<International Circulation>: There is also the controversy of ARBs increasing the risk of myocardial infarction. What is your opinion on this issue?

　　Prof. Sica: Starting in the early 2000s， there was a notion put forward that myocardial infarction risk was higher with angiotensin receptor blockers. Subsequent analysis of the data in large data sets seems not to show that same relationship. The basis of the relationship was presumed to relate to changes in angiotensin II concentrations which occurred in patients treated with ARBs， such that there was unabated stimulation of the AT2 receptor and in so doing， a prothrombotic state would be created. The theory has not been brought out by the data but that is not to say that there may not be differences within other drugs in the class. So direct renin inhibitors do not have the same effect on angiotensin II， in fact their levels are quite low. ACE inhibitors also lower angiotensin II levels. So trying to determine if there is a hierarchy effect may be more relevant here whereby ACE inhibitors and/or direct renin inhibitors may have some superiority over the angiotensin receptor blockers in CHD-related events of a cardiac nature. When ARBs are compared to other drug classes other than those which are members of the RAS pathway (i.e. direct renin inhibitors or ACE inhibitors) then they appear to be quite equal in their risks for myocardial infarction.

　　《国际循环》：ARBs增加心肌梗死风险这一问题上也存在争论，您对此有何看法？

　　Sica教授：早在21世纪初开始，就提出了“应用ARBs的患者心肌梗死风险更高”的概念。随后对大型数据集的分析却并未发现同样的相关性。认为ARBs患者心肌梗死风险增高的理论基础是，应用ARBs的患者其体内血管紧张素II的浓度发生改变，对AT2受体的刺激作用增强，从而使机体处于血栓前状态（即促血栓形成状态）。这个理论并未被相关数据所证实，但并不是说该类药物中的各个药物之间没有差异。直接肾素抑制剂对血管紧张素II无类似的作用。实际上应用肾素抑制剂的患者其体内血管紧张素II的水平是非常低的。ACEI抑制剂也会降低血管紧张素II的水平。故确定RAS系统阻滞剂与心肌梗死风险之间的关系是否存在差异更具有临床意义。与ARBs相比，ACEI类药物和/或直接肾素抑制剂可能更好地降低CHD相关事件。与RAS系统外的其他药物相比，应用ARBs者的心肌梗死风险相当。

　　<International Circulation>: Evidence has suggested that the efficacy and clinical benefits of ARBs is not superior or slightly inferior to that of ACE inhibitors for heart failure， but ARBs might have its own unique characteristics. How should we properly use ARBs in hypertensive patients with heart failure?

　　Prof. Sica: Right now there is no labeled indication for any ARB as a substitute for an ACE inhibitor. The labeled indications are for it to be given together with an ACE inhibitor. If there is ACE inhibitor intolerance， such as cough or more importantly angioedema， then the ARB can be used as initial therapy to block the RAS system. There is a growing wave of concern about ARB and ACE inhibitor therapy given together and the heart failure data is now being re-examined as to whether the risk of hyperkalemia and acute kidney injury is worth the proposed benefit of an ARB on top of an ACE inhibitor in heart failure. We don’t know how that will play out other than the fact that there are strong cautionary notes from most of the regulatory agencies about not using them together in people who are at risk for CAD-related or cardiovascular-related events. It must be said that it is a fast-moving topic and fewer and fewer indications exist for combination therapy. It is my best bet that there will be some revised guideline statements in the package insert for the heart failure use of these drugs in combination that will further emphasize the risk for hyperkalemia and acute kidney injury. European regulatory authorities are looking at this now and it will probably not be far away for the US authorities to be doing the same.

　　《国际循环》：有证据提示，ARBs对心衰患者的疗效及临床获益并不优于或略劣于ACEI类，但却有其独特的特性。在伴有心力衰竭的高血压患者中，我们应如何正确使用ARBs?

　　Sica教授：现在尚无任何迹象表明ARBs可以替代ACEI类药物。确定的适应证是ARBs可与ACEI类药物联用。如果患者因咳嗽或更严重的血管神经性水平而无法耐受ACEI类药物，则我们可以应用ARBs作为初始治疗来阻断RAS系统。目前人们对ARBs与ACEI联用的担忧越来越多，并正在重新评估两者在心衰患者中联用的数据以确定其为心衰患者带来的获益是否能够超过高血钾及急性肾损伤风险。我们不知道其结果会怎样，但大多数监管机构都对两者在CAD相关或心血管相关事件高危人群中的联用做了特别的注意说明。应该说，这是一个不断变化的话题，而支持两者联用的数据越来越少。我认为最好的选择是，在指南中对心力衰竭时两种药物的联用做修订说明，进一步强调其高血钾及急性肾损伤的风险。

　　欧洲监管机构正在这样做，可能美国的监管机构不久也会采取同样的做法。