Novartis pays $422 million to settle DOJ lawsuit 1

Novartis has agreed to pay $422 million to settle a US Department of Justice and whistleblower lawsuit. Although many of the allegations against the company concerned the off-label promotion of the epilepsy drug Trileptal, key additional portions of the lawsuit involved the company’s cardiovascular products, including Diovan (valsartan) as well as Tekturna (aliskiren) and Exforge (valsartan and amlodipine).

The settlement, according to a press release issued by the US Department of Justice, resolves claims that the company

paid illegal kickbacks to health care professionals through mechanisms such as speaker programs, advisory boards, entertainment, travel and meals to induce them to prescribe Trileptal, as well as Diovan, Zelnorm, Sandostatin, Exforge and Tekturna.

The lawsuit included key details from a whistleblower, Jeremy Garrity, who had worked in the Cardiovascular/Metabolic division at Novartis. (Click here to read a fascinating interview with Garrity on Pharmalot.) Here are some of the details:
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Avandia, Meridia… now it’s Aranesp’s turn before the FDA Reply

The FDA Death Panel Cardiovascular and Renal Drugs Advisory Committee will consider the fate of darbepoetin alfa (Aranesp) on October 18. Having failed to impose the death penalty on rosiglitazone (Avandia) and Meridia (sibutramine) in recent months, it appears likely the committee will not recommend withdrawal of the drug, though in the absence of any evidence of substantial benefit additional restrictions appear likely.
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Guest post: My Life as a Mom Reply

Editor’s note: The following guest post is completely off-topic and, further, completely divergent from the cynical, skeptical, and occasional misanthropic perspective usually on display here. It is written by new mom Patricia Moreno, one of the most gifted fitness instructors on the face of the earth.

My Life as a Mom

My daughter Olivia is here. She was born September 18th at 9lbs 13 ounces.  She is beautiful, perfectly healthy and doing all the things you would expect from a newborn: eating, sleeping, crying and then more of the same. It is the most precious thing I have ever seen in my life.
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Guest post: news you can use: sex and your defibrillator Reply

Editor’s Note: The following post was written by Westby G. Fisher, an electrophysiologist at NorthShore University HealthSystem in Evanston, IL and the author of Dr Wes, a popular blog about cardiology, the internet, and anything else that catches his imagination.

Have a defibrillator and feel like getting frisky? For the first time that I can recall, a very helpful article published in Circulation addresses the concerns of implantable cardiac defibrillator(ICD) patients and sexual activity. There’s all kinds of helpful tidbits, like this one:
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Carotid endarterectomy still beneficial at 10 years Reply

Carotid endarterectomy (CEA) in asymptomatic patients under 75 years of age reduces the long-term risk of stroke, according to 10-year results from the Asymptomatic Carotid Surgery Trial (ACST), published in the Lancet. The ACST investigators randomized 3120 asymptomatic patients to immediate CEA or to indefinite deferral of CEA. At 5 years, CEA had been performed on 92.1% of patients in the immediate CEA group compared to 16.5% in the deferral group. At 10 years, the net risk (death or stroke within 30 days and non-perioperative stroke) was 13.4% % in the immediate CEA group versus 17.9% in the deferral group. The relative reduction in risk was independent of whether the patients were taking lipid-lowering therapy, but the absolute risk of stroke was lower in patients on lipid-lowering therapy.
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FDA keeps Avandia on market, re-adjudicates RECORD, halts TIDE; EMA suspends Avandia marketing 3

The FDA announced today that it would not remove rosiglitazone (Avandia) from the market but that it would impose severe new restrictions on its use. It also put on “full clinical hold” the controversial TIDE trial. The FDA is also requiring GSK to “commission an independent re-adjudication of the RECORD study.”

The new REMS will require documentation that risk information about the drug has been received by each patient taking rosiglitazone. For patients not already taking rosiglitazone documentation will be required demonstrating that the patient was unable to achieve glycemic control with other medications and has decided not to take pioglitazone for medical reasons.
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NEJM: fondaparinux effective in superficial-vein thrombosis Reply

In a randomized, double-blind trial, 3002 patients with acute, symptomatic superficial-vein thrombosis in the legs, but without DVT or symptomatic PE, received either fondparinux (2.5 mg) or placebo for 45 days. The primary efficacy endpoint– a composite of all cause death, symptomatic PE or DVT, symptomatic extension to the saphenofemoral junction, or symptomatic recurrence of superficial-vein thrombosis– was reduced by 85% from 5.9% in the placebo group to 0.9% in the fondaparinux group (p<0.001). There was no difference between the groups in mortality. All the other components of the composite endpoint were significantly reduced by fondaparinux. In their report in the New England Journal of Medicine, the CALISTO (Comparison of Arixtra in Lower Limb Superficial Vein Thrombosis with Placebo) investigators calculated that 20 patients would need to be treated with fondaparinux to prevent 1 primary endpoint event, and 88 to prevent DVT  or PE.
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PARTNER: “fundamental breakthrough” for transcatheter aortic-valve implantation 1

Patients with aortic stenosis who are not candidates for aortic valve replacement surgery can benefit from transcatheter aortic-valve implantation (TAVI), according to results of the PARTNER (Placement of AoRTic TraNscathetER Valves) trial published in the New England Journal of Medicine. (The trial will also be presented at the TCT conference on Thursday.) Martin Leon and colleagues randomized 358 patients with aortic stenosis who were judged ineligible for aortic replacement by a surgeon to receive TAVI or standard medical therapy.

At one year the mortality rate (the primary endpoint of the study) was 30.7% in the TAVI group versus 50.7% in the control group, a highly significant difference (HR 0.55, CI 0.40-0.74, p<0.001). The coprimary endpoint, a composite of death from any cause or repeat hospitalization, occurred in 42.5% of the TAVI group versus 71.6% of the control group (HR 0.46, CI 0.35-0.59, p<0.0001). Stroke or TIA, however, occurred in 10.6% of the TAVI group versus 4.5% of controls (p=0.04). Major vascular complications occurred in 16.8% of the TAVI group versus 2.2% of controls (p<0.001).
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FDA panel unanimously recommends approval for dabigatran 2

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-0 in favor of approval of dabigatran (Pradaxa, Boehringer-Ingelheim) for the prevention of stroke in patients with AF. The panel was split on whether both doses (150 mg bid and 110 mg bid) used in the RE-LY trial should gain approval, though in an informal straw poll a majority appeared to favor approval for both doses. (The FDA reviewers had recommended approval for only the higher dosage.) Most panel members also supported language on the label summarizing the superiority of the 150 mg dose over warfarin in RE-LY.
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Soap opera star helps BI prepare the market for Pradaxa (dabigatran) Reply

What can a soap opera star teach us about atrial fibrillation? Not much. But perhaps she can teach us a whole lot about pharmaceutical marketing in the 21st century.

Her first lesson is about market preparation, or creating awareness and demand for a product before it’s available. In this case the product is Pradaxa, and BI needs to convince millions of people they will be better off paying $8-$12 a day for the drug instead of the much cheaper, generic warfarin.
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Guest post: A rich OASIS for Your journal club 2

Editor’s note: This post by Harlan Krumholz is republished with permission from CardioExchange, a new website for cardiovascular healthcare professionals from the New England Journal of Medicine. CardioBrief readers who are healthcare professionals are invited to join the site.

by Harlan Krumholz

I’m always scouting for papers to discuss in journal club with my students. Earlier this month, I found the perfect pair: two simultaneously published articles from the industry-funded CURRENT–OASIS 7 randomized trial, one in the New England Journal of Medicine and the other in the Lancet. Many of the authors of the two papers were the same.
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Red light or green light for AAA screening? 2

Editor’s note: Last week I put up a post, Blue light special: AAA screening at Kmart in the disease-mongering aisle, that attracted some interesting and thoughtful comments. In particular, the exchange between Dan Hackam, an old online friend, and Joe Ross, a researcher who I quoted in the piece, is worthy of more attention than it might otherwise receive buried in the comments section. Here is that exchange:
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FDA announces safety review of pioglitazone (Actos) over cancer risk Reply

The FDA announced today that it was undertaking a safety review of pioglitazone (Actos). The review was initiated after the FDA received data from Takeda, the drug’s manufacturer, suggesting a possible increase in bladder cancer in patients taking the drug for more than 2 years. The data is taken from a planned 5 year analysis of an ongoing 10-year epidemiological study designed to examine the association of the drug with bladder cancer, following earlier studies suggesting a possible risk. Although the current analysis found no overall association between pioglitazone and bladder cancer, a further analysis found an increase in bladder cancer in those taking the highest cumulative doses of the drug and in those with the longer exposure to the drug.
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FDA panel votes 9-5 against approval of lorcaserin Reply

The FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 9-5 against recommending marketing approval for lorcaserin (Lorqess, Arena).

Panel members were underwhelmed by the modest weight-loss efficacy of the drug, and responded to concerns raised by FDA reviewers about the incidence of cancer in rats taking lorcaserin. Some panelists also thought the sponsor had not definitively ruled out the possibility of valvulopathy.

Approval likely for dabigatran as FDA posts positive briefing documents for advisory panel Reply

A positive recommendation for dabigatran appears likely based on the extremely benign briefing documents posted by the FDA in preparation for Monday’s meeting of the Cardiovascular and Renal Drugs Advisory Committee. The panel will discuss the NDA for dabigatran (Pradaxa, Boehringer Ingelheim) for the prevention of stroke in patients with AF.

The conclusions and recommendations of the reviewers suggest that panel members will have an easy time approving the drug. The hard work for the day will involve dosing issues and the precise language for the drug’s label.
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TREAT Analysis: Target Dosing is Tricky Reply

A new analysis of TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) is raising questions about the use of target-based strategies for the treatment of anemia in people with chronic kidney disease. (Last year, the main TREAT results showed that treatment with darbepoetin alfa was not beneficial, and was associated with an increase in the risk of stroke, in people with diabetes, chronic kidney disease, and moderate anemia.)
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FDA advisory panel refuses to put Meridia out of its misery Reply

8 members of the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted in favor of withdrawing sibutramine (Meridia) from the US market. 8 members voted to keep it on the market, though all 8 agreed it needed a boxed warning and 6 thought it also should have its distribution limited to specially trained physicians. No panel members thought it should be allowed to remain on the market without any changes to the current label.

“More bullet than magic!”
Click here to read a comment from panel member Sanjay Kaul…

Blue light special: AAA screening at Kmart in the disease-mongering aisle 8

Now, in addition to all the other stuff  there, you can go to Kmart and get screened for abdominal aortic aneurysm (AAA). Some people will even receive free ultrasound tests. The new program, from the Find the AAAnswers Coalition, was announced on Friday. It’s a perfect example of disease mongering, the selling of a sickness to increase sales of a drug or device.

In this case, the expenses of the program and the coalition are entirely underwritten by Medtronic, which sells abdominal stent grafts used to repair AAAs, and the members of the coalition include organizations like the Peripheral Vascular Surgical Society, the Society for Vascular Surgery, and the Society for Vascular Ultrasound, whose members may derive a significant portion of their income from performing AAA repairs and screening.
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FDA extends review of ticagrelor (Brilinta) until December 1

AstraZeneca announced today that the FDA had extended the PDUFA date for its highly anticipated antiplatelet drug ticagrelor (Brilinta) for 3 months. The deadline  for a decision on the drug’s approval has therefore been moved from  September 16 to December 16.

On July 28 the FDA Cardiovascular and Renal Advisory Committee voted 7-1 in favor of approving ticagrelor for the indication of STEMI and NSTEMI patients, but the committee and the FDA were uncertain about how best to apply the results of the pivotal PLATO trial because the overall positive effects of the drug were not observed in the subset of patients enrolled in the US.

Update: One highly knowledgeable expert provided this sensible perspective on the extension:

Given the difficulty of sorting through how to portray the “complicated” efficacy story in the label, and the limited FDA resources (and all the directions they are currently being pulled), and the FDA’s hypersensitivity to criticism from other corporate entities who might want to cry “foul” through their legislative representatives, I can appreciate how they might want to “get it right” the first time and require a little more time to do just that.
Click here to read the AstraZeneca press release…

FDA posts briefing documents for diet drug lorcaserin, investors get nervous Reply

The FDA has posted the briefing documents for the September 16 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee that will consider the NDA for the diet drug lorcaserin (Lorqess, Arena).

The FDA reviewers agree that the drug met the predetermined measure of efficacy, though only by a slim margin. After briefly skimming the documents I couldn’t find any serious safety concerns raised by the FDA, though there is a lot of discussion about cancers in rats and mice.
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FDA posts briefing material for Meridia death panel Reply

The FDA has posted briefing material for the September 15 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee that will consider the fate of Meridia (sibutramine), Abbot’s embattled diet drug. Two weeks ago the publication of the controversial SCOUT trial in the New England Journal of Medicine was accompanied by a strongly worded editorial from the journal’s editors calling for removal of the drug from the market.

The day-long meeting will culminate with a vote on the committee’s recommendation for regulatory action. The choices range from no change to the current label to withdrawal from the US market. In addition to the option that would add a black box to the label (which Abbot has already accepted) the briefing document offers one somewhat unusual and more extreme choice:
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2 FDA rebels criticize inclusion of Avandia defenders on July advisory panel 1

Two FDA officials who have been highly vocal critics of Avandia (rosiglitazone) are now suggesting that the FDA stacked the deck in favor of rosiglitazone at the July advisory committee meeting by including panel members from the earlier 2007 meeting that recommended against removing the drug from the market.

In a letter published in BMJ, David J Graham and Kate Gelperin note that at the extraordinary meeting this July the FDA invited not only the current members of two advisory committees but also all members from the 2007 meeting, “even though they were no longer active members of either committee.” They observe that half of the 32 committee members had also attended the 2007 meeting, and all but one had voted to keep the drug on the market. They write:

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SYNTAX at 3 years: CABG still winning, but PCI acceptable in low-risk patients Reply

Three-year outcomes from the SYNTAX trial continue to show the overall superiority of CABG over PCI in patients with complex disease but leave room for the use of PCI in patients with low-risk disease. The results of the trial were presented by A. Pieter Kappetein at the European Association of Cardio-Thoracic Surgery annual meeting in Geneva, Switzerland.
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