated in emergency hospitalizations for adverse drug events in U.S. adults 65 years old and older.12
Coagulation Physiology
Unfractionated and low molecular weight heparins act by binding to antithrombin and enhancing the ability of antithrombin to inhibit both thrombin and activated factor Xa.13 However, heparin activity against fibrin-bound thrombin is limited. The anticoagulant activity of heparin originates from the generation of a ternary heparin-thrombin-antithrombin complex, but the thrombin exosites that form this complex are blocked when thrombin is already fibrin-bound. This can mean that with conventional heparin treatment only, there is still fibrin-bound active thrombin to further trigger thrombus growth.14
Thrombin is a target of interest in the development of anticoagulant agents, as it is central in the clotting process. (See Figure 1.) Thrombin is the end product of the coagulation cascade triggered by the interaction with plasma factor VII with tissue factor (exposed on the surface of damaged endothelium). Thrombin then converts soluble fibrinogen to fibrin, amplifies the coagulation cascade by activating factors V, VIII, and XI, stimulates platelets, and activates factor XIII, which helps fibrin molecules form cross-linked bonds and a more stable clot.13,14
Figure 1: Sites of Action of Anticoagulant Agents
Factor Xa is a coagulation factor that is involved in the final step before thrombin formation in the coagulation cascade, where factors Xa and V come together to form the prothrombinase complex, which then catalyzes the formation of thrombin from prothrombin. Factor Xa is a target of interest in anticoagulant drug development.\
Pharmacology
Dabigatran is a synthetic univalent direct thrombin inhibitor, which binds to the active site on the thrombin molecule for both free and clot-bound thrombin.14 Therefore, in contrast to heparins, dabigatran can inactivate fibrin-bound thrombin. Dabigatran is orally administered as a prodrug dabigatran etexilate, which is rapidly converted to active dabigatran. Cytochrome p450 molecules are not involved in dabigatran metabolism. (See Table 3.) Dabigatran has little interaction with drugs other than inhibitors and inducers of the transporter p-glycoprotein such as rifampin, amiodarone, verapamil, clarithromycin, and quinidine, although concomitant proton pump inhibitor administration does reduce absorption.15-17 Dabigatran has few food interactions, and taking it with food does not affect absorption. Dyspepsia (10%) is the major reported side effect. Dabigatran is 80% renally excreted, and peak concentrations are achieved within 2-3 hours of administration.16,17 Dabigatran is unstable if not kept stored in the original bottle or blister pack (needs packaged desiccant).18
Table 3: Comparison of Oral Anticoagulants
Warfarin |
Dabigatran |
Rivaroxaban |
Apixaban |
|
Mechanism of action |
Vitamin K epoxide reductase inhibitor → decreased synthesis of vitamin K-dependent clotting factors II, VII, IX, and X |
Direct thrombin inhibitor |
Factor Xa inhibitor |
Factor Xa inhibitor |
Half-life (hours) |
40 |
12-17 |
5-9 |
8-15 |
Monitoring |
INR-adjusted |
Not required |
Not required |
Not required |
Coagulation assay |
PT/INR |
Ecarin clotting time and Hemoclot© Thrombin inhibitor assay, both not widely available. Can use PTT and thrombin time as qualitative tests for presence of drug. |
Anti-factor Xa chromogenic assay. May be able to use PT as a qualitative test for presence of drug. |
Dilute PT test HepTest |
Metabolism |
CYP450 (liver) |
80% renal, 20% fecal |
66% renal, 33% fecal |
75% fecal, 25% renal |
Drug interactions |
CYP 2C9, 1A2, 3A4 |
Inhibitors and inducers of transporter p-glycoprotein: |
CYP 3A4. |
CYP 3A4 |
Reversal strategies |
Vitamin K |
Charcoal |
Charcoal |
Charcoal |
Dosing |
Typical start dose: 5 mg po qhs, adjust to INR |
150 mg po bid for stroke prophylaxis |
20 mg po qday for stroke prophylaxis; |
5 mg po bid for stroke prophylaxis; |
Rivaroxaban is an oral, highly selective, concentration-dependent inhibitor of Xa that can bind to both prothrombinase-bound and clot-bound factor Xa, thus reducing thrombin formation. Rivaroxaban is rapidly absorbed, with maximal concentrations within 2-4 hours of ingestion and a half-life of 7-11 hours. Rivaroxaban is metabolized by a variety of independent metabolic pathways, limiting its drug-drug interactions, but can also interact with inhibitors and inducers of the transporter p-glycoprotein such as ketoconazole, ritonavir, clarithromycin, erythromycin, and rifampicin. Approximately two-thirds of any dose of rivaroxaban is metabolized to inactive metabolites, and elimination is approximately two-thirds renal and one-third fecal.19 Apixaban is not yet FDA-approved as of June 2012, but approval appears imminent. It is also a direct factor Xa inhibitor, with a time to peak anticoagulant effect of around 3 hours and a half-life of 8-15 hours. It is eliminated primarily fecally (75%), with the remaining 25% by renal elimination.20
Dabigatran and rivaroxaban are predominantly renally excreted. In study subjects with normal or mild renal impairment, renal excretion of dabigatran was basically complete within 24 hours, but prolonged up to more than 96 hours after a single 150 mg dose of dabigatran in patients with severe renal impairment.21 The pharmaceutical manufacturers recommend dose reduction in patients with mild to moderate renal insufficiency (creatinine clearance 15 to 30 mL/min), e.g., dabigatran 75 mg bid.
Major Trials
Research trials on dabigatran and the oral factor Xa inhibitors rivaroxaban and apixaban have focused on three major indications: stroke prevention in nonvalvular atrial fibrillation, VTE prevention in high-risk surgical patients, and VTE treatment. (See Table 4.)
Table 4: Major Trials of New Anticoagulants
Indication |
Dabigatran |
Rivaroxaban |
Apixaban |
Stroke prophylaxis in nonvalvular atrial fibrillation |
RE-LY: n = 18113. Dabigatran 110 or 150 mg bid vs. warfarin. 150 mg dabigatran superior to warfarin in stroke and systemic embolism prevention with no difference in major bleeding |
ROCKET AF: n = 14264. Rivaroxaban 20 mg qday vs. warfarin in pts with CHADS2 score ~3.5. Rivaroxaban noninferior to warfarin in stroke and systemic embolism prevention with no difference in bleeding. |
AVERROES: n = 5599. Apixaban 5 mg bid vs. daily aspirin in patients unsuitable for VKA. Apixaban superior to aspirin in prevention of stroke and systemic embolism. ARISTOTLE: n = 18201. Apixaban 5 mg bid vs. warfarin. Apixaban superior to warfarin in prevention of stroke and systemic embolism and in rates of major bleeding. |
VTE prophylaxis in high-risk orthopedic surgery |
RE-MODEL: n = 2076. Dabigatran 150 mg or 220 mg daily vs. enoxaparin 40 mg subQ daily in TKR. Dabigatran noninferior, no difference in bleeding. RE-NOVATE: n = 3494. Dabigatran 150 mg or 220 mg daily vs. enoxaparin 40 mg subQ daily in THR. Dabigatran noninferior, no difference in bleeding. RE-MOBILIZE: n = 2615. Dabigatran 150 mg or 220 mg daily vs. enoxaparin 30 mg subQ BID in TKR. Dabigatran failed to demonstrate noninferiority. No difference in bleeding. RE-NOVATE II: n = 2055. |
RECORD1: n = 4541. Rivaroxaban 10 mg qday vs. enoxaparin 40 mg subQ daily in patients for THR. Rivaroxaban superior at preventing VTE and/or death. No difference in bleeding. RECORD2: n = 2509. Rivaroxaban 10 mg qday vs. enoxaparin 40 mg subQ daily in patients for THR. Rivaroxaban superior at preventing VTE and/or death. No difference in bleeding. RECORD3: n = 2531. Rivaroxaban 10 mg qday vs. enoxaparin 40 mg subQ daily in patients for TKR. Rivaroxaban superior at preventing VTE and/or death. No difference in bleeding. RECORD4: n = 3148. Rivaroxaban 10 mg qday vs. enoxaparin 30 mg subQ bid in patients for TKR. Rivaroxaban superior at preventing VTE and/or death. No difference in bleeding. |
ADVANCE1: n = 3195. Apixaban 2.5 mg bid vs. enoxaparin 30 mg subQ bid in patients for TKR. Apixaban failed to show noninferiority but with significantly less bleeding. ADVANCE2: n = 3057. Apixaban 2.5 mg bid vs. enoxaparin 40 mg subQ daily in patients for TKR. Apixaban superior for preventing VTE and death. No difference in bleeding. ADVANCE3: n = 1949. Apixaban 2.5 mg bid vs. enoxaparin 40 mg subQ daily in patients for THR. Apixaban superior for preventing VTE and death with no difference in bleeding. |
Acute VTE treatment |
RE-COVER: n = 2564. Dabigatran 150 mg bid vs. INR-adjusted warfarin for 6 months to treat acute VTE. Dabigatran was noninferior for prevention of recurrent symptomatic VTE and/or death assoc. with VTE. |
EINSTEIN-DVT: n = 3449. Rivaroxaban 15 mg bid x 3 weeks, then 20 mg daily for 3-12 mos vs. warfarin. Rivaroxaban noninferior to prevent recurrent symptomatic VTE. No significant difference in bleeding. |
|
ACS |
ATLAS ACS 2-TIMI 51: n = 15526. Randomized patients with ACS to placebo or rivaroxaban 2.5 mg bid or 5 mg bid. Rivaroxaban significantly reduced composite of cardiovascular death, MI, or stroke at both doses compared to placebo. Both doses significantly increased major and intracranial bleeding. |
APPRAISE-2: n = 7392. Prematurely terminated because of increased bleeding with apixaban and no evidence of benefit. |
Dabigatran was the first FDA-approved new oral anticoagulant. Initial approval was for stroke prevention in non-valvular atrial fibrillation, based on the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial.22
RE-LY was a noninferiority trial of 18,113 patients with at least one risk factor for stroke (mean CHADS2 score 2.1). There were 951 sites in 44 countries involved. There were three arms, with dabigatran dosed at 110 mg twice a day or 150 mg twice a day, compared with warfarin dosed for a goal INR of 2-3. The primary outcome was incidence of stroke or systemic embolism, with major bleeding (defined as a reduction in the hemoglobin level of at least 20 g/L, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ) as the primary safety outcome. Patients were followed up for a median of 2.1 years. Dabigatran 150 mg twice daily, the dose ultimately approved by the FDA for stroke prophylaxis in patients with nonvalvular atrial fibrillation, demonstrated a relative risk of 0.66 (95% CI 0.53-0.82), statistically significant for noninferiority versus warfarin. One would need to use dabigatran 150 mg twice daily rather than warfarin in 172 patients to prevent the primary outcome of stroke or systemic embolism.
A separate publication by Eikelbloom et al conducted a safety analysis of the RE-LY study population.23 Major bleeding was significantly lower only in the dabigatran 110 mg twice daily arm. Rates of combined minor and major bleeding were lower in both dabigatran arms versus warfarin, reaching statistical significance for both dosages of dabigatran. Dabigatran 150 mg twice a day compared with warfarin demonstrated similar risks of major bleeding and extracranial bleeding, significantly increased gastrointestinal bleeding, and significantly less intracranial (0.30% vs. 0.74%, p = 0.001) and life-threatening bleeding (1.49% vs. 1.85%, p = 0.030). This translates to a number needed to treat (NNT) of 400 to prevent one episode of major bleeding, and an NNT of 227 to prevent one episode of intracranial bleeding with dabigatran 150 mg twice daily versus warfarin. Why is there more gastrointestinal bleeding with dabigatran? The authors postulated there are local effects of dabigatran on diseased mucosa. Dabigatran has a low bioavailability after oral ingestion, and it is possible that metabolism of dabigatran etexilate by esterases leads to progressively higher concentrations of the active drug during transit of the gastrointestinal tract. The prevalence of gastrointestinal tract pathology, such as diverticulosis and angiodysplasia, increases with age, and the risk of bleeding from affected areas might be increased by direct exposure to dabigatran.
Dabigatran at either dose did not increase major bleeding at surgical sites compared with warfarin in the RE-LY safety analysis, and the total numbers for bleeding at nongastrointestinal, extracranial sites were small. Dyspepsia was the only adverse effect that was significantly more common in the dabigatran treatment arms.
This safety analysis also looked at the effects of age. Intracranial and extracranial bleeding rates increase with age in all treatment arms. Both doses of dabigatran compared with warfarin were associated with lower risks of major and extracranial bleeding in patients younger than 75 years old, and similar risks of major and extracranial bleeding in those 75 years old and older, demonstrating a significant interaction between treatment and age. However, the risk of intracranial bleeding was lower with both doses of dabigatran compared with warfarin, irrespective of age. The authors postulated that by selectively targeting thrombin and not interfering with the formation of tissue factor-factor VIIa complexes, dabigatran preserves hemostatic mechanisms in the brain. Tissue factor is found in high concentrations in the brain, where it is believed to provide additional hemostatic protection in the case of injury. In contrast, warfarin blocks vitamin K-dependent carboxylation of factor VII and therefore suppresses production of factor VIIa.
Dabigatran is renally excreted, while warfarin is not. It is reasonable to expect higher drug levels and more bleeding in renally impaired patients, but Eikelbloom et al interestingly found more bleeding across all treatment arms in all patients with creatinine clearance (CrCl) < 50. However, there were relatively few patients enrolled with CrCl < 50 and/or who were underweight (< 50 kg), so making generalizations from this limited subpopulation is difficult.
When comparing medication efficacy against warfarin, it is important to keep in mind factors that impact warfarin's efficacy, namely time in therapeutic range or TTR. TTR varies widely in clinical practice, with the best results (TTR upwards of 80%) seen in pharmacist-run models,24,25 and a recent study demonstrating a mean TTR of 58% in the VA system nationally.26 In the RE-LY multinational trial, TTR ranged between 44% and 77% among the various countries (mean 64%), with the average TTR for U.S. patients at 66%, above the threshold at which warfarin is thought to be superior to dual antiplatelet therapy (TTR 59%). Wallentin et al looked at dabigatran efficacy compared with warfarin stratified by TTR quartile within the RE-LY dataset.27 They found that in the third quartile (TTR 65.5-72.6%) and fourth quartile (TTR > 72.6%), there was no difference between 150 mg dabigatran and warfarin in reducing risk of ischemic stroke, which is, of course, the main outcome anticoagulation therapy is meant to prevent. Also, with higher quality TTRs, major gastrointestinal bleeding rates on warfarin are less, making the increased gastrointestinal bleeding seen with dabigatran use seem even more problematic. But in the second quartile (57.1-65.5% TTR), there is a difference in ischemic stroke with dabigatran 150 mg. TTR affects the evaluation of how warfarin and dabigatran compare with each other.
Each of the new oral anticoagulants has been studied for the same potential indications. In the ROCKET AF trial, researchers compared rivaroxaban 20 mg daily to warfarin adjusted for INR 2.0-3.0 for stroke prevention in nonvalvular atrial fibrillation.28 This double blind, noninferiority trial had 14,264 patients with atrial fibrillation at moderate to high risk for stroke, with a mean CHADS2 score of 3.48 in the rivaroxaban arm and 3.46 in the warfarin arm, a median age of 73 years, and 40% were female. Patients were followed up for about two years. The median TTR in the ROCKET AF patients in the warfarin arm was 57.8%, around what is probably the national average.29 The primary efficacy endpoint was the composite of stroke (ischemic or hemorrhagic) and systemic embolism, and the primary safety endpoint was a composite of major and nonmajor clinically relevant bleeding events. A little more than one-fifth of patients in both arms terminated therapy before the study termination date and without an endpoint event. Stroke or systemic embolism occurred at 2.1%/year (269/7081 patients) in the rivaroxaban group, compared to 2.4%/year (306/7090 patients) in the warfarin group for a hazard ratio of 0.88 (95% CI 0.75-1.03). This represents an absolute risk reduction (ARR) of 0.5% and an NNT of 193. This study demonstrated noninferiority of rivaroxaban to warfarin in the prevention of stroke and systemic embolism. There were no significant differences in rates of major and clinically relevant nonmajor bleeding between the two study groups. There was, however, significantly more need for transfusion in the rivaroxaban arm. Conversely, there was significantly less fatal and intracranial bleeding in the rivaroxaban arm as well.
The AVERROES trial (n = 5599) randomized patients with atrial fibrillation and CHADS2 score of at least one (mean CHADS2 ~2) to apixaban 5 mg twice daily or to aspirin 81 or 324 mg daily. These were patients unsuitable for warfarin either due to demonstrated problems with prior warfarin usage, or expected to be unsuitable due to anticipated interactions, patient preference, or anticipated compliance difficulties.30 The primary outcome was the occurrence of stroke or systemic embolism. Fifty-one primary outcome events occurred (1.6%/yr, 51/2808 patients) in the apixaban arm, as compared to 113 events (3.7%/yr, 113/2791) in the aspirin arm, for a significant hazard ratio of 0.45 (95% CI 0.32-0.62). This represents an absolute risk reduction of 2.2% and an NNT of 44. There was no significant difference in bleeding. This study was terminated early due to benefit of apixaban.
The ARISTOTLE trial (n = 18201) randomized patients with atrial fibrillation and at least one CHADS2 risk factor to apixaban 5 mg twice daily compared to INR-adjusted warfarin.31 This trial found apixaban to be superior to warfarin in the primary outcome of stroke or systemic embolism over the median follow-up period of 1.8 years. The rate of stroke or systemic embolism was 1.27%/year (212/9120 patients) in the apixaban arm versus 1.60%/year (265/9081) in the warfarin arm, for a significant hazard ratio of 0.79 (95% CI 0.66-0.95), or an ARR of 0.5% and an NNT of 168. Apixaban also demonstrated a significant decrease in major bleeding (including subgroups of intracranial and gastrointestinal bleeding) compared to warfarin (hazard ratio 0.69, 95% CI 0.60-0.80). Despite these results, the FDA has not yet granted approval.
VTE Prevention
Rivaroxaban is approved in the United States, Europe, and Canada for VTE prophylaxis in patients undergoing knee or hip replacement surgery. Each of the new oral anticoagulants was studied for this indication. Particularly as other indications for prolonged hospitalization in the perioperative period diminish, there is much interest in outpatient oral regimens for VTE prophylaxis in the setting of high-risk orthopedic surgeries. Also, patient preferences for prophylaxis regimens vary widely, especially in VTE prophylaxis and treatment, so having more oral anticoagulant options may improve overall compliance.32 Of note, VTE prophylaxis regimens with enoxaparin differ between North America (enoxaparin 30 mg subcutaneously twice daily) and Europe (enoxaparin 40 mg subcutaneously once daily). Both types of regimens are studied below.
Dabigatran at 150 mg and 220 mg once daily was compared to enoxaparin 40 mg subcutaneous injection once daily, both started the night before either total knee replacement (RE-MODEL) or total hip replacement (RE-NOVATE).33,34 Both studies were double blind, randomized, multicenter, multinational trials that found dabigatran at either dose to be noninferior to enoxaparin in regard to the primary outcome of VTE or all-cause mortality. There were no significant differences in bleeding between dabigatran and enoxaparin. RE-MODEL and RE-NOVATE both have very low numbers of primary outcome events. In contrast, the RE-MOBILIZE study that compared dabigatran at 150 mg and 220 mg daily to enoxaparin 30 mg subcutaneous injection twice daily failed to demonstrate noninferiority for VTE prophylaxis after knee arthroplasty.35
Rivaroxaban is approved for VTE prophylaxis in joint replacement surgery based on a series of RECORD trials, which all found rivaroxaban to be superior to enoxaparin.36-39 RECORD1 and RECORD2 were randomized, double-blind studies comparing 10 mg of rivaroxaban daily with enoxaparin 40 mg subcutaneously once daily. In RECORD1, patients in either arm took study medications for 36 days. In the enoxaparin arm, 3.7% (58/1558 patients) developed VTE or death during the study period, compared with 1.1% (18/1595 patients) in the rivaroxaban arm. This absolute risk reduction of 2.6% calculates out to an NNT of 38. In RECORD2, patients took rivaroxaban for 31-39 days and enoxaparin injections for 10-14 days. RECORD2 demonstrated an absolute risk reduction of 7.3% with use of rivaroxaban, which calculates to an NNT of 14. Both studies showed nonsignificant mild increases in combined major and nonmajor bleeding in the rivaroxaban groups. There were extremely low numbers of major bleeding, with just one incident of major bleeding in either arm in the RECORD2 trial, and no bleeding leading to re-operation.
RECORD3 and RECORD4 were randomized, double-blind studies comparing rivaroxaban 10 mg daily with enoxaparin 40 mg once daily in patients undergoing total hip replacement. In RECORD3, patients took study medications for 13-17 days, with a primary outcome of VTE or death. Rivaroxaban demonstrated an absolute risk reduction of 9.2% (18.9% vs. 9.6%) for an NNT of 11. Adverse events and bleeding showed no significant differences, although there was a trend toward more transaminase elevations in the rivaroxaban arm. RECORD4 showed an absolute risk reduction of 3.19% (10.1% vs. 6.9%) for an NNT of 31. There were no significant differences in bleeding complications, with extremely low numbers of major bleeding in both arms in both studies.
Finally, apixaban was studied in a series of ADVANCE trials, with mixed results.40-42 ADVANCE1 was a randomized, double-blind study comparing apixaban 2.5 mg twice daily with enoxaparin 30 mg twice daily. Apixaban did not meet criteria for noninferiority, but did show significantly less composite major and clinically relevant nonmajor bleeding. ADVANCE2 compared apixaban 2.5 mg twice daily with enoxaparin 40 mg once daily in patients undergoing total knee replacement. Nearly half of the patients randomized were excluded from the primary efficacy analysis due to technical problems with lower-extremity ultrasonography. Of those included, 24.37% of patients on enoxaparin developed VTE or death compared to 15.06% of patients on apixaban, demonstrating superiority of apixaban (NNT 11). There were no significant differences in major bleeding and no bleeding at critical sites in either arm. ADVANCE3 compared apixaban to enoxaparin 40 mg daily in patients receiving total hip replacement. Apixaban demonstrated superiority with an absolute risk reduction of 2.5% (3.9% vs. 1.4%) in VTE and/or death. There was no difference in bleeding.
A recently published meta-analysis of factor Xa inhibitors and VTE prophylaxis in joint replacement surgery identified no difference between oral factor Xa inhibitors rivaroxaban and apixaban and LMWH in all-cause mortality and nonfatal PE.43 Factor Xa inhibitors compared with LMWH did decrease symptomatic DVT by 3 events per 1000 patients treated. There may be, however, increased bleeding of 2 major bleeding events (CI, 0 to 4 more events) per 1000 patients treated for 1 to 5 weeks (I2 = 68%).
VTE Treatment
The RE-COVER trial compared dabigatran 150 mg twice daily versus warfarin for six months' therapy to treat acute VTE.44 It showed dabigatran to be noninferior to warfarin for treatment of acute VTE, with 2.4% of patients in the dabigatran group and 2.1% of patients in the warfarin group developing recurrent VTE and/or death attributable to VTE. There were no significant differences in bleeding, with most of the major bleeding in the dabigatran arm being gastrointestinal in nature, with no intracranial bleeds, and the bleeding in the warfarin arm more varied, including 3 intracranial bleeds.
The EINSTEIN-DVT trial randomized patients to rivaroxaban versus warfarin for treatment of acute DVT.45 Rivaroxaban was noninferior to warfarin for the prevention of recurrent, symptomatic VTE. There were again no significant differences in major or clinically relevant nonmajor bleeding. EINSTEIN-PE compared rivaroxaban versus warfarin for treatment of acute PE with similar results of noninferiority.46 There was a significant decrease in bleeding from 2.2% of patients in the conventional therapy arm with major bleeding versus 1.1% in the rivaroxaban group (p = 0.003).
Acute Coronary Syndrome
The phase II RE-DEEM trial randomized patients with acute coronary syndrome (ACS) already on dual antiplatelet therapy with aspirin and clopidogrel to the addition of dabigatran versus placebo. Dabigatran was associated with a dose-dependent increase in bleeding events without a clear reduction in ischemic clinical events.47 Finally, two trials looked at factor Xa inhibitors in patients with acute coronary syndromes.48,49 The majority of these patients were already on dual antiplatelet therapy with aspirin and clopidogrel. APPRAISE-2 compared apixaban and placebo, and was terminated early due to no demonstrated benefit from apixaban and demonstrated increased bleeding rates. ATLAS-2 compared rivaroxaban at two doses and placebo, and demonstrated benefit in the composite of cardiovascular death, myocardial infarction, and stroke while also showing increased bleeding rates. The APPRAISE-2 and ATLAS-2 trials demonstrated conflicting efficacy results but consistent three- to four-fold increase in bleeding rates.
Coagulation Assays
While a stated advantage of the newly developed drugs is the lack of a requirement for regular anticoagulation monitoring, this can translate into a disadvantage in actual clinical practice, as there is a lack of laboratory monitoring in case of bleeding or thrombosis. (See Table 5.) Whether the patient is compliant with the anticoagulation regimen, exactly what degree of anticoagulation is present when a patient needs urgent surgery, or whether there is an overdose present are questions not easily answered with newer anticoagulants. Because of the shorter half-lives of these new oral anticoagulants compared with warfarin, poor compliance can leave the patient at greater risk for developing thrombosis.
Table 5: Need for Monitoring
|
There are no widely available laboratory assays specific for dabigatran activity, but dabigatran has some varied effects on conventional coagulation assays. The PTT concentration-response curve is curvilinear and flattens at concentrations ≥ 200 ng/mL, making it useful primarily as a qualitative test of whether dabigatran and other direct thrombin inhibitors are present and active. In other words, PTT < 30 has a good negative predictive value for presence of dabigatran. It is not suitable for precise quantification of anticoagulant effect, especially at high plasma concentrations, and therefore cannot help determine if an overdose is present. Prothrombin time (PT) has a relatively flat concentration-response curve and is not useful to measure dabigatran activity. Thrombin time (TT) directly assesses the activity of thrombin in a plasma sample and is particularly sensitive to the effects of dabigatran, displaying a linear dose-response. However, thrombin times cannot be standardized across laboratories due to nonstandardized reagents. Also, at dabigatran concentrations > 600 ng/mL, the test frequently exceeds the maximum measurement time of coagulometers. TT is also best used clinically as a qualitative test for dabigatran activity. Activated clotting time (ACT) is a bedside assay frequently used in the cardiac catheterization lab or in the operating room setting, which has a concentration-response curve similar to PTT.50,51 Finally, ecarin clotting time (ECT) and a proprietary Hemoclot© Thrombin Inhibitor assay are direct measures of dabigatran activity, but only available for research purposes currently.50
There are anti-factor Xa assays commercially available (originally used for measuring levels of heparin, LMWH, and fondaparinux) that may be useful for the quantitative measurement of rivaroxaban provided that a standard curve is generated with a known amount of rivaroxaban, but no simple, reliable, and standardized assay with high sensitivity is yet available for routine use in the clinical setting. The Rotachrom anti-Xa activity assay is the most widely used chromogenic anti-Xa test in North America and does demonstrate a linear relationship between apixaban concentration and anti-Xa activity in plasma samples.52 Rivaroxaban does prolong PT in a dose-dependent fashion, but PT is not sensitive enough at lower rivaroxaban plasma concentrations. PT is not prolonged at rivaroxaban concentrations < 50 ng/mL, a level that is still within measured plasma concentrations in phase II VTE prevention trials for patients on therapeutic doses of rivaroxaban.53 Also, there exists great variability in what plasma concentration of rivaroxaban or apixaban will result in prolonged PT depending on which commonly available PT assay used.52 So, an elevated PT may support presence of direct Xa inhibitors, but a normal PT may not exclude direct Xa inhibitor activity. The low sensitivity and variability of PT make it problematic to quantitatively assess drug levels. Both rivaroxaban and apixaban also cause minimal prolongations of PTT, but PTT is not sensitive or reliable enough to be clinically useful.54
Reversal of New Anticoagulants
The most feared complication of anticoagulation is bleeding. As with any bleeding, supportive care and local control of the bleeding site when possible are cornerstones of therapy. For patients who have severe or life-threatening bleeding in which discontinuation of the drug, local control of bleeding, and supportive therapy with fluids and/or blood transfusion are not sufficiently effective, physicians traditionally turned to reversal agents for patients with bleeding while taking warfarin.
The issue of possible reversal agents is interesting because of the medical community's experience with warfarin-based anticoagulation. While studies are mixed about whether pre-hemorrhage warfarin use increases mortality as a marker of co-morbidities or mechanistically increases mortality, warfarin use does seem to independently predict worse outcomes in traumatic bleeding.55 For example, with intracranial hemorrhage, patients on warfarin demonstrate a two- to five-fold increase in mortality compared with similar patients not on anticoagulation.55-57 Early reversal of warfarin activity in patients with intracranial hemorrhage reduces mortality.58,59 Given the difference in half-life between the newer oral anticoagulants and warfarin, there is a question of whether a focus on reversal is warranted. I argue that it is still relevant, as many critically ill patients develop or have underlying problems with renal failure or gut motility that potentially delay the clearance of dabigatran, rivaroxaban, and apixaban.
For patients with severe life-threatening bleeding while taking dabigatran, there is no definitive reversal agent. There are laboratory and animal studies, and case reports of various reversal attempts. Unfortunately, traditional reversal agents such as protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran, as dabigatran is a direct thrombin inhibitor at the end of the coagulation cascade. Fresh frozen plasma and systemic hemostatics such as tranexamic acid or aminocaproic acid are also not likely to be useful.60 Activated charcoal is one conventional method that is potentially useful, as dabigatran is a lipophilic molecule and therefore should be adsorbable with charcoal for acute ingestions. Charcoal adsorption was successfully demonstrated in two in vitro studies.61
Dabigatran is only approximately 35% protein-bound, and therefore dialyzable.62,63 In a study of patients on hemodialysis given a single 150 mg dose of dabigatran, the mean fractions of the drug removed by dialysis were 62% at 2 hours and 68% at 4 hours.62
It is unlikely that recombinant factor VIIa (rFVIIa) should be effective, as its effect is proximal to thrombin in the coagulation cascade. In vitro studies showed that rFVIIa did not reverse the effects of dabigatran,64 although a study of serum from healthy volunteers showed some success with rFVIIa.65 Hypothetically, prothrombin complex concentrates (PCC) could overcome the anticoagulant effect induced by thrombin and factor Xa inhibitors because PCC contains the coagulation factors II, VII, IX, and X in a high concentration and enhances thrombin generation. However, the data to support this are conflicting. In healthy volunteers, administration of 50 U/kg PCC had no effect on PTT, TT, and ECT.66 In animal models with dabigatran, PCCs reversed prolonged bleeding times and decreased blood loss.67,68
Similarly, there is no specific reversal agent or antidote for the factor Xa inhibitors rivaroxaban and apixaban. Charcoal may be useful. Hemodialysis is unlikely to be helpful because rivaroxaban is highly protein-bound. Several in vitro and animal studies demonstrate partial reversal of the effects of rivaroxaban with rFVIIa.64,69,70 Hypothetically, 4 factor prothrombin complex concentrates (PCC) could overcome the anticoagulant effect induced by thrombin and factor Xa inhibitors because 4 factor PCC (Beriplex®, Octaplex®, Cofact®) contains the nonactivated coagulation factors II, VII, IX, and X in a high concentration and in general enhances thrombin generation. There is a small theoretical risk of thrombogenicity. In healthy volunteers, the effect of rivaroxaban on coagulation assays (PT and endogenous thrombin potential, ETP) was completely reversed immediately after PCC infusion in all subjects, with an effect that persisted out to 24 hours.66 However, 4 factor PCCs are not currently available in the United States. There are no studies on the effect of rVIIa or PCC on apixaban. FEIBA (factor VIII inhibitor bypass activity), which contains nonactivated factors II, IX, and X, and activated factor VII, targets the prothrombinase complex of factor Xa and factor Va. Some animal studies and a human healthy volunteer study of FEIBA and rivaroxaban use show partial reversal. FEIBA at 20 U/kg appeared to be more effective than PCCs or rVIIa in a study of healthy volunteers for reversal of both rivaroxaban and dabigatran.71 There are some in vitro studies of plasma-derived or recombinant factor Xa antidotes that hold promise.72
In summary, the data on reversal agents for the new anticoagulants are sparse and sometimes conflicting. The studies are generally done in vitro, in animals, or in healthy volunteers given a single dose of medication, none of which are similar to true clinical scenarios. No studies exist looking at overdose levels of medication administration or other cases in which serum levels might increase beyond normal therapeutic levels, such as acute renal impairment. Dosages for rVIIa, 3 or 4 factor PCC, and FEIBA in these studies also have not gone through rigorous dose finding studies.
Until the evidence is more robust, or until therapies based on factor Xa antidotes or monoclonal antibodies become more viable, what is an emergency physician to do? Expert guidelines endorse use the following:
- for dabigatran, activated charcoal, hemodialysis, hemoperfusion with activated charcoal, and possibly 4 factor PCCs (50 U/kg);
- for rivaroxaban and apixaban, activated charcoal, possibly hemoperfusion with activated charcoal, and possibly 4 factor PCCs.73
Additional Aspects
As use of new anticoagulants becomes more widespread, what are some potential questions that may arise? New issues inevitably arise in the postmarketing phase of any medication, and dabigatran is no exception, with concerns especially for increased risk of myocardial infarction, as demonstrated by a nonsignificant trend in the RE-LY study.74 A recent meta-analysis showed that dabigatran increased risk for myocardial infarction or ACS compared to warfarin, enoxaparin, or placebo in various clinical settings, with an absolute risk increase for MI or ACS of 0.27%,75 for an NNH of 370. This does not seem like excess clinically important harm, but more data are to come.
Another question of interest is what the true bleeding rate on new anticoagulants will be with widespread use in the general population as opposed to study populations. One multicenter observational study of patients undergoing radiofrequency ablation for atrial fibrillation compared patients on uninterrupted dabigatran versus warfarin.76 The dabigatran group had a significantly higher major bleeding rate (6% vs. 1%, p = 0.009). This reported rate is higher than seen in the RE-LY trial. In general, the noninferiority trials establishing dabigatran and rivaroxaban as alternatives to warfarin have excluded patients planned for procedures. While the rates of surgical wound bleeding have been low in the VTE prophylaxis trials, perhaps different types of interventional procedures would demonstrate different bleeding rates.
How will the convenience and costs weigh against warfarin if there is more of a move toward self-monitoring for select patients?77 A cost-effectiveness analysis comparing dabigatran with warfarin for stroke prevention in atrial fibrillation showed dabigatran to be a cost-effective alternative for patients with CHADS2 score ≥ 1 up to a price of $13.70 per day for dabigatran 150 mg twice daily.78 The wholesale price for dabigatran in the United States is roughly $6.75 per day. Will the ability to self-monitor warfarin use change the average patient's calculus for preferring the new oral anticoagulants over warfarin or vice versa?
If the cost-effectiveness works out, especially if hospitalization can be avoided in VTE prophylaxis or treatment, how many patients will prefer a new oral anticoagulant over warfarin? It has been suggested that patients with new-onset atrial fibrillation might be especially interested in new oral anticoagulants to avoid the hassle of high-frequency INR monitoring and dietary changes when first starting out with warfarin.79
Summary
New anticoagulants have been developed targeting thrombin and factor Xa in the coagulation cascade. The use of these new anticoagulants is rapidly increasing, as they potentially offer improved efficacy, as well as improved ease of use with less drug and food interactions, oral administration, and no requirement for regular INR checks. However, if a patient presents to the ED with acute bleeding or new thrombosis while on therapy, the lack of readily available coagulation monitoring assays can make it difficult to determine if an overdose is present, if the patient was noncompliant, or if there was just treatment failure. In the event of acute bleeding, there are no reversal agents or antidotes to the direct thrombin or factor Xa inhibitors, although in some cases dialysis, rFVIIa, and/or PCCs may be helpful. Emergency physicians can expect to see increasing numbers of patients on these new oral anticoagulants, and will need to manage bleeding complications.
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