Current Strategies to Achieve Further Cardiac and Renal Protection through Enhanced Renin-Angiotensin-Aldosterone System Inhibition
Current Strategies to Achieve Further Cardiac and Renal Protection through Enhanced Renin-Angiotensin-Aldosterone System Inhibition
复制标题
DOI：
10.2174/157488711795177912
复制
发表时间：
2011-01-01
影响因子：
1.9
通讯作者：
Waisman, G. D.
中科院分区：
文献类型：
--
作者：
Alfie, J.;Aparicio, L. S.;Waisman, G. D.
血管紧张素转换酶抑制剂(ACEI)或血管紧张素受体阻滞剂(ARB)治疗高血压、糖尿病、慢性肾病和心力衰竭患者，尽管血压得到明显控制，但肾素-血管紧张素-醛固酮系统(RAAS)的不完全抑制可能是导致残留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疾病中，额外的抗蛋白尿作用，以及已经接受单一RAAS拮抗剂治疗的心力衰竭患者住院时间的减少，已经通过双重治疗递增抑制RAAS或在常规剂量之上增加单个药物而实现。然而，血浆肾素活性(PRA)的协同增加和血管紧张素II的逃逸可能会降低双重治疗所获得的预期益处。OnTarget的结果显示，与单一疗法相比，ACEI/ARB缺乏额外的结果益处，伴随着高钾血症、肾损害和低血压风险的增加，阻碍了在心血管事件高危患者中使用ACEI/ARB组合。尽管双重RAAS阻断的白蛋白排泄量比单一RAAS阻断的白蛋白排泄量更低，但这种情况还是发生了，这表明递增的抗蛋白尿作用不会自动转化为临床结果的好处。ACEI/ARB联合疗法与单一疗法治疗显性蛋白尿患者的有效性和安全性目前正通过LICICO和VA NEPHRON-D临床试验进行评估。长效的直接肾素抑制剂阿利吉伦作用于RAAS级联反应的第一步，也是限速步骤，与ACEI、ARB或利尿剂联合使用时，可防止PRA的反应性增加。Aspire Higher计划涉及3.5万多名高血压、心力衰竭、肾脏疾病和糖尿病患者，目前正在评估阿利吉伦在标准治疗之外的疗效和安全性。在常规治疗的基础上加用盐皮质激素受体阻滞剂(MRB)在控制难治性高血压、蛋白尿肾病和防止心力衰竭患者死亡方面的临床益处证明，未充分抑制的醛固酮是导致对传统RAAS抑制反应不佳的原因之一。目前的综述将集中在病理生理学基础，以及临床试验提供的证据，评估最近通过增强RAAS抑制来预防心血管事件和靶器官损害进展的策略的有效性和安全性。
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 benefit. 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.