与抗凝血剂有关的 ICH 正在增加

　　January 9, 2007 — 一篇新的研究认为，1990年代因为使用抗凝血剂而造成颅内出血(ICH)比率增加五倍，若是老年人则增加十倍。
　　
　　研究者表示，增加的原因是心房纤维颤动（AF）病患使用 warfarin者增加，过去十年的诸多研究确定这种治疗可以减少此类病患之中风，但也发现会增加ICH，ICH已证实是warfari治疗的风险，他们认为，对许多病患来说，治疗利益已不再大于风险。
　　
　　主要研究者，辛辛那提大学医学中心的Matthew L. Flaherty医师在美国神经医学学会的新闻稿中表示，我们的发现并不是不鼓励正当使用warfarin，医师可以藉由这些研究发现去衡量病患使用warfarin时的利益与风险；对研究者来说，这些结果可以帮助发展更安全的替代warfarin治疗病患脑出血的方法。
　　
　　本报告刊载于一月九日的神经学(Neurology)期刊。
　　
　　【使用 warfarin者增加】
　　Warfarin在1990年代“心房纤维颤动中风预防 (SPAF) ”这篇堪称据具有指标意义的研究发表之后，使用率就一直增加，而其他研究也显示warfarin的抗凝血效果可以显著降低AF病患的中风风险；高中风风险病患的治疗风险/利益比很好，但是当用在年长者的预防用途时，治疗利益可能会被出血风险抵销。
　　
　　虽然 ICH 是最令人恐惧的治疗并发症，但对于抗凝血剂有关的 ICH并没有精确的数据；在这篇研究中， Flaherty医师和同事针对大辛辛那提/肯塔基州北部地区的病患，在以下三个时期：1988年、1993–1994年和1999年，曾因初发ICH住院者加以分析，这三个时期就是在前述的主要AF试验前后期间；如果病患有使用warfarin或者 heparin，其出血就被视为与抗凝血剂相关。
　　
　　他们发现，抗凝血剂有关的ICH (AAICH)在这三个时期逐年增加，一如整体ICH案例所表现的百分比。
　　
　　【1998–1999年抗凝血剂有关的ICH比率】

终点	1988	1993/94	1999	趋势 P 值
每 100,000 人 AAICH 年度发生率 (95% CI)	0.8 (0.3–1.3)	1.9 (1.1–2.7)	4.4 (3.2–5.5)	< .001
所有 ICH 案例百分比 %	5	9	17	< .001

　　Flaherty医师等人指出，为了了解AAICH 发生的来龙去脉，其整体发生率目前仅稍低于蛛网膜下腔出血，我们所研究的区域内的每100,000人发生率是 6.6。
　　
　　对于那些 80岁以上的病患，发生率显著更高 ，从1988年的每100,000人发生率2.5增加到1999 年的每100,000人发生率 45.9 (趋势P < .001)。
　　
　　另外，他们也着眼于后面两个时期之初发缺血性心因性中风而住院的病患发生率，以评估warfarin的利益，他们指出，在1988和1999年间，差距是四倍；报告指出，整体或因AF所致之心因性中风发生率在1993–94和1999年之间没有显著改变。
　　
　　【大辛辛那提/肯塔基州北部地区心因性缺血性中风年度发生率 (每 100,000 人)】

终点	1993–94 (95% CI)	1999 (95% CI)	趋势 P 值
心因性缺血性中风	31.1 (27.9–34.3)	30.4 (27.3–33.5)	.65
因 AF 导致之心因性缺血性中风	22.0 (19.3–24.7)	20.6 (18.1–23.2)	.44

　　不过，他们指出，这些结果和其他研究所称之降低AF之缺血性中风相比并不奇怪；此外，他们指出，美国的各年龄层的AF发生率一直增加，基此事实，可预期心因性中风发生率是增加的，因此我们相信统计的发生率还是支持使用warfarin可以预防缺血性中风。
　　
　　本研究部分受国家神经异常与中风研究中心的赞助。

Anticoagulant-Associated ICH on the Rise

By Susan Jeffrey
Medscape Medical News

January 9, 2007 ??A new study suggests that the rate of intracerebral hemorrhage (ICH) associated with the use of anticoagulants increased five-fold during the 1990s and up to 10-fold in the elderly.

Most of the increase, the researchers say, is explained by the growing use of warfarin in patients with atrial fibrillation (AF), after a number of studies during that decade confirmed that treatment reduced stroke in this population. These findings of an accompanying increase in ICH, a known risk with warfarin therapy, do not mean that the benefits may not still outweigh the risks for many people, they say.

"Our findings should not discourage the use of warfarin when it's appropriate," lead author Matthew L. Flaherty, MD, from the University of Cincinnati Medical Center, in Ohio, said in a press release from the American Academy of Neurology. "Doctors can use these findings to make sure they are weighing the risks and benefits of warfarin use for their patients. For researchers, these results may stimulate efforts to develop safer alternatives to warfarin and better treatments for people with brain hemorrhages."

The report is published in the January 9 issue of Neurology.

Growing Warfarin Use

Warfarin use has increased since publication during the 1990s of such landmark studies as the Stroke Prevention in Atrial Fibrillation (SPAF) trials, among others, showing that anticoagulation with warfarin could significantly reduce the risk for stroke in patients with AF. The risk/benefit ratio for warfarin treatment is good when patients are at high risk for stroke but "narrower" when used in primary prevention in the elderly, where the benefit may be offset by bleeding risk, they write.

Although ICH is the "most-feared" complication of treatment, precise estimates of anticoagulant-associated ICH are not available, they note. In this study, Dr. Flaherty and colleagues identified all patients in the Greater Cincinnati/Northern Kentucky area who were hospitalized with first-ever ICH during 3 periods: 1988, 1993??4, and 1999 ??that is, before and after the major anticoagulant trials in AF. The hemorrhages were considered anticoagulant-associated if the patient was on warfarin or heparin.

They found the annualized rate of anticoagulant-associated ICH (AAICH) increased significantly over the 3 periods, as did the percentage of overall ICH cases that it represented.

Anticoagulation Associated Intracerebral Hemorrhage Rates 1998??999

End Point	1988	1993/94	1999	P for trend
Annual incidence rate of AAICH per 100,000 (95% CI)	0.8 (0.3??.3)	1.9 (1.1??.7)	4.4 (3.2??.5)	< .001
% of all ICH cases	5	9	17	< .001

"To place the burden of AAICH in context, its overall incidence is now only slightly less than subarachnoid hemorrhage, which occurs at a rate of 6.6 cases per 100,000 persons in our metropolitan area," Dr. Flaherty et al note.

For those patients 80 years of age and older, the rate increased even more significantly, from 2.5 cases per 100,000 persons in 1988 to 45.9 cases in 1999 (P < .001 for trend).

They also looked at the incidence rates of patients hospitalized with first-ever ischemic cardioembolic stroke in the latter 2 of these periods, to assess the benefit of warfarin, the use of which quadrupled on a per-capita basis between 1988 and 1999, they note. They report that the incidence of cardioembolic stroke either overall or due to AF did not change significantly between 1993??4 and 1999.

Annualized Incidence Rates (per 100,000 Persons) of Cardioembolic Ischemic Stroke in the Greater Cincinnati/Northern Kentucky Population

End Point	1993??4 (95% CI)	1999 (95% CI)	P for trend
Cardioembolic ischemic stroke	31.1 (27.9??4.3)	30.4 (27.3??3.5)	.65
Cardioembolic ischemic stroke due to AF	22.0 (19.3??4.7)	20.6 (18.1??3.2)	.44

However, these results are at odds with other studies that have shown declines in ischemic stroke in AF, they point out. In addition, they note, the prevalence of AF in the United States appears to be increasing over time, regardless of age. "Given this fact, rates of cardioembolic stroke might have been expected to increase and therefore we believe that our static incidence rates likely represent benefit from warfarin use in prevention of ischemic stroke."

The study was supported in part by the National Institute for Neurological Disorders and Stroke.

Neurology. 2007;68:116-121.