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REVERSAL, REPLETION, AND RATIONAL USE

reversalBecause of the aging of the population and the continued success in prolonging the lifespans of patients with cardiovascular disorders such as atrial fibrillation and severe valvular disease, more and more patients—particularly among elderly cohorts—are on chronic oral anticoagulation therapy. Because of the aging of the population and the well-recognized obesity epidemic, a generally more sedentary lifestyle, longer survival with and after cancer, and shorter hospitalizations for acute medical illness and the proliferation of outpatient/short-stay surgery, the incidence of venous thromboembolism (VTE, inclusive of deep vein thrombosis [DVT] and pulmonary embolism] is increasing and therefore more patients are on oral anticoagulation therapy for 6-month periods or longer, sometimes even lifelong. Over the past ten years, as the frequency and intensity of therapy have increased, approaches to oral anticoagulation have become safer and less onerous for patients and providers. Nonetheless, even the safest anticoagulation regimen can cause or exacerbate pathologic bleeding, up to and including hemorrhagic death or devastating intracranial hemorrhage, compared to matched patients not being anticoagulated.

Fortunately for patients and providers, life-threatening hemorrhage on approved doses of oral anticoagulants is rare. When bleeding complications occur, they often require only conservative management such as local measures, anticoagulant dose adjustment, or temporary discontinuation of therapy. This is true of both warfarin, a vitamin K antagonist that prevents the synthesis of several coagulation factors (namely II, VII, IX, and X), and the direct oral anticoagulants (DOACs), which competitively inhibit only specific factors in the coagulation cascade (dabigatran inhibits both free and clot-bound thrombin [Factor IIa], while apixaban, betrixaban, edoxaban, and rivaroxaban inhibit Factor Xa); most “bleeding complications” present as easy bruising, gingival bleeding or epistaxis, mild hematuria, or limited gastrointestinal bleeding (GIB).

More rarely, hemodynamically significant bleeding or hemorrhage into a critical organ/space occurs. Whether warfarin- or DOAC-related, the most common source of atraumatic hemorrhage is GIB, and the highest morbidity and mortality with OAC-related bleeding is intracranial. Overall, major bleeding associated with DOACs (~1.5 events per 100 patients per treatment year) is less frequent, less severe, and less likely to be fatal than with warfarin (2-5 events/100/year), and in a key subcohort in an era of aging demographics, that distinction is much more likely to hold in patients 75 years of age and older. Trauma-related bleeding is more likely to be serious in the anticoagulated patient, and is more likely to require operative care than non-traumatic blood loss. For patients with hemodynamically significant, life-threatening bleeding related to OAC use, there are now FDA-approved reversal and repletion agents that may be employed in the ED, intensive care, or perioperative setting, that can be expected to remove the clinical impact of iatrogenic coagulopathy in these patients.

It is important to keep in mind that prothrombin complex concentrates (PCC), idarucizumab, and andexanet alfa are not hemostatic agents. These agents, even when used under absolutely ideal conditions, do not stop bleeding. The hope is that these agents remove the antithrombotic effect that is “working against” the clinician while hemorrhage is being treated. They should be used as part of a multimodal approach to severe hemorrhage, which might include aggressive fluid resuscitation, blood product transfusion, pressor agents, and surgical bleeding control. Adequate removal of the anticoagulant agent has the potential to enhance the impact of these other interventions. We therefore speak of “reversing” anticoagulation, but the actual mechanism by which we produce “reversal” clinically may be either “reversal” or “repletion.”

4-Factor PCC effects “repletion.” It is a concentrated infusion of the vitamin K-dependent factors, and as such, it has been studied primarily (and is approved only) for reversal of warfarin-associated hemorrhage. In the acute setting of bleeding in a patient who is anticoagulated with warfarin, the clinician may assume that the patient has no appreciable levels of functional coagulation factors II, VII. IX, and X; 4-factor PCC quickly repletes those levels and allows the normal coagulation cascade to once more perform as expected. Again, PCCs reverse anticoagulation by repleting factors. Idarucizumab and andexanet alfa are reversal agents for dabigatran and the anti-FXa anticoagulants, respectively. They reverse anticoagulation by “disinhibiting” the target coagulation factors of the DOACs. Idarucizumab disinhibits thrombin and thereby frees it up to participate once more in the coagulation cascade by binding very avidly to dabigatran. In fact, idarucizumab binds dabigatran with some 350x the attraction that thrombin holds for dabigatran. With a standard (5g) IV dose from a ready-to-administer vial, idarucizumab rapidly, reliably, and safely reverses the anticoagulation activity of dabigatran. Because the binding of idarucizumab to dabigatran is irreversible, no infusion is needed, and only very rarely—in cases where dabigatran levels might be quite high (such as overdose or acute renal shutdown)—is a repeat dose needed. Idarucizumab is widely available in the US and its hospital price is comparable to that of 4-factor PCC. Andexanet alfa is a competitive blocker of the anti-FXa DOACs, temporarily disinhibiting Factor Xa once again to contribute to clotting. The drug must be reconstituted, is dosed according to the FXa inhibitor being used (if known) and time of last dose (if known), and is administered as a bolus-plus-infusion. After discontinuation of the infusion, measurable aFXa activity levels revert to pre-andexanet levels.

Andexanet alfa has not been widely available, and although recent FDA approval of its “Generation 2” production process/facility is now leading to broader distribution among hospitals, it remains quite expensive (5-7x the price of 4-factor PCC), and therefore it is not readily accessed by many emergency physicians in the US. For that reason, some centers prefer (or have no choice than) to treat aFXa-associated with 4-factor PCC. This use if off-label, is not supported by a Phase 3 study, and in fact is counterintuitive, in that apixaban- or rivoaroxaban-treated patients do not have deficient levels of FXa, but instead have (presumably) normal factor levels; it’s just that those factor levels are inhibited. Administering concentrated Factors—not just X, but also II, VII, and IX—can readily result in supratherapeutic coagulation factor levels and pre-dispose patients to post-repletion thrombosis—not a desirable outcome in the hemorrhaging aFXa-treated patient. These theoretical considerations aside, there have been sporadic case series of treatment of such patients with 4-factor PCC and these reports have not to date indicated a heavy burden of thromboembolic complications. Pending more formal study, emergency physicians are advised to consult with their hematology and pharmacy colleagues and develop an approach to hemorrhage in aFXa-treated patients proactively, so that there is no uncertainty or hesitation in the management of a hyperacute situation such as the presentation of an anticoagulated patient with an intracranial hemorrhage, or an exsanguinating GIB, or a belly/retroperitoneum full of blood after blunt trauma.

Following are the key takeaways from the most important studies of these three agents:

4-Factor PCC:

Sarode R et al: Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013;128:1234-43.

This was a randomized, controlled Phase IIIb study in 212 evaluable subjects. The study compared 4f-PCC (Kcentra®) + vitamin K with fresh-frozen plasma (FFP) + vitamin K for urgent warfarin reversal in patients with acute major bleeding. 4f-PCC achieved the endpoints of hemostatic efficacy with respect to the adequacy of stopping a major bleed assessed at 24 hours from the start of infusion (72.4% of patients receiving 4f-PCC versus 65.4% receiving plasma) and INR reduction (1.3) at 30 minutes post treatment (62.2% of patients receiving 4f-PCC versus 9.6% receiving plasma). The secondary endpoints included plasma levels of major clotting factors (Factors II, VII, IX, X, proteins C and S); time to INR correction; and safety and tolerability (including all-cause mortality). A single 4f-PCC infusion produced a rapid and sustained increase in plasma levels of clotting factors II, VII, IX, and X within 30 minutes post-treatment (p <0.0001) with 87% less volume (105 mL +/-37 mL versus 865 mL +/- 269 mL) than FFP. Additionally, infusion time with 4f-PCC was seven times faster than with FFP (24 minutes versus nearly 3 hours for FFP). The most common adverse reactions (frequency 2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension. The most serious adverse reactions were rare thromboembolic events including stroke, pulmonary embolism and deep vein thrombosis.

Idarucizumab:

Pollack CV et al: Idarucizumab for dabigatran reversal: Full cohort analysis. N Engl J Med 2015; 373:511-520

The primary endpoint of RE-VERSE AD was reversal of the anticoagulant effect of dabigatran (Pradaxa®) within four hours as measured by diluted thrombin time (dTT) and ecarin clotting time (ECT), and was observed in 100% of patients (95% CI, 100-100). Reversal became evident immediately after administration of idarucizumab and was maintained for 24 hours in most patients. Reversal was independent of age, sex, kidney function, or dabigatran concentration at baseline. A single 5g dose of idarucizumab was sufficient in 98% of patients. The clinical outcomes captured as secondary endpoints provide insights into the clinical relevance of anticoagulation reversal: in patients enrolled with acute bleeding (Group A), who could be assessed for time to cessation of bleeding, it took a median of 2.5 hours until the bleeding had stopped; in patients enrolled with a need for urgent surgery or intervention (Group B), the required procedures could be initiated after a median of 1.6 hours. In 93.4% of patients requiring procedures, hemostasis during the procedure was described as normal.

There were no adverse safety signals related to idarucizumab observed in the study. Patients in this study were elderly, had numerous comorbidities and presented with serious index events such as intracranial hemorrhage, multiple trauma or sepsis. Mortality rates at 90 days were 18.8% (Group A) and 18.9% (Group B). At 90 days, thrombotic events had occurred in 6.3% of Group A patients and 7.4% of Group B patients, which is consistent with rates reported after major surgical procedures or hospitalization for uncontrolled bleeding.

Andexanet alfa:

Connolly SJ et al: Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380:1326-1335

352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor were treated in open-label fashion with andexanet alfa. All patients received a bolus of andexanet, followed by a 2-hour infusion. The co-primary outcomes were the percent change in aFXa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion. Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti–factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti–factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.

Of interest, here is a retrospective study of 4f-PCC for aFXa-related hemorrhage.

Smith MN et al: Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study. J Thromb Thrombolysis 2019;48:250-255.

Andexanet alfa comes to market with limited data and an unclear safety profile, and imparts a substantial financial burden. This has led to the off-label use of 4f-PCC for this indication. This study aimed to assess the safety and efficacy of 4F-PCC for the management of major bleeding related to oral FXa inhibitors. This observational, retrospective study included adult patients admitted from 2014 to 2018 who received 4F-PCC for FXa inhibitor-related major bleeding. Efficacy was assessed using criteria described by Sarode et al. Secondary outcomes included the incidence of thromboembolism, mortality, and a cost analysis comparing 4f-PCC to andexanet alfa for reversal of oral FXa inhibitors. Thirty-one patients received 4f-PCC for major bleeding associated with apixaban (55%) or rivaroxaban (45%). Intracranial hemorrhage (58%) and pericardial effusion (16%) accounted for the majority of bleeding events. Most patients received a single weight-based 4f-PCC dose of 25 units/kg (38.7%) or 50 units/kg (51.6%). Effective hemostasis was achieved in 80.6% of patients. Five patients (16%) died due to acute bleeding and no thromboembolic events were observed. Administration of 4F-PCC was effective for most patients requiring emergent reversal of anticoagulation with apixaban or rivaroxaban and was associated with a low risk of thromboembolic events. Considerable cost differences limit the use of andexanet alfa and may warrant further study of 4f-PCC for FXa inhibitor reversal in the face of acute hemorrhage.

This monograph was part of the EMCREG Symposium at the American College of Emergency Physicians Scientific Assembly in Denver in October, 2019. Follow the robust educational opportunities offered by EMCREG at https://www.emcreg.org/publications-archive, https://www.emcreg.org/symposia, and https://www.emcreg.org/emcreg-on-the-go. CME credit is offered for EMCREG programs.

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