{"id":29191,"date":"2012-05-21T15:37:27","date_gmt":"2012-05-21T19:37:27","guid":{"rendered":"http:\/\/blogs.nejm.org\/cardioexchange\/?post_type=news&p=29191"},"modified":"2012-05-21T15:37:27","modified_gmt":"2012-05-21T19:37:27","slug":"rivaroxaban-for-acs-gets-positive-fda-review-but-questions-about-atlas-trial-conduct-persist","status":"publish","type":"post","link":"https:\/\/blogs.nejm.org\/cardioexchange\/2012\/05\/21\/rivaroxaban-for-acs-gets-positive-fda-review-but-questions-about-atlas-trial-conduct-persist\/","title":{"rendered":"Rivaroxaban for ACS Gets Positive FDA Review, but Questions About ATLAS Trial Conduct Persist"},"content":{"rendered":"

The FDA will offer generally positive – but also highly mixed – advice to the FDA\u2019s Cardiovascular and Renal Drugs Advisory Committee when it meets\u00a0on Wednesday to consider the\u00a0supplemental new drug application for\u00a0rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy.\u00a0The FDA posted the briefing documents on its website this morning.<\/a><\/p>\n

The primary clinical review and the statistical review support approval for the new indication (the drug is already approved for venous thromboembolism prophylaxis and stroke prevention in AF). However, one reviewer, Thomas Marciniak, the Medical Team Leader, issued a blistering memorandum suggesting that the supporting data, plagued by missing and inconsistent records in\u00a0the pivotal ATLAS ACS 2-TIMI 51 trial<\/a>, \u201cmay not support the favorable statistical results.\u201d<\/p>\n

The primary clinical reviewer, Karen Hicks, recommended approval for the 2.5-mg BID dose (but not the 5-mg dose) of rivaroxaban for ACS. She noted that the lower dose reduced the combined endpoint of CV death, nonfatal MI, or nonfatal stroke in the ATLAS trial, with most of the benefit driven by a reduction in CV death, with little or no difference in MI or stroke. The higher 5-mg dose increased bleeding risk in the trial without providing additional efficacy, she concluded. She did not recommend a mortality indication for the label. Her views generally coincide with the reception of the ATLAS trial<\/a>\u00a0following its presentation and\u00a0publication in the New England Journal of Medicine<\/em><\/a>.<\/p>\n

It should be noted that Hicks hedged her endorsement with a potentially significant caveat:<\/p>\n

For the reasons stated above, I recommend approval. Should additional information become evident in the next two months that affect overall trial interpretability, I may choose to reconsider this recommendation.<\/p><\/blockquote>\n

The reasons for her statement are spelled out by Marciniak in his memorandum near the end of the FDA briefing document. Marciniak raises concerns about the high 12% rate of incomplete follow-up in ATLAS, writing: \u201cbecause of the extent of missing follow-up in ATLAS we cannot have confidence in either the calculated mortality or CV endpoint benefits.\u201d\u00a0Marciniak raises a number of other issues, including, most ominously, an audit that uncovered three uncounted deaths in the trial which \u201cmay be the trip of the iceberg regarding problems with missing data.\u201d<\/p>\n

Marciniak has been down this path before, with mixed results. During\u00a0the marathon 2-day Avandia meeting,<\/a> Marciniak thoroughly discredited the RECORD trial, and this played a role in the generally unfavorable committee recommendations. By contrast, although Marciniak and others were highly critical of the pivotal PLATO trial during the ticagrelor (Brilinta) advisory committee meeting, the committee and the FDA ultimately approved ticagrelor. Finally, we should remember that\u00a0the FDA reviewers initially recommended against approval of rivaroxaban for the AF indication<\/a>\u00a0due to concerns about the ROCKET trial but that the committee ultimately recommended approval, based on\u00a0their support of large, pragmatic trials<\/a>. Compared with the drama of\u00a0that<\/em>\u00a0hearing, Wednesday\u2019s session is likely to be much less contentious.<\/p>\n","protected":false},"excerpt":{"rendered":"

The FDA will offer generally positive – but also highly mixed – advice to the FDA\u2019s Cardiovascular and Renal Drugs Advisory Committee when it meets\u00a0on Wednesday to consider the\u00a0supplemental new drug application for\u00a0rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy.\u00a0The FDA posted the briefing […]<\/p>\n","protected":false},"author":196,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[495],"tags":[239,1009,1238,366],"class_list":["post-29191","post","type-post","status-publish","format-standard","hentry","category-anticoagulation-2","tag-acs","tag-atlas-acs","tag-fda-advisory-panel","tag-rivaroxaban"],"_links":{"self":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/29191","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=29191"}],"version-history":[{"count":0,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/posts\/29191\/revisions"}],"wp:attachment":[{"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/media?parent=29191"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/categories?post=29191"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.nejm.org\/cardioexchange\/wp-json\/wp\/v2\/tags?post=29191"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}