Apixaban may be the DOAC of choice for AF patients at risk for GI bleeding

While current guidelines recommend using direct oral anticoagulants (DOACs) over warfarin in patients with non-valvular atrial fibrillation (NVAF), there is a lack of head-to-head trial data to guide the choice of DOAC. Esteemed expert Dr Teo Wee Siong, Consultant Cardiologist & Cardiac Electrophysiologist from Mount Elizabeth Medical Centre, Singapore, reviewed the latest data on the comparative effectiveness and safety of DOACs in AF, provided valuable insights on considerations for the selection of DOACs, and shared his clinical experience with apixaban (Eliquis, Pfizer).

The preferential use of DOACs over warfarin has surged in recent years owing to recent treatment guideline updates and minimal monitoring requirements during the COVID-19 pandemic. [Open Heart 2021;8(2):e001784] “DOACs have been clearly shown to be as effective as warfarin and associated with much less intracranial bleeding. They are easy to use and there is no necessity for regular INR monitoring,” said Teo.

However, clear guidance on DOAC choice for AF is lacking in the absence of evidence from head-to-head randomized clinical trials, which are costly and challenging to conduct. “There is unlikely to be a head-to-head comparison study among the various DOACs,” conceded Teo. “Thus, network meta-analysis and real-world observational studies will have to be analysed to look for evidence as to which DOAC is better,” he added.

Comparative effectiveness and safety of DOACs
A multinational population-based cohort study compared different DOACs, namely apixaban, dabigatran, edoxaban, and rivaroxaban, in terms of  rates of ischaemic stroke or systemic embolism, intracranial haemorrhage (ICH), gastrointestinal bleeding (GI), and all-cause mortality. Data were culled from five electronic healthcare databases in France, German, the UK, and the US. The study included 527,226 patients who were diagnosed with AF and had received a new DOAC prescription from 2010 to 2019, of which 281,320 received apixaban, 61,008 received dabigatran, 12,722 received edoxaban, and 172,176 received rivaroxaban. [Ann Intern Med 2022;175:1515-1524]

“This is a very useful study as it is using very large databases from 4 different countries with a study population of more than half a million patients. It is also the first large database that included edoxaban for comparison,” commented Teo. “The study showed that apixaban was associated with a lower risk for GI bleeding compared with the other DOACs, with a similar efficacy in preventing ischaemic stroke or systemic embolism.”

Apixaban was associated with a lower risk of GI bleeding than dabigatran (hazard ratio [HR], 0.81; 95 percent confidence interval  [CI], 0.70–0.94), edoxaban (HR, 0.77; 95 percent CI, 0.66–0.91), and rivaroxaban (HR, 0.72; 95 percent CI, 0.66–0.79). Notably, these results were consistent in the high-risk population of patients aged >80 years old or with chronic kidney disease (CKD) (Table 1). [Ann Intern Med 2022;175:1515-1524]

“Patients aged >80 years old or those with CKD are at very high risk for thromboembolic stroke from AF and are also at high risk for bleeding. Thus, a DOAC which has high efficacy and minimal risk for bleeding will be a clear drug of choice. The study suggests that apixaban use was associated with lower risk for GI bleeding in this group of patients,” said Teo.

GI bleeding has serious consequences, explained Teo. “When a major bleed occurs, the patient may develop shock requiring urgent blood transfusion or rarely, this could lead to death. More importantly, any bleeding will deter the patient from taking anticoagulants. Temporary cessation of anticoagulation may be needed, putting patients at even higher risks for developing a stroke during this period,” he added.

Further, associations were consistent between lower GI bleeding risk and apixaban use vs rivaroxaban among patients receiving the standard dose (HR, 0.72; 95 percent CI, 0.64–0.82) and those receiving a reduced dose (HR, 0.68; 95 percent CI, 0.59–0.77.) Among patients who received a reduced dose of a DOAC, rates of ischaemic stroke or systemic embolism were lower with apixaban than rivaroxaban (HR, 0.68; 95 percent CI, 0.4–1.01]) and lower with dabigatran than rivaroxaban (HR, 0.67; 95 percent CI, 0.49–0.94]). [Ann Intern Med 2022;175:1515-1524]

“A reduced dose of DOAC can be appropriate when it is corrected because of age, renal dysfunction, body weight, or use of concomitant drugs that can influence the level of the DOAC. In such cases, the efficacy and safety has been shown to be similar to the standard dose of DOAC. However, not infrequently, DOACs are given at an inappropriately low dose, which studies have shown to be less efficacious, and not safer than the correct dose,” he cautioned.

“Given the data from this study and other previous comparison studies, apixaban appears to be considered as first-line in patients who have history of GI bleeding, or are at high risk for GI bleeding. Also, because apixaban is less dependent on renal clearance, it remains the only drug approved in patients with known end-stage CKD,” he emphasized.

Clinical experience-sharing and key takeaways
“My clinical experience with apixaban since it was first available in Singapore in 2012 has been generally good. Importantly, there was a suggestion of a reduction in all-cause mortality in the ARISTOTLE study. Subsequent studies showed there was a lower risk of GI bleeding with apixaban and it was safe in the elderly and patients with CKD. As such, I consider apixaban as the first-line in these groups of patients,” Teo shared.

The most important thing in managing AF is to establish the diagnosis early, he added. “Screening for AF in older patients, especially those with high CHA₂DS₂-VASc scores, is likewise important. Such patients may consider getting a smartwatch which can record a 30-second ECG to detect AF.”

Once the diagnosis of AF is confirmed, it is important to stratify the patient for risk of thromboembolic stroke. Patients with high CHA₂DS₂-VASc scores should be quickly started on oral anticoagulation.

Patients should also be assessed for their suitability for rhythm control with antiarrhythmic drugs or catheter ablation. Recent studies have shown that early treatment with rhythm control can be successful and prevent disease progression.[J Am Coll Cardiol 2022;79:1932-1948]