January 18th, 2013
A Possible Treatment for “Methods Myopia”
Leslie Curry, PhD, MPH
As a social scientist, I did not start my career in the orbit of cardiologists, nor was it an orbit I had even contemplated entering. But for about eight years now, I have been working with leading heart doctors in this extraordinarily fast-paced, innovative, competitive specialty that often leads the healthcare field.
Another opportunity for cardiology to lead has presented itself — in the typically homeostatic arena of scientific methods. For the past decade, interest has been slowly building in the use of mixed methods in clinical and health-services research, first with a reluctant embrace and a fair amount of skepticism but more recently with growing awareness of its value.
What is mixed-methods research? How is it relevant to the everyday practice of medicine and to leadership in healthcare? For detailed answers to those questions, see an article in Circulation: Cardiovascular Quality and Outcomes that I coauthored with my colleagues. For the basics, here’s my quick overview:
Mixed-methods studies combine statistics and conversations (quantitative and qualitative methods) to elucidate not only “how many” and “how much” of something is happening or should happen, but also why and how things transpire in the complex world of healthcare. For example, we know it’s a problem that 14% of patients stop taking their clopidogrel after getting a heart stent. But there are two distinct dimensions to the dilemma:
- Quantitative: How big a problem is cessation of clopidogrel for the patient?
- Qualitative (and just as important): Why did the patient stop taking clopidogrel?
Both types of information are needed to deliver good care to patients and to design effective interventions that improve systems.
Take another example — a cardiologist, in a leadership role at a hospital, who’s responsible for reducing readmissions for patients with heart failure. To allocate resources, she can use evidence about strategies statistically associated with readmissions, such as close coordination with post-hospital care providers (quantitative information). Yet, to be effective, she also needs to understand the nuanced features of close coordination (qualitative information).
The momentum toward mixed-methods modeling is fueled in part by the recognition that large-scale statistical computations and sophisticated multilevel modeling, though useful, cannot alone address contemporary research challenges. Those challenges present themselves when, for example, we seek to understand highly complex systems of care; the intersection among healthcare financing, delivery, and quality; nuanced interactions between social and medical dimensions of health; how to foster authentically patient-centered care; and the critical role of context in all kinds of interventions. Such issues demand new forms of measurement and ways of understanding, including mixed methods.
Methods myopia can limit our understanding to mere P values and squelch the opportunity for discovery that motivates researchers of all stripes. Mixed methods offer great potential to move cardiovascular research and practice forward, if the field is ready to lead.
What are your thoughts about mixed-methods research and what role leading cardiologists should play in advancing it?
January 17th, 2013
Revisiting Novel Anticoagulants in Atrial Fibrillation
John Ryan, MD and Christian Thomas Ruff, MD, MPH
With all that’s changed in the swiftly evolving world of novel anticoagulants, we invited Christian Thomas Ruff, MD, MPH, and Andrew E. Epstein, MD to answer our questions—and yours—on the use of these agents in patients with AF. Do you agree with their perspectives? What questions do you have for them or for your colleagues here at CardioExchange?
Dr. Ryan: Has the availability of new anticoagulants expanded the number of AF patients that you are anticoagulating? How are you deciding which anticoagulant to start with in these patients?
Dr. Ruff: There is a real systemic failure in our healthcare community to anticoagulate patients with atrial fibrillation who are at risk for stroke. I believe the addition of the 3 currently approved novel anticoagulants (dabigatran, rivaroxaban, and apixaban) will eventually translate into a greater proportion of eligible patients being treated; it certainly has in my practice for two main reasons: First, there are many patients who simply refuse to take warfarin because they don’t like the inconvenience of frequent INR monitoring or are concerned about the numerous food and drug interactions that interfere with their dosing. The second, and I think most compelling reason, is that all the new agents are significantly safer than warfarin with respect to intracranial bleeding (approximately a 50% reduction), which is the most feared and devastating complication of anticoagulant therapy.
About initiating anticoagulant therapy, I have found it easier to start a novel anticoagulant in a recently diagnosed treatment-naive patients with AF than to switch a patient who has been stable on warfarin for several years. As far as which agent to start with, I think all the novel anticoagulants are more similar than they are different. They are all at least as effective as warfarin in preventing strokes, and they are all vastly safer with respect to intracranial hemorrhage. There are several differences, however, that do influence which agent I prescribe. Some patients strongly prefer once a day medication and, and rivaroxaban is the only novel anticoagulant that can be dosed this way. In patients with renal dysfunction, I would be inclined to start rivaroxaban or apixaban because they have dose adjustments that were tested in their respective clinical trials and also allow dose adjustment in patients with more mild renal dysfunction compared with dabigatran.
Dr. Epstein: In addition to the points highlighted by Dr. Ruff, the randomized trials clearly showed remarkable efficacy of the novel anticoagulants. However, the risks of any therapy have to always be considered. First, it is highly unlikely that a direct comparison of the new anticoagulants will ever be done. Thus, we will have to choose between one or another based on pharmacokinetics, convenience, and perhaps formulary availability. Substudy analyses are also important: there are data from RE-LY that cardioversion may be safely performed on dabigatran, from ROCKET AF that patients with particularly high CHADS2 scores, especially from prior stoke benefit from rivaroxaban, and from ARISTOTLE that apixaban decreases not only the risk of stroke and bleeding but also of death, the latter not reaching statistical significance in either RE-LY or ROCKET AF. Second, there has been interest in the HAS-BLED score that quantifies the risk for bleeding. This score should not be used to find reasons to not anticoagulate. Instead, it should be employed to identify patients for whom extra precautions be undertaken to minimize the risk for bleeding. Third, I am concerned that although the elderly often have the most to gain from the new anticoagulants, they are also the patients at greatest risk for bleeding, especially if renal function is labile with drugs cleared by the kidneys. For such patients, warfarin should be considered.
Dr. Ryan: Some of the hesitancy surrounding novel anticoagulants remains the lack of reversibility. How do you counsel your patients regarding this, especially in light of the increased risk of intracranial bleed?
Dr. Ruff: Although I think it is important to continue to develop reversal agents for the novel anticoagulants, I don’t think the lack of such an agent is sufficient reason to avoid using a novel anticoagulant. As for intracranial bleeding, even in warfarin-treated patients it is far better to prevent this side effect than to use a reversal agent once a bleed occurs. As I mentioned, the novel anticoagulants reduce intracranial bleeding by approximately 50%, which will have a much more substantial clinical impact than the use of a reversal agent. Also, the anticoagulant effect of the novel agents is much shorter than warfarin. Although it varies according to the specific agent and the patient’s renal function, most of the anticoagulant effect of these drugs disappears after 48 hours. If a serious bleed occurs, providing supportive measures and waiting 1-2 days will be adequate in the vast majority of cases.
Dr. Epstein: Recall that for every intracranial hemorrhage, over 20 ischemic strokes are prevented. And since strokes resulting from atrial fibrillation cause greater morbidity and mortality than do strokes from other causes, the risk-benefit ratio clearly favors anticoagulation.
Dr. Ryan: Have you found the price points of new anticoagulants restrictive for patients?
Dr. Ruff: I think that price is one of the most important factors that has hindered uptake of the novel agents. Although these drugs may well be “cost-effective” in complicated analyses that focused on the costs and benefits to society at large, it is the out of pocket expense for the drugs that really matters to patients, and the new agents are substantially more expensive than warfarin. This is an especially important issue for anticoagulants because the guidelines for stroke prevention in patients with AF recommend indefinite, potentially life-long therapy. For each patient considering anticoagulant options, I have a frank conversation about the pros and cons of all of the agents and this discussion includes cost. I find it helpful to contact the patient’s pharmacy to get the actual cost for that individual as it varies depending on his or her insurance policy. Having a patient start a new anticoagulant and stop because they realize they can’t afford can result in serious safety risks for patients.
Dr. Epstein: Dr. Ruff raised the issue of stopping a new anticoagulant and changing to warfarin. We need to be aware that this action carries important risk for stroke during the transition. In the ARISTOTLE study patients were switched from study drug to warfarin at the end of the trial. During this transition there was an increased risk for stroke likely due to subtherapeutic anticoagulation in the cross-over period. Thus, withholding anticoagulants is not without risk. The package inserts for these drugs give guidance on how to manage transition between anticoagulants and bridging therapy for surgical procedures.
January 16th, 2013
No Benefit of Darbepoetin Alfa in Heart Failure Patients with Anemia
Larry Husten, PHD
The bad news continues for Aranesp (darbepoetin alfa), Amgen’s long-acting erythropoietin-stimulating agent. The company today announced the top-line results of a large phase 3 heart-failure trial of the drug and said that the trial had failed to meet its primary endpoint.
The RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure) Trial, which started in 2006, had randomized 2278 patients with heart failure and anemia to receive either Aranesp or placebo. Patients in the trial started with hemoglobin levels between 9 and 12 g/dL. Physicians then sought to achieve hemoglobin concentrations between 13 and 14.5 g/dL. The company said the drug did not reduce the primary composite endpoint of time to death from any cause or first hospital admission for worsening heart failure (hazard ratio, 1.01; 95% CI, 0.90-1.13).
Amgen said no new safety issues were identified in the study. The company said it would share the results with global regulatory agencies and present the results at an upcoming medical meeting.
Aranesp was first approved for use in 2001. It is currently indicated for the treatment of anemia associated with chronic renal failure (CRF) in patients on dialysis and patients not on dialysis and for the treatment of anemia caused by concomitantly administered chemotherapy in patients with nonmyeloid malignancies.
In 2009 serious criticism of Aranesp emerged with the publication of the TREAT trial, which found no clinical benefit for the drug in patients with chronic kidney disease. Results of TREAT prompted a dramatic FDA advisory committee meeting in 2010, followed by a major label revision in 2011. In December 2012 Amgen pleaded guilty in federal court to U.S. government accusations that the company had marketed Aranesp for indications not approved by the FDA and other illegal marketing practices.
January 16th, 2013
“Nostalgic Professionalism” or Actually Caring About Patients?
Ajay J Kirtane, MD, SM
The other night my pager buzzed at 2 AM with a call from the emergency room. I was technically not “on call,” but because I was concerned that the ER was trying to reach me in the middle of the night, I answered the page. It turned out that an emergency physician needed help with one of my patients, beyond what he could derive from our electronic medical record. I assisted the physician, who used what I told him to help treat my patient, and he thanked me.
However, if one of my medical trainees at New York-Presbyterian Hospital answered an off-hours patient call, it might be pejoratively described as a form of “nostalgic professionalism,” according to a recent viewpoint article in JAMA. Among the examples of residents’ practices that need to be remedied are, apparently, staying past the end of a hospital shift to make sure your patients are (to use hospital slang) “tucked in”; remote checking of labs from home; and following up on a patient’s progress while off duty.
The rationale behind eliminating these practices among medical trainees (our future independent physicians) is to limit their work hours, thereby improving patient care. Advocating for a “new professionalism,” the JAMA authors cite the need for systems and processes that are based on optimized “shift work” paradigms from law enforcement and the aviation industry. These changes would (the argument goes) make patient care more efficient and safe.
No one would dispute that, from a systems level, reducing medical errors by “overworked” trainees is desirable. But what happens when those trainees enter the real world? Perhaps it is a sign of changing times that (professional) concern for patients, whether we’re on or off duty, is no longer noble but rather deemed “nostalgic.”
As a physician who cares for — and about — individual patients and families (and as someone with numerous family members who have received such care from other physicians), I hope I never see the day when we as doctors don’t wonder about and help our sick patients when we’re not in the hospital.
A core concept that we strive to instill in all our medical trainees is to care about patients, not just care for them. Call me “nostalgic,” but to me that’s not a sin.
How often do you take off-duty calls? And what’s your opinion of “nostalgic professionalism”?
January 16th, 2013
FDA Releases Warning Letter to St. Jude About ICD Leads
Larry Husten, PHD
The FDA on Tuesday released the full text of a warning letter sent last week to St. Jude Medical. The company had previously disclosed the existence of the letter in an SEC filing but did not make clear the full extent of the FDA warning. The letter from the FDA is the latest in a series of setbacks and challenges to the company’s Durata and Riata ICD leads.
The letter makes clear that an FDA inspection last year of a California plant that manufactures the ICD leads turned up serious violations, and that the company’s response to those violations has not been adequate. In addition to numerous manufacturing, testing and documentation deficiencies, the letter states that the company failed to report within 30 days malfunctions relating to Durata leads that “would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur.”
The FDA said it will no longer approve premarket approval applications of devices “reasonably related” to the violations until the violations have been corrected.
January 15th, 2013
Large Meta-Analysis Finds No Harm Associated with Eggs
Larry Husten, PHD
No food has had more ups and downs over the last century or so than the common egg. Following a long period in which eggs were ubiquitous and highly regarded, eggs fell from favor with the rise of concerns over cholesterol. Currently, the American Heart Association recommends that people restrict dietary cholesterol to 300 mg per day, which effectively limits people to 1 egg per day at most. However, the relationship of dietary cholesterol and serum cholesterol is, at best, tenuous, and a significant number of experts now believe that egg consumption poses no risk to cardiovascular health.
In a new paper published in BMJ, a group of researchers from China and Boston performed a meta-analysis of 8 studies that included 263,938 participants for coronary heart disease (CHD) and 210,404 participants for stroke and followed them for 8 to 22 years. The authors found no evidence for an association between egg consumption and either CHD or stroke:
- Relative risk of CHD for adding 1 egg per day: 0.99 (CI 0.85- 0 1.15, p=0.88)
- Relative risk of stroke for adding 1 egg per day: 0.91 (CI 0.81 – 1.02, p=0.10)
However, an increased risk for CHD was observed in the subgroup of patients with diabetes in the group of participants with the highest egg consumption compared with those with the lowest consumption (relative risk 1.54, CI 1.14 – 2.09, p=0.01). No similar increase in the risk of stroke was observed in this group, though a protective effect against hemorrhagic stroke was observed in those with the highest egg consumption (relative risk 0.75, CI 0.57 – 0.99, p=0.04). The authors cautioned that the findings in the diabetes subgroup required confirmation in additional studies.
The authors concluded that the findings of their meta-analysis “do not support a positive association between egg consumption and cardiovascular disease outcomes in the general population.”
Related content on CardioExchange: Read Richard Lehman’s amusing perspective on eggs and this study.
January 15th, 2013
Is HDL Fool’s Gold?
Peter Paul Toth, MD, PhD
Merck recently announced that Tredaptive, its compound of extended-release niacin and laropiprant, failed to meet the primary-endpoint goal in the HPS2-THRIVE trial, a comparison with statin therapy alone. We at CardioExchange asked Dr. Peter P. Toth for his perspective on recent trials of niacin, including HPS2-THRIVE and AIM-HIGH. Here is a sampling of his remarks. (See also previous remarks on this topic from William E. Boden and Harlan M. Krumholz.)
In AIM-HIGH, patients had a baseline LDL-cholesterol level of 71 mg/dL, a non-HDL level of 107 mg/dL, and an HDL-cholesterol of 35 mg/dL, and most were chronically treated with a statin. This is not the clinical scenario where niacin is used. It is typically used in patients with low HDL-c, elevated triglycerides, and often residual LDL-c elevation despite statin therapy. The AIM-HIGH patients essentially had pristine control of their atherogenic lipoprotein burden and isolated, mildly low HDL-c. The Framingham study showed that in the absence of insulin resistance, such patients do not have elevated risk compared to patients with more elevated HDL-c.
In HPS-2 THRIVE, the stated hypothesis was “Does niacin combined with extended- release niacin/laropiprant 2 g daily prevent vascular events in high-risk patients who are receiving intensive LDL-lowering treatment?” The trial was not designed to ascertain whether or not raising HDL with niacin affects risk, as low HDL was not an inclusion criterion. It’s also possible that laropiprant may adversely affect vasculoprotective or atheroprotective pathways that niacin therapy influences, but that is conjectural. Gratefully, the FDA insisted that the niacin/laropiprant combination be evaluated in a large randomized prospective study before it considers drug approval. In the type of patient population studied in HPS-2 THRIVE, clearly the addition of Tredaptive to statin therapy did not improve outcomes. Subsequent investigation will have to determine whether Tredaptive offset potential benefit from the combination of statin/niacin used in the trial.
We simply don’t yet have a trial involving high-risk patients specifically with low HDL and high triglycerides to determine whether or not niacin reduces event rates beyond that observed against a background of statin therapy. I’d suggest an average baseline HDL of 28 or 30 mg/dL and triglycerides >200 mg/dL to really put niacin to the test. Otherwise, it’s like trying to treat a cancer with a drug that is not designed to intercept any growth or proliferative feature of the cell type in question. Who would design such a trial?
In ARBITER 2 and 6, the use of adjuvant niacin clearly affected rates of progression of carotid intima-media thickness. Granted, we do not know whether CIMT regression correlates with reductions in cardiovascular events, but most of us believe regression is a good thing. Niacin does appear to limit atherosclerosis disease progression against a statin background. Is the benefit from raising HDL-c? No one can answer that yet. I believe the antiatherogenic efficacy of niacin stems from its effect on all components of the lipid profile.
My concern is that physicians will write HDL therapeutics off before we even begin to understand it. There is evidence that HDL antagonizes inflammation, oxidation, thrombosis, and endothelial dysfunction; it is a modulator of insulin sensitivity and participates in the activation of islet-cell insulin secretion; it comprises many species with variable functionality. In addition, five decades of epidemiology have shown that low HDL is a categorical risk factor for CHD regardless of race, sex, or ethnicity. The list of suggestive evidence goes on.
I personally do not believe that CETP inhibition will reduce cardiovascular event rates because (1) studies with torcetrapib and dalcetrapib revealed no benefit; (2) I see no positive role for inhibiting indirect cholesterol transport to the liver; and (3) epidemiologically, low CETP activity correlates with increased risk for CHD events in multiple studies around the world. We know that HDL’s capacity to stimulate macrophage efflux capacity in humans correlates with risk for CHD-related events. This is an extremely difficult issue to investigate, characterize, and apply therapeutically. It is simply premature to conclude that HDL is fool’s gold. The issue is far more complex than we have thus far envisioned. For now, I will continue to use niacin in patients with low HDL-c, elevated triglycerides, and residual elevations in LDL-c despite appropriate, or maximally tolerated, doses of statins.
What do you think the future of HDL-modifying therapy will be?
January 14th, 2013
Selections from Richard Lehman’s Literature Review: January 14th
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.
BMJ 12 Jan 2013 Vol 346
Egg Consumption and Risk of CHD and Stroke: “I had an excellent repast—the best repast possible—which consisted simply of boiled eggs and bread and butter. It was the quality of these simple ingredients that made the occasion memorable. The eggs were so good that I am ashamed to say how many of them I consumed ….It might seem that an egg which has succeeded in being fresh has done all that can be reasonably expected of it.” Henry James here expresses himself soundly on the question of eggs, though many would argue that scrambled eggs are even better, since they incorporate larger amounts of butter. Nor should one’s egg consumption be confined to those of the hen. Most birds and fish produce eggs which are perfectly delicious, and seagull eggs combine the qualities of both. As for the fabled eggs of the sea-urchin, however, these are not eggs at all, but the delicious gonads of the spiny creatures. By contrast, the eggs of snails and slugs, while attractive, are for the most part insipid and earthy. Why anyone should be troubled by the consumption of eggs as a medical issue, I cannot imagine, but this dose-response meta-analysis of the subject simply reinforces my advice to eat lots of eggs. They do not increase your risk of stroke or coronary disease, but even if they did, it would simply be a good reason to eat as many as you can while you still have the chance.
January 14th, 2013
You’re Sick: To Work, or Not to Work?
Harlan M. Krumholz, MD, SM
Our hospital, like many others, is experiencing a surge in patients with influenza-like-illness. According to CDC statistics, this year’s viruses are causing more illness than those in the recent past.
We received a notice yesterday from our hospital that urged healthcare workers to stay at home if they have fever, respiratory symptoms, or diarrhea. As doctors, though, we rarely give in to illness. We know that if we do not work many people will be inconvenienced. We tend to work through illness until we are incapacitated. But is that approach really in the best interests of our patients – especially during an influenza epidemic? I fear that we often act as vectors of illness in our attempt to be responsible about our commitments.
So my questions are: What is your approach? How sick do you need to be to cancel your appointments and obligations and stay home? What do you think would be the ideal approach – and what really happens? And what do you tell the healthcare personnel around you?
January 14th, 2013
Atrial Fibrillation Linked to Increased Risk for Sudden Cardiac Death
Larry Husten, PHD
Although atrial fibrillation (AF) is well known to be associated with an increase in the risk of stroke and coronary heart disease, a similar association with sudden cardiac death (SCD) has been suspected but not demonstrated in the past. Now, a new study examining data from two large population studies offers evidence that AF is also an independent risk factor for SCD.
In a paper published in JAMA Internal Medicine (formerly Archives of Internal Medicine), Lin Chen and colleagues analyzed data from 15,439 participants in the Atherosclerosis Risk in Communities (ARIC) Study and 5,479 participants in the Cardiovascular Health Study (CHS). The analysis shows that AF patients were at significantly elevated risk for SCD. The increase in SCD was roughly similar to the expected increase in nonsudden cardiac death.
SCD hazard ratios adjusted for risk factors:
- ARIC: 3.26 (CI 2.17-4.91), p<0.001
- CHS: 2.14 (CI 1.60-2.87), p<0.001
- Combined: 2.47 (CI 1.95-3.13), p<0.001
The authors concluded that their finding, if confirmed, “adds to our evolving understanding that AF is not a benign condition. Not only does AF predispose to stroke, heart failure, and death, but the arrhythmia per se may increase the risk of death from ventricular tachyarrhythmias.”
In an invited commentary, Kyndaron Reinier and Sumeet Chugh write that despite the statistical adjustments the study may have been unable to demonstrate a cause-and-effect relationship between AF and SCD, since the findings “may be due to shared risk factors.” They also point out that some of the SCD cases may have been really caused by a cerebrovascular accident.
They urge caution regarding attempts to apply the findings of the study to clinical practice:
“…it is important that we are cautious about extending these findings into the clinical domain. Until such time that a causal association is confirmed between AF and SCD, it is difficult for these results to influence clinical management of AF or SCD. Whether it is control of the heart rate, control of the rhythm, or stroke prophylaxis, present management of the patient with AF should be governed largely by current evidence-based guidelines aimed at reduction of AF symptoms and hospitalization and the need to minimize risk of future cerebrovascular accidents.”
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