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November 19th, 2013

Does It Matter that I Miss Another Late-Breaking (“Heart-Breaking”) Session at AHA?

Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal RamjeeSiqin YeSeth MartinReva Balakrishnan, and  Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.

As I sit on the plane flying back to New York well aware that I am missing the rest of the AHA conference, I ask myself if I really am missing out.

Besides the fact that I came with a group of wonderful co-fellows who are now likely enjoying some delicious Texas barbecue without me, I’ll also be missing another late-breaking session and the highly anticipated Prevention guidelines session (did they really have to save that for the last day?).

Given that the majority of the late-breaking sessions were somewhat disappointing (is there anything that will ever work for HFPEF?) which seems to have been a trend for the past 2 conferences, it seems like the conference organizers should change the name from “late-breaking sessions” to “heart-breaking sessions.” I understand that results from negative trials can be just as important as ones from positive trials in advancing the practice of evidence-based medicine, but there is something to be said for the excitement of being in the presence of the first announcement of an exciting new discovery.

Attendance overall seemed more sparse this year compared to the previous year. I remember the first time I attended the AHA conference (the year before I started fellowship) — there were so many people in attendance that popular session rooms would often overflow into other rooms where you were relegated to watching the presentation on a TV with a headset. This year, most sessions I attended had an abundance of empty chairs.

So what will keep me coming in the future? I appreciate the feeling of camaraderie in a shared learning environment; the ability to find inspiration in exciting new ideas; and the opportunities of meeting people with shared interests and goals. This year the Go Red for Women networking lunch was a great opportunity to hear from women in all phases of their careers and to gain valuable advice; I wish I had discovered it earlier. As I transition from a fellow to the “real world,” I plan on continuing to attend these conferences for these very reasons.

I think that fellows initially have difficulty with navigating the overwhelming options for learning and networking at these conferences. Some comment on the feeling that they are always “missing out” on something – and then all of a sudden the conference is over. The FIT events the first day temper this somewhat, but if there were more of a structure to the “early career” pathway for the rest of the conference, perhaps younger fellows and those early in their careers would be more encouraged to participate and attend.

What do other fellows think about this? Do you have similar impressions of the usefulness and difficulties of these conferences?

November 18th, 2013

Super-Cells & Chimeras: Mission Impossible 5 or Transformative Approaches to New Heart?

Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal RamjeeSiqin YeSeth MartinReva Balakrishnan, and  Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.

Wow – I was in the late afternoon, late-breaking basic science talks not too long ago, and the only word that comes to mind is: Wow!

Just when you think you’ve heard it all, a whole new set of transformative approaches to regenerate heart is brought to the table. This afternoon, Mark Sussman and Sean Wu, in particular, wow-ed me with their new ideas in addressing regenerative approaches.

Dr. Sussman stunned the audience with the Powerpoint-equivalent of a chalk-talk, in which he underscored the slow rate of progress in wielding the power of stem cells and the need for transformative out-of-the-box approaches. His group at San Diego State University has worked hard to create two novel tools that may be a first step in that direction: CardioChimeras and CardioClusters.

CardioChimeras are essentially super-cells that are comprised of multiple cell lines that have been induced to fuse into a single cell with synergistic reparative potential. Thus far, his group has fused c-kit positive cardiac progenitor cells with bone marrow mesenchymal stem cells. CardioClusters play off a similar concept of recapitulating the native heterogeneous niche, but do not use fusion technology. Instead, they are hundreds of cells (like those above) engineered into a bundle surrounded by endothelial cells. They are structurally undamaged when injected through needles, but results regarding efficacy in animal models are still pending. Perhaps this is something we can look for at the next meeting.

Dr. Wu ended the session with an eye-opening approach of using chimera technology to grow human hearts in animals and then have them available for transplantation. Dr. Sussman brought up the important point of immune reaction as a result of the chimera organ in the host animal, and Dr. Wu assured that based on his findings thus far that it is not a concern.

Both approaches are exciting and transformative. I do wonder whether having so many disparate approaches being considered (at least half a dozen if you sort them conservatively) is a good or bad thing. Perhaps it would be better to have all of our top-tier scientists work together to resolve the most promising one or two approaches.

What do you think of this potentially transformative research and the number of disparate approaches?

November 18th, 2013

How to Have a Solid Foundation in Clinical Research and Data Analysis

Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal RamjeeSiqin YeSeth MartinReva Balakrishnan, and  Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.

Several early-career individuals have been confounded by the question of how to get a good foundation in the basics of handling and analyzing data to arrive at meaningful and relevant conclusions. Having been tormented by this difficulty and, to this day, needing more experienced and advanced counsel, I thought a primer on how to set oneself up for a career in clinical research would help other fellows.

I had the chance to talk one-on-one with Dharam Kumbhani, MD, SM, MRCP, of UT Southwestern in Dallas, who has dispensed similar advice over the years and who has had a productive career in outcomes research. He is also the Clinical Trials Team Leader of Cardiosource.org, the educational portal of the American College of Cardiology, where he  reviews many late- breaking clinical trials and presents his perspective on the pluses and minuses in a forum widely read by the academic cardiology community. He recently won the Junior Faculty award at the Northwestern University Young Investigator Forum.

In 2004, he had written an essay for Student BMJ suggesting formal training in quantitative methods before initiating clinical training — especially for folks interested in research. I think a few snippets of his advice may be of significant benefit for the “recently initiated.”

After graduating from one of the top medical schools in India, Dharam opted for a path less traveled — he decided to pursue a masters in epidemiology and quantitative methods from the Harvard School of Public Health. His years as a post-doctoral research fellow at Harvard provided him with a solid grounding in outcomes research that enables him to analyze and produce high-quality manuscripts using large administrative and population datasets. This endeavor was ongoing during his internal medicine training at University of Pennsylvania, his cardiology fellowship at the Cleveland Clinic, and his interventional cardiology fellowship at Brigham and Women’s Hospital/Harvard Medical School. The rigorous training in epidemiology has enabled him to formulate search questions, identify potential datasets for testing the hypothesis, and collaborate with interested researchers across the country, efforts that have culminated in the production of widely read and cited manuscripts.

For early-career individuals interested in research, what do you find confounding in your career path? For more established clinical researchers, what advice do you wish that you had received?

November 18th, 2013

The Best Way to Spend a Morning at AHA?

Several Cardiology Fellows who are attending AHA.13 in Dallas this week are blogging for CardioExchange. The Fellows include Vimal RamjeeSiqin YeSeth MartinReva Balakrishnan, and  Saurav Chatterjee. You can find the previous post here. For more of our AHA.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our AHA.13 Headquarters.

For the past two mornings at the Scientific Sessions, the poster sessions have been a highlight for me. Even without a strategic location in the Exhibit Hall (as at ACC) and without any lattes in sight, the poster sessions were buzzing.

Although I did present a poster, I was much more proud to see first-time AHA presentations by two residents whom I have worked with. Kris Swiger and Mo Al-Hijji did a fabulous job presenting their work from the Very Large Database of Lipids at the session titled “Lipoprotein Metabolism: Clinical and Population Studies.” Like other presenters at the session, they examined the topics of HDL cholesterol and gender differences, but what I want to elaborate upon is not all the details of the science. A short blog cannot do the science justice.

What I do want to say is that these poster sessions are exactly what will keep me coming back to AHA. I moved from circle of people to circle of people, engaging in topics ranging from interpretation of data, to additional analyses on a particular project, to the new guidelines, to job hunting. The poster sessions bring together scientists at all stages of their careers to exchange ideas, provide or receive mentorship, and discuss cardiovascular science. What better way is there to spend your morning?

I have heard it suggested that with modern technology, these meetings could — almost entirely — happen online. Some have wondered whether any need remains to incur the time, expense, and jet fuel for us all to travel to the same city each year for AHA. I’d say that while teleconferences and video conferences are great and essential to scientific collaboration, nothing replaces the face-to-face interactions that occur here at the Scientific Sessions, especially in the poster hall.

What keeps you coming back to the AHA?

November 18th, 2013

No Evidence That Statins Impact Cognitive Function

In 2012 the FDA revised the label of statins to include a warning about reports that the drugs had been linked to memory loss or confusion. The FDA action appeared to be based largely on case reports. Despite concerns about this topic that have appeared sporadically in recent years, no high-quality review of the topic has appeared until now. In a paper published in Annals of Internal Medicine, Karl Richardson and colleagues report on a systematic review of the literature to assess the effect of statins on cognitive function.

The authors reviewed 25 trials, including randomized, controlled trials and cohort, case-control, and cross-sectional studies, that evaluated cognition in patients taking statins.

Their review found little evidence to support any adverse effect on cognitive function:

“… low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance in procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment, nor any change in cognitive performance related to global cognitive performance scores, executive function, declarative memory, processing speed, or visuoperception.”

In a second analysis of the FDA post-marketing surveillance databases, the investigators found similar reporting rates for cognitive-related adverse events for statins and two other widely used drugs, losartan and clopidogrel.

The reviewers noted, however, that much of the data were not high quality and, in particular, there was a sparsity of data for high-dose statins, which are increasingly used.

They concluded that the available evidence does not support concerns linking statin use to cognitive impairment. “Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition.”

 

November 18th, 2013

AHA.13 Headquarters

CardioExchange is dedicated to bringing you the latest from AHA.13. Check out our coverage of the conference ─ and some of the great debates these posts have sparked ─ then tell us what you think!

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November 18th, 2013

Selections from Richard Lehman’s Literature Review: November 18th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

NEJM 14 Nov 2013 Vol 369

Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy (pg. 1892): Blockade of the renin-angiotensin-aldosterone system has been one of the therapeutic triumphs of the last 30 years. Or has it? It has certainly brought in tens of billions of dollars in profit to drug companies. For patients with systolic heart failure, ACE inhibitors, or ARBs can bring about modest improvements in survival for some patients, though we do not know how these drugs would compare with, say, the old aldosterone blocker spironolactone used in low doses as first-line treatment. ARBs and ACE inhibitors also provide extra options for the treatment of high blood pressure, but they seem less effective at preventing stroke than thiazide diuretics. And they reduce albuminuria in diabetes, but there is only weak evidence that they confer any greater protection against end-stage renal failure than other BP lowering agents. Despite three decades of hype, I suspect the world would not be much different without them. As for combining ACE inhibitors with ARBs in diabetic patients with albuminuria, don’t go there: the VA NEPHRON-D trial reported here is only one of three which has been stopped early for harm, despite reducing albumin excretion in these patients. A mournful editorial observes that ” The results suggest that improvement in surrogate markers—lower blood pressure or less albuminuria—does not translate into risk reduction. Does this invalidate the relatively new risk marker albuminuria and the classic risk factor blood pressure as therapeutic targets in our patients with type 2 diabetes?” Well, yes, actually. There are no short cuts. With every single agent, you need to find out what happens to patients.

Publication of Trials Funded by the National Heart, Lung, and Blood Institute (pg. 1926): Failure to publish the results of clinical trials is a breach of medical ethics, argued Iain Chalmers over 20 years ago, and I agree. In a BMJ editorial a couple of years ago I suggested it should be a matter for disciplinary action. And this doesn’t by any means apply just to the pharmaceutical industry. In this paper, researchers from within the US National Heart, Lung, and Blood Institute (NHLBI) Division of Cardiovascular Sciences look at the publication of reports from research funded by their institution. At 30 months after data collection was complete, only 57% of the trials had been published. Fortunately this figure included most of the most heavily funded trials with patient important outcomes.

JAMA Intern Med 11 Nov 2013

Sex Differences in ACS Symptom Presentation in Young Patients (pg. 1863): Medical lore has it that women with myocardial infarction are more likely than men to present without typical chest pain, and this is confirmed in this study which looked at the presentation of MI in 1015 patients aged 55 or less: 19 % of women presented without chest pain compared to 13.7% of men. “Patients without chest pain reported fewer symptoms overall and no discernable (sic) pattern of non–chest pain symptoms was found.” But then the authors suggest that “Strategies that explicitly incorporate assessment of common non–chest pain symptoms need to be evaluated.” I don’t see how that can be done if they follow no discernable (sic) pattern. But you must be patient and wait for the Yale VIRGO study, if you want to know everything that can be known about the presentation of MI in younger women.

Intensive Glucose Regulation in Hyperglycemic ACS (pg. 1896): The Less is More article this week provides one more piece of evidence that when patients coming into hospital with acute coronary syndrome have hyperglycaemia, you do more harm than good if you try to control their sugar within tight limits. Many previous studies (which I haven’t commented on) have shown this, and here it is demonstrated in a single-centre, prospective, open-label, randomized clinical trial in a large teaching hospital.

Lancet 16 Nov 2013 Vol 382

Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II) (pg. 1638): Here is a paper which has got into The Lancet but would have been equally at home in JAMA Intern Med‘s excellent Less is More series. The German IABP-SHOCK II trial recruited patients with cardiogenic shock complicating acute myocardial infarction, who were undergoing early revascularisation and receiving optimum medical therapy. Half of them were randomized to receive intra-aortic balloon pump (IABP) circulatory support. This gave cardiologists something to do while these very sick patients either died or survived, but it did not make any difference to 30-day mortality. This study confirms that there was no all-cause mortality benefit at 12 months either.

 

November 18th, 2013

No Value for Renal-Artery Stenting in CORAL

Previous small studies have failed to find any benefit associated with renal-artery stenting, but the trials have been small and were not powered for clinical outcomes. Now, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial, presented at the American Heart Association meeting and published simultaneously in the New England Journal of Medicine, offers strong and persuasive evidence that renal-artery stenting is not beneficial.

A total of 947 patients with renal-artery stenosis and either systolic hypertension, despite taking two or more antihypertensive agents, or chronic kidney disease were randomized to medical therapy plus stenting or medical therapy alone. There were no significant differences after 43 months in the primary composite endpoint of cardiovascular and renal events (death from cardiovascular or renal causes, MI, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy):

  • 35.1% for  patients in the stent group versus 35.8% for patients in the medical-treatment group (HR 0.94, CI 0.76-1.17, p=0.58)

There were also no significant differences in the individual components of the endpoint or in any of the major subgroups. There was a small but significant difference in systolic blood pressure, favoring the stent group (-2.3 mm Hg, CI -4.4 to -0.2, p=0.03).

“Beyond A Reasonable Doubt”

In an accompanying editorial, John Bittl writes that the trial “establishes beyond a reasonable doubt that renal-artery stenting is futile for the target population enrolled in the study. Patients who have atherosclerotic disease with a mean renal-artery stenosis of 73%, as assessed visually on angiography, in addition to hypertension while receiving two or more antihypertensive drugs or stage 3 chronic kidney disease, should not undergo renal-artery stenting, because the only tangible consequence is the procedure-related risk of bleeding or vascular complications.”

Bittle notes that although CORAL included patients with stenoses as low as 60%, the results were no different in the subgroup of patients with stenoses of at least 80%. This finding “suggests that a benefit of renal-artery stenting even for patients with fairly severe disease is difficult to predict.”

CardioExchange’s Rick Lange and David Hillis ask whether CORAL should lead clinicians to stop screening for renal artery stenosis. Join the conversation.

November 18th, 2013

What’s the Moral from CORAL?

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The Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study has shown that when added to a background optimal medical therapy, renal artery stenting provides no incremental benefit in people with atherosclerotic renal artery stenosis and either hypertension or chronic kidney disease. Specifically, renal artery stenting did not reduce the composite endpoint of death from cardiovascular or renal causes, MI, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for dialysis. Further details are available in CardioExchange’s news coverage of CORAL.

Given these findings, should we stop screening for renal artery stenosis? Why or why not?

November 18th, 2013

Controversy Erupts Over Accuracy of Cardiovascular Risk Calculator for Guidelines

In the face of a highly critical story in the New York Times by Gina Kolata about the new cardiovascular guidelines, authors of the guidelines and leaders of the American Heart Association (AHA) and the American College of Cardiology (ACC) defended the value and integrity of the guidelines.

The Times story claims that the cardiovascular risk calculator used to assess individual risk in the new guidelines is deeply flawed: “In a major embarrassment to the health groups, the calculator appears to greatly overestimate risk, so much so that it could mistakenly suggest that millions more people are candidates for statin drugs.” The story quotes former ACC president Steve Nissen: “It’s stunning. We need a pause to further evaluate this approach before it is implemented on a widespread basis.”

But the guideline authors and AHA/ACC officials strenuously defended the guideline at a news conference Monday morning at the AHA meeting in Dallas. They said the new risk calculator is far superior to previous efforts, incorporating far more data that now includes stroke assessment and, for the first time, provides specific predictions for African Americans.

The assembled officials rejected any call to delay implantation of the guidelines, but one author, Donald Lloyd-Jones, said that “over time we will modify the risk scores so that they get better and better.”

“We think we’ve done our due diligence,” said AHA president Mariell Jessup. “We have faith and trust in the people who developed the guidelines.”

The Times story is based on a commentary scheduled for publication in the Lancet on Tuesday that is highly critical of the new calculator. The paper, written by Harvard Medical School’s Paul Ridker and Marcia Cook, states that the calculator overpredicts risk by 75% to 150%. At a hastily assembled meeting on Saturday night at the AHA meeting in Dallas, Ridker presented his findings to leaders of the AHA and ACC.

One source of confusion is that Ridker and Cook had sent their criticism to the National Institutes of Health’s National Heart, Lung, and Blood Institute (NHLBI) a year ago, but, according to Kolata, their concerns were never passed on to the AHA and the ACC. At the Saturday night meeting Ridker presented data showing that the risk calculator calculated much higher risk for the population of people who had been followed in three large studies: the Women’s Health Study, the Women’s Health Initiative, and the Physician’s Health Study. Kolata writes:

“…the calculator overpredicted risk by 75 to 150 percent, depending on the population. A man whose risk was 4 percent, for example, might show up as having an 8 percent risk. With a 4 percent risk, he would not warrant treatment — the guidelines that say treatment is advised for those with at least a 7.5 percent risk and that treatment can be considered for those whose risk is 5 percent.”

In a draft of the Lancet article I obtained, Ridker and Cook write:

“…it is possible that as many as 40 to 50 percent of the 33 million middle-aged Americans targeted by the new ACC/AHA guidelines for statin therapy do not actually have risk thresholds exceeding the 7.5 percent level suggested for treatment. Miscalibration to this extent should be reconciled and addressed in additional external validation cohorts before these new prediction models are widely implemented.”

But, according to the guideline authors, Ridker’s position is not new and is discussed in the guidelines. The people included in the three trials presented by Ridker are unusually healthy and are “not really representative of the broad risk,” said Lloyd-Jones. “So it doesn’t surprise me at all that our equations overestimate risk in these groups.” He also said that he thought the overestimation of risk was largely because patients with the highest risk were already taking risk-reducing statins.

AHA president Mariell Jessup said that she wished “there had been this much attention in the past when we used prior risk calculators. If you were an African American and had a stroke” the guidelines didn’t help.

Lipid panel co-chair Neil Stone said that  7.5% is not “an absolute cutoff. This is not the end of the discussion, it’s the start of the discussion.”

Press Conference