From the Departments of Neurology (C.C.C., D.K., N.R., B.B.T., R.N.J., K.L.F., M.R.), Emergency Medicine (T.E.M.), Neurosurgery (B.B.T., M.R.), and Psychiatry (R.N.J.), Brown University, Alpert Medical School, Providence, RI; Icahn School of Medicine at Mount Sinai (R.K.), New York, NY; and Department of Pharmacy (L.M.), Rhode Island Hospital, Providence.
Neurology. 2021 Nov 23;97(21):e2054-e2064. doi: 10.1212/WNL.0000000000012856. Epub 2021 Sep 23.
Andexanet alfa was recently approved as a reversal agent for the factor Xa inhibitors (FXais) apixaban and rivaroxaban, but its impact on long-term outcomes in FXai-associated intracerebral hemorrhage (ICH) is unknown. We aimed to explore potential clinical implications of andexanet alfa in FXai-associated ICH in this simulation study.
We simulated potential downstream implications of andexanet alfa across a range of possible hemostatic effects using data from a single center that treats FXai-associated ICH with prothrombin complex concentrate (PCC). We determined baseline probabilities of inadequate hemostasis across patients taking FXai and those not taking FXai via multivariable regression models and then determined the probabilities of unfavorable 3-month outcome (modified Rankin Scale score 4-6) using models comprising established predictors and each patient's calculated probability of inadequate hemostasis. We applied bootstrapping with model parameters from this derivation cohort to simulate a range of hemostatic improvements and corresponding outcomes and then calculated absolute risk reduction (relative to PCC) and projected number needed to treat (NNT) to prevent 1 unfavorable outcome.
Training models using real-world patients (n = 603 total, 55 on FXai) had good accuracy in predicting inadequate hemostasis (area under the curve [AUC] 0.78) and unfavorable outcome (AUC 0.78). Inadequate hemostasis was strongly associated with unfavorable outcome (odds ratio 4.5, 95% confidence interval [CI] 2.0-9.9) and occurred in 11.4% of patients taking FXai. Across simulated patients taking FXai comparable to those in A Study in Participants With Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study, predicted absolute risk reduction of unfavorable outcome was 4.9% (95% CI 1.3%-7.8%) when the probability of inadequate hemostasis was reduced by 33% and 7.4% (95% CI 2.0%-11.9%) at 50% reduction, translating to projected NNT of 21 (cumulative cost $519,750) and 14 ($346,500), respectively.
Even optimistic simulated hemostatic effects suggest that the costs and potential benefits of andexanet alfa should be carefully considered. Placebo-controlled randomized trials are needed before its use can definitively be recommended.
Andexanet alfa 最近被批准为因子 Xa 抑制剂（FXais）阿哌沙班和利伐沙班的逆转剂，但它对 FXai 相关脑出血（ICH）的长期结果的影响尚不清楚。我们旨在通过一项使用治疗 FXai 相关 ICH 的凝血酶原复合物浓缩物（PCC）的单中心数据，探索 Andexanet alfa 在 FXai 相关 ICH 中的潜在临床意义。
我们通过多变量回归模型确定了接受 FXai 和未接受 FXai 的患者之间的基线止血不足概率，然后使用包含已建立的预测因子和每个患者计算的止血不足概率的模型确定了 3 个月的不良预后（改良 Rankin 量表评分 4-6）的概率。我们使用来自该推导队列的模型参数进行了 bootstrap 模拟，以模拟一系列止血改善和相应的结果，然后计算了绝对风险降低（相对于 PCC）和预防 1 个不良结果所需的治疗人数（NNT）。
使用真实世界患者（共 603 例，55 例服用 FXai）训练模型在预测止血不足（曲线下面积 [AUC] 0.78）和不良预后（AUC 0.78）方面具有良好的准确性。止血不足与不良预后密切相关（比值比 4.5，95%置信区间 [CI] 2.0-9.9），在接受 FXai 的患者中发生率为 11.4%。在模拟的接受 FXai 的患者中，与 ANNEXA-4 研究中的患者类似，当止血不足的概率降低 33%时，不良预后的预测绝对风险降低 4.9%（95%CI 1.3%-7.8%），当降低 50%时，预测绝对风险降低 7.4%（95%CI 2.0%-11.9%），分别相当于预测 NNT 为 21（累计成本 519750 美元）和 14（346500 美元）。
即使是乐观的模拟止血效果也表明，应该仔细考虑 Andexanet alfa 的成本和潜在益处。在其使用能够得到明确推荐之前，需要进行安慰剂对照随机试验。
