May 8th, 2012
In AF, Women Have a Higher Stroke Risk Than Men
Larry Husten, PHD
When compared to elderly men with atrial fibrillation, elderly women with AF have a significantly elevated risk for stroke. This increased risk occurs regardless of warfarin use, according to a new study published in JAMA.
Meytal Avgil Tsadok and colleagues reviewed data from Quebec, Canada on more than 80,000 AF patients at least 65 years of age. Much of the increased risk occurred in women over the age of 75.
Overall crude stroke incidence:
- Women versus men: 2.02 versus 1.61 per 100 person-years, p<0.001
The risk for stroke among women remained elevated after adjustment for baseline risk factors, individual components of the CHADS2 score, and warfarin treatment:
- Adjusted hazard ratio: 1.14, CI 1.07-1.22, p<0.001
The authors wrote that “women older than 75 years represent the most important target population for stroke prevention in patients with AF, and the effectiveness of novel anticoagulants in this population in real-world practice will need to be closely monitored.”
May 8th, 2012
Selections from Richard Lehman’s Literature Review: Week of May 7th
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 2 May 2012 Vol 307
Abciximab vs. Manual Aspiration Thrombectomy in STEMI (pg. 1817): For mere bystanders, the world of interventional cardiology never ceases to amaze with its profusion of trials seeking to compare one odd-sounding intervention with another. The bottom line of this paper about the INFUSE-AMI is that intracoronary abciximab is superior to manual aspiration thrombectomy in patients with large anterior myocardial infarction. I guess you have to be either an interventional cardiologist or a trial methodology dweeb to find this very interesting. Bear with me: I am becoming somewhat of the latter, and to me this looks like a complex marketing trial, and intrigues me like a rare fungus (you can skip to the next section at this point). “Atrium Medical was involved in the design and conduct of the study and site selection and had the right to a nonbinding review of the manuscript.” Atrium Medical make coronary artery catheters for drug delivery, so they have a natural interest in promoting the use of intracoronary drug delivery. And one way to do that is to compare it with a technique that has already been shown to fail in the majority of trials – coronary clot aspiration. The thing not to do is compare it with intravenous abciximab delivery, because that might prove just as good. It pains me to list all the other potential defects of this trial, but basically it had a 2×2 factorial design, was single blinded, enrolled only 7.2% of MI patients presenting at 37 sites in 6 countries, used an end-point (infarct size at 30 days) which was not accurately determined in a significant proportion of patients, with a difference in pooled groups of small statistical significance, plus four other disadvantages you can read about from the authors themselves in the Comment section. And by the standards of the trials which regularly appear in the top journals, it is not even particularly bad.
The State of the Union’s Clinical Trials (pg. 1838): When I was a GP in the prime of life, Muir Gray bade me read a book called Clinical Epidemiology written by a number of Canadians. Reading Sackett et al by day and by night, I suddenly became aware of the wonders of randomized controlled trials, the potential of the internet, the intellectual challenge of using diagnostic tests according to Bayesian principles, the need to seek evidence, evidence, evidence. My heart still aches for the simple optimism of that vision. Instead, most of what we deal with in medicine is complexity made worse by inadequate knowledge. Surely the way forward must lie with further clinical trials. These days, if you want the results of your trial to appear in a peer-reviewed journal, it has to be registered; and the US registry is known usefully as ClinicalTrials.gov. Here the past and present custodians of this site look at the quality of the trials registered between 2007 and 2010. They “are dominated by small trials and contain significant heterogeneity in methodological approaches, including reported use of randomization, blinding, and data monitoring committees.” In other words, these trials are never going to yield clinically dependable data; most of them are futile, and therefore by definition unethical. Something is terribly wrong with the system which governs clinical trials: it is failing to protect patients and failing to generate useful knowledge. Most of what it produces is not evidence, but rubbish. And with no system in place to compel full disclosure of the data, it is often impossible to tell one from the other.
NEJM 3 May 2012 Vol 366
Two-Year Data on PARTNER (pg. 1686): The Placement of Aortic Transcatheter Valves (PARTNER) trial did what it says on the can: placed a lot of new aortic valves via a catheter (TAVR), so sparing patients the ordeal of open surgery. One part of the trial randomized patients at high risk of decompensation to one or other procedure, and at one year the two procedures yielded very similar results for mortality, symptoms and haemodynamic measures. This report gives the two-year results: there is now a divergence towards paravalvular regurgitation in the TAVR group which is associated with higher mortality.
TAVR in Inoperable Decompensating Stenosis (pg. 1696): Another part of the PARTNER investigation randomized patients with inoperable decompensating aortic stenosis to either TAVR or standard management (which often included balloon valvuloplasty). In these unfit elderly patients (mean age 83) with severe heart failure (mostly NYHA III-IV) survival for 2 years was 56.7% in the TAVR group and 32% in the others. So worth a go in “appropriately selected patients”, as the usual phrase has it. The fittest survive the best, even at this level.
Lancet 5 May 2012 Vol 379
Clopidogrel Genetic Testing (pg. 1705): “Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial”. Spartan Biosciences have developed a bedside test which allows rapid genotyping for the CYP2C19*2 allele. The simple story is that patients with this allele don’t respond to clopidogrel but do better with prasugrel, and that you can test this by measuring platelet reactivity, which was the outcome measure for this trial. But the evidence from randomized trials of clopidogrel v prasugrel is a good deal less clear. Moreover, I can’t see why a bedside test is needed for patients who have just had percutaneous coronary intervention and are lying in a hospital bed close to a proper pathology laboratory. So the concept that this trial proves is that you can get a Lancet paper out of a genetic test that predicts a surrogate marker, immediately and expensively. What it does not prove, thankfully, is the concept that the future of medicine lies in double rip-off – ripping off for the genetic test and then ripping off for the expensive drug.
Ann Intern Med 1 May 2012 Vol 156
Reducing MI Mortality (pg. 618): Here’s a study of Hospital Strategies for Reducing Risk-Standardized Mortality Rates in Acute Myocardial Infarction: an impeccable paper about an important topic, and moreover one which marries the insights of qualitative research with rigorous quantitative analysis of observational data. Am I praising this too much? I don’t think so, though I have to confess that I’ve been working for the best part of a year among the team that produced it. I thought they were incomparable before, and now I know it for a certainty. So call me biased, but do read this paper: it shows that virtuous care is rewarded, but sadly not by very much. Standardized MI mortality in the 537 US hospitals examined varies by about 10% in a near-normal distribution, but only just over 1% can be accounted for by the factors which emerged from qualitative interviewing of hospital staff: a culture that encouraged physicians to solve problems creatively, physicians and nurses acting as quality-of-care champions, hospital and emergency department clinicians meeting at least monthly to review care, cardiologists always being present in the hospital, and not cross-training nurses to work in both intensive care and cardiac catheterization settings.
May 8th, 2012
Persistent Concerns About Lorcaserin (Lorqess) from FDA Reviewers
Larry Husten, PHD
The FDA has posted briefing documents for Thursday’s meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to reconsider the new drug application for the obesity drug lorcaserin (Lorqess, Arena). The same panel recommended against approval of the drug in September 2010, citing weak efficacy and safety concerns.
The FDA reviewers do not appear to have substantially altered their view of lorcaserin. There are no major new safety concerns, but the limited efficacy of the drug gives little reason for panel members to take a risk.
The same safety signals — in particular, lingering concerns about heart valve problems — remain. It is unclear whether new, previously unpublicized data submitted by Arena on the effect of lorcaserin on the serotonin receptor (the source of previous heart valve problems with phen/fen) will move the dial on this issue. One important note of caution here: Although no statistically significant increase in risk for valve disease was found by the FDA (relative risk 1.16, 95% CI 0.81-1.67), the reviewer noted that the “upper bound exceeds the 1.5 upper bound requested by FDA to rule out an excess risk of VHD.”
The cancer issue seems less important this time, although its earlier significance may have been overstated.
Although the draft discussion questions for the committee mostly focus on the safety issues, I suspect that the efficacy data will actually play a more important role in determining how the committee votes. The efficacy data have not substantially changed since the previous meeting. A new trial, BLOOM-DM, is consistent with the previous trials, demonstrating a modest effect that meets some but not all of the FDA predefined criteria for efficacy.
Here’s how the FDA’s statistical reviewer summarized the efficacy findings:
All three studies had similar estimates of the placebo-adjusted effect of lorcaserin 10 mg bid at 52 weeks (TABLE 1). The consistency of the efficacy results across Studies 010, 009 and 011 supports the collective evidence for the efficacy of lorcaserin 10 mg bid. However, the efficacy endpoints, while statistically significant, do not fully meet the benchmarks for clinical significance that are described in the Agency’s Weight Management Guidance (2007):
For the continuous endpoint, the guidance states that the difference in mean weight loss between the active product and placebo-treated groups should be at least 5% and the difference should be statistically significant. For all three studies, the placebo-adjusted percentage change from baseline at week 52 was statistically significant. However, in each of the three studies, the placebo-adjusted effect of lorcaserin was statistically significantly less than 5%.
For the categorical endpoint, at least 5% of weight loss at week 52, the guidance states that the observed percentage of responders should be at least 35% and at least double the percentage in the placebo-treated group. These criteria are met in all three studies, when the last observation carried forward (LOCF) method was used to impute the 52week results from subjects who discontinued early. However, these results are somewhat sensitive to the imputation method. When early dropouts are classified as non-responders, Studies 009 and 011 meet the criteria for the categorical endpoint but Study 010 does not.
In my opinion, the 5% responder endpoint is a key endpoint because of the substantial percentage of early withdrawals in all three studies. Because of the relationship between dropping out and being less successful at weight loss in these studies, I believe it is reasonable to classify dropouts as non-responders. This approach may be a reasonable way to extend the study results to the intended target population.
May 7th, 2012
All Dressed Up and No Place to Go: False-Positive Activation of the Cath Lab for Primary PCI
Larry Husten, PHD
Primary PCI is widely recognized as the best early option for patients with ST-segment elevation myocardial infarction (STEMI). However, efforts to deliver primary PCI to the broadest possible population inevitably result in an increased number of false-positive activations of the cardiac catheterization laboratory. Now, a new study published in the Archives of Internal Medicine finds that the rate of false-positive activations is higher than expected.
James McCabe and colleagues analyzed data from 411 STEMI activations at two primary PCI centers. More than one-third — 36% — were judged to be false-positive. Patients with high BMIs or with chest pain or pressure at presentation were less likely to have a false-positive activation. The following factors were independently associated with an increased risk for a false-positive STEMI activation:
- Left ventricular hypertrophy on ECG: adjusted odds ratio (AOR) 3.15, CI 1.55- 6.40, p=0.001
- History of coronary disease: AOR 1.93, CI 1.04-3.59, p=0.04
- History of illicit drug abuse: AOR 2.67, CI 1.13-6.26, p=0.02
The authors conclude:
While a certain percentage of false-positive STEMI activations are essential to ensuring adequate diagnostic sensitivity, the point of equipoise between necessary diagnostic sensitivity and patient safety requires further investigation, particularly in light of increasing resource limitations.
In an accompanying commentary, Fouad Bachour and Richard Asinger note that the higher-than-expected rate of false-positives in the study may be partly due to “the variability of definitions.” They recommend that primary PCI programs adopt “a systematic protocol for the diagnosis and emergent treatment of STEMI including pivotal medical history for comorbid features, patient preference, continuous review of clinical experience, and direct feedback.” They suggest that an “acceptable rate of inappropriate activations … is probably in the 15% to 20% range.”
May 7th, 2012
Politics and Transcatheter Aortic Valve Replacement
Larry Husten, PHD
From the first early stages of its development, the prospect of transcatheter aortic valve replacement (TAVR) provoked two broad and competing fears:
1. Regulatory safeguards would kill a promising new technology, denying its life-saving benefits to many thousands of desperately sick people.
2. The stampede to stake a claim in a promising, highly lucrative new territory would lead to the exploitation and mistreatment of many thousands of desperately sick people.
Remarkably, neither scenario occurred. Instead, at a very early stage, medical societies, regulators, and industry worked together to ensure the smooth introduction of TAVR in the U.S. The final decision earlier this week by the Centers for Medicare & Medicaid Services (CMS) to provide reimbursement for TAVR was the latest step in a long, ongoing process that, for once, didn’t appear broken, and, in fact, represented an unusual consensus among physicians, regulators, insurers, and other involved parties.
However, in an apparent attempt to inject politics where it’s neither needed nor wanted, Scott Gottlieb, a conservative activist who is a former FDA deputy commissioner and CMS adviser, concludes that the CMS ruling means “that for costly procedures, Washington will be making more of these choices for us.” In a posting on the American Enterprise Institute’s The Enterprise Blog, Gottlieb writes that the decision “is a vivid example of how our healthcare is going to get reimbursed now that Washington calls more of the shots.”
Gottlieb doesn’t make a clear statement that explains his hostility to the CMS decision. Instead, he cites several facts that he thinks makes his case for him. He’s wrong.
For instance, Gottlieb writes:
CMS is also restricting the number of doctors that can perform the new procedure.
Actually, CMS has done nothing of the sort. It has insisted that doctors who perform the procedure have adequate training and that the hospitals where the procedures are performed have sufficient experience and adequate facilities. Perhaps Gottlieb would be happy to send an elderly relative for TAVR to a local community hospital with little experience in the procedure. It was precisely to avoid this scenario that the American College of Cardiology and the Society of Thoracic Surgeons supported CMS in this coverage decision. I fail to see how anyone would benefit by widespread proliferation of TAVR by novice operators at inexperienced centers.
Gottlieb again:
CMS is also going to tightly control the ability for the device to be used in less sick patients. It will require any patient who wants the procedure to be assessed by two separate cardiac surgeons to certify they were not suitable for open-heart surgery.
I suppose it’s possible to view this as government intrusion in the medical decision-making process between a doctor and a patient. I tend to think this represents CMS providing some reasonable safeguards to protect elderly patients from being victims of a system that in the past has sometimes ruthlessly exploited this same population. Again, however, it should be noted that the CMS decision is based on the evidence, as coverage is only given for a population in which benefit has been demonstrated.
Gottlieb takes a strong stand against clinical trials:
CMS only agreed to cover the device for its FDA approved use and only if the manufacturer agrees to continue studying the device in its FDA approved indication. The FDA approval, already based on unusually large and long-term trials that enrolled thousands of patients, was not enough to secure clear Medicare coverage.
Why is it a bad thing to insist that the manufacturer continue to study the device? To be sure, the TAVR trials were enough to gain FDA approval, but we are still very far from knowing the ideal role that TAVR can and should play in our healthcare system. Time and again problems with devices and drugs have popped up years after approval. Requiring continuing studies with this extremely complex device is a no-brainer. If the device is as good as many people seem to feel, these followup studies will provide convincing evidence for expanded use of the device. If not, not. In either case we will be better off than we would be without additional studies.
Gottlieb also criticizes CMS for refusing to cover patients who are eligible for open-heart surgery unless they are being treated within the context of a clinical trial. What exactly is the basis for Gottlieb’s objection here? At this point, we should remember, TAVR does not even have an FDA-approved indication for patients who are surgical candidates. The FDA will soon review an expanded indication for these patients. It seems likely CMS will expand its own coverage when and if the new indication is approved.
But Gottlieb misses another key point here. He fails to recognize that if the procedure were to become more widely available it would then become nearly impossible to establish its true worth through a clinical trial, as the interests of industry, hospitals, and physicians would converge and destroy all chance of enrolling patients in such a trial. This has happened on many occasions in the past with new devices and procedures. By insisting on trials, CMS is helping to insure that we won’t get fooled again.
Gottlieb believes TAVR should be widely available:
The same device has been approved in Europe for almost 5 years and has gained widespread use by patients who want to forgo very invasive open-heart surgeries—for good reason. The minimally invasive approach poses a lot less hardship on patients… This ruling will force people to get open-heart surgeries that might have been avoidable.
This certainly sounds good. After all, who wouldn’t want to avoid open-heart surgery? The problem is, as the literature makes clear, the choice of TAVR or surgery in patients eligible for surgery is extremely complex. The FDA, as I mentioned, is about to take up this issue, and it seems likely that the device will gain approval for this indication, but the decision to choose TAVR over surgery is by no means easy. In a discussion about the trial comparing TAVR to surgery, the editorialist in the New England Journal of Medicine wrote:
for those who are candidates for either transcatheter or surgical replacement, the findings present a dilemma in balancing the risks of increased neurologic complications against the benefits of avoiding sternotomy and cardiopulmonary bypass.
This assessment isn’t as simple as Gottlieb’s, but it has the virtue of being the product of a careful review of the actual data. But, of course, idealogues like Gottlieb never let a few facts get in the way of a compelling story.
May 7th, 2012
Another Surrogate Endpoint Falls Short
Brahmajee Kartik Nallamothu, MD, MPH
A recent paper in the Lancet explores whether carotid intima–media thickness (CIMT) is an adequate surrogate marker of risk for cardiovascular events. Matthias Lorenz and colleagues combined data from 16 longitudinal observational studies of CIMT progression, involving about 37,000 patients. In their patient-level meta-analysis, less CIMT progression was not associated with a lower likelihood of subsequent cardiovascular events. An accompanying editorial by Vijay Nambi and colleagues strikes the right chord, particularly with respect to heterogeneity in techniques for assessing CIMT and measurement errors (or noise) associated with its use.
As a backdrop to this newly published information, current guidelines make a class IIa recommendation for a single CIMT measurement to enhance risk-stratification in asymptomatic adults. Single CIMT “snapshots” may indeed be useful in certain clinical settings, but it’s unclear what CIMT progression over time means for an individual patient’s clinical outcomes, as the Lorenz study makes clear. Furthermore, that study is consistent with two recent meta-analyses that used similar data from clinical trials on novel therapeutic agents; one was led by my colleague at the University of Michigan, Zach Goldberger. Collectively, the three studies should discourage reliance on CIMT progression as a surrogate endpoint.
Some have argued, though, that CIMT avoids the substantial costs and lengthy follow-up required for trials that focus on “hard” but uncommon outcomes such as death. Presumably, many of these folks will remain unconvinced by the accumulating data and point to the inherent limitations of meta-analyses while highlighting some strengths of CIMT.
Overvaluing surrogate endpoints is nothing new, of course. Cardiologists have learned this lesson many times, beginning with the infamous CAST trial, which demonstrated that successful suppression of premature ventricular contractions by encainide and flecainide was not just ineffective at improving outcomes but also associated with higher rates of death.
Nevertheless, unlike serum biomarkers, CIMT (along with IVUS) has achieved something of a unique status as a tool in clinical trials. That’s because of its advantage in actually visualizing atherosclerosis directly in the vessel wall, making it appear to be less of a “surrogate” endpoint. However, oncologists would not be surprised that imaging does not correlate with hard outcomes. They have long understood that tumors that initially melt away with chemotherapy can come back. Cardiologists, too, must be willing to admit that although our ability to view changes in atherosclerosis in the vessel wall over time is better than ever, we still don’t know what those changes mean in terms of the outcomes that matter most to patients.
Questions:
1. What do you think about the use of CIMT, IVUS, and other imaging modalities as surrogate endpoints in clinical trials?
2. Can studies be better designed to identify surrogate endpoints that might be valuable early in a drug or device evaluation?
3. How do we reconcile our need for tools to evaluate potentially useful therapies early in their development, given that it is impossible to imagine conducting large clinical trials with hard outcomes for every promising drug?
May 7th, 2012
Roche Terminates Development of CETP Inhibitor Dalcetrapib
Larry Husten, PHD
Roche announced today that it has ended development of dalcetrapib, its entry into the once-promising class of HDL-raising CETP inhibitors. A data and safety monitoring board recommended that the dal-OUTCOMES phase 3 trial be stopped due to a lack of clinically meaningful efficacy. The DSMB found no evidence of safety problems.
May 6th, 2012
Patent Foramen Ovale — Are the Choices Patently Obvious?
Shelby Kutty, MD and John Ryan, MD
CardioExchange editor John Ryan interviews Shelby Kutty, of the University of Nebraska College of Medicine, about his recent state-of-the-art paper in JACC. In the article, Kutty and his colleagues explore what we know and what we don’t know about patent foramen ovale.
THE PAPER
About a quarter of adults have a patent foramen ovale (PFO). When this normal anatomic variant for infants persists into adulthood, it can be associated with cryptogenic stroke, transient ischemic attack, migraines, and other conditions. Available management strategies include observation, medical therapy, percutaneous intervention, and surgery. Here are some highlights from Kutty’s article:
1. PFO is more common in patients with cyptogenic stroke than in the general population (roughly 50% vs. 20%).
2. In some series, patients with an atrial septal defect or PFO who had suffered multiple recurrent events and then underwent transcatheter defect closure experienced a reduction in the recurrence rate of focal neurological events.
3. The FDA has not approved any currently available PFO-closure devices. Closures are performed off-label using devices approved for other indications.
4. The recently published CLOSURE I randomized trial failed to demonstrate the superiority of PFO device closure plus medical therapy (6 months of aspirin and clopidogrel, followed by 18 months of aspirin) over best medical therapy (24 months of warfarin or aspirin, or a combination).
THE INTERVIEW
Ryan: What precisely is the link between PFO and cryptogenic stroke?
Kutty: A stroke may be labeled “cryptogenic” at the time of diagnosis because no clear cause has been identified. Paradoxical embolization of a small venous thrombus through a PFO is one of many causes of cryptogenic stroke. The diagnosis is one of exclusion, as in nearly all cases the thrombus has already moved through the PFO by the time the stroke occurs. Other causes of cryptogenic stroke should be actively considered. If none are found, it may be reasonable to consider paradoxical embolus as a potential cause.
Ryan: Why have randomized trials failed to show definitively whether PFO device closure works or, at the very least, to point to a definitive practice?
Kutty: I think the studies have actually shown that PFO closure, followed by relatively benign antiplatelet therapy, is about as effective as taking powerful anticoagulation drugs such as warfarin. Closing the PFO was not “better” at preventing later strokes, so the trial designs have made some of the trials appear to be failures, but the data tend to show that PFO closure may be a reasonable alternative to lifelong anticoagulation. Interestingly, the causes of later recurrent stokes were often identifiable, so most of them were not “cryptogenic.” It’s not clear whether better screening would have identified the causes before the trial participants were enrolled.
Ryan: Is the frequent off-label use of closure devices a good thing? And what’s the practice in Europe, where regulations are more lenient?
Kutty: I still feel that in selected patients who have truly had a cryptogenic stroke, PFO closure is one alternative for trying to prevent stroke recurrence. I believe we went through a period of over-enthusiasm, when some were suggesting PFO closure as first-line treatment rather than carefully considering it as one option for particular patients. This enthusiasm still seems to be prevalent in Europe.
Ryan: Do you expect the new generation of anticoagulants to improve medical therapy and, specifically, to change the options available to patients with a PFO?
Kutty: We’ll have to see how safe and well tolerated the new medications are. Remember that for a paradoxical embolus to occur, there must first be a clot in the venous system and then the potential for that clot to embolize through a PFO. Eliminating either the clot or the PFO can be protective. Many patients find it difficult to take powerful, expensive medications every day. If PFO closure plus milder, less expensive antiplatelet drugs such as aspirin are as effective as powerful, expensive new medications, some patients may opt to undergo PFO closure and not worry so much about the medications. The REDUCE trial of the Helex device is designed to test whether PFO closure significantly improves outcomes (evident strokes and, also, silent MRI changes) over simple antiplatelet medications alone (which many feel are as good as more-powerful anticoagulants for cryptogenic stroke).
Ryan: If a 30-year-old woman on birth control with a family history of stroke and an atrial septal aneurysm >3 cm comes into your clinic, what do you offer her?
Kutty: I think the birth control pill has a stronger association with possible stroke than the PFO does. The data are not consistent with respect to aneurysms associated with PFO, and I don’t personally consider those to be a large additional risk factor. I would recommend stopping the pill and no treatment for the PFO. Aspirin may be reasonable, since it is cheap and low risk and may have a significant beneficial effect, as I’ve noted. But I don’t currently recommend even considering PFO closure in the absence of a likely paradoxical embolic event.
Ryan: On her way out, the woman realizes she forgot to tell you that she has migraines with aura. Do you ask her to sit back down to discuss PFO closure?
Kutty: I consider PFO closure to be only a last option as a treatment for migraines. I would want a migraine expert to explore all other possibilities first. If the migraines cannot be controlled after trying several other better-proven therapies, PFO closure may be considered after a long review with the patient. Experience and data have shown that PFO closure can have dramatic effects in some individuals, but overall it is no better than placebo.
Share your views about Dr. Kutty’s review of the evidence base on PFO and about how to manage patients with a PFO in clinical practice.
May 4th, 2012
Reanalyzed Chantix Data Yield Smaller CV Risk, New Controversy
Physician's First Watch, CardioExchange Staff
A new meta-analysis criticizes earlier work warning that the smoking-cessation drug varenicline (Chantix) poses increased cardiovascular risks.
The analysis appears in BMJ. It was performed by researchers with no current ties to the drug maker, but one of whom had received a Pfizer investigator-initiated research award.
The new analysis examined the risk of treatment-emergent serious cardiovascular events during 22 randomized placebo-controlled trials comprising over 9200 participants. Events were those defined as occurring within 30 days of stopping treatment (the earlier analysis included events up to 1 year later). Contrary to the earlier findings, the new analysis found a cardiovascular event rate of 0.63% with varenicline and 0.47% with placebo.
Calling the risk estimate of the earlier analysis “inflated,” the authors say that, on the contrary, the risk associated with varenicline use “is statistically and clinically insignificant.” Sonal Singh, author of the earlier meta-analysis, says he stands by his results and that “people need to look at the data and make up their own minds.”
[Editor’s note: Although the paper has passed its embargo time, it is not yet available on BMJ‘s site. BMJ‘s press office has assured us that it will be there shortly. Here is a link to BMJ‘s “Just Published” page.]
This post is reprinted from Physician’s First Watch, a part of the Journal Watch family. PFW is a free daily alert on current news that affects your practice — from medical journals, government agencies, scientific conferences, and major media reports.
May 4th, 2012
Company Fails To Disclose Details About Heart Failure Risk of Drug
Larry Husten, PHD
Boehringer Ingelheim failed to fully disclose data suggesting that one of its drugs, pramipexole, a dopamine agonist sold under the brand name of Mirapex, is associated with a significantly increased risk of heart failure, according to a recent news report. The drug, which was originally developed for the treatment of Parkinson’s disease, is now also used to treat restless legs syndrome.
Although cardiac failure was an adverse event observed during clinical trials, and is mentioned in the drug’s label, a more definite association had not been established in the literature until recently. According to Pharmalot’s Ed Silverman, however, Boehringer Ingelheim appears to have been aware of the stronger association previously but made no effort to publish or disseminate its findings.
A study published in Pharmacoepidemiology & Drug Safety found an increased risk of cardiac failure associated with pramipexole and another dopamine agonist, cabergoline. But buried in the text of the report lies evidence that the finding should not have come as a surprise to Boehringer. Silverman writes:
The introduction to the study, which was entitled ‘Dopamine Agonist Use and The Risk of Heart Failure,’ noted that, “recently, adverse events of heart failure have been observed in association with the dopamine agonist pramipexole (the chemical name of Mirapex) in randomized trials.” The authors cited Boehringer “internal data” and a “personal communication from Dr. Bartels.”
The reference was to Dorothee Bartels, who is corporate vice president and head of global epidemiology at the drugmaker. She provided the results of a pooled analysis from randomized Mirapex trials. Specifically, the introduction mentions a “signal of a potential risk of heart failure arose in pooled data from 26 placebo-controlled, randomized trials” in Parkinson’s and RLS patients.
Those trials involved 4,157 patients who were taking Mirapex and another 2,280 on a placebo, but the outcome was too small to draw reliable conclusions, the authors wrote, and raised questions about the potential for the risk to occur with other dopamine agonists. This led them to conduct the study. Yet those 26 trials were never made available. It is also not clear how far back they go in time.
A study author told Silverman that Boehringer did not supply him with the underlying data. The author told Silverman that “the only data I have are in the paper – rates, numbers, etc.”
Silverman asked Boehringer about the data, but only received information about new product labeling for the drug which contains “language related to cardiac events, and specifically heart failure or cardiac failure. Post-marketing surveillance studies continue to assess the safety and efficacy of our products… We continue to work closely with the FDA to ensure our products are appropriately labeled and are used safely.”
Silverman notes that the current label is identical to the 2006 label, but with the addition of one sentence in the post-marketing experience section: “In a pharmacoepidemiological study, pramipexole (Mirapex) use was associated with an increased risk of cardiac failure compared with non-use.”
Silverman quotes extensively from Harlan Krumholz (editor-in-chief of CardioExchange), who spoke about the issue:
I am disturbed that there seems to be a pooling of internal data indicating a potential problem with heart failure and there has been no opportunity for independent review.
This is an ideal situation where sharing of individual patient-level data with the entire research community, or at least with independent investigators, can provide information about the risk that was conveyed in the company’s personal communication to their consultant.
Such sharing would deflect concerns that the company is hiding something and allow a fair evaluation of the risk. With no record in the medical literature and no sharing of the data, we are left to wonder about these risks and the reason that the company has not been more forthcoming. I applaud them for doing analyses on harm, but they need to go further.
The privilege of selling a product should be accompanied by the responsibility to share data you have that is germane to the risks and benefits of the drug. Patients deserve access to information that could influence their decisions about clinical strategies. If it is true that the company has data from their trials that is relevant to concerns about the drug’s safety profile and that data has not been shared, then I hope they will move quickly to make it available.
NEJM — Recent Cardiology Articles- Seeing the Left Main Coronary Artery Clearly — Is IVUS Always Necessary? June 11, 2026Treatment of the left main coronary artery with percutaneous coronary intervention (PCI) in the absence of previous surgical revascularization, also referred to as an unprotected left main coronary artery PCI, is one of the riskier tasks that interventional cardiologists are asked to perform. Stent implantation in the left main coronary...
- IVUS — A Zigzag Path to Success June 11, 2026The use of intravascular ultrasound (IVUS) imaging for assessment of the coronary arteries has an almost 40-year history. In an editorial comment on an early ex vivo assessment of the accuracy of IVUS in evaluating human coronary arteries, Yock and Linker1 posed three questions that remain relevant today:...
- Prescription without Precision — Dangers of Dosing on the Basis of Race as Biology June 11, 2026Despite recognition that racial and ethnic categories are poor proxies for genetic diversity, race is still used to guide pharmaceutical use, posing risks of ineffectively low or dangerously high dosing.
- Case 16-2026: A 14-Year-Old Girl with Hypertension June 11, 2026A 14-year-old girl was admitted to the hospital because of hypertension and headache. She had hypokalemia, an elevated blood level of C-reactive protein, and an elevated erythrocyte sedimentation rate. A diagnosis was made.
- Antidotes for Anticoagulation Reversal June 11, 2026The authors review current strategies for anticoagulation reversal in major bleeding events or urgent surgery as well as specific antidotes, limits of available evidence, thrombotic risks, unmet therapeutic needs, and ongoing research.
- Seeing the Left Main Coronary Artery Clearly — Is IVUS Always Necessary? June 11, 2026