October 6th, 2011
J&J Pleads Guilty, Pays $85 Million to Settle Natrecor Case
Larry Husten, PHD
The U.S. Department of Justice announced that Johnson & Johnson has pleaded guilty to a misdemeanor and has agreed to pay an $85 million criminal fine to settle charges about the company’s marketing of Natrecor (nesiritide) for off-label use.
The government said that Scios, the J&J subsidiary that marketed the drug, “admitted that it intended Natrecor to be used off-label for infusing chronic (non-acute) CHF patients on a scheduled, serial basis and that it understood that this was not an approved use of the drug.”
October 6th, 2011
Rivaroxaban Roundup: ATLAS-ACS an AHA Late-Breaker, NEJM Perspective, NYT Overview
Larry Husten, PHD
Rivaroxaban (Xarelto, Bayer and Johnson & Johnson) is in the news today.
In a rare move, the AHA has added the ATLAS ACS 2-TIMI 51 trial to its roster of Late-Breaking Clinical Trials to be presented next month at the AHA’s Scientific Sessions in Orlando. C. Michael Gibson will present the results on Sunday, November 13, at 5:13 PM.
Last week, Bayer announced the top-line results of the trial, and said that rivaroxaban had met the study’s primary endpoint, “showing a statistically significant reduction in the rate of events for the primary composite endpoint of cardiovascular death, myocardial infarction and stroke in patients with ACS, compared to standard therapy plus placebo.” However, the company also announced a significant increase in major bleeding events associated with rivaroxaban.
In a perspective about the FDA’s advisory panel on rivaroxaban published in the New England Journal of Medicine, Thomas Fleming (a member of the advisory panel) and Scott Emerson review some of the controversial aspects of the ROCKET AF trial discussed by the panel, which ultimately voted to recommend approval of the drug for stroke prevention in AF. They note that although rivaroxaban was superior to warfarin in the overall trial, the time in the therapeutic range (TTR) for patients taking warfarin was only 55%, which was low compared with other trials. In centers where the TTR was 67% or higher, by contrast, there was little difference between the two drugs in the main outcome.
Another problem with ROCKET was that the on-treatment analysis didn’t include events that occurred more than 2 days following discontinuation of the drug. This is potentially significant, write the authors, since the half-life of rivaroxaban is substantially shorter than that of warfarin (5-9 hours vs. 40 hours). When events that occurred between days 2 and 7 after drug discontinuation are included in the analysis, rivaroxaban is no longer superior to warfarin.
Fleming and Emerson also discuss the recent arrival of dabigatran, which is now approved for stroke prevention in AF and which demonstrated superiority to warfarin in the RE-LY trial. They express concern “that rivaroxaban could be inferior to either dabigatran or warfarin, particularly when the latter is ‘used skillfully.'” Approval of rivaroxaban, they write, “could lead to an unproven treatment displacing an effective treatment on the basis of overzealous promotion of more convenient once-daily dosing.”
Finally, rivaroxaban is included in an upbeat roundup of the new generation of anticoagulants in the New York Times. Cardiologists Christopher Granger and Jessica Mega are quoted extensively, generally praising the new drugs. The one downside to the new drugs is cost, according to the story. But the appearance of several new drugs may create a “downward pressure on costs,” writes Paula Span. Granger offers additional hope: “We may be able to persuade pharmaceutical companies that it’s better to have broader use at lower prices than less use at higher prices.”
October 5th, 2011
Does Intuition Lead to Bad Medical Decisions?
John E Brush, MD
Discussing how medical practitioners use intuition and cognitive shortcuts (heuristics) to make decisions can elicit strong reactions. Some people heartily agree that reflecting on their use is informative and helpful; others believe that to entertain this topic is to condone sloppy thinking and to renounce rationality and hard science. These critics are concerned that heuristic shortcuts are quick and dirty, favoring speed over accuracy. But research in cognitive psychology suggests otherwise.
Take, for example, a study in which Dawes and Corrigan compared the accuracy of the tallying heuristic (discussed in my previous post) with that of statistical linear regression. The investigators’ conclusion: For most practical decisions, a sum of unweighted variables beats models that use regression equations (Psychological Bulletin 1974; 81:95). Specifically, they found that linear regression can “over-fit” the data, resulting in perfect explanations of the past but imperfect predictions of the future. So, simply tallying in our heads is often better than making complicated calculations. As Dawes and Corrigan wrote, “The whole trick is to decide what variables to look at and then to know how to add.”
Herbert Simon coined the term “satisficing” to describe how we modify our decision making for speed and simplicity. Rather than performing exhaustive searches for the best answer to a problem, we stop when we reach a sufficiently adequate solution. A medical example of this heuristic is a mental process called early-hypothesis generation. We know from the work of Arthur Elstein that expert physicians generate 3 to 5 hypotheses very early in the evaluation of a complicated patient. They learn through experience that early-hypothesis generation improves the speed and accuracy of such an evaluation: It leads to targeted questioning and testing that reduces the random effects of a broader “shotgun” approach.
Other critics of intuitive reasoning say that we should rely only on deductive reasoning and evidence-based medicine — that we should simply follow the scientific rules. Unfortunately, that is usually not possible. Tricoci and colleagues recently examined the 16 current ACC/AHA guidelines and found that only 275 (10%) of the 2711 recommendations have the level of evidence (Ia or IIIa) that would enable the use of deductive logic (JAMA 2009; 301:831); another 26% are just instructions based on expert opinion (Ic or IIIc); the remaining 64% (the rest of the level designations) require judgment and reasoning. Furthermore, guideline recommendations pertain to only a fraction of medical practitioners’ daily decisions. In general, psychologists estimate that 9 out of 10 decisions are made with intuition — a figure consistent with the data in Tricoci et al.’s analysis of cardiology guidelines.
Whether heuristics are helpful or flawed has been a subject of hot debate in the psychology literature for the past several decades. Just like more “rational” modes of thinking, heuristics have their advantages and limitations (see my previous post for a discussion of the work of Gerd Gigerenzer and of Daniel Kahneman and Amos Tversky, respectively). The bottom line: Heuristics are here to stay because they help us effectively manage the uncertainty that is inescapable in medical practice.
I doubt that “rational” analytical methods and computers will someday replace our use of intuition and heuristics. After all, there is still no computer program that can reliably pick stocks or predict economic downturns. Computers remember things better than we do and can aid in decision making, but overall they don’t reason any better than the human mind. Practicing medicine involves science and common sense. To improve our thinking, we need a common understanding of how we use common sense. We must continue to advance science, but we also need to give greater attention to how we use medical reasoning to apply the science in daily practice.
Where do you stand on the question of how we do — and how we should — make decisions in our daily practice?
October 4th, 2011
Is “Stent and Send” Safe for Older Patients?
Richard A. Lange, MD, MBA and L. David Hillis, MD
Should older patients who undergo elective coronary artery stenting be sent home the same day?
Using data from the CathPCI Registry, Rao and colleagues examined outcomes in Medicare-eligible patients who underwent elective, first-time PCI. The investigators identified 107,018 patients (<11% of the million-plus older patients undergoing PCI during 2005–2008 after exclusion of those with ACS or shock and those transferred from another hospital or undergoing an urgent, emergent, or salvage procedure) and compared patients who were discharged the same day with those who were observed in the hospital overnight (see CardioExchange News blog).
What did the study authors find?
1. Only 1.3% of older patients undergoing elective PCI were discharged the same day of the procedure.
2. Compared with overnight observation, same-day discharge was not associated with an increased risk for death or readmission, either within 2 days or at 30 days after discharge.
Were the same–day-discharge and overnight-observation patients similar?
Not really. Compared with the overnight-observation patients, those discharged on the same day were more likely to have vascular closure devices and less likely to have received glycoprotein IIb/IIIa inhibitors, bivalirudin, or multivessel PCI.
The authors conclude that “selected low-risk patients may be considered for same-day discharge.”
What do you think?
Do their observational data support their conclusion?
What percentage of patients 65 years or older in your practice are low-risk and eligible for same-day discharge after PCI?
Should we be making policy decisions based on data from the CathPCI Registry (which is a voluntary, unaudited registry)?
Given that inpatient PCI in the U.S. is reimbursed at a higher rate than outpatient PCI (in-hospital observation for 23 hours or less), do you perceive a financial incentive to avoid same-day discharge in favor of hospital admission?
October 4th, 2011
Same-Day Discharge After PCI: Safe but Rarely Used
Larry Husten, PHD
Same-day discharge after low-risk PCI is safe but only rarely used, according to a study published in JAMA.
Sunil Rao and colleagues analyzed data from 107,018 Medicare patients who underwent PCI at sites taking part in the CathPCI Registry. Only a small percentage (1.25%) of patients in the study were discharged on the day of the procedure. These patients were similar to the patients with overnight stays, although same-day patients had shorter procedures, had fewer multivessel procedures, were more likely to have procedures using a transradial approach, and were more likely to receive a vascular closure device. Same-day discharge patients also had less hypertension and dyslipidemia. In addition, they were less likely to receive GP IIb/IIIa inhibitors or bivalirudin.
Rates of death or rehospitalization at 2 days or at 30 days did not differ significantly between patients discharged on the same day and those discharged after an overnight stay:
- 2 days: 0.37% in the same-day group and 0.50% in the overnight group (p=0.51)
- 30 days: 9.63% and 9.70% (p=0.94).
For both groups, the median time to death or rehospitalization was almost the same (13 days in the same-day group, 14 days in the overnight group).
One “nonclinical reason” for the low rate of same-day discharge is that inpatient PCI is reimbursed at a higher rate than outpatient PCI, the authors note. The study results, they write, “suggest that a proportion of low-risk patients currently observed overnight may be eligible for same-day discharge without an increase in early or intermediate-term adverse events.”
Our Interventional Cardiology moderators, Rick Lange and David Hillis, pose some thoughtful questions about the implications of this study here. Take a look, then tell them what you think.
October 3rd, 2011
Guidelines for Managing Peripheral Artery Disease Updated
Larry Husten, PHD
The ACC and the AHA have released updated guidelines for managing peripheral artery disease (PAD). The document is available online in the Journal of the American College of Cardiology and in Circulation.
The new guidelines place a greater emphasis on tobacco cessation, requesting healthcare providers to consistently ask patients about their smoking status and to offer support to help them quit through counseling and formal smoking cessation programs. Pharmacotherapy for smoking cessation gains a class I recommendation, with the guidelines stating that at least one of following should be offered: varenicline, bupropion, or nicotine replacement therapy.
The updated guidelines recommend measurement of the ankle-brachial index (ABI) in patients 65 years of age or older. In the 2005 guidelines, the recommendation was for ABI to be used in patients 70 years or older.
Antiplatelet therapy can be used in asymptomatic patients with an ABI of 0.90 or lower, but is not recommended for those with a borderline ABI. Oral anticoagulants are not recommended as an addition to antiplatelet therapy.
Bypass surgery is described as a reasonable initial treatment in patients with limb-threatening ischemia and a life expectancy greater than 2 years.
Open and endovascular repair are said to be nearly equivalent in terms of safety and efficacy for the treatment of aortic aneurysms.
September 29th, 2011
Rivaroxaban Meets Primary Endpoint in ATLAS ACS TIMI 51
Larry Husten, PHD
Bayer AG announced today that in the ATLAS ACS TIMI 51 trial, rivaroxaban (Xarelto, Bayer and Johnson & Johnson) had met the primary efficacy endpoint in patients with acute coronary syndrome (ACS). The drug was associated with “a statistically significant reduction in the rate of events for the primary composite endpoint of cardiovascular death, myocardial infarction and stroke in patients with ACS, compared to standard therapy plus placebo.”
However, the company also announced that rivaroxaban-treated patients showed a statistically significant increase in major bleeding events not associated with CABG surgery, the primary safety endpoint of the trial. The results of the trial will be presented at a scientific meeting in the future, the company said.
In July, the announcement of the APPRAISE 2 results with apixaban in ACS appeared to dash hopes that oral anticoagulation therapy could be added to dual antiplatelet therapy in ACS. One difference that may turn out to be key is that patients enrolled in ATLAS ACS were stratified on the basis of whether the investigator planned to give aspirin alone or aspirin plus a thienopyridine such as clopidogrel or prasugrel. The Bayer announcement did not include any information about outcomes in the different strata.
At the recent FDA advisory committee panel about the ROCKET AF trial, many panel members expressed concern about the once-daily dosage of rivaroxaban used in ROCKET AF. In ATLAS ACS, by contrast, rivaroxaban was given twice daily, as either a 2.5-mg or 5-mg pill.
Additional resources:
September 29th, 2011
Meta-Analysis Explores Real World CV Risk of NSAIDs
Larry Husten, PHD
A new meta-analysis sheds additional light on the cardiovascular risk of NSAIDs as used in the real world, including low doses of the most popular drugs, over short periods, and in low-risk populations.
In a paper published online in PLoS Medicine, Patricia McGettigan and David Henry analyzed data from 30 case-control studies including 184,946 CV events and 21 cohort studies with outcomes in more than 2.7 million people.
Among the NSAIDs with extensive data, rofecoxib and diclofenac had the highest CV risk while ibuprofen and naproxen had the lowest risk:
- rofecoxib, 1.45 (95% CI 1.33-1.59)
- diclofenac, 1.40 (1.27-1.55
- ibuprofen, 1.18 (1.11-1.25)
- naproxen, 1.09 (1.02-1.16)
The authors point out that diclofenac was associated with elevated risk even at over-the-counter doses and that etoricoxib “is similar to drugs that have been withdrawn because of safety concerns.” Indomethacin also showed high risk; the authors write that the drug “has a range of gastrointestinal and central nervous system effects that, combined with the evidence presented here on cardiovascular risk, should lead to questioning of its continued clinical use.”
September 28th, 2011
Troponin Elevation in Skeletal Muscle Disease: Vindication for the Consulting Cardiologist?
Beth Waldron, MA
In an elegant study that will resonate with the anecdotal experience of many consulting cardiologists, Jaffe and colleagues provide strongly suggestive evidence that elevations in “cardiac” troponin T may not be quite as specific for cardiac muscle injury as has been claimed (see CardioExchange News blog). Among patients with skeletal myopathies who had elevations in cTnT but not cTnI, the investigators first excluded (within the limits of clinically available testing) a likely cardiac source of cTnT elevation. Then, from skeletal muscle biopsy specimens, they identified cTnT immunoreactivity within skeletal muscle.
I think it is clear that, in an era of increasingly sensitive troponin assays, we have a specificity problem when >50% of troponin elevations among hospitalized patients result from processes other than an acute coronary syndrome. Usually, such elevations arise from nonischemic causes of cardiac injury. These new findings, however, suggest that at least in some individuals with advanced skeletal muscle injury or chronic disease, cTnT elevation may not indicate cardiac injury at all. Whether this phenomenon is restricted to rare patients with advanced skeletal muscle disease or explains an important proportion of the “unexplained” cTnT elevations we see in the hospital is not clear. Moreover, although the limited data available suggest that skeletal muscle expression is more common with cTnT than with cTnI, we do not yet know whether similar or related issues contribute to specificity problems with cTnI as well.
We need to be careful not to over-interpret these findings, since the large majority of “non-ACS” troponin elevations do reflect cardiac injury. Because we have no good data to guide our care of patients with troponin elevations that do not appear to arise from ACS, our job as consultants is to arrive at a prudent, common-sense strategy that recognizes that these individuals are at high risk but that does not expose them to misguided over-testing. Recent work suggests that structural heart disease (LVH, LV dysfunction), rather than coronary disease, is frequently the culprit source of injury. In such cases, the troponin elevation is typically low-level and chronic, and there is really no indication for inpatient evaluation. In other cases, transient hemodynamic stressors may “unmask” structural heart disease and lead to transient troponin elevations. In the hospital, when I get the standard “troponin consult,” and no evidence supports acute ischemia or pulmonary embolism (which must be considered in the differential diagnosis), my strategy is to perform an echocardiogram to evaluate for structural heart disease, treat with low-dose aspirin with or without a beta-blocker, and “let the dust settle” before determining if any additional testing is needed.
What is your approach to the “unexplained” troponin elevation?
September 28th, 2011
Study Finds Noncardiac Sources of Positive Troponin T Tests
Larry Husten, PHD
Cardiac troponin T (cTnT) is not always cardiac specific and in some cases may lead to a false-positive diagnosis of cardiac injury, according to a study in the Journal of the American College of Cardiology.
The study was prompted by a case seen by a senior clinician at the Mayo Clinic in which a patient, who was ultimately found to have a form of muscular dystrophy and no heart disease, had persistent cTnT elevations despite a slew of other negative tests, including negative cardiac troponin I (cTnI). Allan Jaffe and colleagues then sought to find similar myopathy patients treated at the Mayo Clinic’s Neuromuscular Clinic by measuring both cTnT and cTnI.
The authors identified 16 myopathy patients without cardiovascular disease who had increased cTnT but not cTnI. A Western blot analysis demonstrated that skeletal muscle proteins were capable of provoking a positive cTnT response.
In their discussion, the authors acknowledge that the clinical significance of this problem is not known, but “it appears likely that there are at least some circumstances in which increases appear to be due to noncardiac sources of cTnT, and these certainly could lead to confusion in individual clinical cases.” Previous studies further suggest “that the frequency of such clinically undetected myopathies may not be trivial.” The authors note that “even if the frequency of false-positive increases is extremely low, given the large numbers of patients evaluated with this testing, the absolute numbers of patients who could have increases due to skeletal muscle disease could be substantial.”
For an expert’s take on the findings, see the latest post from CardioExchange’s James de Lemos here.
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