뇌졸중의 2차 예방을 위한 실로스타졸, Cilostazol, secondary prevention of stroke

항혈소판 제제인 실로스타졸은 말초동맥질환 환자에서 간헐적 파행을 위해 주로 사용되는 phosphodiesterase 3 inhibitor입니다. 몇 개의 대조 시험에서 실로스타졸이 뇌졸중(뇌경색)을 예방하는데 효과적임을 발견하였습니다.

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일본에서 위약과 비교한 시험으로 뇌졸중 위험을 의미 있게 감소시켰습니다.

● In the CSPS trial of over 1000 patients from Japan, cilostazol (100 mg twice daily) compared with placebo significantly reduced the risk of stroke (relative risk reduction [RRR] 42 percent, 95% CI 9.2-62.5 percent).

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위약보다는 당연히 나은 것 같다. 그렇다면 다른 항혈소판제인 아스피린이나 클로피도그렐 등과 비교한다면? 아스피린과 비교한 다음 시험은 중국에서 이루어진 것인데 12-18개월째 composite endpoint (any stroke, ischemic or hemorrhagic)에서 아스피린과 통계적으로 의미가 없었습니다.

● In the CASISP trial from China of 720 patients with recent ischemic stroke, the composite endpoint (any stroke, ischemic or hemorrhagic) at 12 to 18 months of follow-up was lower in the cilostazol group compared with the aspirin group (3.3 versus 5.6 percent, hazard ratio [HR] 0.62, 95% CI 0.30-1.26) but this result was not statistically significant.

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일본에서 위약과 비교한 시험이 CSPS trial이라면 CSPS II trial은 아스피린과 비교한 시험입니다. 이 시험에서는 실로스타졸이 아스피린과 비교하여 열등하지 않았습니다. 출혈 사건도 아스피린보다 더 적었습니다.

● In the noninferiority CSPS II trial, 2757 patients in Japan with a recent noncardioembolic cerebral infarction were randomly assigned to cilostazol (100 mg twice daily) or aspirin (81 mg daily). At a mean follow-up of 29 months, the yearly rates of recurrent stroke (infarction or hemorrhage) for cilostazol and aspirin were 2.7 and 3.7 percent (HR 0.74, 95% CI 0.56-0.98), confirming that cilostazol is noninferior to aspirin for stroke prevention. Annual rates of hemorrhagic events (intracerebral hemorrhage, subarachnoid hemorrhage, or other hemorrhage requiring hospitalization) were lower with cilostazol than with aspirin (0.8 versus 1.8 percent, HR 0.46, 95% CI 0.30-0.71). However, headache, diarrhea, palpitation, dizziness, and tachycardia were more frequent with cilostazol, and more patients discontinued cilostazol than aspirin (20 versus 12 percent).

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아스피린 또는 클로피도그렐 단독보다는 아스피린+실로스타졸, 클로피도그렐+실로스테졸에서 재발성 허혈성 뇌졸중이 더 적었습니다. 이것은 당연한 것 같습니다.

● The open-label CSPS.com trial in Japan enrolled 1884 adult patients with noncardioembolic ischemic stroke who had ≥50 percent stenosis of a major intracranial or extracranial artery, or two or more vascular risk factors. The patients were assigned in a 1:1 ratio to antiplatelet monotherapy using either aspirin or clopidogrel, or to dual antiplatelet therapy (DAPT) using cilostazol combined with either aspirin or clopidogrel. During a median follow-up of 1.4 years, the rate of recurrent ischemic stroke was lower for the DAPT group compared with the monotherapy group (3 versus 7 percent, HR 0.49, 95% CI 0.31-0.76). The rates of serious adverse events and bleeding events were similar between the groups. Limitations to this trial include early stopping before reaching the planned 4000 enrollment due to slow recruitment, resulting in a lower number of event rates, the varying combinations of antiplatelet medications and dosages of aspirin, and, most importantly, the unblinded treatment.

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이 자료는 아시아 인구에서 뇌졸중 2차 예방을 위한 실로스타졸의 안정성과 효능을 지지합니다. 그러나 비아시아 그룹에서 뇌졸중 2차 예방을 위한 실로스타졸 사용에 관한 높은 질의 데이터가 아직 없습니다. 또한 하루 2회 복용, 낮은 내약성, 높은 약제 비용(아스피린과 비교하여)은 뇌졸중 예방을 위한 많은 광범위 사용을 제한하는 것 같습니다.

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뇌졸중 2차 예방을 위한 아스피린, 클로피도그렐, 디피리다몰, 실로스타졸 선택에 대한 UpToDate 내용

- 클로피도그렐 단독 또는 aspirin-extended-release dipyridamole을 제안합니다.

- 아스피린 단독 또는 아스피린+클로피도그렐을 제안하지는 않습니다.

- 실로스타졸은 아시아인에서 합리적인 선택이고, 아시아인이 아니더라도 언급된 다른 약제들을 사용할 수 없거나 내약성이 없는 경우 인종에 상관없이 선택될 수 있는 약제입니다.

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CHOOSING THERAPY

Immediate treatment of acute stroke or TIA — Antithrombotic treatment for patients in the first days after onset of acute ischemic stroke or transient ischemic attack (TIA) is summarized in the algorithms (algorithm 1 and algorithm 2) and discussed in detail separately.

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Long-term treatment — Aspirin, clopidogrel, and the combination of aspirin-extended-release dipyridamole are all acceptable options for preventing recurrent noncardioembolic ischemic stroke. Cilostazol is a reasonable option for patients of Asian ethnicity, and for all patients if the other agents are not available or tolerated. ​Given the available data, we suggest treatment with either clopidogrel 75 mg daily as monotherapy, or aspirin-extended-release dipyridamole 25 mg/200 mg twice a day, rather than Aspirin alone. Aspirin is effective for secondary stroke prevention in patients with noncardioembolic TIA or noncardioembolic ischemic stroke. However, compared with aspirin for the long-term secondary prevention of serious vascular events (ie, nonfatal stroke, nonfatal myocardial infarction, or vascular death), the benefit is greater with clopidogrel alone and with aspirin-extended-release dipyridamole.

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Some experts still prefer aspirin as the first-line agent, noting that the alternative antiplatelet regimens ( clopidogrel or aspirin-extended-release dipyridamole) have an apparent modest advantage in benefit that is potentially offset by a disadvantage in cost.

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For patients at increased risk of gastroduodenal toxicity from antiplatelet agents, particularly those 75 years of age or older, it is reasonable to co-administer a proton pump inhibitor.

 

Immediate-release dipyridamole cannot be routinely recommended for secondary prevention of ischemic stroke, given the limited evidence supporting its effectiveness and the significant pharmacokinetic differences between it and extended-release dipyridamole. Ticlopidine is rarely used because of its side-effect profile and lack of clear superiority over the other available agents. Aspirin and clopidogrel should not be used in combination for long-term stroke prevention, given the lack of greater efficacy compared with either agent alone, and given the substantially increased risk of bleeding complications.

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REF. UpToDate 2019.09.22