Alfie J, Aparicio L S, Waisman G D
Hospital Italiano de Buenos Aires, Hypertension Section, Internal Medicine Unit, Argentina.
Rev Recent Clin Trials. 2011 May;6(2):134-46. doi: 10.2174/157488711795177912.
An incomplete inhibition of the renin angiotensin aldosterone system (RAAS) may be responsible for the residual organ damage and event rate that still occur in spite of an apparent blood pressure control in patients with hypertension, diabetes, chronic kidney disease and heart failure treated with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Additional antiproteinuric effect in diabetic and non diabetic chronic kidney disease, and reduction in hospitalizations in patients with heart failure already receiving a single RAAS antagonist, has been achieved by incremental inhibition of the RAAS with dual therapy or uptitration of an individual agent above conventional dosages. However, the synergistic increase in plasma renin activity (PRA) and the angiotensin II escape could reduce the expected benefit obtained with dual therapy. Results from ONTARGET showing a lack of additional outcome benefit over monotherapy, with a concomitant increase risk of hyperkalemia, renal impairment, and hypotension, discourage the use of the ACEI/ARB combination in patients at high risk of cardiovascular events. This occured despite a lower albumin excretion in dual versus single RAAS blockade, indicating that an incremental antiproteinuric effect is not automatically translated into clinical outcome benefits. The efficacy and safety of ACEI/ARB combination versus monotherapy in patients with overt proteinuria is currently evaluated by LIRICO and VA NEPHRON-D clinical trials. The long lasting direct renin inhibitor aliskiren, acting at the first and rate limiting step of the RAAS cascade, prevents the reactive increase in PRA when combined with ACEIs, ARBs or diuretics. The ASPIRE HIGHER programme, involving more than 35,000 patients with hypertension, heart failure, kidney disease and diabetes, is currently evaluating the efficacy and safety of aliskiren on top of standard therapy. The clinical benefit of adding mineralocorticoid receptor blockers (MRBs) in the control of resistant hypertension, proteinuric kidney diseases, and prevention of mortality in patients with heart failure on top of conventional treatment, evidences the pathogenic role of inadequately suppressed aldosterone as a cause of suboptimal response to conventional RAAS inhibition. The present review will focus on the pathophysiological ground, and the evidence provided by clinical trials assessing the efficacy and safety of recent strategies for the prevention of cardiovascular events and target organ damage progression via enhanced RAAS inhibition.
肾素血管紧张素醛固酮系统（RAAS）抑制不完全可能是导致高血压、糖尿病、慢性肾脏病和心力衰竭患者尽管使用血管紧张素转换酶抑制剂（ACEI）或血管紧张素受体阻滞剂（ARB）后血压看似得到控制，但仍出现残余器官损害和事件发生率的原因。在糖尿病和非糖尿病慢性肾脏病中，通过双重治疗或将单一药物剂量增加至高于常规剂量来进一步抑制RAAS，可实现额外的抗蛋白尿作用，并减少已接受单一RAAS拮抗剂治疗的心力衰竭患者的住院次数。然而，血浆肾素活性（PRA）的协同增加和血管紧张素II逃逸可能会降低双重治疗预期获得的益处。ONTARGET研究结果显示，与单药治疗相比，双重治疗在结局方面并无额外益处，同时高钾血症、肾功能损害和低血压风险增加，这使得心血管事件高危患者不倾向使用ACEI/ARB联合治疗。尽管双重RAAS阻断与单一阻断相比白蛋白排泄更低，但这表明额外的抗蛋白尿作用并不会自动转化为临床结局益处。目前，LIRICO和VA NEPHRON-D临床试验正在评估ACEI/ARB联合治疗与单药治疗相比在显性蛋白尿患者中的疗效和安全性。长效直接肾素抑制剂阿利吉仑作用于RAAS级联反应的第一步和限速步骤，与ACEI、ARB或利尿剂联合使用时可防止PRA反应性增加。涉及超过35000例高血压、心力衰竭、肾脏疾病和糖尿病患者的ASPIRE HIGHER项目目前正在评估阿利吉仑在标准治疗基础上的疗效和安全性。在常规治疗基础上加用盐皮质激素受体阻滞剂（MRB）在控制顽固性高血压、蛋白尿性肾脏疾病以及预防心力衰竭患者死亡方面的临床益处，证明了醛固酮抑制不足作为常规RAAS抑制反应欠佳原因的致病作用。本综述将聚焦于病理生理学基础，以及评估通过增强RAAS抑制预防心血管事件和靶器官损害进展的近期策略的疗效和安全性的临床试验所提供的证据。
