The Remarkable Story of a Wonder Drug, Which Now Comes to an End in the Primary Prevention Setting: Say Bye-bye to Aspirin!

https://www.medscape.com/viewarticle/909825?src=wnl_edit_tpal&uac=97756AZ&impID=1926992&faf=1

Marco Valgimigli,  Eur Heart J. 2019;40(7):618-620. 

Aspirin is to date the most used drug worldwide and, in 2018, with some dispute about its real birth date, celebrated its 121st birthday; 2018 will most probably be remembered as the year when aspirin came of age, whereby multiple studies re-examined, and at least partially questioned, its risk/benefit ratio in various clinical settings.[1–4] While aspirin remains the cornerstone treatment for secondary prevention in patients with established cardiovascular disorders, three large, independent, and high quality randomized controlled trials have shed new light on aspirin in primary prevention.[2–4] These recent results now have to be incorporated within the context of previously existing evidence, which altogether questions the somewhat liberal use of aspirin that has so far been recommended by some,[5] but not by other, guidelines committees.[6]

In this issue of the European Heart Journal, Mahmoud and colleagues furnish the findings on a meta-analysis and trial sequential analysis of randomized trials evaluating the efficacy and safety of aspirin among patients without prior known history of atherosclerotic cardiovascular disease.[7] A total of 11 studies with 157 248 participants met the pre-defined inclusion criteria, amongst which were (i) a randomized study design; (ii) comparing aspirin vs. placebo/no aspirin control; (iii) in ***** patients without prior history of atherosclerosis; and (iv) including 500 patients or more. It should be emphasized that unlike some previous meta-analyses,[8] which also were claimed to focus on primary prevention, studies including patients with known atherosclerosis and peripheral vascular disease without having yet experienced an ischaemic event or revascularization (the so-called 1.5 prevention setting) had been excluded for the analysis. Yet, a sensitivity analysis, which also included patients with an established atherosclerotic disorder, mainly in the peripheral system, is provided and yields almost identical implications for practice.

This updated meta-analysis focused on mortality as the principal endpoint. This did not differ between the aspirin and control groups [4.6% vs. 4.7%; relative risk (risk ratio (RR)) = 0.98, 95% confidence interval (CI) 0.93–1.02, P = 0.30], without heterogeneity across studies and no signal of any treatment effect at interaction testing across pre-defined subgroups including the 10-year risk, diabetes, mid-enrolment year, aspirin dose, risk of bias, and follow-up duration.

The incidence of major bleeding was higher with aspirin, yielding a 47% higher RR and a number needed to harm (NNH) in the range of 250.

Similarly, the risk of intracranial bleeding, which was a pre-defined component of the major bleeding definition in all except one study,[9] was increased with a 33% relative and 0.1% absolute (NNH =1000) difference.

Cardiovascular mortality or stroke did not differ in patients with or without aspirin, which seriously contributes to the unfavourable risk/benefit profile of aspirin in the primary prevention setting.

However, the incidence of myocardial infarction (MI) was lower with aspirin [2.0% vs. 2.3%, 95% CI 1.7–2.8%; RR = 0.82, 95% CI 0.71–0.94, P = 0.006, number needed to treat (NNT) = 333]. One may wonder whether trading a single MI for bleeding would be an acceptable option. The comparative prognostic implications of bleeding vs. a non-fatal MI for mortality have been investigated at least in the secondary prevention setting and, unsurprisingly, the outcomes depend on the severity of bleeding, with intracranial episodes greatly exceeding the prognostic role of an MI in terms of mortality.[10] Yet, the key upstream question remains of whether the effect of aspirin on MI prevention is real and reproducible in contemporary practice. When looking at the current pooled analysis, the effect size of aspirin on MI was characterized by a high degree of heterogeneity between the studies included (I 2 = 67%) and a secondary analysis excluding older trials with mid-enrolment year prior to 2000 showed the lack of aspirin benefit even on MIs in more recent trials (RR = 0.90, 95% CI 0.79–1.02, P = 0.10). This observation may have multiple and not necessarily mutually exclusive explanations. Mahmoud and colleagues place emphasis on the fact that old studies pre-dated the universal definitions of MI and used relatively insensitive cardiac markers for the diagnosis of an MI.

If one plots the use of statins and the relative risk reductions for MI across the 11 included studies, an obvious association emerges between no or minimal use of statins and greater absolute effect of aspirin on MI prevention (Figure 1).

Among the contemporary studies evaluating aspirin in primary prevention, only the Japanese Primary Prevention Project observed a significant MI benefit with aspirin.[9]Interestingly, in this study, >70% of the patients had known dyslipidaemia, but only 51% of them received statins during the course of the study.[9]

In the HOT trial, allocation to aspirin was also associated with a significant 35% MI risk reduction.[11] Yet, only 7% of the patients were treated with lipid-lowering drugs, and the mean total cholesterol was 235 mg/dL, suggesting a non-negligible proportion of patients with hypercholesterolaemia who may have derived benefit from lipid-lowering agents.[11] In primary prevention trials, the use of statins is known to be associated with a 25% decrease in the risk of major vascular events for every 1 mmol/L decrease in the LDL cholesterol level (rate ratio with statin vs. placebo, 0.75; 95% CI 0.69–0.82).[12] This statistically significant benefit was associated with an excellent safety profile and was not associated with the bleeding risks observed consistently throughout all aspirin trials.

Moreover, an intriguing observation regarding cholesterol levels and MI benefit of aspirin in the primary prevention setting comes from the Physicians' Health Study, which ante-dated the availability of statins.[13] In this trial, a significant interaction was noted between baseline cholesterol level and relative risk reduction for MI, with greater benefit observed in patients with the highest baseline cholesterol levels. Hence, taken together, current evidence raises concerns that aspirin can significantly contribute to MI prevention in patients when properly treated with lipid-lowering agents as per todays' practice and guidelines.

The recent results of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), where high-dose icosapent ethyl led in the primary prevention setting to a consistent reduction of the primary composite ischaemic endpoint, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, without a significant increase in bleeding risk—albeit with a higher incidence of atrial fibrillation or flutter whose implications and mechanisms need to be better understood—further highlights the key role of lipid-lowering agents even in patients in whom the median LDL cholesterol level was 75.0 mg/dL at baseline.[14]

Whether routine antiplatelet agents, other than aspirin, will still have a possible role in high-risk patients in the truly primary prevention setting remains unclear, but it appears rather unlikely given the well-known trade-off between risks and benefits observed consistently across all antithrombotic agents investigated so far.

The issue of the management of patients fulfilling the 1.5 prevention setting, i.e. in whom an atherosclerotic disorder has been established prior to the occurrence of an ischaemic event or to the development of related symptoms, still remains unresolved. A pragmatic approach in this setting might be a selected use of aspirin only for patients on the low bleeding risk spectrum in the hope that this strategy might maximize the benefits over the risks.[15]

The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS, NCT01991795) is designed to evaluate the efficacy and safety of ticagrelor in >20 000 patients aged 50 years or more with type 2 diabetes with known coronary artery disease but without a history of an MI or stroke. Patients are being randomized to ticagrelor 60 mg twice daily or placebo in a double-blinded fashion. The primary endpoint is the composite of cardiovascular death, MI, or stroke at 48 months. Results of the THEMIS trial are expected in early 2019 and will greatly contribute to our current understanding about the future role of antiplatelet agents as a primary means to avoid the consequences of plaque rupture in patients who may have ongoing yet asymptomatic plaque rupture episodes. Meanwhile, we should get ready to say a farewell to aspirin even in asymptomatic patients in whom an atherosclerosis disorder is not established, irrespective of the anticipated risk of future ischaemic events or concomitant cardiovascular risk factors.

题目：The Remarkable Story of a Wonder Drug, Which Now Comes to an End in the Primary Prevention Setting: Say Bye-bye to Aspirin!

一种神奇药物的非凡故事，现在在一级预防阶段可以跟阿司匹林说拜拜了！

https://www.medscape.com/viewarticle/909825?src=wnl_edit_tpal&uac=97756AZ&impID=1926992&faf=1

Marco Valgimigli,  Eur Heart J. 2019;40(7):618-620. 

1. Aspirin is to date the most used drug worldwide and, in 2018, with some dispute about its real birth date, celebrated its 121st birthday; 2018 will most probably be remembered as the year when aspirin came of age, whereby multiple studies re-examined, and at least partially questioned, its risk/benefit ratio in various clinical settings.[1–4] While aspirin remains the cornerstone treatment for secondary prevention in patients with established cardiovascular disorders, three large, independent, and high quality randomized controlled trials have shed new light on aspirin in primary prevention.[2–4] These recent results now have to be incorporated within the context of previously existing evidence, which altogether questions the somewhat liberal use of aspirin that has so far been recommended by some,[5] but not by other, guidelines committees.[6]

到目前为止，阿司匹林是世界上使用最广泛的药物。2018年，阿司匹林迎来了其有争议的121岁生日。2018年很可能会被人们铭记为阿司匹林成熟的一年，在这一年里，多项研究对阿司匹林在不同临床环境下的风险/效益比进行了重新检验，也提出了一些质疑[1-4]。尽管阿司匹林仍然是心血管疾病患者二级预防的基础治疗，但三项大型、独立、高质量的随机对照试验为阿司匹林一级预防提供了新的思路[2-4]。这些最近的研究结果必须纳入先前已有的证据范围内，这些证据对迄今为止一些指南[5](而不是其他指南[6])所建议的、多少有些自由使用阿司匹林的做法提出了质疑。

2. In this issue of the European Heart Journal, Mahmoud and colleagues furnish the findings on a meta-analysis and trial sequential analysis of randomized trials evaluating the efficacy and safety of aspirin among patients without prior known history of atherosclerotic cardiovascular disease.[7] A total of 11 studies with 157 248 participants met the pre-defined inclusion criteria, amongst which were (i) a randomized study design; (ii) comparing aspirin vs. placebo/no aspirin control; (iii) in ***** patients without prior history of atherosclerosis; and (iv) including 500 patients or more. It should be emphasized that unlike some previous meta-analyses,[8] which also were claimed to focus on primary prevention, studies including patients with known atherosclerosis and peripheral vascular disease without having yet experienced an ischaemic event or revascularization (the so-called 1.5 prevention setting) had been excluded for the analysis. Yet, a sensitivity analysis, which also included patients with an established atherosclerotic disorder, mainly in the peripheral system, is provided and yields almost identical implications for practice.

在本期的《European Heart Journal》杂志上，Mahmoud及其提供了一项关于评估阿司匹林在没有动脉粥样硬化性心血管疾病病史的患者中的疗效和安全性结果的meta分析和随机试验的序贯分析[7]。共有包含157248名参与者的11项研究符合预先定义的纳入标准：(i)随机研究设计；(ii)比较阿司匹林与安慰剂/无阿司匹林对照；(iii)无动脉粥样硬化病史的*****患者；(iv)患者数大于500人。需要强调的是，与之前的一些所谓的侧重一级预防的meta分析[8]不同的是，包含已知的动脉粥样硬化和周围血管疾病的患者，而没有经历过缺血事件或血运重建(所谓的1.5预防设置)的研究被排除在分析之外。然而，一个包括有动脉粥样硬化性疾病（主要是在周围系统）患者的敏感性分析，为实践提供了几乎相同的含义。

3. This updated meta-analysis focused on mortality as the principal endpoint. This did not differ between the aspirin and control groups [4.6% vs. 4.7%; relative risk (risk ratio (RR)) = 0.98, 95% confidence interval (CI) 0.93–1.02, P = 0.30], without heterogeneity across studies and no signal of any treatment effect at interaction testing across pre-defined subgroups including the 10-year risk, diabetes, mid-enrolment year, aspirin dose, risk of bias, and follow-up duration.

该最新更新的荟萃分析将死亡率作为主要终点。在阿司匹林和对照组之间没有差异[4.6% vs. 4.7%；相对危险度(RR) = 0.98，95%置信区间(95% CI) 0.93-1.02，P = 0.30]，各研究间无异质性；在包括10年风险率、糖尿病、中位数年限、阿司匹林剂量、偏倚风险和随访持续时间在亚组间无效果。

4. The incidence of major bleeding was higher with aspirin, yielding a 47% higher RR and a number needed to harm (NNH) in the range of 250.

阿司匹林具有更高的大出血发生率，其RR高于47%，已有约250个病例。

5. Similarly, the risk of intracranial bleeding, which was a pre-defined component of the major bleeding definition in all except one study,[9] was increased with a 33% relative and 0.1% absolute (NNH =1000) difference.

同样，除了一项研究外，作为预定的大出血的颅内出血的风险相对危险度为33%，绝对危险度为0.1% (NNH =1000)。

6. Cardiovascular mortality or stroke did not differ in patients with or without aspirin, which seriously contributes to the unfavourable risk/benefit profile of aspirin in the primary prevention setting.

心血管死亡率或中风在服用或不服用阿司匹林的患者中没有差异，这严重影响了阿司匹林作为一级预防用药的不利风险/效益谱。

7. However, the incidence of myocardial infarction (MI) was lower with aspirin [2.0% vs. 2.3%, 95% CI 1.7–2.8%; RR = 0.82, 95% CI 0.71–0.94, P = 0.006, number needed to treat (NNT) = 333]. One may wonder whether trading a single MI for bleeding would be an acceptable option. The comparative prognostic implications of bleeding vs. a non-fatal MI for mortality have been investigated at least in the secondary prevention setting and, unsurprisingly, the outcomes depend on the severity of bleeding, with intracranial episodes greatly exceeding the prognostic role of an MI in terms of mortality.[10] Yet, the key upstream question remains of whether the effect of aspirin on MI prevention is real and reproducible in contemporary practice. When looking at the current pooled analysis, the effect size of aspirin on MI was characterized by a high degree of heterogeneity between the studies included (I 2 = 67%) and a secondary analysis excluding older trials with mid-enrolment year prior to 2000 showed the lack of aspirin benefit even on MIs in more recent trials (RR = 0.90, 95% CI 0.79–1.02, P = 0.10). This observation may have multiple and not necessarily mutually exclusive explanations. Mahmoud and colleagues place emphasis on the fact that old studies pre-dated the universal definitions of MI and used relatively insensitive cardiac markers for the diagnosis of an MI.

但阿司匹林组心肌梗死(MI)发生率较对照组低[2.0% vs. 2.3%， 95% CI 1.7-2.8%；RR = 0.82, 95% CI 0.71-0.94, P = 0.006，需治疗数(NNT) = 333]。有人可能会想，仅仅为了治疗心梗而引起出血是否可以接受呢？出血与非致死性心梗对死亡率的预后影响已至少在二级预防中进行了研究，结果并不令人意外，取决于出血的严重程度，颅内出血在死亡率方面大大超过心梗[10]。然而，关键的上游问题仍然是阿司匹林对心梗预防的作用在当代实践中是否真实和可复制。当回顾当前的汇集分析，阿司匹林对心梗的治疗效果在所包含的研究中具有高度的异质性(I 2 = 67%)，排除中位起始年限在2000年之前的旧研究的二次分析显示，即使在最近的研究中，也缺乏阿司匹林具有好处的证据(RR = 0.90, 95% CI 0.79 - -1.02, P = 0.10)。这种观察可能有多种解释，但不一定相互排斥。Mahmoud及其同事强调，以往的研究早于心梗的普遍定义，使用相对不敏感的心脏标志物来诊断心梗。

8. If one plots the use of statins and the relative risk reductions for MI across the 11 included studies, an obvious association emerges between no or minimal use of statins and greater absolute effect of aspirin on MI prevention (Figure 1).

如果在11项纳入的研究中增加他汀类药物的使用情况和心肌梗死的相对风险降低情况，就会发现，不使用或极少使用他汀类药物与阿司匹林对心肌梗死预防的更大绝对效果之间存在明显的关联(图1)。

9. Among the contemporary studies evaluating aspirin in primary prevention, only the Japanese Primary Prevention Project observed a significant MI benefit with aspirin.[9]Interestingly, in this study, >70% of the patients had known dyslipidaemia, but only 51% of them received statins during the course of the study.[9]

在当前评估阿司匹林在一级预防中的作用的研究中，只有日本一级预防项目发现阿司匹林对心肌梗死有显著的益处[9]。有趣的是，在这项研究中，超过70%的患者知道血脂异常，但只有51%的患者在研究过程中服用了他汀类药物[9]。（此处参考文献引用是否有错误？全文都没有10号参考文献）

10. In the HOT trial, allocation to aspirin was also associated with a significant 35% MI risk reduction.[11] Yet, only 7% of the patients were treated with lipid-lowering drugs, and the mean total cholesterol was 235 mg/dL, suggesting a non-negligible proportion of patients with hypercholesterolaemia who may have derived benefit from lipid-lowering agents.[11] In primary prevention trials, the use of statins is known to be associated with a 25% decrease in the risk of major vascular events for every 1 mmol/L decrease in the LDL cholesterol level (rate ratio with statin vs. placebo, 0.75; 95% CI 0.69–0.82).[12] This statistically significant benefit was associated with an excellent safety profile and was not associated with the bleeding risks observed consistently throughout all aspirin trials.

在HOT研究中，服用阿司匹林也能显著降低35%的心肌梗死风险[11]。然而，只有7%的患者接受降脂药物治疗，平均总胆固醇为235 mg/dL，这表明高胆固醇血症患者中不可忽视的一部分可能受益于降脂药物[11]。在一级预防研究中，LDL胆固醇水平每降低1 mmol/L，使用他汀类药物可降低25%的主要血管事件风险(他汀类药物与安慰剂的比率为0.75；95% CI 0.69-0.82)[12]。这一统计学上显著的获益与良好的安全性有关，与所有阿司匹林试验中观察到的一致出血风险无关。

11. Moreover, an intriguing observation regarding cholesterol levels and MI benefit of aspirin in the primary prevention setting comes from the Physicians' Health Study, which ante-dated the availability of statins.[13] In this trial, a significant interaction was noted between baseline cholesterol level and relative risk reduction for MI, with greater benefit observed in patients with the highest baseline cholesterol levels. Hence, taken together, current evidence raises concerns that aspirin can significantly contribute to MI prevention in patients when properly treated with lipid-lowering agents as per todays' practice and guidelines.

此外，一项关于阿司匹林在一级预防中的胆固醇水平和心肌梗死益处的有趣观察来自Physicians' Health研究，该研究早于他汀类药物的使用[13]。在本研究注意到，在基线胆固醇水平和心肌梗死相对风险降低之间存在显著的相互作用，在基线胆固醇水平最高的患者中观察到更大的益处。因此，综合来看，目前的证据表明，如果按照今天的实践和指南，适当地使用降脂剂治疗，阿司匹林可以显著预防心梗。

12. The recent results of the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), where high-dose icosapent ethyl led in the primary prevention setting to a consistent reduction of the primary composite ischaemic endpoint, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, without a significant increase in bleeding risk—albeit with a higher incidence of atrial fibrillation or flutter whose implications and mechanisms need to be better understood—further highlights the key role of lipid-lowering agents even in patients in whom the median LDL cholesterol level was 75.0 mg/dL at baseline.[14]

二十碳五烯酸乙酯降低心血管事件干预研究（REDUCE-IT）的最新结果显示，高剂量的二十碳五烯酸乙酯在一级预防中能一致降低一级复合缺血终点，包括心血管死亡、非致命性心肌梗死和非致命性卒中，尽管房颤或房扑的发生率较高，但出血风险没有显著增加(其影响和机制需要更好地理解)，这进一步强调了降脂药物的重要作用，即使患者基线LDL胆固醇的中值为75.0 mg/dL也是如此[14]。

13. Whether routine antiplatelet agents, other than aspirin, will still have a possible role in high-risk patients in the truly primary prevention setting remains unclear, but it appears rather unlikely given the well-known trade-off between risks and benefits observed consistently across all antithrombotic agents investigated so far.

常规抗血小板药物(阿司匹林除外)是否仍将在真正的一级预防中对高危患者发挥积极作用，目前尚不清楚，但是，考虑到迄今为止所有研究的抗血栓药物所观察到的风险与益处之间的众所周知的平衡，这种情况似乎不大可能发生。

14. The issue of the management of patients fulfilling the 1.5 prevention setting, i.e. in whom an atherosclerotic disorder has been established prior to the occurrence of an ischaemic event or to the development of related symptoms, still remains unresolved. A pragmatic approach in this setting might be a selected use of aspirin only for patients on the low bleeding risk spectrum in the hope that this strategy might maximize the benefits over the risks.[15]

对于满足1.5级预防的患者，如已确定动脉粥样硬化性疾病但未发生缺血性事件，其治疗问题仍未解决。解决这种问题的一种实用的方法可能是选择性对出血风险范围较低的患者使用阿司匹林，以期能最大限度地提高疗效[15]。

15. The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study (THEMIS, NCT01991795) is designed to evaluate the efficacy and safety of ticagrelor in >20 000 patients aged 50 years or more with type 2 diabetes with known coronary artery disease but without a history of an MI or stroke. Patients are being randomized to ticagrelor 60 mg twice daily or placebo in a double-blinded fashion. The primary endpoint is the composite of cardiovascular death, MI, or stroke at 48 months. Results of the THEMIS trial are expected in early 2019 and will greatly contribute to our current understanding about the future role of antiplatelet agents as a primary means to avoid the consequences of plaque rupture in patients who may have ongoing yet asymptomatic plaque rupture episodes. Meanwhile, we should get ready to say a farewell to aspirin even in asymptomatic patients in whom an atherosclerosis disorder is not established, irrespective of the anticipated risk of future ischaemic events or concomitant cardiovascular risk factors.

替格瑞洛对糖尿病患者影响的干预研究(THEMIS，NCT01991795)的目的是评估替格瑞洛对超过20 000例50岁及以上2型糖尿病伴明确的冠状动脉疾病但没有心肌梗死或中风史患者的有效性和安全性。患者被随机分为两组，每日两次服用替格瑞洛60 mg或安慰剂，采用双盲法。主要终点是48个月内心血管死亡、心梗或中风。THEMIS研究的结果预计将于2019年初公布，这将极大地促进我们目前对抗血小板药物未来作用的理解，即抗血小板药物是避免斑块破裂的主要手段，可用于可能正在发生但无症状斑块破裂事件的患者。