Strike 2 For Once Promising GSK ‘Stinkbomb’ Heart Drug Reply

GSK said today that a large phase 3 trial of a once highly-promising drug had failed to meet its primary endpoint. Last year the company  announced that another phase 3 trial with the same drug had  failed. GSK said it would “further analyse the data and better understand the findings” but that, for now at least, it would not seek regulatory approval for the drug.

The SOLID-TIMI 52 (Stabilisation Of pLaques usIng Darapladib – Thrombolysis In Myocardial Infarction 52) trial randomized more than 13,000 patients within 30 days of an acute coronary syndrome to receive either placebo or darapladib, an anti-inflammatory drug designed to stabilize atherosclerotic plaques. GSK reported today that the drug did not significantly reduce major coronary events.  The full results of the trial will be presented at a future scientific meeting.

Click here to read the full post on Forbes.


FDA Once Again Rejects New Indication For Rivaroxaban Reply

The third time wasn’t the charm. The FDA today turned turned down– for the third time– the supplemental New Drug Application (sNDA) for rivaroxaban (Xarelto, Johnson & Johnson) for use in acute coronary syndrome patients to reduce MI, stroke or death. In addition, the FDA– for the second time– turned down the sNDA for rivaroxaban in the same population for the reduction of stent thrombosis.

Click here to read the full post on Forbes.


Younger Women With Acute Coronary Syndromes Less Likely To Have Classic Chest Pain Reply

Younger women with an acute coronary syndrome are slightly less likely than men to present with the classic symptom of chest pain, according to a new study published in JAMA Internal Medicine. In recent years there has been a growing understanding that women with ACS are less likely to have chest pain and, partly as a result, often fail to receive a correct diagnosis in the emergency department. However, there has only been limited data on whether this pattern is also true for younger women.

Nadia Khan and colleagues prospectively analyzed data from more than 1,000 ACS patients 55 years of age or younger– 30% of whom were women– participating in the GENESIS PRAXY study.  When compared with older cohorts in previous studies, patients in the study were more likely to have chest pain, but even in these younger patients women were less likely to have chest pain than men…

Click here to read the full story on Forbes.



New Test Could Speed Heart Attack Treatment In The Emergency Department Reply

Only 1 in 10 patients with acute chest pain in the emergency department turn out to have an actual heart attack (myocardial infarction), yet many are not released from the hospital until after 6-12 hours of cardiac monitoring and multiple ECG and troponin tests. The search for a test that can rule out MI early in the process has proved elusive.

The Biomarkers in Cardiology-8 (BIC-8) trial, presented at the European Society of Cardiology meeting in Amsterdam, was designed to determine the utility of the combination of troponin and copeptin testing. Copeptin is a marker of severe hemodynamic stress. After an acute MI copeptin levels increase rapidly. In earlier observational studies the combination test was found to have a negative predictive value of 99%.

902 patients with suspected ACS who were troponin negative were randomized to standard treatment or an experimental strategy in which patients with a negative  copeptin test were discharged early. At 30 days there were no significant differences in the rate of major adverse cardiovascular events between the two groups:

Click here to read the full post on Forbes.


FDA Turns Back New Indication For Rivaroxaban To Prevent Stent Thrombosis In ACS Patients Reply

Johnson & Johnson said today that it had received a complete response letter from the FDA for the supplemental new drug application for rivaroxaban (Xarrelto) for the prevention of stent thrombosis in patients with acute coronary syndromes (ACS). Earlier this year the FDA turned down for the second time the sNDA for the  general use of rivaroxaban to treat ACS patients.

Click here to read the full story on Forbes.


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FDA Again Rejects ACS Indication for Rivaroxaban (Xarelto) Reply

For the second time the FDA has turned down the supplemental new drug application (NDA) for the proposed indication of rivaroxaban (Xarelto, Johnson & Johnson) to treat patients with acute coronary syndrome (ACS).

In a new press release issues on Monday afternoon, the company restated its confidence “in the robustness and results of the ATLAS ACS 2 TIMI 51 trial.” Criticism of ATLAS from the FDA and the advisory panel members had focused on missing data from the ATLAS trial. In today’s press release J&J provided more information about its efforts to address this question:

Click here for the complete story on Forbes.

Expert Consensus Document Offers Advice On Troponin Tests Reply

A newly published document provides practical advice on the use of the popular and potent troponin tests. The Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations was developed by the American College of Cardiology Foundation in collaboration with several other societies to help address the many complex issues raised by the introduction of the tests in clinical practice.

Sanjay Kaul, a co-author of the document, said the document does not contain new information, but was written to respond to the request of clinicians “for help regarding the considerations for ordering, interpreting, and using troponin as a decision aid in the management of patients with ACS and non-ACS conditions.” The document provides “a roadmap for the proper use of troponin in the setting of appropriate clinical context. The hope is to avoid unnecessary testing and referral as well as inappropriate utilization of downstream diagnostic and therapeutic interventions.”

The document helps physicians understand when they should order troponin tests and how to interpret the results. The recommendations are designed to work in coordination with the recently updated universal definition of MI, and provide detailed information about the use of troponins in acute coronary syndromes, PCI, CABG, and a variety of nonischemic clinical conditions.

“There are many things that can cause damage to the heart muscle that would allow troponin to leak in the circulation where we can measure it, and it’s not always due to heart attack,” said L. Kristin Newby, the co-chair of the writing committee, in an ACC press release. “So if we are indiscriminate in how we order these tests or we aren’t paying attention to the clinical scenario before us, we may miss something important.”

“We need to be thinking about why we are ordering the troponin test before we order it,” said Newby. “We hope this document provides a road map to help clinicians be more deliberate when ordering these tests and interpreting the results.”
Click here to read the ACC press release…

“Dramatic” Increase In Bleeding Accompanies Addition Of Oral Anticoagulant Therapy In ACS Reply

The newer oral anticoagulants may help reduce ischemic events after an acute coronary syndrome (ACS), but only at the cost of a “dramatic” increase in bleeding complications, according to a new meta-analysis published in the Archives of Internal Medicine.

Hungarian researchers performed a systematic review and meta-analysis of seven trials in which 31,286 ACS patients were randomized to placebo or a new oral anticoagulant, either an anti-Xa or direct thrombin inhibitor. All patients also received antiplatelet therapy. Here are the odds ratios for bleeding events and important clinical endpoints with the newer agents:

  • TIMI major bleeding events: OR 3.03 (2.20-4.16)
  • Overall mortality: OR 0.90 (0.76-1.06)
  • Composite ischemic events: OR 0.86 (0.79-0.94)
  • Stent thrombosis (definite or probable): OR 0.73 (0.54-0.98)

“These results suggest that the unrestricted use of new-generation oral anticoagulant agents as an adjunct to dual antiplatelet therapy after an ACS cannot be recommended,” the authors concluded. However, they left open the possibility that the newer oral anticoagulants may be beneficial in the 6%-21% of ACS patients who require long-term anticoagulation for atrial fibrillation and other conditions.

In an accompanying comment, Adrian Hernandez writes that “the conclusions of the meta-analysis seem to be robust.” He points out that the large differences in the relative risk of bleeding and clinical events found in the meta-analysis translate into smaller differences in absolute risk. Nevertheless, he writes, “the benefit is largely canceled by the harm; therefore, the routine use of [novel oral anticoagulants] among patients with ACS is unwarranted.”


TRILOGY At ESC: No Advantage For Prasugrel Over Clopidogrel In Medical ACS Patients Reply

The newer antiplatelet agent prasugrel was no better than the old standby clopidogrel for treating patients with acute coronary syndrome (ACS) who are not undergoing revascularization. The results of the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial were presented by Matt Roe at the European Society of Cardiology meeting in Munich and published simultaneously in the New England Journal of Medicine.

In the primary analysis of the trial, prasugrel (10 mg daily) was compared with clopidogrel (75 mg daily) in 7243 ACS patients younger than age 75. At 17 months, the rate of CV death, MI, or stroke did not differ significantly between the two groups:

  • 13.9% in the prasugrel group versus 16.0% in the clopidogrel group (hazard ratio [HR] for prasugrel, 0.91; 95% CI, 0.79-1.05, P=0.21)

The results were similar in a secondary analysis, which also included 2083 patients who were age 75 or older and who received either  low-dose prasugrel (5 mg daily) or the standard clopidogrel dose.

In a separate prespecified analysis, prausgrel patients under age 75 had a decreased risk for multiple recurrent ischemic events (HR, o.85; 95% CI, 0.72-1.00, P=0.04). According to the TRILOGY investigators, this finding is consistent with results from the earlier TRITON trial. TRITON compared prasugrel with clopidogrel in ACS patients undergoing revascularization; recurrent ischemic events in the prasugrel group were reduced by 30%, with most of the reduction occurring later in the trial. “Although this observation is exploratory,” the TRILOGY investigators wrote, ” it raises the question of whether investigation of the multiplicity of ischemic events is warranted in future secondary-prevention trials, rather than solely analyzing the time to the first event, as has been traditional” in previous studies.

The prasugrel and clopidogrel groups did not differ significantly in the rate of severe and intracranial bleeding. However, within the younger subgroup (taking the higher prasugrel dose), prasugrel recipients had more major and minor bleeding complications than clopidogrel recipients did — a reflection, the authors wrote, of “the more intense platelet inhibition with prasugrel.”

An exploratory analysis found that in the main group of patients under the age of 75, the Kaplan-Meier curves for the primary endpoint and for the individual components of the endpoint were not different for the first year but diverged afterward in favor of prasugrel. “The reasons for this finding remain uncertain,” the investigators wrote.

A subgroup analysis suggested the possibility that prasugrel might be more effective than clopidogrel in current or recent smokers, in patients who underwent angiography prior to randomization, and in patients taking a proton-pump inhibitor.

Sanjay Kaul provided the following comment:

“I find the TRILOGY investigators’ focus on time-dependent treatment effect (greater benefit after 12 months of treatment exposure) and recurrent events, both of which favor prasugrel, an attempt at cherry picking the data that portray prasugrel in the best light. The bottom line is that given the lack of a statistically discernible difference in the primary efficacy endpoint coupled with an increase in TIMI major or minor bleeding and increased cost associated with prasugrel, it is hard to make a case for prasugrel over clopidogrel treatment in low- to moderate-risk patients with unstable angina and NSTEMI who do not undergo revascularization. Although TRILOGY was not adequately powered to detect a cancer signal, the lack of increase in new nonbenign neoplasms is somewhat reassuring.”

Republished with permission from CardioExchange, a NEJM group publication.

FDA Rejects ACS Indication for Rivaroxaban (Xarelto) 2

The FDA has issued a complete response letter to the supplemental new drug application (NDA) for the proposed indication of rivaroxaban (Xarelto, Johnson & Johnson) in patients with acute coronary syndrome (ACS). The action was expected, since last month the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against recommending the new indication, which was based on the pivotal ATLAS ACS 2-TIMI 51 trial.

In a press release a J&J company official said the company remains “confident in the robust results of the ATLAS ACS 2 TIMI 51 trial and the positive benefit-risk profile of rivaroxaban in patients with ACS. We will continue to work with the FDA to fully address their questions as quickly as possible.” Rivaroxaban is currently approved for the prevention of clots following knee replacement and hip replacement surgery and for the prevention of strokes and blood clots in people with atrial fibrillation.

Click here to read the press release from J&J…

FDA Advisory Committee Recommends Against ACS Indication For Rivaroxaban 1

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against adding an indication for acute coronary syndromes (ACS) to the label  of the anticoagulant rivaroxaban (Xarelto). The vote was 6 to 4 against approval, with 1 abstention.

The advisory panel spent most of the day trying to reconcile diametrically opposed views of the pivotal ATLAS ACS 2-TIMI 51 trial. On the one hand, the sponsor (Johnson & Johnson) and the TIMI investigators (Jessica Mega, C. Michael Gibson, and Eugene Braunwald) portrayed a robustly positive trial that strongly demonstrated the beneficial effects of low dose rivaroxaban in ACS when added to dual antiplatelet therapy. On the other hand, one FDA reviewer, Medical Team Leader Tom Marciniak, raised multiple questions about the validity of the trial and its conclusions because of an alarming amount of early withdrawals and missing data. His view was largely endorsed by several committee members, including Steve Nissen and Sanjay Kaul.

In a press release, J&J said it “will ensure the questions raised today are addressed with the FDA.”

See my previous post for a detailed live account of the advisory committee meeting.

Live Blog: The FDA Advisory Panel For Rixaroxaban for ACS 1

Here’s my live-blogg of the FDA’s Cardiovascular and Renal Drugs Advisory Committee meeting to consider the supplemental new drug application (sNDA) for rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy. Here is a link to the FDA briefing documents.


4:48: Meeting adjourned! J&J has just issued a press release saying they will “ensure the questions raised today are addressed with the FDA.”

4:45: Temple is raising the possibility that the FDA might ultimately approve rivaroxaban for ACS. I would not be shocked if this were to happen.

4:38: Now discussing whether the FDA should say about the use of rivaroxaban with thienopyridine. All agree that people should be on a thienopyridine. What about prasugrel and ticagrelor? Nissen says the reality is that rivaroxaban will be given with these drugs, even though there’s no evidence. This was part of his reasoning in voting no. Sager said he would be more concerned about prasugrel, because of the excess risk of bleeding associated with prasugrel. But he notes there is no evidence to support use with either drug.

4:33: Moving on to questions about what to do if rivaroxaban is approved. Everyone agrees that the 2.5 dose is the dose that would get approved.

4:30: Kaul said he wished he had had the courage to abstain (to general laughter) and said he agrees with Fleming that he’d rather advise than vote, and that there was a very fine line between yes and no today.

4:24: Nissen thinks the decision to use mITT– which is counting events at 30 days after stopping treatment– is what doomed ATLAS. With mITT, he says, you’re telling the investigators and the patients that you don’t care so much about what happens to them long term. Nissen thinks the drug could be approvable if there were a second trial, but he also says its possible that the mortality benefit would not be replicated. He’s worried about exposing hundreds of thousands of patients to a three-drug regimen and causing lots of bleeding complications.

4:18: Results: Yes 4, No 6, 1 Abstain!

Voting breakdown:
Click to continue reading…