Optimizing NOAC use for stroke prevention in patients with AF
Prevention of AF-related stroke with NOACs
“The 2020 European Society of Cardiology [ESC] guidelines for AF management recommend oral anticoagulation, preferably with NOACs over vitamin K antagonists in NOAC-eligible patients, except in those with mechanical heart valves or moderate-to-severe mitral stenosis,” said Diener. [Eur Heart J 2020, doi: 10.1093/eurheartj/ehaa612]
NOACs in special populations: Focus on edoxaban
Edoxaban, in particular, has demonstrated consistent benefits in stroke prevention for specific populations in several subgroup analyses of the randomized, double-blind ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial.
One such population was patients at increased risk of falling. In the ENGAGE AF TIMI 48, such patients were generally older (median age, 77 years vs 72 years; p<0.001) and had a higher prevalence of comorbidities. Although patients at increased risk of falling experienced more bone fractures caused by falling, major bleeding, life-threatening bleeding and all-cause death, there was no increased risk of ischaemic events including stroke/systemic embolism (SSE) (adjusted hazard ratio [HR], 1.16; 95 percent CI, 0.89 to 1.51; p=0.27). In these patients, edoxaban (30 mg or 60 mg once daily) was also associated with a greater absolute risk reduction in severe bleeding events and all-cause mortality vs warfarin. [J Am Coll Cardiol 2016;68:1169-1178]
“ENGAGE AF-TIMI 48 included a large number of elderly patients. After stratifying according to age [<65 years (n=5,497), 65–74 years (n=7,134) and ≥75 years (n=8,474)], edoxaban’s benefit vs warfarin in reducing haemorrhagic stroke, intracranial haemorrhage [ICH] and fatal bleeding events was more pronounced in patients ≥75 years,” noted Diener. [J Am Heart Assoc 2016;5:e003432] “These results demonstrate that once-daily edoxaban provides consistent efficacy and safety in patients at increased risk of falls, with improved primary net clinical benefit vs warfarin in elderly patients.”
NOACs for secondary stroke prevention in AF
“The most important risk factor for stroke in patients with AF is a history of stroke or transient ischaemic attack [TIA],” said Diener. [Eur Heart J 2020, doi: 10.1093/eurheartj/ehaa612]
In the multinational, multicentre observational ETNA-AF-Europe study, absolute recurrent stroke rates were higher in patients with previous stroke/TIA. These patients also had higher rates of total mortality and cardiovascular mortality, but not major bleeding or ICH. [Int J Stroke 2020, doi: 10.1177/1747493020963387, e-poster 3420]
“The increased absolute recurrent stroke rates in patients with previous stroke/TIA underscores the importance of providing adequate and prompt anticoagulation to these patients,” stressed Diener. “According to the ESC guidelines, oral anticoagulation is the recommended strategy for stroke prevention in the secondary setting, with NOACs preferred over vitamin K antagonists in NOAC-eligible patients.” [Eur Heart J 2020, doi: 10.1093/eurheartj/ehaa612]
Edoxaban vs warfarin
Patients with AF and previous history of ischaemic stroke or TIA remain at high risk of recurrent cerebrovascular events despite anticoagulation. A subgroup analysis of ENGAGE AF-TIMI 48 showed that patients with previous stroke/TIA were at higher risk of both thromboembolism and bleeding vs those without previous stroke/TIA (stroke/SSE events, 2.83 percent vs 1.42 percent per year; adjusted HR, 1.97; 95 percent CI, 1.73 to 2.24; p<0.001) (major bleeding, 3.03 percent vs 2.64 percent per year; p<0.001) (ICH, 0.70 percent vs 0.40 percent per year; p<0.001). [Stroke 2016;47:2075-2082]
In patients with previous stroke/TIA, annualized ICH rates were lower for those who received high-dose edoxaban (60/30 mg QD) vs warfarin (0.62 percent vs 1.09 percent; HR, 0.57; 95 percent CI, 0.36 to 0.92; p=0.02). Similar benefits with high-dose edoxaban vs warfarin were observed in patients without prior stroke/TIA. (Figure) These results indicate that the benefits of high-dose edoxaban extend to patients with previous stroke/TIA who have a strong indication for anticoagulation for secondary stroke prevention.
Stroke prevention in Hong Kong
“Results of a local study assessing trends in AF-related stroke and TIA, prior anticoagulant use and risk factors demonstrated an approximately three-fold increase in AF-related stroke/TIA in the Chinese population over a 15-year period in 1999–2014. More than 70 percent of AF-related stroke/TIA occurred in non-anticoagulated patients, and this proportion increased with age, highlighting the fact that many vulnerable patients were not properly anticoagulated and received antiplatelet therapy instead,” noted Soo. [J Neurol Neurosurg Psychiatry 2017;88:744-748]
NOAC use remains suboptimal
“We continued to monitor trends in AF prevalence and outcomes in the New Territories East Cluster in Hong Kong,” said Soo. “Data from 2015 to October 2020 showed a continuous increase in AF cases with the ageing population, which was most pronounced among those 60–79 years of age with CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, previous stroke/TIA, vascular disease, age 65–74 years, sex category] score ≥3.”
“NOACs were introduced to public hospitals in Hong Kong about 10 years ago. In 2019, the criteria for their subsidized use in public hospitals were expanded to include prevention of AF-related stroke in patients with CHA2DS2-VASc score ≥5,” noted Soo. “This has resulted in >60 percent growth in NOAC use in high-risk patients since 2015.”
“Nonetheless, >40 percent of patients with AF across all age groups were still not receiving anticoagulants in 2019 [n=15,913],” she pointed out. “Furthermore, <30 percent of AF patients received echocardiography, which may imply inadequate assessment for NOAC eligibility.”
Opportunities to optimize NOAC use
“Aside from the improved patient outcomes associated with NOACs, our preliminary cost analysis showed that NOACs are more cost-effective in preventing AF-related stroke than warfarin,” Soo added. “We estimated total savings per patient per year of >HKD 20,000 with NOACs vs warfarin.”
“Efforts are needed to further expand and optimize NOAC use in patients with moderate risk of stroke [ie, CHA2DS2-VASc score of 3–4]. Risk factors such as major bleeding have become manageable and should not be considered as absolute contraindications to NOAC use,” she suggested. [J Am Coll Cardiol 2020;76:594-622]
Current evidence and guideline recommendations support the use of NOACs in both primary and secondary prevention of AF-related stroke in NOAC-eligible patients. Edoxaban, in particular, has demonstrated consistent efficacy and safety in patients at increased risk of falling, with improved net clinical benefit for vulnerable elderly patients. Strategies to properly evaluate patients are crucial to optimizing NOAC use and improving clinical outcomes.