Generic Atorvastatin Hits the Market Reply

The first generic version of Lipitor (atorvastatin) became available today as the exclusive patent held by Pfizer finally expired. Lipitor was by far the most successful prescription drug in history.

Watson Pharmaceuticals announced an authorized generic version. One other company, Ranbaxy, has been authorized to market atorvastatin, but has struggled to gain FDA approval of its manufacturing plant. The company has said it will launch its generic version of atorvastatin later this week.

For the next six months Pfizer, Watson and Ranbaxy are the only companies that will be authorized to sell atorvastatin. In 6 months, however, the floodgates will open, and the price of atoravastatin will drop to pennies per day.

Here are links to a few of the many news reports and features about this major story:

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Apixaban Gains Priority FDA Review for Stroke and VTE Prevention in AF Reply

Bristol-Myers Squibb and Pfizer announced today that the FDA will give a priority-review to the new drug application (NDA) for apixaban (Eliquis) for the prevention of stroke and systemic embolism in AF patients. The FDA said a decision would be reached by March 28, 2012. The NDA is based on results from the large phase 3 AVERROES and ARISTOTLE trials.

The decision to grant expedited review raises some intriguing issues, according to Ed Silverman on Pharmalot, since two other drugs,  rivaorxaban (Xarelto, Johnson & Johnson) and dabigatran (Pradaxa, Boehringer Ingelheim) have received approval in recent years for the same indication:

…why should Eliquis be granted a priority review when the others were already approved? A priority review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists, according to the FDA (read here). This suggests, in other words, that the agency views Eliquis as a significant addition to the medical armament.

Silverman notes that dabigatran, the first new anticoagulant to challenge warfarin, also received a priority review, but that rivaroxaban did not. With the approval of dabigatran there was “no longer an unmet medical need,” according to Wall Street analyst Marc Schoenebaum. Rivaroxaban, it should be remembered, received a black box warning on its label after a highly contentious FDA review and advisory committee. Schoenebaum believes that the priority designation for apixaban suggests that the FDA will be more likely to agree that apixaban is superior to warfarin on both safety and efficacy, thereby making it the “dominant player in the a-fib market.”
Click here to read the press release from Pfizer and Bristol…

Study Finds 10% of PCI Patients Readmitted to Hospital Within 30 Days Reply

One in 10 PCI patients is readmitted to the hospital within 30 days, according to a new study published in the Archives of Internal Medicine. The study is a good example of the increased focus on rehospitalization, which is being used more frequently as a key measure of outcome.

Farhan Khawaja and colleagues analyzed data from 15,498 PCI hospitalizations at Saint Marys Hospital in Rochester, MN. Within 30 days after discharge 9.4% of patients had been readmitted and 0.68% had died. The key independent factors associated with readmission were female sex, Medicare insurance, having less than a high school education, unstable angina, cerebrovascular accident or TIA, moderate to severe renal disease, COPD, peptic ulcer disease, metastatic cancer, and a length of stay of more than 3 days. The authors write that “even though these variables are not modifiable, interventions to improve access and follow-up care should be studied to assess impact on readmission rates.”
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Long Transfer Delays for STEMI Patients at Most Hospitals Without Primary PCI Reply

Fewer than 10% of STEMI patients eligible for PCI who arrive at a hospital without PCI capability are transferred within the recommended times, according to a new study published in Archives of Internal Medicine. Although dramatic improvements in door-to-balloon times have been achieved in recent years in PCI-capable hospitals, the new report suggests that hospitals without PCI capability are failing to achieve a door-in to door-out (DIDO) time within 30 minutes.

Jeph Herrin and colleagues analyzed CMS data from 13,776 STEMI patients who were transferred to another hospital for PCI. The median DIDO time was 64 minutes. Only 9.7% were transferred within 30 minutes and 31% were transferred in longer than 90 minutes. Women, non-white patients, older patients, and patients with a contraindication to fibrinolytic therapy had significantly longer DIDO times.

The authors write that their “findings suggest that many patients may have benefitted from fibrinolytic therapy at the transferring hospital rather than from transfer for primary PCI.”
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CardioMEMS CHAMPION Trial Undergoes Scrutiny From Wall Street Ahead of Next Month’s FDA Panel Reply

Note to readers: An earlier version of this story stated that the FDA may be concerned about the conduct of the CHAMPION trial. This statement could be construed as an implication of ethical misconduct or negligence on the part of the trial sponsors or investigators. I apologize if I conveyed this impression in the earlier story. This story has been further updated below, as indicated in the text.

Next month’s meeting of the FDA’s Circulatory System Devices Panel has stirred controversy, though it may be a tempest in a teapot. On December 8 the committee is scheduled to review the PMA for the implantable CardioMEMS HF Pressure Measurement System (HF System), which provides daily pulmonary arterial pressure measurements for the purpose of guiding heart failure treatment. The potential controversy involves the possible unblinding of patients during the pivotal CHAMPION trial. (Note: The earlier version of this story stated that concerns had been raised about the unblinding of the trial investigators. As the trial publication clearly states, CHAMPION was a single-blind trial in which only the patients but not the investigators were blinded to their treatment assignment.)

On Wednesday morning Wells Fargo analyst Larry Biegelsen reported that

…the FDA has recently visited a number of sites that participated in the CardioMEMS pivotal trial because the FDA has concerns with how the trial was conducted. It is our understanding that FDA is concerned that physicians in the study may have been coached on how to treat the patients in the treatment group and this may have led to bias in the study.

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ESC May Re-Examine Guidelines in Wake of Poldermans Dismissal Reply

In the wake of the dismissal of Don Poldermans from the Erasmus Medical Center due to scientific misconduct (for background see this and this) the European Society of Cardiology has announced that Poldermans has resigned from his position as chairperson of the task force that created the ESC practice guidelines for preoperative cardiac risk assessment and preoperative cardiac management in non-cardiac surgery.

The ESC also stated that it is “looking into” the guidelines “in order to decide if these need to be re-examined in the light of recent events.” Here is the ESC statement:

 ESC Guidelines are based on the contributions of many European experts and on available evidence based medicine, including many studies from different nations. They are, therefore, the result of a group discussion and not of an individual position. We are saddened by Prof Poldermans’ situation and, although we are confident that our Guidelines are supported by reliable data, we are carefully looking into the Guidelines for Pre-operative Cardiac Risk Assessment. Supplying the best possible guidance to physicians in order to improve medical practice and ensure patients receive the best treatment, is our main objective and we will continue to work towards this goal.

Long Term Followup of HPS Shows Extended Benefits of Statins Reply

Long-term followup of patients enrolled in the Heart Protection Study (HPS) demonstrates continued benefits in the group originally randomized to receive simvastatin instead of placebo. The main results of the HPS, published in 2002, showed a significant 23% reduction at 5.3 years in major vascular events associated with simvastatin treatment among the 20,536 patients with coronary disease enrolled in the trial.

Now the HPS investigators report the followup results after a mean of 11 years in a paper published online in the Lancet. After the trial ended statin use and, consequently, LDL levels were similar between the two groups. In the first post-trial year patients who had been randomized to simvastatin during the trial had an additional 14% reduction in events compared to patients who had been randomized to placebo (p=0.05). After the first post-trial year there were no further additional differences between the former groups, but the relative difference between the two groups remained unchanged.
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Merck Pleads Guilty and Pays $950 Million for Illegal Promotion of Vioxx Reply

The US Department of Justice announced today that Merck, Sharp & Dohme will plead guilty to illegal promotion of Vioxx (rofecoxib) and will pay a $950 million in fines and penalties to the US government and individual states.

The criminal plea is tied to Merck’s off-label promotion of rofecoxib for rheumatoid arthritis (RA) from 1999 until 2002, since the drug did not have an indication for RA at that time. The civil settlement is tied to a broader range of allegedly illegal conduct by Merck, including statements about the cardiovascular safety of rofecoxib made by Merck representatives. The company will also enter into an expansive corporate integrity agreement with the government.

In  its own press statement, Merck said that the civil portion of the settlement “does not constitute any admission by Merck of any liability or wrongdoing.” Merck also said:

As part of the plea agreement, the United States acknowledged that there was no basis for a finding of high-level management participation in the violation. The government also recognized Merck’s full cooperation with its investigation.

Click to read the US DOJ and the Merck press releases…

More Details Emerge About the Dutch Research Scandal 5

More details have emerged about the research scandal in the Netherlands, in which prominent Erasmus Medical Center cardiovascular researcher Don Poldermans was fired for scientific misconduct. Anonymously leaked portions of a report from the Erasmus Medical Center investigation first appeared on Scribd over the weekend [Editor's note: the Scribd link is no longer working]. Later an executive summary of the report, dated November 16, appeared on the Erasmus website. All the documents are in Dutch. Here is a brief summary, based on help received from Google Translate, Babel Fish, and native Dutch speakers.

As previously reported, the committee found “serious deficiencies” in obtaining informed consent in at least one and possibly another of the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) studies led by Poldermans (see the table below). Although some patients may have had procedures they would not have received otherwise, the committee found no evidence that any patients had been hurt by these procedures.
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Prominent Dutch Cardiovascular Researcher Fired for Scientific Misconduct 7

Updated– Don Poldermans, a well-known researcher in cardiovascular medicine in the Netherlands, has been fired for scientific misconduct by the Erasmus Medical Center in Rotterdam.

According to a statement from Erasmus Medical center, an investigation found that Poldermans was

careless in collecting the data for his research. In one study it was found that he used patient data without written permission, used fictitious data and that two reports were submitted to conferences which included knowingly unreliable data.

Poldermans, according to Erasmus, has accepted the conclusions of the committee and “expressed his regret for his actions,” but said his actions were “unintentional.”

CardioBrief has learned that some researchers closely familiar with Poldermans work had been suspicious for years about his perioperative studies. (See update below)

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ELEVATE TIMI 56: One New Piece of the Clopidogrel Puzzle Reply

Jessica Mega

Tripling the maintenance dose of clopidogrel in most but not all patients with a common genetic variation will lower platelet reactivity to levels achieved in patients without the variation, according to results of the ELEVATE TIMI 56 trial. The finding helps solve one piece of the clopidogrel puzzle, but does not provide a path to a major change in clinical practice. Results of the trial were presented by Jessica Mega at the AHA and published simultaneously in JAMA.

The TIMI investigators randomized 333 patients already taking clopidogrel. After genetic screening, 86 carriers of the CYP2C19*2 loss-of-function allele received clopidogrel doses of 75, 150, 225, or 300 mg daily. 247 patients without the allele received 75 or 150 mg daily. After 14 days platelet function testing was performed.
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Experts Clash Over Interpretation and Value of AIM-HIGH 1

Philip Barter

Sparks flew at the AHA press conference this morning when the designated discussant for the AIM-HIGH trial, Australia’s Philip Barter, said that “the design was such that in no way could it test the hypothesis” that niacin therapy may be beneficial. “This trial disturbs me greatly,” he said. The trial co-principle investigator, William Boden, defended his trial, but admitted that it was far from perfect.

Barter case begins with the trial’s design, as it was only powered to detect a 25% reduction in cardiovascular events. However, although HDL levels in the trial increased by 25% with niacin in the trial, substantial increases in HDL were also observed in the placebo group, so that there was only a 4 mg/dl difference in HDL between the groups. In addition, LDL levels reached similar levels in the groups (68 and 63 mg/dl in the placebo and niacin arms, respectively). According to Barter, these small differences between the groups  would predict a best a 12.5% reduction in CV events, only half the amount for which the trial was powered.
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Hype Aside, Hope for Stem Cell Therapy May Be Emerging From Hibernation 3

Two small studies of cardiac stem cells for the treatment of heart failure have shown promise, but ABC NewsCBS News and other media outlets are throwing around words like “medical breakthrough” and “heart failure cure.” ABC News correspondent Richard Besser was so enthusiastic that anchor Diane Sawyer commented that she had never seen him “so excited.” The first author of one of the studies, Roberto Bolli, said the work could represent “the biggest advance in cardiology in my lifetime.”

The reality may be somewhat more prosaic. In the first paper, published in the Lancet, Roberto Bolli and colleagues, including senior author Pierro Anversa, report on a phase 1 study still in progress in which 16 patients with post-infarction left ventricular (LV) dysfunction received cardiac stem cells (CSCs) harvested during bypass surgery and subsequently expanded. Seven patients served as controls.
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SATURN Regression Trial: Gorilla Statin and Statin King Battle to a Draw 1

An epic battle comparing the two most potent statins– the reigning king atorvastatin versus “gorilla statin” rosuvastatin– ended with a quiet draw. Results of SATURN (Study of CoronaryAtheroma by InTravascular Ultrasound: Effect of Rosuvastatin Versus AtorvastatiN) were presented at the AHA and published simultaneously in the New England Journal of Medicine.
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AIM-HIGH: No Benefit for Niacin on Top of Statins 2

The AIM-HIGH investigators aimed for the lofty target of proving the beneficial effects of niacin therapy. They did not succeed.

The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) investigators randomized 3414 patients with CV disease, low HDL and elevated triglycerides to extended-release niacin or placebo in addition to simvastatin. During the trial niacin increased HDL by 25% and decreased triglycerides by28.6%. In the statin group HDL increased by 9.8% and triglycerides decreased by 28.6%. Results of the trial were presented at the AHA and published simultaneously in the New England Journal of Medicine.

Followup of the trial was stopped early due to futility. The primary endpoint– the first event of the composite of CHD death, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization– occurred in 16.4% of patients in the niacin group versus 16.2% in the placebo group (HR 1.02, CI 0.87-1.21, p=0.79).
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PALLAS: Poor Results for Dronedarone in Permanent AF Reply

Stuart J. Connolly

After a brief announcement earlier this year that the trial had been terminated early, the full results of PALLAS  (Permanent Atrial Fibrillation Outcomes Study Using Dronedarone on Top of Standard Therapy) have now been presented at the AHA and  published simultaneously in the New England Journal of MedicinePALLAS shows that dronedarone (Multaq, Sanofi)  should not be used in patients who have permanent atrial fibrillation (AF). The larger question, which the trial can’t answer, is whether anyone else should be taking the drug.

3236 elderly patients with permanent AF were randomized to dronedarone or placebo. The study was stopped  for safety reasons by the data monitoring committee less than a year after enrollment began.

A first coprimary outcome (stroke, MI, systemic embolism, or cardiovascular death) event occurred in 43 dronedarone patients versus 19 placebo patients (HR 2.29, CI 1.34-3.94, p=0.002):
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MI FREEE: How Much Do Free Medications Really Cost? Reply

Could getting rid of co-payments improve adherence to post-discharge medications, leading to better  outcomes and reduced costs? That’s the theory tested by the MI FREEE (Post-Myocardial Infarction Free Rx Event and Economic Evaluation) trial, which was presented at the AHA and  published simultaneously in the New England Journal of Medicine.

Niteesh Choudhry and colleagues randomized 5855 post-MI patients with Aetna insurance to either full prescription coverage or usual prescription coverage for statins, beta-blockers, ACE inhibitors, or ARBs. The rate of adherence increased for all drug categories with full prescription coverage (p<0.001 for all categories):
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ATLAS ACS 2-TIMI 51: Rivaroxaban Beneficial in Low-Risk ACS Population 1

Results of the highly anticipated ATLAS-ACS 2–TIMI 51 demonstrate that ACS patients receiving standard therapy, including dual antiplatelet therapy, may benefit from the addition of the factor Xa inhibitor rivaroxaban, although at the cost of some additional bleeding complications. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome  trial was  presented by C. Michael Gibson at the American Heart Association and published simultaneously in the New England Journal of Medicine.

15,526 patients with ACS were randomized to placebo or either 2.5 mg or 5 mg of rivaroxaban for 13 months. The rate of cardiovascular death, MI, or stroke was reduced in the patients taking rivaroxaban:
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ADOPT Fails to Support Extended Oral Anticoagulation with Apixaban in High Risk Post-Discharge Patients Reply

Although medically ill patients remain at risk for VTE after hospital discharge, a strategy of extended oral anticoagulation with apixaban did not prove successful in the ADOPT (Apixaban Dosing to Optimize Protection from Thrombosis) trial, which was presented by Samuel Z Goldhaber at the American Heart Association and published simultaneously in the New England Journal of Medicine.
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Controversy Over Cholesterol Testing for Children 3

New guidelines from the NHLBI and the American Academy of Pediatrics recommend that all children between the age of 9 and 11 should undergo cholesterol screening. Screening should then be repeated at 17 and 21 years of age. The new guidelines are scheduled to be officially introduced by panel member Patrick McBride at the AHA in Orlando on Sunday.

“Previous targeted screening missed more than 50 percent of children with high cholesterol,” McBride told ABC News. “Atherosclerosis begins very early in life, even in infancy for children with genetic cholesterol problems. So increased screening is a necessary step.”

But the guidelines are likely to meet with considerable skepticism. One highly knowledgeable expert told CardioBrief that the new recommendations are not justified:

I do not think it is evidence based.  I think it is a real reach.  It muddles together different messages about finding genetic dyslipidemias – which need drug treatment – and improving lifestyle.  For those without genetic dyslipidemia, you don’t need screening to advise about  healthy lifestyle changes, and there is zero evidence that scaring people  – especially children – leads to successful behavior change.  For those with genetic dyslipidemia – lets remember FH only affects 1/500 – 2/3 are picked up by targeted screening.  So for every 750 kids we screen, we find one kid with FH and put him or her on a drug 10 years earlier than we otherwise would have.  Not much of a gain for the expense, pain, anxiety, and potential labeling/stigmatization of all the others.  And we do not know the safety of these drugs in teens – we take for granted that they are safe because drug companies and the FDA said so.  This is a distraction from the real changes our society needs, increases the cost of health care, and is a huge boon for the makers of cholesterol drugs and screening tests.  I would refuse to let my kids get screened.”

Two Year Delay?

One other interesting sidenote to this story: although the news broke two days earlier than anticipated because of some aggressive reporting from the AP (here’s  a look behind-the-scenes), the guidelines have been languishing at the NHLBI for two years or more. Note that the publication of the guidelines in Pediatrics discloses that the manuscript was accepted for publication on August 4, 2009. I have been told that several frustrated panel members threatened to resign over NHLBI delays in moving forward with the project.

Click here to read CardioBrief’s previous coverage about cholesterol screening guidelines in children from the National Lipid Association.

TAVI at TCT: Enthusiasm Tempered by Poor Transapical Outcomes 1

Continued enthusiasm for transcatheter aortic valve implantation (TAVI) with the Edwards’ Sapien device was tempered somewhat by poor outcomes observed in the group of patients for whom the procedure was performed through the transapical instead of the transfemoral approach. Results of 3 new studies from the PARTNER trials and a controversial new trial, STACCATO, were presented on Thursday at the TCT conference in San Francisco.

The overall good news for TAVI came from the 2-year results of the PARTNER B trial. In this trial of patients who were not eligible for open heart surgery, the advantages for TAVI over medical therapy previously observed at 1 year have now been extended out to two years. The rate of all cause mortality at 2 years was 18.2% in the TAVI group versus 35.1% in the control group. Repeat hospitalization was cut in half from 72.5% in the control group to 35% in the TAVI group. However, the stroke rate at 2 years remained higher in the TAVI group: 13.8% versus 5.5%. 3 strokes and 2 TIAs occurred in TAVI patients in the second year.

“The ultimate value of TAVR in ‘inoperable’ patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR and render the intervention futile,” concluded Raj Makkar, who presented the results at TCT.

Transapical Approach Under Scrutiny

Two other PARTNER studies presented at TCT cast a shadow on the value of TAVI in patients who require the transapical approach. The quality of life study of the PARTNER A trial, presented by David Cohen, found an improvement in quality of life in patients whose TAVI was performed via the transfemoral approach but not via the transapical approach, when compared to surgery. In fact, said Cohen, the results raised the possibility of a worse quality of life in the TAVI TA group.
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CardioBrief Poll: Should the ACC Train Industry Reps? 2

The American College of Cardiology has announced a new series of education programs for industry employees. The ACC claims that the program will provide “a comprehensive, thorough and non-biased education in the field of cardiology” so that the employees “can become partners to health care providers — supporting positive health outcomes for patients.”

…graduates of the program will be granted the use of an American College of Cardiology Foundation (ACCF) industry training logo and notation as having received “ACCF Industry Training” on their business card, resume and promotional materials, and recognition of employee participation may appear on your company website.

The program, according to the ACC, will also benefit health care professionals and will “ensure” that their “interactions with pharmaceutical and medical device company representatives are effective and efficient.” The ACC informs its members that the program is not a one shot deal: “industry representatives will be required to stay current by participating every two years, ensuring that they stay up-to-date on the most important topics.”

The ACC advises its members:

Look for the ACCF Training logo on your representatives’ business cards.

What do you think? Take the poll and add a comment to this post.

Obstructive Lesions Found in Patients with Calcium Score of Zero Reply

A small but significant number of symptomatic patients with calcium scores of zero have obstructive coronary artery disease (CAD), according to a new study published in the Journal of the American College of Cardiology.

Todd Villines and colleagues studied 10,037 symptomatic patients without known CAD enrolled in the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry who underwent CT angiography (CTA). Half of the patients (51%) had a coronary artery calcium (CAC) score of 0 and although most (84%) had no CAD, 13% had a non-obstructive stenosis, 3.5% had a stenosis greater than 50%, and 1.4% had a 70% stenosis. 3.9% of patients with a CAC score of 0 and obstructive CAD had an adverse event during followup as compared to 0.8% in the group with a CAC score of 0 and no obstructive CAD.

The authors write that their results reaffirm “the importance of properly assessing patient pretest probability for obstructive CAD” when calcium scores are used in symptomatic patients. They concluded that “the absence of CAC reduces but does not fully eliminate the occurrence of obstructive CAD” and that calcium scoring “does not appear to offer significant incremental prognostic information when combined with clinical risk factors and CAD severity on CCTA.”