September 20th, 2012
FDA Warns of Possible Heart Failure Risk with Pramipexole
The FDA is investigating the possibility that pramipexole (Mirapex) increases the risk for heart failure.
In a pooled analysis of randomized trials, the drug — used to treat Parkinson disease and restless legs syndrome — showed an increased incidence of heart failure relative to placebo, but the results weren’t statistically significant. Further review of two epidemiologic studies also found an increased risk, but confounding factors may have influenced the results, according to the FDA.
Until the agency completes its review, it is instructing clinicians to continue prescribing pramipexole according to the recommendations on the label. Patients should be counseled about the potential risk.
Reprinted with permission from Physician’s First Watch
September 20th, 2012
Why I Applaud the Skeptical Physicians
Joseph S. Ross, MD, MHS
In this week’s New England Journal of Medicine, Kesselheim and colleagues publish findings from their randomized study of 269 internists who were asked to interpret the results, described in scientific abstracts, of three hypothetical clinical trials of three made-up drugs: lampytinib, bondaglutaraz, and provasinab. The participants knew that the trials were not real and that the study’s aim was to investigate the role that disclosure of funding plays in physicians’ interpretation of clinical trial research.
The trials were randomly configured as having high, medium, or low methodological rigor, depending on the use of randomization and blinding, sample sizes and dropout rates, length of follow-up, and endpoints. In addition, the trials were randomly identified as being funded by industry, the NIH, or having no external funding.
To the great relief of teachers of evidence-based medicine, who have spent countless hours instructing medical students and house staff in how to evaluate articles in the medical literature, physicians appeared to appropriately assess the trials’ methodological rigor: They were least willing to prescribe drugs tested in low-rigor trials and most willing to prescribe drugs tested in high-rigor trials.
But to the consternation of industry and the Journal’s Editor-in-Chief, who wrote the accompanying editorial, disclosure of industry funding was associated with physicians’ propensity to downgrade the rigor of a trial, their confidence in the results, and their willingness to prescribe the drugs. And physicians had the greatest confidence in NIH-funded trials.
Dr. Drazen writes in his editorial: “We think that decisions about how trials influence practice should be based on the quality of the information conveyed in the full study report.”
I can only partially agree with this statement. Although the full study report is the major consideration in evaluating any study, I believe that physicians were right to be skeptical of industry-funded trials.
Kesselheim and colleagues varied several different aspects of the hypothetical trials’ designs in order to create differences in their rigor. However, a large number of details and decisions are made in the process of designing, conducting, and reporting on a trial, so it would be impossible to capture them all in a scientific abstract. And in truth, it’s even impossible to capture them all in an 8-page article.
Physicians’ experiences with rofecoxib, rosiglitazone, Epogen, gabapentin, olanzapine, and many other pharmaceuticals have taught them the hard lesson that when the stakes are high with billions of dollars at risk, the stakeholders try to cast the drugs in the most positive light possible.
Maybe negative studies are never published. Maybe adverse events are not reported. Maybe a primary outcome is swapped for a secondary outcome that had a larger magnitude of effect. Maybe the comparator is less potent.
But decisions are made that do not obviously affect the apparent rigor of the trial — the trial is still randomized, blinded, with a large sample and long follow-up. So at first glance, it appears to be of high quality. But these decisions distort the trials’ findings and have distorted the medical literature.
While we wait for better evidence in today’s world — which requires trial registration before enrollment, prespecification of primary and secondary outcome measures and safety outcomes, and reporting of results within a year of trial completion — I think physicians are right to remain skeptical.
Are you with me in siding with these skeptics?
September 19th, 2012
Certification Exam Prep: An FAQ
Benjamin Howard Freed, MD
The cardiovascular board exam is fast approaching and this is about the time (some) people start making arrangements for how they are going to prepare. With the countless board review courses, online tools, books and videos currently available, it can be difficult to figure out which materials are most useful, especially when one considers the time constraints of most fellows and new faculty. After many years of schooling, most people sitting for the cardiovascular boards have a pretty good idea of how they study best. Still, I’ve been asked many questions by fellows since I took the boards last November. Here’s an FAQ that reflects my experience
How did you start preparing for the exam?
A: The first thing I did was get a good sense of the format of the exam. You can do this easily by going to the ABIM website. They will give you a breakdown of which topics will be covered and how much of the test will be devoted to that topic.
Did you put a timeline together for how you were going to prepare?
Yes. I think it is best to first identify your strengths and weaknesses based on the exam blueprint. This will help you in strategizing how to make the most out of the time you have left. If you’ve got ample time to study, consider spending it strengthening your weak subjects, but as the exam gets closer, pump up the topics you are strong in regardless of what preparations you’ve already made. I ramped up my studying so that, by approximately 2-3 weeks prior to the test, I was spending at least a couple of hours each day (if I had time) preparing for the exam.
Do you recommend any board review courses?
I watched the Mayo DVDs and went to the ACC course. I think they were both very helpful but you certainly don’t have to do both. Going to a course forces you to focus for a finite period of time but watching the DVDs from home allows you to stop and go as needed and pick the topics that you really want to hear. The important thing for me was to take my own notes on each topic. By the end of my studying, I had my own little book with tons of notes that I had obtained from various sources. I used this book to study for the last couple of weeks.
Was there a difference between the Mayo and ACC board review courses?
I thought the Mayo board review course was geared more towards people who were taking the test for the first time and was, therefore, more comprehensive than the ACC course. The ACC course, however, provided many excellent questions that were I think more similar to the actual exam content compared with the Mayo questions.
What did your colleagues think about the different courses?
Many of my colleagues, who were first-time test takers, liked the Mayo review course and said it was an essential part of their preparation. Some of my colleagues went to the Cleveland Clinic board review course and thought it was very helpful.
Did you use any other board review material?
Be sure to know the guidelines. Don’t read every detail, but focus on the items in bold or the executive summaries. Know Class I and Class III indications the best because it is hard for them to ask you a Class II question. Have a basic understanding of the appropriate use criteria for various subjects. I also used the ACC SAP CD to help supplement topics that I still felt uneasy about after taking the board review courses.
Where did you find practice multiple-choice questions?
That was more difficult than you might expect. Unlike the internal medicine boards, there really isn’t a MKSAP for the cardiovascular exam. The board preparation courses have questions to help you prepare. The Mayo question book is a great book covering all topics. ACC SAP also has great questions. I spent most of my time right before the exam taking mock tests. Be sure to practice timing yourself.
How did you prepare for the EKG and imaging coding section?
This was slightly more difficult because most of the board preparation material out there is for the MCQs. O’Keefe is a great book for the EKG coding part but keep in mind that it might be a little more difficult than the actual exam. The board review courses have sections on how to code and will provide both EKG and imaging questions. Best to know the coding sheet nearly memorized. The reason is that you won’t have to spend much time looking for the proper code during the actual test.
How much time did you spend studying?
I started thinking about studying and how I was going to prepare for the exam in the summer but really didn’t start studying until end of August/early September. Even then, I spent little time actually studying. The ACC board review course was a week-long in early September. After that I started devoting more of my day to studying and slowly ramped it up from there.
What would you do differently in preparing if you had to do it over again?
I would have probably spent even more time just taking mock exams. If there is an opportunity to take a proctored exam at a board review course, I recommend it. I suspect that it can give you a better idea of what the actual exam environment is like and how much time you have to complete the test. For the EKG and imaging sections, I think there is a tendency to review the EKGs/images you are most comfortable with, but avoid that temptation. Focus on finding EKGs/images that are less familiar. Google images sometimes helped if I couldn’t find it any other place.
Obviously, these suggestions might not be best for everyone, so please share here what’s working for you — or what worked if, like me, you’re already done with the boards. I wish you all the best of luck!
September 19th, 2012
Studies Examine Less Burdensome Dual Antiplatelet Regimens
Larry Husten, PHD
Two new studies published in the Journal of the American College of Cardiology offer hope but not, yet, compelling evidence to support less burdensome requirements for dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation.
In the first study, Spanish investigators followed 1622 consecutive patients who received a DES for 1 year. They found that 10.6% of the patients interrupted at least one antiplatelet drug during the first year. Two-thirds (64.5%) of the interruptions were temporary, lasting a median of 7 days. After discontinuation of therapy, 4.1% of patients had an acute coronary syndrome (ACS) — not significantly different from the 5.5% rate of major cardiac events in patients who remained on DAPT.
The authors conclude that early discontinuation of DAPT “is not exceptional and is usually temporary. Although further knowledge about individual risk is desirable, our results suggest that discontinuation for a few days (median: 7 days) of [DAPT] after the first month of DES implantation may be reasonably safe in terms of major cardiac events.”
In an accompanying editorial, Bernhard Witzenbichler points out several limitations of the study, and concludes that “the data can only suggest that a brief interruption of DAPT does not have a large impact on ischemic risk.”
In the second study, Korean investigators randomized 2117 patients to receive either the Endeavor zotarolimus-eluting (ZES) stent plus 3 months of DAPT therapy, or standard therapy consisting of another DES with a full year of DAPT. There was no difference between the two groups in the primary endpoint (the composite of CV death, MI, stent thrombosis, TVR, or bleeding), which occurred in 4.7% of patients in each group, and there were no significant differences in any of the components of the endpoint. The authors conclude that the Endeavor ZES plus 3 month DAPT “could be safe and beneficial for the selected patients with coronary artery disease who may need to stop DAPT early after DES implantation.”
In his editorial, however, Witzenbichler urges caution in interpreting the trial, noting, among other factors, that the trial was underpowered to demonstrate safety, and that the low overall event rate in the trial “makes it difficult to translate the findings to a broader all-comer population.”
Witzenbichler asks whether it is time to “slacken the reins” of DAPT after DES implantation, but concludes the evidence is still insufficient to change standards:
With newer-generation DES, 6 months DAPT might be sufficient, and 3 months not completely off the wall in low-risk groups. Brief interruption of DAPT beyond 4 weeks might not be associated with a dramatic risk increase. However, the patient- and device-related criteria safely allowing early DAPT withdrawal or interruption still have to be determined. Until then, we should be cautious and do our best to avoid unplanned discontinuation of DAPT.
Please click here for additional commentary about this topic by Deepak Bhatt, Rick Lange, and David Hillis.
September 19th, 2012
Stopping DAPT for DES Before 12 Months: Cutting-Edge or Dangerous?
Deepak L. Bhatt, MD, MPH, Richard A. Lange, MD, MBA and L. David Hillis, MD
According to current recommendations, dual antiplatelet therapy (DAPT) should be administered for a minimum of 12 months after drug eluting stent (DES) implantation to prevent late stent thrombosis. However, prolonged DAPT is associated with higher bleeding rates when compared with treatment with aspirin alone.
According to two recently published studies, temporary discontinuation of antiplatelet therapy is safe, and DAPT needs to be given for only 3 months with the newer DES. Ferreira-González and colleagues report that discontinuation of antiplatelet therapy for a few days (median, 7 days) after the first month of DES implantation is safe in terms of major cardiac events. In patients who received the second generation Endeavor zotarolimus-eluting stent (Medtronic, Santa Rosa, California) in the RESET* Trial, 3 months of DAPT was noninferior to standard therapy (12 months of DAPT with other DES) with respect to the composite endpoint of cardiovascular death, MI, stent thrombosis, bleeding, and target lesion or vessel revascularization at 1 year.
What does our resident expert on the topic, Dr. Deepak Bhatt, think about these findings?
1. Your patient had a DES placed 3 months ago and now needs an elective knee replacement. Do you advise her to wait until she’s completed 12 months of DAPT or to temporarily discontinue her antiplatelet therapy to have the surgery now?
This is a very common and challenging scenario in cardiovascular medicine. I wish there were an easy or standard answer, but there is not. First of all, if I had implanted a stent 3 months ago, I would have asked if there were any potential surgeries coming up in the next several months. Let us assume that she did not feel she needed surgery 3 months ago, but now she feels she does. I would still try to stretch out the waiting period to 12 months of dual antiplatelet therapy if at all possible, but would likely settle for 6 months if her knee pain was severe and could not be controlled with oral medications or knee injections. But it depends… If she had come in with a large STEMI, I would push harder for the 12 months. If it were an LAD/diagonal bifurcation stent (and I try to avoid placing bifurcation stents unless really necessary), I might push harder for 12 months. So, the clinical indication and the anatomy both matter to me. And regardless of when she decides to have the surgery, I would insist on aspirin being continued uninterrupted.
2. If patients receive one of the newer stents, is it time to loosen up on DAPT duration?
This is a bit of a weak answer, but I would say we need more data. I really want the answer to be yes, as do almost all cardiologists. But we need to wait for the results of large randomized clinical trials such as DAPT, which is testing durations of dual antiplatelet therapy longer than 12 months, as well as a number of smaller trials that are testing shorter durations of DAPT. The dilemma, of course, is that stent thrombosis is an infrequent event, whereas bleeding and the need for surgery are both relatively common events. Therefore, only large trials and meta-analyses of smaller trials may provide insight into the “right” answer to this question. Until such a time, I would stick with the guideline recommendations and continue for 12 months, assuming that the patient is not at high risk for bleeding. But if the patient did run into trouble with bleeding — including frequent “nuisance” bleeding — or needed surgery that ideally would not wait, I would not be overly dogmatic about the 12 months with the newer-generation DES and would allow good clinical sense to prevail.
September 19th, 2012
An Ad That Doesn’t Tell the Entire Story — Part 2: Niaspan
Harlan M. Krumholz, MD, SM
Although I do not include advertisements on my reading list, I can’t help but notice them as I leaf through journals (no, I’m still not quite completely digital). I wonder if anyone else was bothered by Abbott’s print advertisement for Niaspan, an extended-release formulation of niacin. The ad, shown below, focuses on Niaspan’s effect on HDL-cholesterol levels without any reference to patient outcomes.
Click to enlarge
This ad makes no mention of AIM-HIGH, the NIH trial showing that adding extended-release niacin (supplied by Abbott) to simvastatin provided no benefit to patients with established cardiovascular disease. The trial did show that extended-release niacin could increase HDL-c levels by 21%, consistent with the ad’s claims — but (and this is a big “but”) the drug did not reduce the risks for myocardial infarction, ischemic stroke, symptom-driven revascularization, or death from coronary heart disease.
I can’t blame Abbott for omitting information about AIM-HIGH. The FDA has retained an indication for Niaspan in lowering the risk for heart attack in people with high cholesterol who have previously had a heart attack. The Abbott ad does mention the lack of additional benefit in preventing heart disease from Niaspan in combination with simvastatin or lovastatin over that from simvastatin or lovastatin monotherapy. You can see the potential for confusion. Also confusing is the fact that the indication names specific statins, not statin therapy in general: Does the FDA think that Niaspan is likely to improve outcomes when added to, say, atorvastatin?
By the way, I was curious what the NIH says about extended-release niacin to consumers, given that it funded the multimillion-dollar AIM-HIGH trial. Interestingly, the NIH’s consumer webpages on niacin provide no context about AIM-HIGH. One page, revised in June 2012, doesn’t mention AIM-HIGH at all; another, last reviewed in August 2011, has AIM-HIGH in a reference list at the bottom but provides no findings from the study. Wouldn’t you want to educate the public about the science you funded? Maybe we should suggest that when the NIH publishes important research, it should update its information for patients as well.
A Merck-sponsored trial of extended-release niacin is due out next year. While we await any new information about this drug, I am concerned at seeing an ad that touts an effect on HDL-c levels without making clear that the only large contemporary trial of the drug in the statin era failed to show that it improved outcomes.
What do you think of this Niaspan ad?
September 18th, 2012
Screening for AAA Comes Under Renewed Scrutiny and Criticism
Larry Husten, PHD
A 2007 Medicare initiative to increase AAA (abdominal aortic aneurysm) screening in appropriate patients failed to prevent AAA rupture or reduce all-cause mortality, according to a new study published in the Archives of Internal Medicine. The larger implications of the study are unclear, but two accompanying papers, an invited commentary and a perspective, emphasize the darker side of AAA screening.
Jacqueline Baras Shreibati and colleagues examined the effect of the 2007 Screening Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) Act, which provided Medicare coverage for a one-time ultrasound screening for new Medicare patients who were men and had a history of smoking or were men or women and had a family history of AAA. The SAAAVE Act was based on 2005 U.S. Preventive Services Task Force recommendations.
Using Medicare data from 2004 to 2008, the investigators found a modest increase in AAA screening among eligible 65-year-old men during the study period, from 7.6% in 2004 to 9.6% in 2008. The SAAAVE Act resulted in no significant differences in the rates of AAA repair, AAA rupture, or all-cause mortality, they concluded.
In an invited commentary, Russell Harris, Stacey Sheridan, and Linda Kinsinger write that the evidence about AAA screening has changed since the 2005 USPSTF recommendations. In the past 10 to 15 years, they write, mortality from ruptured AAA has been cut nearly in half. AAA screening, they maintain, has had little to do with this change; rather, the change is more likely due to long-term trends in the reduction of smoking prevalence and the incidence of MI.
An additional trend over this period is the increased use of endovascular aneurysm repair (EVAR) instead of open aneurysm repair (OAR) in patients with AAA. Although EVAR and OAR have had similar long-term outcomes in randomized trials, in clinical practice EVAR is more likely to be performed in patients with AAAs below the 5.5-cm treatment threshold. The authors also point out that even if patients with small AAAs do not undergo an unnecessary procedure, they may suffer from the “negative psychological effects from diagnosis of small AAAs.”
One of the commentary authors, Russell Harris, was a member of the 2005 USPSTF committee and voted in favor of the screening recommendation. A reconsideration of the guidelines may lead to a tightening of these recommendations, the authors suggest:
Sometimes it takes time to fully understand the effects of a new screening policy within the context in which it is introduced. If AAA mortality is declining without much contribution from AAA screening; if EVAR is a technology that is hard to control; if AAA screening leads to substantial harms by labeling and overdiagnosis, then perhaps it is a good thing that the USPSTF will get a chance to reevaluate its positive recommendation before more and more people develop the habit of screening. The outcome this time may be different.
In the accompanying perspective, Vinay Prasad presents the case history of a 65-year-old former smoker with a history of MI who had a 6-cm AAA. After consultation with his physician and his surgeon Mr. R underwent EVAR. After numerous complications causing significant reductions in his quality of life, Mr. R came to regret his decision. Prasad writes that the case raises several difficult issues:
First, Mr R was appropriately consented for surgery; however, in hindsight he wishes different information were presented to him. The informed consent process is often long and complicated, but it remains unclear if it best communicates what some patients want to know. Second, translating data from RCTs to individual patients, who often differ from those participants in the RCTs, remains an uncertain affair. Third, data are often extrapolated from older studies. The data from the cited screening example were collected between 1997 and 1999, prior to the development of endovascular repair. Finally, how quickly should physicians respond to new data, and are data from only 1 or 2 studies sufficient to change practice?
Further reading: Blue light special: AAA screening at Kmart in the disease-mongering aisle.
September 18th, 2012
International Cardiology Groups Push for Aggressive Public Health Goals
Larry Husten, PHD
Cardiovascular disease is the largest cause of death in the world and accounts for almost half of all deaths from noncommunicable diseases (NCDs). Earlier this year, in response to a high-level UN meeting on NCDs in 2011, the World Health Assembly set a global target to reduce premature NCD mortality by 25% by the year 2025.
Now, the Global Cardiovascular Disease Taskforce, including representatives from the World Heart Federation, the American Heart Association, the American College of Cardiology Foundation, the European Heart Network, and the European Society of Cardiology, have proposed a set of aggressive measures to help achieve this goal.
The Global Cardiovascular Disease Taskforce is urging governments and medical groups to adopt four global targets:
- Reduce the prevalence of insufficient physical activity by 10%
- Reduce the prevalence of hypertension by 25%
- Reduce salt/sodium intake by 30%, with the aim of achieving the recommended level of less than 5 g/day
- Reduce the prevalence of tobacco smoking by 30%
The Taskforce also expressed support for a halt in the increase in obesity and reductions in saturated fat intake, cholesterol, and alcohol (when excessive). The group also called for increased use of drugs to prevent MI and stroke.
“The number of people with CVD is growing and its impact is disproportionately felt by those in the developing world, where people die younger; we now have the opportunity of a lifetime to stem its rise with concerted international action that will help countries tackle the preventable causes of CVD,” said Sidney Smith, Jr., president of the World Heart Federation and chair of the writing group, in a press release.
The Taskforce paper can be downloaded in the journals Global Heart, Circulation, the European Heart Journal, and the Journal of the American College of Cardiology.
September 17th, 2012
Resuming Warfarin After a GI Bleed: Benefits Appear to Outweigh the Risks
Nicholas Downing, MD
Many patients who’ve had a warfarin-associated gastrointestinal bleed can safely resume warfarin therapy soon after the bleeding event, according to an industry-funded, retrospective study in the Archives of Internal Medicine.
Researchers identified some 440 adults who experienced a GI bleed while taking warfarin; nearly 60% either stayed on warfarin continuously or resumed treatment within about a week (median time to retreatment, 4 days). Compared with patients who did not restart warfarin, those who continued or resumed treatment had a significantly lower 90-day incidence of thrombosis (0.4% vs. 5.5%) and death (6% vs. 20%). The most common causes of death were cancer, infection, and cardiac disease.
Patients who continued or restarted warfarin did have more recurrent GI bleeds (10% vs. 6%), but this difference did not achieve statistical significance. None of the recurrent bleeds were fatal.
Archives commentators conclude: “We believe that most patients with warfarin-associated GI bleeding and indications for continued long-term antithrombotic therapy should resume anticoagulation within the first week following the hemorrhage.”
Reprinted with permission from Physician’s First Watch.
