New Insights into Anticoagulation in Atrial Fibrillation

J Arrhythmia

Vol 27 No 3 2011

Review Article

New Insights into Anticoagulation in Atrial Fibrillation Xiaohan Fan MD, Shu Zhang MD Department of Cardiology, Cardiovascular Institute & FuWai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Oral anticoagulation in atrial fibrillation (AF) is important for stroke prevention. Warfarin, one of the commonly used vitamin K antagonists (VKAs), is underused in clinical practice due to its well-known limitations and complexity. Identification of patients at high risk of bleeding and weighing up the embolism and bleeding risk can help to refine anticoagulation to minimize bleeding risk. New oral anticoagulants with different mechanisms of action may replace the VKAs for a number of indications, especially AF. The oral direct thrombin and Xa inhibitors are furthest along in development. Dabigatran etexilate, a thrombin inhibitor, has recently gained a class I recommendation as an alternative option to anticoagulants for prevention of stroke in patients with AF. The percutaneous transcatheter closure of left atrial appendage has been successfully developed in recent years for reducing the future stroke risk. On the basis of the recent progress, we suggest to improve warfarin therapy and balance the stroke prevention and bleeding risk. Clinicians may benefit from these new insights into anticoagulation in AF. (J Arrhythmia 2011; 27: 186–192)

Key words: Atrial fibrillation, Oral anticoagulation, Bleeding, Risk assessment

Introduction Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Many patients with AF receive no prophylactic anticoagulants in spite of strong evidence supporting the efficacy of anticoagulants in preventing thromboembolism related to AF.1,2) The vitamin K antagonists (VKAs), especially warfarin as the most widely used oral anticoagulant (OAC), is underused in clinical practice due to its well-known limitations and complexity.2) In order to help clinicians choose appropriate anticoagulation strategy, the recent ESC guidelines have recommended several scoring sys-

tems to grade the risk of stroke or bleeding among patients with non-valvular AF, according to the presence of coexisting clinical factors.3) Several new oral anticoagulant medications, which are designed to be given in fixed doses without coagulation monitoring, are being developed rapidly and may replace warfarin in the future. This review aims to provide new insights into recent progress in anticoagulation therapy of AF as well as novel oral anticoagulants. Risk schemes for stroke and thrombo-embolism CHADS2 score [congestive heart failure, hypertension, age 75, diabetes, stroke (doubled)] is one

Address for correspondence: Shu Zhang, Department of Cardiology, Cardiovascular Institute & Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Bei Li Shi Lu, Beijing 100037, China. Tel: +86 (10) Fax: +86 (10) E-mail: [email protected]

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widely used risk scheme for predicting stroke, in which 2 points are assigned for a history of stroke or TIA and 1 point each is assigned for age 75 years, a history of hypertension, diabetes, or recent cardiac failure.4) This scheme is simple and can easily be applied in general clinical practice. However, some data have suggested that this risk scheme is only moderately accurate at separating patients into different categories of stroke risk.5–7) The new 2010 ESC guidelines on AF recommended a new risk scheme — CHA2 DS2 VASC score [congestive heart failure, hypertension, age 75, diabetes, stroke, vascular disease, age 65–74, and sex category (female)], in which age is weighted differently, and female sex and a history of vascular disease are considered to be significant risk factors for stroke.6) Recently, a few studies compared the performance of the CHA2 DS2 VASC score with the CHADS2 score. The results of C statistics showed that the new scheme CHA2 DS2 VASC does seem to be better than CHADS2 at identifying patients at truly low risk for thromboembolism.7,8) Because age 65 or more and female sex are considered relevant risk factors, the people who meet the ‘‘truly low risk’’ criteria are men under 65. Therefore, the CHA2 DS2 VASC based approach to assessing stroke risk is recommended to be used in patients with multiple clinically-relevant non-major risk factors for stroke. Bleeding risk assessments in AF patients Although the clinical benefit of OAC clearly outweighs the bleeding risk of OAC therapy in AF patients, major bleeding events (especially intracerebral haemorrhage) may be devastating when they do occur. However, clinical scores for bleeding risk assessment are not nearly as well validated as stroke risk scores in ‘‘real-world’’ clinical practice. Established bleeding risk factors include age, international normalized ratio (INR) range, prior stroke, history of bleeding, anaemia, co-morbidities (uncontrolled hypertension, hepatic and renal insufficiency), and use of concomitant medication or alcohol. Based on a combination of treatment- and personassociated factors, several bleeding risk predicting rules have been proposed, including the modified Outpatient Bleeding Risk Index (mOBRI),9) the HEMORR2HAGES score,10) the HAS-BLED score,11) the ATRIA score (data from the ATRIA study presented in abstract form). These bleeding risk schemes may help physicians stratify patients into categories of increasing risk of bleeding (low, intermediate, and high risk). The HAS-BLED score has been recommended by the 2010 ESC guidelines

New Insights into Anticoagulation in Atrial Fibrillation

for the management of AF and the Canadian guidelines12) for its good predictive accuracy.6,11) Therefore, bleeding risk stratification should be considered, either prior to starting or during anticoagulation treatment in AF patients. Existing problems with VKAs For as many as 50 years, VKAs remain the only form of oral anticoagulant medication approved for long-term use. Warfarin, the most commonly used VKAs, has been an important drug for the prevention of thromboembolic events in AF patients. Solid evidence exists that warfarin reduces AF-related stroke risk by two-thirds compared to placebo (64%), whereas aspirin decreases stroke risk only by 22%.13) Warfarin also reduces the risk of stroke by 42% compared with the combination of acetylsalicylic acid and clopidogrel, as recently shown in the ACTIVE W trial.14) However, a recent systematic review still demonstrates the underuse of oral anticoagulation therapy for real-world atrial fibrillation patients with an elevated risk of stroke.2) The widespread underuse of warfarin for AF patients can be attributed to its well-known limitations and complexity: 1) The frequent and specialized blood test monitoring is required because: a. the dose response is unpredictable; b. warfarin has a narrow therapeutic INR range of 2.0–3.0, above which or below which bleeding or thromboembolism can occur; c. the metabolism of warfarin is affected by multiple factors, like diet, concomitant conditions (smoking and alcohol use), drugs, and genetic polymorphisms — variations in two genes, the cytochrome P450 family 2 subfamily C polypeptide 9 enzyme (CYP2C9) gene and the vitamin K epoxide reductase complex 1 (VKORC1) gene, contribute significantly to the variability among patients in dose requirements for warfarin. 2) The inter- and intra-patient variability of effective dose causes many patients to spend large amounts of time outside the therapeutic INR window, which increases the risk of bleeding or thromboembolism. 3) The side effect associated with the use of warfarin, hemorrhage, could be serious and devastating. The fear of iatrogenic hemarrhage is one of the most important reasons why physicians do not prescribe warfarin for a substantial number of AF patients who are likely to benefit from it.15)

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Other limitations include delayed onset and offset of action, slow reversibility of anticoagulant effect, and requirement of labor-intensive follow up, expert dose management, and frequent patient communication. New oral anticoagulants The limitation and complexity of VKAs have led clinicians, patients, and investigators to search for alternative agents. An anticoagulant that is noninferior to warfarin in reducing thromboembolic events, has a low rate of bleeding risk (especially of major bleeding), few drug interactions, a wide therapeutic index, and no need for laboratory monitoring, may represent a significant improvement over warfarin and other currently available VKAs. Recently, two classes of new oral anticoagulant drugs are being developed for stroke prevention in AF — the oral direct thrombin inhibitors and the oral factor Xa inhibitors. Dabigatran Etexilate — A direct thrombin inhibitor: Dabigatran etexilate is an oral prodrug and is rapidly converted to an active direct thrombin inhibitor after oral administration and hepatic processing independent of the cytochrome P-450.16) Dabigatran has a low potential for drug-drug and drug-diet interactions and is predominantly renally excreted. Dabigatran directly inhibits both free and clot-bound thrombin, and is administered in fixed doses without laboratory monitoring of anticoagulation intensity. Dabigatran etexilate (Pradaxa, Boehringer Ingelheim) has been approved in Europe and Canada since 2008 for venous thromboembolism (VTE) prophylaxis in hip and knee surgery patients based on clinical evidence of three major phase-3 studies: RE-MODEL,17) RE-MOBILIZE18) and RENOVATE.19) The clinical evidence for the efficacy of dabigatran in patients with nonvalvular AF comes from the multinational, randomized, parallel group the RE-LY trial,20) which compared 2 blinded doses of dabigatran (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target an INR of 2 to 3) in nonvalvular AF patients at a higher risk of stroke. The RE-LY trial demonstrated that as compared with warfarin, dabigatran 150 mg twice daily was associated with lower rates of stroke and systemic embolism (1.69% vs. 1.11%, P < 0:001 for superiority) but similar rates of major hemorrhage (3.36% vs. 3.31%). Dabigatran 110 mg twice daily was associated with similar rates of stroke and systemic embolism and lower rates of major hemorrhage as compared to warfarin. Dabigatran etexilate was approved by the FDA for the prevention of

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stroke and systemic embolism in patients with nonvalvular AF on October 19, 2010. Then, dabigatran was added to the U.S. guidelines with a Class I recommendation on March 15, 2011.21) Dabigatran has been the first new OAC to become available for clinical use in >50 years. Oral direct factor Xa inhibitors: Rivaroxaban is the first available orally active direct factor Xa inhibitor. Rivaroxaban inhibits both the ‘‘free’’ and prothombinase-complex-bound forms of Factor Xa.22) Rivaroxaban does not inhibit thrombin, and no effects on platelets have been demonstrated. Rivaroxaban is metabolized partially by cytochrome P450 (CYP) 3A4 and is partially eliminated by the kidney and fecal routes.23) Rivaroxaban is currently approved in Europe and Canada for venous thromboembolism prevention following orthopedic surgery. The ROCKET AF trial24) is a phase III trial of rivaroxaban for prevention of stroke and embolism in more than 14,000 patients with nonvalvular AF. The preliminary results from ROCKET AF trial presented at the American Heart Association (AHA) 2010 Scientific Sessions showed that rivaroxaban was noninferior to warfarin without an increase in major bleeding. However, rivaroxaban is suggested as an ‘‘alternative’’ to warfarin in moderate- or highrisk patients with AF due to poor adherence with rivaroxaban. Apixaban is also an oral direct factor Xa inhibitor administered twice daily. Apixaban (2.5 mg BID) was compared with aspirin (81–324 mg QD) for stroke prevention in AF (AVERROES trial) in more than 6000 patients who have failed or who are unsuitable for warfarin. This study was recently stopped due to the superiority of apixaban over aspirin in these patients, without excess bleeding. The ARISTOTLE phase III study25) compares apixaban (5 mg BID) to warfarin for stroke prevention in more than 18,000 AF patients with a median CHADS2 score of 2. This randomized, event driven, double-blind, noninferiority study will be reported in 2011. Edoxaban, another oral factor Xa inhibitor, has recently been studied in a phase III trial (ENGAGE AF-TIMI 48) comparison to warfarin for the prevention of thromboembolism in AF patients. The future for anticoagulation in AF 1. Are new oral anticoagulants really better?

New oral anticoagulant agents have many potential advantages over warfarin, including their rapid onset of action, predictable therapeutic effect, and limited drug-drug interactions. These advantages may allow the physician to potentially use agents

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without routine coagulation monitoring. All of this may result in a greater use of anticoagulants, especially for conditions like AF, which is widely undertreated. However, several potential issues will be encountered as these new oral anticoagulants will become available in the near future. Some potential complications including liver enzyme elevation and cardiac irregularities have been reported in the use of dabigatran, rivaroxaban and apixaban.26) Because dabigatran and rivaroxaban are predominantly eliminated by the kidney, use of these medications should be used cautiously in elderly patients who may have an age-related reduction in drug clearance and in those patients with marginal renal clearance. There are also known drug interactions with some of these new agents. Dabigatran is contraindicated with the concomitant use of quinidine, verapamil, clarithromycin, or amiodarone, and other P-glycoprotein inhibitors.26) The lack of a requirement for monitoring makes it difficult to tailor the intensity of anticoagulant therapy, or determine if the specific therapy has failed. Short half-lives of new agents also make the adherence of medication extremely important, especially for AF patients. The absence of specific antidotes may be problematic for patients who are at a high risk of bleeding or for those who present with a bleed. Fortunately, the use of fresh frozen plasma and prothrombin concentrates have been shown to be able to reverse anticoagulation with several of the new agents.27) In addition, new agents will be significantly more expensive than warfarin, and patients may not take them due to financial stresses. Therefore, it remains to be established whether newer oral anticoagulants will be better alternatives to the current standard-of-care in ‘‘real world’’ clinical practices. 2. What can we do to improve warfarin therapy

Warfarin still remains the mainstay of treatment for patients with nonvalvular AF. There is still a need for developing methods to improve the care of warfarin-treated patients. Different interventions have been proposed in the past, which include specialized anticoagulation clinics, home INR selfmonitoring, adherence interventions, and dosing algorithms.28) Anticoagulation clinics have been shown to improve anticoagulation control and outcomes.29) Home INR monitoring seems not to delay the time to a first stroke, major bleeding episode, or death,30) but self-monitoring and self-management of dosing improve the quality of oral anticoagulation.31) Dosing algorithms that incorporate genotypes and clinical characteristics might be useful during the

New Insights into Anticoagulation in Atrial Fibrillation

initiation phase of warfarin therapy. Most algorithms share in common the inclusion of age, measures of body size (such as body surface area or weight), the genetic variants of CYP2C9 and VKORC1, and some additional variables like diabetes, sex, interacting medications, target INR, and valve replacement.28) Recently, a pharmacogenetic dosing algorithm using variations in CYP2C9 and VKORC1 genes produces recommendations that are significantly closer to the required stable therapeutic dose than those derived from a clinical algorithm or a fixed-dose approach.32) When a steady state is reached, adherence to interventions might be most beneficial and logistically applicable during maintenance phase. Finally, it might be helpful to identify an appropriate anticoagulation intensity for reducing the risk of hemorrhage or thromboembolism in different populations. Although the overwhelming evidence supports that an INR of 2.0–3.0 is likely the optimal range for prevention of stroke and systemic embolism in patients with non-valvular AF, there is controversy as to whether the low intensity of anticoagulation therapy will be as effective as the standard intensity. Low intensity therapy of warfarin (INR 1.5–2.0) has been reported to be safe and effective for prevention of systemic embolism.33,34) In elderly Japanese with AF,35) the low intensity warfarin (INR1.5–2.1) treatment seems to be associated with a low rate of stroke (1.7% per year) and significantly low bleeding complications (0% per year) as compared with conventional intensity treatment (INR2.2–3.5). Another study of Japanese patients also showed that low intensity of warfarin therapy (INR1.5–2.0) is efficacious in treating left atrial thrombus formation in patients with nonvalvular AF.36) For elderly patients, the new 2010 ESC guidelines on AF recommended a lower target INR range (1.8–2.5) with low large trial evidence base. 3. Left atrial appendage closure

In atrial fibrillation, blood clots arise from the left atrial appendage (LAA) in more than 90% of cases.37) Surgical closure of the LAA at the time of mitral valve surgery has been practiced and recommended by guidelines,38) but with suboptimal results.39) The percutaneous transcatheter LAA exclusion has been successfully developed in recent years for reduction of future stroke risk.40,41) The PROTECT AF study was designed to demonstrate the safety, efficacy, and non-inferiority of the Watchman device compared to chronic warfarin therapy in those patients with nonvalvular AF who are eligible for long-term OAC.41) Device closure of the LAA using the

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Watchman device (Atritech, Plymouth, MN) was associated with a reduction in hemorrhagic stroke risk vs. warfarin, and all-cause stroke and all-cause mortality outcomes were noninferior to warfarin. However, an important risk of serious procedural complications was observed in the device group, but these have decreased over time with procedural modifications and enhanced training. The Amplatzer Cardiac Plug (ACP) is one of new LAA closure devices, and initial results are encouraging.42) Therefore, percutaneous closure of the LAA is a novel alternative for the treatment of patients with AF at a high risk of stroke, in whom long-term anticoagulation therapy is not possible or not desired. Maintenance of sinus rhythm The best therapy for prevention of stroke might be the successful restoring and maintenance of sinus rhythm in AF patients, which could also avoid the adverse bleeding events of anticoagulation. Dronedarone, a new antiarrhythmic drug specifically developed for the management of AF, has been recommended by 2010ESC3) and 2011AHA guidelines for the prevention of recurrent AF and maintenance of sinus rhythm in patients with recurrent paroxysmal or persistent AF. Because of the better safety and potential outcome benefit, dronedarone can be administrated as the first antiarrhythmic option in AF patients without structural heart disease and in stable patients with underlying cardiovascular disease, including ACS, chronic stable angina, hypertensive heart disease, and stable NYHA class I–II heart failure. The development of new antiarrhythmic drugs may bring new light to the management of AF. However, the efficacy and safety of dronedarone still need to be assessed in real world clinical practice. In both the ACC/AHA/HRS and the ESC new guidelines, catheter ablation gains a improved recommendation (class I) when performed in experienced centers for selected patients who have failed a trial of antiarrhythmic medication and have normal or mildly dilated left atria, normal or mildly reduced LV function, and no severe pulmonary disease. For symptomatic persistent and paroxysmal AF in patients with significant left atrial dilation or with significant left ventricular dysfunction, catheter ablation can also be considered as a reasonable treatment option. Balancing the stroke prevention and bleeding risk Both the risk for stroke and the risk for bleeding

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are not homogenous in AF. Because of the bleeding risk of anticoagulation therapy in patients with AF, stroke risk stratification schemes have been devised to identify ‘‘high risk’’ AF patients for whom the absolute benefits of OAC exceed its risks. However, it has been increasingly recognized that many of the known factors that increase stroke risk overlap with bleeding risk factors.43) Both stroke and bleeding risk assessment have been recommended by 2010ESC guidelines before deciding anticoagulation strategy in AF patients (CHA2 DS2 VASC and HAS-BLED score). In fact, most patients with AF, including those at high bleed risk, can benefit from anticoagulant treatment, because bleeding risk is significantly lower than stroke risk.44) The selection of OAC or ASA, as well as dosage, should be made cautiously to preserve the delicate balance between stroke risk and bleeding. Furthermore, additional bleeding risk should be considered in some special situations, such as periablation, peri-devices (implantable cardioverter-defibrillator, pacemakers), acute coronary syndrome or percutaneous coronary intervention, and surgical procedures. In conclusion, the anticoagulation therapy should be stressed in real world practice because the bleeding risk is almost inevitably lower than stroke risk in patients with AF. The widespread underuse of warfarin implicates a great need of interventions to improve warfarin therapy. In addition, identification of patients at high risk of bleeding and weighing up the embolism and bleeding risk can help to refine anticoagulation to minimize bleeding risk. The new oral anticoagulants have the potential to play a significant role in a wide range of clinical settings. Also, non-pharmacological methods to prevent stroke (like LAA) should be further developed in the future. Conflict of Interest There is no conflict of interest.

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