Heart Rhythm Editor Douglas Zipes Defends Peer Review 4

Rejecting an extraordinary request from industry to retract a controversial paper, Douglas Zipes, the editor-in-chief of HeartRhythm, has written a rare, highly pointed editorial defending the publication process. “If one disagrees with facts/statements in a publication,”  writes the editor, Douglas Zipes, “there is a well-defined approach that can begin with a letter to the editor or submission of one’s own data for peer review to counter the conclusions in the article.”

Zipes was responding to a request from St. Jude alleging numerous mistakes and oversights in an article by Robert Hauser published online in HeartRhythm linking the company’s Riata and Riata ST leads to 20 or more deaths. The company publicly asked the journal, which is published by the Heart Rhythm Society, to retract the article.

“The peer review process is a time-honored, well-choreographed procedure that has served the intellectual world for several hundred years,” writes Zipes. “While occasional decisions may be incorrect, and fail to identify a submission of low (or high) quality, containing incorrect data, or even one that is fraudulent, in the main the system works.”

The publication of an editorial by Zipes was itself unusual, he noted: “I do not write many editorials because I feel my role as editor-in-chief is to be as impartial as possible.” In this case, “however, the recent events that transpired… have compelled me to speak out.”

The Hauser article has received additional public support from electrophysiologist Edward J Schloss. In a detailed review of the Hauser and St. Jude papers, Schloss noted that they  had applied different methodologies in their search of the MAUDE database.

Schloos offered the following comment in response to the Zipes editorial: “I applaud Dr. Zipes and HeartRhythm for publishing Dr. Hauser’s study.  This important work should serve as a call to the cardiology community to increase their vigilance in detecting electrical failures in Riata/Riata ST ICD leads.”

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Cameron Health’s Subcutaneous ICD Sails Through FDA Advisory Panel 1

The FDA’s Circulatory System Devices panel voted 7-1 on Thursday that the benefits of the Cameron Health subcutaneous ICD system (S-ICD) outweigh the risks in appropriately selected patients.

Unlike all previous ICDs, the S-ICD is much easier to implant because it is does not require threading a lead to connect the device to the heart. Panel member Rick Lange said the S-ICD was an example of “I-should-have-thought-of-that technology”, according to Heartwire reporter Reed Miller on twitter. That sentiment was echoed by device giant Boston Scientific in March when it agreed to acquire Cameron Health for $150 million initially, and as much as $1.2 billion in additional payments based on future performance, according to Reuters.

The advisory panel also voted 7-1 that the S-ICD was effective and 8-0 that it was safe.

Earlier this week, FDA reviewers posted the previously unavailable results of the pivotal trial for the S-ICD. The FDA review set the tone for a generally supportive panel meeting, finding that the trial met its primary safety and efficacy endpoints, though it identified several potential safety issues.

Click here to read the press release from Cameron Health…

FDA Advisory Panel Gives Green Light To HeartWare Ventricular Assist System Reply

The FDA’s Circulatory System Devices panel voted 9-2 on Wednesday to recommend approval of the HeartWare Ventricular Assist System as a bridge to heart transplantation for patients with end-stage heart failure. The panel agreed unanimously (11-0) that the new device is effective. The panel was more divided about safety but ultimately voted  8-3 that the device was safe.

In briefing documents published online earlier in the week, FDA reviewers  raised a number of questions about the safety of the device and the reliability of the data from the pivotal ADVANCE trial, in which 140 patients received the Heartware device and were compared to historical controls who had received Thoratec’s HeartMate II device. The FDA had not previously permitted historical controls to be used in this fashion. Safety questions focused on stroke and thrombosis.

Unlike the HeartMate II VAS, which is surgically implanted in an abdominal pouch, the HeartWare VAS is implanted next to the heart.

“I think this device is of incredible benefit to patients who are very ill,” said panelist Ralph Brindis, as reported by MedPage Today. Acting panel chair Rick Page said the device represented “a real advance in technology,” as reported by Heartwire.
Click here to read the press release from HeartWare…

The Medicines Company Collaborates with AstraZeneca To Sell Brilinta (ticagrelor) Reply

The Medicines Company will collaborate with AstraZeneca to help sell Brilinta (ticagrelor), AstraZeneca’s struggling oral antiplatelet drug. The collaboration is the first stage of  “a global collaboration for acute ischemic heart disease compound” announced by the two companies today.

AstraZeneca will pay $15 million per year for The Medicines Company’s Brilinta-related sales activities, scheduled to begin in May. The two companies also plan to collaborate on two other drugs from The Medicines Company, Angiomax (bivalirudin), the direct thrombin inhibitor, and cangrelor, an acute intravenous antiplatelet agent. Details of these collaborations have not yet been established.

Like many other large pharmaceutical companies, AstraZeneca has been seeking new sources of revenue after the expiration of patents for many of its key drugs. Initial hopes that Brilinta would provide a much-needed boost to the company have so far not been realized. The Medicines Company has also sought to find a successor to Angiomax, which has been the company’s mainstay.

Click here to read the press release from AstraZeneca and The Medicines Company…

When You’re Hot You’re Hot: Salim Yusuf Second Most Influential Scientist in 2011 1

McMaster University’s Salim Yusuf has tied for second place in the annual ranking of the “hottest” scientific researchers, according to Thomson Reuter’s Science Watch.  Yusuf was a co-author of 13 of the most cited papers in 2011. Only one other researcher, genomic pioneer Eric Lander of the Broad Institute of MIT, had more highly-cited papers than Yusuf.

Two of Yusuf’s most-cited papers tested novel anticoagulants in the setting of atrial fibrillation: the RE-LY trial with dabigatran and the AVERROES trial with apixaban. “It’s a new experience to be called a hottie,” Yusuf joked in an interview with the Hamilton Spectator“This means it has impact on other scientists. It’s nice to know you’re doing something useful.” The Science Watchreport also included a list of “red-hot” research papers published in 2011. Five of the top 38 papers were cardiology-related:

Click here to read the press release from Thomson Reuters…

Study Sheds Light on Cardiac Device Infective Endocarditis Reply

A new study sheds light on a rare but highly dangerous complication associated with device implants: cardiac device infective endocarditis (CDIE). Approximately 10-23% of device infections result in CDIE, leading, in one estimate, to an overall rate of 1.14 cases per 1,000 device-years.

In a paper published in JAMAEugene Athan and colleagues analyzed data from 3,284 patients who were enrolled in the International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS). Among patients with a definite diagnosis of infective endocarditis (IE), 6.4% had CDIE. Mortality rates were high:

  • in-hospital mortality: 14.7%, CI, 9.8%-20.8%
  • 1-year mortality: 23.2%, CI 17.2%-30.1%

Compared with other IE patients, CDIE patients were more likely to be male, older, and diabetic. Staphylococci infections accounted for most of the cases. Co-existing valve infection occurred in more than a third of the cases, and these patients were more likely to die. Device removal during the initial hospitalization was associated with a lower mortality rate at at 1 year (19.9% versus 38.2%, HR 0.42, CI 0.22- 0.82).

Electrophysiologists John Mandrola and Wes Fisher told CardioBrief that they were not surprised by the findings of the study. Both agreed that an infected device is dangerous and should be taken out when an infection is suspected. Or, as succinctly stated by Fisher: “When in doubt, take the whole thing out.”

Click here to read the press release from JAMA…

Meta-Analysis Compares Drug-Eluting and Bare-Metal Stents for Primary Angioplasty Reply

A new meta-analysis comparing drug-eluting stents (DES) and bare-metal stents (BMS) in patients with myocardial infarction has provoked opposing take-away messages from an author of the study and an editorialist. The authors emphasize the reduction in target-vessel revascularization (TVR) associated with DES, but the editorialist focuses on several potential DES weaknesses suggested by the study.

In the paper, published in Archives of Internal Medicine, members of the Drug-Eluting Stent in Primary Angioplasty (DESERT) Cooperation pooled patient data from more than 11 clinical trials in which more than 8,600 patients were randomized to either sirolimus-eluting or paclitaxel-eluting stents or BMS.  After a mean follow-up of 1201 days, DES was associated with a significant reduction in TVR but there were no significant differences in death, reinfarction, or stent thrombosis (ST):

  • TVR: 12.7% for DES vs 20.1% for BMS, HR 0.57, CI 0.50-0.66, p<.001
  • Mortality: 8.5% vs 10.2%, HR 0.85, CI 0.70- 1.04, p = .11
  • Reinfarction: 9.4% vs 5.9%, HR 1.12, CI 0.88-1.41, p = .36
  • Stent thrombosis: 5.8% vs 4.3%, HR 1.13, CI 0.86-1.47, p = .38

However, after two years there was a significant increase in the risk of stent thrombosis associated with the DES group (HR 2.81, CI 1.28-6.19, p=0.04).

The findings, write the authors,

provide strong evidence of the beneficial effects of SES and PES during primary PCI in STEMI. With follow- up as late as 6 years, a robust and sustained decrease in TVR was noted with use of these DES. Although the rates of late reinfarction and ST progressively increased, with the difference becoming statistically significant after 2 years in patients receiving SES and PES, the HR for mortality, while not significantly different between DES and BMS, favored DES.

Click to continue reading, including a comment from Gregg Stone…

FDA Posts Results of Cameron Subcutaneous ICD Pivotal Trial Reply

In preparation for Thursday’s meeting of the FDA’s Circulatory System Devices advisory panel, the FDA has released the results of the pivotal trial for the Cameron Health subcutaneous ICD system (S-ICD). The results have not been previously available. Unlike previous ICDs, which require threading a transvenous lead to the heart, the S-ICD system contains no leads to connect the device to the heart.

The S-ICD pivotal trial was a prospective, non-randomized, single-arm study performed at 33 sites. The trial enrolled 330 patients, 314 of whom received the S-ICD system. Mean followup was 321 days.

The FDA found that the trial met the primary safety and effectiveness endpoints.

For safety, the system-complicaton-free rate at 180 dayswas 97.9%, which was well above the performance goal of 79%. 8 patients died during the trial, but none of the deaths were tied to the S-ICD system. Four patients had systemic infections requiring explant of the device, while 14 had incision or superficial infections that did not require an explant. The FDA noted that when compared to traditional transvenous ICDs, the S-ICD system had “higher rates of infection, increased time to delivered therapy, and reduced device service life.”

Inappropriate shocks occurred in 38 patients (11.8%); 32 of these patients were managed noninvasively with system reprogramming and drug therapy. Overall, 30.6% of shocks were deemed inappropriate. The FDA reviewer said that a literature review found that about one-third of shocks were inappropriate in a similar group of patients with standard ICDs.

The efficacy rate was 100%. Acute VF conversion was successful in 304 instances, with no failures. 16 episodes were non-evaluable. The FDA calculated that even if all the non-evaluable cases were assumed to be failures, the lower confidence interval for the efficacy rate would have been 91.7%, still well above the performance goal of 88%.

Aliskiren (Tekturna) Gets New Warning and Contraindication From FDA Reply

The FDA has issued new warnings about antihypertensive drugs containing the direct renin inhibitor aliskiren (including Tekturna, Amturnide, Takamio, and Valturna) when used in combination with ACE inhibitors or angiotensin receptor blockers (ARBs). The FDA now states that these drug combinations are contraindicated in patients with diabetes, and it is adding a new warning to avoid the use of this combination in patients with moderate to severe renal impairment (GFR <60 mL/min).

The new warnings are based on preliminary data from the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) clinical trial. As previously reported here, ALTITUDE was terminated last December when the independent Data Monitoring Committee (DMC) found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after a median followup of about 27 months. More than 8,500 patients  with type 2 diabetes and renal disease were randomized to receive aliskiren or placebo in addition to an ACE inhibitor or an ARB.

Click here to read the FDA Drug Safety Communication.

Arizona Cardiac Surgeons Pay $100,000 To Settle HIPAA Violations Reply

An Arizone cardiac surgery group has agreed to pay $100,000 to resolve an investigation into potential violations of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). In the agreement the surgical group did not offer an admission of liability but did agree to implement a corrective action plan in addition to the payment.

According to the Health and Human Services Office for Civil Rights (OCR), the investigation of Phoenix Cardiac Surgery, PC, which is owned by two cardiac surgeons, Pierre Tibi and H. Kenith Fang, began when OCR received a report that the group’s clinical and surgical appointments were available to the public on an internet-based calendar. As part of its investigation OCR discovered that the group had failed to implement policies and procedures to comply with HIPAA and “had limited safeguards in place to protect patients’ electronic protected health information.”

OCR listed a number of specific problems:
Click to continue reading…

Periodontal Disease and CV Disease: Just Friends? 1

Demonstrating once again that association and causation should not be confused, the American Heart Association today published a scientific statement in Circulation asserting that there is no convincing evidence showing that periodontal disease causes cardiovascular (CV) disease or that treating periodontal disease will reduce CV disease. The statement does not rule out the possibility that periodontal disease can cause CV disease, and even notes that a cause and effect relationship is “biologically plausible,” but it concludes that statements that claim “a causative association…   or claim that therapeutic interventions may be useful on the basis of that assumption are unwarranted.”

“There’s a lot of confusion out there,” said Peter Lockhart, co-chair of the statement writing group and professor and chair of oral medicine at the Carolinas Medical Center in Charlotte, N.C., in an AHA press release. “The message sent out by some in healthcare professions that heart attack and stroke are directly linked to gum disease, can distort the facts, alarm patients and perhaps shift the focus on prevention away from well known risk factors for these diseases.”

In recent years there has been an explosion of studies exploring the relationship of PD disease and CV disease, many looking at inflammation as a common factor underlying both diseases. However, sorting out the precise nature of the relationship is difficult because both diseases share common risk factors, including cigarette smoking, age, and diabetes.

Click here to read the AHA press release…

Preoperative Statins Found to Reduce AF and Length of Stay But Not Mortality Reply

In a systematic review published in the Cochrane Library investigators at the University of Cologne in Germany analyzed data from 11 trials that tested the effects of preoperative statins in 984 patients undergoing heart surgery. Preoperative administration of statins reduced the risk of developing atrial fibrillation (AF) and shortened the length of stay on the ICU and in the hospital, but did not have a statistically significant effect on mortality or MI:

  • Post-operative AF: OR: 0.40, CI: 0.29 to 0.55, p<0.01
  • Short-term mortality: OR: 0.98, CI: 0.14 to 7.10, p=0.98
  • ICU length of stay: WMD (weighted mean difference): -3.39 hours, CI -5.77 to -1.01
  • Hospital length of stay: WMD: -0.48 days, CI: -0.85 to -0.11
  • MI: OR: 0.52, CI: 0.2. to 1.30

The authors noted that the studies mostly contained patients undergoing myocardial revascularization, so the findings may not apply to other cardiac procedures.

“To get a clearer picture of the potential benefits of taking statins before a heart operation, we need to have more clinical trials and find out whether clinical outcomes can be further improved if patients use special statin dosing regimens shortly before a heart procedure,” said  lead researcher Oliver Liakopoulos, in a Cochrane Library press release.
Click here to read the press release from the Cochrane Library…

New Perspective on the Dutch Cardiovascular Research Scandal Reply

New information and details have  emerged about the cardiovascular research scandal in the Netherlands. One prominent cardiologist with close ties to the central character in the scandal has been cleared of wrongdoing by his institution and a feature magazine article sheds new light on that central character, Don Poldermans.

As previously reported here last November, Poldermans was fired for scientific misconduct by the Erasmus Medical Center in Rotterdam. Poldermans had been a professor of medicine and the head of perioperative cardiac care at the Erasmus Medical Center. He was widely published and active in the field, serving as a member of the European Society of Cardiology committee for practice guidelines and as the chairperson of the ESC guidelines on pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. He was also the lead author of the influential (but controversial) 1999 New England Journal of Medicine DECREASE study on the use of bisoprolol during vascular surgery. An investigation at Erasmus found that Poldermans used patient data without written permission, used fictitious data, and submitted two reports to conferences which included knowingly unreliable data.

A few weeks after the Poldermans affair became public, another medical center in the Netherlands, Leiden University Medical Center, announced that it was conducting its own investigation specifically looking at “a professor who had published frequently” with Poldermans. Although no names were publicly disclosed, it subsequently became clear that the primary focus of the investigation was Jeroen Bax, a cardiologist at LUMC who had co-authored more than 350 papers with Poldermans. Bax is an ESC board member and the chairman of the ESC guidelines committee.

LUMC has now completed its investigation and concluded that no “scientists at the Leiden University Medical Centre [were] involved in the violation of academic integrity by” Poldermans. However, the investigation also expressed concern about the large number of papers co-authored with Poldermans by LUMC scientists.

A feature article in the Dutch language publication Medisch Contact provides a much more detailed portrait of Poldermans and fills in much of the background of the entire affair.

Following the initial media storm last fall, the subsequent silence has been received with gratitude by Poldermans. Although he refused to give Medisch Contact an interview, in a phone conversation with the publication he said that he is “happy with the radio silence and that “it is the only way to survive.” He said he’s looking for a new job and expects to find one shortly.
Click to continue reading…

Million Dollar Bonuses For Five Ohio State University Electrophysiologists 1

Five Ohio State University electrophysiologists received 2011 bonus payments greater than $1 million, resulting in total pay for the year for each cardiologist of about $2 million. The news was first reported by the Dayton Daily News and subsequently covered by Heartwire.

Five out of the 7 bonuses that topped $1 million at OSU went to the electrophysiologists. The football coach and the basketball coach were the recipients of the additional million dollar bonuses. Here are the compensation figures for the seven OSU employees who received bonuses greater than $1 million, as reported by the Daily News:

Name

Title

Base earnings

Bonus

Other

Total 2011 pay

Steven Jack Kalbfleisch

Professor, clinical

$658,150

$1,383,141

NA

$2,041,291

John David Hummel

Professor, clinical

$650,856

$1,383,137

NA

$2,033,993

Emile Georges Daoud

Professor, clinical

$650,856

$1,330,548

NA

$1,981,404

Ralph Sayre Augostini

Assistant professor, clinical

$650,856

$1,329,604

NA

$1,980,460

Raul Weiss

Associate professor, clinical

$652,902

$1,311,966

NA

$1,964,868

Thad Matta

Men’s basketball coach

$563,508

$1,095,000

$545,004

$2,203,512

Jim Tressel

Football coach

$330,037

$1,047,920

$435,000

$1,812,957

The Daily News quoted Richard Vedder, professor of economics at Ohio University and director of the Center for College Affordability and Productivity: “I have never seen anything like this — never.”

OSU spokesman Jim Lynch told Heartwire that the compensation system at OSU is modeled on other public and private universities and colleges. The Daily News reported that OSU officials said that medical school and athletic department bonuses were “self-funded and don’t draw from tax or tuition dollars.” Lynch told the Daily News that the five electrophysiologists “were hired five years ago to build a nationally respected program in cardiac electrophysiology. Today, that program is the largest in the state and treats patients from throughout a multistate region.”

Comment: I have many thoughts about this story, but for the moment at least I’ll hold off any commentary. But I am eager to hear from my readers– particularly those who are cardiologists. Let me just raise one very small question: although this is a story about big numbers that raises many big questions, I’m intensely curious to learn why Kalbfleisch’s bonus was precisely $4 larger than Hummel’s bonus.

Related Stories on CardioBrief:

Guest Post: After an Unprecedented Request for a Retraction, A Close Look at the Data 3

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

After an Unprecedented Request for a Retraction, A Close Look at the Data

by Edward J Schloss MD

Last week, St. Jude Medical took the unusual step of requesting a retraction of an article accepted for publication in Heart Rhythm Journal.  In this article Deaths Caused by the Failure of Riata and Riata ST Implantable Cardioverter-Defibrillator Leads, Dr. Robert Hauser et al analyzed patient deaths in the FDA MAUDE database associated with St. Jude Medical and Medtronic ICD leads.  This week, Dr. Douglas Zipes, Heart Rhythm editor, declined that request. (Please see my previous Cardiobrief coverage of Hauser’s article.)

In a company news release, St. Jude accused Hauser’s group of “inaccurate facts and biased analysis.”  The sub-headline reads:  “Research undercounted and excluded MAUDE data reports for Medtronic resulting in substantial factual errors.”

St. Jude’s most prominent concern revolves around the number of reported deaths in the analysis of Riata/Riata ST leads and the comparison lead, Medtronic Quattro Secure.  St. Jude wrote: “using the same search criteria outlined in the manuscript, the company has identified that Dr. Hauser’s research substantially undercounted total deaths in the MAUDE database for Quattro Secure.”  St. Jude counts 377 deaths compared to Hauser’s 62.

In an effort to clarify the reasons for this discrepancy, I undertook an independent analysis of the facts available.  My sources are the original Hauser article and the PDF file from St. Jude listing the details of their database search.  I then examined the methodology of both database searches to compare consistency of data entry.  Finally, I performed an independent review of all MAUDE database entries supplied by St. Jude and attempted to classify the 377 deaths Quattro Secure deaths identified by St. Jude into Hauser’s defined categories:  lead-related, indeterminate, and not lead-related, using the methods he described in his paper.

I hypothesized that differences in search methodology may explain the large discrepancy in numbers of deaths found by Hauser and St. Jude.

Results

The Hauser study queried the MAUDE data using the “simple search feature” entering term “Quattro Secure death.”  Results were “refined” to include only model 6947 leads.  Finally, “Reports were excluded from the study if there was no known lead problem or allegation of lead malfunction, and if a returned product analysis found no anomalies that were not caused by the explant procedure.”  With this methodology, the query returned 62 Medtronic Quattro Secure deaths.

The St. Jude data collection methodology is discussed on page one of the PDF document.  The “simple search” function specified by Hauser is not used.  Rather in the standard search fields, individual entries are made for Brand:  Quattro, Manufacturer:  Medtronic, and Event:  Death.  Results were then refined to model 6947 excluding duplicates.  Also in contrast to the Hauser data, no pre-specified exclusions were indicated. This query listed 377 Medtronic Quattro Secure deaths.

Hauser categorized his 62 deaths as 5 (8%) lead-related, 25 (40%) indeterminate, and 32 (52%) not lead-related.

St. Jude did not categorize the 377 deaths. My individual analysis found 7 (2%) lead-related, 129 (34%) indeterminate, and 241 (64%) not lead-related. (Lead-related death MDR Identifiers were 71402, 1438305, 1523151, 1760409, 1944512, 2016463, and 2025526.) I have asked St. Jude for their own analysis of the data into these categories, but have not received a reply.

Discussion

My review confirmed significant methodological differences in the database query specified by Hauser and St. Jude that may explain the differences in the numbers of deaths reported.  This stands in contrast to St. Jude’s assertion that they used “the same search criteria outlined in the manuscript.”
Click to continue reading…

Study Evaluates Losartan Efficacy in Heart Failure Reply

The angiotensin II-receptor blocker (ARB) losartan has labored under the perception that it is not as potent as other ARBs, and some evidence has suggested that it may not confer the same clinical benefits as other ARBs in heart failure patients. In a paper from Denmark published in JAMA, Henrik Svanström and colleagues performed a country-wide registry study in which they compared heart failure patients who were new users of losartan and candesartan.

Overall there were no significant differences in mortality between the two groups:

  • Adjusted hazard ratio (HR) for losartan: 1.10, CI 0.96-1.25

When compared with high-dose candesartan (16-32 mg), however, low-dose (12.5 mg) and medium-dose  (50 mg) losartan were linked to an increased risk for death, but this was not observed with high-dose (100 mg) losartan:

  • Low-dose losartan: HR 2.79, CI 2.19-3.55
  • Medium-dose losartan: HR 1.39, CI, 1.11-1.73
  • High-dose losartan: HR 0.71, CI, 0.50-1.00

The authors concluded that their “findings do not support the hypothesis of differential effects of specific ARBs in patients with heart failure.”
Click here to read the press release from JAMA…

Round Two: Heart Rhythm Editor Rejects St Jude Request to Retract Riata Paper Reply

Douglas Zipes, the editor of Heart Rhythm, said the journal will not retract a controversial paper that has raised new safety concerns about St. Jude’s embattled Riata leads.

On Friday (as reported here) St. Jude issued a press release alleging numerous mistakes and oversights in an article by Robert Hauser published online in Heart Rhythm linking the company’s Riata and Riata ST leads to 20 or more deaths. The company publicly asked the journal, which is published by the Heart Rhythm Society, to retract the article.

On Tuesday, the New York Times reported that Zipes stood by the journal’s peer review process and would not retract the article. Zipes said there will be “some changes” to the article “involving what he called ‘inflection'” but that “‘the bulk of the manuscript stays as it is.”

Earlier Tuesday, St. Jude continued its assault on the Hauser article by issuing a press release and posting a link to findings from the MAUDE database. The company contended that Hauser had grossly undercounted the number of deaths tied to Medtronic’s Quattro Secure lead, thereby making its own Riata leads appear far worse by comparison.

Hauser and Zipes have not responded in detail to the St. Jude accusations, but Hauser told CardioBrief on Friday that the authors “stand by the conclusion of our study.” In a series of tweets, electrophysiologist Edward J Schloss (who has published guest posts about Riata on CardioBrief), noted that Hauser and St. Jude had applied different methodologies in their search of the MAUDE database, and that St. Jude may have failed to exclude Quattro deaths with no known lead problems.

Mark Midei Can’t Get a Job Taking Blood Pressure At A Walmart 8

Earlier this year I had the extraordinary experience of spending several hours on the phone with Mark Midei, the poster-boy (or scapegoat, depending on whom you ask) for all that’s wrong with interventional cardiology in the US. I approached the conversation with some trepidation and discomfort. I’d followed his story closely– but not obsessively– and had written harshly about him. I wasn’t sure why he wanted to speak with me.

It turns out he wanted to get his side of the story across to cardiologists and others interested in the case. I listened to Midei with interest and astonishment, and over the course of our two long phone conversations I found it hard not to feel a certain amount of sympathy for the man. In his absolute fall from a position of enormous success to the disgrace and humiliation of a widely reviled public figure, I saw the elements of a tragic figure. Once a highly successful and admired physician, he was now, in his own words, a man who couldn’t get a job taking blood pressures at a Walmart. On the other hand, it was clear that Midei still refused to accept responsibility for his own role in his downfall. He painted a portrait of himself as a victim, but no matter what you ultimately think of his case, he was always much more than a passive victim of circumstances.

In the first part of this post I will try to summarize Midei’s story from his perspective, as he told it to me. Along the way I will inject some additional information and commentary as seems necessary and appropriate. In the second part I will offer my thoughts on his story.

PART ONE: Midei’s Story

Midei began by talking about his long career at MidAtlantic Cardiovascular Associates, which for many years had been the dominant cardiology group in Maryland, and where he had achieved a position as the premiere interventional cardiologist in the state.

The extraordinarily successful MidAtlantic was formed in 1995. The seeds of the current case, Midei claims, were planted when the MidAtlantic cardiologists and the cardiac surgery group at St. Joseph’s Hospital, where Midei mostly worked, had a bitter falling out after a failed merger attempt. Midei says that he played no significant role in this episode. “I wasn’t involved– I was a junior partner at that time,” he told me. (It should be noted here, however, that Midei was one of the four founding partners of MidAtlantic, and was always considered the dominant figure in the group.)

“So we shook hands and walked away from them and we hired four surgeons who joined our group,” said Midei. “And if you could point to one thing that led to all this, this is it.” Midei’s view is that the embittered surgeons then complained to federal investigators about illegal ties between MidAtlantic and St. Joseph’s, thereby initiating the federal probe that ultimately led to his spectacular fall.

(In his comments to me Midei glossed over the extraordinarily bitter turf war sparked by MidAtlantic’s effort to achieve dominance in the cardiovascular marketplace in the Baltimore region. By all accounts, MidAtlantic engaged in a highly aggressive campaign to take business from the surgeons, and in 2010 St. Joseph’s agreed to pay $22 million to resolve a Federal investigation, based on the surgeons’ complaints, that the hospital had provided kickbacks to MidAtlantic.)

But before those allegations surfaced, MidAtlantic “became disaffected with St Joe for various reasons,” according to Midei. In 2006 MidAtlantic began to develop closer relations with a rival hospital, Union Memorial. Midei was disappointed by this development. “I had a big emotional attachment” to St. Joseph’s and “had moved my family” to be near the hospital, he explained.

Although he was the dominant figure in this group, he told me: “I didn’t really have a great deal of influence, and the group began a much closer affiliation with Union Memorial.” The CEO of MidAtlantic had a close relationship with Union Memorial and in 2008 Union Memorial started negotiations to purchase MidAtlantic. According to Midei, the negotiations were completely in the hands of the two CEOs, and he felt left out. “In late 2008 I became almost despondent” about the deal.

Midei then learned that the “whole deal was contingent on my moving from St Joe to Union Memorial. That was made clear to me: if this [deal] happened I was going to have to go” to Union Memorial. “I didn’t feel like I had an option. Although I was despondent, I was more or less resigned, I didn’t take any action to prevent it, other than tell my partners that I wasn’t happy about it.”

(One important piece of background information here is that all the MidAtlantic partners were paid equally. According to a reliable source, MidAtlantic partners received $600,000 per year at the time of these events. This is at the high end for most cardiologists, but clearly Midei could have commanded a far greater salary on his own.)

In late November 2008 Midei said he was approached by St Joseph leadership for “a private conversation.” They outlined a plan to hire Midei  because “they really wanted me to stay at St Joe’s.” To Midei “it was like a gift from God, they offered to triple my salary… and I could stay at St Joe.”

Midei soon reached an agreement with St. Joseph, and this effectively scuttled the midAtlantic deal with Union Memorial. In court records, the MidAtlantic CEO was quoted as saying at that time that he would “make it my mission to destroy him [Midei] personally and professionally.”

Midei claims that he “didn’t realize it at the time how disturbing it was to members of my group. Others had left and nobody batted an eye, but when I did it it was like Armageddon.” (I have much more to say about this episode in the second part of this post.)

Six months after Midei moved, St. Joseph received a subpoena from the federal government for records of the hospital’s contracts with MidAtlantic physicians. Midei says he was not concerned at the time by the subpoena. “I was certain that this was a whistleblower suit filed by the disgruntled surgeons who were not having any luck with St Joe’s.” (But another plausible scenario is that it might have been an embittered cardiologist or administrator at MidAtlantic. The Baltimore Sun reported that the investigation began when “a MidAtlantic cardiologist informs one of Midei’s patients — an St. Joseph’s employee — that his stent was unnecessary. The man reports the concern to hospital staff.”)
Click to continue reading…

St. Jude Seeks Retraction of Hauser Article On Riata Leads 3

St. Jude Medical is seeking the retraction of an article by Robert Hauser in Heart Rhythm linking the company’s Riata and Riata ST leads to 20 or more deaths. In a press release (see below) issued on Friday afternoon, St. Jude alleges numerous mistakes and oversights in the Hauser paper.

In a brief statement to CardioBrief, Hauser wrote:

We stand by the conclusion of our study, namely: “Riata and Riata ST ICD leads appear prone to high-voltage failures that have resulted in multiple deaths.”

In response to a message thread on CafePharma,  St. Jude seeks retraction of Hauser’s manuscript, one anonymous observer started a new thread: Patients seek retraction of their STJ leads.

Dr. Wes has a great perspective on this story.

Click here to review our previous coverage of the Riata controversy.
Click here to read the St. Jude Medical press release…

Failure of Another Trial Testing Guided Antiplatelet Therapy Prompts Debate 4

Updated, Saturday, April 7

Yet another trial has failed to prove the hypothesis that guided antiplatelet therapy with platelet function testing or genetic testing improves outcomes. Although there has been no public announcement so far, the TARGET-PCI (Thrombocyte Activity Reassessment and GEnoTyping for PCI) was suspended last October, according to the TARGET-PCI page on ClinicalTrials.Gov.

TARGET-PCI was a large study in which 1,500 PCI patients were randomized to guided antiplatelet therapy with genotyping and platelet function tests or standard antiplatelet therapy. The primary endpoint was major adverse cardiovascular events at 6 months. The principal investigator was Paul Gurbel of Sinai Hospital of Baltimore, where the study was performed.

Here is what one cardiologist who wished to remain anonymous commented about the trial:

It was an ambitious study that was probably underpowered to look at efficacy outcomes. The positive predictive value of the CYP2C19*2 allele is reported as being < 20%. My guess is that the study was halted due to futility, and they discovered that it would be unlikely that any difference in outcome would be apparent with either personalized guided therapy or with routine care, even if the study was carried to completion.

This mirrors what we saw with the TRIGGER-PCI study and GRAVITAS, with the addition of the genetic testing by the Verigene assay.   It seems that both the Verify-now and Verigene assays are solutions still looking for problems to solve.

Sanjay Kaul offered the following comment:

The prognostic utility for genotype testing is not substantial or consistent. The outcome most strongly associated with CYP2C19 loss of function genotype is stent thrombosis (hazard ratio of 3 to 4), a rare but potentially life-threatening event. However, given the rare occurrence of stent thrombosis, the positive predictive value of genotype is only 3-4%, too small to be clinically directive. A randomized controlled trial to definitively address the role of genotype is currently lacking. Given the paucity of thrombotic events, a trial with a sample size of 20,000-30,000 would be required to adjudicate the clinical utility of genotype testing, a number that might be understandably viewed as being prohibitive. With a sample size of around 1500 and a follow-up up to 6 months, the TARGET-PCI is woefully underpowered to address this. Not surprisingly, and given the null results of GRAVITAS and premature stopping of TRIGGER-PCI for futility, the decision to suspend TARGET-PCI does not seem unwarranted.

Based on the totality of evidence, personalized antiplatelet therapy using genotype testing cannot be routinely recommended at the present time. The CYP2C19 polymorphisms affecting clopidogrel metabolism offers a cautionary tale about the unlimited power of genetic technology to generate ‘bountiful’ information on one hand, and our limited ability to properly analyze, reliably interpret, and judiciously translate it into clinical practice on the other hand. The CYP2C19 polymorphisms were heralded with much fanfare to catapult genomics to prominence in personalized cardiovascular medicine. However, the cold hard facts are that not only is the use of genetic testing to improve risk stratification premature, but whether the power of genomics can be harnessed to improve decision making and clinical outcomes also remains to be defined. The unbridled (and uncritical) enthusiasm for genomics revolutionizing personalized medicine has often blurred the distinction between hope, hype and reality. While the progress in DNA sequencing technology and bioinformatics is undeniably breathtaking, the translation of this knowledge to clinical practice has lagged behind. Genomics will eventually get there, but it cannot be expected to move faster than the speed of science.

Eric Topol offered this response to Kaul’s statement:

With at least 30% of individuals carrying DNA loss-of-function sequence variants for metabolizing clopidogrel, it should be standard of care to genotype individuals who are undergoing coronary stenting. The recent RAPID GENE publication in the Lancet (from last week), the first randomized trial of rapid, point of care genotyping , demonstrated unequivocal and marked improvement in platelet suppression using genotype-guided information as compared with no DNA data. The resistance to use genomic data to improve patient care is indefensible, and does not require “a trial with a sample size of 20,000-30,000 would be required to adjudicate the clinical utility of genotype testing.” That trial will never be done, is not even warranted, and while the debate for its need ensues, too many patients will experience stent thrombosis unnecessarily. And the stakes are high, since most stent thrombosis results in MI or death. In next week’s JAMA correspondence, there will be important perspectives published on this matter.

Update, Saturday, April 7:  Sanjay Kaul provided the following response to Topol’s statement. CardioBrief has invited Topol to respond:

The message I take away from the RAPID GENE trial is that point-of-care genetic testing is clinically feasible and might facilitate rapid personalization of anti-platelet therapy. However, genomic data is best utilized to “improve patient care”, not to “improve platelet suppression” – a surrogate marker of unclear clinical relevance. Although the trial was not powered to address clinical outcomes, bleeding episodes occurred in 5/91 of the rapid genotyping patients compared with 2/96 of standard therapy patients.

Individualizing antiplatelet therapy should ideally be based on a biomarker that precisely measures drug responsiveness, accurately characterizes low and high risk patients, is readily available and affordable, and reliably guides treatment decisions to optimize outcomes in a cost-effective manner. Unfortunately the quest for such a biomarker remains elusive as none of the currently available genetic tests (or platelet function tests) exhibits these desirable attributes.

Despite the inordinate attention being given to genomic and personalized medicine, the body of evidence continues to be insufficient to justify the clarion calls for “standard of care” use of genotype testing in the care of patients undergoing coronary stenting.

CardioBrief will be happy to provide a forum for additional discussion and debate about this topic.

Investigation Begins in the Korean Plagiarism Case 1

An investigation has been initiated in the case of suspected plagiarism first reported on CardioBrief. The Editor-in-Chief of Korean Circulation Journal, where the suspected article was published, wrote me to say that the article is now being investigated by the publishing committee of the Korean Society of Cardiology and that an additional investigation has been requested from the Ethics Commission of  the Korean Association of Medical Journal Editors.

As we wrote last month, an article in Korean Circulation Journal appears to plagiarize from a similar article in the Journal of the American College of Cardiology (JACC). In 2009, Franz Messerli, a well-known hypertension expert at St Luke’s Roosevelt Hospital Center in New York, and Gurusher Panjrath, at Johns Hopkins Hospital, published a Viewpoint and Commentary in JACC: The J-Curve Between Blood Pressure and Coronary Artery Disease or Essential Hypertension: Exactly How Essential?  Less than two years later, two Korean physicians, Chang Gyu Park and Ju Young Lee, published an article with striking similarities to the JACC article: The Significance of the J-Curve in Hypertension and Coronary Artery Diseases.

Here is the relevant text from Dr. Youn’s email message. Although he is clearly not a native English speaker, his message is clear:

We’ve found the possibility of plagiarism, although the article was published through an appropriate evaluation with peer-review. Currently, we have begun to investigate and reveal the truth of the case-under the discussion in Publishing Committee of KSC(Korean Society of Cardiology) while requesting examination at the Ethics Commission of Kamje(Korean Association of Medical Journal Editors). In accordance of the result, we’ll cope with the situation.

 

NIH Appoints Gary Gibbons As Next Director of the NHLBI Reply

Gary Gibbons will be the next Director of the National Heart, Lung, and Blood Institute (NHLBI). The selection of Gibbons was announced today by the National Institutes of Health Director Francis Collins. Gibbons is the founder and current director of the Cardiovascular Research Institute, chairperson of the Department of Physiology, and professor of physiology and medicine at the Morehouse School of Medicine in Atlanta. Susan Shurin, who has been serving as the acting director of NHLBI, will return to her position as the NHLBI’s deputy director when Gibbons assumes his position this summer.

NHLBI Acting Director Dr. Susan Shurin, NIH Director Dr. Francis Collins, and the selected new NHLBI director, Dr. Gary Gibbons

“It’s an honor to join the NIH and lead the Heart, Lung, and Blood Institute,” said Gibbons, in an NHLBI press release. “The globally recognized research and training supported by the NHLBI continues to advance biomedical knowledge in fields related to heart, lung, and blood diseases. I look forward to working with the institute staff and with the many researchers supported by the Institute to foster multidisciplinary approaches to improve disease prevention, diagnosis, and treatment that will advance the health of all Americans.”

Gibbons was an undergraduate at Princeton University and graduated magna cum laude from Harvard Medical School. He completed his residency and cardiology fellowship at Brigham and Women’s Hospital. Before going to Morehouse in 1999 he served on the faculty at Stanford University and Harvard Medical School.

Here is the description of Gibbons research program on his Morehouse webpage:

One of the long-term goals of Dr. Gibbons’ research program is to utilize new genomic technologies to integrate the areas of physiologic genomics, functional genomics and human molecular genetics in the field of vascular biology and medicine. Dr. Gibbons’ translational research laboratory has a longstanding interest in elucidating the molecular mechanisms involved in vascular remodeling in health and disease. His laboratory is interested in discovering novel mediators of vascular disease that may constitute candidate disease susceptibility variants. His program is actively involved in collaborative projects designed to study the functional significance of epigenetic and genomic variation and the potential role of genetic variation in promoting the susceptibility to cardiovascular disease in both clinical and community-based settings. One of the ultimate goals of his program is to take a multi-level, multi-disciplinary approach to understanding and ameliorating racial/ethnic disparities in cardiovascular health.

Click here to read the NIH press release…

Suicide and CV Death Increase After Diagnosis of Cancer Reply

The risk of suicide and cardiovascular death rises sharply after cancer is diagnosed, according to a new study from Sweden published in the New England Journal of Medicine. Fang Fang and colleagues analyzed data from more than 6 million Swedes, including more than half a million who received a first diagnosis of cancer.

Following a sharp initial increase in suicide and CV death, risk rapidly declined thereafter, but remained elevated during followup. The increased risk in suicide and CV death was greatest among people with highly fatal cancers. A second, case-crossover analysis confirmed the broad findings of the nationwide cohort study.

Here are the main results of the cohort study:

Relative risk (RR) compared with cancer-free people and incidence of suicide after cancer diagnosis:

  • First week: RR 12.6 (CI 8.6-17.8); incidence rate: 2.50 per 1000 person-years)
  • First year: RR 3.1 (2.7-3.5); incidence rate: 0.60 per 1000 person-years

Relative risk (RR) compared with cancer-free people and incidence of cardiovascular death after cancer diagnosis:

  • First week: RR 5.6 (CI 5.2-5.9); incidence rate: 116.80 per 1000 person-years)
  • First 4 weeks: RR 3.3 (3.1-3.4); incidence rate: 65.81 per 1000 person-years

The authors concluded that their “findings suggest that a cancer diagnosis constitutes a major stressor, one that immediately affects the risk of critical, fatal outcomes. We speculate that our findings show only a portion of the range of effects induced by the emotional distress associated with a cancer diagnosis.”

Medical Societies Release Lists of Overused Tests and Procedures Reply

The American College of Cardiology (ACC) and other medical societies have released lists of commonly overused or misused tests of procedures. The action is part of Choosing Wiselya broad initiative from the ABIM foundation.

Here are the five tests or procedures identified by the ACC:

  1. Cardiac imaging tests (particularly, stress tests or advanced non-invasive imaging) should not be given if there are no symptoms of heart disease or high-risk factors like diabetes or peripheral arterial disease (PAD) are not present.
  2. Cardiac imaging tests (particularly, stress tests or advanced non-invasive imaging) should not be given as part of a routine annual follow up in patients who have had no change in signs or symptoms.
  3. Cardiac imaging tests (particularly, stress tests or advanced non-invasive imaging) should not be given prior to performing low-risk surgery that is not related to heart disease.
  4. Echocardiography, which uses sound waves to create images of the heart, should not be used as routine follow-up care in adults with mild heart valve disease who have had no change in signs or symptoms
  5. Patients experiencing a heart attack and undergoing a procedure called percutaneous coronary intervention (PCI) should not have stents placed in an artery or arteries beyond those responsible for the heart attack.

Here is the list from the American Society of Nuclear Cardiology:
Click to continue reading…

St Jude Withdraws Older LV CRT Leads From Market Reply

St. Jude Medical today issued an advisory about its QuickSite and QuickFlex Left-Ventricular (LV) Leads, which connect to Cardiac Resynchronization (CRT) devices. The company said it would no longer sell these leads, but that it had received no reports of death or serious injury associated with the problem.

The problem with the LV leads closely parallels the previously-reported problem with the company’s Riata leads. In both cases, there have been reports of externalization of lead conductors with silicone insulation, though the ultimate clinical implications of the reports are unclear.

St. Jude reported that there have been only 39 confirmed cases of externalized conductors, out of 171,000 leads sold worldwide. However, based on its own analysis, the company estimates that 3-4% of QuickSite and QuickFlex leads “may exhibit externalized conductors.”

The company said its newer QuickFlex µ or Quartet LV leads were not affected by the advisory. These leads use the company’s Optim insulation, and there have no reports of externalization in these models.
Click here to read the St. Jude press release…