[MP Test] Increasing trend in DOAC-related intracerebral haemorrhage: How to improve outcomes?

New local findings presented at HKMF 2024 show an increasing trend in intracerebral haemorrhage (ICH) among patients on direct oral anticoagulants (DOACs) between 2013 and 2022. Early initiation of reversal agents may improve outcomes in select cases with DOAC-related ICH.

In clinical trials, DOACs demonstrated efficacy in preventing ischaemic stroke and systemic embolism in patients with atrial fibrillation (AF), with low annual rates of haemorrhagic stroke and intracranial bleeding. [N Engl J Med 2009;361:1139-1151; N Engl J Med 2011;365:883-891; N Engl J Med 2011;365:981-992; N Engl J Med 2013;369:2093-2104] “However, due to their frequent use in elderly patients, the trend of DOAC-related ICH has increased in the real world,” pointed out Dr Kay-Cheong Teo of School of Clinical Medicine, the University of Hong Kong.

“Our stroke registry data showed a 50 percent increase in anticoagulant-related ICH, rising from approximately 5 percent of all ICH cases during 2013–2018 to approximately 10 percent during 2019–2022, with DOAC-related ICH being the main driver,” Teo reported. “Among patients with DOAC-related ICH [n=103], mortality rates were 45.6 percent at 1 month and 54.4 percent at 6 months, with 78.6 percent experiencing poor outcomes including death and dependence.”

“Prevention of haematoma expansion is key in acute ICH management, … as every 1 mL increase in haematoma [volume] is associated with a 5 percent increased risk of death or dependence,” he noted. [Neurol Res Pract 2023;5:36; Neurology 2012;79:314-319]

To rapidly achieve haemostasis, idarucizumab and andexanet alfa are recommended reversal agents for AF patients with life-threatening bleeding on dabigatran and factor Xa (FXa) inhibitors (ie, edoxaban, apixaban, rivaroxaban), respectively. [J Am Coll Cardiol 2024;83:109-279] “In Hong Kong, idarucizumab is widely used, and andexanet alfa will hopefully become available later this year,” said Teo.

Idarucizumab rapidly reversed anticoagulation in dabigatran-treated patients with acute major bleeding in the phase III single-arm REVERSE AD trial. A systematic review of six studies reported lower mortality rate in idarucizumab-treated patients with dabigatran-associated intracranial haemorrhage vs literature. [N Engl J Med 2017;377:431-441; Front Neurol 2021;12:727403]

In the phase IIIb/IV single-arm ANNEXA-4 trial, andexanet alfa markedly reduced anti-FXa activity in patients with acute major bleeding on a FXa inhibitor. Supported by positive interim results, the phase IV, randomized ANNEXA-I trial comparing andexanet alfa (n=263) vs usual care (n=267) for ICH in 530 patients on FXa inhibitors will be stopped early. [N Engl J Med 2019;380:1326-1335; N Engl J Med 2024;390:1745-1755; https://bit.ly/4dFJHSV]

In ANNEXA-I, significantly more patients receiving andexanet alfa achieved haemostatic efficacy (defined as ≤35 percent haematoma volume expansion at 12 hours after baseline, <7 points increase in National Institutes of Health Stroke Scale score at 12 hours, and no rescue therapies required in 3–12 hours) vs those receiving usual care (67.0 vs 53.1 percent; p=0.003). Within 30 days, thrombotic events occurred in 10.3 percent of andexanet alpha recipients vs 5.6 percent of usual care recipients (p=0.048). Ischaemic stroke rates were 6.5 vs 1.5 percent, and myocardial infarction rates were 4.2 vs 1.5 percent. [N Engl J Med 2024;390:1745-1755]

“[Therefore,] andexanet alfa may benefit patients presenting <4.5–6 hours after ICH onset with salvageable brain tissues and a low thrombotic risk,” suggested Teo.

When DOAC-specific reversal agents are unavailable, 4-factor prothrombin complex concentrate (4F-PCC) should be considered. “However, 4F-PCC cannot reverse anticoagulation effects of DOACs and requires about 10 hours to normalize thrombin levels,” Teo reminded. [J Am Coll Cardiol 2024;83:109-279; J Thromb Haemost 2015;13:S187-S194; J Thromb Haemost 2014;12:1428-1436]