June 11th, 2013
People with Sleep Apnea at Increased Risk for Sudden Cardiac Death
Larry Husten, PHD
Although people with obstructive sleep apnea (OSA) have an increased risk for death and cardiovascular disease, the relationship between OSA and sudden cardiac death (SCD) has not been clear. Now a new study published in the Journal of the American College of Cardiology provides evidence that OSA is in fact associated with an increase in the risk for SCD.
Researchers at the Mayo Clinic analyzed 10,701 consecutive patients who received a first polysomnography at their institution and who had no history of SCD. After an average followup of 5.3 years, 142 people had either a fatal SCD or were successfully resuscitated. The analysis showed that people who had OSA were at increased risk for SCD and that the most severe cases of OSA had the highest risk for SCD. OSA was found to be associated with SCD even after other well known risk factors for SCD were taken into account.
Low nighttime levels of oxygen in the blood, which the researchers noted is an “important pathophysiological feature of OSA, strongly predicted SCD independently of well-established risk factors.” The researchers, who previously reported that people with OSA were more likely than the rest of the population to die from cardiac causes at night, concluded that the increase in SCD at night “may represent ‘excess’ deaths, rather than simply a shift of SCD from other times of the day to the night.”
“The prevalence of obstructive sleep apnea in Western populations is high and will likely only continue to grow given the obesity epidemic and direct relationship between obesity and sleep apnea,” said Apoor Gami, lead author of the study, in an ACC press release.
June 10th, 2013
Selections from Richard Lehman’s Literature Review: June 10th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
JAMA 5 June 2013 Vol 309
Roux-en-Y Gastric Bypass vs. Intensive Medical Management for the Control of Type 2 Diabetes, Hypertension, and Hyperlipidemia (pg. 2240): Last week, Edwin Gale’s brilliant Lancet essay reminded us that type 2 diabetes is a category error. It can be treated with glucose-lowering agents and “cured” by bariatric surgery, but in the end only one thing matters: do these treatments improve life for patients? Measurements like fasting blood sugar, HbA1c, body mass index, and blood pressure are after all just surrogates. Age also comes into the equation: if, in retirement, my enjoyment of food causes me to get fatter and develop “type 2 diabetes,” I really won’t care very much. But if I were a Bangladeshi woman aged 40 with a BMI of 38 and diabetic neuropathy, expected to stay at home and look after five children and a couple of elderly relatives, I might take a quite different view. It is long term quality of life which counts. Quantity of life is also a factor. And for bariatric surgery, as for every other diabetes treatment, we know too little about these to make a clear judgement. The results of this trial are nonetheless very useful, because the comparator was the most intensive lifestyle modification possible, and the population from the US and Taiwan had a mean age of 49 and BMIs ranging from 30 to 40. The patients randomized to Roux-en-Y gastric bypass lost 26% of their body weight and ended up requiring much less medication for glucose, blood pressure, or lipids. But there were some unpleasant surgical complications, including one case of brain and limb damage. This was a smallish trial (n=120) with a huge number of exclusions: further individual patient follow-up data, hopefully available to all, will go into the great evidence pool which will eventually give us some clear answers about how to treat diabetes.
Bariatric Surgery for Weight Loss and Glycemic Control in Nonmorbidly Obese Adults With Diabetes (pg. 2250): Here is the same thing, expressed in the words of systematic reviewers who went through as many articles as they could in this fast-developing field (32 surgical studies, 11 systematic reviews on nonsurgical treatments, and 11 large nonsurgical studies published after those reviews). “Current evidence suggests that, when compared with nonsurgical treatments, bariatric surgical procedures in patients with a BMI of 30 to 35 and diabetes are associated with greater short-term weight loss and better intermediate glucose outcomes. Evidence is insufficient to reach conclusions about the appropriate use of bariatric surgery in this population until more data are available about long-term outcomes and complications of surgery.” In fact only three medium sized randomised trials really met the original criteria for this systematic review, and individual patient data were only available for one of them. The science of medicine really cannot advance while so much data that should inform decision making remains beyond reach.
Treating Diabetes With Surgery (pg. 2274): And there is a very good editorial on the subject as well. It ponders this very question—how can you do a systematic review that is both rigorous and clinically useful? “Too limited inclusion criteria result in no guidance for clinicians caring for certain patients and criteria that are too broad lead to recommendations that represent expert opinion. Expert opinion cannot be viewed as evidence or serve as the basis for practice guidelines.” Amen. Is anyone at NICE listening?
BMJ 8 June 2013 Vol 346
Risk of Incident Diabetes Among Patients Treated with Statins: Statins lower plasma HDL-cholesterol markedly in everybody and raise plasma glucose a little in some. These measurements mean nothing in themselves: the only important fact is that statins lower cardiovascular risk in everybody, irrespective of its absolute starting point. The choice of whether to use a statin should be left to the patient on the basis of a calculation of individual risk reduction. “Diabetes” is just a glucose threshold: we have no idea what “diabetes” implies when it used to designate a person who has moved from having a fasting glucose of 6.7 to 7.2 because they are taking a statin. The population study from Canada in this week’s BMJ simply grades the various statins according to their likelihood of raising blood glucose, and shows that this corresponds to their degree of HMG-CoA reductase inhibition. That’s still quite an achievement, and this paper continues the marked improvement in quality of the research section in the BMJ.
Ann Intern Med 4 Jun 2013 Vol 158
Aspirin vs. Low-Molecular-Weight Heparin for Extended VTE Prophylaxis After Total Hip Arthroplasty: Aspirin of course began life as an analgesic, but today if you stopped any doctor in the corridor and asked what the action of aspirin is, you would be told “platelet inhibitor” 19 times out of 20. Aspirin’s mode of action makes it a much weaker anticoagulant for preventing thromboembolism than low molecular weight heparin, but there seems to be one situation where the two are equivalent: in extended prophylaxis for patients who have had total hip replacement. A large Canadian trial randomized patients to receive either dalteparin or aspirin for thromboprophylaxis after ten days on dalteparin following hip arthroplasty. There was no significant difference in either venous thromboembolism or major bleeding.
June 10th, 2013
Dramatic Increase in Use of Radial Artery Access for PCI in the U.S.
Larry Husten, PHD
In the last six years interventional cardiologists have dramatically increased their use of radial access for PCI, according to a retrospective study published in Circulation. Using data from the CathPCI registry on more than 2.8 million procedures between January 2007 and September 2012, Dmitriy Feldman and colleagues found that radial access PCI increased 13-fold, from a negligible 1.2% at the beginning of the study to 16.1% at the end.
Observational data from the registry confirmed findings from earlier studies. There were fewer bleeding complications (2.67% versus 6.08%) and vascular complications (0.16% versus 0.45%) in the radial access PCI group compared with the femoral access PCI group. These differences remained significant after adjusting for differences between the groups. On the other hand, fluoroscopy times were longer in the radial access group (14.2 minutes versus 11.1 minutes).
A major reason for the slow adoption of radial access PCI is that interventional cardiologists need to learn the procedure and undergo a learning curve. Other potential barriers include the fear of lower success rates and the need in some cases for crossover to femoral access.
The authors discussed evidence suggesting that radial access PCI may be associated with a decrease in mortality, but acknowledge that “the mechanisms underlying this benefit remain unclear.” They concluded that “wider adoption of r-PCI in interventional practice, particularly in higher-risk patients, presents an opportunity to potentially improve overall PCI safety.”
In an editorial published in the American Heart Association’s open-access journal, Sunil Rao (also an author of the Circulation paper) and Mitch Krucoff offer their recommendations for bringing radial access to more higher-risk patients:
The patients at highest risk for access site bleeding and vascular complications after PCI are those who stand to gain the most from the radial approach. Once the learning curve for transradial PCI is overcome, developing a ‘radial first’ approach can minimize or even eliminate the risk‐treatment paradox. Given the amount of evidence supporting the benefits of radial access, interventional cardiologists should embrace the radial approach, do it often, become proficient at it, and use it as an opportunity to obtain the best outcomes.”
June 10th, 2013
Research During Fellowship: Perspectives from the Protégé and the Mentor
Stephen Archer, MD and John Ryan, MD
In the first part of this post, CardioExchange’s John Ryan writes about the research he performed during his cardiology fellowship under the mentorship of Stephen Archer. In the second part, originally delivered at the Resident Research Day at Queen’s University, at which he is Professor and Head of the Department of Medicine, Archer gives his “elevator speech”, explaining what it means to start a career in research.
John Ryan: When I was looking for a cardiology fellowship, I was told that I should think about it as a form of apprenticeship. Tom Ryan told me, “Think about when Paul Dudley White started them originally. People would come to work with him one-on-one over the course of a few years.” With that in mind, I was hooked when I met Stephen Archer during my interview day at the University of Chicago and he told me the things we could do in the world of pulmonary arterial hypertension (PAH). Admittedly, I had no idea what he was talking about as he discussed mitochondria, how they divide and rejoin and how they play a role in disease processes such as cancer, heart failure, and PAH. But his enthusiasm, expertise, and interest in me seemed to equate with what Tom Ryan advised me to look for.
After finishing my clinical years of fellowship, I entered into the Archer lab without any identifiable basic science skills. Many months went by, with a lot of failed experiments and contaminated RNA. Despite the mistakes, I had to present my data week after week at every lab meeting, flawed though it was. It took about 6 months before I had reproducible results. Then about a year into our work, I noticed a change. I travelled to a series of meetings to present our preliminary results. I found that I was able to talk the language of the other investigators. I felt like I had completed an immersion course and was now able to converse with the locals. I was far from fluent but I was able to get my point across and, more importantly, understand what they were saying.
This past month our work was published in the Blue Journal. We showed that animal models of PAH could be reversed by fusing the mitochondria of pulmonary artery smooth muscle cells. Furthermore, we showed that the increased rates of proliferation seen in pulmonary artery smooth muscle cells could be repressed by shifting mitochondrial dynamics and metabolism towards a more normal phenotype. Obviously this is all preliminary data, and there is a lot to be done before this translates into clinical practice, if ever. However, that was just part of what I discovered while I did my PAH basic science work. I also learned how to maintain the diligence to see a project to completion, how to problem-solve failed experiments, and — most important — how to develop an awareness that the truth is indeed out there.
Choosing a fellowship is not easy and there are a lot of moving parts, such as geographic considerations, the ability to get “your level 2s”, as well as US News and World Report rankings. But Tom Ryan was right. The most important aspect of fellowship was having someone who was interested in my career and my thought process, because that is what I now use every day.
Stephen Archer: This is my “elevator speech.” A friend in Chicago taught me this term. The elevator speech is the quick headline you tell your boss when he/she asks you, “What are you up to?” It is meant to be quick, concise, and to convey your big idea before you exit the elevator and your boss glides on upward to the penthouse. With that introduction, here are my thoughts on research for medical residents considering a career with a significant research component.
Research is a disruptive process of discovery conducted by skeptical scientists who believe the conventional wisdom is wrong, or at least incomplete. The questions may be practical or exotic but in the process of testing a hypothesis, the ball of knowledge is almost always moved a little further down the field. Over the ages researchers have often found themselves on the wrong side of state and church. Research challenges governments and religions, putting the sun in the center, revealing the relatedness of humans and animals, and even allowing manipulation of our genetic code.
In the past, scientists were defenestrated, excommunicated, and mocked. In the modern era, scientists have been more often lionized for their discoveries, which have lifted us into space, developed treatments for many lethal diseases, given us unprecedented creature comforts, and prolonged longevity. However, even now, science in Canada is under threat with insufficient funding and an ill-informed government agenda to prioritize research, which is “practical” in the very short term.
Each of you has the potential to perform research, to discover, to perfect, and, in so doing, to enrich your community, country, and make a contribution to future generations. It matters not whether the questions you ask are of the molecular, physiologic, medical, ethical, or historical genre. If your question is precisely framed, the measurements and analysis rigorous, and you let the data speak without bias, you are treading the scientific trail.
It’s not easy to be a scientist in an era where fewer than one in five grants is funded. It is particularly difficult to live the divided life of a clinician-scientist, answering both to the patient and the scientific muse.
Of course, not all scientists are inspired and being “in the game” does not make you a genius. A certain rare combination of talents is required for truly great discovery. As Denis Diderot, French enlightenment philosopher and author, noted in the mid-18th century how we discover:
“We have three principal means: observation of nature, reflection, and experiment. Observation gathers the facts, reflection combines them, and experiment verifies the result of the combination. It is essential that the observation of nature be assiduous, that reflection be profound, and that experimentation be exact. Rarely does one see these abilities in combination. And so, creative geniuses are not common.” Denis Diderot, Pensees sur l’interpretation de la nature 1753, XV
For your efforts, conducted in the wee hours and often presented to wee audiences, you will garner that great satisfaction of knowing how things work, of knowing things that others do not, and of changing how we understand our world. You may face rejection, skepticism, and perhaps ridicule. In defense of your sanity, seek out supportive environments that value discovery and innovation. If you are at the beginning of your journey, find a mentor; there’s too much to learn on one’s own. A mentor can give you a sober critique of your approach and your science; often delivering the clear message to change course or improve quality. At all stages of your career, find collaborators and groups of colleagues with whom you can discuss, refine, reject, and perfect ideas. Scientific discovery whether epidemiologic, clinical, qualitative, translational, or molecular builds on the shoulders of fellow scientists who preceded us. As Stella Didacus (Diego de Estella), noted in the mid-16th century:
“Pygmaeos gigantum humeris impositos, plusquam ipsos gigantes videre. (Dwarfs on the shoulders of giants see further than the giants themselves.)”
Research is about independence, honesty, and a belief in the value of fumbling toward a distant truth that may be more than a lifetime’s journey. Science is not about prizes, it is not guided by politicians or clerics, it is not defensive of its errors, and it is not the possession of one people, one country, or one gender. The best of scientific spirits knows that the high-impact discovery of 2013 will be at best partially correct a century on, and more often than not a source of amusement for future generations.
Today is a celebration of your research efforts. Your mentors are proud of you and, as Department Head, I am inspired by your enthusiasm. Today you join scientists through the ages and perhaps share the common experience of Discovery, as summarized by Albert Einstein,
“In the light of knowledge attained, the happy achievement seems almost a matter of course, and any intelligent student can grasp it without too much trouble. But the years of anxious searching in the dark, with their intense longing, their alterations of confidence and exhaustion, and the final emergence into the light – only those who have themselves experienced it can understand that.”
June 7th, 2013
FDA Advisory Panel Backs Looser Restrictions on Avandia
Larry Husten, PHD
After two days of deliberation an FDA advisory panel has recommended that the severe restrictions (REMS) placed on rosiglitazone (Avandia, GlaxoSmithKline [GSK]) be modified. The vote constitutes a modest revival in fortune for the embattled drug and its maker after many years of controversy and bad news.
Only 5 panel members voted to continue the current severe restrictions. One member (the consumer representative) voted for the withdrawal of rosiglitazone. By contrast, 20 members voted to either modify (13 votes) or remove (7 votes) the REMS. But the vote should not be interpreted as a broad statement by the panel that rosiglitazone is safe. Panel members made clear that they still had concerns about the safety of the drug. But their concerns were less pressing than in the past.
The key to restoring at least some of rosiglitazone’s tarnished reputations was the re-adjudication of the RECORD trial by the Duke Clinical Research Institute (DCRI). Despite an attempt by Tom Marciniak, an FDA reviewer acting on his own initiative, to question the reliability of the re-adjudication, the rest of the FDA and the panel members all expressed praise for DCRI’s work. The panel endorsed the FDA’s perspective that the re-adjudication of the trial had been well performed, thus confirming the integrity of the original analysis.
But it would be a mistake to conclude that assurance of the integrity of the RECORD data leads to the conclusion that rosiglitazone is safe. Over the course of the two-day meeting, panel members continually stated their belief that the underlying flaws of RECORD — especially its open-label, noninferiority design and a large amount of missing data — ensured that it could never definitively dispel the cloud of uncertainty over rosiglitazone’s safety. DCRI’s Ken Mahaffey, who was in charge of the re-adjudication, conceded under questioning that although no significant misconduct was observed in the trial, RECORD did not provide strong evidence demonstrating the safety of rosiglitazone. But the DCRI analysis did allay the 2010 fears that RECORD may have been even more severely compromised due to misconduct, incompetence, or fraud.
On the second day of the meeting, panel members spent a significant amount of time considering the impact of the current rosiglitazone REMS, which resulted in a greater than 99% reduction in the use of the drug in the U.S., and asked the FDA about possible modifications of the severe REMS. It was clear that most members wanted to see rosiglitazone become more easily available though they seemed wary about removing all restrictions. The general sentiment of the committee was that the restrictions on rosiglitazone should be loosened but not entirely removed. But the committee could reach no agreement about how to achieve this goal.
Conspicuous by his absence at the panel meeting was Steve Nissen, whose original meta-analysis helped ignite the Avandia controversy and who was a vocal presence at the 2010 advisory panel meeting. Nissen had earlier announced that the FDA had not invited him to present his results to the panel (except as a speaker during the public access portion of the meeting). Nissen provided the following statement:
Little practical impact. Despite maximal efforts by FDA to convince the panel to remove restrictions, the majority voted to continue restricted access. If FDA loosens the requirements, a few additional patients may receive the drug, but effectively, Avandia is gone, which is a good thing.
I disagree with the findings regarding RECORD. Duke used the dossiers supplied by GSK to re-adjudicate. It was a foregone conclusion that they would get a similar answer.
We have three sources of data regarding Avandia. The meta-analyses, include FDA’s, show an increased risk of heart attack ranging from 40 to 80%. The observational data virtually all show an increased hazard for MI. The outlier is RECORD and it was a fatally flawed trial, completely unblinded to patients, physicians, and GSK.
I’m relieved that Avandia will remain restricted and continue to doubt the wisdom of spending taxpayer dollars to try to resurrect this drug.”
GSK issued its own statement. James Shannon, GSK’s Chief Medical Officer, said:
“We appreciate the committee’s thorough examination of the RECORD results and will continue to work with the FDA as it considers the recommendation of the committee. We continue to believe that Avandia is a safe and effective treatment option for type 2 diabetes when used for the appropriate patient and in accordance with labelling.”
June 7th, 2013
“Your Mortality Risk Is 11.827%”
John E Brush, MD
An 85-year-old woman named Betty presents with a non–ST-segment elevation myocardial infarction. Despite her advanced age, she is active, lives by herself, and continues to work as a volunteer in the hospital’s gift shop. She has hypertension, well-controlled diabetes, and a serum creatinine level of 1.8 mg/dL. She also has recurrent angina despite intensive medical therapy, so cardiac catheterization is performed. It reveals a high-grade stenosis of the left-main coronary artery, as well as complex multivessel disease. The Society of Thoracic Surgeons’ online risk calculator estimates Betty’s mortality risk after urgent CABG to be 11.827%.
What does that number mean? And how do you explain it to Betty so that she knows what to expect? Probability is a way to quantify uncertainty about the future. But what exactly does an event’s numeric probability tell us?
What Probability Means
Mathematicians and philosophers have been arguing about the meaning of probability for about 300 years. They have settled on two distinct notions: a frequentist notion and a personal notion. The frequentist dogmatists, such as R.A. Fisher, say that probability is a count of events — how things turn out over the long run, like the number of adverse events documented in an observational study. The personal probability dogmatists, such as Bruno de Finetti, say that probability represents a degree of belief or conviction — a forward-looking way to predict single events, like the chance that it will rain tomorrow or that Betty will make it through a risky operation.
As physicians, we use both notions of probability, even though we don’t give them much thought. We can look back at a database to find the frequency of survival in patients just like Betty. And we can switch to a personal notion of probability to talk with Betty about her chances. Tell Betty she has an 11.827% risk for mortality, and she may laugh at the false precision and the illusion of certainty. She might say, “What do you mean, doc? For me, it’s either 0% or 100%.” We might respond, “If I had 10 patients like you, 9 would survive surgery.” What we mean, of course, is that we are about 90% sure that Betty will make it through the operation. But that’s a tough idea to grasp when you’re the one going under the knife.
Probability’s Many Faces
Probability comes in various forms: simple, compound, conditional, complementary, and cumulative. And there are “odds” — namely, a probability divided by its complementary probability. If there is a 75% probability of rain tomorrow, the odds of rain are 0.75 divided by 0.25, or 3 to 1. Odds are a handy format, because prior odds can be multiplied by other numbers such as likelihood ratios or Bayes factors, to give posterior odds. Using odds, we can calculate probability estimates in our heads or with a calculator. For example, if we think a patient has a 50% prior probability of coronary artery disease, the odds of CAD would be 0.5/0.5, or 1. If an imaging stress test is positive, we multiply the prior odds (1) by the positive likelihood ratio for an imaging stress test (6); that yields a posterior odds value of 6. Converting odds back to probability (p=odds/odds+1) gives us a posterior probability of CAD of 86%.
We often use subjective quantifiers to express probability and make intuitive judgments. We throw around terms such as “unlikely,” “possible,” “probable,” and “almost certain” to express probability. Psychologists tell us that we frequently make mistakes when we subjectively estimate probability. We could turn the whole thing over to computers, but most patients don’t want cold calculations. So it seems important to calibrate our intuition from time to time using hard numbers. But first we have to wrap our minds around the meaning of probability.
We speak about probability all the time in medicine, yet we rarely stop to reflect on it. Philosophers such as Ian Hacking have written extensively about the meaning of probability. I have a chapter on it in my iBook, The Science of the Art of Medicine (free and available for download through the iBookstore). In my book, I discuss the history of probability ideas, how probability is viewed and calculated, and the various mistakes we sometimes make when we try to estimate probability.
What is your concept of probability, and how do you use it in clinical practice? How can we refine our notions of probability to improve medical decision making? I invite you start the conversation with me and other CardioExchange members right here.
June 4th, 2013
Study Finds More Musculoskeletal Problems in People Who Take Statins
Larry Husten, PHD
An observational study published in JAMA Internal Medicine provides new evidence suggesting that people who take statins are more likely to develop musculoskeletal problems.
Ishak Mansi and colleagues analyzed data from 6,967 statin users and an equal number of propensity-matched nonusers who were active-duty soldiers, veterans, and their families in the San Antonio Military Area. They found that the statin users were more likely to have musculoskeletal problems:
- All musculoskeletal diseases: Odds Ratio 1.19, CI 1.08-1.30
- Dislocation/strain/sprain: OR 1.13, CI 1.05-1.21
- Musculoskeletal pain: OR 1.09, CI 1.02-1.18
- Osteoarthritis/arthropathy: OR 1.07, CI 0.99-1.16
The authors calculated that between 37 and 58 people would need to be treated with statins to cause one additional person to develop musculoskeletal disease. However, increased exposure did not appear to raise the risk of statin use.
The results, according to the authors, “indicate that the full spectrum of statin AEs [adverse events] has not been fully explored.” They call for more studies on this topic: “the full spectrum of statin AEs will provide more complete data for cost-benefit and cost-effectiveness analyses of statin use.”
The study appears two weeks after a small study published in the Journal of the American College of Cardiology received considerable attention after it was covered in the New York Times. In that study the investigators found that statins appeared to blunt the beneficial effects of aerobic exercise.
June 4th, 2013
With One Big Exception FDA Reviewers Back More Benign View of Avandia Trial
Larry Husten, PHD
The FDA has released a 538-page briefing document for an advisory panel meeting on Wednesday and Thursday that will reassess a key clinical trial and reconsider the fate of the now-tarnished former blockbuster diabetes drug rosiglitazone (Avandia, GlaxoSmithKline). (Click here for the FDA documents.) As reported last week, the re-adjudication of the RECORD safety trial performed by the Duke Clinical Research Institute (DCRI) confirmed the initial finding of the trial that rosiglitazone was not associated with an increased risk for cardiovascular events.
For the most part, the FDA documents released today express strong support for the DCRI re-adjudication. But one FDA official, Thomas Marciniak, remains highly critical of RECORD and says the trial data and, therefore, the analysis of the data from GSK and DCRI, are completely unreliable. All parties agree, however, that the fundamental underlying design flaws of RECORD — in particular, its open-label design — mean that data from the trial will never provide definitive assurance about the safety of rosiglitazone.
The roster for the panel may also provide some evidence to support assertions by Steve Nissen, the most prominent Avandia critic, that the makeup of the advisory panel was designed to “whitewash” the FDA’s role in the Avandia controversy. By an initial rough count, most of the 16 of the 33 panel members who sat on the 2010 panel and who will not be participating in this week’s panel originally voted either to restrict or withdraw the drug. Nissen has also said that he was denied a request to make a formal presentation to the panel.
One FDA reviewer said the DCRI review of the mortality results in RECORD was “well-conceived and comprehensive” and “no stone was left unturned.” But the same reviewer states:
There is no amount of analytical rigor that can compensate for a weak trial design that is exacerbated by elements of poor execution, both of which afflicted RECORD. Its open-label non-inferiority design was simply problematic, especially for ascertainment of non-mortality MACE during trial execution… Thus, while we agree with the analytical findings of the DCRI mortality re-analysis, we would emphasize that RECORD’s design irreparably hampers its ability to characterize definitively the CV risk of rosiglitazone.
The panel may well accept the findings of the re-adjudication and the FDA analysis. In that case, the terrifying specter looming over the FDA and the rest of the medical establishment — that not just rosiglitazone but the entire drug development and approval process is fundamentally flawed and unreliable — will be put to rest, at least for now.
But acceptance of the re-adjudication does not necessarily mean that the FDA or the panel will want to remove the current strict restrictions on rosiglitazone or that the drug will once again be commercially viable. Certainly the chances for a rosiglitazone rebirth have now improved, but given the remaining serious concerns about RECORD, the panel may well prefer to err on the side of caution and retain most of the restrictions on rosiglitazone.
After two days of discussion the committee will be asked to vote on only one question: whether to remove, continue, or modify the current restrictions on rosiglitazone use, or whether the drug should be withdrawn from the market.
An updated meta-analysis from the FDA of randomized trials continues to suggest an increased risk associated with Avandia, though the results are far from conclusive. FDA reviewers also found evidence hinting that rosiglitazone was less safe than pioglitazone (Actos, Takeda). The FDA reported that rosiglitazone use declined from 5.1 million prescriptions in 2008 to about 12,600 prescriptions last year.
A Bitter Feud
Buried in the massive document is a bitter feud between an FDA rebel, Thomas Marciniak, and his bosses and other senior officials in the FDA’s drug division. (Marciniak was the subject of a recent New York Times article that publicly revealed another dispute with some of the same officials over the safety of angiotensin receptor blockers.)
Marciniak unleashes a barrage of rhetoric and data in an attempt to discredit RECORD and the DCRI. He argues that the DCRI is inherently unreliable because it relies on industry funding. He also points to DCRI’s involvement in the ARISTOTLE and PLATO trials, which have come into question. Finally, he invokes the name of a disgraced Duke researcher (but who had no connection with DCRI):
I would have thought that the two words ‘Anil Potti’ are sufficient for convincing anyone that Duke University is a poor choice for a contractor whose task it is to confirm the integrity of scientific research.
The panel will undoubtedly spend a great deal of time assessing Marciniak’s criticism of the data. The FDA goes to great lengths to respond to Marciniak. In one extraordinary memo, top FDA officials Norman Stockbridge, Ellis Unger, and Robert Temple write:
Dr. Marciniak’s memoranda were neither assigned by his supervisors in the Division of Cardiovascular and Renal Products nor solicited by the Division of Metabolic and Endocrine Product… He did not seek supervisory review or concurrence prior to filing his memoranda… Thus, although Dr. Marciniak’s documents are part of the official FDA record… his views do not necessarily reflect official FDA positions.
…
At CDER, we encourage, even cherish, scientific debate. Although Dr. Marciniak did not request supervisory concurrence for his reviews, we support and respect his right to express his scientific views. Regrettably, however, some of the views expressed in his memoranda go beyond scientific and regulatory principles and issues. They include disparaging remarks about FDA staff and review units, as well as serious allegations regarding the competence and behavior of DCRI and GlaxoSmithKline, and, indeed, all investigations and organizations that are paid by a drug company for any clinical trial conduct or analysis activity. The Division of Cardiovascular and Renal Products and the Office of Drug Evaluation-I reject these personal remarks…
…
In essence, Dr. Marciniak alleges that parties involved in the sponsorship, the re-adjudication, the statistical review, and the inspection of RECORD were all unreliable because of contractual arrangements, flaws in some unrelated matter, or both. We disagree with his assessment.
…
Apart from the content and basis for Dr. Marciniak’s critique, we find much of the language used in his memoranda regrettable. A number of passages insult our own review staff (Dr. Preston Dunnmon), our Biostatistical staff, DCRI, and the applicant. We find this language unprofessional, inappropriate, and not commensurate with our standards. As noted, we welcome and thrive on honest debate, but it is unprofessional to insult someone because he or she disagrees with you.
…After re-adjudication, we do not find a cardiovascular ‘signal’ of concern in RECORD. The mortality data are, in fact, reassuring.
The FDA reviewers also point out that although Marciniak has been extremely critical of other analyses of RECORD, his own evaluation suffered from serious flaws, even, notably, a less than rigorous blinding process. According to one reviewer:
Regrettably, the case reviews in his original consult were not blinded; although he states that some type of blinding occurred, it appears that he himself did the redactions, then followed with his own review. This is not an acceptable review procedure if one wants to put forth one’s review work as blinded.
June 4th, 2013
Day Two At the NLA: Interviewed On The Radio
Reva Balakrishnan, MD, MPH
June 2– The early part of my second day at the NLA conference started out in an exciting way. As a third place winner of the Young Investigators abstract competition I was invited to talk about my research on “Lipid Luminations,”XM radio’s Reach MD station hosted by Dr. Alan Brown. My research, titled “Prevalence of unrecognized prediabetes, diabetes and metabolic syndrome in patients undergoing non-urgent PCI,” found that using A1c levels nearly 1 out of every 10 patients admitted had diabetes without a prior diagnosis. An even larger proportion had prediabetes (57%) and metabolic syndrome (54%).
I have presented posters at prior conferences but had never been on the radio. It was not quite a formal oral presentation, but also not as casual as a poster presentation. I spent several hours prior to the interview preparing for questions that might be asked. My nervous energy settled down and I found myself focused and at ease when I finally sat down at the microphone and started chatting about my research with Dr. Brown, who was very insightful and genuinely interested in the results.
I was told that the show was one of the most popular on the station. It made me realize the growing importance of multimedia in the field of medicine – from blogs, to twitter accounts, TV shows, and radio. In most cases, whether intentional or not, the main audience is the general public.
As fellows, we are sometimes discouraged from using social media to voice our medical opinions as we are employees of a hospital and thus are thought to be representing our employers, or for fear that it might result in the inappropriate release of private information. With the growing use of multiple forms of media in medicine, we may find ourselves “behind the times” when we graduate into practice if we don’t know how to use it appropriately in the context of our work.
Has your fellowship program incorporated the use of social media in your training? If they have, in what manner? Are you encouraged or discouraged to participate?
June 3rd, 2013
Selections from Richard Lehman’s Literature Review: June 3rd
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 30 May 2013 Vol 368
Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation (pg. 2084): A neat study from Canada seeks to discover whether patients who need to stay on anticoagulants should continue warfarin or change to heparin while having a pacemaker or implantable cardioverter-defibrillator fitted. The main outcome measure was clinically significant device-pocket haematoma. The heparin group had more than four times as many pocket bleeds as the continued-warfarin group. There’s more on the general issue of antithrombotic treatment during invasive procedures in a clinical review article on 2113.
BMJ 1 June 2013 Vol 346
Diagnostic Accuracy of Conventional or Age Adjusted D-dimer Cut-Off Values in Older Patients with Suspected VTE: A Dutch systematic review usefully confirms that the cut-off level of D-dimer for detecting venous thromboembolism in people at low and medium risk needs to be adjusted for age. “The application of age adjusted cut-off values for D-dimer tests substantially increases specificity without modifying sensitivity, thereby improving the clinical utility of D-dimer testing in patients aged 50 or more with a non-high clinical probability.”
JAMA Intern Med 27 May 2013 Vol 173
Implantable Cardioverter-Defibrillator Shocks (pg. 859): Implantable cardioverter-defibrillators stop some people from dying suddenly. The only other things they are capable of doing are (a) going wrong and/or (b) delivering inappropriate shocks. People who have these things fitted need to know their individual odds, as far as that is possible. I know several researchers who are trying to bring shared decision making into this difficult arena, and this descriptive review of the literature about outcomes by Fred Masoudi and colleagues will be useful to them. It should also be read by all interventional cardiologists. “Implantable cardioverter-defibrillators reduce the risk of sudden cardiac death and prolong life in selected populations; however, many patients will receive an ICD shock, either appropriate or inappropriate. It is imperative that patients be counseled regarding this risk and adverse outcomes associated with shocks. Reduction of ICD shock should be individualized to ensure that patients receiving these devices experience the maximal benefits of therapy while minimizing the adverse consequences.”