Updates in anticoagulation reversal and hyperkalaemia management in emergency setting

Major bleeding secondary to intake of direct oral anticoagulants (DOACs) and hyperkalaemia are two potentially fatal conditions encountered in the Accident and Emergency (A&E) department. At an industry-sponsored meeting organized by the Hong Kong College of Emergency Medicine, Professor Adam J Singer of the Stony Brook University Hospital in Stony Brook, New York, US, shared updates on management of these conditions, focusing on the role of andexanet alfa in reversing the effects of factor Xa (FXa) inhibitors, and discussed the emergence of sodium zirconium cyclosilicate (SZC) as the preferred potassium binder to treat life-threatening hyperkalaemia.

Specific and rapid reversal agent needed for oral anticoagulants
“Thanks to their similar or improved efficacy and better safety profiles, in the last decade, DOACs, specifically FXa inhibitors, have replaced most of the vitamin K oral antagonists such as warfarin for Stroke prevention in patients with nonvalvular atrial fibrillation and for treatment of thrombotic conditions,” said Singer. [Eur Cardiol 2017;12:40-45; N Engl J Med 2015;373:2413-2424; N Engl J Med 2011;365:981-992; J Am Coll Cardiol 2014;63:2141-2147; N Engl J Med 2011;365:883-891]

“However, major bleeding [ie, intracranial haemorrhage and gastrointestinal (GI) bleeding] still occurs in up to 6 percent of patients treated with oral FXa inhibitors, which may be fatal in about 20 percent of cases,” he added. [J Am Coll Cardiol 2014;63:2141-2147; Eur Heart J 2014;35:1873-1880; JAMA Netw Open 2021;4:e2037438; Am J Emerg Med 2018;36:396-402; Future Cardiol 2021;17:127-135]

4F-PCC not an optimal FXa inhibitor antidote
Nonspecific treatments such as four-factor prothrombin complex concentrate (4F-PCC) were previously used to manage FXa inhibitor–associated bleeding. However, these agents have not been shown to provide adequate replacement of inhibited factors. [N Engl J Med 2015;373:2413-2424; Stroke 2019;50:529-536; Future Cardiol 2021;17:127-135]

“Unlike patients treated with warfarin, there is no deficiency in clotting factors in patients treated with FXa inhibitors,” explained Singer. “Therefore, there is no mechanistic rationale for treating FXa inhibitor–associated bleeding with [nonspecific] agents such as 4F-PCC.” (Table 1) [N Engl J Med 2015;373:2414-2424; Stroke 2019;50:529-536]

Andexanet alfa: Recommended reversal agent for FXa inhibitors
“Reversal agents for oral anticoagulants should be specific and rapid,” Singer emphasized. “Andexanet alfa, a recombinant modified human FXa, is currently the only specific reversal agent for apixaban and rivaroxaban approved in the US for patients with life-threatening or uncontrolled bleeding.” [N Engl J Med 2015;373:2413-2424; Drugs 2018;78:1049-1055; Res Pract Thromb Haemost 2020;4:1282-1294]

Andexanet alfa exerts its procoagulant effect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban, restoring native FXa activity and thrombin generation. [N Engl J Med 2015;373:2413-2424; Nat Med 2013;19:446-451]

“In the prospective, single-arm, open-label phase IIIb/IV ANNEXA-4 trial, treatment with andexanet alfa was associated with rapid reduction in anti-FXa activity – within 2 minutes after administration of the initial bolus in patients with acute bleeding due to FXa inhibitor treatment,” said Singer. “It also showed excellent/good haemostatic efficacy in approximately 80 percent of patients across different bleeding types, with thrombin generation restored and sustained for ≥24 hours.” [Circulation 2023;147:1026-1038; N Engl J Med 2019;380:1326-1335]

Meanwhile, real-world evidence from a multicentre, retrospective survey in the US demonstrated that in-hospital mortality was lowest (4 percent) for all bleeds managed with andexanet alfa (vs 10 percent with 4F-PCC) in adults hospitalized for FXa inhibitor–related bleeding. Importantly, andexanet alfa was associated with the lowest rate of in-hospital mortality across all bleed types, including intracranial haemorrhage (9 percent) and gastrointestinal bleed (1 percent). (Figure) [Future Cardiol 2021;17:127-135]
 

“These data support the use of andexanet alfa as the preferred specific reversal agent for the anticoagulant effects of apixaban and rivaroxaban, which are consistent with recommendations of current treatment guidelines and consensus statements,” noted Singer. (Table 1) [Res Pract Thromb Haemost 2020;4:1282-1294; Crit Pathw Cardiol 2019;18:143-166; Ann Emerg Med 2020;76:470-485]

Unmet needs in hyperkalaemia
“In hyperkalaemia, a combination of rapid potassium-lowering strategies is recommended in patients at high risk of hospitalization and mortality [ie, those with moderately to severely elevated potassium levels or with electrocardiogram changes],” explained Singer. [Resuscitation 2021;161:152-219; Clin Exp Emerg Med 2017;4:73-79] “Unfortunately, traditional hyperkalaemia treatments have limited efficacy or are poorly tolerated by patients.” (Table 2)

“Real-world data from a multicentre, prospective study in the US also demonstrated that use of multiple standard therapies [ie, β₂ adrenergic agonists, sodium bicarbonate, calcium, diuretics, insulin/glucose, sodium polystyrene sulfonate (SPS)], except for dialysis, did not result in median potassium level <5.0 mmol/L after 4 hours in patients with hyperkalaemia in the A&E department,” he added. [J Emerg Med 2018;55:741-750]

“SPS, in particular, has been the traditional potassium-binding agent for several decades, but we haven’t used it in our emergency room in the last 10–25 years because GI side effects were quite common and challenging to manage in the A&E department,” commented Singer. “It is also associated with an increased risk of intestinal necrosis when combined with sorbitol.” [Eur J Emerg Med 2020;27:329-337]

SZC: Potassium binder of choice for acute hyperkalaemia
Sodium zirconium cyclosilicate (SZC), a novel potassium binder, has become the agent of choice in the emergency setting since it rapidly reduces potassium levels and is generally well tolerated by patients. [Resuscitation 2021;161:152-219; Sodium zirconium cyclosilicate Hong Kong Prescribing Information; JAMA 2014;312:2223-2233]

In the phase III, multicentre, randomized, double-blind, placebo-controlled HARMONIZE trial, treatment with SZC 10 g TID in the initial 48-hour open-label phase resulted in rapid reduction of serum potassium in patients with hyperkalaemia, with levels significantly decreasing by 0.2 mmol/L, 0.4 mmol/L, 0.5 mmol/L, 0.7 mmol/L and 1.1 mmol/L at 1 hour, 2 hours, 4 hours, 24 hours, and 48 hours, respectively (all p<0.001). [JAMA 2014;312:2223-2233]

“Although oedema may be a common adverse reaction associated with SZC, this can generally be managed with diurectics and by restricting sodium intake,” added Singer. [Sodium zirconium cyclosilicate Hong Kong Prescribing Information]

Hypokalaemia (serum potassium <3.5 mmol/L) has been reported in 4.1 percent of patients treated with SZC. However, this resolved with dose adjustment or discontinuation of SZC. [Nephrol Dial Transplant 2019;34(Suppl 3):iii45-iii50; Sodium zirconium cyclosilicate Hong Kong Prescribing Information]

“SZC has thus been a tremendous addition to our armamentarium for hyperkalaemia management, especially in the emergency setting,” noted Singer. (Table 3)

Summary
“FXa inhibitor–related bleeding and acute hyperkalaemia are relatively rare but potentially fatal conditions encountered in the A&E department,” said Singer. “These conditions have become more manageable in the emergency setting with the availability of andexanet alfa as a specific antidote for FXa inhibitors and the rapidly-acting SZC for acute hyperkalaemia.”