Here are two small but important changes in the anticoagulation field:
Here are two small but important changes in the anticoagulation field:
Using an unconventional mathematical approach, a group of Japanese researchers say there may be no good reason to reduce LDL cholesterol more than 40 mg/dl. Their research letter has been published online in JAMA Internal Medicine.
According to the authors, members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group, most meta-analyses use linear models that assume “a constantly increasing or decreasing risk as the exposure increases or decreases.” Linear models, however, can be “misleading,” they write, because they assume a specific dose-response relationship. By contrast, their new analysis utilizes “flexible” models that can more readily uncover “threshold effects.”
(Updated) Earlier this week the stock of Edwards Lifesciences tanked after the company announced weak Sapien sales and lowered its sales guidance for the rest of the year. The stock, which had been trading in the low 80s for the past month, dropped a heartbreaking 22% on Wednesday in response to the news and closed at 65 on Thursday.
But Edwards chairman and CEO Michael Mussallem didn’t suffer along with his shareholders. As reported by GuruFocus, Mussallem sold 35,000 shares of his stock on April 10 at 83.37 per share netting him nearly $3 million. Another executive, the corporate VP of Japan and Intercontinental, Huimin Wang, sold 4,850 shares at $81.74 per share.
The dramatic drop in Edwards’ stock is another sign that the market for transcatheter heart valves has not grown as rapidly as many had expected. “Edward’s initial 2013 guidance clearly proved to be overly aggressive on U.S. TAVR sales as capacity constraints and the complexities of bringing a 20+ person team up the learning curve clearly tempered the adoption curve more than expected,” said a Leerink Swann analyst quoted by Bloomberg.
Update: I have been informed by Edwards that the recent sale was part of a predetermined plan to sell shares. Mussallem has sold 35,000 shares each month since June of 2012.
Two new trials have ended up reporting conflicting results regarding the expansion of the indication for cardiac resynchronization therapy (CRT) for patients without a wide QRS interval. The positive results of the smaller trial seem likely to be undermined by the early stopping of the much larger trial.
The first trial, NARROW-CRT, published in Circulation: Arrhythmia and Electrophysiology, concluded that CRT “improved clinical status in some patients with ischemic cardiomyopathy, mild-to-moderate symptoms, narrow QRS duration, and mechanical dyssynchrony on echocardiography.” The second trial, EchoCRT, which was testing CRT in heart failure patients with narrow QRS, was terminated early due to futility.
A new study from the Cleveland Clinic research group headed by Stanley Hazen offers more evidence in support of the hypothesis that TMAO (trimethylamine-N-oxide) may play a role in the development of heart disease. The new research, published in the New England Journal of Medicine, follows closely on a related study published recently in Nature Medicine that received broad public attention.
The Nature Medicine paper demonstrated that digestive tract bacteria metabolize carnitine into trimethylamine-N-oxide (TMAO), which had previously been linked to atherosclerosis in animals. The new research in NEJM focuses on another pathway that leads to TMAO production and provides for the first time a credible association between TMAO and cardiovascular disease in humans.
Patients with atrioventricular (AV) block generally receive right ventricular pacing; cardiac resynchronization therapy (CRT) has been restricted to patients with a low ejection fraction and a wide QRS duration. However, RV pacing may worsen LV dysfunction in AV block patients with low ejection fractions. Previous studies have raised the possibility that these patients may benefit from biventricular pacing with a CRT device.
Now, results from the Medtronic-sponsored BLOCK HF (Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block) trial, published in the New England Journal of Medicine, lend more support for the expansion of CRT devices into this population. Anne Curtis and colleagues randomized 691 patients to standard RV pacing or biventricular pacing. After 37 months of followup, a primary outcome event– death, urgent care visit for heart failure that required intravenous therapy, or a 15% or more increase in the LV end-systolic volume index– occurred in 55.6% of the RV pacing group versus 45.8% in the biventricular pacing group (HR 0.74, CI 0.60-0.90).
The use of perioperative beta-blockade for noncardiac surgery has been declining as a result of the controversial POISE study, which turned up evidence for harm associated with extended-release metoprolol in this setting. Now a large new observational study published in JAMA offers a contrary perspective by suggesting that perioperative beta-blockade may be beneficial in low- to intermediate-risk patients. But without better evidence the debate about this topic is unlikely to be resolved.
Martin London and colleagues performed a retrospective analysis of 136,745 patients who underwent noncardiac surgery at VA hospitals, 40% of whom received beta-blockade.
Shalom “Shal” Jacobovitz will be the new chief executive officer of the American College of Cardiology, the ACC announced today. Jacobovitz is currently the president of the US division of Actelion Pharmaceuticals, best known for its pulmonary hypertension drugs.
In recent years the FDA has come under increasing fire for approving drugs on the basis of surrogate endpoints without any evidence of greater clinical benefit. The most famous example of this is the diabetes drug rosiglitazone. Despite strong evidence demonstrating that it was effective at lower blood glucose levels– the surrogate endpoint– serious questions emerged about the cardiovascular safety of the drug, eventually leading to its near withdrawal from the market in the US (and full withdrawal in Europe). Questions have also been raised about the long term health effects of drugs targeting a specific endpoint– including cholesterol and other lipids, blood glucose, weight loss, and blood pressure.
Despite what some believe is a long-term trend against the use of surrogate endpoints, the FDA is actually seeking to make it easier for manufacturers of one therapeutic category, antihypertensives, to claim cardiovascular benefit for their drugs despite the absence of evidence to support most of these drugs.
Although the actual changes proposed by the FDA are small, I thought the issue bore further exploration. I first spoke with Norman Stockbridge, the director of the Division of Cardiovascular and Renal Products (DCaRP) in the Office of Drug Evaluation 1 at the FDA. I then asked Harlan Krumholz, Sanjay Kaul, and Franz Messerli and Sripal Bangalore to comment on this topic.
Although the internet represents “a new frontier in medicine” for physicians and patients it also presents numerous and novel challenges to professionalism, according to a position paper from the American College of Physicians and the Federation of State Medical Boards published in Annals of Internal Medicine.
The paper offers physicians a new conceptual “framework for analyzing medical ethics and professionalism issues” on the internet and provides recommendations for physicians on the use of email, blogs, social media sites, and more.
When communicating with patients, physicians should “consistently apply ethical principles for preserving the relationship, confidentiality, privacy, and respect for persons to online settings and communications.” The authors note that “the ease of use and immediacy of social media tools… can lead to unintended outcomes or messages.” They recommmend “pausing before posting” and warn about the potential dangers of “patient-targeted Googling.”
Three substudies of the influential TNT (Treating to New Targets) trial have been retracted after the sponsor of the trial, Pfizer, discovered that blood samples from the study had been matched to the wrong participants.
The main results of TNT, published in 2005 in the New England Journal of Medicine, had a major impact on clinical practice and statin prescription patterns. The trial supported the increasingly aggressive use of statins and helped to solidify the enormous commercial success of atorvastatin (Lipitor, Pfizer).
The 3 newly-retracted substudies do not appear to affect the main finding of TNT. Two papers were published in the Journal of the American College of Cardiology. The third was published in the American Heart Journal. (The AHJ retraction notice has not yet been published, but the editors have confirmed the retraction.) Here are the 3 retracted articles:
In response to my post yesterday about why health stories should nearly always be received with caution, I received the following comment from a distinguished cardiovascular researcher:
One lost point is the role of the investigators and media in hyping their research. Hazen (principal investigator of the first study) is a bright and thoughtful guy, but through the Cleveland Clinic PR department, his nice hypothesis-generating research got turned into the missing link between red meat and heart disease, which obviously is a huge leap. The paper itself is much more measured than the press release and subsequent coverage. Same for the carnitine meta-analysis It is a meta-analysis of small studies published in a 3rd tier medical journal. I haven’t read the original article, but I bet it is pretty measured in its discussion and conclusion. But then comes the press release and the media, and boom, we have a cure for heart disease that conflicts with a cause for heart disease. Both studies are hypothesis-generating and non-conclusive. They are important additions to our medical knowledge base, but offer nothing for the public right now.
So here I blame the PR departments, but the investigators go along with this, so they get some of the blame, as well as the media who hype it. By the way, from the standpoint of the investigators, the institutions, and the journals they published in, this media frenzy was considered a huge success. For the rest of the medical community and the patients, it was a nuisance, a distraction, led to confusion, and then phone calls to doctors.
I’d like to offer one additional caveat about the L-carnitine metaanalysis. This is a perfect example of a topic that might be seriously distorted by publication bias. In other words, a potentially important finding– in this case, a result showing that carnitine is beneficial after a heart attack– is much more likely to be published than a negative finding. This doesn’t mean that the metaanalysis is necessarily wrong, but it does provide yet another reason why we should always be careful when looking at studies like these.
Once again the controversial diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) will be the subject of a 2 day FDA hearing. According to a meeting announcement scheduled to be published in the Federal Register on Monday, the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee will meet on June 5 and June 6 to ”discuss the results of an independent readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial.”
Partial Rosiglitazone/RECORD Chronology
Don’t believe the the hype! That’s the cardinal rule to obey when reading health news. “Breakthroughs” and “cures” are rare, and should always be viewed with caution and skepticism.
This week was a great example. Last Sunday, the New York Times, the major networks, and a host of other media outlets (including this one) reported on a paper in Nature Medicine about the discovery of a novel and potentially significant pathway linking red meat to heart disease. Briefly, the research suggested that carnitine, which is found naturally in high concentrations in red meat, can lead to atherosclerosis when it is converted by gut bacteria to a chemical called TMAO. Almost immediately I received a lot of comment from experts who raised serious questions about the research. Then today, a separate study was published with an entirely different perspective on carnitine. Although the two studies don’t directly contradict each other, they suggest that the real truth about carnitine is likely to be quite complex and will never be adequately summarized in a headline.
Jose Katz, a 68-year-old cardiologist with offices in New York and New Jersey, has pleaded guilty to charges that he committed health care fraud, the US Attorney for New Jersey announced yesterday. Katz admitted that he billed Medicare Part B, Medicaid, and numerous private insurers “for unnecessary tests and unnecessary procedures based on false diagnoses and for medical services rendered by unlicensed practitioners.”
Katz spent over $6 million advertising on Spanish-language advertising. For most of his patients he performed the same battery of unnecessary diagnostic tests and falsified records. He then gave a false diagnosis or coronary artery disease and intractable angina and prescribed EECP (enhanced external counterpulsation) to these patients. According to the government, Katz billed Medicare and Medicaid more than $15.6 million for EECP treatment from 2005 through 2012. In total, Katz billed Medicare and Medicaid more than $70 million during this period.
Some of Katz’s patients were treated by Mario Roncal, who was called “Dr. Roncal” in the office, though he did not have a valid medical license in the United States. According to the government, “to conceal this illegal and unlicensed practice of medicine, Roncal forged Katz’s signature on paperwork associated with Roncal’s unlawful medical services, including on patient charts. During the conspiracy, Katz used his own billing numbers to bill Medicare Part B and Medicaid for the illegal services Roncal provided as though they were provided by Katz.”
A large new study from Cuba shows the impressive benefits that can be achieved with weight loss and increased exercise. Much more ominously, the same study shows the dangers associated with weight gain and less exercise.
In the study, published in BMJ, researchers took advantage of a “natural” experiment that occurred in Cuba as a result of a major economic crisis in the early 1990s. Relying on 30 years of superb health statistics available in the country, the researchers analyzed the dramatic health effects associated with the economic crisis, which last from 1991 through 1995, and the subsequent recovery.
During the economic crisis caloric intake decreased and physical activity increased, resulting in a 5.5 kg reduction in weight and a very high (80%) proportion of the population classified as physically active…
The Journal of the American College of Cardiology has published a Notice of Duplication about a review article written by a respected European cardiology researcher who has played a central role in the development of fractional flow reserve (FFR). The brief statement from JACC provides few details and could lead to various interpretations, but a further investigation suggests that the story may be fairly simple.
The notice states that a 2012 review article by Nico H.J. Pijls and Jan-Willem E.M. Sels, Functional Measurement of Coronary Stenosis, “duplicates to a considerable extent both the text and figures of a prior article,” Fractional flow reserve: a review” published in 2008 in Heart, by two different authors, Bernard De Bruyne and J. Sarma. Here is the JACC editors explanation:
Dr. Piljs attributes this duplication to the close collaboration that he has had over many years with Dr. De Bruyne, and the fact that both authors drew text and figures for these reviews from the same repository of material used for a joint educational program. He acknowledges his lack of care in the preparation of the manuscript and apologizes for the duplication. While the Editors accept this apology, we lament the replication of information that prevented the pages devoted to Dr. Piljs’ article from being filled with new material.
De Buyne and Pijls are longtime colleagues who have played a central role in the development of fractional flow reserve, serving as principal investigators of the seminal FAME and FAME II clinical trials. I asked them for a response to this situation. Here is their statement:
The cryptical phrasing “repository of……..” is not ours, but made by JACC.
The “repository” they mean is a keynote lecture from the bi-annual Aalst-Eindhoven-Course on Coronary Physiology, which we organize once or twice a year in Brussels since 2001. The Course is endorsed by the European Society of Cardiology and has been organized by us already 17 times.
The opening lecture of that course (keynote lecture) is always entitled: ”Practice and advanced applications of Coronary Pressure Measurement” and alternatively given by Dr de Bruyne and Dr Pijls.
That lecture has been built up by us and developed carefully over the years and has been streamlined for optimum educational content and benefit, including phrasing and slides.Not a single word is not ours.
The slides are always distributed among the participants and used by many of them for their own lectures or presentations or any educational purposes. In fact , they are public domain. Consequently, we have seen (parts of) our text and slides been used by others a myriad of times and are proud to have contributed to the dissemination of valuable medical knowledge.
When Dr De Bruyne wrote his review for HEART in 2008 , he used that keynote lecture as the basis of his paper.
When Dr Pijls wrote his State-of-the-Art paper ( i.e also a review) on the invitation of JACC in 2012, he also used text and slides of that keynote lecture (extended in the meantime) without realizing that Dr De Bruyne had done the same some years earlier. As a result, the first part of Dr Pijls paper is very close to Dr De Bruyne’s review, wheras the second part of Dr Pijls paper reflects the new data and insights obtained in those last 4 years.
So, there is nothing mysterious about that “repository” and we explained this to JACC in a similar way as we do now to you.
And by the way, when Dr Pijls submitted his paper to JACC, he mentioned explicitely in the submission letter that – as the nature of this paper was a State-of-the-Art paper – it was a concise reflection of the knowledge in the field and not original data.
Answering your last question: Neither Dr De Bruyne nor Dr Pijls ever received any financial or other compensation from whoever or in whatsoever way for writing any of these papers.
Writing these papers was on the strict invitation of the editors of Heart and JACC respectively and except the authors and staff of the Journals, nobody was even aware of it before they were published.
And as stated above: any single word or figure in any of these papers is completely our own work to which we equally contributed.
Comment: When I first read the notice it seemed to me like the case was an indication of a larger wrongdoing. I’m glad my initial suspicions were proven wrong. This is a great example of why editor’s notes should be much more detailed. The truth needs to come out no matter which way it falls.
Quinidine– the only drug known to be effective in preventing lethal ventricular arrhythmias in people with several rare conditions, including Brugada syndrome, idiopathic ventricular fibrillation, and early repolarization syndrome– is no longer available in much of the world.
In a study published online in the Journal of the American College of Cardiology, Sami Viskin and colleagues surveyed physicians around the world about the availability of quinidine in their country and received responses from 273 physicians in 131 countries. In 76% of the countries quinidine was not available at all. In another 10% quinidine was available only through a regulatory process that can take several days to several months to obtain the drug. Quinidine was easily obtained in only 14% of countries.
Responding to recent episodes of scientific misconduct in cardiovascular research involving once prominent cardiovascular researchers, the editor of the ￼European Heart Journal, Thomas Lüscher, has written an editorial discussing the significance of the new cases and placing them in a historical context that includes allegations of scientific misconduct by Mendel and Darwin, among many others.
Poldermans was the first or the senior author in 7 papers published in EHJ. Lüscher writes that the chairman of the Poldermans investigative committee “made it clear that the vast amount of publications led by Poldermans over the last decades made it impossible to assess their scientific validity in all cases.” As a result, Poldermans announces that “the editors of the European Heart Journal therefore would like to make an expression of concern related to the papers where Poldermans was the responsible author.”
Comment: Without more information there will continue to be a large cloud of uncertainty hanging over the cardiovascular literature. The statement of the chairman of the Poldermans committee bears repeating: “the vast amount of publications led by Poldermans over the last decades made it impossible to assess their scientific validity in all cases.”
A new line of preliminary research has turned up a novel pathway linking atherosclerosis to red meat and a common supplement contained in energy drinks. If the research is upheld, the findings may have important implications for dietary recommendations and our understanding of atherosclerosis. The research also provides a quite surprising example of the previously unsuspected health effects of bacteria in the intestine.
Published online in Nature Medicine, the new studies suggest a possible major role in atherosclerosis for carnitine, which is commonly added to energy drinks and is found naturally in high concentrations in red meat. The new theory combines several lines of evidence from studies in both animals and humans.
Led by Stanley Hazen, researchers at the Cleveland Clinic and elsewhere found that digestive tract bacteria metabolize carnitine into trimethylamine-N-oxide (TMAO), which has previously been linked to atherosclerosis in mice, though the exact mechanism is still unknown. The researchers found that these bacteria were able to flourish, and produce large amounts of TMAO, only in an environment of a carnitine-rich diet. For instance, after taking carnitine supplements, or eating a steak rich in carnitine, vegetarians produced far less TMAO than omnivores.
As the first new oral anticoagulant since warfarin, dabigatran (Pradaxa, Boehringer-Ingelheim) has been subject to intense concerns over its safety and efficacy in a real-world population. Last November an FDA investigation found no indication that bleeding rates for dabigatran were any higher than bleeding rates for warfarin. A new study from Scandinavia, published in the Journal of the American College of Cardiology (see note at bottom of story), provides more real-world information that helps to confirm the safety and efficacy of the new drug.
Using data from the Danish Registry of Medicinal Product Statistics, researchers compared 4978 patients treated with dabigatran to 8936 matched patients who received warfarin. They found similar rates of stroke or systemic embolism and major bleeding with dabigatran and warfarin. In addition, mortality, intracranial bleeding, pulmonary embolism,and myocardial infarction were significantly lower in the dabigatran-treated group.
Here are the adjusted hazard ratios (and 95% confidence intervals) for dabigatran 110 mg and 150 mg, respectively, compared with warfarin:
The authors concluded that ”previous concerns about an excess of bleeding events or myocardial infarction amongst dabigatran treated patients were not evident in this propensity-matched comparison against warfarin in a large post-approval registry study.” However, they noted one limitation of their study: The Danish AF patients included in the study were at lower risk and had a lower event rate than the patients studied in the pivotal RE-LY randomized trial of dabigatran.
Note to readers: This study is now available on Science Direct and the manuscript has been posted on CardioSource. Due to technical problems the article will be published online in the Journal of the American College of Cardiology website on Wednesday, April 10.
Although the benefits of statins are among the best documented in all of medicine, continuous lifelong statin therapy is not always easy to achieve in clinical practice. Now a new retrospective study suggests that although clinical events causing temporary cessation of statin therapy occur often, most of these patients are later able to resume statin therapy.
In a paper published in Annals of Internal Medicine, researchers analyzed data from 107,835 patients with a statin prescription treated by physicians associated with Massachusetts General Hospital and Brigham and Women’s Hospital. 18,778 of these patients had documented events that were statin related, resulting in 11,124 patients who stopped taking statins. Within a year more than half of these (6,579) were rechallenged with a statin, and most of these (92.2%) were taking a statin a year after the initial statin-related event.
(Updated) The publication in JAMA of the NIH’s Trial To Assess Chelation Therapy (TACT) trial has provoked a fascinating debate in the blogosphere. The vast majority of responsible physicians and healthcare professionals have little interest in chelation therapy per se, but the TACT trial has raised many important questions about the nature of medical evidence. Here’s a brief guide with links to some of the more interesting discussions (let me know if you are aware of other worthwhile discussions):
In the first of two accompanying editorials, the JAMA editors discuss some of the complex issues relating to TACT and explain why they decided to publish the TACT paper.
In a second accompanying editorial, Steve Nissen, while agreeing in principle with the idea that randomized controlled trials should be published, argues that the TACT investigators “fell short of the minimum level of quality necessary to adequately answer the question they sought to investigate.”
TACT investigator Daniel Mark provided CardioBrief with a detailed response to Nissen’s criticism. (Nissen declined to respond to Mark.)
Harlan Krumholz, in a blog post on Forbes, asked “what to do with inconvenient evidence”? He agrees with just about everyone else that TACT does not provide a reason to administer chelation therapy, but he argues forcefully that the results of the trial should not be simply dismissed.
Responding to Krumholz, Peter Lipson, also on Forbes, takes a position similar to Nissen’s that the trial was poorly performed and the results are highly questionable. The important things here are the responses to Lipson from Krumholz himself, Forbes pharma reporter Matt Herper, and Sanjay Kaul.
The most sustained assault on TACT, and on Krumholz’s position, comes from the highly-regarded skeptic blog Respectful Insolence written by Orac (the pseudonym of David Gorski, a surgical oncologist). In his take-no-prisoners assault on TACT, JAMA, and Krumholz, Orac writes “that JAMA is every bit as guilty as The Lancet was in 1998 when it published Andrew Wakefield’s antivaccine nonsense…. If published at all, TACT should have been published in some crappy, bottom-feeding journal, because that’s all that it deserves.” The comments section includes worthwhile exchanges between Orac and Sanjay Kaul and Matt Herper.
Finally (for now), Sanjay Kaul today summarized his defense of TACT (though he does not, of course, endorse chelation) in a blog post on CardioExchange. ”Bottom line,” he writes, “in my opinion, the arguments that the TACT results are dubious or not valid are overstated. While the debate surrounding TACT is clearly warranted and welcome, I hope it generates more light than heat.”
Responding to the attacks on TACT from Orac and other members of the skeptical community, TACT investigator Dan Mark sent me the following comment on email, which he has agreed to share with my readers. The comment moves the debate in an entirely new and philosophical direction:
Although skepticism has an important role to play in critical debates, it is easy to overplay that hand. The people you mention seem to have a very naïve view of science, very far removed from the messy realities of daily work of people doing science. It is also important to remember that even the most hard core scientists can have some pretty eccentric views when they venture outside their narrow field of expertise. What does that imply about science and the people who wish to guard its borders?
There has been a project in philosophy to identify firm demarcation criteria that will allow for a distinction between science and pseudoscience. While some useful work has resulted, the overall attempt failed. Gets into some deep waters, but the harder the philosophers tried to find that electrified fence that marked off “real science” from the rest of human thought, the more they undermined the borders of science itself. Interestingly, “real scientists” rarely worry about whether they are doing science. They consider the question uninteresting, leaving it for the philosophers, sociologists and (now) the bloggers!
The FDA said today that it had approved canaglifozin (Invokana, Johnson & Johnson), the first of a new class of diabetes drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors. Canaglifozin is indicated to improve glycemic control in adults with type 2 diabetes in conjunction with diet and exercise. The drug has been studied as monotherapy and in combination with other common treatments for type 2 diabetes including metformin, sulfonylurea, pioglitazone, and insulin.
A 79-year-old Florida cardiologist has been sentenced to 7 years in prison for his participation in the Fen-Phen fraud, according to a report by John Martin on Philly.Com. The article notes that other cardiologists have been convicted for similar reasons in the Fen-Phen case, but Tai’s case is unusual because of the length of the sentence.
The cardiologist, Dr. Abdur Razzak Tai, was convicted last September. Here is how the US Department of Justice summarized the case at the time:
Between 1997 and 2009, Tai… reviewed the echocardiograms of more than 1,100 patients who filed claims with the American Home Product Settlement Trust in Philadelphia and falsely certified that the patients’ tests showed that they had sustained heart damage. In reality, many of those claimants had not been harmed.