利伐沙班用于临床实践的事件发生率较低

新奥尔良——德国卡尔·古斯塔夫·卡鲁斯大学医院的Jan Beyer-Westendorf医生在美国血液病学会(ASH)年会上报告，利伐沙班在真实世界中用于非选择性房颤患者的卒中预防，心血管和大出血事件的发生率相对较低。

前瞻性德累斯顿新口服抗凝剂(NOAC)注册研究显示，在1,194例每日服用利伐沙班(拜瑞妥)的德国萨克森患者中，由中心判定的卒中年发生率为1.4%。

作为美国2011年批准利伐沙班用于该适应证的基础，ROCKET-AF试验显示卒中年发生率为1.7%。在NOAC注册研究中，每年有21.6%的患者发生不明显但具有临床意义的出血，而大出血发生率为3.4%/年。这一发生率也低于ROCKET-AF试验(3.6%/年)和接受维生素K拮抗剂治疗的患者(高达8%)。

作为利伐沙班的已知副作用，消化道出血是最常见的大出血。颅内出血很罕见，仅发生了3例。

12个月时患者对口服Xa因子直接抑制剂的依从率较高(13.7%)，相比之下，有多达25%的患者在第1年内停止维生素K拮抗剂治疗。“在我们的研究队列中停药率仅为14%，所以我们基本上并不担心利伐沙班治疗会将患者置于危险境地。”

根据这篇报告，自2011年10月以来，已有2,345例患者被前瞻性纳入NOAC注册研究。1,194例房颤患者接受抗凝药治疗以预防静脉血栓栓塞(VTE)或卒中。无患者失随访，目前已随访2,313患者-年。

NOAC受试者基线时的年龄略大于ROCKET-AF受试者(74.8岁vs. 73岁)，曾使用维生素K拮抗剂的比例更低(37% vs. 62%)，CHADS2(心力衰竭、高血压、年龄、糖尿病卒中系统)评分更低(平均，2.4 vs. 3.48)。CHADS2评分更高与结局更差相关，包括大出血发生率更高。

在截至2013年10月的随访期间，53例NOAC受试者(4.4%)发生了主要血管事件，包括22例卒中、短暂性脑缺血发作(TIA)、全身性血栓，15例急性冠脉综合征，以及4例VTEs。共有56例患者死亡(4.7%)。

利伐沙班20 mg/d组与15 mg/d组相比，卒中(定义为新发卒中、TIA或全身性血栓)年发生率明显更低(0.9% vs. 2.3%；P=0.052)。

与接受利伐沙班20 mg治疗的患者相比，15 mg组患者具有更高的基线CHADS2评分(平均，2.2 vs. 2.8)，年龄更大(73岁 vs. 79岁)，更可能曾发生过卒中(12.5% vs. 17%)或曾接受过维生素K拮抗剂治疗(36% vs. 40%)，同时服用的药物种数更多(平均，5.4 vs. 6.4)。

“这些患者降服用较低剂量的伐沙班剂量并不令人意外，因为他们有更多的共病，有更高的出血风险，也正因为这样，他们的事件发生率略高。” Beyer-Westendorf医生指出，减少利伐沙班剂量并未降低出血风险。

NOAC注册研究获得了拜耳医疗保健、勃林格殷格翰和辉瑞的支持。Beyer-Westendorf医生报告称研究资金来自这些公司，自己也担任了这些公司的讲者。

详细说明了出血并发症

在本次ASH年会上，Beyer-Westendorf医生还另外报告了NOAC试验中房颤或VTE患者采用利伐沙班、达比加群或阿哌沙班预防卒中的出血并发症特征和处理。

这些并发症是临床医生的主要担忧，原因是基层医院缺乏急诊实验室检查条件或急救药物。

在迄今发生于879例患者的1,241例出血事件中，742例轻微(60%)，425例不明显但具有临床意义(34.2%)，74例为大出血(6%)。

在接受利伐沙班治疗的房颤和VTE患者中，治疗期间大出血年发生率分别为3.4%和4.4%。接受达比加群110 mg和150 mg治疗的房颤患者，大出血事件发生率分别为2.6/100患者-年和2.0/100患者-年。由于接受达比加群和阿哌沙班治疗的患者的随访时间较短、例数较少，无法就事件发生率得出确切结论。Beyer-Westendorf医生强调，由于这些患者来自不同队列，而不是来自同一项随机试验，因此不应当对上述不同类型药物进行事件发生率的比较。

对于多数出血(93.3%)采取严密观察、压迫、填塞或输红细胞等常规方式处理。所有轻微出血和多数(84%，416/499)不明显但具有临床意义的出血不需要手术或干预治疗。很少使用新鲜冻血浆和凝血酶原复合物(各用于7例患者)。没有患者接受重组活化因子Ⅶ治疗。

所有发生出血并发症的患者的死亡率为0.4%，大出血患者的死亡率为6.8%。接受达比加群治疗的患者的出血后30天和90天全因死亡率分别为5.3%(1/19)和17.6%(3/17)，接受利伐沙班治疗者分别为5%(5/99)和6.8%(6/88)，接受阿哌沙班治疗者在这2个时间点的死亡率均为50%(1/2)。接受维生素K拮抗剂治疗的大出血患者，在发生导致住院的出血后90天时死亡率达到14%，房颤患者在出院后1周内的死亡率为18%。

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By: PATRICE WENDLING, Cardiology News Digital Network

NEW ORLEANS – Real-world use of rivaroxaban produced comparatively low rates of cardiovascular and major bleeding events when used for stroke prevention in unselected patients with atrial fibrillation.

The centrally adjudicated annual stroke rate was 1.4% among 1,194 patients given once-daily rivaroxaban (Xarelto) by 230 physicians from private practices and community hospitals across Saxony, Germany, in the prospective Dresden Novel Oral Anticoagulant (NOAC) registry.

This result falls within the annual stroke rate of 1.7% seen in the ROCKET-AF trial, which served as the basis for rivaroxaban’s November 2011 U.S. approval in this setting, Dr. Jan Beyer-Westendorf reported at the annual meeting of the American Society of Hematology.

Nonmajor, clinically relevant bleeding occurred in 21.6% of patients per year in the NOAC registry, while major bleeding was 3.4% per year.
 
Again, this is within the range of the phase III ROCKET-AF results (3.6% per year) and lower than the rate of up to 8% seen in the daily care of patients on vitamin K antagonists, he said. Gastrointestinal bleeding, a known side effect of rivaroxaban, was the most common major bleed. Intracranial bleeds were rare at three events.

Adherence to the oral direct factor Xa inhibitor was high at 12 months (13.7%), compared with up to 25% of patients who discontinue vitamin K antagonist therapy in the first year.

"In our population, the discontinuation rate was 14%, so basically we don’t have any concern that we put these patients at more risk in a daily care situation by treating them with rivaroxaban," said Dr. Beyer-Westendorf of the University Hospital Carl Gustav Carus, Dresden, Germany.

According to the analysis, 2,345 patients have been prospectively enrolled in the NOAC registry since October 2011; 1,194 with atrial fibrillation have been treated with anticoagulation to prevent venous thromboembolism (VTE) or stroke. No patients have been lost to follow-up, which now stands at 2,313 patient-years.

NOAC patients were slightly older at baseline than were those in ROCKET-AF (74.8 years vs. 73 years), less likely to have had prior vitamin K antagonists (37% vs. 62%), and had lower CHADS2 (Cardiac failure, Hypertension, Age, Diabetes Stroke system) scores (mean, 2.4 vs. 3.48). Higher CHADS2 scores are associated with worse outcomes, including higher rates of major bleeding.

During follow-up through October 2013, 53 NOAC patients (4.4%) experienced a major vascular event including 22 strokes, transient ischemic attacks (TIA), systemic emboli; 15 acute coronary syndromes; and four VTEs, he said. In all, 56 patients died (4.7%).

Patients on rivaroxaban 20 mg/day vs. 15 mg/day had a significantly lower annual stroke rate (0.9% vs. 2.3%; P = .052), defined as a new stroke, TIA, or systemic embolism.

Compared with those on rivaroxaban 20 mg, patients on the lower dose had higher baseline CHADS2 scores (mean, 2.8 vs. 2.2), were older (79 years vs. 73 years), more likely to have had a prior stroke (17% vs. 12.5%) or prior vitamin K antagonist therapy (40% vs. 36%), and took more concomitant drugs (mean, 6.4 vs. 5.4).

"It’s no surprise that these patients get a dose reduction because they have more comorbidities; they are at high risk of bleeding, and so it’s not a surprise that they have a slightly higher event rate," said Dr. Beyer-Westendorf, who noted that the lower dose did not reduce the risk of bleeding.

The NOAC registry is supported by scientific grants from Bayer Healthcare, BoehringerIngelheim, and Pfizer. Dr. Beyer-Westendorf reported research funding from and serving as a speaker for these firms.

Bleeding complications detailed

In a separate presentation at ASH, Dr. Beyer-Westendorf detailed the pattern and management of bleeding complications in NOAC patients treated for stroke prevention in atrial fibrillation or VTE with rivaroxaban, dabigatran (Pradaxa), or apixaban (Eliquis).

These complications are a major concern for practitioners because there isn’t an emergency lab test available or rescue medications.

Of the 1,241 bleeding events that have occurred so far in 879 patients, 742 were minor (60%), 425 were nonmajor clinically relevant (34.2%), and 74 were major (6%).

Major bleeds per year of therapy were reported with rivaroxaban in 3.4% of patients with atrial fibrillation and in 4.4% with VTE. The major bleeding event rate with dabigatran in patients with atrial fibrillation was 2.6/100 patient-years at the 110-mg dose and 2.0/100 patient-years at the 150-mg dose. Short-term follow-up and low numbers of dabigatran and apixaban patients did not allow for sound event-rate calculations, according to Dr. Beyer-Westendorf, who stressed that no direct comparisons should be made between event rates for the different agents since the patients were in different cohorts and not in a randomized trial.

Most bleeds (93.3%) were managed conservatively with watchful waiting, compression, tamponade, or red blood cell transfusion. None of the minor bleeds and 16% (83/499) of the nonmajor clinically relevant and major bleeds required surgical or interventional treatment, he said.

Fresh frozen plasma and prothrombin complex concentrate were rarely used (seven patients each). No patient received recombinant activated factor VII.

Mortality was 0.4% for all patients with bleeding complications and 6.8% in those with major bleeds.

Death from any cause at 30 days and 90 days post bleeding occurred in 1 of 19 (5.3%) and 3 of 17 (17.6%) patients on dabigatran, respectively; in 5 of 99 (5%) and 6 of 88 (6.8%) on rivaroxaban; and in 1 of 2 (50%) at each time point for the few patients on apixaban.

With vitamin K antagonists, the case-fatality rates of major bleeding reach 14% at 90 days after bleeding leading to hospitalization and 18% within a week of discharge in atrial fibrillation patients, Dr. Beyer-Westendorf observed.