{"id":39806,"date":"2013-11-09T09:30:49","date_gmt":"2013-11-09T14:30:49","guid":{"rendered":"http:\/\/blogs.nejm.org\/cardioexchange\/?post_type=news&#038;p=39806"},"modified":"2013-11-09T10:14:40","modified_gmt":"2013-11-09T15:14:40","slug":"yet-another-blow-to-combination-renin-angiotensin-aldosterone-system-blockade","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/cardioexchange\/2013\/11\/09\/yet-another-blow-to-combination-renin-angiotensin-aldosterone-system-blockade\/","title":{"rendered":"Yet Another Blow to Combination Renin-Angiotensin-Aldosterone System Blockade"},"content":{"rendered":"<p>ACE\u00a0inhibitors and angiotensin-receptor blockers have been found to effectively slow progression of kidney disease. It has been theorized that dual blockade of the renin-angiotensin-aldosterone system (RAAS) might prove even more beneficial, but these hopes have not been realized. Now a new trial published in the\u00a0<em>New England Journal of Medicine<\/em>\u00a0throws further cold water on the once-promising hypothesis.<\/p>\n<p>In the\u00a0<a href=\"http:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa1303154?query=featured_home\">Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial<\/a>,\u00a0Linda Fried and colleagues randomized type 2 diabetics with proteinuric kidney disease already receiving the angiotensin-receptor blocker losartan to either the\u00a0ACE\u00a0inhibitor lisinopril or placebo. The trial was stopped early by the data and safety monitoring committee due to safety concerns and the low likelihood that the trial would be able to yield a significant difference in the primary end point.<\/p>\n<p>In the end, 1,448 patients were randomized and followed for 2.2 years. The primary endpoint\u00a0\u2014 decline in estimated glomerular filtration rate (GFR), end-stage renal disease (ESRD), or death\u00a0\u2014 occurred in 152 patients in the monotherapy group versus 132 in the combination group (hazard ratio for combination therapy: 0.88, CI 0.70-1.12, p=0.30). There was a trend toward benefit for the secondary endpoint of GFR decline and ESRD (HR 0.78, CI 0.58-1.05 p=0.10). There were no significant differences in mortality or cardiovascular events.<\/p>\n<p>There was a significant increase in risk for hyperkalemia and acute kidney injury in the combination group compared with the monotherapy group:<\/p>\n<ul>\n<li>hyperkalemia: 6.3 versus 2.6 events per 100 person-years (p&lt;0.001)<\/li>\n<li>acute kidney injury: 12.2 versus 6.7\u00a0events per 100 person-years (p&lt;0.001)<\/li>\n<\/ul>\n<p>The authors note that the results are consistent with the\u00a0<a href=\"http:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa0801317\">ONTARGET<\/a>\u00a0trial, in which the combination of an\u00a0ACE\u00a0inhibitor and an\u00a0ARB\u00a0also resulted in an increased risk for adverse events. Combination therapy also proved unsafe in the ALTITUDE trial, which tested the direct renin inhibitor aliskiren in addition to an\u00a0ACE\u00a0inhibitor or an\u00a0ARB.<\/p>\n<p>In an <a href=\"http:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMe1312286\">accompanying editorial<\/a>, Dick de Zeeuw wonders whether these trials indicate the end of the dual therapy hypothesis. He writes that these &#8220;failed&#8221; trials &#8220;suggest that improvement in surrogate markers\u00a0\u2014 lower blood pressure or less albuminuria\u00a0\u2014 does not translate into risk reduction.&#8221; Combination therapy &#8220;can be resuscitated only if we can show renal and cardiovascular protection in a defined group of patients in whom the desired decreases in blood pressure, albuminuria, or both are achieved without major increases in potassium levels or other side effects.&#8221;<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>ACE\u00a0inhibitors and angiotensin-receptor blockers have been found to effectively slow progression of kidney disease. It has been theorized that dual blockade of the renin-angiotensin-aldosterone system (RAAS) might prove even more beneficial, but these hopes have not been realized. Now a new trial published in the\u00a0New England Journal of Medicine\u00a0throws further cold water on the once-promising [&hellip;]<\/p>\n","protected":false},"author":196,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1,7],"tags":[865,2051,2052,358,1580],"class_list":["post-39806","post","type-post","status-publish","format-standard","hentry","category-general","category-prevention","tag-angiotensin-receptor-blockers","tag-combination","tag-esrd","tag-kidney-disease","tag-renin-angiotensin-system-antagonists"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/39806","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/users\/196"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/comments?post=39806"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/39806\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=39806"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=39806"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=39806"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}