Rivaroxaban Meets Primary Endpoint in ATLAS ACS TIMI 51 1

Bayer AG announced today that the ATLAS ACS TIMI 51 trial of rivaroxaban (Xarelto, Bayer and Johnson and Johnson) in patients with acute coronary syndrome (ACS) had met its primary efficacy endpoint, “showing a statistically significant reduction in the rate of events for the primary composite endpoint of cardiovascular death, myocardial infarction and stroke in patients with ACS, compared to standard therapy plus placebo.”

However, the company also announced that there was a statistically significant increase in rivaroxaban-treated patients in major bleeding events not associated with CABG surgery, the primary safety endpoint of the trial. The results of the trial will be presented at a scientific meeting in the future, the company said.

In July the announcement of the APPRAISE 2 results with apixaban in ACS appeared to dash hopes that oral anticoagulant therapy could be added to dual antiplatelet therapy in ACS. One difference that may turn out to be key is that patients enrolled in ATLAS ACS were stratified based upon whether the investigator planned to give aspirin alone or aspirin plus a thienopyridine such as clopidogrel or prasugrel. The Bayer announcement did not include any information about outcomes in the different strata.

At the recent FDA advisory committee panel about the ROCKET AF trial many panel members expressed concern about the once daily dosage of rivaroxaban used in ROCKET AF. In ATLAS ACS, by contrast, rivaroxaban was given twice-daily, as either a 2.5 mg or 5 mg pill.

Click here for links to additional resources and the text of the Bayer statement…

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Meta-Analysis Explores Real World CV Risk of NSAIDs 2

A new meta-analysis sheds additional light on the cardiovascular risk of NSAIDs as used in the real world, including low doses of the most popular drugs, over short periods, and in low-risk populations.

In a paper published online in PLoS Medicine, Patricia McGettigan and David Henry analyzed data from 30 case-control studies including 184,946 CV events and 21 cohort studies with outcomes in more than 2.7 million people.

Among the NSAIDs with extensive data, rofecoxib and diclofenac had the highest CV risk while ibuprofen and naproxen had the lowest risk:

  • rofecoxib, 1.45 (95% CI 1.33-1.59)
  • diclofenac, 1.40 (1.27-1.55
  • ibuprofen, 1.18 (1.11-1.25)
  • naproxen, 1.09 (1.02-1.16)
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Study Finds Noncardiac Sources of Positive Troponin T Tests Reply

Cardiac troponin T (cTnT) is not always cardiac specific and in some cases may lead to a false-positive diagnosis of cardiac injury, according to a study in the Journal of the American College of Cardiology.

The study was prompted by a case seen by a senior clinician at the Mayo Clinic in which a patient, who was ultimately found to have a form of muscular dystrophy and no heart disease, had persistent cTnT elevations despite a slew of other negative tests, including negative cardiac troponin I (cTnI). Allan Jaffe and colleagues then sought to find similar myopathy patients treated at the Mayo Clinic’s Neuromuscular Clinic by measuring both cTnT and cTnI.
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Easy Come, Easy Go? ESC To Review Dronedarone’s Role in AF Guidelines 5

Just over a year after speeding with unprecedented haste into the European Society of Cardiology’s atrial fibrillation guidelines with a class 1 recommendation, the role  of dronedarone (Multaq, Sanofi) in the treatment of AF will be reconsidered. Responding to an announcement last week from the European Medicines Agency (EMA), the ESC again announced that it would issue a focused update of the AF Guidelines to be published next year.

In last week’s statement, the EMA’s Committee for Medicinal Products for Human Use (CHMP) recommended new restrictions on dronedarone (Multaq). CHMP said that dronedarone should only be used for maintaining sinus rhythm in patients with paroxysmal or persistent AF after successful cardioversion. CHMP said that it was recommending that dronedarone no longer be used in patients who still have AF.

Since the publication of the ESC guidelines last September, dronedarone has been the subject of concerns regarding  several cases of severe liver injury and the early termination of the PALLAS trial due to an increase in cardiovascular events in patients with permanent AF treated with dronedarone.

Editor’s Note: This is an updated version of a story originally published on August 4, 2011 when the ESC first announced the focused update in response to the news about the early termination of the PALLAS trial.

Click here to read the ESC press release…

The Pen Is Mightier Than the Scold 2

Pharma journalist Matt Herper, who’s generally quite savvy about these issues, argues on his Forbes blog that little things like free meals and modest speaking fees don’t really influence doctors. He says that as a journalist he avoids quoting physicians who receive tens or hundreds of thousand of dollars from industry, but small payments don’t bother him. Pharma may no longer give out free pens like in the old days but marketing will never go away. Get over it and get used to it, he argues.

But I think he misses an important point here. For many people, small things like pens or meals are a litmus test: if you’re against them then you’re an acidic pharamscold, wasting your time on the most trivial of matters; if you’re ok with them then you’re a base defender of industry.

Admittedly, there is something silly about the whole pen discussion. I certainly don’t believe that any decent doctor is going to change his or her prescribing practices because of one free pen. And that’s often the way the discussion gets framed. Doctors say that they are insulted by these sort of accusations.

But let’s face it, pens are just the entry-level drug in industry’s armamentarium, the first step of the slippery slope.
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Experience Counts in Carotid Artery Stenting Reply

According to a new study published in JAMA,  experience really does count when it comes to carotid artery stenting(CAS). And that may be a big problem, since the explosive growth in the procedure after gaining FDA approval in 2004 means that most current operators do not have substantial experience with the procedure.

Brahmajee Nallamothu and colleagues analyzed Medicare data from 24,701 CAS procedures performed between 2005 and 2007. The overall 30 day mortality rate was 1.9%, but there was a significant increase in the risk of death in the group of patients treated by the lowest volume operators.

30 day mortality and adjusted odds ratio based on annual volume of operator:
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Statins for Primary Prevention: the Debate Continues 1

Several leading cardiologists have taken issue with the assertion made by Rita Redberg and the editors of Archives of Internal Medicine that using statins for primary prevention is an example “of the widespread use of medications with known adverse effects despite the absence of data for patient benefit for these indications.”

In a research letter published in ArchivesC. Michael Minder and colleagues (including Sanjay Kaul and Roger Blumenthal) write that they “believe there is compelling evidence to support the use of statins for primary prevention in patients at high risk… for developing coronary heart disease (CHD) over the next 10 years.” They assert that by focusing on short-term mortality the Archives editors overlook the substantial benefits of statin therapy for primary prevention in appropriately selected patients.
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Former NEJM Editor Criticizes Publication and Peer Review of ARISTOTLE Trial 9

Editor’s note: The following guest post is reprinted with permission from the blog of Alison Bass. Bass is the author of Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial, and was a longtime medical and science writer for The Boston Globe.

New heart medication study was too flawed for publication, former journal editor says

by Alison Bass

At a Harvard event last night honoring the former Sen. Grassley investigator Paul Thacker, someone in the audience wanted to know how the topic of Thacker’s talk — Dollars for Doctors: Who owns your physician? — was related to the soaring cost of medical care in this country.

As Thacker noted at the outset of his talk, Medicare and Medicaid are now a larger portion of the federal budget than the Pentagon and health care now equal 23 percent of all federal expenditures. Part of the problem, he noted, is the fact that our medical system is stacked towards the widespread adoption of expensive new drugs over older generics even when the new agents are not necessarily safer or more effective than cheaper drugs.

It was left to Dr. Arnold Relman, professor emeritus at Harvard Medical School, to showcase a fresh-off-the-page example of how studies that are funded by drug makers and conducted by researchers who have financial ties to the industry present skewed research results that favor expensive new drugs over generics.
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Rivaroxaban (Xarelto) Gets Positive Recommendation for AF and DVT in Europe 1

The European Committee for Medicinal Products for Human Use (CHMP) has recommended that rivaroxaban (Xarelto) be approved for the prevention of stroke and systemic embolism in AF and also for the treatment of DVT and prevention of recurrent DVT and PE following acute DVT, according to Bayer HealthCare, which is developing the drug in conjunction with Johnson & Johnson.
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Dronedarone (Multaq) Gets Another Drubbing in Europe Reply

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended new restriction on dronedarone (Multaq), Sanofi’s embattled and controversial antiarrhythmic drug. CHMP says that dronedarone should only be used for maintaining sinus rhythm in patients with paroxysmal or persistent AF after successful cardioversion. CHMP said that it was recommending that dronedarone no longer be used in patients who still have AF.

Because the drug increases the risk of liver, lung and cardiovascular adverse events, CHMP recommends that dronedarone should be used only after alternative treatments have been considered. People already taking dronedarone should “have their treatment evaluated by their doctor at their next scheduled appointment.”
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Diet Drugs Get a New Slim Chance at Approval Reply

Contrave, the investigational diet pill combination of naltrexone and bupropion, has been granted a possible new lease on life by the FDA. In January of this year the FDA issued a complete response letter to Orexigen, the drug’s sponsor. Now Orexigen says that it has received guidance from the FDA that could lead to approval of the drug in 2014.

The FDA has “identified a very clear and feasible path forward for this important therapy,” said the company president and CEO.

To gain approval Orexigen will have to perform a cardiovascular outcomes trial (CVOT). The trial will enroll less than 10,000 patients and could lead to conditional approval after about two years, the company said. At the interim analysis, which would take place after about 87 events had occurred, the trial would have to rule out a hazard ratio of 2.0  At trial completion the trial would need to rule out a hazard ratio of 1.4. The company said it hoped to initiate such a trial in the first half of 2012 after discussions with the FDA.
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More Data But No Answers About Platelet Function Testing Reply

The RECLOSE 2–ACS (Responsiveness to Clopidogrel and Stent Thrombosis 2–ACS) trial from Italy provides new information about platelet reactivity but doesn’t answer any of the key questions about the possible role of platelet function testing in clinical practice.

In a paper published in JAMA, Guido Parodi and colleagues report on 1,789 ACS patients who underwent PCI and who had their platelet reactivity measured. Patients who were found to have high residual platelet reactivity (HRPR) received a larger dose of clopidogrel or were switched to ticlopidine.
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Significant Declines Observed in Cardiovascular Procedures Performed in Hospitals Reply

More evidence is starting to emerge that the overall volume of cardiovascular procedures in US hospitals is in decline. The trend should come as no surprise to those who have been following news about cardiovascular medicine in recent years, as the field has been repeatedly struck by debate, scandal and controversy related to the potential overuse of expensive and invasive therapies.

A monthly report from Wells Fargo that tracks hospital volume found a 9.37% drop in inpatient cardiovascular surgeries and procedures in July 2011 compared to July 2010. This continues a trend of similar monthly declines in the range of 6%-11% each month this year compared to 2010. The trend is partially offset by a modest increase in some months in outpatient procedures, though in July  cardiovascular outpatient procedures also decreased by 6.28%.

The broad trend observed by Wells Fargo is confirmed by HCA, the large hospital company. In its quarterly financial report HCA said that overall demand for its cardiovascular services has been declining by approximately 3% each year for several years, despite a slight growth in the hospital chain’s share of the overall market. Samuel Hazen, the president of  HCA, said the decline “appears to be consistent with information from cardiac medical device companies’ public reports.”
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FDA Approves Watson Pharmaceuticals Generic Lovenox (Enoxaparin) 1

The FDA has granted approval to Amphastar’s generic version of Lovenox (enoxaparin sodium), Watson Pharmaceuticals has announced. The low molecular weight heparin will be sold by Watson under an arrangement with Amphastar.

In July 2010 the FDA approved the first generic version of enoxaparin, manufactured by Sandoz and marketed in the US by Momenta, after a long and contentious battle. Although enoxaparin is not technically a biologic drug, approval of generic versions of the drug appear to provide a model pathway for the FDA to approve generic biologics.

A US Senate report released in May provided details of attempts by Sanofi, manufacturer of Lovenox, to orchestrate a negative perspective on generic versions of the drug by the FDA.
Click here to read the press release from Watson Pharmaceutcals…

Study Identifies Slow Spots in Transfer of Primary PCI Patients Reply

In recent years great progress has been made in speeding the delivery of primary PCI to STEMI patients, but lingering problems remain, especially involving the transfer of patients from centers without primary PCI capability. Now a new study published in Circulation helps identify the precise causes for delays with these patients.

Michael Miedema and colleagues analyzed data from 2,034 patients transferred to the Minneapolis Heart Institute from March 2003 to December 2009. 30.4% of the patients received treatment within 90 minutes and 65.7% within two hours.
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Xanthelasmata Identified as Independent CV Risk Factor Reply

A large new study from Denmark finds that xanthelasmata (raised yellow patches around the eyelids) but not arcus cornae (white or grey rings around the cornea) is an independent risk factor for cardiovascular disease.

In a paper in BMJ, Mette Christoffersen and colleagues report on 12,745 adults in Copenhagen without cardiovascular disease at baseline who were followed for a mean of 22 years. At baseline 4.4% had xanthelasmata and 24.8% had arcus corneae. Here are the main results, comparing the group without xanthelasmata to the group with xanthelasmata:
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Meta-Analysis Finds Reduction in Stent Thrombosis with Everolimus-Eluting Stents Reply

Stent thrombosis and other complications are less likely to occur when an everolimus-eluting stent (EES) is used, according to a large new meta-analysis appearing in the Journal of the American College of Cardiology.

Usman Baber and colleagues analyzed data from 13 trials that included 17,101 patients who were randomized to either an EES or a non-EES. They found significant reductions in stent thrombosis (ST), MI, and target vessel revascularization (TVR), but did not find a significant difference in cardiac mortality:
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Study Sheds Light on Consequences of Bicuspid Aortic Valve Reply

Although bicuspid aortic valve  (BAV)is the most frequently occurring congenital heart defect, little is known about the long-term prognosis of people with BAV. Now a new study published in JAMA shows that although the overall rate of aortic complications remains low in people with BAV, their risk is nevertheless about 8 times greater than the risk of those without BAV.

Hector Michelena and colleagues followed 416 BAV patients for 16 years. During that period, 2 patients had an aortic dissection, representing an incidence of 3.1 cases per 10 000 patient-years, which is more than 8 times the risk of the general population. Risk was higher in people 50 years of age or older (17.4  cases per 10,000 patient years) and in people with aortic aneurysms at baseline (44.9 cases per 10,000 patient years).
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HHS Announces Initiative to Prevent One Million Heart Attacks and Strokes 1

The US Department of Health and Human Services (HHS) is launching a campaign to prevent one million heart attacks and strokes in the next 5 years. The announcement was published in the CDC’s Morbidity and Mortality Weekly Report (MMWR) and in a perspective published in the New England Journal of Medicine by Thomas Frieden, the director of the CDC, and Donald Berwick, the CMS administrator.

Nearly half (49.7%) of US adults in 2007-2008 had at least one of the three main risk factors for CV disease– uncontrolled hypertension, uncontrolled high levels of LDL cholesterol, and current smoking. This represents a significant decline from the 57.8% prevalence reported in 1999-2000. The decrease, according to the CDC, “might, in part, reflect improved treatment and control of hypertension and high levels of LDL-C and implementation of effective smoking interventions.”
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Study Finds Risks and Costs Associated with Infection After Device Implantation 1

A large new study has found significant risks and costs associated with infections following the implantation of CIEDs (cardiovascular implantable electronic devices, including ICDs, CRT/Ds, and pacemakers).

In a paper published in Archives of Internal Medicine, Muhammad Sohail and colleagues analyzed Medicare data from more than 200,000 patients admitted for CIED implantation, replacement, or revision in 2007, including  5817 admissions with infection. Infection was associated with an increase in the rate ratio for admission mortality (4.8- 7.7) and long-term mortality (1.6-2.1). The researchers noted that about half of the increased long-term mortality occurred after hospital discharge.
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Global Monitor: Early Signs of Possible Problems with ICD Leads, Dabigatran Reply

Reports from Ireland and New Zealand may herald new concerns about the Riata defibrillator leads (St. Jude Medical) and dabigatran (Pradaxa).

A poster presented at the European Society of Cardiology meeting last month by researchers at the Royal Victoria Hospital in Belfast found that  15% of 212 patients who received Riata leads had an insulation breach on screening. The researchers reported that 20% of the patients had “clinically significant events.”

Quoted in an article in the Minneapolis Star Tribune. the chief of the Arrhythmia Service at Brigham and Women’s Hospital, Laurence Epstein, acknowledges the small size of the single-center study but states that “it could ultimately be a big issue… we’re just starting to scratch the tip of the iceberg of what the scope of the problem is.” Although the Riata leads were discontinued last year, more than 227,000 were sold worldwide.

In New Zealand, meanwhile, health authorities are struggling with a surge in bleeding complications following the government’s decision to fund dabigatran (Pradaxa). According to an article in the Star Times, the country’s drug monitoring agency “has received around 50 reports of people experiencing bleeding since the drug was introduced two months ago as a replacement” for warfarin.

The Star Times reports that about 56,000 people in New Zealand take warfarin and that thousands have been switched to dabigatran. The reports quotes an official of the country’s Haematology Society: “We do have concerns about the way it was rolled out. It was rolled out very rapidly without a lot of forethought and planning. In particular the fact that general practitioners could have widespread access to this drug from day one was a concern to us, when some of them did not know how to use it.”

Live Blog– FDA Advisory Panel on Rivaroxaban (Xarelto) 7

Click here for a brief summary and commentary on the FDA panel hearing.

Panel Adjourns! Good night everyone.

4:58– Lincoff asks if anyone thinks the transitioning study should be done pre-approval? Everyone seems ok with a post-marketing study.

4:55– Nissen wants to see the drug tested in a BID regimen. Papdemetriou wants a post-marketing study on transitioning.

4:54: Last question:

9. If rivaroxaban were to be approved for stroke prevention in patients with atrial fibrillation, …

9.1. … are there any constraints you would place on the population in whom it would be indicated?

9.2. … are there any issues you would want to resolve post- marketing?

4:53– I missed this earlier: Fleming was the abstention.

4:50– Kaul recommends R be given a third-line indication. Nissen says it can be used in rare situations. I don’t think anyone has supported a superiority claim. McGuire makes the point that it can’t be claimed to be as effective as warfarin but that it is effective. Most panelists seem to go with this idea.

4:49– 10 minutes to answer the last 2 questions:

8. If you voted to approve rivaroxaban to prevent strokes in patients with

atrial fibrillation, does it merit …

8.1. … a superiority claim to warfarin?

8.2. … a claim as an effective alternative to warfarin?

8.3. … a claim as effective?

8.4. … a claim for patients failing other anticoagulant therapy? If so, what constitutes failure?

Folks– despite the lopsided vote this is NOT a strong endorsement of rivaroxaban. This committee has LOTS of concerns about R, but they want to see alternatives to warfarin and dabigatran.
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Stenting Worse Than Medical Therapy for Intracranial Stenosis Reply

In recent years stenting for intracranial arterial stenosis has become widespread. Now, however, a trial testing the procedure has been terminated early, raising serious questions about both the safety and efficacy of the technique.

In the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial, which has now been published online in the New England Journal of Medicine, 451 patients with a recent TIA or stroke attributed to a 70-99% stenosis of a major intracranial artery were randomized to either aggressive medical therapy (consisting of aspirin, clopidogrel, and management of primary risk factors) or the same medical therapy plus stenting with the Wingspan stent system. The trial was terminated early due to a much higher rate of stroke or death in the stenting group. Here are the main results of the trial, with a mean followup of 11.9 months:
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FDA Reviewers Recommend Complete Response Letter for Rivaroxaban (Xarelto) 6

FDA reviewers have recommended against the approval of rivaroxaban (Xarelto, Johnson & Johnson), which will be the subject of a Cardiovascular and Renal Drugs Advisory Committee meeting on Thursday. The recommendation comes as a surprise, as many physicians and analysts had expected an easy approval for the drug.

The bottom line from the FDA reviewers is that the pivotal ROCKET trial failed to demonstrate that rivaroxaban was as effective as warfarin, since warfarin was not “used skillfully” in the trial. The reviewers note that the time in the therapeutic range (TTR) for warfarin-treated patients was lower in ROCKET than in similar trials with other drugs. The mean TTR for warfarin in ROCKET was 55%, compared to 63%-73% in other recent warfarin-controlled studies, according to the reviewers. Thus, although the trial was technically a success because it demonstrated that rivaroxaban was noninferior to warfarin, this finding does “not take into account other factors, such as the quality of anticoagulation in the warfarin arm.”

The FDA explained its recommendation:

if the underlying goal of protecting public health is to be advanced, the logical course is to reject the new therapy because it has not been convincingly demonstrated to be as effective as approved therapy.

The FDA also raised concerns about the safety of rivaroxaban, noting “an excess of strokes in the rivaroxaban arm during the transition from blinded study drug to open label warfarin at the end of the study.”
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