US Senate Unanimously Endorses Campaign Against Atrial Fibrillation 7

On a day when Americans watched nervously as its government sought to contend with unprecedented turmoil and peril in the economic and political life of the country, the US Senate put aside all divisions and partisan politics to act decisively and unanimously to express support for “promoting increased awareness, diagnosis and treatment of atrial fibrillation.”
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Controversial IOM Report Highly Critical of 510(k) Process Reply

The Institute of Medicine (IOM) has released a report highly critical of the FDA’s 510(k) medical device clearance process and called on the FDA to develop “a new framework that used both premarket clearance and improved postmarket surveillance of device performance to provide reasonable assurance of the safety and effectiveness of Class II devices.” The IOM said the current process is unable to provide “a reliable premarket screen of the safety and effectiveness” of these devices.

The FDA’s director of the Center for Devices and Radiological Health said in a press release that “the 510(k) process should not be eliminated” but said that the FDA was “open to additional proposals and approaches for continued improvement of our device review programs.” The IOM report had been originally commissioned by the FDA.

As reported earlier this week in the New York Times, the IOM report was the subject of a preemptive attack by the medical device industry before the report was even released. AdvaMed, the medical device industry association, released a statement rejecting the conclusions of the report, saying they “do not deserve serious consideration.”
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AstraZeneca Sets Premium Price for Ticagrelor (Brilinta) Reply

[Updated with statement from AstraZeneca]– AstraZeneca will be charging a premium price for its new antiplatelet drug Brilinta (ticagrelor). Bernstein analyst Timothy Anderson reports that the daily treatment cost for the drug will be $7.24 on a wholesaler acquisition cost (WAC) basis, which is approximately 20% higher than the daily cost of $6.08 for clopidogrel (Plavix) and about 25% higher than the daily cost of $5.78 for prasugrel (Effient).
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Mixed Results For New Implantable Device For the Treatment of Resistant Hypertension Reply

A phase III pivotal trial has yielded mixed results for an experimental implantable device that uses baroreflex activation therapy (BAT) to treat resistant hypertension. The paper on the Rheos Pivotal Trial by John Bisognano and colleagues has been published online in the Journal of the American College of Cardiology.

265 patients with resistant hypertension had the Rheos device implanted. After 1 month they were then randomized on a 2:1 basis to have the device activated immediately (Group A) or after 6 months (Group B). There were 5 coprimary endpoints. The trial demonstrated sustained efficacy, BAT safety, and device safety, but was not successful in meeting the endpoints for acute systolic blood pressure (SBP) response or procedural safety:
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Study Finds Differences in Heritability of Coronary and Cerebrovascular Disease Reply

Although a family history of coronary or cerebrovascular disease usually receives equal weight when assessing risk, a new study suggests that family history may play a more important role in MI and ACS than in stroke or TIA.

In a paper published in Circulation: Cardiovascular Genetics, Amitava Banerjee and colleagues report the results of a population-based study in which they assessed the relative heritability of cerebral and coronary events in 906  patients with ACS and 1015 patients with cerebral disease. For the ACS patients, parental MI was strongly associated with MI in one or more siblings:
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Adding HbA1c Measurements Improves CV Risk Prediction in Diabetics Reply

Current risk prediction models classify diabetes as equivalent to established CV disease.  Now, a new report from the Women’s Health Study and the Physician’s Health Study II suggests that adding HbA1c measurements to the model can improve risk prediction and lead to downward classification of some diabetics.

In a paper published in Archives of Internal Medicine, Nina Paynter and colleagues analyzed data from 24,674 women and 11,280 men. 685 women and 563 men were diabetic at baseline. CV events occurred in 125 diabetic women and 170 diabetic men. In women, including HbA1c levels improved the C statistic by 0.177 (p<0.001) and improved the risk category assignment. The results were less dramatic in men, but the C statistic was improved by 0.039 (p<0.02) as well as the risk category assignment.
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APPRAISE-2 Dashes Hope of Adding Anticoagulant to Antiplatelet Therapy in ACS 1

The factor Xa inhibitor apixaban (under joint development by Bristol Myers Squibb and Pfizer as Eliquis) has been the subject of intense interest in recent years, showing great promise for thromboprophylaxis after surgery and for stroke prevention in AF. Some pundits now believe apixaban will become the anticoagulant of choice for the AF indication, although the basis for this is only a press release about the ARISTOTLE trial, which has not yet been presented or published. So far the only major disappointment concerning the drug has been the APPRAISE-2 trial in ACS patients, which was terminated early last November. The results of the trial have now been presented at the International Society on Thrombosis and Haemostasis Congress in Kyoto and published in the New England Journal of Medicine.

APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events – 2) was a phase 3 trial comparing apixaban to placebo in patients with acute coronary syndrome (ACS) already receiving standard antiplatelet therapy and who had at least 2 additional risk factors for recurrent ischemic events. The trial was stopped early after 7,392 patients had been enrolled (the original plan had been to enroll 10,800 patients) due to an increase in major bleeding events in patients treated with apixaban.

Here are the main results of the trial, after a median followup of 241 days:
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Less May Be More, But Stents Are Neither Good Nor Bad 4

A few days ago the distinguished healthcare writer Shannon Brownlee wrote a provocative blog post  about the overuse of stents. A key piece of evidence that she used was a paper co-authored by Grace Lin and Rita Redberg in which focus groups of cardiologists cheerfully admitted that they would give stents to hypothetical patients who were, according to the current guidelines, not eligible for stents. Here’s a paragraph from her post:

The really unsettling part of Lin and Redberg’s paper? The conversation they quote among the cardiologists from one of the focus groups that suggests that once a patient is in their clutches, he or she is going to get a procedure. One cardiologist says, “There’s no chance of escaping.” Another responds, “That’s the end of it. He [the patient] is not going to get out [...] without a stent.”

But when I looked at the original Archives paper I saw that it had been published in 2007.  I follow cardiology fairly closely, and it’s my impression that much, but certainly not everything, has changed since 2007, which happened to be a very important year for cardiology: several months before the Archives paper was published, the groundbreaking COURAGE trial was published in the New England Journal of Medicine. 

COURAGE provoked a long and complex debate in the cardiology world. This debate is by no means over, but it is fair to say that almost no one doubts the main conclusion of the trial today, which is that stents are no better than optimal medical therapy (drugs and lifestyle changes) in people with stable chronic angina in delivering important long-term health benefits like reducing death, heart attacks, or other adverse cardiovascular events.

COURAGE provided the intellectual basis for a less aggressive approach to interventions. One Wall Street analyst who follows the stent market told me that PCI volume dropped about 10% in the year after COURAGE. Now that may not sound like a lot, but since non-urgent PCI for stable angina composes about 40% of the market, the 10% overall drop likely translates to a 25% reduction in non-urgent, elective procedures, which is where the overuse was most likely to occur.

And then the Mark Midei case came along.
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FDA and EMA Issue Updates on Dronedarone, Varenicline, and Pioglitazone Reply

The FDA has issued an update on dronedarone (Multaq, Sanofi Aventis) and the European Medicines Agency (EMA) has provided updates on its reviews of dronedarone and 2 other drugs which also have been the subject of recent controversies: pioglitazone (Actos and other names, Takeda) and varenicline (Champix, Pfizer):

The FDA and dronedarone– The FDA issued a safety communication about dronedarone and an increased risk of death and serious CV events. The agency said it was reviewing data from the PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard therapy) trial, which Sanofi announced on July 7 had been prematurely stopped. The PALLAS trial was testing the effect of dronedarone in patients with permanent AF, which is not an indication for dronedarone currently. According to the FDA:
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Sapien Transcatheter Heart Valve Receives Strong Support from FDA Advisory Panel 1

(Updated to include the FDA’s brief summary of the panel)–The FDA Circulatory Systems Devices Panel has given a strong vote of support in favor of the Sapien Transcatheter Heart Valve (THV)  for use in patients with inoperable severe aortic stenosis and with no co-morbidities precluding benefit from correction of the aortic stenosis. By  large majorities, the panel voted that the procedure was safe (7-3),  that the procedure was effective (9-1), and that the benefits of the device outweighed the risks (9-0, 1 abstention).

During the course of the meeting the FDA and panel members expressed a fair amount of concern that excessive enthusiasm for the device might cause a stampede of early usage. Panel members were concerned that the device might be used in patients who were not ideal candidates and by operators and centers who lacked sufficient experience.
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AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval 2

The FDA has approved ticagrelor (Brilinta, AstraZeneca). In a press release, the FDA said that the drug was approved to reduce cardiovascular death and MI in patients with acute coronary syndromes (ACS).

The drug’s label will include a boxed warning about bleeding risks and, of considerable significance in light of the enormous amount of discussion about the topic, will state that aspirin doses greater than 100 mg/day decreases the efficacy of the drug. Said the FDA’s Norman Stockbridge, the director of the Division of Cardiovascular and Renal Products in the FDA’s Center for Drug Evaluation and Research:

“In clinical trials, Brilinta was more effective than Plavix in preventing heart attacks and death, but that advantage was seen with aspirin maintenance doses of 75 to 100 milligrams once daily.”

The FDA said that the drug was approved with a Risk Evaluation and Mitigation Strategy, which will require the company to educate physicians about the risk of using higher doses of aspirin.

Click here to download a PDF of the Brilinta label.

Click here to read the AstraZeneca press release.
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Study Suggests Possibility that CETP Inhibitors May Improve Glycemic Control Reply

A new analysis of the ILLUMINATE trial raises the possibility that CETP inhibitors like torcetrapib may have the unexpected beneficial effect of improving glycemic control in addition to their intended effect of raising HDL cholesterol. Development of torceptrapib was halted several years ago following the early termination of the large ILLUMINATE trial due to an excess of deaths and cardiovascular events in patients treated with torcetrapib. Other CETP inhibitors (anacetrapib from Merck and dalcetrapib from Roche) are under active development, however, as many researchers believe that the adverse effects of torcetrapib were due to off-target effects of the drug which may not be found with other drugs in the class.

In a post-hoc analysis analysis published in Circulation, Philip Barter and colleagues studied the 6,661 diabetic patients enrolled in ILLUMINATE. At baseline there were no differences in glycemic parameters. At 3 months, however, compared to patients receiving atorvastatin alone, patients receiving torceptrapib in addition to atorvastatin had:
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FDA Releases Briefing Documents for Advisory Panel on the Edwards Sapien Transcatheter Aortic Valve Implant Reply

The FDA has posted the briefing documents for the much-anticipated meeting on Wednesday of the Circulatory Systems Devices Panel for the Edwards Sapien transcatheter heart valve system in patients with severe aortic stenosis who are not eligible for surgical valve replacement, as studied in the PARTNER B trial. Overall the FDA documents suggest that the committee will likely recommend approval of the device. The document raises no major unexpected concerns about the pivotal PARTNER B trial, and states that the “trial met the pre-specified criteria for study success, as defined by the primary safety and effectiveness endpoint of all-cause mortality throughout the duration of the study, demonstrating superiority of the SAPIEN THV as compared to the Control group.”

Much of the discussion will likely focus on the questions surrounding the rate of strokes in PARTNER B (see the FDA text below) and the details of a post-approval study and risk mitigation strategy. Edwards has proposed a post-approval study of an anticoagulation/antiplatelet regimen to help reduce the risk of stroke.
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The Mark Midei Cases: Patient A Reply

The document containing the final decision of the Maryland State Board of Physicians revoking the medical license of Mark Midei includes extensive details about 5 cases (Patients A-E) reviewed by the Administrative Law Judge (ALJ), along with expert testimony about the cases by Midei himself, William O’Neill, Midei’s expert witness, and Matthews Chacko, the state’s expert witness. Due to the great interest in the Midei case, as well as the many important issues raised by the case, CardioBrief will present the key details of these cases, along with the accompanying testimony about these cases, as contained in the document. Here are the details of Patient A, the first case reviewed in the document.

The judge wrote that Patient A had chronic stable angina with “at most a moderate calcification of the mid-LAD.” Her angiogram showed no flow-limiting lesion or plaque rupture. She was referred to Midei by the referring cardiologist, Chitrachedu Naganna, when a coronary CT showed an 80% lesion in the LAD.

In his cath report Midei said the patient had unstable angina, but there was no mention of this in the letter to Midei from Naganna, where she is described as having “chest pain precipitated by exertion and relieved by rest.” The judge stated: “there is nothing in Dr. Naganna’s medical records to support the diagnosis of unstable angina.”
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Maryland Revokes Mark Midei’s Medical License 1

Mark Midei’s license to practice medicine has been revoked by the Maryland Board of PhysiciansIn its Final Decision and Order the Maryland Board found that Midei was guilty of unprofessional conduct, willfully making a false report, gross overutilization of health care services, violating the standard of quality care, and failure to keep adequate medical records.

The Maryland board issued its final decision today, following a 7-day evidentiary hearing in which Midei was present (and in which he was represented by 9 attorneys), and a subsequent oral appeal on June 22, 2011.

The finding was based on a detailed review of 5 cases. This review, according to the board, was entirely distinct and separate from the investigation of Midei performed by St. Joseph Medical Center.

The board found that Midei “implanted cardiac stents unnecessarily in four of the five patients in question. In every one of the patients, he falsified the extent of blockage of the patients’ coronary arteries by reporting that it was 80% when it was in reality lower– and in most cases much lower.” In 3 cases Midei said the patients had unstable angina when they did not. In addition, in all cases he failed to obtain the Active Coagulation Time (ACT) and “instead simply administered heparin while inserting the catheter,” endangering one patient who had already received an anti-coagulant.
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Therapeutic Hypothermia Network Benefits Cardiac Arrest Patients Reply

Previous studies have shown that therapeutic hypothermia (TH) improves outcomes in patients who have an out-of-hospital cardiac arrest (OHCA). In a new paper published in Circulation, Michael Mooney and colleagues report on their experience with 140 OHCA patients in Minnesota who received treatment within a regional network of care that transfers OHCA patients to a TH-capable hospital. Prior to arrival at the specialized TH center patients are cooled with ice bags.
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Study Finds Sodium-Potassium Ratio Strongly Tied to Mortality and CV Disease Reply

The separate roles of sodium and potassium in cardiovascular disease have been extensively observed in epidemiologic studies. Now a study published in Archives of Internal Medicine examines their joint effect.

Quanhe Yang and colleagues analyzed data from 12,267 adults participating in the 3rd National Health and Nutrition Examination Survey. As expected, they found that higher sodium intake was associated with an increased risk of death while higher potassium intake was associated with a lower risk of death. However, potassium intake but not sodium intake was  significantly associated with cardiovascular and coronary mortality. A higher sodium-potassium ratio was strongly tied to all outcomes: here are the hazard ratios (HRs) comparing the highest quartile with the lowest quartile sodium-potassium ratios:
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OAT Trial Had Little Impact on Clinical Practice Reply

Once again a study finds that  cardiologists don’t always pay attention to the literature and guidelines. In 2006 the Occluded Artery Trial (OAT) showed no benefit for routine PCI in patients with persistently occluded infarct-related arteries identified at least one day after a MI. But the study appeared to have minimal impact on clinical practice, according to a report published in Archives of Internal Medicine.

To assess the impact of OAT, Marc Deyell and colleagues used data from the CathPCI Registry to identify 28,780 patients treated from 2005 to 2008 who met the eligibility criteria for OAT. They report finding no signficant decline in the rate of PCI in their population following the publication of OAT (OR 1.018; CI, 0.995-1.042). Following a subsequent revision of the guidelines (stating that PCI “should not be performed” in these patients) they detected a trend indicating fewer procedures (OR, 0.963;CI, 0.920-1.000). Overall, the crude rate of PCI for total occlusions was 54.2% before the publication of OAT, 52.8% after the publication, and 51.9% after the guidelines were changed.
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Guest Post: “Creepy” invasion of pharma into patient-targeted social media space 3

Editor’s Note: Recently I wrote about why patients should be subject to the same critical scrutiny as anyone else when their views about medical and scientific topics are presented in news coverage of medical stories. One aspect of the subject that I didn’t consider is that those patient views may well have been influenced by industry, as suggested in this guest post by Gary Schwitzer, which originally appeared on his Health News Review blog. CardioBrief readers may also recall that I outlined similar heavy-handed efforts by industry to influence familial hypercholesterolemia guidelines (the same disease discussed below) in a series of articles on the National Lipid Association (here, here, and here).

“Creepy” invasion of pharma into patient-targeted social media space

by Gary Schwitzer

Marilyn Mann is a very smart woman. She’s a securities lawyer. But she’s also educated herself about health care out of necessity. She’s a breast cancer survivor and she has a daughter with heterozygous familial hypercholesterolemia, a genetic disease causing very high LDL-cholesterol. She is one of the administrators of a Facebook group called
Familial Hypercholesterolemia (FH) Discussion Group – intended primarily for people with FH or their family members.

Recently, Mann got a message from a PR woman who had joined the Facebook page.
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Guest Post: Multaq’s Off Again, On Again, Then Off Again Ride Reply

CardioBrief welcomes this guest post, reprinted with permission, from Dr. Westby Fisher, an electrophysiologist practicing at NorthShore University HealthSystem in Evanston, Illinois, and a Clinical Associate Professor of Medicine at University of Chicago’s Pritzker School of Medicine. This piece originally appeared on his blog, Dr. Wes.

Today was another tough day for Sanofi’s dronedarone antiarrhythmic medication (marketed as Multaq®) after the prospective randomized PALLAS Trial was stopped early. The PALLAS Trial was a trial that studied the safety and efficacy of patients with chronic atrial fibrillation (as opposed to the already-approved patient population with intermittent (or paroxysmal) atrial fibrillation). It seems there was an increased number of “cardiovascular events” in the drug-treatment arm of the trial and was NOT related to problems with hepatic toxicity as previously reported earlier this year.
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Dronedarone (Multaq) Study for Permanent AF Stopped Early 2

The PALLAS trial of dronedarone (Multaq) for permanent AF has been stopped early, according to a press release (below) issued by Sanofi. PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard therapy) was a double-blind, placebo-controlled, phase IIIb trial comparing dronedarone to placebo in patients with permanent AF.

The company said the discontinuation of the trial resulted from recommendations from the study’s Operations Committee and the Data Monitoring Committee (DMC) following “a significant increase in cardiovascular events in the dronedarone arm.” The company said the study termination “was not related to any hepatic adverse event.” (Earlier this year the FDA warned about liver injury associated with dronedarone.) The company has informed regulatory authorities and has instructed PALLAS clinical investigators to tell patients enrolled in the study to stop taking the study medication. The company said that it remained “committed to Multaq as an essential treatment option for non-permanent AF patients.” (Dronedarone is currently approved for use only in patients with non-permanent AF.)
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ASCEND-HF: No Harm or Benefit with Nesiritide Reply

With the publication of the final results of the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial) in the New England Journal of Medicine, the once intense controversy over the use– or misuse– of the drug nesiritide in patients with acute decompensated heart failure has finally been resolved. The results, which were first presented last November at the AHA, demonstrate unequivocally that the drug was neither harmful nor beneficial.
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Lower Sudden Cardiac Death Rates Observed in Women With Healthy Lifestyles Reply

It probably won’t come as a big surprise, but a new study finds that women who live a healthy lifestyle have a lower risk of sudden cardiac death (SCD). In a paper published in JAMA, Stephanie Chiuve and colleagues analyzed data from 81,722 women enrolled in the Nurses’ Health Study. They used 4 factors to identify a low-risk lifestyle:

  • not smoking,
  • BMI <25,
  • exercise lasting 30 minutes or longer per day, and
  • adherence to the Mediterranean diet.

Each factor was individually associated with a significant reduction in risk of SCD. Here are the absolute risks and adjusted relative risk of SCD in women with:
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Comment: ACC Circling the Wagons, Once Again Reply

Once again the ACC is circling the wagons. In response to a paper in JAMA finding that about half of all nonacute PCI procedures may be inappropriate, the ACC released a statement assuring everyone that there’s nothing to be concerned about and that all the experts and officials are hard at work mending whatever slight problems may exist. Don’t worry, be happy is the message they want to convey.

Let’s be clear here. The JAMA/NCDR study is no cause for panic, and there’s a very important and reassuring nugget of information at the core of the report (ie, that the overhwelming majority (98.6%) of  PCIs for acute indications are appropriately done). But, on the other hand, the study also raises the possibility that as many as half of all nonacute PCI procedures may be performed with no clear evidence base or expert recommendation. This should not really surprise anyone who’s been paying attention. One prominent cardiologist told me that he was indeed “shocked” by the finding, but only because the study found “that only half of the elective procedures were deemed inappropriate.”

But the ACC statement tries to weasel its way out of this conclusion, summarizing the finding in this yawn-inducing manner:
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