卒中治疗不增加华法林使用者的出血风险

Ying Xian博士

《美国医学会杂志》(JAMA)6月26日发表的一项观察性研究显示，在合用华法林的患者中，静脉应用组织型纤溶酶原激活物(TPA)溶栓治疗急性缺血性卒中不会增加脑出血风险。

这项研究由北卡罗莱纳州杜克临床研究所的Ying Xian博士及其同事进行，受试者是美国心脏协会“遵循指南-卒中注册”系统收录的2009年4月~2011年6月在1,203家注册医院接受静脉TPA治疗的23,437例成人患者。

共1,802例(8%)患者在接受TPA治疗的同时合用华法林。共1,107例(5%)患者在TPA治疗后发生症状性颅内出血(sICH)。华法林组患者的国际标准化比值(INR)≤1.7，现行美国心脏协会/美国卒中协会(AHA/ASA)指南建议对此类患者应用静脉TPA。

尽管华法林使用者的未校正出血发生率显著高于非华法林患者(6% vs. 5%，P＜0.001)，但在校正后，两组的出血发生率无显著差异[校正比值比(OR)，1.01]。不论风险校正中是否包含患者的美国国立卫生研究院卒中量表(NIHSS)评分，均得出相似结果。同样，华法林组危及生命的或严重全身性出血的发生率与非华法林组无显著差异(均为0.9%)，并且两组的TPA并发症(11% vs. 8%)和院内死亡率(11% vs. 8%)也无显著差异。

由于华法林组50%适合接受再灌注治疗的合格患者未接受静脉TPA治疗，因此存在明显治疗不足的可能。对INR 1.5~1.7的患者进行亚组分析和对INR≤2.0的患者进行探索性分析，结果均显示华法林的应用与sICH之间无显著相关性。

与非华法林组患者相比，华法林组患者的年龄明显更大，并且NIHSS评分更高，这可能是华法林组未校正sICH发生率较高的原因。

该研究的局限性在于采用回顾性设计及缺乏所有患者的NIHSS信息。尚需进行更多研究，以探讨静脉TPA对INR不在指南建议范围内的患者的有效性。

在随刊述评中，Mark J. Alberts博士指出，该研究结果令人惊讶，但仍令人放心，因为华法林使用者通常年龄较大，且更常患有房颤，总体上具有较多的颅内出血危险因素。该研究的部分缺陷在于大部分患者的INR低于1.5。研究结果总体显示INR较高的患者的颅内出血发生率稍高，有待进一步证实。然而，研究结果支持对合格患者应用TPA。如果不对合格患者进行治疗，他们可能会出现长期的卒中后遗症，这才是真正的风险。

该研究获美国心脏协会制药圆桌联盟和David and Stevie Spina支持。Xian博士声明无经济利益冲突。其他研究者与勃林格殷格翰等多家公司存在联系。Alberts博士为美国联合委员会及杨森、基因泰克和勃林格殷格翰公司担任顾问，并从这些公司获得酬金。

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BY HEIDI SPLETE
Elsevier Global Medical News
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Thrombolysis with intravenous tissue plasminogen activator for the treatment of acute ischemic stroke does not increase the risk of brain hemorrhage in patients who are also taking warfarin, based on data from an observational study of more than 23,000 patients.

The patients in the study had an international normalized ratio (INR) of 1.7 or lower, which is the same population of warfarin-treated patients for whom intravenous tissue plasminogen activator (TPA) is recommended in the current American Heart Association/American Stroke Association guidelines.

Symptomatic intracranial hemorrhage (sICH) is an adverse event associated with intravenous TPA that may occur more often in patients receiving warfarin, according to Dr. Ying Xian, who was lead investigator on the study, published June 26 in JAMA. But “the true absolute risk of sICH in this population remains a matter of significant debate,” and previous studies of bleeding risk associated with warfarin have been small, with inconsistent results, wrote Dr. Xian of the Duke Clinical Research Institute in Durham, North Carolina, and his colleagues.

The investigators reviewed data from 23,437 adults in the American Heart Association’s Get With the Guidelines - Stroke Registry. The study participants were treated with intravenous TPA at 1,203 registry hospitals between April 2009 and June 2011 (JAMA 2012;307:2600-8).

A total of 1,802 (8%) of the patients were receiving warfarin at the time of treatment with TPA. A total of 1,107 patients (5%) developed sICH after TPA.

Although the unadjusted rate of hemorrhage was significantly higher in warfarin-treated patients, compared with non-warfarin patients (6% vs. 5%, P less than .001), there was no significant difference in hemorrhage rates after risk adjustment (adjusted odds ratio, 1.01). The results were similar regardless of whether or not the patients’ scores on the U.S. National Institutes of Health Stroke Scale (NIHSS) were excluded from the risk adjustment, the researchers noted.

Similarly, there was no significant difference in the rates of life-threatening or serious systemic hemorrhage between the warfarin and non-warfarin groups (0.9% for both) and no significant differences between the two groups in TPA complications (11% vs. 8%, respectively) or in-hospital mortality (11% vs. 8%, respectively).

“We found the potential for substantial undertreatment, because up to 50% of warfarin-treated patients who might have been eligible for reperfusion therapy did not receive intravenous TPA,” the researchers wrote.

The results also indicated that there was no significant relationship between warfarin use and sICH in a subgroup analysis of patients with INRs between 1.5 and 1.7 or in an exploratory analysis of patients with INRs of 2.0 or lower.

The higher unadjusted incidence of sICH in warfarin patients may be a result of the differences in risk profiles between the warfarin and non-warfarin patients, because those receiving warfarin were significantly older and had higher NIHSS scores, the researchers noted.

The study was limited by several factors, including its retrospective design and a lack of NIHSS information for all patients. More research is needed to explore the effectiveness of intravenous TPA for patients with INRs outside of the range recommended by the guidelines, they added.

In an accompanying editorial (JAMA 2012;307:2637-8), Dr. Mark J. Alberts wrote that “these results are surprising, yet reassuring, because patients receiving warfarin were in general older and more likely to have atrial fibrillation and overall had more risk factors for intracranial hemorrhage.”

The study was limited in part by the fact that the majority of the patients had INRs lower than 1.5. “The overall suggestion of slightly higher rates of intracranial hemorrhage among patients with higher INRs warrants further monitoring,” he noted.

The findings, however, support the use of TPA for eligible patients. “The real risk is in not treating otherwise eligible patients, who may then have prolonged morbidity from their stroke,” said Dr. Alberts of Northwestern University in Chicago.

The study was supported in part by the American Heart Association – Pharmaceutical Roundtable and from David and Stevie Spina. Dr. Xian had no financial conflicts to disclose. Several coauthors disclosed financial relationships with multiple companies, including Boehringer Ingelheim, Merck, Bristol-Myers Squibb, and Sanofi-aventis, which have supported the Get With the Guidelines – Stroke Program in the past, and Janssen Pharmaceutical Companies of Johnson & Johnson, which currently supports it. Boehringer Ingelheim markets TPA in the United States as Activase. Dr. Alberts reported serving as a consultant for and receiving honoraria from Genentech and Boehringer Ingelheim, and serving as a consultant for Janssen and the U.S. Joint Commission.