Specific antagonists versus indirect prohaemostatic agents for the reversal of direct oral anticoagulants.

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1 Lithuanian University of Health Sciences

Medical Academy, Faculty of Medicine Dept. of Disaster Medicine

Specific antagonists versus indirect prohaemostatic agents for

the reversal of direct oral anticoagulants.

MASTERS THESIS

Koldo Percaz Ibero Supervisor: Dinas Vaitkaitis, MD, PhD

KAUNAS 2019-2020

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1. SUMMARY

Author: Koldo Percaz Ibero

Title: Specific antagonists versus indirect prohaemostatic agents for the reversal of direct oral anticoagulants.

Aim: To evaluate the administration of anticoagulant specific reversal agents and non-specific hemostatic agents in direct oral anti-coagulant patients requiring emergent reversal. Methods: This systematic review was designed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). A literature search was conduct-ed through PubMconduct-ed, collecting studies analyzing clinical outcomes of f DOAC-anticoagulation reversal with antidotes or prohaemostatic agents in real patients. Studies were selected ac-cording an inclusion and exclusion criteria, and data was extracted and synthesized. Risks of bias was screened

Results: 9 observational studies were included in the review. PCCs were shown to improve thrombin generation parameters ETP and Cmax by x and x respectively, in a cohort of 14

pa-tients receiving rivaroxaban. Idarucizumab was shown to reverse diluted thrombin time and ecarin clotting time to baseline values in 98% of subjects and to reduce dabigatran concen-trations to sub-therapeutic levels. Another study reported that andexanet-alfa was effective in reducing the anti-factor Xa activity for rivaroxaban and apixaban-treated patients. Pooled co-hort data indicated that for factor Xa inhibitor treated patients, the incidence of thrombotic events was lower among those treated with PCCs versus andexanet; and that mortality dur-ing follow up was lower among those treated with andexanet versus PCCs. The pooldur-ing of cohort outcomes and their comparisons were done for merely orientative purposes, disre-garding heterogeneity and individual study strength and should not be considered reliable evidence in any way.

Conclusions: Evidence regarding the effects of DOAC antidotes and prohaemostatic agents on the clinical outcomes of DOAC research stems from a set of observational studies with heterogeneous inclusion/exclusion criteria, methods and outcomes. Idarucizumab and an-dexanet-alfa have proved to be effective in the reversal of dabigatran and factor Xa-inhibitors, respectively, according to laboratory measures. PCCs have shown some degree of restora-tion of endogenous thrombin generarestora-tion. The correlarestora-tion between laboratory surrogate end-points and clinical outcomes is not ascertained.

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2. ACKNOWLEDGEMENTS

The author would like to express gratitude to Prof. Dr. Dinas Vaitkaitis, for accepting to su-pervise this work.

Thanks also to every person who helped me during the process of writing this work, they are too many to name.

3. CONFLICT OF INTEREST

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4. ABBREVIATIONS

DOAC – Direct oral anticoagulant VKA – Vitamin K antagonist AF-Atrial fibrillation

TE – Thromboembolism

VTE – Venous thromboembolism MBE-Major bleeding event

DTI – Direct thrombin inhibitor

FXaI, FXa-inhibitor – Factor Xa inhibitor PCC – Prothrombin complex concentrate

aPCC- Activated prothrombin complex concentrate PICO – Population, intervention, comparison, outcome

PRISMA – Preferred reporting items for systematic review and meta-analysis q.d. – Quaque diem, every day

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5. INTRODUCTION

In the last ten years, Direct Oral Anti-Coagulant (DOAC) drugs have become a popu-lar alternative to vitamin-K antagonists (VKA), especially for prevention of stroke in non-valvular atrial fibrillation (AF). Since their introduction, their prescription has steadily grown in Europe and the U.S.A., while warfarin prescription has declined. (1; 2) DOACs offer a wider therapeutic range, more predictable response effect and less food and drug interactions than VKAs, while also having a faster onset (1-4h) and shorter half-life (7-12h). This makes them an attractive treatment option, as regular INR measurements are not required, periprocedural anticoagulation management is simplified and patients spend less time outside the therapeu-tic range.

There are not, however, evidence-based reversal strategies defined for DOACs, and since data from clinical trials and real-world analyses shows major bleeding events (MBE) in approximately 3% to 4% of DOAC-treated patients and that another 2% will need to undergo urgent procedures that require normal haemostasis (3; 4; 5; 6), this lack of certainty and/or reversal methods could be a major limiting factor in their use.

Two DOAC antagonists have been approved in recent years to address this issue. Idarucizumab (Praxbind ® , Boehringer Ingelheim Pharmaceuticals Inc., Germany) and an-dexantet-alfa (Andexxa®, Portola Pharmaceuticals, USA). Previous to their introduction, co-agulation factor replacement therapies have been the most used and studied method of re-versal. Options include prothrombin complex concentrates (PCC), activated PCC (aPCC) ( FEIBA ® , Shire US Inc., UK/USA; Cofact ® , Sanquin, The Netherlands) and recombinant factor VIIa (rFVIIa)(Novoseven ® , Novo Nordisk, Denmark).

This study aims to review the latest publications on DOAC reversal therapy in real patients, perform a comparison between both approaches to reversal, and to present current evidence in a readily understandable manner.

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6. AIMS AND OBJECTIVES OF THE THESIS

AIM: To evaluate the administration of anticoagulant specific reversal agents and non-specific hemostatic agents in direct oral anti-coagulant patients requiring emergent reversal. OBJECTIVES:

1. To evaluate the effectivity and safety of oral anticoagulant antidotes in the emergency reversal of DOAC action.

2. To evaluate the effectivity and safety of indirect haemostatic agents in the emergency reversal of DOAC action.

3. To perform a comparison between DOAC antidotes´ and prohaemostatic agents´ ef-fectivity and safety.

4. To gather relevant evidence regarding DOAC reversal and present it in a readily un-derstandable manner.

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7. LITERATURE REVIEW

7.1 Direct oral anticoagulants:

The term DOAC encompasses a group of anticoagulants with two common traits: (I) Oral administration and (2) direct inhibition of a specific coagulation factor. This sets them apart from VKAs, which act on all vitamin K dependant coagulation factors and were until 2010 the only per os administered anticoagulants.

Other terms are interchangeably used to describe these drugs, such as “new/novel anticoagulants” and “non-vitamin K oral anticoagulants”, but DOAC is the term recommended by the International Society on Thrombosis and Haemostasis. (7)

As of December 2019 five have been approved for clinical use by the FDA: Dabigatran, a direct thrombin inhibitor (DTI), and the factor Xa inhibitors (FXa-Inhibitor) apix-aban, edoxapix-aban, betrixaban and rivaroxaban. They are indicated for the treatment of venous thromboembolism (VTE) (8) and prevention of stroke in patients with atrial fibrillation (AF) (9; 3; 5; 4). FXa inhibitors are also indicated for thromboembolism prophylaxis following major orthopaedic surgeries (10; 11; 12).

DOACs have demonstrated non-inferior effectivity to warfarin in the prevention of stroke and systemic embolism (SE) in DVT and non-valvular AF with reductions in death, stroke, intracranial haemorrhage and an overall lower risk of major bleeding, although with higher rates of GI bleeding reported in several studies for high-dose dabigatran and edoxa-ban and for standard-dose rivaroxaedoxa-ban . (9; 13; 5; 4; 14; 15; 16; 17)

7.2 Idarucizumab:

Idarucizumab, a specific antidote for dabigatran, was approved for clinical use in Oc-tober 2015. Idarucizumab is a humanized monoclonal antibody that irreversibly binds dabigatran with high affinity (350 times more than thrombin), making it inactive (18). It is indi-cated for the treatment of dabigatran-related life threatening or uncontrolled bleeding and for

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9 dabigatran reversal before emergent procedures that require normal haemostasis and cannot be postponed (19)

Idarucizumab comes in single-use 2.gram vials and is administered as a total 5-gram dose, either by administering 2 infusions of 2.5 5-grams each over 15 minutes or by IV bolus, one vial after the other (19).

In vivo trials on healthy volunteers:

In a randomised, placebo-controlled, phase 1 study conducted by Glund et al. (20) in 47 healthy male volunteers. Participants received oral dabigatran etexilate 220 mg b.i.d for 3 days plus a last dose on day 4. Idarucizumab (1 g, 2 g, 4 g as 5min IV infusion; or 5 g plus 2.5 g in two infusions 1 h apart) was then administered 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events; as additional end-points, changes in diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT) and thrombin time (TT) from baseline to post idarucizumab ad-ministration were examined. No adverse effects were reported and Idarucizumab was found to completely reverse dabigatran-induced anticoagulation in a dose-dependent manner.

A similar study by Glund et al (21) recruited 46 volunteers that were either healthy middle-aged, elderly or renally impaired. Interventions and endpoints were identical to the previous study with the addition of unbound plasma dabigatran levels. The study reported that idarucizumab was well tolerated under all conditions tested and that the administration of 5 g or 2x2.5 g led to sustained reversal of dabigatran induced anticoagulation in male and female subjects of different age and renal function. Authors concluded that results supported the use of an effective total dose of 5 g in further clinical testing.

7.3 Andexanet-alfa:

The only specific reversal drug for FXa-inhibitors, Andexanet alfa was granted FDA approval in 2018. [20] Andexanet is a modified recombinant FXa inactive molecule, that is, a decoy FXa protein to which FXa-inhibitors will bind but takes no part in the coagulation cas-cade (22). In this manner andexanet sequesters FXa-inhibitors and prevents them from bind-ing to FXa.

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10 Andexanet-alfa is indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. (23)

Andexanet-alfa is administered intravenously following two possible regimens, “High-dose” and “Low “High-dose” depending on the individual FXa-inhibitor to be reversed, its dosage and time of last dose. Detailed descriptions of each regimen and guidelines for regiment elec-tion are presented in Table 1. and Table 2.

Table 1. Dosage regimens for andexanet-alfa

Dose Initial IV bolus Follow-on IV infu-_sion Low dose 400mg at a target rate _{of 30mg/min} 4mg/min for up to 120 _minutes. High dose 800 mg at a target

rate of 30mg/min

8 mg/min for up to 120 minutes.

(Extracted from the FDA package insert for AndexXa™)

Table 2. Criteria for andexanet-alfa regimen selection FXa-inhibitor FXa-inhibitor last

dose

<8 hours or

un-known >= 8 hours

Rivaroxaban <= 10 mg Low dose

Low dose > 10 mg or unknown High dose

Apixaban <= 5 mg Low dose

> 5mg or unknown High dose

(Extracted from the FDA package insert for AndexXa™)

In vivo trials on healthy volunteers:

In a phase II trial (24) 54 healthy volunteers were recruited and dosed with 5mg apix-aban b.i.d for 6 days. Patients were randomly assigned to six cohorts receiving incremental doses of andexanet or placebo. Andexanet was found to rapidly (≤2 minutes) reduce the un-bound apixaban concentration when compared to placebo (51%-89% vs. 5%), decreased anti-FXa activity (67.8%-95.0% vs. 7.1%), and restored thrombin generation in 67%-100% vs. 6% of subjects. All values changed in a dose-dependent manner. After treatment with andex-anet, anti-FXa activity returned to placebo levels after 1-2.5 hours in cohorts 1 to 3 (90mg, 210mg and 420mg) and after 3.3-4.3 hours in cohorts 4-6 (420mg + 4mg/min for 45 min, 420mg+180mg and 420g+4g/min for 2 hours). A similar phase II (25) trial in which patients were previously administered apixaban, rivaroxaban or enoxaparin also found that andexanet

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11 reversed the anti-FXa activity for every FXa inhibitor and restored thrombin generation values. Andexanet was found to be well tolerated in both phase II trials with no thrombotic events or adverse events beyond mild to moderate infusion reactions.

Two further trials (ANNEXA-A and ANNEXA-R) (26) studied the effectivity of andex-anet for reversal of apixaban or rivaroxaban, respectively. Participants included healthy men and women 50 to 75 years old. Volunteers who had a history of abnormal bleeding or throm-bosis, active bleeding, adult asthma, used inhaled medications, or had risk factors for bleed-ing or thrombosis were excluded.

Patients in the ANNEXA-A study received 5mg of apixaban b.i.d for 3.5 days and pa-tients in the ANNEXA-R study received 20mg of rivaroxaban q.d for 4 days. ANNEXA-A par-ticipants were administered andexanet as a 400-mg intravenous bolus (30 mg per minute) or a 400-mg IV bolus followed by a continuous infusion of 4 mg per minute for 120 minutes. ANNEXA-R subjects received andexanet as an 800-mg intravenous bolus (30 mg per minute) or as an 800-mg intravenous bolus followed by a continuous infusion of 8 mg per minute for 120 minutes. The primary outcome in both studies was the percentage of reduc-tion in anti-FXa activity from baseline to 2-5min after treatment or placebo. Secondary out-comes included the number of participants with >80% reduction in anti-fXa activity from base-line to 2-5 minutes, change in free factor Xa inhibitor concentration from basebase-line to 2-5 minutes, changes in thrombin generation, and number of participants with thrombin genera-tion above the lower limit of normal range. Among the apixaban-treated subjects, anti–factor Xa activity was reduced by 94% (vs. 21% with placebo), and un-bound apixaban concentra-tion was reduced by 9.3 ng/ml (vs. 1.9 ng/ml with placebo); thrombin generaconcentra-tion was fully re-stored in 100% (vs. 11% with placebo) of the participants within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti–factor Xa activity was reduced by 92% (vs. 10% with placebo) in those who received an andexanet bolus, and unbound rivaroxaban concentration was reduced by 23.4 ng/ml (vs. 4.2ng/ml); thrombin generation was fully restored in 96% (versus 7% with placebo) of the participants. All participants had a >80% reduction in anti-FXa activity. The effects were sustained for the duration of the infusion in all cases andex-anet was administered as a bolus plus an infusion. In a subgroup of participants transient in-creases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which re-solved within 24 to 72 hours, but levels normalized within 24-72h. No serious adverse or thrombotic events were reported.

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7.4 Prothrombin complex concentrates:

PCCs are preparates derived from plasma that contain high concentrations of vita-min-K dependant coagulation factors. Three kinds exist: 3 factor (3F-PCC), containing factors II, IX and X; 4 factor (4F-PCC), containing factors II, VII, IX and X along with varying amounts of proteins C and S and activated PCC (aPCC) which contains activated factor VII along with factors II, IX, and X.

3F and 4F PCCs are indicated for the urgent reversal of coagulation factor deficiency induced by VKA therapy in adult patients with acute major bleeding, while aPCC is indicated in the control of bleeding, preoperative management and general prophylaxis in haemophilia A and B patients with inhibitors. Nevertheless these agents have seen off-label use as DOAC reversal agents. The reason for this is presumed to be the limited accessibility to specific-agents due to their novelty and/or elevated price.

The approved PCC doses for VKA reversal range from 25 to 50 IU/kg, varying on the pre-treatment INR levels. There is no approved dose for DOAC reversal. Included studies propose 25-50 IU/Kg or 2000 IU administered as a continuous infusion.

Trials on healthy volunteers:

One study, conducted by Eerenberg et al. (27) examined the effectivity of 4F-PCC in 12 healthy volunteers that received either rivaroxaban 20 mg b.i.d or dabigatran 120 mg b.i.d for 2.5 days, followed by a single bolus of 50 IU/kg or saline. After eleven days the procedure was repeated changing the DOAC agent for each cohort. Changes in ETP values, ECT, aPTT and thrombin time (TT) from baseline to after PCC administration were used to assess reversal. ETP was suppressed by rivaroxaban (29-73%) followed by normalisation with PCC (88-140%), while saline had no effect. Dabigatran increased the aPTT, ECT, and TT; but administration of PCC did not restore their values.

Similar studies were conducted by Nagalla et al. (28) and Zahir et al. (29) in 12 healthy apixaban treated and 110 edoxaban treated volunteers. Nagalla et al. found that peak thrombin generation was 76% higher at 30 min post-infusion with 25 U/kg 4F‐PCC, but found no differences in anti-FXa activity levels between 4F-PCC and placebo. Zahir et al. found that 4F-PCC dose-dependently reversed the effects of edoxaban, with complete rever-sal of ETP and partial reverrever-sal of prothrombin time following 50 IU/kg.

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13 On a parallel-group study by Levi et al (30), 35 healthy volunteers received rivaroxa-ban 20 mg b.i.d during 4 days, and were then randomized to receive a single 50 IU/kg bolus dose of 4F-PCC, 3F-PCC or saline, 4 h after the last dose of rivaroxaban. The effects of the-se interventions on PT and ETP were measured. The study found that in 30 min, 4F-PCC reduced mean PT by 2.5-3.5 s, whereas 3F-PCC PCC produced only a 0.6-1.0-s reduction. However, 3F-PCC reversed changes in thrombin generation more than 4F-PCC.

8. METHODS

8.1 Research question

The question was formulated following the Population, Intervention, Control, Out-come (PICO) format. The research question is illustrated in Table 3.

Table 3. Research question, PICO format.

Population DOAC receiving patients requiring emergent anticoagulation reversal.

Intervention Reversal of anticoagulation with direct reversal _agents.

Comparison intervention Reversal of anticoagulation with indirect rever-sal agents.

Outcome

(1)Reversal of anticoagulation, (2)Death (3)Thrombotic events

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8.2 Search strategy

A systematic literature search was conducted on the MEDLINE electronical database through PubMed, using combinations of the following keywords: Direct oral anticoagulant, novel oral anticoagulant, non-vitamin K oral anticoagulants, DOAC, NOAC, dabigatran, riva-roxaban, apixaban, edoxaban, reversal, bleeding, haemorrhage, procedure, idarucizumab, andexanet-alfa, adexanet, prothrombin complex concentrate, activated, PCC, 4F-PCC, 3F-PCC, aPCC

The search was limited to publications written in English between the years 2010 and 2020. Systematic literature reviews, meta-analyses, opinion articles and letters were all ex-cluded from the search through the PubMed filter tools.

8.3 Study selection

The goal of this search was to identify studies on real patients treated with acute re-versal therapy of DOAC anticoagulation. Inclusion and exclusion criteria are presented in Ta-ble 4.

Table 4. Inclusion criteria

Inclusion criteria

Randomized controlled trials, non-randomized controlled trials or observational studies.

Availability of type and dose of DOAC. Availability of type and dose of reversal agent. Clinical outcome measures for anticoagulation reversal,

death and thrombotic events.

Excluded were: Reviews, meta-analyses, publication formats not providing original data, studies not reporting type and dosage of DOAC or reversal agents and studies not re-porting the aforementioned outcomes of interest.

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15 Search results were evaluated and selected following the PRISMA 2009 Flow Dia-gram. In a first screening, duplicates and updates on the same study were removed. On the second-level screening, title and/or abstract of the articles were assessed for eligibility ac-cording the inclusion criteria. At last, adequacy of the full-text studies was evaluated paying attention to all characteristics that may determine their incorporation or omission from the re-view.

8.4 Data extraction

The study type, year of publication, subject characteristics (n, indication for anticoag-ulation, indication for anticoagulation reversal), DOAC treatment, reversal agents (and dos-age), follow up time, rates of clinical reversal, thromboembolic events and death were ex-tracted. In addition, significant results of laboratory measures of anticoagulation reversal were also extracted if present.

Anticoagulation reversal was defined as in the original studies, including bleeding cessation, arrested haematoma expansion seen in computerized tomography (CT), stabiliza-tion of the clinical condistabiliza-tion and evaluastabiliza-tion of periprocedural haemostasis by the treating cli-nician.

8.5 Data synthesis

Participants were categorized in four groups according to the received anticoagulant and reversal agent: DTI-specific, DTI-indirect, FxaI-specific and FxaI-indirect; and the pooled incidences of the relevant outcomes (reversal, thrombosis and death) were calculated along their 95% confidence interval (CI).

Fisher's test was used to compare the outcome incidences of both interventions for each DOAC class (DTI-specific vs. DTI-indirect and FxaI-specific vs. FxaI-indirect). Two sid-ed P < .05 was considersid-ed statistically significant.

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8.6 Risk-of-bias assessment:

Risk of bias was assessed using a tool developed and by Tornkvist et al. for the as-sessment of observational studies in a similar review. The tool is comprised of a series of 19 checkpoints that evaluate possible sources of bias. The tool calls for inter-reviewer agree-ment to rate studies as having a high, moderate or low risk of bias.

Since this review is authored by a single person and classification would be arbitrary, it has not been made.

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9. RESULTS

9.1 Study selection:

A total of 334 articles, published in the previous ten years were identified. First 5 du-plicates were removed. After assessment of the publications’ titles and abstracts, 311 did not meet the inclusion criteria. 18 studies underwent full-text assessment, of which 9 further stud-ies were excluded. 9 studstud-ies were finally selected for systematic review. The study selection process is illustrated in Figure 1. for the PRISMA flowchart.

Fig. 1 PRISMA flowchart for study selection. Records identified through

database searching (n = 334)

Additional records identified through other sources

(n = 0)

Records after duplicates removed (n = 329)

Records screened (n =329)

Records excluded (n =311)

Full-text articles assessed for eligibility

(n = 18)

Full-text articles excluded (n=9)

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9.2 Study characteristics:

The studies that met the inclusion criteria were all uncontrolled observational cohort studies, 6 prospective and 3 retrospective.

All studies included DOAC patients requiring anticoagulation reversal due to major or life threatening bleeding, while only three (31; 32; 33) included patients in need of reversal for an emergent procedure. One study (34) only included patients presenting with intracranial haemorrhage (ICH). Six studies (35; 32; 36; 37; 38; 34) excluded patients that had received fresh frozen plasma or other prohaemostatic agents apart from the investigated treatment. 5 studies excluded patients who had a history of acute coronary syndrome or ischaemic stroke. (35; 36; 32; 37; 38)

In addition to the clinical effectivity and safety, three studies´ (32; 31; 36) outcomes included laboratory evaluations of anticoagulation reversal.

Schenk et al. (32) examined the difference in the thrombin generation (TG) parame-ters endogenous thrombin potential (ETP) and peak thrombin generation (Cmax) between the

baseline and 10 minutes after PCC administration (primary outcome); and the evolution of coagulation parameters and single coagulation factor profiles from baseline to 30 days.

Conolly et al (36) measured anti-factor Xa activity at baseline and after end of an-dexanet administration.

Pollack et al. (31) assessed the maximum percentage of reversal of dabigatran, by measuring changes in ECT, dTT and unbound plasma dabigatran at 4h after end of the last idarucizumab infusion. ECT and DTT were chosen as a measure of reversal because they correlate linearly with unbound dabigatran concentrations. (39; 40)

Characteristics of the selected studies along with their incidences of clinical out-comes are summarized in Table 5.

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Table 5. Study characteristics

Author (year) Study type Participants DOAC Reversal _agent Follow _up Reversal, _{(95% CI)} TE Death

Majeed et al. (2017) (37) Observational prospective multicentre 84 Apixaban (n=39) PCC _days30 _(58-78.7)69% 2.4% (0.3-8.3) 32.1% (22.4-43.2) Rivaroxaban (n=45) Schenk et al. (2018) (34) Observational prospective single-centre

14 Rivaroxaban PCC (Beri-_plex®) _days30 78.6% (49.2-95.3) 0% 21.4% (4.7-50.8) Schulman et al. (2018) (39) Observational prospective multicentre 66 Apixaban (n=29) PCC 30 days 68.2% (55.6-79.1) 9% (3.4-18.7) 12.1% (5.4-22.5) Rivaroxaban (n=37) (Beriplex® and Octa-plex®) Schulman et al. (2017) (40) Observational prospective multicentre 14 Dabigatran aPCC 30 days 64.3% (35.1-87.2) 0% 7.1% (2-33.9) (FEIBA NF®) Arachchillage et al. (2018) (43) Observational retrospective single-centre 344 Rivaroxaban (n=40) PCC N/A _(62.7-83)73.7% 3.7% (1-10.6) 32.5% (22.4-43.9) Apixaban (n=40) Warfarin (n=264) Tao et al. (2018) (35) Observational retrospective single-centre 43 Rivaroxaban (n=21) 4F-PCC N/A 93% (80.9-98.5) 2.3% (0.1-12.3) 4.6% (0.6-15.8) Apixaban (n=22) (Kcentra®) Harrison et al. (2018) (36) Observational retrospective multicentre 42 Rivaroxaban 4F-PCC N/A 92.8% (66.1-99.8) 0% 14.2% (1.8-42.8) Apixaban V Warfarin (n=28) Conolly et al. (2019) (38) Observational prospective multicentre 352 Rivaroxaban (n=128) Andexanet-alfa days 30 81.7% (76.1-86.5) 9.6% (6.8-13.2) 13.9% (10.5-18) Apixaban (n=194) Edoxaban (n=10) Enoxaparin (n=20) Pollack et al. (2017) (33) Observational prospective multicentre

503 Dabigatran Idarucizumab _days30 79.5% (75.2-83.4) 6.8% (4.7-9.3) 12.9% (10.1-16.2)

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9.3 Study subjects:

The selected studies enrolled 1462 participants. 1150 (79%) were anticoagulated with a DOAC, 292 (20%) received warfarin and 20 (1%) enoxaparin. All warfarin patients were excluded from the review. The only study in which the reversal agent was andexanet-alfa reported its safety outcomes pooled for 352 patients treated with FXa-inhibitors, 20 of them with enoxaparin, which is not a DOAC. The author decided their inclusion into the safe-ty population to avoid exclusion of the whole cohort.

The primary outcome (reversal) was evaluated for 945/1150 DOAC patients (efficacy population). The haemorrhage could not be visualized in 195 patients, making their clinical evaluation impossible and Conolly et al. did not report clinical evaluation of reversal for 10 edoxaban-treated patients. Safety outcomes (thromboembolism, death) were evaluated for all 1150 DOAC patients plus 20 enoxaparin patients (safety population).

The most commonly used DOAC was dabigatran (517/1150, 45%), followed by apix-aban (324/1150, 28%), rivaroxapix-aban (285/1150, 25%) and edoxapix-aban (10/1150, <1%).The in-dividual drug was not specified for 14 (1%) patients receiving apixaban or rivaroxaban.

The indications for DOAC use were AF in 996/1150 patients (86%), VTE in 103/1150 (9%), both in 8/1150 (<1%), a previous stroke in 14/1150 (1%) and recent orthopaedic sur-gery in 3 (<1%). Indications were listed as “other” in 26/1150 (2%) patients and were not rec-orded in 14 (1%).

The most frequent indication for reversal was uncontrolled, life threatening or major bleeding (948, 82%), followed by “surgery or other invasive procedure that could not be de-layed for at least 8h and for which normal haemostasis was required” (202, 18%). Specific bleeding sites, by location and study are presented in Table 6.

Treatments [dose] for DOAC reversal included Idarucizumab [5g] (503, 44%), andex-anet-alfa (400mg + 480mg infusion or 800mg + 960mg infusion) (352, 31%), PCC (1500-2000U or 25 U/kg or 50 U/kg) (301, 26%) and aPCC (14, 1%).

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Table 6. Bleeding locations by study

9.4 Pooled cohort outcomes:

Of the 945 patients in the efficacy population, reversal was achieved in 740 (78.3%, 95% CI: 75-80). Among the patients anticoagulated with DTIs, reversal was achieved in 79.5% (95% CI: 75.2-83.4) of those treated with idarucizumab (318/400) and in 64.3% (95% CI: 35.1-87.2) of those treated with aPCC (9/14), P =.1836. For patients receiving FXa-inhibitors, reversal was achieved in 81.7% (95% CI: 76.1-86.5) of those treated with andexanet-alfa (188/230) and in 74.8% (95% CI: 69.4-79.6) of those treated with PCC (225/301), P=.058.

A thromboembolic event was reported in 80 of the 1170 patients in the safety popula-tion (6.8%, 95% CI: 5.5-8.4). 6.75% (95% CI: 4.7-9.3) of patients on the DTI-specific group suffered a thromboembolic event (34/503) while none of the fourteen patients on the DTI-indirect group suffered one, P=.61. On the FXaI-specific group, 9.65% (95% CI: 6.8-13.2) (34/352) of patients suffered an embolic event while the rate was 3.98% (95% CI: 2.1-6.9) for the FXa-indirect group (12/301), P=.0054

12.9% (95% CI: 10.1-16.2) (65/503) of the patients on the DTI-specific group died during follow up compared to 7.1% (95% CI: 2-33.9) (1/14) of the patients on the DTI-indirect group, P=1. On the FXaI-specific group 13.9% (95% CI: 10.5-18) of the patients died (49/352), while 22.59% (95% CI: 18-27.7) of the patients on the FXaI-indirect group died (68/301), P=.0042

Pooled outcomes are presented in Table 7.

Study ICH, n GI, n Visceral, nGenitourinary, n ME, n Traumatic, n Retroperitoneal, n Other, n Not identified, n

Majeed et al. (37) 59 13 5 4 3 0 0 0 0 Schenk et al. (34) 10 1 1 1 0 0 0 0 0 Pollack et al. (33) 98 137 7 0 14 78 10 53 4 Conolly et al. (38) 227 90 0 0 0 0 0 0 0 Arachchillage et al. (43) 46 24 6 1 3 0 0 0 0 Schulman et al. (2017) (40) 5 5 1 0 3 0 0 0 0 Schulman et al. (2018) (39) 36 16 3 0 2 25 3 7 0 Harrison et al. (36) 14 0 0 0 0 0 0 0 0 Tao et al. (35) 16 17 0 0 0 5 0 5 0 Total 511 303 23 6 25 108 13 65 4

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22 Table 7. Outcome incidences by intervention group

Intervention group Efficacy population, n Reversal incidence, (95% CI) Safety population, n Thrombosis incidence, (95% CI) Death incidence, (95% CI) DTI/specific 400 _(75.2-83.4)79.5% 503 _(4.7-9.3)6.75% _(10.1-16.2)12.9% DTI/indirect 14 _(35.1-87.2)64.3% 14 0 _(2-33.9)7.1% FXa-inhibitor/specific 230 (76.1-86.5) 81.7% 352 (6.8-13.2) 9.65% (10.5-18) 13.9% FXa-inhibitor/indirect 301 (69.4-79.6) 74.8% 301 (2.1-6.9) 3.98% (18-27.7) 22.59%

9.5 Laboratory assessments of reversal:

Schenk et al. (32) reported that mean ETP increased by 68% as a result of admin-istration of PCC. Peak thrombin generation (Cmax) increased by 54%. Maximum clot firmness

(MCF) decreased by 3% (p =0.019) and remained significantly decreased until one hour after PCC administration. CT was significantly decreased only after 6 hours. Evaluation of coagu-lation status following the administration of PCC showed significant increase in PT (28%) and a significant decrease of 7% in aPTT. The coagulation factor assays showed an increase in activation of all coagulation factors contained in PCC (II, VII, IX, X).

Pollack et al. (31) found that DCT or ECT returned to normal values in 98% of the pa-tients after 4 hours of idarucizumab administration. Median baseline unbound dabigatran was 110 ng/ml for patients presenting with uncontrolled bleeding and 73.6 ng/ml for patients re-quiring emergent surgery. After 4h of idarucizumab administration, unbound dabigatran con-centrations were <20 ng/ml for all patients.

Conolly et al. (36) reported that after two hours of andexanet administration median anti-FXa activity decreased from 149.7 ng/ml to 11.1 ng/ml in patients receiving apixaban and from 211.8 ng/ml to 14.2 ng/ml in patients receiving rivaroxaban.

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23

10. DISCUSSION:

This review was planned to gather real patient data regarding the effectivity and safe-ty of specific antidotes and non-specific prohaemostatic agents, aiming to compare both ap-proaches to emergent DOAC reversal. All selected studies were uncontrolled observational studies, six prospective and three retrospective, with cohort sizes ranging from 14 to 503. No RCTs that met the inclusion criteria were found in the search. A naïve-indirect comparison was then performed with the pooled cohort data.

Laboratory assessments of effectivity in patients indicate that a total dose of 5g of idarucizumab reduces the anticoagulant action of dabigatran rapidly and durably, and that administration of andexanet-alfa as per the FDA guidelines reduces anti-FXa activity to non-significant levels for as long as the infusion is continued, in rivaroxaban or apixaban treated patients. PCCs showed to significantly restore the ETP and Cmax in 14 rivaroxaban treated

patients. The correlation between the laboratory measures of reversal and clinical outcomes was not investigated by the authors.

The comparison of the pooled cohort data concluded that incidence of thromboem-bolic events was higher in patients receiving andexanet-alfa versus PCCs for FXa-inhibitor reversal, 9.65% (95% CI: 6.8-13.2) versus 3.98% (95% CI: 2.1-6.9) respectively (P=.0054) and that all-cause mortality during follow-up was lower for patients treated with andexanet-alfa (13.9%, 95% CI: 10.5-18) than in those treated with PCC (22.59%, 95% CI: 18-27.7) (P=.0042). Other differences in outcome rates were deemed to be of no statistical signifi-cance.

Great caution must be exercised in the interpretation of these pooled cohort results, which just represent a vague trend in the existing literature. The reviewed studies are differ-ent types, have differdiffer-ent inclusion-exclusion criteria, populations, intervdiffer-entions and outcome assessment methods. The pooling of data was performed disregarding individual study strength and statistical heterogeneity. This means that the pooling of data performed is inap-propriate and should not be considered a proper meta-analysis. The author decided in favor of its performance only to get a general idea of reversal and safety outcomes in clinical prac-tice.

The absence of RCTs is a major limiting factor in the level of evidence available to guide clin-ical practice. Observational studies are inherently subject to a high risk of bias due to their

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24 lack of placebo-control, and their prospective/retrospective recruitment of subjects leads to samples that do not necessarily reflect the characteristics of the population of interest.

Interpretation of clinical outcome rates is tricky in cohorts in which the patients have such a high degree of clinical heterogeneity; the question is raised: To which degree are the obtained rates of clinical outcomes a result of the used reversal agents, and to which degree are they a result of the characteristics of the patients in the sample? Randomized, placebo controlled trials evaluating the outcomes among patients with similar bleeding locations or surgical requirements are needed to get an accurate answer. Other characteristics, patholo-gies, and lifestyle factors that could affect the outcomes should also be accounted for.

The lack of RCTs most likely stems from the negative ethical implications of assign-ing critical patients to placebo when a treatment is available. RCTs performassign-ing a head to head comparison of specific and indirect reversal agents in separate intervention arms could be an appropriate way to approach this problem in the future.

Based on the existing literature, the north American Anticoagulation Forum released a series of statements to guide clinical providers in the subject of DOAC reversal. These statements support the use of 5g IV of idarucizumab as first line treatment of dabigatran as-sociated major bleeding or pre-procedural reversal; and andexanet-alfa (following FDA ap-proved dosage) for the reversal of FXa-inhibitor associated major bleeding and pre-procedural reversal (including off-label use for edoxaban and betrixaban with “high-dose” reg-imens.)

In the case of not having access to direct antidotes, the statements support the use of IV aPCC 50 U/kg for treatment of dabigatran-associated major bleeding and pre-procedural reversal and 2000 U IV PCC for FXa-inhibitor reversal.

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25

11. CONCLUSIONS

1. Idarucizumab and andexanet-alfa effectively and safely reverse the pharmacological ac-tion of direct oral anti-coagulants.

2. PCCs are capable to restore some degree of endogenous thrombin generation in FXa-inhibitor-treated patients.

3. The correlation between the reversal of DOAC action and clinical outcomes is unclear, and difficult to assess.

4. The available body of literature is limited by it its heterogeneity and ethical limitations in-herent to the field of study.

5. Further research is needed in the form of randomized controlled trials to ascertain the su-periority of direct agents over prohaemostatic agents in the clinical practice.

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26

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27 16. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral

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28 31. Pollack C, Reilly P, van Ryn J, Eikelbloom J. Idarucizumab for dabigatran reversal - Full cohort analysis. s.l. : N Engl J Med, 2017, Vol. 377:5.

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29

ANNEX 1

Table 8. Results of risk of bias assessment

Pol-lack et al. Conol ly et al. Majee d et al. Sche nk et al. Arachchil-lage et al. Schul-man et al. Schul-man et al. Ta o et al. Harri-son et al.

Was the study population well

de-fined? Y Y Y Y Y Y Y Y Y

Were the study subjects

prospective-ly recruited? Y Y Y Y N Y Y N N

Well defined inclusion/exclusion

crite-ria? Y Y Y Y Y Y Y Y Y

Were the study subjects recruited from different geographical

loca-tions?

Y Y Y N N Y Y N Y

Were the outcome impervious to

detection bias? N N N N N N N N N

Were the outcome evaluators blinded

to the study subject groups? N N N N N N N N N Were the outcome evaluators

impar-tial? N N N N N N N N N

Was the outcome defined in a

appro-priate manner? Y Y Y Y Y Y Y Y Y

Was the outcome measured in a adequate way with standardized

methods?

Y Y Y Y N Y Y N N

Was the outcome measured with

validated methods? N N N N N N N N N Was the outcome measured in

opti-mal time frames? Y Y Y Y Y Y Y Y Y Was the attrition satisfyingly low in

relation to the size of the study popu-lation?

Y Y Y Y Y Y Y Y Y

Were the statistical management of

the attritions adequate? Y Y Y Y Y Y Y Y Y Did the study follow a predefined

protocol? Y Y Y Y Y Y Y Y Y

Were the outcomes relevant? Y Y Y Y Y Y Y Y Y Were complications measured

sys-tematically? Y Y Y Y Y Y Y Y Y

Based on the writers declared con-flicts of interest, does a low or absent

risk of bias exist?

N N N Y N N N Y NR

Based on the financing of the study, does a low on absent risk of bias exist regarding economical interests?

N N Y Y Y N N Y Y

Is a low or absent risk of any other conflict of interest existing (e.g. the writers have developed the

interven-tion of the study)?

Y Y Y Y Y Y Y Y Y

Y: Yes N: No NR: Not reported

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Specific antagonists versus indirect prohaemostatic agents for the reversal of direct oral anticoagulants.