March 22nd, 2012
ACC 2012 at Chicago: Hosting the World
John Ryan, MD
Welcome to Chicago
Chicago is a great conference city. At least that is what my friends tell me, and since I moved to Chicago, quite a few conferences have been held.
However, hosting a conference in one’s own town proves difficult. First of all, because of the convenience of not having to travel, one typically does not free up time, and work combined with conference attendance can quickly overwhelm a schedule.
For me, this year’s conference is going to be particularly busy because on Sunday, the Annual Shamrock Shuffle is being held — an 8k charity run through downtown Chicago, which will not only interfere with traffic around the convention center but also require me to burn some calories after fine dining the night before.
Also this year, we have the CardioExchange Board review meeting at Spiaggia, home to Top Chef runner-up Sarah Grueneberg. You can learn more about the event here.
Then, of course, there’s the meeting itself.
Conference Preview
Within the meeting, there are many events to look forward to. For information on late-breaking sessions, go here.
Two-year results from PARTNER-A will be presented, as this nonsurgical option begins to be unrolled around the country.
Already during my fellowship, several studies have been published comparing PCI and CABG in multivessel disease. This issue will be addressed once more with results coming from the ASCERT database, which is focused on high-risk patients.
Some more information on novel anticoagulants will be presented, possibly extending the roles that can be played by rivaroxaban (studied in pulmonary embolism in EINSTEIN PE) and vorapaxar (studied in heart attack and stroke prevention in TIMI 50).
There will also be fellow-focused events being held throughout the meeting, in particular a Mix & Mingle event on Saturday from 3:30-4:30 p.m. in Bistro ACC, where fellows can meet with various leaders in the field.
A Guide for Novices
Check out previous posts on the experience of being a first-time presenter (here and here).
Last November, Dr. Thomas Ryan gave a great historical perspective on medical meetings (focused on the AHA) and offered excellent advice for how fellows should break down their time.
For a previous meeting in Chicago, I listed plentiful options for a great Chicago meal.
Finally, at the very launch of CardioExchange, James de Lemos offered a useful overview for how cardiology fellows can get the most out of conferences.
It is going to be a busy couple of days, but all in all, I am proud of the enthusiasm that visitors have for attending conferences in Chicago.
March 22nd, 2012
Uncertainty Over the Clinical Importance of the Diabetes Risk of Diuretics and Statins
Harlan M. Krumholz, MD, SM
With all of the hullaballoo about statins and diabetes last week I wanted to point out a paper that was published online this week in Circulation: Cardiovascular Quality and Outcomes. This study examined the long-term effects of incident diabetes on cardiovascular outcomes in patients enrolled in ALLHAT. As you may remember, this trial included more than 20,000 subjects and compared different strategies to treat hypertension. They reported that chlorthalidone therapy was associated with a lower risk of clinical cardiovascular outcomes than amlodipine and lisinopril. As expected, incident diabetes was higher in the chlorthalidone group, a known adverse effect of thiazide diuretics.
In this study the authors show that incident diabetes in the chlorthalidone group conferred less risk of CHD outcomes than incident diabetes for those on lisinopril or amlodipine. In other words, although more subjects developed diabetes in the chlorthalidone group, incident diabetes was more benign in this group. The follow-up period was almost 7 years. They conclude that concerns about incident diabetes in those treated with thiazide diuretics should not inhibit its use. While I am sure that this study will not put to rest concerns about thiazide-associated incident diabetes, it does raise questions about whether the blood glucose elevation in these patients really confers much risk. And the outcomes in this study – the outcomes that patients actually experience – did favor the diuretic group. This may have relevance for the statin story – in which the trials show strong benefits for outcomes that patients’ experience – and there is uncertainty about the clinical importance of the elevation in blood glucose. The FDA expressed the same uncertainty.
March 20th, 2012
Meta-Analysis Adds New Evidence for Cancer Benefits of Daily Aspirin
Larry Husten, PHD
Although daily aspirin was originally proposed to reduce cardiovascular events, aspirin’s effects on cancer have become increasingly apparent while the vascular benefits, especially in primary prevention, have become less clear. Now a meta-analysis in the Lancet adds important new details to our understanding about the effects of aspirin and increases the evidence in support of a long-term beneficial effect in preventing cancer.
Peter Rothwell and colleagues analyzed data from 51 primary and secondary prevention trials including more than 80,000 patients. They report several key findings
- Daily aspirin reduced deaths from cancer by 15% (p=0·008).
- After 5 years, there was a particularly striking 37% reduction in cancer deaths (p=0·0005), which largely accounted for a reduction in nonvascular deaths overall (p=0·003).
- Aspirin was associated with an initial reduction in major vascular events, but this was offset by increases in major bleeding. With longer follow-up, the vascular effects diminished, so that after 3 years only the reduced risk for cancer was significant.
The authors write that “in view of the very low rates of vascular events in recent and ongoing trials of aspirin in primary prevention, prevention of cancer could become the main justification for aspirin use in this setting…”
In an accompanying comment, Andrew Chan and Nancy Cook point out that the meta-analysis did not include the two largest primary prevention studies, the Women’s Health Study and the Physician’s Health Study, because they used alternate-day aspirin rather than daily aspirin. Both trials failed to find an effect on cancer. Nevertheless, they write, the researchers “show quite convincingly that aspirin seems to reduce cancer incidence and death across different subgroups and cancer sites, with an apparent delayed effect.
“For most individuals, the risk-benefit calculus of aspirin seems to favour aspirin’s long-term anticancer benefit,” they state. However, current evidence does not support “a definitive conclusion about population-based recommendations regarding routine use of aspirin for cancer prevention.” They conclude that in the future, guidelines “can no longer consider the use of aspirin for the prevention of vascular disease in isolation from cancer prevention.”
March 19th, 2012
Questions Raised About Antiplatelet Therapy in Chronic Kidney Disease
Larry Husten, PHD
Many people develop chronic kidney disease (CKD) as they grow older, and many people with CKD take antiplatelet agents to prevent cardiovascular events. However, the efficacy of antiplatelet therapy in CKD has not been examined, despite the fact that people with CKD are more likely to die from nonatherosclerotic conditions and are more likely to have bleeding complications due to antiplatelet agents.
In a systematic review and meta-analysis published in the Annals of Internal Medicine, Suetonia Palmer and colleagues examined data from trials that enrolled nearly 10,000 CKD patients with ACS and nearly 12,000 CKD patients with stable or no cardiovascular disease.
- In the ACS group, the investigators found that antiplatelet therapy — either glycoprotein IIb/IIIa inhibitors or clopidogrel, increased the risk for serious bleeding but had little or no effect on overall mortality, CV mortality, or MI.
- In the non-ACS group, the investigators found that antiplatelet agents helped prevent MI but had an “uncertain” effect on mortality and increased minor bleeding.
In both groups, the investigators acknowledged that the evidence was of “low or very-low quality.” They concluded that “bleeding hazards and lack of clear efficacy in reducing cardiovascular morbidity and mortality need to be acknowledged when patients with CKD are being counseled about acute or long-term antiplatelet therapy.”
March 19th, 2012
Merck Drops Development of Oral Vernakalant for Atrial Fibrillation
Larry Husten, PHD
Merck has discontinued its development of oral vernakalant for the long-term prevention of atrial fibrillation (AF) recurrence. Cardiome Pharma, Merck’s partner in the drug, said today that the “decision was based on Merck’s assessment of the regulatory environment and projected development timeline.”
Merck and Cardiome will continue their partnership with the intravenous formulation of vernakalant, Brinavess, which is approved in 37 countries outside the U.S. for the rapid conversion of recent-onset AF.
March 19th, 2012
Selections from Richard Lehman’s Literature Review: Week of March 19th
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.
Week of March 19th
NEJM 15 March 2012 Vol 366
Percutaneous Patent Foramen Ovale Closure (pg. 991): In my last year as a proper GP, I presented two cases from my practice of young women who had suffered cryptogenic stroke and had been found to have patent foramen ovale. OK, foramina ovales. I gathered together myself and a GP partner and a local stroke doctor and some interventional cardiologists from Oxford, and we had a high old time congratulating ourselves on our diagnostic acumen while the receptive audience admired real-patient videos showing the technical wizardry of percutaneous PFO closure. Clearly, we had saved these ladies from the dangers of recurrent stroke by the timely deployment of sophisticated interventions based on impeccable mechanistic insight. But even during the presentation, there was a slight feeling of unease when the evidence base for this presumption was interrogated: PFOs can be found in 25% of the population and there didn’t seem to be an adequately powered study to compare device closure of PFOs with medical therapy. Well, now there is, with a follow-up period of two years, and there is no difference in outcomes so far. So while I was trying for one last time to share some of the glamour of sophisticated sexy medicine, perhaps all that these patients needed was what I had tried to provide them with for the whole of my working life – good primary care.
Arch Intern Med 12 Mar 2012 Vol 172
Dabigatran Risks (pg. 397): About ten years ago, I advised you to train your larynx to pronounce the word ximelagatran, the name of the first direct thrombin inhibitor which seemed poised to replace warfarin for numerous clinical indications. If you followed my advice, you abraded your vocal cords and twisted your palate to no avail, since the drug was withdrawn in 2006 following reports of hepatotoxicity. Its successor dabigatran is easier to pronounce, works well at a fixed dose, and generally seems harmless to the liver. Boehringer Ingelheim seemed to have a winner on its hands. But alas, a cloud no bigger than a man’s hand has appeared on the horizon. Here is a meta-analysis which shows that dabigatran is associated with an increased risk of MI or ACS in a broad spectrum of patients when tested against different controls, and that is not something one likes to hear about a drug designed for long term thromboprophylaxis.
March 16th, 2012
Helping Patients Understand the Statins Controversy
Harlan M. Krumholz, MD, SM
After the Topol op-ed in the New York Times last week I began to get a lot of inquiries about the safety of statins. At the beginning of his piece he emphasizes that our use of statins could cause a “sharp increase in the incidence of Type 2 diabetes.” At the end, he states emphatically that “the problem of statin-induced diabetes cannot be underplayed.” Many patients reading these words were worried about their decision to take statins. I decided to write a missive to patients to help them sort through all the information about statins– and to help them in their decisions about treatment. I told them that there were five things that they needed to know:
- It is your decision.
- Statins reduce risk.
- Statins have risks.
- Your risks matter.
- Minimize your statin risk.
You may find it useful for your patients. The title is Five Things You Need to Know When Deciding on a Cholesterol Lowering Drug. Feel free to share your thoughts about it – or to use it if you think it may be helpful to you.
March 15th, 2012
Strongest Evidence to Date for Causative Role of Inflammation in Heart Disease
Larry Husten, PHD
Two large new meta-analyses published in the Lancet provide the first strong evidence demonstrating a cause-effect relationship between a specific inflammatory protein and the development of coronary heart disease (CHD). Both studies illuminate the role of interleukin-6 receptor (IL6R) by focusing on the common Asp358Ala variant of the IL6R gene. The variant is known to dampen the inflammatory effect of IL6R.
In one study, members of the IL6R Genetics Consortium Emerging Risk Factors Collaboration found that Asp358Ala was present in 39% of the population and was not significantly related to other risk factors. 358Ala increased concentrations of IL6R and decreased concentrations of CRP and fibrinogen. Notably, each copy of 358Ala was associated with a 3.4% reduction in the risk for CHD.
In the other study, members of the Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium performed a Mendelian randomization to analyze the impact on CHD of tocilizumab, an anti-inflammatory monoclonal antibody that blocks IL6R, in patients with rheumatoid arthritis (RA). They found that the effect of the 358Ala variant was similar to the effect of tocilizumab in RA trials and resulted in increased levels of interleukin-6 and decreased levels of CRP and fibrinogen. The investigators also observed a significant reduction in the risk for CHD in a second analysis of more than 25,000 people with CHD and 100,000 controls. They conclude that IL6R signaling appears to “have a causal role in development” of CHD and that “IL6R blockade could provide a novel therapeutic approach to prevention” of CHD.
In an accompanying comment, S Matthijs Boekholdt and Erik SG Stroes write that the presence of inflammation in atherogenesis has long been recognized, but it has been difficult to establish a causative role. Although CRP has been shown to predict risk, an earlier Mendelian randomization analysis failed to establish a causative role. Further, they note, “there is currently no evidence to show that selective targeting of inflammatory pathways modulates cardiovascular risk.” The consistent results of the two Lancet papers, they write, “lend strong support to the concept that inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk.”
Paul Ridker offered CardioExchange the following perspective on the studies:
The new studies are both very important for the inflammatory hypothesis of atherothrombosis, as they provide clear linkage between IL-6, its receptor, and clinical events. Moreover, the new data provide confirmatory evidence to consider agents that alter the IL-6 pathway as potential therapeutic agents. As one example, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) that my group coordinates is evaluating a novel monoclonal antibody that targets IL-1-beta and results in lower levels of fibrinogen, CRP, and IL-6. CANTOS is underway in 25 countries and is a hard outcomes trial in secondary prevention. So this field is becoming very exciting and the new data support the concept of lowering inflammation to potentially lower vascular risk.
CardioExchange editor Rick Lange generously offered his own summary and analysis of the papers:
Despite strong evidence associating inflammation with atherosclerosis, a causal role for C-reactive protein or fibrinogen in atherogenesis has remained highly controversial, especially since inflammation is linked with other conditions (i.e., obesity, hypertension, dyslipidemia, diabetes, smoking, etc.) that are known to increase cardiovascular risk. In addition, Mendelian randomization analyses showed that variants in the gene for C-reactive protein associated with high concentrations of the protein were not associated with risk of coronary heart disease, making a causal role for C-reactive protein itself in atherogenesis less likely. Lastly, there is currently no evidence to show that selective targeting of inflammatory pathways modulates cardiovascular risk.
The 2 Lancet studies report data from individuals with genetic abnormalities in the inteleukin-6 receptor gene (ILR6) that lead to reduced concentrations of the membrane-bound form of interleukin 6 (i.e., hence reduced activation of the inflammatory pathways in hepatocytes, monocytes and macrophages that are upstream of C-reactive protein). This genetic difference lead to (a) an anti-inflammatory effect (lower serum levels of C-reactive protein and fibrinogen) and (b) a reduction of coronary heart disease (3.4% to 5% per-allele reduction) and (c) no change in BP, lipids, obesity, hyperglycemia or smoking). So this is the strongest evidence to date that inflammation has a causative role in cardiovascular disease. Whether or not inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk is a separate issue, since anti-inflammatory strategies may increase the risk of infection or malignancy.
March 15th, 2012
Hospital Readmission Calculator? There’s an App for That!
Harlan M. Krumholz, MD, SM
Last year our group at Yale posted online a readmission calculator for patients hospitalized with AMI, heart failure and pneumonia. The calculator was based on medical record chart models developed for the Centers for Medicare and Medicaid Services to validate the publicly reported models. The calculator produces an estimated risk of readmission based on a patient’s demographic and clinical characteristics. In response to requests from users, we have made the calculator available for free as an iPhone app. You can download if from the iTunes store or find it at this link: (CORE) Readmission Risk Calculators iPhone App
Please let us know about your experience with it – and how you are using it. Thanks!
March 14th, 2012
Achieving CLOSURE: Final Act of PFO Closure Device Trial
Larry Husten, PHD
You can choose from myriad metaphors — closing the book, sealing the deal, fixing a hole — but the story is simple: the publication of CLOSURE 1 in the New England Journal of Medicine is the final act in the long and sad melodrama of the CLOSURE 1 trial. As initially reported at the American Heart Association in 2010, Anthony Furlan and the CLOSURE I investigators randomized 909 patients with crytpogenic stroke or TIA to either medical therapy or PFO closure with the STARFlex Septal Closure System. There were no significant differences in the composite endpoint or its components (stroke or TIA in the first 2 years, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years):
Composite endpoint: 5.5% in the closure group and 6.8% in the medical-therapy group (HR 0.78, CI 0.45 to 1.35, p=0.37):
- Stroke: 2.9% and 3.1% (p=0.79)
- TIA: 3.1% and 4.1% (p=0.44).
- Deaths at 30 days and deaths from neurologic events at 2 years: zero in both groups
As expected, there were more major vascular complications related to the procedure in the treatment group, as well as a higher incidence of atrial fibrillation:
- Major vascular procedural complications: 3.2% vs 0% (p<0.001)
- Atrial fibrillation: 5.7% vs 0.7% (p<0.001)
In an accompanying editorial, S. Claiborne Johnston discusses the troubling issues raised by the trial. Because of competition with off-label use of closure devices, enrollment in the trial took 5 years and forced a reduction in the sample size of the trial. He continues:
During the 9 years it took for the results of this trial to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.
To comment on this topic, please go to Rick Lange’s and David Hillis’s blog post: The $800 Million Gamble: Jumping Aboard or Jumping the Gun?
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