International Circulation: Combination of ACE inhibitors with ARB seems a counterintuitive idea. Yet the option might provide additional benefits in target organ protection. What’s your opinion of this issue? What is the rationale for the combination??
《国际循环》: ACEI和ARB联用似乎有背常理，然而这一选择可能提供额外的靶器官保护。对这个问题您怎么看？联用的基本原理是什么？
Jay Cohn: ACEI和ARB联用的基本原理是肾素血管紧张素系统有多种激活机制，目前使用的药物没有一种能完全抑制该系统。如果我们的目标是抑制血管紧张素（AT）的生成或者阻断它在受体水平的作用，常规剂量的ACEI是不能充分ATII的。常规剂量的ARB能部分抑制AT-1受体，却不一定能抑制AT-2受体。直接肾素抑制剂能抑制肾素作用。这是三种不同的抑制肾素血管紧张素系统的方式。在Val-HeFT 试验中， 服用ACEI抑制剂的患者加用ARB后获益更多；但ONTARGET试验却未能证明在ACEI基础上加用ARB能进一步获益。目前尚无明确的指南指导这种联合用药，但有证据表明如患者服用小剂量ACEI时，加用ARB，能进一步改善左室结构，进一步改善肾功能、抑制蛋白尿和降低血压。在ARB或ACEI基础上加用肾素抑制剂后获益也会进一步增强。因此，有理由认为联合治疗会使适合的病人受益。由于每种药物的剂量不能产生完全的抑制效果，所以联合用药可能使获益增加。如果服用大剂量的ARB，可能就不必使用其他药物了。但使用大剂量的担忧是某些患者血压可能降得太低。我个人通常确实使用ACEI和ARBs联合治疗高血压，并非常小心地观察血压，我相信患者能从这种联合中受益。
 

Jay Cohn: The rationale for the combination is that the renin/angiotensin system has multiple stimulating mechanisms and none of the drugs we use totally inhibit the system.  If our goal is to block angiotensin and the formation of angiotensin at the receptor level， ACE inhibitors at the doses that we currently use them do not adequately suppress angiotensin II.  Angiotensin receptor blockers at the doses we use them produce partial inhibition of the AT-1 receptor and not necessarily the AT-2 receptor.  The renin inhibitors， which are now being used， produce， obviously， an inhibition at the primary site of renin and influence quite differently angiotensin II and the receptor mechanisms.  So these are three different way of inhibiting this system.  In the Val-HeFT trial， we were able to show that patients taking an ACE inhibitor are able to demonstrate further benefit if they are given an ARB in addition.  The hope was that this would also be observed in trials of other clinical conditions.  The ON TARGET trial failed to show that the addition of an ARB and an ACE inhibitor had a further beneficial effect.  In fact there was， if anything， an adverse effect.  We are left without a clear clinical guideline to use the drugs in combination but evidence that at least when patients are taking a low dose， or at least not a high dose of an ACE inhibitor， you can see further structural benefit on the left ventricle， further improvement in renal function and inhibition of albuminuria， further reduction of blood pressure when you give an ARB on top of an ACE inhibitor， and further benefit when you give renin inhibitor on top of an ARB or ACE inhibitor.  Therefore， there is reason to believe that in the proper patients the combination will be beneficial.  In the large trials that have been done， other than for heart failure， there has been no documentation that that combination will produce further benefit.  The issue is then， unresolved.