Very Little New Light Shed on the Archives Meditation Paper Fiasco 1

Update, June 30-- Jann Ingmire, the director of media relations for JAMA and the Archives Journals, sent the following clarification late this afternoon: “The authors submitted the additional data in a letter just prior to publication.  That letter was submitted by the authors in response to a request for changes from the NIH program director (not the journal).” This information is helpful, but it still does not shed any light on the substance of the problems with the Archives paper or the issue concerning the last-minute timing of events, and it raises a new question about the NIH’s involvement with this study.

Over on his blogs Retraction Watch and Embargo Watch, Ivan Oransky has published statements about the mystery of the disappearing paper from the editor of the journal that pulled the paper and the first author of the paper.   Unfortunately, the statements don’t really shed a whole lot of light on the unprecedented event, in which the publication of a paper was halted only 12 minutes before its scheduled debut.

Rita Redberg, the editor of  Archives of Internal Medicine told Oransky that she did not know when (if ever) a revised version of the paper would be published: “we are awaiting a revised version that contains additional data which must be reviewed and analyzed,” she said.

In response to Oransky’s question about peer review of the study, she said:

The study was peer reviewed, as are all Archives articles, and in general peer review works well as long as all data are provided as required by Instructions to Authors. We thought we had all the data when the manuscript underwent peer review, but it turned out there was additional data to be considered.

Here is the comment Oransky received from the first author of the paper, Robert Schneider:
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New Concerns Raised About Withdrawn Archives Meditation Paper 8

I don’t know why Archives of Internal Medicine stopped the publication of a paper only moments before its scheduled debut (see my previous post for the details). But a news story on the study (published despite the withdrawal of the paper, and provoking further questions about gullible journalists) provides firm evidence that the study’s authors are clearly guilty of gross scientific exaggeration and misstatement. And a closer look at the paper intended for publication raises additional questions.

Transcendental meditation can cut heart attacks and strokes by 50%, writes Richard Alleyne in a news article in the Telegraph that contains not a single caveat or statement of caution. He quotes Dr. Norman Rosenthal of the NIMH, who calls the study results “a seminal finding.” Even more:
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Archives Decides At Last Minute Not to Publish a Scheduled Paper 7

Here’s something I’ve never seen: 12 minutes before the scheduled publication of a paper the journal publishing the paper announced that it had “made the decision not to publish” the paper. Here’s what happened:

Last Thursday the JAMA/Archives media team issued a press package to  accredited media about several articles scheduled for publication in Archives of Internal Medicine on Monday (today) at 4 PM ET. The package included a press release (see below) about an article, “Stress Reduction in the Secondary Prevention of Cardiovascular Disease: A Randomized Controlled Trial of Transcendental Meditation and Health Education in African Americans.” The first author was Robert Schneider, MD, from the Maharishi University of Management, Maharishi Vedic City, Iowa. Co-authors from the same institution were: Maxwell Rainforth PhD, Sanford Nidich. EdD, Carolyn Gaylord-King, PhD, John Salerno, PhD, and Charles Alexander, PhD. Two other authors, Clarence Grim and Theodore Kotchen are from the Medical College of Wisconsin in Milwaukee.

Today (Monday), at 3:48 PM ET, 12 minutes before the scheduled publication of the paper, the following message appeared in my inbox:

Subject: Important Notice from Archives of Internal Medicine — Please Open Immediately!

The editorial office of the Archives of Internal Medicine has made the decision not to publish,  “Stress Reduction in the Secondary Prevention of Cardiovascular Disease: A Randomized Controlled Trial of Transcendental Meditation and Health Education in African Americans,” by Schneider et al, and the accompanying Commentary by Mehta and Bairey Merz that was to post Online First at 3 PM central time today.

The decision is to allow time for review and statistical analysis of additional data not included in the original paper that the authors provided less than 24 hours before posting. We apologize for the short notice, but hope you will understand and not run your stories on this study today.

Sincerely,

JAMA/Archives Media Relations

Without more information it’s difficult to comment at this point, but I strongly suspect that we will hear more about this story in the future. It should be noted that the study was funded by the NHLBI. In addition, the same study was presented at the AHA Scientific Sessions in 2009. The first author, Robert Schneider, is the Dean of the College of Maharishi Consciousness Based Health Care at Maharishi University of Management and Director of the Institute for Natural Medicine and Prevention, which is funded by the NIH’s National Center for Complementary and Alternative Medicine. Schneider is a specialist in clinical hypertension and has published extensively, including papers in the American Journal of Cardiology, Stroke, and Hypertension.

[Update: the NCCAM has written to inform me that it "does not currently fund research at Maharishi University of Management; we last provided grant funding to the institution in FY 2004." The information in the article was taken directly from the website linked above.]

For more on this story see my next post.
Click here to read the press release originally issued by JAMA/Archives…

Asprin Dosage in US May Explain Disparity in Ticagrelor Results in PLATO 1

Although the PLATO trial succeeded in demonstrating the overall superiority of ticagrelor (Brilinta, AstraZeneca) to clopidogrel in more than 18,000 ACS patients worldwide, approval of the drug in the US has been delayed because of ticagrelor’s lack of effect in the prespecified subgroup of patients from North America. Now, two  analyses of the trial, presented at the American Heart Association’s Emerging Science Series (a new peer-reviewed venue from the AHA), suggest that the North American results may be the result of more use of high dose aspirin in patients from the US. The paper has now also been published online in Circulation.

Ken Mahaffey presented the results from the analyses, which were performed by the Duke Clinical Research Institute and AstraZeneca. The analyses were not able to rule out the play of chance as an explanation for the North American subgroup, but did show that high dose aspirin >300 mg/day was used far more often in the US than in the rest of the world (53.6% vs 1.7%).

Mahaffey reported that in patients taking low-dose aspirin, the outcomes were better in the ticagrelor group than in the clopidogrel group. The difference was statistically significant in the rest of the world but not in the US:
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Diabetes Growth Termed a Rising Global Hazard Reply

In 2008 347 million people in the world had diabetes, more than twice the 153 million in 1980, according to estimates contained in a report in the Lancet from the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group. The papers appears in conjunction with the annual meeting of the American Diabetes Association.

Throughout  the world diabetes prevalence has risen or, at best, stayed the same over the last 30 years, the authors report. Although most of the increase was due to population growth and an increased proportion of elderly people, 30% of the increase was due to an increase in risk factors such as obesity.
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Limited Benefit Found for Early Aggressive Management of Diabetes Reply

In the ADDITION-Europe trial, 3055 patients without diabetes were randomized to either routine care or screening followed by intensive treatment of multiple risk factors. The results were presented at the American Diabetes Association meeting and published online in the Lancet, After five years, cardiovascular risk factors– HbA1c, lipids, and blood pressure– were “slightly but significantly better in the intensive treatment group,” according to the authors. However, the primary endpoint of the study, the first cardiovascular event, was not significantly different between the groups, though the difference favored intensive treatment: 7.2% in the intensive treatment group versus 8·5% in the routine care group (HR 0·83,CI 0·65–1·05). All-cause mortality was 6·2% versus 6·7% (HR 0.91,0·69–1·21).
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FDA Recommends More Conservative Dosing of ESAs 1

The FDA today said that it was recommending more conservative dosing of ESAs (erythropoiesis-stimulating agents) in patients with chronic kidney disease (CKD). The possible beneficial effects of the drugs to decrease the need for transfusions in CKD patients should be weighed against the increased risk of cardiovascular events, the FDA said. ESA therapy should be given at the lowest possible dose to reduce the need for transfusions. Currently available ESAs include epoetin alfa, marketed as Epogen (Amgen) and Procrit (J&J) and darbepoetin alfa, marketed as Aranesp, (Amgen).
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Pundits Declare Victory in Anticoagulant Contest But It’s Not Over Yet 3

The pundits and analysts have called it: apixaban (Eliquis), the oral, direct factor Xa inhibitor being jointly developed by BMS and Pfizer, is the winner. Dabigatran (Pradaxa) and rivaroxaban (Xarelto) will fight for the remainder of the market. Yesterday’s announcement of the topline results from ARISTOTLE indicates a clear victory for the drug, say the experts.

But hold on a second. Remember: we’ve only seen a press release from the companies. The only thing they’ve told us is that the trial met its primary endpoint and its secondary endpoint. No actual numbers. No subgroups. No analyses. At this point no one knows the full tale of this trial. And who knows what outside experts or the FDA will find when they get ahold of the details?
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Apixaban (Eliquis) Meets Primary Endpoint in ARISTOTLE 1

Pfizer and Bristol-Myers Squibb said today that their new oral direct Factor Xa drug apixaban, which will be marketed under the brand name of Eliquis, had met the primary endpoint of the ARISTOTLE study.

The Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) study was designed to compare the factor Xa inhibitor apixaban with warfarin for the prevention of stroke and systemic embolism in atrial fibrillation (AF) patients with additional risk factors for stroke. The primary outcome was the time to first occurrence of either stroke or systemic embolism. According to the company, apixaban met the criteria for noninferiority to warfarin in the trial.
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JAMA: Skeptical Perspectives on Consumer Cardiac Tests and Vitamin D 1

Two commentaries published in JAMA offer skeptical perspectives on the roles of direct-to-consumer (DTC) cardiac tests and vitamin D in cardiovascular health.

In the first commentary, Kimberly Lovett and Bryan Liang write that DTC screening tests “likely pose more risk than benefit to patients,” and point out that for companies selling these tests there is no requirement “for full disclosure in advertising, informed consent, pretest evaluation, or posttest counseling.” Some screening tests, including tests for carotid artery stenosis, PAD, AF, and AAA, are not recommended for most people by organizations like the USPSTF and the ACC/AHA. Other tests, like CRP, lipid tests, and coronary calcium, have received limited endorsements, but only in carefully selected patients, the authors write.
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Meta-Analysis Examines Risk of Diabetes Associated with Statins 2

Although the cardiovascular benefits of statin therapy are well-characterized, recent studies have raised concerns that intensive statin therapy increases the risk of developing type 2 diabetes. Now, a new meta-analysis published in JAMA provides a more precise estimate of the risk of diabetes associated with statin therapy and also weighs that risk against the cardiovascular benefits of statins.
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Study Finds Critical Delay in Most MI Patients Transferred for Primary PCI Reply

MI patients who arrive at hospitals unable to perform primary PCI need to be promptly transferred to another hospital in order to receive the full benefits of reperfusion. Unfortunately, these patients often have prolonged door-to-balloon times. A key element in the delay is the time spent at the first hospital, referred to as the door-in to door-out (DIDO) time. A new study published in JAMA demonstrates that a DIDO time of 30 minutes or less is associated with shorter reperfusion delays and lower in-hospital mortality, but the study also showed that only a small proportion of patients are currently transferred this rapidly.
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FDA Says Varenicline (Chantix) May Increase Risk of CV Events 2

The FDA said that the anti-smoking drug varenicline (Chantix) may increase the risk of cardiovascular events in people who already have cardiovascular disease. The new information will be added to the drug’s label and Medication Guide for patients.

The FDA does not recommend that people with cardiovascular disease discontinue taking varenicline, but says that physicians and patients should weigh the known benefits of varenicline with the potential risks. Pfizer, which manufactures the drug, will be required to conduct a large meta-analysis.
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FDA Says Pioglitazone Use Is Linked to Bladder Cancer Reply

The FDA has issued a safety announcement stating that the use of pioglitazone (Actos) for more than 1 year may be  associated with increased risk for bladder cancer. The FDA announcement follows last week’s suspension of the drug in France and Germany by regulatory authorities in those countries.

The FDA said that pioglitazone should not be used in patients with active bladder cancer and should be used “with caution” in patients with a history of bladder cancer.

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NEJM: FDA Officials Explain the New Simvastatin Label Reply

(Updated with comments from Joe Ross and Steve Nissen)– In a perspective published in the New England Journal of Medicine, two FDA officials, Amy Egan and Eric Colman, explain in some detail the recent changes made by the FDA regarding simvastatin. They note that in the SEARCH trial myopathy developed in 52 (0.9%) patients in the 80 mg group compared to only 1 (0.02%) patient in the 20 mg group. There were 22 cases of rhabdomyolysis in the high dose group compared to no cases in the low dose group. Further, patients at high risk usually developed myopathy early in the course of treatment.

Click to continue reading, including comments from Joe Ross and Steve Nissen…

Twice a Stent Pioneer, J&J Abandons the Stent Market Reply

Johnson & Johnson, the company which pioneered the original stent market in the 1990s and the drug-eluting stent market in the 2000s, is abandoning the stent market. On both occasions the company completely revolutionized the field of interventional cardiology, and on both occasions the company spectacularly lost its leading position and failed to build a successful long-term stent business. On each occasion, according to critics, the company sought to exploit its early monopoly position by  charging exorbitant prices for its stents. The result, on each occasion, was that the company alienated its core customers, hospitals and interventional cardiologists. As soon as alternative devices became available they were rapidly adopted by a marketplace weary of J&J’s strongarm tactics.

In a press release (see below) the company announced that it was discontinuing development of the Nevo sirolimus-eluting stent and that it would also stop making its original Cypher stent by the end of the year.
Click here to read the press release from J&J…

CRT for HF Patients With Moderately Prolonged QRS Interval: Unethical? 4

Approximately 40% of cardiac resynchronization therapy (CRT) devices are implanted in patients with QRS intervals below 150 msecs, but a meta-analysis published in Archives in Internal Medicine finds that these patients may not benefit from the device.

Ilke Sipahi and colleagues performed a meta-analysis that included 5 CRT clinical trials (COMPANION, CARE-HF, REVERSE, MADIT-CRT, RAFT) with designs that enabled them to examine the effect of QRS duration on outcome. Although patients with severely prolonged QRS had a 40% reduction in risk associated with CRT therapy (CI 0.53-0.67, p<.001), no benefit at all was observed in the patients with only moderately prolonged QRS. The same finding was observed in patients with class 1 and 2 heart failure as in patients with class 3 and 4 heart failure. The presence or absence of an ICD did not alter the pattern.
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Increased Mortality Found in MI Patients During Ambulance Diversion Reply

MI patients treated who are diverted to other emergency departments (EDs) while their local EDs are closed have an increased risk of death, according to a new study published in JAMA. Yu-Chu Shen and Renee Hsia analyzed data from 4 California counties of all Medicare patients with MI who were admitted to the hospital between 2000 and 2005.

At 1 year, the rates of death were:
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A New Biomarker From the Lungs Reply

A new study raises the possibility that a protein produced in the lungs may improve the prediction of cardiovascular disease. In a paper in the European Journal of Cardiology, John Hill and colleagues report on their research with surfactant protein-D (SP-D), which is produced in the lungs and whose levels are increased in the general circulation following lung injury and lung inflammation.

The researchers first measured SP-D levels in 806 patients undergoing coronary angiography in order to determine its value in predicting cardiovascular risk. In the second stage they measured SP-D levels in a replication cohort of 4,486 current and former smokers with no known history of coronary disease.
Click to continue reading, including a comment from James De Lemos…

Pioglitazone (Actos) Suspended in France Over Cancer Concerns 2

Update–June 10: Following the example of France, Germany has also suspended the use of pioglitazone. Click here for the announcement (in German).

Sales of the popular diabetes drug pioglitazone (Actos, Takeda) have been suspended in France after a study carried out by the French health insurance fund (CNAM)  found that the drug may increase the risk of bladder cancer. The French regulatory agency (AFSSAPS) said that new prescriptions for drugs containing pioglitazone may no longer be written but that people who are already taking the drug may continue to do so.
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SHARP Results Published in Lancet 4

The main results of SHARP (Study of Heart and Renal Protection) have now been published in the Lancet, following their preliminary presentation last November at the American Society of Nephrology meeting. The results are also posted online on the trial’s website.

In brief, SHARP randomized 9270 patients with chronic kidney disease (one-third of whom were on dialysis) to either placebo or the combination of simvastatin and ezetimibe. After a median followup of 4.9 years the rate of major atherosclerotic events (defined as nonfatal MI or coronary death, non-hemorrhagic stroke, or arterial revascularization excluding dialysis access procedures) was significantly reduced from 13.4% in the placebo group to 11.3% in the combination therapy group (RR 0.83, CI 0.74-0.94, p=0.0021).
Click to continue reading, including comments from James Stein and Merck…

FDA Recommends Limiting Usage of High Dose Simvastatin 1

The FDA today recommended significant limitations in the use of high dose (80 mg) simvastatin because of the increased risk of myopathy. The FDA said the 80 mg dose of simvastatin should be used only in people who have been taking the high dose for at least one year and have had no evidence of myopathy. The high dose should not be started in new patients, including those already taking lower doses of the drug.
Click to continue reading, including comments from Jim Stein and Allen Taylor…

FDA Sets July 20 Date for Advisory Panel on Sapien Transcatheter Aortic Valve Reply

An FDA advisory panel will review the premarket approval (PMA) application for the Sapien transcatheter aortic valve on July 20, the device’s manufacturer, Edwards, has announced. The application is based on results from the PARTNER B trial, which compared the Sapien valve to optimal medical therapy in patients with severe aortic stenosis who were not eligible for surgery.
Click to read the press release from Edwards…

ProPublica Investigates Heart Check America 1

Editor’s Note: The following post is reprinted with permission from ProPublica.

Body Imaging Business Pushes Scans Many Don’t Need — Including Me

by Marshall Allen, ProPublica, June 7, 2011, 5 a.m.

The telemarketer called in February with an unusual offer: free heart scans for me and my wife, an $800 value, from a company called Heart Check America.

The procedure would be “non-invasive,” he promised. No needles. “Just lie on a table and hold your breath.” The scans could identify heart disease and might just save our lives, he added.

Three weeks later, at a clinic in a stucco Las Vegas office park, Tom, a salesman for the company, led us through an ominous PowerPoint presentation that was a prerequisite for getting the scans.

He gave example after example of athletes and celebrities – figure skater Sergei Grinkov, baseball player Darryl Kile, newsman Tim Russert – who seemed to be in the prime of life, then dropped dead of heart attacks.

“You never know when it could happen. … Boom, you’re dead!” he exclaimed, slapping a desk for emphasis.
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