Risk-Treatment Paradox of Anticoagulation Therapy in Atrial Fibrillation

Atrial fibrillation (AF) remains a global health issue, carrying a great burden of stroke and systemic thromboembolism.¹ In 2050, it is estimated that there will be 1 million AF patients in Japan.² Previous randomized trials and meta-analyses have provided very solid evidence in regard to the efficacy of oral anticoagulants (OACs) such as warfarin,³ but a significant limitation of randomized trials has been the strict inclusion/exclusion criteria for selecting a representative population of patients. Therefore, in addition to well-controlled randomized trials, we need add-on data sets, “clinical registries”, to examine whether these data findings apply more broadly over the patient populations.

Article p 2166

To date, multiple AF registries have been published and include community, hospital, and emergency department settings.^4–8 Of those we reported, the J-RHYTHM Registry,^5,6 is a nationwide cohort study that enrolled 7,937 Japanese patients with AF (Figure 1). We found that nearly 90% of the patients were being treated with OACs because most of the patients were enrolled by cardiologists and electrophysiologists, and the major objective of this study was to determine the optimal anticoagulation levels for preventing thromboembolic and bleeding events.

Figure 1.

Distribution of the CHADS₂ score and rates of the anticoagulation therapy in the J-RHYTHM Registry and the Fushimi AF registry. CHADS₂ comprises Chronic heart failure, Hypertension, Age ≥75 years, Diabetes, transient ischemic attack or Stroke. (Modified with permission from Atarashi H, et al⁵ and Akao M, et al.⁹)

The study by Akao et al⁹ in this issue of the Journal is timely for bettering our understanding of the actual situation of antithrombotic therapies and outcomes in the Japanese AF population (Figure 1). The Fushimi AF Registry is a community-based prospective survey of AF patients in an urban setting. The authors enrolled 3,282 AF patients and a 1-year follow-up was completed in 2,914 patients (a rate of nearly 90%). The strength of this registry was that most of the patients were enrolled by internal medicine/primary care physicians. The risk of stroke was assessed by CHADS₂ score;¹⁰ overall, the mean CHADS₂ score was 2.0, 55% of the patients were anticoagulated and 30% received an antiplatelet drug. They show a higher use of OACs in low-risk patients and relatively lower use of OACs in high-risk patients; this risk-treatment paradox¹¹ continued after a 1-year follow-up.¹² Although well-validated risk scores for stroke have been published, the real-world decisions on anticoagulation were quite different from the guidelines. The study provides other, important data: an annual rate of stroke of 2.7% and mortality rate of 8%! We need to keep these data firmly in mind when managing AF patients.

Another important aspect of the study was the lack of effect between OAC treatment and outcome. We expected that OAC use would be associated with substantially lower rates of stroke and higher rates of major bleeding, but the rates of both stroke and major bleeding were similar, irrespective of OAC treatment. This result is probably related to under-dosage of OACs, in addition to under-usage of OACs. Of note, the authors found that the clinical factors that accounted for the physician’s decision to use anticoagulation were long-standing AF, stroke and heart failure, and there was a tendency to undervalue hypertension and diabetes, which make up CHADS₂ as predictors of risk. Higher age (≥85 years) seemed to make physicians refrain from using anticoagulation. However, a 1-year follow-up was too short to draw any definite conclusions, and we would like the authors to present any bleeding risk data they may have, as well as the relationship between the CHADS₂ score and rates of stroke.

Recently, a prospective registry of AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation registry, ORBIT-AF), enrolling approximately 10,000 patients from outpatient practices in the USA, was published.⁸ Those authors examined the factors related to the discrepancy between empirical stroke and bleeding risk, and the physician-assigned risk. They assessed the empirical stroke risk by CHADS₂ score, and the bleeding risk by the ATRIA bleeding score.¹³ Separately, the physicians were asked to categorize their patients’ stroke and bleeding risks as low, intermediate or high. Overall, 72% of the patients were categorized as having a high-risk for stroke (CHADS₂ score ≥2), but only 16% were assessed as having a high stroke risk by the physicians (Figure 2A). Further, 17% had a high ATRIA bleeding risk (≥5) but only 7% were considered so by physicians (Figure 2B). The study also showed that being frail¹⁴ and not living independently were strong factors associated with physician-empirical risk mismatch. These findings indicate the identification of patients perceived to be at risk of a stroke is often not based on evidence-based risk schemes, but rather on patient factors such as being frail or not living independently. We would like to know more about the accuracy between the evidence-based risk schemes and physician-assigned risk observed in this trial.

Figure 2.

The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Categorization of physician-assigned risk and empirical risk of stroke (A) and bleeding (B). ATRIA, Anticoagulation and Risk Factors in Atrial Fibrillation. (Modified with permission from Steinberg BA, et al.⁸)

New OACs (NOAC) have been shown to potentially circumvent the many drawbacks of warfarin. Recent subanalyses of Phase 3 clinical trials in Asian patients consistently show that NOACs offer effective and safe options for stroke prevention when compared with warfarin.¹⁵ Despite this evidence, the Fushimi AF registry showed that the process of switching warfarin to NOACs is slow, and only 2.4% of patients were on dabigatran. The J-RHYTHM Registry 2 (UMIN-CTR 000007967) is now investigating the rate of switching of warfarin to NOAC to elucidate the long-term prognosis of Japanese AF patients and to improve the clinical guidelines for AF pharmacotherapy with warfarin and NOACs.

The Fushimi AF Registry⁹ demonstrated a significant risk-treatment paradox in the application of anticoagulation therapy in Japanese AF patients. There is still discord between the empirical validated scores that are used by the guidelines and physician-assigned risk. It seems clinicians have been slow to embrace the validity of the stroke or bleeding scores and better education might help with that. We look forward to the Fushimi AF Registry providing prospective data on how management strategies and patient outcomes evolve over time and thus bridge the gap between the guidelines and “real-world” clinical practice.

Disclosures

Lecture fees from Bayer Healthcare and Boehringer Ingelheim.

References

• 1.    Chugh  SS,  Havmoeller  R,  Narayanan  K,  Singh  D,  Rienstra  M,  Benjamin  EJ, et al. Worldwide epidemiology of atrial fibrillation: A Global Burden of Disease 2010 Study. Circulation 2014; 129: 837–847.
• 2.    Inoue  H,  Fujiki  A,  Origasa  H,  Ogawa  S,  Okumura  K,  Kubota  I, et al. Prevalence of atrial fibrillation in the general population of Japan: An analysis based on periodic health examination. Int J Cardiol 2009; 137: 102–107.
• 3.    Hart  RG,  Benavente  O,  McBride  R,  Pearce  LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999; 131: 492–501.
• 4.    Nieuwlaat  R,  Capucci  A,  Camm  AJ,  Olsson  SB,  Andresen  D,  Davies  DW, et al. Atrial fibrillation management: A prospective survey in ESC member countries: The Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005; 26: 2422–2434.
• 5.    Atarashi  H,  Inoue  H,  Okumura  K,  Yamashita  T,  Kumagai  N,  Origasa  H, et al; J-RHYTHM Investigators. Present status of anticoagulation treatment in Japanese patients with atrial fibrillation: A report from the J-RHYTHM Registry. Circ J 2011; 75: 1328–1333.
• 6.    Inoue  H,  Okumura  K,  Atarashi  H,  Yamashita  T,  Origasa  H,  Kumagai  N, et al. Target international normalized ratio values for preventing thromboembolic and hemorrhagic events in Japanese patients with non-valvular atrial fibrillation. Circ J 2013; 77: 2264–2270.
• 7.    Oldgren  J,  Healey  JS,  Ezekowitz  M,  Commerford  P,  Avezum  A,  Pais  P, et al. Variations in cause and management of atrial fibrillation in a prospective registry of 15,400 emergency department patients in 46 countries: The RE-LY Atrial Fibrillation Registry. Circulation 2014; 129: 1568–1576.
• 8.    Steinberg  BA,  Kim  S,  Thomas  L,  Fonarow  GC,  Hylek  E,  Ansell  J, et al. Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circulation 2014; 129: 2005–2012.
• 9.    Akao  M,  Chun  YH,  Esato  M,  Abe  M,  Tsuji  H,  Wada  H, et al; on behalf of the Fushimi AF Registry Investigators. Inappropriate use of oral anticoagulants for patients with atrial fibrillation: 1-year outcomes of the Fushimi AF Registry. Circ J 2014 78: 2166–2172.
• 10.    Gage  BF,  Waterman  AD,  Shannon  W,  Boechler  M,  Rich  MW,  Radford  MJ. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864–2870.
• 11.    Sandhu  RK,  Bakal  JA,  Ezekowitz  JA,  McAlister  FA. Risk stratification schemes, anticoagulation use and outcomes: The risk--treatment paradox in patients with newly diagnosed non-valvular atrial fibrillation. Heart 2011; 97: 2046–2050.
• 12.    Akao  M,  Chun  YH,  Wada  H,  Esato  M,  Hashimoto  T,  Abe  M, et al. Current status of clinical background of patients with atrial fibrillation in a community-based survey: The Fushimi AF Registry. J Cardiol 2013; 61: 260–266.
• 13.    Fang  MC,  Go  AS,  Chang  Y,  Borowsky  LH,  Pomernacki  NK,  Udaltsova  N, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 2011; 58: 395–401.
• 14.    Singh  M,  Stewart  R,  White  H. Importance of frailty in patients with cardiovascular disease. Eur Heart J 2014; 35: 1726–1731.
• 15.    Chiang  CE,  Wang  KL,  Lip  GY. Stroke prevention in atrial fibrillation: An Asian perspective. Thromb Haemost 2014; 111: 789–797.