September 12th, 2011
Study Finds Risks and Costs Associated with Infection After Device Implantation
Larry Husten, PHD
A large new study has found significant risks and costs associated with infections following the implantation of CIEDs (cardiovascular implantable electronic devices), including ICDs, CRT-Ds, and pacemakers.
In a paper published in Archives of Internal Medicine, Muhammad Sohail and colleagues analyzed Medicare data from more than 200,000 patients admitted for CIED implantation, replacement, or revision in 2007, including 5817 admissions with infection. Infection was associated with an increase in the rate ratio for admission mortality (4.8- 7.7) and for long-term mortality (1.6-2.1). The researchers noted that about half of the increased long-term mortality occurred after hospital discharge.
Infection was also associated with longer length of stay (RR, 2.5- 4.0) and an increase in hospital costs ($14,360-$16,498). About 40% of the extra cost was due to the need for intensive care. The increases in mortality and cost were greatest in the group of patients who received pacemakers.
In an accompanying commentary, Ronan Margey notes that the rate of infections related to CIED implantation has been accelerating. The study, he writes, “is a warning siren to physicians to be sure ICD implantation is appropriate per professional society guidelines and to monitor patients at risk of developing infection closely and intervene promptly.”
September 12th, 2011
Arrest: When to Check the Rhythm?
Daniela J Lamas, MD
Editor’s Note: The following guest post by Daniela Lamas is reprinted with permission from Now@NEJM, a blog for physicians about NEJM.
The woman slumps to the floor beside her office desk… No one sees her go down… A colleague hears a thud and rushes in….. He calls her name… No response… He checks for a pulse: nothing… “Call 911!” he yells.
EMS arrives quickly, and finds the co-worker panicked, but performing good quality chest compressions he learned in a life support class.
The emergency medical technicians take over CPR while setting up the defibrillator, as dictated by current standard of care. But when in this un-witnessed arrest should they pause, analyze the rhythm and shock if indicated?
At this point the recommendations become shaky. Analyze first? That was the standard until 2005, when guidelines from the American Heart Association-International Liaison Committee on Resuscitation were revised to suggest, instead, that EMS personnel provide 2 minutes of CPR before the first analysis of cardiac rhythm. The theory behind this change is that increasing myocardial perfusion could result in more effective first defibrillation. But this hasn’t been clearly borne out in studies, which have offered inconsistent evidence. Thus, in 2010, in the face of conflicting data, the AHA committee revised their guidelines to say there was actually no clear evidence to back up early or later analysis.
All this leaves those EMS personnel at the scene of this out-of-hospital, un-witnessed arrest with some uncertainty. Should they analyze the rhythm as soon as possible, after a brief period of CPR? Or should they wait for a full round of CPR before first analysis? In a situation with such dismal outcomes, would this change make any difference at all?
The answer is: No, there’s no benefit to waiting. That is based on results of a large-scale, randomized trial of adults with out-of-hospital cardiac arrest, “Early versus Later Rhythm Analysis in Patients with Out-of-Hospital Cardiac Arrest,” published in last week’s issue of NEJM. In this study, Stiell and colleagues enrolled 9933 patients with out-of-hospital cardiac arrest in sites throughout the United States and Canada. The early analysis group was assigned to receive 30-60 seconds of EMS-administered CPR before rhythm analysis. In the later analysis group, EMS was to administer 180 seconds (3 minutes) of CPR directly upon arrival at scene.
The primary endpoint was survival to hospital discharge with “satisfactory functional status” – which study investigators defined as a score of 3 or less on the Rankin scale, which measures disability or dependence in daily activities. (A score of 3 describes moderate disability, requiring some help but able to walk unassisted, for instance).
There was no significant difference in the primary outcome between the two study groups: 6.0% of the patients with shorter CPR, and 5.9% of the patients with longer CPR left the hospital with a satisfactory functional status. When the authors looked at survival as a function of actual time to rhythm analysis (regardless of how the patients had been assigned), they again found that the chance of a satisfactory outcome didn’t improve with more time to first rhythm analysis. Interestingly, the rate of survival actually declined with longer EMS-administered CPR in those who had received CPR first from a bystander and whose first analyzed rhythm was ventricular tachycardia or ventricular fibrillation.
The authors conclude, “Overall, our data suggest that the administration of 2 minutes of CPR by EMS personnel before the first analysis of rhythm…is unlikely to provide a greater benefit than CPR of shorter duration.”
What about no CPR at all, prior to first analysis? That question remains unanswered, as the study investigators write that they “deliberately insisted on some CPR for the early-analysis group, in the belief that good patient care required cardiopulmonary support while the defibrillator was being prepared.”
While the data showed no benefit to waiting a longer time for rhythm analysis, it’s important to note that 36% of the patients in the study did not receive the assigned compression-to-analysis time. Does this negate the results? The authors argue that this limitation points to the difficulties inherent in performing a randomized controlled trial in a life-or-death, often messy and uncontrolled situation with so many potential variables.
In an accompanying editorial, Arthur B. Sanders, an emergency medicine physician who researches efficacy of resuscitation, addresses precisely this challenge. He writes that perhaps randomized-controlled trials are not the best way to answer these questions: “The urgency of the setting, the heterogeneity of initiating causes and clinical features of the arrests, the fact that informed consent must be waived…all makes trials problematic. It may be more useful to consider out-of-hospital cardiac arrest as a public health problem rather than as a disease process.”
Which leaves us with our patient. EMS is at the scene. How to give her the best chance to leave the hospital with as little disability as possible?
They’ve been performing CPR for a minute now. Should they pause and analyze the rhythm? It seems, on the basis of this study, that there’s no benefit in waiting, and it’s probably time to see what’s going on.
Question: How would you acquire more data on resuscitation? If randomized controlled trials aren’t the way to go, what would you suggest?
September 9th, 2011
Asymptomatic Carotid Stenosis: Medical Management or Revascularization?
Allan Brett, MD
Every so often, one of my patients with no history of stroke or transient ischemic attack asks my opinion on what to do about a carotid ultrasound — not ordered by me — showing high-grade stenosis. I am a general internist, and I don’t obtain these studies in patients without a history of cerebrovascular symptoms. Guidelines don’t endorse carotid screening in such patients, yet they end up getting screened in various ways: Some cardiologists and vascular surgeons routinely get carotid studies in their patients with coronary disease; some clinicians order ultrasound for patients with asymptomatic carotid bruits; some clinicians include routine carotid ultrasound inappropriately in their “syncope workup”; and companies offer direct-to-consumer ultrasound screening. Because many of these patients are told “you need surgery” or “you need stenting” as if there’s no choice in the matter, a brief look at asymptomatic carotid stenosis is warranted.
Two large randomized trials compared carotid endarterectomy (CEA) and medical therapy in patients with asymptomatic carotid stenosis — a North American study published in 1995 (JAMA 1995; 273:1421) and a European trial published in 2004 (Lancet 2004; 363:1491). In both trials, the 5-year risk for stroke (including perioperative stroke or death) was significantly lower with CEA than with medical therapy, but the difference was only about 5 percentage points (5%–6% vs. 11%–12%), and no benefit was seen in women (Curr Opin Neurol 2007; 20:58). Given the 2% to 3% rate of perioperative stroke or death, it took several years for the benefit of CEA to clearly surpass that of medical therapy.
Because medical therapy has improved since these trials were conducted, researchers have examined whether stroke rates in patients with asymptomatic carotid stenosis have declined during the past decade. In fact, rates have fallen to around 1% annually in medically treated patients (Stroke 2010; 41:e11 and Stroke 2009; 40:e573). Thus, we must ask whether CEA has any role in patients with asymptomatic carotid stenosis. Recently, researchers have proposed several imaging findings that might identify high-risk subgroups — plaque echolucency, plaque ulceration, and embolic signals on transcranial Doppler ultrasound of the ipsilateral middle cerebral artery.
In one study of 435 patients with asymptomatic carotid stenosis (>70% stenosis by ultrasound), only 10 patients (2%) had strokes during an average follow-up of 2 years (Neurology 2011; 77:751). However, 4 of these strokes occurred among the 27 patients with both echolucent plaque and embolic signals (15% stroke rate). In contrast, only 1.5% of patients without these 2 findings had strokes.
In another study of 253 patients with asymptomatic carotid stenosis (>60% stenosis by ultrasound), only 6 patients (2.5%) had strokes during an average follow-up of 3 years (Neurology 2011; 77:744). Three of these strokes occurred in the 42 patients with at least 2 carotid ulcerations (7%); in contrast, the stroke rate was only 1.4% in the 211 patients with one or no ulcers. In addition, the stroke rate was 13% in patients with embolic signals (2 of 15 patients) but only 1.7% in those without embolic signals (4 of 238 patients).
The most striking aspect of these 2 studies is their confirmation of a very low overall incidence of stroke — about 1% per year. Thus, many asymptomatic patients who now undergo CEA (or carotid stenting, which is not safer than CEA) are likely risking harm without commensurate benefit. The use of embolic signals and plaque characteristics to identify candidates for CEA is promising but requires larger numbers and assurance that the techniques are reliable in community settings. Editorialists argue for “intensified medical management rather than revascularization procedures in patients with asymptomatic carotid stenosis,” until strategies to identify high-risk patients have been thoroughly investigated (Neurology 2011; 77:710). I find their position, which happens to reinforce my previous thinking on this topic, to be compelling. What’s your point of view?
September 8th, 2011
FDA Advisory Panel Gives Yellow Light to Rivaroxaban
Larry Husten, PHD
The FDA Cardiovascular and Renal Drugs Advisory Committee voted 9-2 (with 1 abstention) in support of rivaroxaban (Xarelto, Johnson & Johnson) for stroke prevention in patients with atrial fibrillation, but the vote did not represent a ringing endorsement of the drug. The committee wrestled throughout the day with the numerous concerns raised by FDA reviewers, who had recommended that the drug be rejected. The committee left three key issues for the FDA to resolve if it approves the drug:
- Although rivaroxaban was noninferior to warfarin in the pivotal ROCKET trial, warfarin was not used as skillfully in ROCKET as in RE-LY and other recent trials, thereby making it difficult to assess the true efficacy of rivaroxaban.
- Because of a high number of events observed in patients when they discontinued use of rivaroxaban, there is no firm guidance for how to transition patients to warfarin or other drugs when rivaroxaban is discontinued.
- The optimal dose of rivaroxaban is still unclear. Many on the committee thought rivaroxaban might perform better as a twice-a-day drug.
September 8th, 2011
When Is the Patient “Too Old” for an ICD?
Tariq Ahmad, MD, MPH and James Fang, MD
An 86-year-old man presents to you for the first time with lightheadedness and increasing dyspnea on exertion, which he reports experiencing for the past 4 months. He has a history of coronary artery disease requiring 3-vessel bypass, dyslipidemia, hypertension, and chronic lymphocytic leukemia (CLL) that has been stable for many years.
His vital signs upon presentation are as follows: blood pressure, 110/80 mm Hg; heart rate, 35 bpm; afebrile; oxygen saturation of 98% on room air. His physical exam is significant for a 2/6 holosystolic murmur at the apex. He has no evidence of jugular venous pressure elevation, third-heart sound, rales, hepatosplenomegaly, or lower-extremity edema. ECG reveals sinus bradycardia at 35 bpm, a first-degree atrioventricular block, and a left bundle-branch block with a QRS duration of 160 ms. Lab tests show a creatinine level of 1.5 mg/dL and hematocrit of 30%.
A transthoracic echocardiogram reveals an LV ejection fraction of 30%. Records from the patient’s previous cardiologist document an LVEF of 30% more than 1 year ago. The patient has been on a stable regimen of an ACE inhibitor, furosemide, aspirin, and a statin. He was taking a beta-blocker for many years until 2 weeks back, when his primary care physician took him off the medication “due to slow heart rate.” The patient denies a history of syncope or cardiac arrest.
The patient lives alone, but his daughter visits him weekly and prepares food that lasts the entire week. His mobility is limited; at most he walks to a store down the street. He and his family want “everything done.” When questioned about the patient’s life expectancy with CLL, his oncologist says, “Your guess is as good as mine.”
Questions:
- Would you consider pacemaker/ICD therapy for this patient? If so, would you suggest cardiac resynchronization therapy (or CRT with defibrillator)?
- What aspects of the patient’s clinical profile would influence your decision? How would you approach the conversation about an implanted device?
- How important should age be in choosing an expensive therapy such as an ICD? Should the decision be left to the patient and his family or to the caring physician?
- If an ICD is chosen, would you discuss the option of turning it off with the patient and his family?
Response:
James Fang, MD
September 29, 2011
This elderly man has symptomatic systolic heart failure from chronotropic incompetence and electromechanical dyssynchrony (e.g., wide left bundle-branch block) despite medical therapy. Pacing and cardiac resynchronization therapy (CRT) should be offered in this situation, given that there is reasonable evidence (although extrapolated from randomized trials involving patients younger than 70) to suggest biventricular pacing would enhance his quality of life by improving both the chronotropic incompetence and the dyssynchrony. Although the patient has chronic lymphocytic leukemia, it appears to be clinically stable (indeed, stable CLL can persist for years).
However, the evidence is modest that octogenarians, specifically, derive a clinically relevant improvement in overall survival with ICD therapy. The patient should be given the alternative of CRT without ICD, although that option is rarely offered in the U.S. The patient and his family need to know that concomitant ICD therapy will not improve his quality of life and could potentially make it worse, as the chance of receiving inappropriate shocks (e.g., from rapid atrial arrhythmias) is increased.
In ICD trials, the survival curves took at least one year to separate, and it is not known when (or if) this separation occurs in octogenarians. Notably, subsequent survival following an appropriate ICD shock is related to heart failure, which will not improve with ICD therapy alone. Thus, patients should be counseled that ICD therapy will simply change the mode of their ultimate demise from sudden death (which many people prefer) to an insidious decline in health, functional capacity, and loss of independence that accompany chronic heart failure.
Finally, patients and families should clearly understand that “turning off” the ICD is not tantamount to “turning the patient off.” Rather, it is an inactivation of an electrical discharge that would interfere with the peace and dignity of end of life when it inevitably comes.
Update:
Tariq Ahmad, MD, MPH
October 10, 2011
After long discussions among the patient, his family, and the cardiologists, spanning several outpatient clinic visits, a decision was made to implant a CRT device with ICD capabilities. Although it was believed that the patient would be likely to benefit from pacing and cardiac resynchronization, the decision regarding an ICD was more difficult. After input from the oncologist, the patient’s life expectancy was predicted to be at least 1 year. The patient and his family were told about the risks versus the benefits of an ICD, and they elected in favor of it. They were also heavily influenced by input from a family friend whose ICD had apparently “saved his life many times.”
The patient was brought in as an outpatient, the device was implanted without complications, and he was discharged the next day. He was seen in the EP device clinic 3 months after discharge and, according to the clinic note, appeared to “have more energy.” He was also seen in the heart-failure clinic, where he reiterated his improved HF symptoms. However, objective assessments of his functionality, such as peak VO2 testing, have not been performed. Also, discussions about turning the ICD off under certain clinical scenarios have not been broached.
September 7th, 2011
Medical Therapy Wallops Stenting for Intracranial Stenosis
Larry Husten, PHD
In recent years stenting for intracranial arterial stenosis has become widespread. Now, however, a trial testing the procedure has been terminated early, raising serious questions about both the safety and efficacy of the technique.
In the SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) trial, which has now been published online in the New England Journal of Medicine, 451 patients with a recent TIA or stroke attributed to a 70-99% stenosis of a major intracranial artery were randomized to either aggressive medical therapy (consisting of aspirin, clopidogrel, and management of primary risk factors) or the same medical therapy plus stenting with the Wingspan stent system. The trial was terminated early due to a much higher rate of stroke or death in the stenting group. Here are the main results of the trial, with a mean follow-up of 11.9 months:
- Stroke or death at 30 days: 14.7% in the stent group versus 5.8% in the medical group (p=0.002)
- nonfatal stroke: 12.5% versus 5.3%
- 5 stroke-related deaths in the stent group; 1 non-stroke-related death in the medical group
- Stroke or death at 1 year: 20.0% versus 12.2%
In an accompanying editorial, Joseph Broderick points out that SAMMPRIS joins two trials of intracranial-extracranial bypass surgery in failing to demonstrate a benefit for intracranial revascularization. The trial, he writes, offers evidence that intracranial revascularization is technically challenging and provides further evidence of the benefits of aggressive medical management.
Broderick also praises CMS for refusing to provide reimbursement for the Wingspan stent outside of its use in a randomized trial, thereby encouraging enrollment in SAMMPRIS. “The FDA and CMS must be consistent gatekeepers for the distribution and diffusion into clinical practice of technology that affects the quality and cost of clinical care,” he concludes.
September 6th, 2011
FDA Reviewers Recommend Complete Response Letter for Rivaroxaban (Xarelto)
Larry Husten, PHD
FDA reviewers have recommended against the approval of rivaroxaban (Xarelto, Johnson & Johnson), which will be the subject of a Cardiovascular and Renal Drugs Advisory Committee meeting on Thursday. The recommendation comes as a surprise, as many physicians and analysts had expected an easy approval for the drug.
The bottom line from the FDA reviewers is that the pivotal ROCKET trial failed to demonstrate that rivaroxaban was as effective as warfarin, since warfarin was not “used skillfully” in the trial. The reviewers note that the time in the therapeutic range (TTR) for warfarin-treated patients was lower in ROCKET than in similar trials with other drugs. The mean TTR for warfarin in ROCKET was 55%, compared with 63%-73% in other recent warfarin-controlled studies, according to the reviewers. Thus, although the trial was technically a success because it demonstrated that rivaroxaban was noninferior to warfarin, this finding does “not take into account other factors, such as the quality of anticoagulation in the warfarin arm.”
The FDA explained its recommendation:
…if the underlying goal of protecting public health is to be advanced, the logical course is to reject the new therapy because it has not been convincingly demonstrated to be as effective as approved therapy.
The FDA also raised concerns about the safety of rivaroxaban, noting “an excess of strokes in the rivaroxaban arm during the transition from blinded study drug to open label warfarin at the end of the study.”
The single daily dose of rivaroxaban was also criticized. The FDA reviewers noted that clinical pharmacology studies had suggested that twice-daily dosing might have been more safe and effective. (At the press conference for the ARISTOTLE trial at the ESC, the investigators noted that the pharmacology of apixaban, which is given twice-daily, is not substantially different from that of rivaroxaban.)
The FDA reviewers said a single study could be performed that would address all the major issues raised by the review. No other safety concerns were raised by the reviewers.
It comes as no surprise then that the FDA reviewers strongly rejected J&J’s request for a superiority claim:
Superiority language in labeling might induce physicians to switch patients who are doing well on warfarin to rivaroxaban. However, the study data do not support an advantage for such a switch.
The reviewers did hold out hope that rivaroxaban might gain approval with a weak second- or third-line indication:
…if the medical community is currently in great need of an additional oral anticoagulant for use in AFib patients, it might not be unreasonable to approve rivaroxaban as second or third line treatment. It might be useful in patients who are poorly controlled on warfarin or refuse to take it. However, given that dabigatran has been shown to be superior to warfarin when it [is] used reasonably well, and robustly non-inferior to warfarin when it is used extremely well, it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran.
The advisory committee meeting will undoubtedly feature some heated discussion, especially since both Steve Nissen, the noted industry skeptic, and Sanjay Kaul, a tough critic of clinical trials, will be members of the panel. Duke’s Rob Califf will present and defend the ROCKET results for J&J. It should be noted that Califf has clashed with Nissen in the past, most notably during the rosiglitazone (Avandia) controversy.
Here are links to the FDA briefing documents:
- September 8, 2011: Cardiovascular and Renal Drugs Advisory Committee Meeting Announcement
- Draft Agenda for the September 8, 2011 Meeting of the Cardiovascular and Renal Drugs Advisory Committee (PDF – 66KB)
- Draft Questions for the September 8, 2011 Meeting of the Cardiovascular and Renal Drugs Advisory Committee (PDF – 153KB)
- Draft Meeting Roster for the September 8, 2011 Meeting of the Cardiovascular and Renal Drugs Advisory Committee (PDF – 60KB)
- Committee Roster for the September 8, 2011 Meeting of the Cardiovascular and Renal Drugs Advisory Committee (PDF – 29KB)
- Briefing Information for the September 8, 2011 Meeting of the Cardiovascular and Renal Drugs Advisory Committee
September 5th, 2011
Base-Rate Neglect: A Common Clinical Fallacy
John E Brush, MD
In my previous post, “Numbers Traps in Clinical Practice,” I ended with this quiz question:
An emergency department decides to perform serum troponin testing on all patients with any type of chest complaint. They suspect that the incidence of documented myocardial infarction in this subgroup is only 1%, but they are determined not to miss a single MI. They choose a high-sensitivity troponin assay with a sensitivity of 95% and a specificity of 80%. For one of these patients with a positive troponin, what are the odds of having an MI?
About two thirds of online respondents selected the correct multiple-choice answer: 1 to 24. In this post, I’d like to delve a bit deeper into how we make calculations like this in clinical practice. Conditional probabilities are hard to calculate in our heads, but easy with a branching algorithm or a 2×2 table. For this problem, assuming there are 1000 total patients, we can set up the following table:
| Patients with MI | Patients without MI | Predictive Value | |
| Positive test | 9 true positives | 198 false positives | 9 /207 = 4% |
| Negative test | 1 false negative | 792 true negatives | 792/793 = 99.9% |
| Total | 10 | 990 | 1000 |
The posttest probability of an MI, given a positive troponin result when the test is used relatively indiscriminately, is only 4%. The odds (probability divided by the complementary probability) are 4 to 96. Thus, the odds are 24 to 1 against you if you are betting that your patient is having an MI — not a very good bet.
As the table shows, it’s relatively easy to calculate posttest probability if you work through the numbers. You can also calculate the posttest odds by multiplying the pretest odds by the likelihood ratio, or by simply plugging the numbers into an app on your smartphone. But for individual patients, we rarely do formal calculations. We seem to prefer subjective probabilities, perhaps acknowledging that pretest probability is usually just an estimate and that posttest probability is a number that doesn’t necessarily yield an obvious clinical decision.
According to cognitive psychologists, we tend to eschew formal calculations in favor of a heuristic called anchoring and adjusting and, thereby, subjectively estimate conditional probabilities. We estimate an anchor, which is the pretest probability or the base rate. We then adjust the anchor using new information. Studies show that decision makers are often over-influenced by the adjustment or new information. They often forget about the base rate and incorrectly estimate the probability. It’s a fallacy known as base-rate neglect. Base-rate neglect can lead to poor design of testing strategies, such as indiscriminate troponin testing.
Let’s imagine that we revise the strategy of troponin testing and instead take a history and physical, plus an electrocardiogram, from patients before ordering the test. We do not order the troponin test for patients with an obvious noncardiac etiology but remain fairly liberal about ordering it for other patients. To identify patients who need troponin testing, we estimate that the sensitivity of our initial clinical screen is 90% but, by casting a wide net, that our specificity is only 50%.
With our new strategy of combining an initial evaluation with troponin testing, we reduce the number of false positives from 198 to 99 without a loss of true positives or an increase in false negatives. Just by changing the sequence of our evaluation — talking to the patient and more selectively ordering tests — we can improve the accuracy of our evaluation.
As the hard calculations show, indiscriminate testing driven by the desire not to miss a single MI makes no sense. False-positive results lead to frequent diagnostic cascades of further testing, potentially exposing patients to unnecessary radiation and procedure-related risks, as well as increasing costs. Of course, we all know that defensive medicine is the reason for this illogical behavior. Our logic is further distorted by third-party payment incentives that make the clinician and patient insensitive to the monetary costs.
It would be more productive — and less defensive — to see this situation as an opportunity for shared decision making with the patient and the family. But single-event probabilities can be baffling, so some explanation is in order. After all, an individual patient’s chances of having an MI are either 0 or 100%.
Cognitive psychologists tell us that people tend to think about single-event probabilities in two ways: either as a frequentist or as a Bayesian. Frequentists usually think of single-event probabilities as the relative frequency with which an event occurs in a population over time. Bayesian thinkers, on the other hand, view a single-event probability as an expression of belief, conviction, or doubt about an event. Consider weather prediction: When a forecaster reports the chance of rain for tomorrow, he is describing a single event, and we will likely act differently if given a number of 30% rather than 70%.
Many cognitive psychologists think that the frequentist approach is easier for the mind to grasp. So it is probably best to explain a single-event probability to a patient by describing how often an event would occur in a theoretical population of similar patients. You might use plain language like this: “If I had 100 patients just like you, I would expect 5 to experience a complication.”
Patients want us to reduce the uncertainty about what they are feeling or fearing. They want clear-cut diagnoses and predictions. Probability is uncertainty quantified. As we convey information to our patients, we must be careful about how we estimate probability. By calibrating our decision-making strategies with objective calculations of probability — and remaining mindful about base rates — we can do a better job of diagnosing, informing, and treating patients.
Can you think of ways to reduce base-rate neglect in your practice? Please share them here.
September 4th, 2011
Montreal Heart Institute Researcher Fired After Investigation of Retracted Papers
Larry Husten, PHD
Zhiguo Wang, a researcher at the Montreal Heart Institute (MHI), has been fired less than a month after wide publicity over the retraction of two papers that he had coauthored, Retraction Watch reports. MHI director Jean-Claude Tardif said at a press conference that a hospital investigation had resulted in a recommendation that three more of Wang’s articles be retracted.
Wang, a widely published author of research on the genetics of arrhythmias, had received funding from the Canadian Institute of Health Research and the Canadian Diabetes Association. He held a faculty appointment at the University of Montreal.
The Journal of Biological Chemistry first posted the retractions in its August 12 issue. Tardif said that the MHI was first informed about the retractions at the end of June, prompting an investigation by an independent expert committee. The committee concluded that Wang “was found to have deviated from MHI’s ethical standards of proper scientific conduct and his responsibilities as a researcher.” Tardif said that Wang’s research privileges and status as researcher had been revoked and that his laboratory had been closed.
At the press conference, Tardif emphasized that Wang was “not a physician. His activities at the MHI consisted in conducting fundamental research studies at the cellular level. Mr. Wang’s research work did not involve patients and was not associated with any drug testing.”
In response to the original August 8 article on Retraction Watch, a number of readers offered additional information and speculation about Wang and the nature and scope of his scientific misconduct.
Here are links to the two withdrawn papers, published in 2007 and 2008:
September 2nd, 2011
Rosuvastatin Fails to Best Atorvastatin in IVUS Study of Atherosclerosis Progression
Larry Husten, PHD
AstraZeneca announced today that its lipid-lowering agent rosuvastatin (Crestor) was not superior to atorvastatin (Lipitor, Pfizer) in reducing the progression of atherosclerosis, as assessed by IVUS.
The company announced the top-line results of SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin Versus AtorvastatiN), which is scheduled to be presented at the American Heart Association meeting in November. The trial compared rosuvastatin (40 mg) with atorvastatin (80 mg) in 1300 high-risk patients.
AstraZeneca said that there was no significant difference between the two groups in the primary endpoint of the study, which was the change from baseline in percent atheroma volume (PAV), as measured by IVUS, but that the absolute numbers favored rosuvastatin. It also reported that the secondary endpoint, the change from baseline in total atheroma volume (TAV), did achieve a statistically significant difference in favor of rosuvastatin.
Analysts and journalists have noted that SATURN was designed to reach completion around the time when Pfizer would lose its patent on Lipitor and that the company had hoped to use the results to persuade people to pay for rosuvastatin in the face of generic atorvastatin. This task will likely be more difficult in the aftermath of SATURN.
In the Wall Street Journal, Sten Stovall wondered if SATURN represented a self-inflicted wound on the part of AstraZeneca. In Forbes, Matt Herper questioned the company’s efforts to diminish the impact of the news:
The result could be worse. AstraZeneca said in its release that there was a trend toward better performance on Crestor and that using a different way of calculating the amount of plaque in the artery the difference was significant. But clinical trials live and die by their primary endpoints, to prevent findings that are just due to chance. This study failed.
Many reports have mentioned the controversy over the ENHANCE trial several years ago, which was also an IVUS trial that missed its endpoint. But rosuvastatin has substantial evidence of benefit in placebo-controlled trials, and no concerns have been raised about the management of SATURN. By contrast, the drug tested in the ENHANCE trial, ezetimibe (Vytorin), had never been shown to produce clinical benefits, and allegations of company tampering with the analysis of the ENHANCE trial provided fuel for the controversy over the trial.
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