Andexanet alfa effectiveness and safety versus four-factor prothrombin complex concentrate (4F-PCC) in intracranial hemorrhage while on apixaban or rivaroxaban: A single-center, retrospective, matched cohort analysis

Parsels, Katie A; Seabury, Robert W.; Zyck, Stephanie; Miller, Christopher D.; Krishnamurthy, Satish; Darko, William; Probst, Luke A.; Latorre, Julius Gene; Cwikla, Gregory M.; Feldman, Elizabeth A.

doi:10.1016/j.ajem.2022.02.036

Cited by 20 publications

(31 citation statements)

References 4 publications

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“…Several other smaller studies have shown the use of 4F-PCCs as a viable reversal option for DOAC-related ICH for anticoagulation reversal (reversal rates, 54.5%-94.7%) and safety (mortality rates, 4.7%-63.6%; thrombotic event rate, 0%-17.2%). 8 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 Albeit with significant heterogeneity, our meta-analysis found a combined proportion of anticoagulation reversed of 77%, a mortality rate of 26%, and a thromboembolic event rate of 8% ( Figures 1 - 3 ).…”

Section: Discussionmentioning

confidence: 72%

“…Thirty-six studies were included in the meta-analysis (eAppendix 1 in the Supplement ). Twenty-two studies with 967 participants evaluated 4F-PCC for reversal 8 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ; 17 studies with 525 participants evaluated AA 13 , 35 , 36 , 37 , 39 , 40 , 41 , 42 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ; and 5 studies with 340 participants evaluated idarucizumab, 12 , 53 , 54 , 55 , 56 consisting of a total of 1832 patients with ICH while receiving treatment with a DOAC. Eight studies had data on more than 1 agent.…”

Section: Resultsmentioning

confidence: 99%

“…Eight studies had data on more than 1 agent. 35 , 36 , 37 , 39 , 40 , 41 , 42 , 44 The characteristics of the studies are in the Table and eAppendix 3 in the Supplement .…”

Section: Resultsmentioning

confidence: 99%

“…After the exclusion of these 2 studies, the data on the comparison of 4F-PCC and AA were derived from 8 retrospective studies. 35 , 36 , 37 , 39 , 40 , 41 , 42 , 44 We found that 4F-PCC had a comparable proportion of successful anticoagulation reversal (RR, 0.95; 95% CI, 0.85-1.06; I 2 = 0%; 95% CI, 0%-75%), proportional mortality (RR, 1.40; 95% CI, 0.68-2.86; I 2 = 65%; 95% CI, 17%-86%), and thromboembolic event rate (RR, 0.89; 95% CI, 0.36-2.21, I 2 = 0%; 95% CI, 0%-79%) when used for the reversal of FXaI in patients with ICH ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…ANNEXA-4 was a multicentered, prospective study 13 that enrolled 171 patients with FXaI-associated ICH and reported an anticoagulation reversal rate of 80.7%, a mortality rate of 14%, and a thromboembolic complication rate of 10%. Since then, multiple small retrospective studies in patients with ICH 13 , 35 , 36 , 37 , 39 , 40 , 41 , 42 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 52 have reported rates of anticoagulation reversal between 50% and 91%; mortality, between 9% and 39%; and thrombotic complications, between 0% and 31%. Our meta-analysis showed a combined proportion of anticoagulation reversal of 75%, a mortality rate of 24%, and thromboembolic event rate of 14% ( Figures 1 - 3 ).…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage

et al. 2022

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ImportanceDirect oral anticoagulant (DOAC)–associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited.ObjectiveTo evaluate the safety and outcomes of DOAC reversal agents among patients with ICH.Data SourcesPubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022.Study SelectionThe eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded.Data Extraction and SynthesisPreferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model.Main Outcomes and MeasuresThe primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent.ResultsA total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events.Conclusions and RelevanceIn the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.

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Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

“…Eight studies had data on more than 1 agent. 35 , 36 , 37 , 39 , 40 , 41 , 42 , 44 The characteristics of the studies are in the Table and eAppendix 3 in the Supplement .…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage

et al. 2022

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Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: A systematic review with meta‐analysis

White,

Caroti,

Bessada

et al. 2024

Pharmacotherapy

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Previous meta‐analyses assessed andexanet alfa (AA) or prothrombin complex concentrate (PCC) products for the treatment of Factor Xa inhibitor (FXaI)‐associated major bleeding. However, they did not include recent studies or assess the impact of the risk of bias. We conducted a systematic review with meta‐analysis on the effectiveness of AA versus PCC products for FXaI‐associated major bleeding, inclusive of the studies' risk of bias. PubMed and Embase were searched for comparative studies assessing major bleeding in patients using FXaI who received AA or PCC. We used the Methodological Index for NOn‐Randomized Studies (MINORS) checklist and one question from the Joanna Briggs Institute (JBI) Critical Appraisal of Case Series tool to assess the risk of bias. Random‐effects meta‐analyses were performed to provide a pooled estimate for the effect of AA versus PCC products on hemostatic efficacy, in‐hospital mortality, 30‐day mortality, and thrombotic events. Low–moderate risk of bias studies were meta‐analyzed separately, as well as combined with high risk of bias studies. Eighteen comparative evaluations of AA versus PCC were identified. Twenty‐eight percent of the studies (n = 5) had low–moderate risk and 72% (n = 13) had a high risk of bias. Studies with low–moderate risk of bias suggested improvements in hemostatic efficacy [Odds Ratio (OR) 2.72 (95% Confidence Interval (CI): 1.15–6.44); one study], lower in‐hospital mortality [OR 0.48 (95% CI: 0.38–0.61); three studies], and reduced 30‐day mortality [OR 0.49 (95% CI: 0.30–0.80); two studies] when AA was used versus PCC products. When studies were included regardless of the risk of bias, pooled effects showed improvements in hemostatic efficacy [OR 1.36 (95% CI: 1.01–1.84); 12 studies] and reductions in 30‐day mortality [OR 0.53 (95% CI: 0.37–0.76); six studies] for AA versus PCC. The difference in thrombotic events with AA versus PCC was not statistically significant in the low–moderate, high, or combined risk of bias groups. The evidence from low–moderate quality real‐world studies suggests that AA is superior to PCC in enhancing hemostatic efficacy and reducing in‐hospital and 30‐day mortality. When studies are assessed regardless of the risk of bias, the pooled hemostatic efficacy and 30‐day mortality risk remain significantly better with AA versus PCC.

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Efficacy and Safety of Andexanet Alfa Versus Four Factor Prothrombin Complex Concentrate for Emergent Reversal of Factor Xa Inhibitor Associated Intracranial Hemorrhage: A Systematic Review and Meta-Analysis

Sarhan,

Mohamed,

Elmahdi

et al. 2024

Neurocrit Care

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Factor Xa inhibitors (FXaI) are increasingly used for anticoagulation therapy, yet their association with intracranial hemorrhage poses a significant challenge. Although andexanet alfa (AA) and four-factor prothrombin complex concentrate (4F-PCC) have shown promise in reversing FXaI effects, their comparative efficacy and safety remain uncertain. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a literature search on electronic databases to obtain the relevant studies until May 16, 2024. Our primary outcomes were successful anticoagulation reversal, overall mortality (including 30-day and in-hospital mortality), and thromboembolic events. Secondary outcomes were length of hospital and intensive care unit stay and hematoma volume expansion. Data were pooled using a random-effects model. We included 16 eligible studies with a total of 2,977 patients. A statistically significant improvement in hemostatic efficacy rates was in favor of the AA group (risk ratio [RR] 1.10, 95% confidence interval [CI] 1.01–1.20, P = 0.02). Lower overall mortality rates were found in the AA group (RR 0.67, 95% CI 0.51–0.88, P = 0.004). However, no difference was found in 30-day mortality rates (RR 0.82, 95% CI 0.58–1.16, P = 0.26). In terms of thromboembolic events, more events were found in the AA group (RR 1.47, 95% CI 1.01–2.15, P = 0.046). AA was associated with a longer duration of hospital stay compared to 4F-PCC (mean difference [MD] 0.64, 95% CI 0.07–1.22, P = 0.03). Neither a significant difference in length of intensive care unit stay (MD 0.25, 95% CI − 0.36 to 0.86, P = 0.41) nor a significant difference in hematoma volume expansion was reported (MD − 0.89, 95% CI − 3.11 to 1.34, P = 0.435). Our results suggest that AA is superior to 4F-PCC in enhancing the hemostatic efficacy and reducing the overall and in-hospital mortality rates. More thromboembolic events are thought to be associated with the use of AA. However, more studies are required to validate whether the better results of AA in improving hemostatic efficacy are enough to make up for their higher cost and their possible risk of thromboembolic events.

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Andexanet alfa effectiveness and safety versus four-factor prothrombin complex concentrate (4F-PCC) in intracranial hemorrhage while on apixaban or rivaroxaban: A single-center, retrospective, matched cohort analysis

Cited by 20 publications

References 4 publications

Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage

Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage

Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: A systematic review with meta‐analysis

Efficacy and Safety of Andexanet Alfa Versus Four Factor Prothrombin Complex Concentrate for Emergent Reversal of Factor Xa Inhibitor Associated Intracranial Hemorrhage: A Systematic Review and Meta-Analysis

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