Role of NOACs in stroke prevention for multimorbid AF patients

Prof. Tze-Fan Chao
Taipei Veterans General Hospital
12 Jul 2021

Optimizing stroke prevention in patients with atrial fibrillation (AF) should be carried out without compromising the common comorbidities. At an industry-sponsored webinar, Professor Tze-Fan Chao of the Taipei Veterans General Hospital in Taipei, Taiwan, discussed the advantages of using non-vitamin K antagonist oral anticoagulants (NOACs) vs the traditional vitamin K antagonist (VKA), warfarin, specifically in patients with AF and comorbidities, including the very elderly population (ie, >85 years of age), those with diabetes mellitus (DM), and those with renal dysfunction.

Burden of AF and comorbidities

“The prevalence of AF is projected to increase due to improved diagnostic screening and population ageing,” said Chao. “In Taiwan, the projected prevalence of AF is estimated to increase to 4.01 percent in 2050. Importantly, the incidence of AF increases with patients’ age. Comorbidities also tend to occur more frequently in older AF patients.” [Chest 2018;153:453-466]

According to the Taiwan National Health Insurance Research Database (NHIRD), hypertension is the most prevalent comorbidity, occurring in 62.9 percent of patients with AF. This is followed by congestive heart failure (38.7 percent), DM (26.9 percent), previous stroke/transient ischaemic attack (20.5 percent), and previous vascular disease (15.3 percent). [Heart Rhythm 2016;13:46-53]

NOACs preferred vs warfarin for stroke prevention in AF

“The 2020 European Society of Cardiology [ESC] AF guidelines provide a holistic approach to the management of patients with AF through the Atrial Fibrillation Better Care [ABC] approach,” explained Chao. “This integrated management strategy comprises ‘Anticoagulation/Avoid stroke,’ ‘Better symptom management’ and ‘Cardiovascular [CV] and comorbidity risk reduction’.” [Eur Heart J 2021;42:373-498]

In terms of stroke prevention in patients with AF who are eligible for oral anticoagulation, the guidelines recommend NOACs (ie, apixaban, edoxaban, dabigatran and rivaroxaban) vs VKAs, except in patients with mechanical heart valves or moderate to severe mitral stenosis (Class IA). [Eur Heart J 2021;42:373-498]

Real-world evidence for NOACs in Asian patients

Advantages of NOACs vs warfarin have been demonstrated in a systematic review and meta-analysis of available observational real-world studies comparing apixaban, edoxaban, dabigatran and rivaroxaban vs warfarin in Asian patients with nonvalvular AF (NVAF). [Cardiovasc Drugs Ther 2019;33:701-710]

“The analysis included 18 studies from China, Hong Kong, Japan, Korea, Singapore and Taiwan, with most patients receiving rivaroxaban [n=61,619],” Chao noted.

“Overall, NOACs were associated with lower risks of thromboembolism, acute MI [AMI], mortality, major bleeding, intracranial haemorrhage [ICH], gastrointestinal bleeding [GIB] and any bleeding vs warfarin in Asian patients with NVAF,” he said. “In particular, rivaroxaban was associated with significantly lower risks of thromboembolism [hazard ratio (HR), 0.76; 95 percent confidence interval (CI), 0.70 to 0.83; p<0.0001], AMI [HR, 0.82, 95 percent CI, 0.72 to 0.93; p=0.002], mortality [HR, 0.70, 95 per-cent CI, 0.56 to 0.88; p=0.002], major bleeding [HR, 0.69; 95 percent CI, 0.49 to 0.96; p=0.03], and ICH [HR, 0.65; 95 percent CI, 0.46 to 0.91; p=0.01] vs warfarin.”

NOACs in very elderly patients

“In patients with AF, old age is associated with increased risks of ICH, major bleeding and ischaemic stroke, making stroke prevention strategies with oral anticoagulants more challenging,” explained Chao. [Chest 2020; 157:1266-1277]

“We conducted a retrospective study using data from the Taiwan NHIRD and identified a total of 15,361 patients aged ≥85 years with AF on oral anticoagulants [ie, apixaban, dabigatran, rivaroxaban, warfarin],” said Chao. Study endpoints included ischaemic stroke, ICH, major bleeding, all-cause mortality and composite adverse events (ie, ICH or major bleeding or all-cause mortality). [Eur J Clin Invest 2021;e13488]

Compared with warfarin, only rivaroxaban was associated with significantly lower risks of both ischaemic stroke (HR, 0.781; 95 percent CI, 0.649 to 0.941; p=0.009) and ICH (HR, 0.453; 95 percent CI, 0.309  to 0.663; p<0.001). (Figure 1) [Eur J Clin Invest 2021;e13488]


“These findings were consistent with findings of a prospective cohort study that compared the bleeding risk of rivaroxaban vs VKAs among French geriatric patients with NVAF aged ≥80 years,” said Chao. [Heart 2020;doi:10.1136/heartjnl-2020-317923]

“The results indicate that NOACs are the more favourable option for stroke prevention in older patients with AF due to comparable or better efficacy and safety vs warfarin,” commented Chao. “The significant risk reductions in both stroke and ICH associated with rivaroxaban makes it appropriate for very elderly patients, based on our data from Taiwan.” [Eur J Clin Invest 2021;e13488]

NOACs in patients with AF and DM

Patients with AF and comorbid DM are at increased risk of ischaemic stroke, acute coronary syndrome and CV events. [JAMA Cardiol 2017;2:442-448; Cardiovasc Diabetol 2020;19:63]

Previously, subgroup analyses of patients with AF and DM in four pivotal trials showed that rivaroxaban was associated with the lowest risk of CV death vs warfarin among all studied NOACs (HR, 0.80; 95 percent CI, 0.64 to 0.99). (Figure 2) [Am Heart J 2015;170:675-682.e8; Eur Heart J Cardiovasc Pharmacother 2015;1:86-94; Int J Cardiol 2015;196:127-131; Int J Cardiol 2020;304:185-191]


“Aside from assessing NOACs in terms of risk of major adverse CV events [MACE], reducing major adverse limb events [MALE] is also an important endpoint for patients with DM due to their high vascular risk,” stressed Chao. “We conducted a nationwide retrospective cohort study based on the Taiwan NHIRD to investigate the effectiveness, safety and risk of MALE of NOACs vs warfarin among patients with AF and DM.” [Cardiovasc Diabetol 2020;19:63]

“We included a total of 20,967 and 5,812 patients with NVAF and DM taking NOACs and warfarin, respectively,” he continued. “Results showed that compared with warfarin, NOACs were associated with significantly lower risks of MACE [adjusted HR, 0.88; 95 percent CI, 0.78 to 0.99; p=0.0283], MALE [adjusted HR, 0.72; 95 percent CI, 0.57 to 0.92; p=0.0083], and major bleeding [adjusted HR, 0.67; 95 percent CI, 0.59 to 0.76; p<0.0001].” (Figure 3)


“Looking at the individual NOACs, only rivaroxaban was associated with a significantly reduced risk of MALE, making it a valid option for patients with both AF and DM,” Chao noted. (Figure 3)

NOACs and renal disease

“The risk of AF is increased with declining renal function, which negatively affects patient outcomes,” said Chao. [Kidney Int 2015;87:1209-1215]

To balance the risks and benefits when selecting an anticoagulation regimen, the 2019 American College of Cardiology (ACC), American Heart Association (AHA) and Heart Rhythm Society (HRS) AF management guidelines recommend evaluating patients’ baseline renal function before initiating NOAC therapy and re-evaluating it at least annually thereafter. [Circulation 2019;140:e125-e151]

“NOACs, particularly dabigatran and rivaroxaban, may be associated with lower risks of adverse renal outcomes over time vs warfarin in patients with AF,” he explained. [Circulation 2019;140:e125-e151]

This was observed in a US retrospective cohort analysis of 9,769 patients with NVAF on oral anticoagulants (ie, apixaban, dabigatran, rivaroxaban, warfarin). When comparing each NOAC vs warfarin, dabigatran was associated with lower risks of ≥30 percent decline in estimated glomerular filtration rate (eGFR) and acute kidney injury (AKI), while rivaroxaban was associated with lower risks of ≥30 percent decline in eGFR, doubling of serum creatinine, and AKI. [J Am Coll Cardiol 2017;70:2621-2632]

“In terms of drug metabolism, rivaroxaban and apixaban have lower renal clearance compared with other NOACs [approximately 35 percent for rivaroxaban, 27 percent for apixaban, 80 percent for dabigatran and 50 percent for edoxaban],” noted Chao. [Europace 2021;euab065]

“We also demonstrated in a retrospective study based on daily practice in Taiwan that renal function declines more slowly and is preserved better with rivaroxaban vs warfarin,” he added. [J Am Heart Assoc 2019;8:e013053]


NOACs are recommended and preferred vs warfarin for stroke prevention in patients with AF, including very elderly patients and those with comorbidities. [Eur Heart J 2021;42:373-498] Compared with other NOACs, rivaroxaban may be preferred for AF patients with comorbid DM due to the associated significant reduction in MALE vs warfarin, and for patients with renal impairment due to the associated lower risks of adverse renal outcomes over time. [Cardiovasc Diabetol 2020;19:63; J Am Coll Cardiol 2017;70:2621-2632; Circulation 2019;140:e125-e151; J Am Heart Assoc 2019;8:e013053]


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