October 4th, 2012
Beta-Blockers May Not Work as Well as We Thought: So What Does “Optimal Medical Therapy” Really Mean?
Ajay J Kirtane, MD, SM
In this week’s issue of JAMA, Bangalore and colleagues report outcomes from the REACH registry stratified by the use of beta-blocker therapy. Enrolling patients with either 3 or more traditional risk factors or established cardiac, peripheral vascular, or cerebrovascular disease, REACH was a large, multinational observational study that examined long-term outcomes in patients at risk for atherothrombotic events. In the present analysis, the outcomes of patients taking beta-blockers were not statistically different from the outcomes of patients not taking these agents. These findings were confirmed in separate cohorts of post-MI patients, patients with known CAD without MI, and patients with risk factors for CAD alone.
Although these data draw attention to the need for more current studies examining the clinical efficacy of established agents such as beta-blockers, particularly in an era of “modern reperfusion,” they should be even more sobering for proponents of optimal medical therapy (OMT) used for the treatment of stable ischemic heart disease (SIHD). Proponents of OMT have repeatedly held to the tenet that the benefits of coronary revascularization for SIHD were demonstrated in outdated studies conducted prior to the institution of contemporary OMT, which on its own could reduce hard cardiovascular outcomes. So in the wake of this REACH analysis, what really is so beneficial about contemporary OMT: aspirin and statins alone? If the data for beta-blockers are scant, the data for nitrates (in terms of a reduction in hard events) are even worse. Calcium channel blockers and ranolazine are additionally unproven classes of agents when it comes to reductions in hard clinical outcomes in SIHD patients.
Frankly, it is probably fair to say that we have as little evidence about the “hard” benefits of OMT (beyond aspirin and statins) as we do about the benefits of coronary revascularization in the present era. Despite its limitations as an observational study, this contribution by Bangalore and colleagues helps to illustrate the potential weaknesses of the evidence base for what many physicians consider one of the mainstays of OMT.
[EDITOR’S NOTE: Comments on this post are closed; we invite readers to engage in a wide-ranging dialog over at Bangalore’s post on this study here]
October 3rd, 2012
CRP and Cholesterol Emerge as Equally Strong Predictors of Cardiovascular Risk
Paul Ridker, MD, MPH
In this week’s issue of the NEJM, the Emerging Risk Factors Collaboration, led by Stephen Kaptoge, present data confirming that the inflammatory biomarker C-reactive protein (CRP) provides incremental risk information comparable to that of total cholesterol (TC) and HDL cholesterol (HDL-c). (I am a member of this study group.) The analysis makes four important points.
Click to enlarge
Point 1: As shown in the upper left panel of Figure 1 (right), for a prediction model that already includes age, smoking, systolic blood pressure, and diabetes status, the magnitude of change in the C-statistic associated with adding TC to the model was 0.0043; subsequently adding HDL-c to the latter model changed the C-statistic by 0.0050. These are critical benchmarks for comparison, as all cardiovascular screening programs worldwide include TC and HDL-c.
Point 2: Once TC and HDL-c are included in the prediction model, the incremental change in the C-statistic associated with adding CRP was 0.0039, an effect magnitude fully comparable with that of the two prior benchmarks. As each new biomarker is added to a prediction model, the bar it must clear becomes progressively higher. Therefore, these data confirm that CRP’s value in predicting cardiovascular risk is at least similar to that of standard lipid measures. This is borne out by the observation, shown in Table 1, that the multivariable-adjusted hazard ratio associated with a one standard-deviation increase in CRP level was 1.20 (versus 1.17 for a comparable 1-SD increase in TC level). In other words, if on the basis of discrimination and magnitude of effect lipids are considered important for risk prediction, so too must be CRP.
Point 3: Compared head-to-head, the incremental predictive value of CRP was modestly greater than that of fibrinogen, and the value of combining the two was broadly similar to that of either alone.
Point 4: Most important, by affirming that the role of inflammation in atherothrombosis is comparable to that of cholesterol, these analyses provide support for ongoing trials that target inflammation as a novel treatment strategy. We have recently initiated two large-scale, multinational randomized trials directly testing the inflammatory hypothesis of atherothombosis: one evaluating the interleukin-1-beta inhibitor canakinumab (CANTOS) and the other evaluating low-dose methotrexate (CIRT). If either or both of these trials are positive, we will have direct evidence that reducing inflammation reduces vascular risk.
Whether clinicians ought to use any biomarkers for risk prediction should be based on hard trial evidence and on the concepts of “what works?” and “in whom?”. In primary prevention, randomized trials have shown statins to be highly effective at reducing event rates among patients with elevated LDL-c levels (WOSCOPS), low HDL-c levels (AFCAPS/TexCAPS), and elevated CRP levels (JUPITER). A simple set of evidence-based prevention guidelines, derived from these hard trial outcomes, is easy to follow.
Disclosure: Dr. Ridker, a member of the Emerging Risk Factors Collaboration, is listed as a co-inventor on patents, held by Brigham and Women’s Hospital (BWH), that relate to the use of inflammatory biomarkers licensed to AstraZeneca and Siemens. He is also the principal investigator of the NHLBI-supported CIRT trial and the Novartis-supported CANTOS trial. However, neither Dr. Ridker nor the BWH receives any royalties related to these patents for use of the CRP test in either clinical trial.
Share your thoughts on the CRP findings from the Emerging Risk Factors Collaboration.
October 3rd, 2012
What Is the Benefit of Adding CRP to Risk Factor Assessment?
Larry Husten, PHD
In recent years, controversy has swirled around the role of inflammation in cardiovascular disease and the relative worth of measuring novel risk factors like C-reactive protein (CRP). Now, in a paper published in the New England Journal of Medicine, researchers from the Emerging Risk Factors Collaboration provide detailed calculations that estimate the benefits of adding inflammatory markers to risk factor models.
In an analysis containing nearly a quarter million people enrolled in 52 studies, the investigators examined the effect of adding CRP and fibrinogen to a model including age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol. They concluded that the effect of adding CRP or fibrinogen to the model was roughly similar to the effect of adding HDL to the model. In a secondary analysis, they found that CRP and fibrinogen improved risk prediction in men but not in women and had more predictive power in smokers than in nonsmokers.
The authors conclude that “targeted assessment of CRP in people at immediate risk for a cardiovascular event could help to prevent one additional event over the course of 10 years for every 440 people so screened.” Here’s how they calculated this conclusion:
In a population of 100,000 adults 40 years of age or older, with an age profile similar to that in the European standard population and with age-specific and sex-specific incidences of cardiovascular events that are assumed to be the same as those observed in the current study… 15,025 persons would initially be classified as having a predicted risk of cardiovascular disease of 10% to less than 20% over a period of 10 years when the risk is calculated with conventional risk factors alone. … Assuming that allocation to statin treatment would be conducted according to the ATPIII guidelines (i.e., persons with a predicted risk of ≥20% and those with risk factors, such as diabetes, irrespective of their predicted 10-year risk), 13,199 participants at intermediate risk would currently not be eligible for statin treatment. Additional assessment of CRP in these 13,199 participants would reclassify 690 participants (5.2%) to a predicted risk of 20% or more, of whom approximately 151 would be expected to have a cardiovascular event within 10 years… Assuming that persons reclassified as being at a predicted risk of 20% or more would begin statin therapy, in accordance with the ATPIII criteria, such targeted assessment of CRP could help to prevent about 30 (i.e., 0.20 × 151) additional cardiovascular events over a period of 10 years…
Paul Ridker, a member of the Emerging Risk Factors Collaboration, shares his take on the findings with CardioExchange. Read his analysis, and share your comments or questions, here.
October 3rd, 2012
ACC Fellows in Training Push Congress for Sustainable Health Care Reform
Michael Tempelhof, MD MSc
As a Fellows in Training (FIT) representative, I was honored to be one of the 450 American College of Cardiology members to attend the 21st Annual ACC Legislative Conference in Washington, D.C. This year, an unprecedented, 70 FITs attended the conference.
The event began with educational sessions discussing how the proposed health care policies will have a detrimental effect on the quality of cardiovascular disease care, physician autonomy, reimbursement, and the future of medicine in America. Then, expert lobbyists and ACC advocacy committee members reviewed the specific message and issues we were to discuss with our respective representatives in the U.S. House and Senate. Between sessions, FITs had the opportunity to meet with one another, interact with ACC council leaders, and network with the cardiovascular thought leaders from across the country. The final day of the conference was spent at the Capitol building where, in private sessions, we conveyed the ACC’s strong message advocating for meaningful and sustainable health care reform.
The ACC advocates for a restructured health care program that emphasizes and rewards physicians who provide high-quality, cost-effective, and evidence-based medicine to their patients. Payment model reform incorporating a quality improvement initiative (similar to the ACC’s appropriate use criteria) was presented to Congress as a model for future, sustainable health care payment programs that rewarded quality and not volume of patient care. The ACC also identified Medicare sequestration, the Sustainable Growth Rate (SGR), Multiple Procedure Payment Reduction (MPPR), medical liability reform, and spending cuts to the Accreditation Council for Graduate Medical Education (ACGME) as the priorities for the 2012 Legislative Meeting.
FITs were well adept to communicate how the proposed spending cuts to the ACGME will dramatically impact the future of American medicine. In addition to the proposed cuts reducing the number of training positions, programs will also be compensated less for teaching and mentoring, threatening the quality of education to our future physicians. In the context of a pre-existing shortage of well-trained cardiologists, these proposed cuts will be detrimental to the future of cardiovascular care in America. Our message to Congress of implementing cost-effective health care reform through the utilization of physician accountability and appropriate use criteria was well received.
As trainees, our time outside of patient care is limited. A short week away from the bedside, in an environment where decisions are based on the messages of others, I appreciate the impact physicians may have on patients’ lives outside of the hospital. As our health care system evolves at this time of significant reform, we as practitioners and future cardiologists must actively advocate for a meaningful and sustainable health care reform in order to protect the future quality of our patients’ care.
October 2nd, 2012
Long-Term Use of Beta-Blockers Questioned in Certain Patients
Sripal Bangalore, MD, MHA
Use of beta-blockers was not associated with a lower rate of cardiovascular events in an analysis of data from the Reduction of Atherothrombosis for Continued Health (REACH) registry published in JAMA. Over 44 months’ follow-up, the lack of association was observed in patients with only risk factors for coronary artery disease, known CAD without myocardial infarction, or prior history of MI. The study’s first author, Dr. Sripal Bangalore, shares some of his insights with CardioExchange.
1. What are the clinical implications of this study right now?
The implications are that we should not be extrapolating the beneficial effects of beta-blockers seen in heart failure trials and older post-MI trials to other cohorts such as those with CV risk factors alone or those with CAD without MI. Even in stable patients with prior MI but without heart failure, the study questions the long-term utility of beta-blockers in that cohort.
2. Should guidelines be changed?
The latest ESC secondary prevention guidelines recommend beta-blockers long term only in those with LV dysfunction. The revised ACC/AHA secondary prevention guidelines gives Class I indication to beta-blocker use after MI for up to 3 years but class IIa for longer term treatment. We do not know if 3 years is the way to go and if this is based on any evidence. While short-term treatment with beta-blockers after MI is reasonable, we need more data to continue them long term.
3. Do individuals with CAD die of ischemia? We ask because anti-ischemic agents (beta-blockers, calcium-channel blockers and nitrates) have not been shown to improve mortality in subjects with CAD.
This is a fantastic question. We know from observation studies that greater the ischemic burden worse the prognosis. However, what we do not know is whether this increase in events with higher ischemic burden is the result of ischemia per se or if ischemia is a marker for atherosclerotic burden. You are correct in that the medication you have listed have not been shown to improve mortality. In fact, this is what we have shown in the analysis from the REACH registry. However, the perception among physicians is different, and there are many who “believe” that these medications save lives.
October 2nd, 2012
Registry Study Raises Questions About Cardioprotective Effect of Beta-Blockers
Larry Husten, PHD
Although beta-blockers have been a cornerstone of therapy for patients with coronary artery disease for more than a generation, a new study in JAMA suggests that that in the modern era, beta-blockers might not improve outcomes.
Sriapl Bangalore and colleagues analyzed data from 44,708 patients enrolled in the Reduction of Atherothrombosis for Continued Health (REACH registry), of whom 31% had a prior MI, 27% had documented CAD without MI, and 42% had CAD risk factors only. Patients who received beta-blockers were compared with matched controls and were followed for a median of 44 months.
Beta-blocker use was not associated with a significant reduction in the rate of cardiovascular death, nonfatal MI, or nonfatal stroke. Here are the rates:
Among CAD patients with prior MI:
- 16.93% in the beta-blocker group versus 18.60% in the controls, hazard ratio [HR] 0.90, CI 0.79-1.03, p=0.14
CAD patients without prior MI:
- 12.94% versus 13.55%, HR 0.92, CI 0.79-1.08, p=0.31
Patients with risk factors only:
- 14.22% versus 12.11%, HR 1.18, CI 1.02-1.36, p=0.02
In their paper, the REACH investigators point out that the evidence supporting beta-blocker use after MI is now quite old, with most of the trials having been performed prior to the widespread use of modern reperfusion strategies and medical therapy. The presumed “cardioprotective” effect of beta-blockers in patients without MI did not have an evidence base and was an extrapolation from heart failure trials and older post-MI trials. On the other hand, they note, there is evidence to support the use of beta-blockers in acute MI patients without shock or heart block.
Although the finding may be surprising to some clinicians, the results are consistent with recent guidelines, the authors note. In the AHA secondary prevention guidelines, beta-blockers receive a class I recommendation for heart failure, MI, or ACS for up to 3 years after MI but only a IIa recommendation for longer-term therapy. For other patients, beta blockers receive a class IIb recommendation.
For a CardioExchange Q&A with the study’s author – and to share your own comments about the study – see here.
October 1st, 2012
Selections from Richard Lehman’s Literature Review: October 1st
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.
Arch Intern Med 24 Sep 2012 Vol 172
Physical Activity and Mortality in Those with Diabetes:
Of Exercise I sing, and that benignant sweat
Which from six thousand diabetic brows
Exudes. My pen, Hygeia, speed! To save
That honey-urined tribe from mortal pains
Which Indolence doth breed, and glut of food:
That to the treadmill they may go, or healthful jog,
Or bicycle with ever-turning wheel;
These strivings, Muse, assist me to exhort,
That to the height of this great Argument
I may assert eternal Exercise:
For sloth in diabetes hastens death.
I beg your pardon: I was just trying to think of an EPIC way to convey the message of this paper about the mortality benefit of exercise in a cohort of 5859 diabetic individuals followed up from 1992 onwards in the European Prospective Investigation Into Cancer and Nutrition (aka EPIC). I know there’s confounding and reverse causality to be considered, but the burden of all such studies is always the same: even small amounts of regular exercise buy large amounts of added life.
Intensive and Standard BP Targets in Those with Type-2 Diabetes (pg. 1301): Nothing else in diabetes is as straightforward as the benefit of exercise: blood pressure control in type 2 DM for example, is a subject of such intellectual complexity that I sometimes think only Rod Hayward really understands it. The message of this systematic review and meta-analysis seems to be fairly clear: if you set a target BP with an upper limit of 130/80 rather than 140-160/85-100, you will reduce stroke but have no significant effect on total mortality or myocardial infarction. That may be all that a jobbing clinician needs to remember, but if you drill down just a little deeper, things get a good deal more complex. There is no simple—or even complicated—formula that can just give you a read out of numbers needed to treat for risk reduction in type 2 diabetes with hypertension. You must always consider the totality of cardiovascular risk in the individual patient. If you really want to engage with this, combine this study’s findings with the classic Timbie, Hayward and Vijan modelling paper from 2010.
JAMA 26 Sep 2012 Vol 308
Diagnostic Accuracy of FFR from CT Angiography: Interventional cardiologists with itchy fingers will all be citing the FAME study (see NEJM two weeks ago) as a reason to put wires in coronary arteries to measure fractional flow reserve (FFR) in stable coronary artery disease. I promised at the time that I wouldn’t comment further on something so far removed from my own field of practice. Here, however, is a technique for measuring FFR without an invasive procedure, unless you count a hefty dose of ionizing radiation as invasive. It is our old friend coronary computed tomographic (CT) angiography with some extra computing thrown in. In this multinational study, 252 patients with stable CAD underwent both CT scanning and invasive FFR measurement with adenosine stimulation. So this is a nice example of a diagnostic study with a simple gold standard: you can plug the figures into your 2×2 table and come up with specificity (73%), sensitivity (90%) and all the rest. Or you can construct a receiver operator curve (AUC, 0.81). Either way, CT derived FFR doesn’t quite cut the mustard. Further refinement might give us more accuracy, but for now, I struggle to think of a clinical use for this imaging modality. People with stable CAD should keep taking their tablets and try to avoid cardiologists with itchy fingers or shiny new CT machines.
October 1st, 2012
I Want Some of What the American Heart Association is Smoking
Yoni Freedhoff, MD
Dr. Freedhoff is an assistant professor of family medicine at the University of Ottawa and founder and medical director of Ottawa’s Bariatric Medical Institute. Dr. Freedhoff sounds off daily on his award-winning blog, Weighty Matters.
When it comes to public-private partnerships between health organizations and the food industry, there are many shades of grey — but Cheetos orange isn’t one of them. On September 9th of this year, however, the American Heart Association (AHA) Dallas Heart Walk saw Frito-Lay’s Chester the Cheetah riling up the crowd and helping to associate Frito-Lay and Cheetos with the emotions of the day — joy, hope, charity, happiness, spirit, camaraderie, health, and generosity.
And emotional brand polish is not the only benefit Frito-Lay received for being a “My Heart. My Life.” sponsor of the walk. They also enjoyed direct-to-consumer marketing and sampling of their chip products by handing out free samples to walkers who will hopefully be converted into brand-loyal consumers; they were given a great “corporate social responsibility” opportunity with which to defend against future industry-unfriendly legislation and actions; and, last, they saw the AHA itself explicitly support the further normalization of junk food as part of everyday life and as a reward for a job well done.
Of course, the AHA has a long association of partnering up with the food industry. They sell their “Heart Check” branding to products that meet nutritional criteria so meager that V8 Vegetable Juice with 480mg of sodium per glass (that’s more sodium than in a large serving of McDonald’s french fries) and grape juice that contains nearly double the calories and sugar of Coca-Cola qualify and consumers are duped into thinking they’re making healthful choices; and they’ve encouraged consumers to abandon their kitchens and head to Subway instead.
The usual arguments in support of these sorts of decisions are that the checks and partnerships will help lead people to healthier choices. But is “less horrible” truly the same as “good”? And are these choices really even “less horrible”?
Shouldn’t the role of the AHA be to promote truly healthy living, not seeming shortcuts to health that lull consumers into very false senses of security?
Diet and weight-related diseases are ravaging the developed world. Americans are now spending the majority of their food dollar on foods purchased outside of the home, while the purchase of processed foods for consumption inside the home have doubled since 1982. We are not going to solve our nutritional woes by holding hands with the food industry. Instead, we need to aggressively and repeatedly hammer home the message that there are no shortcuts to health, that health can’t be purchased in a box or in a restaurant, that kitchens are the most valuable rooms in our homes, and that health organizations should not serve as sales and marketing teams for Big Food.
We need someone to be our C. Everett Koop: To stand up and call Big Food out for what it is — our modern day Big Tobacco. And just like with Big Tobacco, this challenge requires fight, not friendship.
September 28th, 2012
Subcutaneous ICD Gains FDA Approval
Larry Husten, PHD
The FDA today approved the Subcutaneous Implantable Defibrillator (S-ICD) System from Cameron Health. The device is the first ICD that does not require a lead that connects directly to the heart and therefore does not need to be guided by X-ray fluoroscopy. Instead, the S-ICD lead is implanted along the bottom of the rib cage and breastbone.
The S-ICD System has been approved only for patients who do not also require a pacemaker or pacing therapy. The FDA will require Cameron Health to perform a 5-year postmarketing study, which will include 1616 patients, to measure the long-term safety and efficacy of the device and to test whether the device is equally effective in men and women.
“The S-ICD System provides an alternative for treating patients with life-threatening heart arrhythmias for whom the routine ICD placement procedure is not ideal,” said Christy Foreman, director of the Office of Device Evaluation at the FDA’s Center for Devices and Radiological Health, in a press release. “Some patients with anatomy that makes it challenging to place one of the implantable defibrillators currently on the market may especially benefit from this device.”
In April, the FDA’s Circulatory System Devices panel voted 7-1 that the benefits of the S-ICD outweigh the risks in appropriately selected patients. Approval was based on the pivotal 321-patient study in which 304 patients successfully received the S-ICD. During the 6-month follow-up period, the device detected 78 arrhythmias in 21 patients. According to the FDA analysis, all the arrhythmias were terminated by the device or resolved spontaneously. Common complications of the device include inappropriate shocks, discomfort, system infection, and electrode movement.
Earlier this year Boston Scientific acquired Cameron Health for an initial payment of $150 million. Depending on future performance, the price may reach as much as $1.2 billion.
Rick Lange, who served on the FDA’s Circulatory System Devices advisory panel that reviewed the S-ICD, provided the following comment for CardioExchange:
This will be a niche device… it will have a limited role because it’s not suitable for patients who also need or would benefit from pacing therapy. However, it may be particularly suitable for primary prevention of SCD in children or young adults (i.e., those with HOCM, long-QT, RV dysplasia, Brugada syndrome, family history of SCD, etc.), in whom intravascular lead placement is not attractive because of continued growth of the child or concerns about long-term lead complications. The FDA panel insisted that a postmarketing study be performed to ensure that the device appropriately sensed and treated lethal arrhythmias. Early versions of the sensing algorithm needed tweaking.
September 27th, 2012
FDA Sets New Decision Date for Eliquis (Apixaban)
Larry Husten, PHD
The FDA will decide the fate of apixaban (Eliquis) by March 17, 2013. The new Prescription Drug User Fee Act (PDUFA) goal date was announced yesterday by the drug’s manufacturers, Pfizer and Bristol-Myers Squibb.
The new drug application (NDA) for apixaban for stroke prevention in atrial fibrillation has been delayed twice. Although the pivotal ARISTOTLE trial was highly praised when it was first published, the FDA first extended its review by 3 months and then issued a complete response letter (CRL) on June 25 requesting “additional information on data management and verification from the ARISTOTLE trial.” According to Pfizer and Bristol-Myers Squibb, the FDA has now accepted for evaluation their response to the CRL.
In Europe last week, the Committee for Medicinal Products for Human Use (CHMP) recommended approval for apixaban for the same indication.
