Color Atlas and Synopsis of Electrophysiology, 1st Ed.

28. PREVENTION OF THROMBOEMBOLISM IN ATRIAL FIBRILLATION: FACTOR XA AND THROMBIN INHIBITORS

J. Michael Boyd, PharmD, BCPS

CASE PRESENTATION

A 67-year-old woman presents to the clinic for evaluation of her atrial fibrillation (AF). Her medical history is significant for hypertension and diabetes mellitus. Atrial fibrillation was diagnosed 2 years ago and has been managed with sotalol and warfarin to this point. Her CHADS2 score is 2, and thus her estimated annual stroke risk is 4%. Recent laboratory studies are notable only for an international normalized ratio (INR) of 1.7. An electrocardiogram demonstrates sinus rhythm with a QT interval of 460 ms. The patient notes that there has been considerable variation in her INR values and that she is concerned about her stroke risk, as well as risk for bleeding. She inquires regarding alternative anticoagulants.

EPIDEMIOLOGY

The prevalence of AF in the United States is estimated to be between 2.7 and 6.1 million in 2010.1,2 Patients with AF are nearly 5 times as likely to suffer an ischemic stroke as those without AF.3 In patients with AF deemed to have considerable risk for thromboembolism, treatment has traditionally meant a vitamin K antagonist, such as warfarin. Though proven to be highly effective in the prevention of thromboembolic events, warfarin has many undesirable properties. These drawbacks include:

• Required monitoring of the INR to maintain a narrow therapeutic goal

• Multiple drug and dietary interactions

• Delayed onset and dissipation of effect due to mechanism of action

• Unpredictable dosing in part related to genetic polymorphisms

The worldwide approval of novel oral anticoagulants has provided alternatives to warfarin that may prove attractive for many patients with AF.

FACTOR Xa AND THROMBIN INHIBITORS

Rivaroxaban (Xarelto) and apixaban (Eliquis) are the first factor Xa inhibitors approved for the prevention of stroke and thromboembolism in patients with nonvalvular AF. Several other agents (edoxaban, darexaban, betrixaban, otamixaban) are in various stages of development.4 Whereas warfarin inhibits thrombus formation through inhibition of clotting factor synthesis, factor Xa inhibitors exert their activity through direct inhibition of activated clotting factor X in the common pathway of the clotting cascade (Figure 28-1). Differences in mechanism of action, pharmacokinetic properties (Table 28-1), and drug interactions (Table 28-2) give factor Xa inhibitors several advantages compared to warfarin (Table 28-3).

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FIGURE 28-1 Clotting cascade depicting site of action of factor Xa and thrombin inhibitors. (Used with permission of Erik Abel, PharmD, BCPS.)

TABLE 28-1 Pharmacokinetic Properties of Novel Anticoagulants

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TABLE 28-2 Serious Drug Interactions of Novel Anticoagulants

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TABLE 28-3 Advantages and Disadvantages of Anticoagulants for Prevention of Thromboembolism in Patients with Atrial Fibrillation

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Dabigatran (Pradaxa) is the first direct thrombin inhibitor available for thromboembolic prevention in nonvalvular AF. Dabigatran directly blocks free and clot-bound thrombin (Factor II) in the final step of the clotting cascade (See Figure 28-1). Similar to factor Xa inhibitors, mechanistic and pharmacokinetic properties of dabigatran offer many advantages compared to warfarin (see Tables 28-1 to 28-3).

Similar to warfarin, the primary adverse effect of factor Xa and thrombin inhibitors is increased risk of bleeding. Though clinical trials suggest similar or lower rates of bleeding compared to warfarin, management of severe bleeding presents more challenges with the new agents. Poor sensitivity of clinically available laboratory tests (PT, INR, aPTT) and lack of a specific antidote for the new agents make assessment and reversal of the anticoagulant effect difficult in the setting of acute hemorrhage.

CLINICAL TRIALS

In patients with AF, each of the new anticoagulants has been compared to warfarin for stroke and systemic embolism prevention in large, randomized, noninferiority trials. Dabigatran was assessed by the RE-LY trial, rivaroxaban in the ROCKET-AF trial, and apixaban in the ARISTOTLE study.5-7 Notable similarities of these trials include:

• Large sample sizes

• Common end points—combination of stroke and systemic embolism (efficacy) and similarly defined major bleeding (safety)

• Exclusion of patients with severe renal insufficiency, significant valvular heart disease, or prosthetic heart valves

• Duration of follow-up of about 2 years

Significant differences in the design of these trials include:

• Patients randomized to warfarin were unblinded to treatment in RE-LY but were blinded in ROCKET-AF and ARISTOTLE.

• Adjustments for renal insufficiency were made in ROCKET-AF and ARISTOTLE, but not in RE-LY.

• Higher stroke-risk patients (CHADS2 ≥2) were enrolled in the ROCKET-AF trial.

In RE-LY, patients were randomized to one of 2 doses of dabigatran (110 mg or 150 mg twice daily) or open-label warfarin with an INR goal of 2 to 3. Time in therapeutic INR range for the warfarin group was roughly 65%. Approximately two-thirds of the patients were considered high risk for stroke (CHADS2 ≥2). For the prevention of stroke and systemic embolism, the results of RE-LY demonstrate noninferiority for both doses of dabigatran compared to warfarin as well as superiority for the 150 mg dose (Table 28-4). Compared with warfarin, major bleeding was reduced with the 110 mg dose and similar with the 150 mg dose (Table 28-5). Of note, both doses of dabigatran showed reduced rates of life-threatening bleeding and intracranial hemorrhage versus warfarin while the 150 mg dose was associated with an increased rate of gastrointestinal (GI) bleeding.

TABLE 28-4 Intention-to-Treat Efficacy Results of the Major Clinical Trials of New Oral Anticoagulants Compared to Warfarin for the Combined Primary Endpoint of Stroke or Systemic Embolism5,6,7

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TABLE 28-5 Bleeding Endpoint Results of the Major Clinical Trials of New Oral Anticoagulants Compared to Warfarin5,6,7

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The ROCKET-AF study compared rivaroxaban 20 mg daily (15 mg daily for CrCl 30 to 49 mL/min) with blinded adjusted-dose warfarin (goal INR 2 to 3). Warfarin patients had INR values within the therapeutic range 55% of the time. Patients at low or intermediate risk of stroke (CHADS2 0 to 1) were excluded from ROCKET-AF. The primary outcome of this study by the intention-to-treat analysis revealed that rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolism in this patient population (see Table 28-4). Importantly, a reduction in events in the rivaroxaban group during treatment was offset by a significant increase in events in the rivaroxaban group after discontinuation of study drug. This suggests that patients may be at risk for stroke when discontinuing rivaroxaban in the absence of adequate alternative anticoagulation. Additionally, similar rates of major bleeding were reported for both groups while less intracranial hemorrhage and more GI bleeding was noted with rivaroxaban (see Table 28-5).

Apixaban at a dose of 5 mg twice daily was compared to blinded dose-adjusted warfarin (goal INR 2 to 3) in ARISTOTLE. A reduced apixaban dose of 2.5 mg twice daily was used for patients with 2 or more of the following: age of at least 80 years, weight of 60 kilograms or less, or serum creatinine of 1.5 mg per deciliter or more. Two-thirds of patients had a CHADS2 score of at least 2, and the mean time in therapeutic range for warfarin patients was 62.2%. The results of ARISTOTLE reveal superiority of apixaban compared to warfarin for the combined end point of stroke and systemic embolism (see Table 28-4). Additionally, for the predefined secondary end point of death from any cause, apixaban became the first new agent to show reduced mortality compared to warfarin (3.52% versus 3.94% per year; hazard ratio, 0.89; 95% CI, 0.80 to 0.998; P = 0.047). For safety end points, apixaban reduced all types of bleeding with the exception of GI bleeding for which it showed similar rates (see Table 28-5).

SPECIFIC CLINICAL ISSUES

Holding novel anticoagulants for invasive procedures requires consideration of multiple factors including:

• Thromboembolic risk of the patient in the absence of anticoagulation—may be assessed using the CHADS2 or CHA2DS2-VASc risk assessment tools (Table 28-6). For either tool, a score of 0 is considered low risk, 1 is intermediate, and 2 or higher is high risk for thromboembolism.

TABLE 28-6 CHADS2 and CHA2DS2-VASc Stroke Risk Assessment Tools for Patients with Atrial Fibrillation8,9

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• Bleeding risk of the procedure/surgery—generally any procedure that could result in bleeding in a non-compressible organ (intracranial, intraspinal, intraocular, retroperitoneal, intrathoracic, or pericardial) should be deemed high risk.10

• Pharmacokinetic properties of the specific agent—most importantly elimination half-life (t1/2) and patient characteristics which may affect t1/2 such as renal function (see Table 28-1).

General recommendations for holding the new oral anticoagulants are presented in Table 28-7. Because there are no available specific reversal agents, it is advisable to consider holding doses for longer periods for procedures with high bleeding risk. Considering the rapid onset of the new agents, anticoagulant therapy should be resumed after hemostasis and when bleeding risk has declined, generally 24 to 48 hours after the procedure/surgery. No bridge therapy with parenteral anticoagulants should be administered.

TABLE 28-7 Manufacturer-Suggested Factor Xa and Thrombin Inhibitor

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• Management of bleeding

 Images Minor bleeding may be managed by holding the anticoagulant.

 Images Major or life-threatening bleeding requires the initiation of general resuscitative measures including:

 ■ Stopping the anticoagulant, giving activated charcoal if last dose is recent (<1-2 hours).

 ■ Manage hemodynamic compromise—administer fluid, blood, and vasopressors as needed to maintain tissue perfusion.

 ■ Apply topical thrombin as appropriate.

 ■ Correct deficiencies in essential components of clot formation (ie, fibrinogen, platelets).

 ■ For dabigatran only, consider hemodialysis—low protein binding allows for removal via dialysis.

 ■ Consider the administration of prothrombin complex concentrates (PCCs). Information on the use of PCCs for the reversal of the effects of factor Xa and thrombin inhibitors is limited with variable results.11,12 The clotting factor content of the numerous PCC products varies considerably. Generally, for treatment of major bleeding due to factor Xa inhibitors nonactivated 4-factor PCCs (factors II, VII, IX, X) are preferred over nonactivated 3-factor PCCs (which have very small amounts of factor VII). The use of anti-inhibitor coagulant complex, which is similar to 4-factor PCC with the exception that factor VII is in the activated form, may be useful for the treatment of bleeding associated with dabigatran. Of note, the most safe and effective dose of PCC for the reversal of factor Xa and thrombin inhibitors remains to be determined, and caution should be used in the administration of PCC due to the risk of thrombosis.

PATIENT EDUCATION

• Patients with AF treated with anticoagulants should be counseled to recognize the signs and symptoms of stroke. Facial droop, aphasia, slurred speech, and unilateral arm weakness are all signs of focal neurological deficit caused by a stroke. Patients should be encouraged to seek immediate medical attention at the earliest sign of stroke.

• As the most common adverse effect of thrombin and Xa inhibitors is bleeding, patients must be aware of the signs and symptoms of bleeding. Overt hemorrhage, including hematochezia, hematemesis, retinal hemorrhage, intractable epistaxis, and trauma-induced hemorrhage, requires emergency medical attention. Gastrointestinal adverse effects (dyspepsia, gastritis) may occur with dabigatran likely due to tartaric acid being present in the capsules.

• Patients must be strongly encouraged to avoid abrupt discontinuation of any of the novel anticoagulants. Short half-lives leading to relatively quick dissipation of effect may increase the risk of thromboembolism in the absence of bridging therapy when any of the new agents are discontinued. This is particularly true of rivaroxaban given its short half-life. Post-hoc analysis of the ROCKET-AF trial demonstrated that patients randomized to rivaroxaban had an inordinately high incidence of stroke when they stopped taking the medication in the absence of bridging anticoagulant therapy.13

• Proper storage of dabigatran is critical, and patients should be advised of such. Dabigatran is highly susceptible to hydrolysis and should be stored in its original packaging to minimize moisture exposure. Improper storage, such as in patient pill organizers, could lead to excessive degradation and potential ineffectiveness of dabigatran.

• Due to saturable absorption with rivaroxaban, patients should be told to take doses ≥ 15mg with a large meal (usually dinner). Food slows absorption of rivaroxaban allowing for more complete absorption and better bioavailability.

REFERENCES

  1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001;285(18):2370-2375.

  2. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmstead County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence [published correction appears in Circulation. 2006;114:e498]. Circulation. 2006;114(2):119-125.

  3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke. 1991;22:983-988.

  4. De Caterina R, Husted S, Wallentin L, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis—Task Force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol. 2012;59:1413-1425.

  5. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

  6. Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

  7. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

  8. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-2870.

  9. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on Atrial Fibrillation. Chest. 2010;137:263-272.

 10. Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med. 2013;368:2113-2124.

 11. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol. 2012;87: Suppl 1: S141-S145. [Erratum, Am J Hematol. 2012;87:748.]

 12. Dzik WS. Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion. 2012;52:Suppl 1:45S-55S.

 13. Patel MR, Hellkamp AS, Lokhnygina Y, et al. Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation). J Am Coll Cardiol. 2013;61:651-658.