A missing piece of the Multaq puzzle finally appears: DIONYSOS published to little fanfare Reply

The Greek god Dionysos demanded a great deal of attention. When King Pentheus refused to acknowledge the divinity of Dionysos, the god exacted a terrible and bloody revenge, as recounted in the Bacchae, one of the great tragedies of all time. But the new Dionysos is far less demanding. You might even say he’s shy.

This modern Dionysos isn’t a god but a clinical trial comparing the Sanofi drug Multaq (dronedarone) with amiodarone. But you probably haven’t heard much about DIONYSOS and in the view of Sanofi that’s not a tragedy.

The preliminary results of DIONYSOS were released in a Sanofi press release back in December 2008. Subsequently the data was made available to the FDA’s cardiorenal advisory committee and was incorporated in the critical viewpoint and commentary by Sanjay Kaul’s group and published in JACC . Now, finally, the results of DIONYSOS have been published in the Journal of Cardiovascular Electrophysiology along with an accompanying editorial by Jayakumar Sahadevan and Albert Waldo. But don’t look for a press release or any other efforts to disseminate the findings of the trial from Sanofi.

An experienced cardiologist who wishes to remain anonymous informed me about the publication and offered some pungent commentary. Here’s what he had to say:
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Live-blogging the FDA Brilinta Panel-afternoon session 6

4:52: Panel is adjourned!

The bottom line: the committee voted 7-1 in favor of approving ticagrelor for the indication of STEMI and NSTEMI patients who will be treated either medically or invasively.

4:47: Getting close to the end. Would love to hear any comments or suggestions about this live-blogging experiment. Feel free to add comments at the bottom of the post or send an email.

4:43: Now discussing language of the label and limitations of use.

4:39: Committee members generally support language for stent thrombosis claim but Kaul and D’Agostino don’t think it should be an actual indication. Long discussion about whether or not the stent thrombosis endpoint was retrospective or not. Only at the FDA can you have a long retrospective discussion about whether an endpoint was retrospective. Prospectively I’m going nuts.

4:35: Now they are discussing a claim for reduction of stent thrombosis. They’re not voting electornically but everyone is weighing in.

4:33: Chris Cannon says the TIMI group is planning a trial starting at 1 year after ACS randomizing ticagrelor to placebo. Kaul says that won’t address the immediate problem in US ACS patients.

4:26: Stockbridge asks if a US ACS trial to rule out harm would be ethical? (Same questions raised 2 weeks ago about TIDE). Temple doesn’t see a problem doing a trial.

4:23: Stockbridge says the US/OUS discrepancy is about as big as they’ve ever seen. He asks the committee to consider what would it take for a difference like that to effect their vote.

4:21: Now voting on 6b: medical management of STEMI/NSTEMI. Same result. 7 in favor, 1 against. But Kaul doesn’t support an indication for unstable angina…
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Live-blogging the FDA Brilinta Panel-morning session 2

Click here for the live-blog of the afternoon session.

Lunch. Back at 1 PM.

12:05: Temple summarizes the dilemma: this drug doesnt do what it’s supposed to do in the country in which it’s being asked to get approved. Kaul adds that if aspirin is the answer why isn’t this difference also reflected in the bleeding data.

11:59: Harrington: US guidelines much more tolerant of high dose aspirin than European guidelines. Kaul: but OASIS 7 found no difference in bleeding rates (except for GI bleeding) between high/low dose aspirin.

11:49: Harrington: patients lost to followup very common in large clinical trials– no reason to think any bias involved in PLATO. But panelist Neaton says that the loss of followup in the US was unacceptably high. Harrington responds that vital status followup in US was 100%.

11:46: Henry Black: “so much slicing and dicing I think we’re watching a cooking show”

11:43: Is it fair to say this advantage has not been shown in PLATO? Marciniak hedges.

11:28: Now followup questions for the FDA.

11:27: Missing follow-up and missing data are the number 1 problem in clinical trials today.

11:22: Marciniak: generally a good study but poor followup.

11:19: Marciniak: Data suggests that aspirin is a marker for risk.
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Mixed reviews for Brilinta prior to Wednesday’s FDA panel Reply

The reviews are mixed. Five different FDA reviewers had 5 widely diverging views of ticagrelor. Wall Street analyst predictions range from cautious optimism to concern.

Barclays Capital analyst Brian Bourdot wrote that “the documents read more favorably in support of approval than we had expected,” while Leerink Swann analyst Seamus Fernandez viewed the documents as “mixed to negative” and predicted that the drug would not reach the US market until 2013.

Bernstein analyst Timothy Anderson thinks that ticagrelor will “squeak through with a positive recommendation” but questions “how well the product will sell.” Anderson has a very nice overview of the FDA briefing materials:
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FDA finally posts briefing documents for Brilinta (ticagrelor) advisory panel Reply

Updates: 5:30 PM: The FDA doesn’t make it easy for outsiders to wade through all the documents. A good case in point is the ticagrelor package. The main briefing document contains a summary memorandum by the Medical Team Leader, Thomas Marciniak, dated June 29. You could read the whole thing before realizing that a separate document, available here, contains an updated version of the memo, dated July 16. I’m guessing this is the one single document most casual observers would want to read. (FYI, Marciniak was one of the key critics of  Avandia and other recent controversial drugs, including prasugrel. He’s tough. If he had been one of my high school teachers I’m sure I would have been a high school dropout.)

Marciniak concludes that concerns about efficacy are the chief issues with ticagrelor and PLATO. As mentioned above, the biggest questions are likely to revolve around the lack of effect of ticagrelor in the US population in PLATO, and the possible role of aspirin dose in explaining this difference. The difference between the US and the rest of the world is striking, writes Marciniak:
Click to continue reading, including links to the FDA documents…

DC storm causes delay in release of Brilinta (ticagrelor) briefing materials 1

Due to a delay related to violent thunderstorms in the Washington, DC area on Sunday, the FDA has been so far unable to post the highly anticipated briefing documents for Wednesday’s advisory panel meeting on ticagrelor (Brilinta, AstraZeneca). The committee is scheduled to discuss the proposed indication of ticagrelor in patients with ACS. The FDA told CardioBrief that about 10 FDA buildings were closed because of the storm and that some computer systems were down.  In addition, many FDA staff members couldn’t get to work or were unable to enter their buildings.

CardioBrief will post links to the documents when they are posted by the FDA, along with commentary and excerpts later on. On Wednesday CardioBrief will live-blog and live-tweet the panel meeting.

“Is it safe?” Reply

Is it safe? Like the Nazi dentist played by Laurence Olivier in Marathon Man, we all want an answer to the question: is it safe? And like the poor victim played by Dustin Hoffman, you can torture us as much as you want but we can’t answer the question if we don’t have the data.

Recall that in the movie the Nazi dentist wants Hoffman’s character to tell him whether it’s safe to pick up a horde of valuable diamonds extorted from the victims of Auschwitz, but Hoffman has no idea what’s going on. The dentist keeps repeating the same question: “Is it safe?”

Last week 33 advisory panel members tried to answer the same question about Avandia: is it safe? And, it could be said, for two days they tortured the data, trying to find an answer. Of course they couldn’t succeed because, just like in the movie, you can’t answer a question if you don’t have enough information. We like to think that medicine, as a branch of science, can give us hard facts and certainty, but the truth is that when it comes to clinical reality the world is usually gray and only rarely black or white.
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FDA refers Avandia panelist conflict of interest case to HHS Inspector General 1

In the wake of reports earlier this week that some members of the Avandia advisory committee may have had conflicts of interest, the FDA said on Friday that it had referred the case of one panel member, David Capuzzi, to the Health and Human Services Office of Inspector General.

The FDA sent CardioBrief the following statement:

FDA has completed its fact-gathering process and has referred the Dr. Capuzzi matter to the HHS Office of Inspector General. FDA is prohibited by law to release Dr. Capuzzi’s or any member’s confidential financial disclosure form or to comment on what is or is not disclosed in a form. Dr. Capuzzi has the right to voluntarily provide his form for public review. The agency cannot comment on an ongoing investigation.

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FDA approves first generic low molecular weight heparin Reply

The FDA has approved the first generic low molecular weight heparin (LMWH) for multiple indications including prevention of deep vein thrombosis (DVT). Approval for the generic enoxaparin version of Lovenox was granted to Sandoz, the generic arm of Novartis, on Friday.

Generic forms of enoxaparin and other low molecular weight heparins have been been the subject of past controversy.

The FDA noted in its press release (see below) that the approval process for a “natural product” like enoxaparin is more complex than the process for small molecules. “Before approving generic enoxaparin sodium injection, we expected, among other things, a series of sophisticated analytical tests and a study in healthy volunteers to assure that the drug would be as safe and effective as the brand name product,” said Keith Webber, Ph.D., deputy director of the FDA’s Office of Pharmaceutical Science, in an FDA press release.
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JUPITER: HDL doesn’t predict residual risk in statin-treated patients with low LDL levels Reply

HDL has long been recognized as having a strong inverse correlation with cardiovascular events, but a new analysis of the JUPITER trial suggests that it may not predict residual risk in statin-treated patients who have reached very low LDL levels. The new report by Paul Ridker and colleagues appears in the Lancet.

Among JUPITER patients randomized to placebo, HDL levels were inversely related to vascular risk both at baseline and on-treatment. By contrast, among patients who received rosuvastatin, “no signficant relationships were noted” between HDL levels and vascular risk either at baseline or on-treatment. A similar pattern was observed with apo A1.
Click to continue reading, including a comment from Paul Ridker…

FDA puts TIDE on “partial clinical hold” 1

The FDA has put the controversial Avandia safety trial TIDE on “partial clinical hold.” The action means that new patients may not be enrolled in the trial until the FDA gives the green light. Patients already enrolled in the trial will continue to participate in the trial.

In its statement the FDA said it had instructed GlaxoSmithKline to “update investigators, institutional review boards (IRBs) and ethics committees involved in the TIDE trial” with information about last week’s 2-day panel meeting.

In a statement in response to the FDA announcement, GSK said that it would suspend enrollment of patients in TIDE and “will work with the TIDE Steering Committee” to send new safety data and a summary of the panel meeting to TIDE investigators and IRBs. GSK noted that the advisory panel voted 20-10 in favor  of TIDE being allowed to continue.
Click here to read the FDA statement and the GSK statement…

Guest post: Prophylactic ICDs may not benefit women… Reply

(The following guest post is reprinted with permission from the blog of Dr John Mandola, an electrophysiologist in Louisville, KY.)

The heart of a woman may be much different than that of a man. The “Go Red” campaign would surely agree.  As would most masters of the obvious. But in the case of whether female hearts garner the same benefit from a prophylactic implantable defibrillator (ICD), women may be much different than men.

As published in the increasingly influential journal, Heart Rhythm, researchers from Italy and Austin TX. have published a provocative report (e-version is free) on the gender differences of ICD benefits.  The trial was a systematic review and meta-analysis of the major prophylactic ICD trials.  By culling the 5 major ICD primary prevention trials, a cohort of 1,630 women (23% of the total study populations) was analyzed.

This statistical analysis of the five major primary prevention ICD trials (the trials which current ICD implantation guidelines are based upon) revealed three very important findings:
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2 Avandia panel members found to have received money from GSK and Takeda 4

[This is an update of an earlier story.] At the Avandia panel last week the FDA said it had carefully reviewed disclosure statements from all potential panel members and that all 33 voting members had no relevant conflicts. But two panel members, it now turns out, had received speaking fees, one from GlaxoSmithKline and one from Takeda, which makes Actos (pioglitazone), an Avandia competitor.
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Avandia aftermath: who are the winners and losers? 6

Responses to the Avandia panel have been all over the map, as cleverly noted on the Wall Street Journal health blog. Avandia is “dead” (Forbes), or, perhaps worse, “now a Zombie” (BNET). By contrast, others thought the panel granted Avandia a “reprieve” (Wall Street Journal and that Avandia would now probably be allowed to stay on the market (Los Angeles Times, Pharmalot).

All these views are right though I think they miss some of the complexity of the issue. For instance, in my view Avandia took a big hit, but GSK actually came out better than expected. Here’s my scorecard, with annotations, of the winners and losers:

Avandia (rosiglitazone) lost. 22 out of 33 panelists thought the drug should either be withdrawn from the marketplace entirely or have severe restrictions or limitations imposed on its use. The fact that only a plurality of panelists voted for withdrawal should be cold comfort to the drug’s supporters. You know you’re in trouble if the best argument supporters can make about a drug is that it probably doesn’t kill you or harm you and that maybe in a small percentage of people it will help where other drugs can’t.
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FDA announces safety review of ARBs and cancer 1

The FDA announced today that it was conducting a review of angiotensin receptor blockers (ARBs) following the recent publication (CardioBrief story here) of a metaanalysis last month in the Lancet by Sipahi and colleagues that found a modest but statistically significant increase in the risk of cancer associated with the use of ARBs. The FDA states that the review is ongoing and that it has not concluded that ARBs increase the risk of cancer and that it believes at this time the benefits of ARBs still outweigh the risks.
Click here to read the FDA communication…

Dick Cheney receives an LVAD 2

Former Vice President Dick Cheney received a left ventricular assist device (LVAD) last week, according to reports in USA Today, the Wall Street Journal, and MSNBC. “A few weeks ago, it became clear that I was entering a new phase of the disease when I began to experience increasing congestive heart failure. After a series of recent tests and discussions with my doctors, I decided to take advantage of one of the new technologies available,” Cheney said in a statement to the media. Cheney told the press that the operation went well and that he is feeling “very well.” The procedure was performed at Fairfax Hospital in Virginia.

Here is the complete statement from Cheney:
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Day 2 of the FDA Avandia Panel: Live Blogging the End 5

Meeting Adjourned.

4:33: Konstam: I don’t get him. He’s defended rosi for 2 days and then votes E. Now he votes against TIDE but says it should be cont’d.

4:29: Would love feedback from readers about this live-blogging experiment. This is my first time doing it. Fun but exhausting. Did you find it useful? Any suggestions?

4:27: Should TIDE continue:  yes: 20, no: 10, abstain 2

4:24 Now starting discussion about TIDE. Should it be allowed to continue? (I think given the previous vote they will have to allow TIDE to continue.)

4:21: Konstam says FDA is not broken, doesn’t need to be reorganized, and congratulates Woodcock. I’d like to hear Nissen’s response…

4:01: CardiologyToday’s tweet: “FDA advisory panel voted 20-12 to keep #Avandia on the market.” I hadn’t thought about it in that way exactly. Will this be the headline tomorrow? On the other hand, Matt Herper wrote: “29 voted to strengthen label. It sounds like the mother of all REMS.”

3:55: Vote very hard to interpret. I’m guessing the real winner is D, so that the drug will be allowed to stay on the market but with additional restrictions. This won’t make anyone happy, and there will probably have to be another panel to decide the new restrictions. Does the FDA have a frequent flyer program for drugs?

3:40: RitaRubin:  “so a plurality for withdrawal, but a majority for being on the market???” So this means the Avandia controversy may only be starting! (Why didn’t anyone do the math beforehand?)

3:35: Vote: Withdrawal gets plurality. But note that more total votes to keep it on market. How to interpret?

  • A 0
  • B 3
  • C 7
  • D 10
  • E 12

1 abstention
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Day 2 of the FDA Avandia Panel- Live Blogging the Morning 1

NOON: LUNCH BREAK

11:59: Marciniak claims RECORD suffers from “differential informative censoring”– a great way to influence mortality statistics!

11:57: Marciniak says the problem in reporting events was NOT at the sites, it was from the middlemen. Says GSK tried to influence adjudication.

11:50: GSK clarifying concerns about RECORD.  Nearly all diabetes trials are open label. GSK says apparent imbalance in adjudications is due to endpoint forms vs SAE forms. Also silent MIs were never an endpoint. Also GSK made every attempt to get vital status of patients.

11:42: Moss asks Homes about 2 GSK representatives on steering committee. Moss says on his trials we never let industry reps on steering committee. Homes notes that the steering committee was firewalled from the data. And also concedes that the data was transferred from Quintiles to GSK.

11:33: Furberg to Homes: unacceptable high number of patients in RECORD with missing vital status. “almost unethical.” Homes disagrees, says the number of missing vital status is similar to other trials. We’ve no reason to believe those lost to followup are any different from the rest of the population.

11:28: Gerstein won’t say how TIDE will deal with slower than projected enrollment. The Fleming-Gerstein exchange may be VERY important this afternoon. If the committee agrees with Fleming’s skepticism then it may be all over for Avandia.

11:27: Gerstein: more than a 1/3 of TIDE sites waiting for panel decision before enrolling patients. We think we can recruit the 15,000 remaining patients in 18 months.
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Day 1 of the FDA Avandia Panel: Live Blogging the Afternoon 2

6:21: Kaul winds up to deliver a knock-out punch to the Nissen meta-analysis but Nissen pulls a judo move and turns the question around. Admitting his methodology and data are weak he asks: “who’s fault is it that there’s no better data?” After 11 years on the market GSK can only blame itself if there’s no better data, says Nissen.

6:00: Moritz will actually dare to present the same type of analysis for VADT that was just slammed for BARI 2D. He said he’s old and can take it. If you listen carefully you can hear Kaul and Fleming sharpening their knives. This is not going to be pretty.

5:38: Fleming really rips into the BARI 2D analysis. This type of analysis of BARI 2D is useless for understanding rosiglitazone, he said. “Not all sources of observational data are equally reliable, the conclusions are too strongly stated for a seriously biased study.” Sanjay Kaul completely agrees. Under withering attack Brooks gives up and waves the white flag. BARI 2D doesn’t really say anything about rosi, she agrees.
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Day 1 of the FDA Avandia Panel- Live Blogging the Morning 3

The afternoon will be blogged in a separate post.

Lunch break until 1 PM.

12:05: Ungar: to answer the malfeasance question we may have to audit the entire trial

12:02: Kaul: Did Marciniak unearth malfeasance in RECORD? How many missing MIs in RECORD were biomarker-only or clinical events?

11:59: Ungar says he is concerned about the overall data quality in Avandia trials. Mortality is reassuring, but he agrees that the followup issues raised by Marciniak creates problems for this view. > This is his defense?

11:57: Ungar, agreeing for once with Marciniak, says he doesn’t like CV deaths in a trial that is open label.
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NY Times: GSK concealed negative Avandia study 1

Update: The Senate Finance Committee has released its letter to FDA leaders and documents it unearthed about the missing Avandia trials. GSK issued a response.

GSK began a study comparing the safety of rosiglitazone (Avandia) to pioglitazone (Actos) back in 1999 and spent the next 11 years keeping the study a secret, according to a report in the New York Times by Gardiner Harris.

The Times quotes an email message from 2001 written by a SmithKline executive, Dr Martin Freed, “This was done for the U.S. business, way under the radar. Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK.”
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