次級中風預防方面 Cilostazol優於阿斯匹靈

作者：Caroline Cassels  
出處：WebMD醫學新聞

　　March 9, 2010 (聖安東尼奧) — 新研究認為，對於非心臟栓塞腦梗塞病患，在次級中風預防方面，磷酸二酯酶抑制劑cilostazol比阿斯匹靈(ASA)更有效，且嚴重腦出血的發生率顯著較低。
　　
　　這篇發表於國際中風2010研討會、最新科學會議中的齊頭式試驗結果顯示，使用cilostazol治療者發生中風的風險比接受ASA者低25.7%。再者，相較於ASA組，cilostazol組的病患顯著較少發生顱內出血(intracerebral hemorrhage，ICH)、蜘蛛膜下出血，或者需要住院的出血。
　　
　　此外，Shinohara醫師表示，cilostazol有更佳的安全資料，中風、暫時性缺血性發作(transient ischemic attack，TIA)、心絞痛、心肌梗塞(myocardial infarction，MI)、心衰竭、需要住院的出血等次級合併終點方面的比率顯著較低。
　　
　　主要研究者、日本東京Tachikawa醫院的Yukito Shinohara醫師向Medscape Neurology表示，根據這些發現，我們相信，cilostazol應被視為可以耐受長期服用此藥之病患的次級中風預防選項之一。
　　
　　【需要被治療的病人數目過高、無法接受】
　　根據Shinohara醫師表示，雖然ASA與其他抗血小板藥物如clopidogrel可有效用於次級中風預防，但預防一個事件所需被治療的病人數目過高，需治療26-28名病患3年，這令人無法接受，再者，他指出，抗血小板治療也有明顯的出血副作用風險。
　　
　　Cilostazol的第一篇研究 — 即由Shinohara醫師等人10年前在日本進行的「Cilostazol Stroke Prevention Study (CSPS)」研究顯示，相較於安慰劑，該藥物更有效且出血風險降低。
　　
　　這促使他們進行目前的CSPS-2研究，將該藥和目前用於次級中風預防的照護標準、ASA進行比較。
　　
　　這項隨機、多中心、雙盲研究，包括了來自278個中心的2757名非心臟栓塞中風病患，該研究進行期間為2003年12月至2008年12月。
　　
　　病患被隨機分組接受每天兩次的cilostazol 100 mg，或者每天一次的ASA 81 mg，治療期間持續至少1年，至多5年。
　　
　　【非嚴重副作用的比率較高】
　　該研究的初級終點為發生有症狀的中風— 治療期間腦梗塞、ICH或者蜘蛛膜下出血。
　　
　　次級終點包括復發有症狀的腦梗塞、發生缺血性腦血管事件、任何原因死亡、或發生中風、TIA、心絞痛、MI、心衰竭或者需要住院的出血事件。
　　
　　Cilostazol組的1,337人，在2965.9人-年中，有82名發生中風，其中2人致命，ASA組的1,335人，在3203.6人-年中，有119人中風，包括3人死亡。
　　
　　Shinohara醫師表示，出血性中風或者需要住院的出血事件，cilostazol組有23名病患發生，ASA組有57人，這是相當大的差異。
　　
　　雖然cilostazol組的嚴重副作用比率較低，但是在出血之外的副作用比率比ASA高，例如頭痛、腹瀉、心悸與暈眩，不過，ASA 組的高血壓與便秘比率較高。
　　
　　【比較便宜，但是不一定比較好】
　　Shinohara醫師指出，cilostazol比較貴— 費用約是ASA的40倍，他表示，他們目前正進行經濟分析與次組分析，希望可以找出最適合這種治療的對象。
　　
　　目前，美國核准cilostazol用於治療間歇性跛行，這是週邊動脈疾病患者的主要症狀。
　　
　　阿拉巴馬大學附設醫院綜合中風中心主任Andrei Alexandrov醫師受Medscape Neurology之邀對該研究發表評論時表示，cilostazol讓醫師有另一個可用的治療選項。
　　
　　我們需要替代阿斯匹靈主要是因為阿斯匹靈雖可預防中風和心臟病發作，但是它最好嗎？答案是否定的，阿斯匹靈雖然便宜，但是便宜不代表更好，阿斯匹靈可預防中風，但有出血風險。
　　
　　Alexandrov醫師表示，我們有clopidogrel和Aggrenox (含有ASA與dipyridamole)，但是在一些案例中，你會遇到無法服用這些藥物的病患，cilostazol是我們可以用於預防次級中風的另一種武器。
　　
　　Otsuka Pharmaceutical藥廠支持該研究。Shinohara醫師報告指出接受Sanofi-Aventis、Mitsubishi Tanabe Pharma、Otsuka Pharmaceutical, Bayer HealthCare、Daiichi-Sankyo與Kyorin Pharmaceutical等藥廠的演講費用與獎金，且擔任Otsuka Pharmaceutical藥廠諮詢委員會的顧問。
　　
　　國際中風研討會(ICS)2010:摘要194。發表於2010年2月26日。


Cilostazol Trumps Aspirin in Secondary Stroke Prevention

By Caroline Cassels
Medscape Medical News

March 9, 2010 (San Antonio, Texas) — The phosphodiesterase inhibitor cilostazol is more effective in secondary stroke prevention and has a significantly lower incidence of serious cerebral hemorrhage compared with aspirin (ASA) in patients with noncardioembolic cerebral infarction, new research suggests.

Presented here at a late-breaking scientific session during the International Stroke Conference 2010, the results of the head-to-head trial show that individuals treated with cilostazol were 25.7% less likely to have a stroke than their counterparts who received ASA.

Furthermore, patients in the cilostazol group were significantly less likely to have an intracerebral hemorrhage (ICH), subarachnoid hemorrhage, or hemorrhage requiring hospitalization compared with those in the ASA group.

In addition, said Dr. Shinohara, cilostazol had a superior safety profile, with significantly lower rates on the secondary composite endpoint of stroke, transient ischemic attack (TIA), angina pectoris, myocardial infarction (MI), heart failure, or hemorrhage requiring hospitalization.

"Based on these findings, we believe cilostazol should be considered as a potential treatment option for secondary stroke prevention in patients who can tolerate long-term administration of this drug, " principal investigator Yukito Shinohara, MD, Tachikawa Hospital in Tokyo, Japan, told Medscape Neurology.

Number Needed to Treat Unacceptably High



Dr. Yukito Shinohara  
According to Dr. Shinohara, although ASA and other antiplatelet medications, such as clopidogrel, are effective in secondary stroke prevention, the number needed to treat to prevent a single event is unacceptably high — 26 to 28 patients for 3 years. Furthermore, he added, antiplatelet therapy also carries a significant risk for hemorrhagic adverse effects.

The first study of cilostazol — known as the Cilostazol Stroke Prevention Study (CSPS) — conducted by Dr. Shinohara and colleagues in Japan 10 years ago demonstrated that the drug was more effective compared with placebo, with a reduced risk of bleeding.

This led to the current study, the CSPS-2, which pits the drug against ASA, the current standard of care for secondary stroke prevention.

The randomized, multicenter, double-blind, parallel-group study included 2757 noncardioembolic stroke patients from 278 centers. The study took place between December 2003 and December 2008.

Patients randomized to receive cilostazol received 100 mg twice daily, whereas subjects in the ASA group received 81 mg once daily. The duration of treatment lasted a minimum of 1 year and a maximum of 5 years.

Higher Rate of Nonserious Adverse Effects

The study's primary endpoint was occurrence of symptomatic stroke — cerebral infarction, ICH, or subarachnoid hemorrhage during the treatment period.

Secondary endpoints included recurrence of symptomatic cerebral infarction, occurrence of ischemic cerebrovascular event, death from any cause, or cluster of stroke, TIA, angina pectoris, MI, heart failure, or hemorrhage requiring hospitalization.

Stoke occurred in 82 of the 1337 cilostazol-treated patients, and 2 of these events were fatal during 2965.9 person-years. In the 1335 subjects in the ASA group, there were 119 strokes, including 3 deaths, during 3203.6 person-years.

Hemorrhagic stroke or hemorrhage requiring hospitalization occurred in 23 patients in the cilostazol group and 57 in the ASA group — a difference, said Dr. Shinohara, that was highly significant.

Although the rate of serious adverse events was lower in the cilostazol group, the drug fared worse compared with ASA with respect to adverse events other than bleeding, with higher rates of headache, diarrhea, palpitations, and dizziness. However, those in the ASA group had greater rates of hypertension and constipation.

Cheaper, Not Always Better

Dr. Shinohara pointed out that cilostazol is expensive — with a cost that is about 40 times greater than that of ASA. He said his group is currently conducting an economic analysis and subgroup analyses in the hope of characterizing optimal candidates for this treatment.

Currently, cilostazol is approved for use in the United States for the treatment of intermittent claudication, a common concern among patients with peripheral artery disease.

Asked by Medscape Neurology to comment on the study, Andrei Alexandrov, MD, director, Comprehensive Stroke Center, University of Alabama Hospital in Birmingham, said cilostazol may offer clinicians another potential treatment option.

"We need alternatives to aspirin because the main notion is that aspirin protects against stroke and heart attack but is it optimal? The answer is no. Aspirin is cheap, but cheap doesn't mean better. Aspirin protects against stroke, but it carries a risk of bleeding.

"We have clopidogrel and we have Aggrenox (a combination of ASA and dipyridamole), but in certain cases you run up against patients who can't take these, and cilostazol would give us another drug in our arsenal against secondary stroke," said Dr. Alexandrov.

The study was supported by Otsuka Pharmaceutical. Dr. Shinohara reports that he has received speaking fees and honoraria from Sanofi-Aventis, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Bayer HealthCare, Daiichi-Sankyo, and Kyorin Pharmaceutical and has served as a consultant and on the advisory board of Otsuka Pharmaceutical.

International Stroke Conference (ICS) 2010: Abstract 194. Presented February 26, 2010.