Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease

 

Abstract

Background

Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for those at high risk and those with established cardiovascular disease.

Objectives

To quantify the benefit and harm of adding clopidogrel to standard long-term aspirin therapy for preventing cardiovascular events in people at high risk of cardiovascular disease and those with established cardiovascular disease.

Search methods

The searches have been updated: CENTRAL (Issue 3 2009), MEDLINE (2002 to September 2009) and EMBASE (2002 to September 2009).

Selection criteria

All randomized controlled trials comparing long term use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in patients with coronary disease, ischemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease were included.

Data collection and analysis

Data on mortality, non-fatal myocardial infarction, non-fatal stroke, unstable angina, heart failure, revascularizations, major and minor bleeding, and all adverse events were collected. The overall treatment effect was estimated by the pooled odds ratio (OR) with 95% confidence interval (CI) using a fixed-effect model (Mantel-Haenszel).

Main results

No new studies were identified from the updated searches. A total of two RCTs were found: the CHARISMA and the CURE study. The CURE study enrolled only patients with a recent non-ST segment elevation acute coronary syndrome. The use of clopidogrel plus aspirin, compared with placebo plus aspirin, was associated with a lower risk of cardiovascular events (OR: 0.87, 95% CI 0.81 to 0.94; P<0.01) and a higher risk of major bleeding (OR 1.34, 95% CI 1.14 to 1.57; P<0.01). Overall, we would expect 13 cardiovascular events to be prevented for every 1000 patients treated with the combination, but 6 major bleeds would be caused. In the CURE trial, for every 1000 people treated, 23 events would be avoided and 10 major bleeds would be caused. In the CHARISMA trial, for every 1000 people treated, 5 cardiovascular events would be avoided and 3 major bleeds would be caused.

Authors' conclusions

The available evidence demonstrates that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events and an increased risk of bleeding compared with aspirin alone. Only in patients with acute non-ST coronary syndrome benefits outweigh harms.

 

Plain language summary

Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease

Low-dose aspirin as antiplatelet therapy is still the drug of choice for preventing cardiovascular events, but the protection aspirin gives to people at high risk of cardiovascular events is only relatively modest. This review of 28,165 people in two trials where clopidogrel was given in addition to antiplatelet treatment found that in patients with acute coronary syndromes the benefit - a reduction in cardiovascular events - outweighs the harm of major bleeding. However, clopidogrel plus aspirin has no clear positive risk-benefit profile in people at high risk of cardiovascular events (multiple atherothrombotic risk factors) or in people with established cardiovascular disease (known coronary disease, ischemic cerebrovascular disease or peripheral arterial disease) but not presenting with an acute coronary syndrome, and the combination should not be prescribed routinely to prevent cardiovascular disease.

 

摘要

背景

比較clopidogrel併用aspirin和單獨使用aspirin在預防心血管疾病上的成效

Aspirin是心血管疾病患者預防用抗血小板藥物的首選。然而，在那些高心血管疾病風險的患者身上，投以抗血小板藥物的保護作用卻不是那樣理想。對於那些高風險和本身已經有心血管疾病的病人，加入aspirin以外的第二種抗血小板藥物可能會產生額外的好處。

目標

對於那些高風險和本身已經有心血管疾病的病人，比較長期使用aspirin後再併用clopidogrel和單獨使用aspirin在防止心血管病變發生的效應(包括益處與害處)。

搜尋策略

搜尋CENTRAL(2006年第2期)，MEDLINE資料庫(2002年至2006年5月)和EMBASE資料庫 (2002年至2006年5月)，整理在網路上登記的進行中臨床試驗和參考文獻(包括原創性文章和回顧)。

選擇標準

包括所有在冠狀動脈疾病，缺血性腦血管疾病，週邊動脈疾病，或動脈粥樣硬化性疾病高風險的患者(至少有以上一種疾病)身上，比較長期(大於30天)使用Aspirin加上clopidogrel和aspirin 加安慰劑或單獨使用aspirin的隨機對照試驗。

資料收集與分析

收集資料並分析下列數據：死亡率(死於心肌梗塞，中風，心血管疾病，所有的原因)，非致命性心肌梗塞，非致命性中風，不穩定型心絞痛，心臟衰竭，血管修復術，大出血和小出血，和所有的副作用。定量分析的結果是基於意圖治療原則(intentiontotreat principle)。整體的治療效果使用固定效應模型(Mantel  Haenszel法)來估計勝算比(OR)與95％的信賴區間(CI)

主要結論

搜尋到兩個符合條件的隨機對照試驗。在參加CHARISMA研究的患者中都屬於心血管疾病高風險的族群，(無論之前有或沒有得過心血管疾病)。參加CURE研究的患者最近罹患非ST段上升型急性冠狀動脈症候群。使用clopidogrel加上aspirin和安慰劑加aspirin相比，發生心血管病變的風險較低(勝算比： 0.87 ， 95 ％ 信賴區間為0.81至0.94; p < 0.01)但大出血的風險較高(勝算比1.34 ， 95 ％ 信賴區間為1.14至1.57; p <0.01) 。整體而言，我們預期每一千位病人使用複方療法，可避免13次心血管事件，但有6次大出血事件。在這兩項試驗中的治療效果不同:CURE研究只限於非ST段上升型急性冠狀動脈症候群的病人，有明確的證據證明複方治療是有益處。每1000位病人接受平均9個月的複方治療，可避免23次心血管事件，但有10次大出血事件。在CHARISMA研究中，針對心血管病變高風險的族群，無論之前是否已有心血管疾病或危險因子，治療效果較不明顯。每1000位病人接受平均28個月的複方治療，可避免5次心血管事件，但有3次大出血事件。

作者結論

現有的證據指出，針對非ST段上升型急性冠狀動脈症候群的患者使用clopidogrel加aspirin，比單獨使用aspirin更能降低心血管病變的發生；而在心血管疾病高風險但無急性發作的患者，只有薄弱的證據證明複方療法有益處，而此治療之害處幾乎與益處相當。

翻譯人

本摘要由臺北榮民總醫院邱淳志翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

預防心血管病變的抗血小板治療藥物中，低劑量aspirin仍是首選但針對高危險群而言，aspirin的保護作用相當普通。這次回顧發現在這兩項試驗的28165人中，對急性冠狀動脈症候群的患者的益處(減少心血管疾病事件)大於大出血的害處。然而，clopidogrel 加上aspirin在心血管疾病高風險的族群(具有多種動脈粥樣硬化的危險因子)，或在已有心血管疾病的族群(冠狀動脈疾病，缺血性腦血管病或周邊動脈疾病)，在沒有合併急性冠狀動脈症候群的狀態下，沒有明確的證據有益處，因此不應使用此複方療法來常規性預防心血管疾病。