Role and importance of specific reversal agent for patients on NOACs

Prof. Ken Butcher
University of New South Wales
Australia
13 Nov 2021
Role and importance of specific reversal agent for patients on NOACs

Availability of a specific reversal agent is an important consideration when prescribing non–vitamin K antagonist oral anticoagulants (NOACs) for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). At a recent webinar, Professor Ken Butcher of the University of New South Wales in Sydney, Australia, discussed the role of NOAC reversal agents, including idarucizumab, a specific reversal agent for dabigatran.

Importance of specific reversal agents for NOAC associated bleeding
The most feared side effect of oral anticoagulation is the increased risk of bleeding. [Eur Stroke J 2019;4:294-306] “Based on experience, this fear may contribute to inappropriate underdosing of NOACs, which may result in reduced effectiveness without a safety benefit. This makes the availability of reversal strategies an important consideration when starting patients on oral anticoagulants.” [J Am Coll Cardiol 2017:69:2779-2790]

Reversal of NOACassociated ICH
“Anticoagulation-associated bleeding complications do occur. These include the increased risk of intracerebral haemorrhage [ICH] in patients with AF,” said Butcher. [Stroke 2012;43:1511-1517; Eur Stroke J 2019;4:294-306]

The European Stroke Organisation (ESO) has outlined reversal strategies for patients who develop acute ICH after receiving oral anticoagulants. (Figure 1) Currently, dabigatran is the only anticoagulant with a specific reversal agent – the monoclonal antibody fragment, idarucizumab, which is strongly recommended in patients who develop acute ICH secondary to dabigatran therapy. [Eur Stroke J 2019;4:294-306]

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The multicentre, prospective, open-label RE-VERSE AD study investigated the efficacy of intravenous idarucizumab (5 g) in reversing the anticoagulant effect of dabigatran in patients with uncontrolled bleeding or those who were to undergo an urgent procedure. Results showed that the median maximum percentage reversal of dabigatran within 4 hours of idarucizumab administration was 100 percent (95 percent confidence interval [CI], 100 to 100). [N Engl J Med 2017;377:431-441]

“Importantly, the 30-day mortality rate was 16.4 percent among patients with ICH treated with idarucizumab,” stressed Butcher. “This is less than half of the 30- day mortality rates due to ICH in patients who received either warfarin or dabigatran [ie, 110 mg or 150 mg] in RE-LY.” (Figure 2) [N Engl J Med 2017;377:431-441; Stroke 2012;43:1511-1517; N Engl J Med 2009;361:1139-1151]

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“These results demonstrate that idarucizumab provides both immediate and complete reversal of dabigatran anticoagulation in patients who develop ICH, and reduces mortality risk,” he said.

Idarucizumab in dabigatran-treated patients with ischaemic stroke
“The most common stroke presentation among patients with AF who are maintained on oral anticoagulants is usually an ischaemic stroke, and not an ICH,” noted Butcher. [Neurol India 2019;67:568-570]

Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA) is an approved treatment for patients with acute ischaemic stroke. However, this is contraindicated in patients with AF receiving anticoagulant therapy for stroke prevention. Since idarucizumab 5 g is shown to immediately provide complete reversal of dabigatran’s biological activity, experts have suggested its use before systemic thrombolysis with rt-PA in appropriate patients who develop acute ischaemic stroke while receiving dabigatran therapy. [Int J Stroke 2017;12:9-12]

“Use of local thrombin time may help determine whether these patients will require idarucizumab, especially in situations when the last intake of dabigatran is unknown,” he said. [J Stroke Cerebrovasc Dis 2014;23:1351-1355; Neurol India 2019;67:568-570]

The availability of a direct anticoagulant reversal agent such as idarucizumab to facilitate systemic thrombolysis may represent an important paradigm shift in acute stroke management. [Neurol India 2019;67:568-570]

Re-anticoagulation after embolic stroke
“Secondary prevention in patient who experience ischaemic stroke due to AF remains challenging, especially in terms of increased bleeding risks associated with NOAC use,” said Butcher.

The phase III NAVIGATE ESUS trial showed that rivaroxaban was not superior to aspirin (100 mg QD) for recurrent stroke prevention in patients who had an embolic stroke of undetermined source (ESUS) (annualized rate, 5.1 percent vs 4.8 percent; hazard ratio [HR], 1.07; 95 percent Cl, 0.87 to 1.33; p=0.52), and was associated with a higher risk of bleeding vs aspirin. [N Engl J Med 2018;378:2191-201]

Meanwhile, the randomized, double-blind RE-SPECT ESUS trial showed that dabigatran (150 mg or 110 mg BID) was not superior to aspirin (100 mg QD) in preventing recurrent stroke in patients who had an ESUS. Importantly, the risk of major bleeding was similar between dabigatran and aspirin (1.7 percent/year vs 1.4 percent/year; HR, 1.19; 95 percent CI, 0.85 to 1.66). [N Engl J Med 2019;380:1906-1917]

“These results suggest that dabigatran may be the safer NOAC for re-anticoagulation for secondary stroke prevention, especially since a specific reversal agent is available,” he noted.

Summary 
“Availability of a specific reversal agent should be considered when choosing a NOAC. Other factors to be considered include efficacy, safety, real-world evidence, and patients’ age, comorbidities and renal function,” Butcher concluded.

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