2022 台灣版高血脂治療指引-針對心血管疾病高風險族群 7.Ischemic stroke/TIA LDL-C target

2025-12-09 14:10

2022 focused update of the 2017 Taiwanlipid guidelines for high risk patients:Coronary artery disease, peripheral arterydisease and ischemic stroke

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LDL-C 目標

一項包含24項隨機對照試驗的統合分析表明，他汀類藥物的使用與既往無卒中史人群卒中風險降低有關。低密度脂蛋白膽固醇（LDL-C）每降低10%，中風風險降低7.5%；LDL-C每降低1 mmol/L（39 mg/dL），中風風險可降低15%至21%。 ^35,36 在SPARCL試驗中，4731例先前有非心臟中風或6個月內發生短暫性腦缺血發作（TIA）病史的患者被隨機分配接受阿托伐他汀80 mg/天或安慰劑治療。研究發現，在4.9年的追蹤期間，接受阿托伐他汀治療的患者中風復發率較低（HR 0.84，95% CI 0.71-0.99）。阿托伐他汀組和安慰劑組的平均 LDL-C 水準分別為 73 mg/dL 和 129 mg/dL。 37 最近發表的「治療中風至目標」（Treat Stroke to Target，TST）試驗隨機將 2860 名有 3 個月內缺血性中風史或 15 天內短暫性腦缺血發作史的患者分配到兩個 LDL-C 治療目標組：< 70 mg/dL 和 90-110 mg/dL。 4 為入組此試驗，患者必須有記錄在案的動脈粥狀硬化性疾病，包括顱外或顱內腦動脈狹窄、主動脈弓動脈粥樣硬化斑塊厚度至少為 4 mm，或有冠狀動脈疾病史。在3.5年的追蹤期間，LDL-C < 70 mg/dL組患者發生主要心血管事件的風險低於LDL-C 90~110 mg/dL組（HR 0.78，95% CI 0.61~0.98）。兩組患者的平均LDL-C水準分別為65 mg/dL和96 mg/dL。 ⁴ 出血性中風或新發生糖尿病的風險未顯著增加。在接受強化LDL-C降低治療的患者中，24%接受了高強度他汀類藥物治療，76%接受了中等強度他汀類藥物治療，41%接受了他汀類藥物/依折麥布合併治療。 TST試驗納入了來自法國和韓國的受試者。整體主要終點結果為陽性，且未發現顯著的治療與國家/地區交互作用。然而，韓國隊列亞組分析中未觀察到顯著療效的結果，仍令人擔憂TST試驗的結果可能無法推廣至韓國或亞洲患者。儘管如此，在TST試驗的2860名研究參與者中，2,148名（75.1%）來自法國，而僅有712名（24.9%）來自韓國。此外，法國的中位追蹤時間也遠長於韓國（5.3年 vs. 2.0年）。這些因素可能導致韓國隊列缺乏足夠的統計效力來檢測顯著療效。香港最近一項針對 904 名中國缺血性中風患者的前瞻性隊列研究表明，事件後平均 LDL-C < 70 mg/dL 的患者，在平均 6.5 年的隨訪後，與 LDL-C > 70 mg/dL 的患者相比，發生重大心血管事件的風險較低。 38 平均 LDL-C < 70 mg/dL 也與嚴重大動脈疾病的患者發生腦出血的風險較低有關。38 SPARCL 試驗表明，與安慰劑相比，每天服用 80 毫克阿托伐他汀治療的患者發生出血性中風的風險增加（HR 1.68，95% CI 1.09e2.59）。然而，SPARCL試驗的事後分析表明，出血性中風風險增加與基線血壓升高（收縮壓>160 mmHg或舒張壓>100 mmHg）和出血性中風相關，但與低密度脂蛋白膽固醇（LDL-C）水平無關。 ³⁹一項包含31篇隨機對照試驗的統合分析顯示，他汀類藥物的使用與顱內出血風險增加無關（HR 1.08，95% CI 0.88-1.32）。 ⁴⁰丹麥一項全國性研究表明，與不使用他汀類藥物相比，使用他汀類藥物不會增加基線時存在顱內出血患者的複發性顱內出血風險，並且與基線時存在缺血性卒中患者的顱內出血風險降低相關。 ⁴¹建議：對於缺血性中風或短暫性腦缺血發作（TIA）且伴隨腦或頸動脈粥狀硬化性狹窄的患者，應考慮使用他汀類藥物。對於已知患有冠狀動脈疾病 (CAD) 的患者，將低密度脂蛋白膽固醇 (LDL-C) 控制在 < 70 mg/dL 以降低重大心血管事件的風險是合理的（COR IIa，LOE B）。

LDL-C target

A meta-analysis of 24 randomized controlled trials suggests that statin use is associated with a reduced stroke risk in people without a prior stroke. Every 10% decrease of LDL-C is associated with 7.5% stroke risk reduction and every 1 mmol/ L (39 mg/dL) LDL-C reduction can decrease the risk of stroke by 15%e21%.35,36 In the SPARCL trial, 4731 patients with a history of non-cardioembolic stroke or TIA within 6 months were randomly assigned to receive either atorvastatin 80 mg/day or placebo. The study found that patients received atorvastatin had a lower recurrent stroke during 4.9 years follow up (HR 0.84, 95% CI 0.71e0.99). The average LDL-C levels were 73 mg/dL and 129 mg/dL in atorvastatin and placebo groups, respectively.37 The recently published Treat Stroke to Target (TST) trial randomly assigned 2860 patients with a history of ischemic stroke within 3 months or TIA within 15 days to two LDL-C treatment goals, < 70 mg/dL vs. 90e110 mg/dL.4 To be enrolled in the trial, patients had to have documented atherosclerotic diseases, including stenosis of an extracranial or intracranial cerebral artery, atherosclerotic plaques of the aortic arch measuring at least 4 mm in thickness, or a known history of CAD. During 3.5 years of follow-up, patients in the LDL-C < 70 mg/dL group had a lower risk of major cardiovascular events (HR 0.78, 95% CI 0.61e0.98) compared to those in the 90e110 mg/dL group. The average achieved LDL-C levels were 65 mg/dL and 96 mg/dL in the 2 groups, respectively.4 There was no significantly increased risk of hemorrhagic stroke or newonset diabetes. For patients assigned to the intensive LDLC lowering group, 24% received high-intensity statin, 76% received moderate-intensity statin, and 41% received statin/ ezetimibe combination therapy. The TST trial contains subjects from France and South Korea. The overall primary endpoint is positive and there is no significant treatment-bycountry interaction. However, the neutral outcomes in the subgroup analysis of Korean cohort still raise the concern that the results of TST trial may not be generalizable to Korean or Asian patients. Nevertheless, among the 2860 study participants in TST trial, there were 2148 (75.1%) from France and only 712 (24.9%) from South Korea. The median follow-up time was also much longer in France (5.3 years versus 2.0 years). These factors potentially caused a lack of power to detect a significant effect in Korean cohort. A recent prospective cohort study from Hong Kong with 904 Chinese ischemic stroke patients showed that patients with a mean post-event LDL-C < 70 mg/dL were associated with a lower risk of major cardiovascular events compared to those with LDL-C > 70 mg/dL after a mean follow up of 6.5 years.38 A mean LDL-C < 70 mg/dL was also associated with a lower risk of intracerebral hemorrhage in patients with significant large artery diseases.38 The SPARCL trial showed that patients treated with atorvastatin 80 mg/day were associated with an increased risk of hemorrhagic stroke (HR 1.68, 95% CI 1.09e2.59) compared with the placebo. However, post hoc analysis of the SPARCL trial showed that the increased risk of hemorrhagic stroke was associated with increased blood pressure (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg) and hemorrhagic stroke at baseline, but not the LDL-C levels.39 A meta-analysis including 31 randomized controlled trials showed that statin use was not associated with an increased risk of intracranial hemorrhage (HR 1.08, 95% CI 0.88e1.32).40 A nationwide study conducted in Denmark suggested that stain use compared with no statin use was not associated with an increased risk of recurrent intracerebral hemorrhage in patients with intracerebral hemorrhage at baseline and was associated with a lower risk of intracerebral hemorrhage in patients with ischemic stroke at baseline.41 Recommendation In patients with ischemic stroke or TIA and cerebral or carotid atherosclerotic stenosis or known CAD, it is reasonable to control LDL-C target < 70 mg/dL to reduce the risk of major cardiovascular events (COR IIa, LOE B).