From Medscape Education

Safety Precautions for Asian Patients With Atrial Fibrillation at Risk for Stroke
A. John Camm, MD; Jyh-Hong Chen, MD, PhD; Michael D. Ezekowitz, MB ChB, DPhil; Rungroj Krittayaphong, MD This educational activity is intended for an international audience of non-US healthcare professionals, specifically electrophysiologists, cardiologists, primary care providers, and other healthcare professionals involved in the treatment and care of patients with atrial fibrillation (AF) who require anticoagulation therapy. The goal of this activity is to review stroke risk and prevention strategies in Asian patients with AF who are at risk. Upon completion of this activity, participants should be able to: 1. 2. 3. Discuss the various factors that should be considered when evaluating the risk for bleeding in patients with AF taking anticoagulants Assess increased bleeding risk associated with anticoagulant use in Asian populations and propose explanations for the potential increased risk Evaluate the efficacy of novel anticoagulants in Asian patients

Slide 1.

A. John Camm, MD: Welcome to this Medscape Education program, Safety Precautions for Asian Patients With Atrial Fibrillation at Risk for Stroke. I am A. John Camm, MD, Professor of Clinical Cardiology at St. Georges University of London, as well as Consultant Cardiologist in the Cardiothoracic Department at St. Georges Hospital in London, United Kingdom. I will serve as moderator for this program today. As we are gathered to discuss this important topic, I am joined by Michael D. Ezekowitz, MB ChB, DPhil, Professor of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, and Director, Research and Education for Atrial Fibrillation at The Cardiovascular Research Foundation in New York, New York; Jyh-Hong Chen, MD, PhD, Professor of Medicine, Division of Cardiology, National Cheng Kung University Medical College, Tainan, Taiwan; and Rungroj Krittayaphong, MD, Professor of Medicine, Division of Cardiology, Siriraj Hospital, Mahidol University, Bangkok, Thailand. Welcome, gentlemen.

Slide 2.

In this program, we will be discussing various factors that should be considered when evaluating the risk for bleeding in patients with atrial fibrillation (AF) taking anticoagulants; the increased bleeding associated with anticoagulant use in Asian populations, including potential explanations for this risk; and the efficacy of novel anticoagulants in Asian populations. The World Health Organization has identified stroke as one of the most important components of cardiovascular morbidity and mortality worldwide. It is an especially great concern in many countries in Asia; there is a high incidence of hemorrhagic stroke seen in people taking oral anticoagulants in Southeast Asia. Today, we will look at possible explanations for this increased risk and also discuss how the recent introduction of novel oral anticoagulants that have particular application for the prevention of stroke in the setting of AF may deserve special considerations when used in Asian populations.

Professor Krittayaphong, can you tell us about the epidemiology of stroke throughout Asia, especially with AF as a contributory factor?

Slide 3.

Rungroj Krittayaphong, MD: According to data from the World Health Organization's Global Burden of Disease: 2004 Update, the incidence of stroke, worldwide, is approximately 9 million, while the prevalence of stroke is about 31 million people. Almost half of all individuals with stroke reside in South Asia, East Asia, and the Western Pacific Region, including China, Japan, and Korea. It is estimated that 13 million people will have moderate-to-severe disability because of a stroke.

Slide 4.

A systematic review of more than 50 population-based studies published between 1970 and 2008 analyzed the incidences of ischemic stroke. This study reported a decreased incidence of stroke in highincome countries but an increased stroke incidence in low- to middle-income countries

Slide 5.

The proportion of intracerebral hemorrhage (ICH), relative to other stroke subtypes, is much greater in Asian-Pacific countries such as China and Hong Kong, approximately 30%, compared with Western regions such as the United States and Europe where the incidence is approximately 10%.

Slide 6.

Reports from Asian countries, including China, Japan, Korea, and Singapore, demonstrate that the prevalence of AF in Asia is approximately 50% less than what has been reported in Western countries. However, despite the lower prevalence, Asia contributes to a much higher disease burden due to the much larger population size in Asia, especially in the elderly population. In Asia, the AF prevalence increases with age, and AF is more common in men than woman.

Slide 7.

It has been estimated that by the year 2050, the number of people with AF in Asia will more-than double due to the rising incidence of contributing factors such as hypertension and diabetes. Dr Camm: In that sense, the calculations for the future estimates of AF rates are similar to those in the Western part of the world.

Slide 8.

Dr Krittayaphong: Many reports regarding the risk for stroke in patients with AF from Asian-Pacific countries exist. Data from Japan, China, and Taiwan show that stroke risk in AF patients is approximately 5- to 8-fold greater than the risk for stroke in patients without AF, which is comparable to data from Western countries.

Slide 9.

Dr Camm: What kind of stroke is suffered in patients with AF? Is it primarily ischemic stroke, as it is in Western countries? Dr Krittayaphong: Ischemic stroke mainly. Dr Camm: How do you identify those AF patients in Asia who are at particular risk of developing stroke?

Slide 10.

Jyh-Hong Chen, MD, PhD: Not all AF patients are at an equal risk for stroke; therefore, physicians want an easy method to identify patients at higher risk. The CHADS2 score is a popular stroke risk scoring system used in Asia. The CHADS2 score is easy to use; however, it does not identify "truly low risk" patients well.

Slide 11.

The CHA2DS2-VASc score is a newer stroke risk scoring system that includes some common stroke risk factors (ie, vascular disease, age 65-74 years, and female sex) that the CHADS2 score does not.

Slide 12.

When we treat patients with AF for stroke prevention, we must balance between the need to prevent thrombosis and the need to minimize bleeding risk with anticoagulant therapy.

Slide 13.

The HAS-BLED scoring system is a tool that physician can use to estimate the risk for bleeding in an AF patients taking anticoagulants. Physicians can use this tool to communicate with patients about bleeding risk. However, it is important to emphasize that identifying a certain amount of bleeding risk with the HAS-BLED score does not mean that oral anticoagulants should not be used, if warranted.

Slide 14.

Dr Camm: This is a very important point. When a scoring system is used to determine bleeding risk, it does not necessarily mean that anticoagulants should not be used. Education of the patient is important; physicians should ensure that their patients are taking the right drugs in the right dose at the right time. Physicians should also carefully review and monitor the patient. In addition, physicians should change anything in the patients regimen that increases the bleeding risk unnecessarily.

Slide 15.

In Europe, we have been using the CHA2DS2-VASc scheme now for about 2 years. As you were suggesting, Dr Chen, it is a bit more difficult to understand the CHA2DS2-VASc score than the CHADS2 system; there are 3 more risk factors to consider in the CHA2DS2-VASc score. Many doctors prefer to use the CHADS2 scheme. In the European guidelines, we introduced a very simple scheme. We said that if the patient is 65 years or older or if the patient has any cardiovascular disease, then the physician should probably consider anticoagulation. Do you think that this would be a useful approach in Asia? Dr Chen: This would be a simple scheme for the busy physician in an Asian country to remember. However, physicians must try to consider all the stroke risk factors that a system like the CHA2DS2-VASc score includes.

Slide 16.

Dr Camm: There have been many arguments about whether female sex should be in the CHA2DS2VASc scoring system; in some reports, female sex stood out as a risk factor, and in other reports it did not. I have been impressed at the data that show that female sex multiples the risk for other cardiovascular risk factors such as congestive heart failure, diabetes, and hypertension. On its own, female sex may not necessarily carry a risk, but it increases the risk due to other risk factors.

Slide 17.

Michael D. Ezekowitz, MB ChB, DPhil: The use of aspirin for stroke prevention seems like quite a common practice in Asia, particularly in low-risk patients. In clinical trials, aspirin has not been found to be very effective for stroke prevention compared with anticoagulation. What are your thoughts on this topic? Dr Chen: Data from Taiwan have shown that while these patients are at high risk for stroke, approximately 60% receive aspirin for stroke prevention, while only 25% receive warfarin, and in those receiving warfarin, the international normalization ratio (INR) is often suboptimal. I do not think that physicians should be using aspirin for stroke prevention. Dr Camm: We are also trying to educate in Europe about this same message. Unfortunately, it is difficult to convince physicians that aspirin is not an effective agent and that vitamin K antagonists or the novel oral anticoagulants should be used. What do you think about the fact that the CHA2DS2-VASc scoring scheme was originally validated in a European population? Do you think that it is a valid tool to use in Asia?

Slide 18.

Dr Chen: The CHADS2 score has been validated in a Japanese population. This study demonstrated that the CHADS2 score is a very good predictor of stroke risk in Japanese patients. While this study did not analyze the CHA2DS2-VASc score, I think that it can be confidently used in Asian patients.

Slide 19.

Dr Camm: Is the risk for hemorrhagic stroke greater in Asian AF patients compared with non-Asian AF patients taking oral anticoagulants? Dr Chen: Many physicians prescribe aspirin for stroke prevention in patients with AF because they are concerned about the risk for bleeding and ICH with warfarin. A meta-analysis of 36 studies, which included 8145 patients with ICH who were not taking warfarin, demonstrated that the incidence of ICH was higher in Asian patients compared with black, Indian, Hispanic, or white patients.

Slide 20.

Another study of a multiethnic cohort of 18,867 patients hospitalized with first-time AF and receiving warfarin demonstrated an approximately 4-fold higher risk for ICH in Asian patients compared with Western people.

Slide 21.

In an analysis of the Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study, researchers found a sharp increase in major bleeding in subjects on warfarin with an INR greater than or equal to 2.6. This study recommended an INR of 1.6-2.6 to prevent major hemorrhagic or ischemic events. Dr Camm: What accounts for the increased risk for ICH in Asian AF patients compared with non-Asian AF patients? Is it environmental or is it genetic? What are the explanations?

Slide 22.

Dr Krittayaphong: Several explanations exist for the imbalance in bleeding risk in Asian and non-Asian patients. One explanation may be related to fluctuations or an instability in the INRs observed in Asian patients. Another explanation is related to geneticsthere are differences in the prevalence of certain genetic polymorphisms that influence warfarin pharmacokinetics and pharmacodynamics. In patients on warfarin, the variant cytochrome P450 variant CYP2C9 genotype has conferred an increased risk for major hemorrhage. The incidence of this polymorphism is similar, however, in Western and Asia|n populations. The variant of another enzyme, vitamin K epoxide reductase complex, which increases the risk for bleeding, has been found to be more prevalent in Asian patients, approximately 60% compared with 30% in Western populations. Dr Chen: Another explanation may be due to differences in the vasculature properties of Asian vs nonAsian people. Dr Camm: Mike, can you please tell us a little bit about the data in Asian patients from the large global trials of the novel oral anticoagulants?

Slide 23.

Dr Ezekowitz: A subanalysis of the Randomized Evaluation of Long-term Anticoagulation Therapy (RELY) study was performed, which included subjects from 10 Asian countries. Asian patients comprise approximately 15% of all the patients from the global RE-LY study.

Slide 24.

In my opinion, I think that investigators of these large clinical trials of novel oral anticoagulants erred on the side of underanticoagulating their patients with warfarin because of their fear of potential bleeding. In spite of this, however, the incidence of ICH was higher in Asian patients treated with warfarin compared with the non-Asian patients treated with warfarin. This subanalysis also demonstrated that both doses of dabigatran, to some extent, minimized the predisposition to intracerebral bleeding in Asian patients.

Slide 25.

Many clinicians who prescribe anticoagulation are fearful of inducing ICH because of its devastating consequences. This is one of the reasons that aspirin use and underanticoagulation are so common. The predisposition to bleeding that some Asians experience can be somewhat reduced by the use of one of the novel oral anticoagulants. The largest analysis comes from the RE-LY trial; however, corroborative evidence can be found in analyses of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET) studies.

Slide 26.

The RE-LY subanalysis in Asian patients demonstrated that the incidence of major bleeding was approximately 4% in Asian patients taking warfarin; this was compared with an incidence of approximately 2% in Asian patients taking either dose of dabigatran. Asian patients do extremely well with respect to safety on the 150-mg dose of dabigatran. The corresponding rates of major bleeding in non-Asian patients were lower, as we would expect.

Slide 27.

Japanese-ROCKET-AF (J-ROCKET-AF) was a study conducted among Japanese patients. This was a prospective, double-blind, randomized, phase 3 study of over 1200 patients with nonvalvular AF. This study confirmed noninferiority of rivaroxaban against warfarin for the principal safety outcomes of major and nonmajor clinically relevant bleeding. These results were similar to those observed in the large, global ROCKET-AF study.

Slide 28.

Results of the ARISTOTLE-Japanese (ARISTOTLE-J) study, a phase 2 study that assessed the effects of 2 doses of apixaban vs warfarin in 222 Japanese patients with nonvalvular AF, were not inconsistent with those of RE-LY or J-ROCKET-AF.

Slide 29.

Consistency exists in the clinical trial results of the novel oral anticoagulants in Asian patients. While muck work needs to be done to determine the regional and racial differences in the effects of these agents, the novel oral anticoagulants seem to be a valuable therapeutic option in Asian AF patients at risk for stroke. Dr Camm: I am used to using the 2012 Focused Update of theESC Guidelines for the Management of Atrial Fibrillation and Dr Ezekowitz the American College of Cardiology/American Heart Association/Heart Rhythm Society Guidelines on the Management of Patients With Atrial Fibrillation.[1]Do you have local guidelines that you follow, or do you use one of these international guidelines?

Slide 30.

Dr Krittayaphong: We do have local guidelines, which include the rationale for the use of novel oral anticoagulation as an alternative to warfarin in certain groups of patients. I am interested in the costeffectiveness of the new agents compared with warfarin. Dr Chen: In Taiwan, the first approved novel anticoagulant was dabigatran. We have also put novel oral anticoagulation into our local practice guidelines. Dr Camm: I know that in Japan, dabigatran features in their guidelines. Of note, for lower-risk cases, the Japanese guidelines recommend dabigatran; and for higher-risk cases, either warfarin or dabigatran is recommended. It is a rapidly evolving world. We are going to see more guidelines and more use of these novel oral anticoagulants in the future.

Slide 31.

Thank you very much for the discussion this morning. We have discussed differences between Asian and white populations; AF is certainly present in Asian people, perhaps not as numerous as in the Western population, but it is growing just as quickly. Stroke is certainly common in Asian countries; hemorrhagic stroke is more common than ischemic stroke. AF is associated with an increased risk for stroke. Hemorrhagic risks are more substantial in Asian populations compared with non-Asian populations; this is particularly true in those patients taking warfarin. Of note, in the trials of the novel oral anticoagulants, the likelihood of hemorrhage is less with the novel oral agents than with warfarin. This, of course, is a major development and an advantage in the Asian population. We discussed the results of the 3 major global trials of novel oral anticoagulation and those results specific to the Asian population. I would like to thank you, gentlemen, for your contribution to this program.

Slide 32.

Thank you very much. For those of you who are participating in this activity, do not forget to proceed to the CME post-test; click the Earn CME Credits link on this page.

References
1. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123(1):104-123.

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