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Thromboembolic prevention with low-dose edoxaban in very elderly Japanese high-risk individuals with AF

The Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial was a phase III, multicenter, randomized, double-blind, placebo-controlled superiority trial conducted to investigate the efficacy and safety of low-dose (15 mg once-daily) edoxaban compared to placebo in very elderly (≥80 years (y) of age) Japanese patients with nonvalvular atrial fibrillation (AF) not eligible for oral anticoagulant (OAC) therapy in the recommended dosing for prevention of thromboembolism (TE). Study participants were all above 80 y, diagnosed with AF within one year prior to given consent, had a CHADS2 score of 2 or higher, not considered candidates for existing OACs (warfarin, dabigatran, rivaroxaban, apixaban and edoxaban) or at excessive risk of bleeding due to a low creatinine clearance (15-30 ml/min), prior bleeding, low body weight (≤45 kg) or current treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or antiplatelet therapy. A total of 984 patients were enrolled and randomly assigned 15 mg of edoxaban (492 patients) or placebo (492 patients). 303 patients discontinued the trial, with similar numbers in the two groups. The primary efficacy endpoint was the composite of ischemic stroke (IS) and systemic embolism (SE) and primary safety endpoint was major bleeding according to the definition by the International Society on Thrombosis and Haemostasis (ISTH). The investigators concluded that low-dose edoxaban was superior to placebo in preventing TE (annualized rate 2,3% in the edoxaban and 6,7% in the placebo group; hazard ratio (HR) 0,34; 95% confidence interval (CI) 0,19-0,61; P<0,001) among very elderly Japanese patients. Annualized major bleeding rates were nonsignificantly higher in the edoxaban group, however, bleedings overall were significantly higher in the edoxaban group and particularly gastrointestinal (GI) bleedings. No difference in mortality was seen between the arms but was overall high (9,9% in the edoxaban and 10,2% in the placebo group; HR 0,97; 95% CI 0,69-1,36).



Junior commentary


In the ELDERCARE-AF trial, the investigators shed light on very elderly AF patients with multimorbidity - a growing patient group in the clinic, yet immensely understudied in previous clinical trials. When warfarin, in The Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA), was concluded to be superior to aspirin in thromboembolic prevention and equally safe, the study participants were all elderly ≥75 y, however, they were outpatients implying a lower risk (1). In the pivotal DOAC trials, elderly patients ≥75 y constituted between 31-44% of the study populations with the corresponding numbers being only 4-17% for ≥80 y olds (2). It is widely known that elderly patients constitute a highly heterogenous patient group regarding clinical characteristics with increasing prevalence of comorbidities and organ dysfunction and a significant increase in cardiovascular and bleeding risk, with age (3). To this extent, the conduction of the ELDERCARE-AF trial, where focus lies on very elderly patients with high thromboembolic risk as well as particularly high bleeding risk, is of great importance. The study population of ELDERCARE-AF was indeed of high risk with mean values on age 86,6 y, creatinine clearance 36,3 milliliters (ml)/minute (min), CHA2DS2 VASc score 4,9, HAS-BLED score 2,3 and 35% with a history of falls within the past year and 40,9% considered frail. Unlike the DOAC trials, in which patients with significant organ dysfunction, e.g. severe renal and liver failure, were excluded, the investigators of ELDERCARE-AF contribute to fill a knowledge gap of thromboembolic prevention in elderly patients with dual risk of TE and bleeding, by focusing solely on this vulnerable patient group in their trial.

Subgroup analyses of elderly patients ≥75 y in the phase 3 DOAC trials, showed beneficial effects of DOACs compared to warfarin, results that were consistent with the efficacy results in the overall study populations (4). The studies of safety outcomes did, however, not yield as convincing results in the elderly, except for the incidence of intracranial hemorrhages (ICH) that were significantly lowered also in the higher age category, with DOAC. The dose of 15 mg of edoxaban was chosen based on the fact that it gives a similar plasma concentration of edoxaban in patients with a creatinine clearance between 15-30 ml/min as 30-60 mg of edoxaban yield when creatinine clearance is above 50 ml/min (5). Furthermore, clinically, dose reduction did not seem to alter the efficacy of edoxaban in elderly patients in the ENGAGE AF-TIMI 48 trial, however, it did reduce the incidence of major bleeding, a reduction that increased with age (6). Nevertheless, major bleeding rates were similar in the ELDERCARE-AF trial compared to rates of major bleeding in subanalyses of elderly in the ENGAGE AF-TIMI 48 trial but the incidence of bleedings in general (major or clinically relevant nonmajor bleeding) and particularly GI bleedings were, in the ELDERCARE-AF trial, overall very high and higher with edoxaban compared to placebo (17,7% vs. 10,7%; HR 1,65; 95% CI 1,20-2,27). Notably, also less severe bleedings and especially GI bleedings seem to be associated with a significant short-term mortality in elderly. In a Swedish population-based cohort study, a surprisingly high incidence of 90-day mortality was seen among patients ≥75 y having suffered a GI bleed (16,2%) compared to mortality after ischemic stroke (25,1%) and ICH (31,6%), irrespective of prevalence of antithrombotic treatment (7). Therefore, also secondary safety outcomes and especially GI bleedings, are important to consider in clinical risk evaluation for OAC treatment in the elderly.

Clinical guidelines of today recommend DOAC for prevention of TE in all patients with AF including elderly (8). Although conducting trials on very elderly patients is complicated, with higher rates of discontinuation (nearly one third in the ELDERCARE-AF trial), the clinical impact, with results generalizable to a wider elderly patient group, should be considered important enough to justify the effort. Hence, the ELDERCARE-AF trial will hopefully lead to the conduction of more trials focusing on the patients who challenge us the most in the clinic. Even though treatment with low-dose edoxaban did not reduce mortality compared to placebo in this trial, the significant reduction in thromboembolic events with edoxaban is noteworthy. Considering the impact that occurrence of stroke has on quality of life, it is clinically important to have the opportunity to offer this frail patient group appropriate stroke prevention.

Finally, the ELDERCARE-AF investigated a Japanese population with certain clinical features attributable to East Asian populations, e.g. low body weight, and, from the ENGAGE AF-TIMI 48 trial, high incidence of both thromboembolic and bleeding events compared to non-East Asian populations (9). It is of clinical interest to see whether low-dose edoxaban gives similar efficacy and perhaps improved safety in western populations with a higher body weight.

 

Senior commentary

Elderly patients with bleeding risk factors are often left non-anticoagulated and treated with aspirin or no antithrombotic therapy. This is common in many Asian countries, where prescribers fear bleeding more than the potential beneficial reductions in stroke and mortality (10, 11). The ELDERCARE-AF trial was designed to answer the question whether treatment with an oral anticoagulant (even a low dose DOAC; in this case, edoxaban) would be better than placebo in these clinically fragile patients, ie. let’s treat with something rather than nothing. The trial shows a reduction in stroke but no significant difference in major bleeding.

Stroke and bleeding risks are not static but ‘dynamic’, changing with ageing and incident comorbidities (12). Clinicians also tend to forget that appropriate use of bleeding risk in clinical practice allows mitigation of modifiable bleeding risk factors and the scheduling of high bleeding risk patients for early review and follow-up (8). This was clearly evident in the prospective mAFA-II trial, where appropriate and responsible use of the HAS-BLED score in the intervention arm was associated with less major bleeding and an increase in anticoagulation uptake at 1 year (13). Ultimately the best clinical outcomes are with an integrated or holistic care approach to AF management, based on the ABC (Atrial fibrillation Better Care) pathway (A/Avoid stroke; B/Better symptom management; C/Cardiovascular risk and comorbidity optimization) which has been proven in independent observational (14, 15) and clinical trial cohorts (15-17), hence recommended in the ESC guidelines (8).

References


1. Mant J, Hobbs FDR, Fletcher K, Roalfe A, Fitzmaurice D, Lip GYH, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. The Lancet. 2007;370(9586):493-503.

2. Sardar P, Chatterjee S, Chaudhari S, Lip GYH. New Oral Anticoagulants in Elderly Adults: Evidence from a Meta-Analysis of Randomized Trials. Journal of the American Geriatrics Society. 2014;62(5):857-64.

3. Hiasa KI, Kaku H, Inoue H, Yamashita T, Akao M, Atarashi H, et al. Age-Related Differences in the Clinical Characteristics and Treatment of Elderly Patients With Atrial Fibrillation in Japan - Insight From the ANAFIE (All Nippon AF In Elderly) Registry. Circulation Journal. 2020;84:388-96.

4. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet (London, England). 2014;383:955-62.

5. Koretsune Y, Yamashita T Fau - Kimura T, Kimura T Fau - Fukuzawa M, Fukuzawa M Fau - Abe K, Abe K Fau - Yasaka M, Yasaka M. Short-Term Safety and Plasma Concentrations of Edoxaban in Japanese Patients With Non-Valvular Atrial Fibrillation and Severe Renal Impairment. Circulation. 2015;79.

6. Kato ET, Giugliano RP, Ruff CT, Koretsune Y, Yamashita T, Kiss RG, et al. Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial. LID - 10.1161/JAHA.116.003432 [doi] LID - e003432. J Am Heart Assoc. 2016;5.

7. Komen JJ, Forslund T, Mantel-Teeuwisse AK, Klungel OH, von Euler M, Braunschweig F, et al. Association of Preceding Antithrombotic Therapy in Atrial Fibrillation Patients With Ischemic Stroke, Intracranial Hemorrhage, or Gastrointestinal Bleed and Mortality. LID - pvz063 [pii] LID - 10.1093/ehjcvp/pvz063 [doi]. Eur Heart J Cardiovasc pharmacotherapy. 2019.

8. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstrom-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). European heart journal. 2020.

9. Giugliano RP, Ruff Ct Fau - Braunwald E, Braunwald E Fau - Murphy SA, Murphy Sa Fau - Wiviott SD, Wiviott Sd Fau - Halperin JL, Halperin Jl Fau - Waldo AL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2013;369:2093-104.

10. Chiang CE, Wang KL, Lip GY. Stroke prevention in atrial fibrillation: an Asian perspective. Thrombosis and haemostasis. 2014;111(5):789-97.

11. Kim HK, Tantry US, Smith SC, Jr., Jeong MH, Park SJ, Kim MH, et al. The East Asian Paradox: An Updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease. Thrombosis and haemostasis. 2020.

12. Chang TY, Lip GYH, Chen SA, Chao TF. Importance of Risk Reassessment in Patients With Atrial Fibrillation in Guidelines: Assessing Risk as a Dynamic Process. The Canadian journal of cardiology. 2019;35(5):611-8.

13. Guo Y, Lane DA, Chen Y, Lip GYH, m AFAIITi. Regular Bleeding Risk Assessment Associated with Reduction in Bleeding Outcomes: The mAFA-II Randomized Trial. The American journal of medicine. 2020;133(10):1195-202 e2.

14. Proietti M, Lip GYH, Laroche C, Fauchier L, Marin F, Nabauer M, et al. Relation of outcomes to ABC (Atrial Fibrillation Better Care) pathway adherent care in European patients with atrial fibrillation: an analysis from the ESC-EHRA EORP Atrial Fibrillation General Long-Term (AFGen LT) Registry. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2020.

15. Proietti M, Romiti GF, Olshansky B, Lane DA, Lip GYH. Comprehensive Management With the ABC (Atrial Fibrillation Better Care) Pathway in Clinically Complex Patients With Atrial Fibrillation: A Post Hoc Ancillary Analysis From the AFFIRM Trial. Journal of the American Heart Association. 2020;9(10):e014932.

16. Guo Y, Lane DA, Wang L, Zhang H, Wang H, Zhang W, et al. Mobile Health Technology to Improve Care for Patients With Atrial Fibrillation. Journal of the American College of Cardiology. 2020;75(13):1523-34.

17. Guo Y, Guo J, Shi X, Yao Y, Sun Y, Xia Y, et al. Mobile health technology-supported atrial fibrillation screening and integrated care: A report from the mAFA-II trial Long-term Extension Cohort. European journal of internal medicine. 2020;82:105-11.

 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.