周邊動脈血管疾病的抗血栓用藥參考作法(抗血小板+小劑量抗凝血）

周邊動脈血管疾病 (Peripheral Artery Disease, PAD) 是一種動脈粥樣硬化(atherosclerotic)過程，可導致下肢動脈部分或完全阻塞而下降血流供給，導致從間歇性跛行到休息時疼痛(pain at rest)，甚至組織受損等缺血症狀。可以透過影像學檢查（例如 CT angiography）或ankle-brachial index/toe-brachial index進行診斷。抗血栓藥物和外科介入是主要的治療方法。抗血栓藥物已被證實可以減少major adverse cardiovascular events (MACE)和 Major Adverse Limb Events (MALE)，MALE包含 amputation 和 the need for revascularization。

雙抗血小板藥物(Dual Antiplatelet Therapy, DAPT) ：

• Aspirin是一種COX-1 inhibitor，通過TXA-2阻斷血小板活化。
• Rivaroxaban是factor Xa inhibitor，通過抑制凝血路徑中的thrombin生成，而達到抑制血小板活化。
• 同時使用Aspirin和Rivaroxaban的理論基礎是藉由阻斷兩種不同的血小板活化機制，以進一步降低血栓生成的風險。COMPASS trial和VOYAGER PAD trial兩個試驗研究了Rivaroxaban 2.5mg bid plus Aspirin 100mg qd對PAD的效果。

▲Canonical mechanistic concept of atherothrombosis and potential therapeutic targets (Circulation. 2019;139:2170–2185)

▲Non laminar blood flow resulting in rupture of a thin-capped atheroma subtending a lipid-rich necrotic core exposes potent pro coagulant sub-endothelial factors resulting in rapid generation of thrombin as well as aggressive platelet activation and propagation resulting in atherothrombosis with resultant obstruction of flow due to thrombotic material. (White H, Clin App Thromb Hemost. 2014:20(5):516-523.)

▲Dual pathway inhibition. Low-dose rivaroxaban reduces circulating serum levels of thrombin by inhibiting its production from prothrombin. Thus, decreased conversion of fibrinogen to fibrin predictably occurs resulting in anticoagulation. Decreased thrombin stimulation of the PAR-1 receptor results in a reduction of platelet activation and propagation. COX-1 inhibition via low-dose aspirin predictably results in antiplatelet effect. The combination results in a dual pathway inhibition which is the suggested mechanism for reducing atherothrombotic events in patients with polyvascular atherosclerosis. (Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-30.)

以下僅針對有症狀的周邊動脈疾病做抗血栓藥品使用建議，並排除無症狀PAD病人。 (比較使用SAPT/DAPT/OAC+ASA在PAD效益與安全性)

1. COMPASS trial和VOYAGER PAD trial兩個臨床試驗中使用rivaroxaban 2.5mg bid，與aspirin 81mg or 100mg qd。 
2. 併用Rivaroxaban 和 Aspirin 在高風險族群（見表一）能獲得更多好處。然而，低風險族群也可能受益。  
3. VOYAGER PAD trial 中發現，在post-revascularization使用Rivaroxaban加 Aspirin 是有臨床好處的。
4. 高出血風險包含之前有過ICH、有過重大出血事件、有需要長期使用抗凝血藥品indications(例如AF, DVT, mechanical valve replacement等)、出血傾向、GERD（見表二），使用ASA+OAC較不建議。 
5. COMPASS和VOYAGER trial中得知，未觀察到致命性出血或顱內出血發生率的增加，且出血風險在用藥的第一年最高。
6. 在使用Rivaroxaban 2.5mg bid在PAD前，須評估病人是否有需要使用正常劑量的Rivaroxaban 的適應症(10/15/20mg qd)(例如AF, DVT, mechanical valve replacement等)，如果沒有相關適應症病史者，才可以使用低劑量的Rivaroxaban。  
7. COMPASS trial研究顯示，大部分出血都是胃腸道出血。

▲表一：併用Rivaroxaban 和 Aspirin 能獲得更多好處的高風險共病症

▲表二：高出血風險表

根據以上表一和表二，對照表三選擇適合的抗血栓藥物組合：

▲表三：根據不同共病症，介入措施&出血風險，分別列出病人哪些適合SAPT、DAPT或OAC+aspirin

▲歐/美針對周遍動脈血管疾病抗血栓藥品指引建議。

COMPASS (PAD Subgroup Analysis, 2017):

• Background: This study compared rivaroxaban 2.5mg BID plus aspirin (ASA) 100mg vs ASA alone in stable symptomatic PAD disease.
• Symptomatic PAD was defined as intermittent claudication plus imaging evidence, aortofemoral bypass, limb bypass, PCTA revascularization, limb or foot amputation
• Population: 66% of patients had CAD, 44% had DM, and 6-7% had history of stroke
• Excluded: need for DAPT (post MI), need for other non-ASA therapy, high risk of bleeding, need for oral anticoagulant therapy, severe HF (EF <30%), eGFR <15mL/min, patients on strong CYP3A4 inducer/inhibitor medications
• Included patients with PAD defined as aortofemoral bypass, limb bypass, PTA revascularization of iliac or infra-inguinal arteries, limb or foot amputation, intermittent claudication plus either ABI<0.9 OR PAD stenosis ≥50% on duplex/angio, or finally, carotid revascularization or carotid stenosis >50% on duplex/angio. 
• Rivaroxaban 2.5mg BID with ASA was superior to ASA alone with reductions in MACE by 28% and MALE by 46%; however, major bleeding increased, along with GI-related bleeding. The net risk-benefit analysis was still favorable.

▲Baseline Characteristics by Occurrence of the Net Clinical
Benefit Outcome (Circulation. 2020;142:40–48.)

▲Event Rates of the Net Clinical Benefit Outcome and Its Components (Circulation. 2020;142:40–48.)

• A lower number of net clinical benefit (NCB) adverse outcomes was observed with rivaroxaban 2.5 mg twice daily plus ASA versus ASA alone (hazard ratio, 0.80 [95% CI, 0.70–0.91], P=0.0005), which became increasingly favorable with longer treatment duration. 
• The main drivers of NCB outcomes were “efficacy” events, in particular stroke (0.5%/y versus 0.8%/y; hazard ratio, 0.58 [95% CI, 0.44–0.76], P<0.0001) and cardiovascular death (0.9%/y versus 1.2%/y; hazard ratio, 0.78 [95% CI, 0.64–0.96], P=0.02), whereas the bleeding components of the NCB, in particular fatal bleeding (0.09%/y versus 0.06%/y; hazard ratio, 1.49 [95% CI 0.67–3.33], P=0.32), only represented a minority of NCB events.
• In selected high-risk subgroups, including patients with polyvascular disease (≥2 vascular beds affected with atherosclerosis), impaired renal function, heart failure, and/or diabetes mellitus, a larger absolute risk reduction for experiencing a NCB event was observed.

VOYAGER-PAD (2020): 

• Background: This study compared rivaroxaban 2.5mg BID plus ASA 100mg vs ASA alone in symptomatic PAD disease undergoing revascularization. 
• 32% of patients had CAD, 40% had DM, 9% had known carotid stenosis
• Interventions included endovascular (65%) and surgical (35%)
• Exclusion: revascularization for asymptomatic disease, recent revascularization within 10d, ALI w/n 2wk, ACS w/n 30d, current major tissue loss, need for stronger antiplatelet or AC, need for longer term DAPT >6mo, high risk of bleeding

• Included patients with symptomatic PAD (ischemic symptoms with imaging evidence) who underwent successful revascularization of lower extremity for ischemia. 

• The primary composite MALE and MACE endpoint was reduced by 15% in the rivaroxaban plus ASA group versus ASA alone. 
• No difference was observed in the primary safety outcome of TIMI major bleeding.
• Bleeding risk: There was no difference in TIMI major bleeding, including intracranial bleeding or fatal bleeding between groups. There was a higher rate of ISTH major bleeding.

縮寫：

• ASA=aspirin
• OAC- oral anticoagulant
• ISTH=International Society on Thrombosis and Haemostasis
• MACE- major adverse cardiac event 
• MALE- major adverse limb event
• TIMI=Thrombolysis in Myocardial Infarction

Reference:

1. Dual Pathway Inhibition in Chronic Stable Coronary Artery Disease for the Prevention of Secondary Events – JAVELIN (javelinjournal.org)
2. https://www.nejm.org/doi/full/10.1056/nejmoa1709118
3. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.046048
4. https://www.nejm.org/doi/full/10.1056/nejmoa2000052

First released: 25.April.2023