FAME II: Additional Thoughts About FFR in the Real World 3

Earlier today I reported the news that enrollment in the FAME II study had been stopped early by the DSMB. From the initial presentation of the first FAME trial several years ago, I’ve been fascinated by the potential of this technology, since it offers the tantalizing prospect of helping identify atherosclerotic lesions that actually will benefit from an intervention. But FFR is not a free ride. The downside is that you have to perform a lesser intervention (angiography) in order to determine the validity of the greater intervention (PCI).

FAME II was designed, and will be promoted, as an answer to COURAGE, suggesting that PCI can be generally used in a stable CAD population if FFR detects an ischemic lesion. But it is important to remember that everyone in the trial underwent angiography and FFR prior to randomization, and only those with ischemic lesions were randomized. So it’s fair to conclude that yes, IF someone undergoes angiography it would make sense to give FFR, and if an ischemic lesion is found it would make sense to implant a stent.

BUT it doesn’t say anything about which patients actually should undergo angiography in the first place, and the use (or overuse) of angiography is probably the most important unresolved problem in cardiology today. So we’re back to the floodgate problem. If the floodgates (angiography) are open, then FAME II makes a lot of sense and is widely applicable. But if the floodgates are closed or only opened selectively,the trial really doesn’t help very much.

New Enrollment in FAME II Halted After Interim Analysis Shows Benefits of FFR 3

Following a positive interim analysis showing that fractional flow-reserve-guided PCI was superior to optimal medical treatment, an independent Data and Safety Monitoring Board (DSMB) has recommended that patient enrollment in the ongoing FAME II trial  be stopped. The news was announced by the trial sponsor, St. Jude Medical.

FAME II (Fractional Flow Reserve-Guided Percutaneous Coronary Intervention Plus Optimal Medical Treatment Versus Optimal Medical Treatment Alone in Patients With Stable Coronary Artery Disease) investigators had planned to randomize 1,832 patients with stable coronary artery disease to either PCI guided by FFR plus optimal medical treatment (OMT) or OMT alone. At the time of the announcement 1,219 patients had been randomized.

According to the company, the DSMB recommendation was based on an increase in the risk of major adverse cardiac events (MACE) in patients randomized to OMT alone. “In particular, patients receiving OMT alone experienced a highly statistically significant increased risk of hospital readmission and urgent revascularization, and the DSMB determined that this difference was highly unlikely to change with inclusion of more patients,” the company stated. There were no significant differences in the rates of death or MI.

It should be noted that all patients in FAME II underwent FFR prior to randomization, according to the original announcement of the trial. Patients who had hemodynamically significant lesions as assessed by FFR were then randomized to PCI or OMT. The trial was designed to address the limitations of COURAGE, in which CAD patients as documented by angiography were randomized to PCI or OMT. However, the followup to COURAGE, the ISCHEMIA trial, will randomize ischemic patients to PCI or OMT without prior angiography. FAME II does not appear to address the question of which patients should undergo angiography in the first place.

Click here to read additional commentary about FAME II.

Click here to read the St. Jude press release…

Cangrelor Proposed As Bridge To Surgery Reply

As a potent and reversible platelet inhibitor, cangrelor has been proposed for use in a bridging strategy for patients scheduled for surgery who are currently taking clopidogrel or another thienopyridine. To test this strategy, the BRIDGE investigators randomized 210 ACS or stent patients awaiting CABG and taking a thienopyridine to receive either cangrelor or placebo for at least 48 hours prior to surgery. The results have now been published in JAMA.

During the treatment period platelet reactivity was lower in the cangrelor group than in the placebo group. There was no significant difference in the rate of surgery-related bleeding.
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Resveratrol and Fraud Reply

Last week a new case of scientific misconduct came to light. University of Connecticut resveratrol researcher Dipak Das was accused of serious scientific misconduct. (You can read my brief post about the case or, for all the gory details, you can follow the story on Retraction Watch.)

In this post I’d like to make two fairly simple points about the case:

1. Resveratrol and Fraud, the Bigger Issue

As far as we now know, this case of scientific misconduct occurred in the lab of one researcher with, at best, a modest reputation in his field. I don’t mean to suggest that the case should not be taken seriously, but it is  unclear whether it has any impact at all on the larger body of scientific research involving resveratrol and related areas. (It’s also possible that Das is only the first of dozens of rotten eggs yet to be discovered in this embryonic field.)

On the other hand, the case offers a great example of the far-reaching and dangerous fraud that so often supports the multi-billion dollar supplement industry. Because resveratrol is considered a nutritional supplement for regulatory purposes it is not subject to the rules and regulations that restrict the marketing of drugs. But, of course, all sorts of highly dramatic medical claims are made for these products. Here’s what Bill Sardi, the president of a company that makes Longevinex, a resveratrol product, claimed about reveratrol, in a statement distributed to media (attached below):

Resveratrol is an antidepressant, an anti-inflammatory, an anti-bacterial, anti-fungal, anti-viral, anti-cancer, cholesterol-lowering, liver-cleansing, brain enhancing molecule.  If Americans embraced resveratrol pills en masse, many prescription drugs would not be needed.

I’m not going to bother refuting this absurd statement. Instead I’ll quote a 2011 review article published in PLoS One:

The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources.

(Fun fact: one of the co-authors of the PLoS One review article was Dipak Das.)

2. Western Blots

The above quote from Bill Sardi is part of a long, rambling, often contradictory and bizarre defense of Dipak Das and resveratrol (reprinted below). Again, I have no intention of engaging all his points– I hope that regular readers of CardioBrief have been inoculated against this sort of hokum. But I do want to make sure one point doesn’t achieve any traction. The key item in the UConn report is that Das repeatedly manipulated western blot images. Sardi first argues that the western blots aren’t important at all:

The alleged faulty tests in no way altered the outcome of his research studies.  The western blot test was only one of many tests used to draw scientific conclusions in published studies.

But then Sardi tries out several new explanations, in the course of a few sentences rapidly cycling through different perspectives on the western blots. First, he states that  the images weren’t altered. Then he acknowledges that they were in fact altered, but that these alterations are standard practice. Then he accuses the university of willfully ignoring this “fact.”

I asked Dr. Das directly, did he altered western blot images, or directed others in his lab to do so.  While his initial answer was no, meaning he had not fabricated or altered any scientific finding, altering western blot images are a common practice in laboratories for reasons other than deception.  The university chose to present their findings in a derogatory manner.  Dr. Das explains that editors at scientific publications commonly request researchers enhance faded images of western blot tests so they can be duplicated in their publications.  Western blot tests are frequently altered to remove backgrounds, enhance contrast and increase dots-per-inch resolution so they are suitable for publication.  This had been fully explained to university officials long before. [sic]

The entire statement strikes me as a great example of the pathology of someone desperately seeking to deny, refute or minimize an inconvenient truth. One statement– that editors ask researchers to “enhance” western blots–  requires an immediate response. I contacted a member of the National Academy of Sciences who has published hundreds, if not thousands of western blots during the course of his distinguished career. His response was clear and unequivocal: “manipulating images is considered tampering with data.” He then clarified:

It is one thing to change the dots-per-inch (resolution) to fit a publication’s requirements – that is not crazy. But enhancing contrast and removing background is something that seems to me to be unacceptable. I certainly emphasize to students that that is unacceptable.  I know of cases where students might try to ‘clean-up’ data this way and I can imagine that in some cases a PI may not realize this has been done. But I have never heard an experienced investigator claim that a journal has asked them to remove background from a blot.  Now, maybe that has happened — I cannot say —  but certainly NEVER to me.

Update: Tom Bartlett of the Chronicle of Higher Education talked to a number of experts in the field to determine the significance of Das’s work not the field. In addition, longtime blogger Derek Lowe posted a detailed dissection of Sardi’s statement. Both posts are worth reading.

Click here to read the statement from Bill Sardi…

The Safety of the Long Distance Runner Reply

Long distance runners may be lonely but they are not at high risk for sudden cardiac arrest, according to a study published in the New England Journal of Medicine. The RACER (Race Associated Cardiac Arrest Event Registry) investigators analyzed data from 10.9 million registered participants in marathons and half-marathons that took place in the US during the first decade of this century.

They identified 59 cases of  cardiac arrests; 40 occurred during marathons and 19 occurred during half-marathons. The mean age of the runners with cardiac arrest was 42 years of age. 51 were men and 8 were women.

The rate of cardiac arrest was 1 per 184,000 participants; the rate of death was  1 per 259,000 participants. The authors described this event rate as “relatively low” and compared it with collegiate athletics (1 death per 43,770), triathlons (1 death per 52,630 participants), and previously healthy middle-aged joggers (1 death per 7,620 participants).
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ASSERT Sheds Light on the Role of Subclinical AF in Stroke Reply

A new study published in the New England Journal of Medicine sheds some much-needed light on the precise role of subclinical atrial fibrillation (AF) in the prognosis and development of ischemic stroke. ASSERT (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial) followed 2580 patients with a newly implanted pacemaker or ICD and with no previous diagnosis of AF.

At 3 months, subclinical AF lasting longer than 6 minutes had been detected in 10.1% (261) of the subjects. During 2.5 years of follow-up, 51 patients in the study had an ischemic stroke or systemic embolism. Of these, 11 were in the group with subclinical AF by 3 months. Patients with subclinical AF had more than double the risk for stroke or systemic embolism:
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Director of UConn CV Research Center Accused of Scientific Misconduct 2

[See update at the end of the story] Following an extensive investigation, Depak Das, a professor in the Department of Surgery and director of the Cardiovascular Research Center at the University of Connecticut Health Center, has been accused of serious scientific misconduct. UConn has informed 11 scientific journals about the investigation.

Das had numerous publications on resveratrol and other nutrition-related cardiovascular subjects. According to an online biography, he was a founding editor and editor-in chief of the journal Antioxidant and Redox Signaling, and also served as associate editor of the American Journal of Physiology: Heat and Circulatory Physiology and consulting editor of Molecular and Cellular Biochemistry.

The news was announced by the UConn Health Center and has been reported by Retraction Watch, the Associated Press,  and the Connecticut Mirror.

The University said the investigation had been sparked by an anonymous allegation of research irregularities in 2008, resulting in a 60,000 page report that found Das guilty of 145 counts of fabrication and falsification of data. UConn said it worked closely with the US Office of Research Integrity during the investigation. UConn is now preparing to dismiss Das.
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Researchers Find Lower Sweet Spot for Potassium Levels in MI Reply

Current guidelines for the treatment of acute MI recommend that serum potassium be maintained between 4.0 and 5.0 mEq/L, and some believe that the upper limit could be raised to 5.5, but evidence is based on small, outdated studies. Now a new study published in JAMA suggests that the ideal potassium range should be adjusted downward.

Abhinav Goyal and colleagues performed a retrospective cohort study of 38,689 MI patients. They found a U-shaped relationship between the postadmission potassium level and in-hospital mortality, with the lowest rate of death found in patients with potassium levels between 3.5 and 4.5.

Postadmission Potassium Level and Mortality Rate (Adjusted Odds Ratio):

More…

Excess Risk of Cardiac Events Associated with Dabigatran Reply

Compared with controls, dabigatran (Pradaxa) is associated with a higher risk of myocardial infarction (MI) or acute coronary syndrome, according to a new meta-analysis published online in Archives of Internal Medicine.

Ken Uchino and Adrian Hernandez analyzed data from seven clinical trials comparing dabigatran with warfarin, enoxaparin, or placebo in 30,514 patients. The rate of MI or ACS was significantly higher in the dabigatran groups than in the control groups:
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Statins Elevate Risk of Diabetes in Postmenopausal Women Reply

Statins increase the risk of developing diabetes in postmenopausal women, according to a new study published in Archives of Internal Medicine. The study provides more evidence and details about the previously reported link between statins and the development of diabetes.

Using data from more than 153,000 postmenopausal women who were participating in the Women’s Health Initiative (WHI) and who did not have diabetes mellitus (DM) at baseline, and containing more than 1 million person-years of follow-up, the investigators found a significant increase in the risk of diabetes in women taking statins at baseline:
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Researchers Report a New Placebo Effect: Manipulating Clinical Trials 2

Two Danish diabetes researchers claim that the pharmaceutical industry may be manipulating independent clinical research by controlling access to placebo drugs or devices. In a letter published in the Lancet, Mikkel Christensen and Filip K Knop write that “this could be a major way for the pharmaceutical industry to control scientific information about their drugs.”

They cite an example in which researchers sought to obtain a placebo diabetes medication in a specialized injection pen “for an independently financed trial to investigate the effect of a marketed drug.” Here’s what happened:

Before considering delivery of placebo, the company asked for a full protocol to be scrutinised by an opaque system of evaluation committees. After more than 6 months, the company finally agreed to supply placebo devices provided that the protocol was changed according to their suggestions. The researchers were also obliged to allow the company access to the resulting trial report for 4 weeks before submission for publication.

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Diets Differ in Effect on Weight Gain and Fat and Lean Mass Reply

A new study published in JAMA demonstrates the various effects of overeating of three diets that differed mainly in protein composition.

George Bray and colleagues randomized 25 healthy volunteers to participate in an inpatient study to consume low, normal, or high protein diets which provided 40% more calories than required to maintain their normal weight. After 8 weeks there was less weight gain in the low protein group than in the other groups (p=.002).

Weight gain:

  • low protein group: 3.16 kg
  • normal protein group: 6.05 kg
  • high protein diet group: 6.51 kg

However, there was no difference between the groups in the increase in body fat, and the low protein diet caused no increase in energy expenditure or lean body mass. By contrast, energy expenditure and lean body mass increased with the normal and high protein diets.
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High STEMI Readmission Rate in US Linked to Shorter Hospital Stays Reply

STEMI (ST-segment elevation myocardial infarction) patients in the US are more likely to be readmitted to the hospital within 30 days compared to patients outside the US, but this difference loses significance when length of stay (LOS) is taken into account, according to a new study published in JAMA

Robb Cociol and colleagues analyzed data from 5,745 STEMI patients enrolled in the Assessment of Pexelizumab in Acute Myocardial Infarction trial and found that US patients had a 68% increase in the risk of readmission compared to patients outside the US.
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Missing Data: The Elephant That’s Not in the Room (Guest Post) 2

Editor’s Note: The following guest post by Harlan Krumholz is reprinted with permission from CardioExchange, the cardiology social media website published by the New England Journal of Medicine.

Missing Data: The Elephant That’s Not in the Room

by Harlan M. Krumholz, MD, SM

There is a problem so grave that it threatens the very validity of what we learn from the medical literature. Bad data? Not exactly. Actually, it’s missing data — information, relevant to the risks and benefits of treatments, that is simply not published. In some cases, these data would make a critical difference in the inferences that readers draw from the literature. The absence of the data renders meta-analyses, systematic reviews, and book chapters suspect. Conclusions are made on the basis of incomplete science. In short, publication bias and selective publication are impugning the validity of what we can learn from a PubMed search or even the most careful review of published studies.

This matter demands our immediate attention and speaks to the need to rethink the configuration of clinical medical science. It may be time to adopt strategies to ensure that all relevant studies, results, and supporting documentation are made publicly available. “Out of sight, out of mind” is a dangerous reality in science and medicine. It’s time for a change — and it starts with the recognition that we have a problem.

I urge you to read BMJ this week to explore the evidence of this problem. In full disclosure, the studies include one by me (with others, led by Joe Ross) showing that more than half of trials sponsored by the NIH go unpublished even 30 months after completion. The other articles reveal troubling information, including about how missing data can affect the results of meta-analyses — and how many investigators are ignoring the requirements for mandatory reporting of trial results, raising the question of what “mandatory” actually means.
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Bariatric Surgery Cuts Cardiovascular Deaths and Events Reply

Bariatric surgery results in significant reductions in cardiovascular deaths and events, according to a new study from Sweden published in JAMA. But one expert cautions that the results do not mean that obese patients without other weight-related complications should undergo surgery.

Analyzing data from more than 4,000 obese patients enrolled in the ongoing Swedish Obese Subjects (SOS) study, Lars Sjöström and colleagues found that bariatric surgery was associated with a reduction in cardiovascular events and deaths after a mean followup of 14.7 years. (The investigators had previously reported a reduction in total mortality in the treatment group.)
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Measuring In-Hospital Mortality Favors Hospitals with Short Stays Reply

As a measure of performance and quality, in-hospital mortality systematically favors hospitals with shorter length of stay (LOS) times, according to a new study published in Annals of Internal Medicine. The finding may have important implications for quality improvement initiatives that use mortality as a performance measure.

Elizabeth Drye and colleagues analyzed Medicare data from 3.5 million hospital admissions for acute MI, heart failure, and pneumonia. They observed  wide variations in the LOS for each condition and large differences between the in-hospital and 30-day mortality rates. Performance ratings were different for a substantial number of hospitals based on the mortality assessment used.

Acute MI:

  • Mean LOS varied from 2.3 to 13.7 days
  • In-hospital mortality and 30 day mortality: 10.8% and 16.1%
  • 8.2% of hospitals had a change in performance classification based on type of mortality assessment

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2011 in Review: Rivaroxaban, Sapien, Mark Midei, Conflicts of Interest, and Much More 4

Here’s a completely personal review of the past year in cardiology. Please write a comment if you strongly agree, disagree, or think something is missing.

Drug of the Year: Rivaroxaban (Xarelto)– Despite a highly negative review from FDA reviewers, rivaroxaban gained FDA approval for the coveted stroke prevention in AF indication. The drug was approved earlier in the year for VTE prevention after surgery. The biggest surprise, though, was rivaroxaban’s success in ACS in the ATLAS ACS TIMI 51 trial, which may well have an important impact on the field for years to come.

Device of the Year: Sapien Transcatheter Heart Valve– TAVI entered the marketplace this year. It will take another few years before its full impact is completely understood.

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J&J Submits NDA for ACS Indication for Rivaroxaban (Xarelto) Reply

Based on the promising results of the recently published ATLAS ACS 2 TIMI 51 trial, Johnson & Johnson has submitted a supplemental new drug application to the FDA for the approval of rivaroxaban (Xarelto) to reduce the risk of thrombotic cardiovascular events in ACS patients.

Following a succession of failed trials, ATLAS was the first trial to show a benefit in ACS with an anticoagulant. One key difference highlighted by many experts was the low dose of rivaroxaban used in the trial. In remarks published on CardioExchange, Samuel Goldhaber said that the trial “changes forever the way we’ll think about the pathophysiology of ACS and the way we’ll manage patients with STEMI, NSTEMI, or unstable angina.”

Click here to read the press release from J&J…

No Mortality Benefit Found For Low-Molecular-Weight Heparin in Acutely Ill Patients Reply

Although venous thromboembolism (VTE) is a serious problem for acutely ill patients in the hospital, a new study published in the New England Journal of Medicine failed to find any improvement in mortality associated with thromboprophylaxis.

Ajay Kakkar and the LIFENOX investigators randomized 8307 acutely ill patients to enoxaparin or placebo for 10 days. All patients wore elastic stockings with graduated compression.

There was no difference in 30 day mortality or major bleeding between the groups:
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Nissen and Topol Clash Over Genetics and Personalized Medicine Reply

Steve Nissen and Eric Topol, former colleagues and collaborators, have staked out opposite positions on the future of medicine. Topol has been a leading advocate for genomics and personalized medicine, while Nissen has now publicly questioned whether the enthusiasm for these technologies has outpaced their value in medicine today. In an editorial in JAMANissen writes that “in the popular press, the concept of personalized medicine has taken on a nearly cult like following with public pronouncements describing how future physicians will use therapies that reflect the specific genetic makeupof individual patients.”

For many years Nissen and Topol were colleagues at the Cleveland Clinic, where Topol was the chair of the department of cardiovascular medicine and Nissen served as his deputy. The two collaborated on numerous papers, most famously the JAMA paper that initiated the Vioxx controversy. Topol was replaced by Nissen when Topol lost his bid to become the Clinic’s CEO. The two have not collaborated since.

From his current perch as the chief academic officer at Scripps Health and the director of the Scripps Translational Science Institute Topol has been a staunch and highly vocal advocate for genomics and personalized medicine. His forthcoming book, The Creative Destruction of Medicine, rejects the worth of “one size fits all” medicine based on evidence derived from large clinical trials in favor of highly individualized medicine based on the individual genome, wireless monitors, and other digital technologies.
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Clopidogrel Testing Comes Under Fire Reply

The phenomenon of clopidogrel resistance has been much discussed, but no consensus has emerged about the best, or any, response to the problem. Now a review published in JAMA finds no clinically relevant relationship between the CYP2C19 genotype  and cardiovascular events.

Michael Holmes and colleagues performed a meta-analysis of 32 studies involving CYP 2C19 genotyping and more than 42,000 patients. In the observational studies of patients receiving clopidogrel, the investigators found an association between CYP 2C19 alleles and outcomes. However, they also found evidence of small-study bias, and when only larger studies were included the association was much diminished. In randomized trials, the clopidogrel genotype had no effect on outcome.

In an accompanying editorial, Steven Nissen writes that attempts to integrate clopidogrel testing in clinical practice, including a boxed warning about clopidogrel resistance from the FDA, have been premature:
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Study Finds Role For New Troponin Test in Diagnosis of MI Reply

A new study from Germany provides evidence that a new high-sensitive troponin I (hsTnI) assay may improve and speed the early diagnosis of acute MI. In an article published in JAMA, Till Keller and colleagues report on 1818 patients with acute chest pain in whom numerous biomarker tests were conducted at admission and at 3 and 6 hours after admission. They compared the diagnostic performance of hsTnI with that of contemporary troponin I and other biomarkers.

The hsTnI assay provided more diagnostic information than contemporary TnI, as measured by the area under the receiver operating characteristic (ROC) curve on admission:
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Study Finds MR Superior to SPECT, But Clinical Role Is “Uncertain” Reply

Authors of a new study published online in the Lancet state that multiparametric cardiovascular magnetic resonance (CMR) is superior to single-photon emission computed tomography (SPECT) in patients with suspected coronary heart disease (CHD). But at least one expert states that the future role of the technique in clinical practice remains “uncertain.”

John Greenwood and colleagues compared the diagnostic accuracy of CMR and SPECT in 752 patients with suspected CHD. All the patients also underwent invasive x-ray angiography. The investigators calculated the sensitivity, specificity, positive predictive value (PPV), and the negative predictive value (NPV) of the two tests.
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Ray of Light for the Physician Payment Sunshine Act Reply

The Physician Payment Sunshine Act (PPSA) may shed even more light on payments to physicians than previously expected. PPSA is the part of the health care reform act that will require pharmaceutical and device companies to report their payments to physicians and other healthcare workers and organizations. However, many observers thought a major loophole of PPSA was that it would not require disclosure of payments for continuing medical education (CME) programs funded through third parties like medical education companies, medical schools, professional organizations like the American College of Cardiology, and disease advocacy organizations.

But now CMS has finally published its proposed rules for the implementation of PPSA, and it appears likely that industry will have to disclose payments received by physicians for their participation in CME programs. The proposed rules mean that industry will have to disclose all payments when it is “aware of the identity” of the recipient. CMS gives the example of a third party payment to a department chair at a hospital:
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Study Examines Changes in Resting Heart Rate Over Time 1

Although resting heart rate (RHR) has been long known to be associated with cardiovascular risk, change in RHR over time has not been well studied. A new paper from Norway published in JAMA demonstrates that an increase in RHR over 10 years helps predict the risk of all-cause and ischemic heart disease (IHD) death.

Javaid Nauman and colleagues analyzed data from 46,410 Norwegian adults without known cardiovascular disease who had their RHR measured at baseline and at 10 years.

IHD Mortality and Adjusted Hazard Ratios (AHR):
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