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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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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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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In addition to the PARTNER trial, newsworthy events from TCT on Thursday include the presentation of two trials showing the long-term superiority of the Xience V over Taxus and the surprising announcement that the ACC would be a co-sponsor of TCT 2011.
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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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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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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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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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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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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…

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…

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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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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