November 15th, 2011
Finding Wisdom in Unfamiliar Ways in a Familiar Place
Amit Shah, MD, MSCR
Several Cardiology Fellows who are attending AHA.11 this week are blogging together on CardioExchange. The Fellows include Revathi Balakrishnan, Eiman Jahangir, John Ryan (moderator), and Amit Shah. Read the previous post here. Check back often to learn about the biggest buzz in Orlando.
Over the years, I have come to value the more subtle ways of learning at AHA — notably, the wisdom gained through relationships and the sharing of knowledge by other researchers. While I perused the posters for much of today, I also spent time with friends, reveling in various intellectual topics of interest. I was somewhat disappointed that I did not attend more sessions. Still, I feel content with the nuggets of knowledge that others shared with me throughout the day, such as:
- Researching and analyzing data from various available cohort studies are intricate tasks. While some databases are relatively easy to obtain for the purposes of conducting new epidemiologic studies, others are nearly impossible to access.
- As difficult as it is to get an abstract accepted at AHA and similar meetings, trying to publish a report based on the abstract has its own inherent difficulties.
- Maintaining a successful business model in modern-day cardiology, particularly for those in private practice, is challenging. One cardiologist noted 3 main concepts (the three “A’s”) for a successful practice — availability (most important), affability, and ability (least important).
- The media look for research that is good fodder, but scientists just want good science.
Whether at the convention center or Epcot, the only way you can really go wrong at AHA is to sit idle and do nothing; so long as you are surrounded by your colleagues, you are bound to find science.
In what ways do you value AHA outside the actual sessions?
November 15th, 2011
SATURN Regression Trial: Gorilla Statin and Statin King Battle to a Draw
Larry Husten, PHD
An epic battle comparing the two most potent statins — the reigning king atorvastatin versus “gorilla statin” rosuvastatin — has ended with a quiet draw. Results of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin Versus AtorvastatiN) were presented at the AHA on Tuesday and published simultaneously in the New England Journal of Medicine.
Stephen Nicholls and colleagues randomized 1039 patients with coronary disease to rosuvastatin or atorvastatin for 2 years and measured the progression of atherosclerosis using intravascular ultrasound (IVUS). As anticipated, after 2 years, lipid parameters were more favorable with rosuvastatin than with atorvastatin:
- LDL: 62.6 mg/dL with rosuvastatin versus 70.2 mg/dL with atorvastatin (p<0.001)
- HDL: 50.4 versus 48.6 mg/dL (p=0.01)
However, there was no significant difference in the percent atheroma volume (PAV), the primary efficacy endpoint, which decreased by 0.99% with atorvastatin and 1.22% with rosuvastatin (p=0.17). A secondary endpoint, normalized total atheroma volume (TAV), significantly favored rosuvastatin (-6.39 mm(3) versus -4.42 mm(3), p=0.01). Regression of atherosclerosis, as measured by both PAV and TAV, occurred in a majority of patients in both treatment groups.
Although the trial failed to find a difference between the agents, “it does show that high-dose, intensive statin therapy can be administered safely and can promote regression of atherosclerotic plaque to a greater extent than has previously been reported,” the authors conclude.
November 15th, 2011
AIM-HIGH: No Benefit for Niacin on Top of Statins
Larry Husten, PHD
The AIM-HIGH investigators aimed for the lofty target of proving the beneficial effects of niacin therapy. They did not succeed. Their findings were presented Tuesday morning at the AHA and published simultaneously in the New England Journal of Medicine.
In AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), 3414 patients with CV disease, low HDL, and elevated triglycerides were randomized to either extended-release niacin or placebo in addition to simvastatin. In the niacin group, HDL increased by 25% and triglycerides decreased by 28.6%. In the placebo group, HDL increased by 9.8% and triglycerides decreased by 8.1%.
Follow-up of the trial was stopped early due to futility. The primary endpoint — the first event of the composite of CHD death, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization — occurred in 16.4% of patients in the niacin group and 16.2% in the placebo group (HR 1.02, CI 0.87-1.21, p=0.79).
More patients in the niacin group than in the placebo group had an ischemic stroke as their first endpoint event (1.6% vs. 0.9%). Although the trend persisted when all ischemic strokes were considered, the investigators note that the overall ischemic stroke rate was low and the imbalance could reflect a “play of chance.” They also observe that similar increases have not been found in previous niacin studies.
Speculating about the lack of niacin’s effect in the trial, the investigators note that the beneficial effects of niacin and gemfibrozil (which also raises HDL) were previously observed in study populations with much higher LDL levels. Aggressive statin therapy, in addition to other contemporary therapies, “may make it difficult to show incremental clinical benefit” from niacin or other new therapies, they write. They add that the true effect of niacin will be definitively assessed in the much larger HPS2-THRIVE study, and that additional studies are underway evaluating other HDL-related therapies.
In an accompanying editorial, Robert Giugliano wonders whether niacin, at 56 years of age, is ready for an early retirement. He writes that the modest difference between the groups of 4-5 mg/dL for HDL would be unlikely to show a large difference in outcomes given the background therapies. He says:
“Given the lack of efficacy shown in this trial, the frequent occurrence of flushing with niacin therapy that some patients find intolerable, and the unresolved question of an increased risk of ischemic stroke, one can hardly justify the continued expenditure of nearly $800 million per year in the United States for branded extended-release niacin.”
Until the final answer about niacin arrives with the HPS2-THRIVE trial, Giugliano endorses a suggestion, proposed in an accompanying perspective by Patricia Maningat and Jan Breslow, that niacin be reserved for statin-intolerant patients.
November 14th, 2011
PALLAS Intrigue: What Role Remains for Dronedarone?
CardioExchange Editors, Staff
When the news broke this past summer that that the PALLAS study of dronedarone (Multaq) for permanent AF had been stopped early, CardioExchange convened a panel to discuss what role remained for this agent. Now that the paper has been published in the New England Journal of Medicine and presented at AHA, we invited the same panelists back to tell us whether their views had changed or warranted elaboration, and whether they are surprised by the current usage of the drug. Here are the responses we received:
The published results of PALLAS only strengthen my negative view of dronedarone. Although PALLAS enrolled a selected cohort of older patients with more advanced heart disease, the data are striking and clear: Taking dronedarone was associated with a greater chance of dying, having a stroke or being unexpectedly hospitalized. That an ion-channel-blocking drug worsens outcomes in patients with heart disease is not a surprise. Think AFFIRM. Or even CAST.
Dronedarone use in the real world is approaching zero quickly. In the past, its inability to suppress AF was the primary reason why doctors stopped using it. Now, its important safety concerns have further accelerated the decline. To doctors who persist in recommending dronedarone, I ask only one question: Would you take it for your AF? I sure wouldn’t.
My original view is unchanged: A basic tenet of treating AF is to avoid making the treatment worse than the disease. Thus, I see no role for dronedarone in the treatment of AF.
In my experience of using dronedarone as a first-line agent for AF prevention, it is mildly to moderately effective. However, it’s understandable that others have found it not very useful if they have chosen to use it after agents such as sotalol, propafenone, and flecainide have been ineffective. It would not be worth trying at all in patients who have failed amiodarone. In my patients, dronedarone has exhibited an unusual pattern of either being very effective or not at all, whereas agents such as flecainide can show gradations of suppression in various patients. It is not clear why this occurs with dronedarone.
The results of the PALLAS study will affect my patient selection for dronedarone. While I was never in favor of doing a study in patients with permanent AF, I understood why others felt differently after the ATHENA results were obtained. After the CAST trial, encainide was withdrawn from the market but flecainide is now a very effective drug to suppress AF in patients with minimal heart disease. I would keep this in mind in assessing dronedarone: In my opinion it is still a reasonable choice for patients with no or minimal heart disease, but it should not be used in those with heart failure or significant LV dysfunction. I would like to see more data on its safety in patients with CAD but good LV function—a population that does not have many options if sotalol is not tolerated. Regardless, this substantially reduces my use of dronedarone.
One additional thought–there are 55 authors on the NEJM manuscript for PALLAS; so much for the concept of victory having a thousand fathers, but defeat being an orphan.
My overall analysis remains unchanged. The published results of PALLAS reinforce the narrow therapeutic window for dronedarone. I couldn’t agree more with the editorialist’s concluding statement that the atrial fibrillation guidelines will need to be reexamined, and that dronedarone should be reserved for selected low-risk patients with nonpermanent atrial fibrillation who fail to respond to other antiarrhythmic drugs.
Since its approval in July 2009 through October 2010, around 492,000 dronedarone prescriptions were dispensed and around 147,000 patients filled dronedarone prescriptions. These numbers are clearly lower than the sponsor’s original estimates, and I suspect, some would argue higher than otherwise justified by its benefit-risk profile.
One final note about PALLAS: Most unexpected findings, especially those that are not clinically sensible, are likely to be false-positive. The hypothesis of PALLAS was based on an unexpected post hoc observation in ATHENA that patients with permanent AF derived benefit with dronedarone. The totality of evidence suggests that patients with permanent AF have no reason to receive antiarrhythmic drugs. Nonetheless, this hypothesis was explored in the PALLAS trial driven mostly by marketing considerations to expand the therapeutic window. Trials should ideally be designed to inform and guide clinical practice, not for marketing reasons.”
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For those of you on the front lines of AF treatment, who among these panelists do you agree with—if anyone?
November 14th, 2011
What’s Up, Interventionally?
Eiman Jahangir, MD
Several Cardiology Fellows who are attending AHA.11 this week are blogging together on CardioExchange. The Fellows include Revathi Balakrishnan, Eiman Jahangir, John Ryan (moderator), and Amit Shah. Read the previous post here. Check back often to learn about the biggest buzz in Orlando.
This morning, Martin Leon gave an exciting talk, “The Future is Now in Coronary Intervention.”He discussed stent technology, the expanding role of interventional cardiologist, and procedures that are currently under study. The most interesting is the possibility to perform angiography to improve erectile dysfunction. The ZEN trial is currently looking at using stents to improve arterial flow; in a small sample of patients (approximately 30), erectile dysfunction improved by 60% at 3 months. For a future interventionalist, this is another exciting new procedure to learn. We can add ED angiography to the already long list of potential procedures, including aortic valve placements and renal nerve denervation.
What emerging interventional procedure do you find most intriguing?
November 14th, 2011
Global CV Health Concerns: Macro and Micro
Eiman Jahangir, MD
Several Cardiology Fellows who are attending AHA.11 this week are blogging together on CardioExchange. The Fellows include Revathi Balakrishnan, Eiman Jahangir, John Ryan (moderator), and Amit Shah. Read the previous post here. Check back often to learn about the biggest buzz in Orlando.
First, a full disclosure: I was a Fogarty International Cardiovascular Fellow last year in Buenos Aires, Argentina.
Okay, now I can write about Early Career: Global Cardiovascular Health Opportunities. Well, actually, another disclosure: I only attended the later sessions, when investigators discussed their research in the developing world from Kenya to Argentina.
While it was interesting to hear what was being done in a small subset of the global health research, I feel that overall the session missed the part about “global health opportunities.” Probably the earlier sessions covered the actual “opportunities,” but I felt that the later sessions were not informing listeners about how to pursue such a career.
Dr. Salim Yusuf’s session was most informative. I truly enjoyed hearing from this successful and insightful mentor and researcher. Now I know how I should approach and present myself to a potential mentor. What was a bit concerning was Dr. Yusuf’s statement that an individual should take at least 10 years to train in research. In our society, one is a clinical instructor for 3 years and an assistant professor maybe for 5 years — the 10-year mark seems long. I am not sure that if you told a fellow that he will have to train 10 years to become a researcher that he would leap onto the physician-scientist track. Still, it is probably true that to become a good researcher requires 10 years and that one cannot be both a great researcher and a great clinician.
Regardless of these criticisms, I was very happy to see a session on global cardiovascular health, a topic that is very dear to me. With globalization, which includes both a urbanization of populations and a change in diet and physical activity, cardiovascular disease is the number one killer in the world, is becoming a major issue in developing countries, and disproportionately affects the low and middle income countries. We need to continue to decrease the burden of disease on these countries. In future years, I hope that this session and these concerns will take a larger and larger part of the program at AHA.
Have you found anything at the AHA that missed the mark?
November 14th, 2011
PALLAS: Poor Results for Dronedarone in Permanent AF
Larry Husten, PHD
After a brief announcement earlier this year that the trial had been terminated early, the full results of PALLAS (Permanent Atrial Fibrillation Outcomes Study Using Dronedarone on Top of Standard Therapy) have now been presented at the AHA and published simultaneously in the New England Journal of Medicine. PALLAS shows that dronedarone (Multaq, Sanofi) should not be used in patients who have permanent atrial fibrillation (AF). The larger question, which the trial can’t answer, is whether anyone else should be taking the drug.
In all, 3236 elderly patients with permanent AF were randomized to dronedarone or placebo. The study was stopped for safety reasons by the data monitoring committee less than a year after enrollment began.
A first coprimary outcome (stroke, MI, systemic embolism, or cardiovascular death) event occurred in 43 dronedarone patients versus 19 placebo patients (HR, 2.29; 95% CI, 1.34-3.94; P=0.002):
- CV deaths: 21 versus 10 (HR, 2.11; 95% CI, 1.00-4.49; P=0.046)
- death from arrhythmia: 13 versus 4 (HR, 3.26; 95% CI, 1.06-10.00; P=0.03)
- stroke: 23 versus 10 (HR, 2.32; 95% CI, 1.11-4.88; P=0.02)
In addition, there were 113 unplanned hospitalizations for CV causes in the dronedarone group versus 59 in the placebo group (HR, 1.97; 95% CI, 1.44-2.70; P<0.001).
The investigators write that although the early termination of PALLAS diminished its statistical power, “the assessment of net harm from dronedarone in patients with permanent atrial fibrillation who are at high risk appears to be sound.”
Seeking to explain the difference in outcome between their study and the positive ATHENA study, the authors noted that patients in PALLAS were older and more likely to have heart failure, coronary artery disease, or stroke. A subgroup analysis, however, did not turn up a worse prognosis for the high-risk patients in PALLAS.
Very few PALLAS participants converted to sinus rhythm. The authors speculated that “for high-risk patients with permanent atrial fibrillation, direct and indirect toxic effects of dronedarone are not offset by the benefit of maintaining sinus rhythm, and any benefits that might occur from heart-rate slowing, blood-pressure reduction, antiadrenergic action, and suppression of ventricular arrhythmia were either small or nonexistent.”
In an accompanying editorial, Stanley Nattel writes that “it is possible” that the adverse effects of dronedarone in PALLAS “were due to the fact that all the participating patients had permanent atrial fibrillation, “but in the final analysis, we can not really know for sure.” Dronedarone, he said, should not be used in patients with permanent AF and should be avoided in high-risk patients with nonpermanent AF, particularly those with heart failure. Use of dronedarone, he writes, should be reserved “for selected low-risk patients with persistent or paroxysmal atrial fibrillation, possibly those in whom other antiarrhythmic drugs have failed.”
November 14th, 2011
Stenosis vs. Stroke: Is Treatment Worth the Risk?
Eiman Jahangir, MD
Several Cardiology Fellows who are attending AHA.11 this week are blogging together on CardioExchange. The Fellows include Revathi Balakrishnan, Eiman Jahangir, John Ryan (moderator), and Amit Shah. Read the previous post here. Check back often to learn about the biggest buzz in Orlando.
On Sunday morning, I feel like the conference has really begun. I am sitting in the Chaplin Theater, a very large auditorium that is about half full of people. They’re waiting to hear various presentations and discussions during the “Groundbreaking Studies in the Cardiovascular Medicine: Circulation Editor’s Choice,” a 3-hour session full of presentations and discussions on topics from dabigatran to transcatheter aortic heart valve implantation (TAVI) to racial and ethical differences in the treatment of AMI.
The TAVI discussion really drew my interest. As a future interventional cardiologist, I believe that treating structural heart disease and using procedures such as TAVI are going to be a large portion of my practice over the next decade. Presenters discussed recent results from the PARTNER B trial that evaluated the use of TAVI in old and fragile patients who were unable to obtain surgery and who had many comorbidities. TAVI showed superior 2-year all-cause mortality compared with conventional surgery (approximately 18% vs. 35%) as well as similarly improved rate of repeat hospitalizations. Despite these benefits, patients in the TAVI arm did have increased stroke risk compared to surgery. These results are both exciting and concerning. While aortic stenosis causes severe comorbidity and mortality, the risk of stroke may be too high for some individuals (over 13% in the TAVI arm).
As a physician, nothing scares me more than causing harm to a patient, especially in the form of stroke. I know this harm well because my grandfather had a devastating stroke in the early 1990s after a CABG. Since his stroke, my grandfather has had aphasia and hemiparalysis. He went from a professor of pharmacology to being dependent on others for his care. Stroke is a known and low risk of many procedures, but its impact is severe both to patients and to their families.
Do you think that a 13% risk for stroke is too high for the treatment of aortic stenosis?
November 14th, 2011
At AHA, the Title Says It All
David Martin, M.D.
. . . or almost. Here are some abstract and session titles that have caught my eye so far:
Nightmares in the Cath Lab. A session where fellows presented cases gone wrong. I missed this one and sorry I did. Wonder if TCT had anything similar.
My Most Challenging Cases: Shock and Awe in the Interventional Suite. Along the same theme — and with presentation titles like Coronary Disaster, Peripheral Disaster, and Structural Disaster — you can only imagine what these talks will be like. I think this shows that despite our reputations, we cardiologists can still be very much humbled by patients, disease, and events.
Future of ACS Care: More Drugs or Less Bleeding. You can guess which side this presenter is on.
Exercise Training Fails to Reduce Blood Pressure in Type 2 Diabetes: A Randomized Controlled Trial. In the midst of publication bias toward positive results, this one stands out. The idea is that diabetes stiffens the arteries beyond what conventional antihypertensive therapies can reverse. Probably should have been accepted as an oral instead of a poster. Hope to see this one in print soon.
A Choice Architecture Intervention Improved Healthy Food and Beverage Choices in a Large Hospital Cafeteria. Lesson: Put unhealthy food in hard-to-reach places. I should implement this in my own kitchen — and we could advise patients to do the same.
Power and Suicide: The Might of Mitochondria in the Heart. Not to be outdone, basic scientists can also come up with punchy titles for their sessions. While I’m not qualified to say much about the research, the number of abstracts on mitochondria makes it look like a burgeoning field.
Some Like It Cool — Seasonal Temperature, As Well As Clinical and Demographic Factors, Predicts Compliance with the Wearable Cardioverter-Defibrillator. Enough said.
Upright T Waves in Lead aVR are Associated with Cardiac Death or Hospitalization for Heart Failure in Prior Myocardial Infarction. Yet another reason not to overlook aVR on the ECG.
Increased Blood Pressure Variability During Early Bereavement. Unfortunately, no surprise.
The Remote Monitoring of Unexplained Syncope in the Elderly. In this small RCT, use of an implantable loop recorder, especially in combination with a syncope clinic evaluation, improved diagnostic yield. I’m guessing we’ll see more research in this area in coming years and, with the aging of the population, there will definitely be a need for it.
Incidence of Amiodarone Hypersensivity Reaction in Hospitalized Patients with Prior Allergic Reaction to Iodine or Iodinated Contrast. Guess what, it’s actually less than 1%. Nice pearl.
Effect of Dietary Intake of Kiwi Fruit on 24-Hour Ambulatory Blood Pressure. Reportedly, 3 kiwis a day lowers BP more than an apple a day, potentially due to high concentrations of lutein (an antioxidant). Anyone who can stick to eating 3 kiwis a day for 8 weeks likely has the discipline to do a lot of things. On this one, New Zealanders will obviously have a head start.
Did other presentations (and their titles) stand out for you at this AHA? I’m sure many more pearls, lessons, and interesting tidbits are out there.
November 14th, 2011
“The Center Where It All Happens”
Reva Balakrishnan, MD, MPH
Several Cardiology Fellows who are attending AHA.11 this week are blogging together on CardioExchange. The Fellows include Revathi Balakrishnan, Eiman Jahangir, John Ryan (moderator), and Amit Shah. Read the previous post here. Check back often to learn about the biggest buzz in Orlando.
For this first-year fellow, the AHA has seemed at times like the “light at the end of the tunnel” — although it is only one third of the way through my first year. Deep in the trenches of first-year fellowship, just when it seems like my time is consumed with adapting to call (STEMI page = palpitations) or learning the technical nuances of echo (that darned apical 2 chamber!), this time away has allowed me to take a step back and reflect on where I started out not so many months ago and on where I may want to go with my career.
I was excited Saturday to get a glimpse of what this conference has to offer, but became overwhelmed when browsing the 500+ page program to plan my day. Luckily, I found the conference planner app, which conveniently filters the days by core tracks and topics of interest.
Although the late-breaking sessions are typically the primary focus of interest for attendees, my curiosity was piqued by the concurrently scheduled young investigator oral abstract sessions. How did these presenters begin their careers, and how much further do they need to go to get to where they want to be? If I wanted to, could I traverse that same path? I hope I can find the answer to this question in my own time.
Today, a senior co-fellow told me that being at the late-breaking sessions is an amazing experience, like “being in the center of where everything happens” — and I am excited to finally be a part of it.
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