April 23rd, 2013
Study Suggests Benefit for Beta Blockers During Noncardiac Surgery
Larry Husten, PHD
The use of perioperative beta-blockade for noncardiac surgery has been declining as a result of the controversial POISE study, which turned up evidence for harm associated with extended-release metoprolol in this setting. Now a large new observational study published in JAMA offers a contrary perspective by suggesting that perioperative beta-blockade may be beneficial in low- to intermediate-risk patients. But without better evidence the debate about this topic is unlikely to be resolved.
Martin London and colleagues performed a retrospective analysis of 136,745 patients who underwent noncardiac surgery at VA hospitals, 40% of whom received beta-blockade. Beta-blockers were used more frequently in vascular surgery patients and in patients who were at higher cardiovascular risk, as indicated by a greater number of Revised Cardiac Risk Index factors. Over the course of the study period, from January 2005 through August 2010, the rate of beta-blockade declined from 43.5% to 36.2%, a finding likely related to the publication of the POISE study in 2008.
Overall, the mortality rate was 1.1% and the cardiac morbidity rate was 0.9%. After propensity matching, beta-blockade was associated with lower mortality (RR 0.73, CI 0.65-0.83, p<.001) and cardiac complications (RR 0.67, CI 0.57-0.79, p<.001). The difference was significant only in patients with 2 or more Revised Cardiac Risk Index factors and only in the group of nonvascular surgery patients. The authors speculated that the lack of effect in the nonvascular surgery patients may have been due to the smaller sample size and that some beta-blocker usage in this group may not have been captured in the database. The risk of stroke — which was elevated in the beta-blocker group in POISE — was not significantly different between the groups in the VA analysis.
The authors concluded that their results “highlight a need for a randomized multicenter trial of perioperative beta-blockade in low- to intermediate-risk patients scheduled for noncardiac surgery.”
April 22nd, 2013
Selections from Richard Lehman’s Literature Review: April 22nd
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.
JAMA 17 Apr 2013 Vol 309
Prevalence of a Healthy Lifestyle Among Individuals with CV Disease in High-, Middle-, and Low-Income Countries (pg. 1613): As the saying goes, death is Nature’s way of telling you to slow down. Short of death, coronary heart disease and stroke could be thought of as timely reminders to get fit. But people who have CHD or stroke seem remarkably resistant to heed Nature’s warning: in rich countries and poorer countries alike, they continue to have sedentary lifestyles, and few alter their diet. But at least 50% of them give up smoking.
NEJM 18 Apr 2013 Vol 368
Nonemergency PCI at Hospitals with or without On-Site Cardiac Surgery (pg. 1498): Many hospitals in the USA offer percutaneous coronary intervention although they lack on-site cardiac surgery facilities should things go wrong. This study of Massachusetts hospitals shows that non-emergency PCI has now become such a safe procedure that it there is no difference in outcomes between hospitals with or without on-site surgical rescue.
BMJ 21 Apr 2013 Vol 346
Coronary Artery Calcium Score Prediction of All Cause Mortality and CV Events in People with Type 2 Diabetes: Here’s a systematic review of coronary calcium scoring in type 2 diabetes. The BMJ likes to publish systematic reviews, which are supposed to tell us what to believe from close study and aggregation of the best randomized trials. To read what I think about that, you’ll need to look at a piece of mine called Nullius in Verba which is out in the forthcoming issue of JAMA Internal Medicine. Systematic reviews need taking with a pinch of salt, as last week’s BMJ offerings proved. But back to coronary calcium scoring in diabetes: why do it in the first place? The obvious answer is to select high risk patients for more intensive treatment—the excuse always given for doing all sorts of futile prognostic testing. Coronary calcium scoring is useless for this—it has high sensitivity, but low specificity. Right then, don’t despair—let’s use it for identifying low risk patients for less intensive treatment. In theory, you could do this—but in practice, would you really want to subject all your diabetic patients to an expensive, high radiation procedure which would cause unnecessary anxiety in 20 for every lucky one who could then be offered one (statin) tablet less a day?
April 22nd, 2013
Actelion Executive to Head American College of Cardiology
Larry Husten, PHD
Shalom “Shal” Jacobovitz will be the new chief executive officer of the American College of Cardiology, the ACC announced today. Jacobovitz is currently the president of the U.S. division of Actelion Pharmaceuticals, best known for its pulmonary hypertension drugs.
Shalom “Shal” Jacobovitz
Jacobovitz worked at Hoffmann La Roche, Abbott Canada, Nordic Labs, and Marion Merrill Dow before joining Actelion. He joins the college after a year-long search that was initiated following the sudden departure of the previous ACC CEO, Jack Lewin.
“Shal has a track record that demonstrates he is the right person to lead a strong organization like the ACC and to take it to the next level at a time when health care is undergoing massive changes,” said ACC President John Gordon Harold, in an ACC press release. “He is an innovative and proven leader as well as a successful mentor and team builder. Shal brings a unique perspective at a time when the College is ramping up to meet the evolving needs of cardiovascular professionals domestically and around the globe.”
I asked Harold to comment on the issue of a pharmaceutical executive serving as the CEO of the ACC:
The ACC has long been a leader in transparency and ensuring positive appropriate relationships with industry. Shal Jacobovitz and the ACC are committed to full transparency. Shal has voluntarily divested himself entirely of all personal investments in the pharmaceutical and medical device industries that could be perceived as a conflict of interest. It was never an issue.
As the landscape evolves for physicians, medical professionals, payers, hospitals, and patients we wanted a CEO with the new approaches, perspectives, and skills that Mr. Jacobovitz possesses. He brings a wealth of experience in leading organizations during times of rapid change and in building strong, high-functioning teams to address these changes.”
“It is a privilege for me to join the ACC,” Jacobovitz said in the ACC press release. “The College is a thriving medical professional society that is well positioned to be at the center of rapid changes in health care. I look forward to working with the ACC’s dedicated professional staff and member leaders to build on the College’s legacy of leadership in quality improvement, patient-centered care, clinical education and practice excellence.”
April 22nd, 2013
The FDA, Surrogate Endpoints, and Blood Pressure Drugs
Larry Husten, PHD
In recent years the FDA has come under increasing fire for approving drugs on the basis of surrogate endpoints without any evidence of greater clinical benefit. The most famous example of this is the diabetes drug rosiglitazone. Despite strong evidence demonstrating that it was effective at lower blood glucose levels — the surrogate endpoint — serious questions emerged about the cardiovascular safety of the drug, eventually leading to its near withdrawal from the market in the U.S. (and full withdrawal in Europe). Questions have also been raised about the long-term health effects of drugs targeting a specific endpoint — including cholesterol and other lipids, blood glucose, weight loss, and blood pressure.
Despite what some believe is a long-term trend against the use of surrogate endpoints, the FDA is actually seeking to make it easier for manufacturers of one therapeutic category, antihypertensives, to claim cardiovascular benefit for their drugs despite the absence of evidence to support most of these drugs. A recent FDA guidance document states:
With few exceptions, current labeling for antihypertensive drugs includes only the information that these drugs are indicated to reduce blood pressure; the labeling does not include information on the clinical benefits related to cardiovascular outcomes expected from such blood pressure reduction. However, blood pressure control is well established as beneficial in preventing serious cardiovascular events, and inadequate treatment of hypertension is acknowledged as a significant public health problem. FDA believes that the appropriate use of these drugs can be encouraged by making the connection between lower blood pressure and improved cardiovascular outcomes more explicit in labeling. The intent of the guidance is to provide common labeling for antihypertensive drugs except where differences are clearly supported by clinical data. The guidance encourages applicants to submit labeling supplements containing the new language.
Although the actual changes proposed by the FDA are small, I thought the issue bore further exploration. I first spoke with Norman Stockbridge, the director of the Division of Cardiovascular and Renal Products (DCaRP) in the Office of Drug Evaluation 1 at the FDA. I then asked Harlan Krumholz and Sanjay Kaul to comment on this topic. I first asked Stockbridge for his thoughts about the FDA document:
I don’t think there’s much crisis of faith with regard to hypertension. For many years we were approving antihypertensive drugs without saying anything at all about why we thought it was a good idea to treat it. Now obviously people thought they knew. Because there was a general understanding in the community between blood pressure and CV risk there wasn’t a strong incentive to rectify this many years earlier.”
Stockbridge explained why he thinks it is impractical to require more outcome trials:
The danger I think is that if you become so worried about re-proving the blood pressure reduction hypothesis that you require outcome trials for every new drug or every new class of drugs, you will never see another antihypertensive drug again. Because there are already a fair number of them and if somebody has to do an outcome claim to get another one on the market they’re just not going to do it. We think there’s a fairly robust demonstration that it doesn’t matter how you lower the blood pressure. That doesn’t mean there aren’t other bad things that drugs can do that will more than compensate for the good that these drugs do. We try to make sure that when we approve them we have enough safety data to have confidence about that aspect of it. But the idea that you’d have to do an outcome trial every time you got a new antihypertensive drug would just kill the market, would just kill drug development.”
I asked Stockbridge to comment on the recent trend by the FDA to require outcomes data in diabetes drugs:
The agency has taken that position, that’s true, and we’ll have to see. And it’s fair to say that there are other places in the agency where similar concerns have been raised. There is more talk now about other clinical areas needing some kind of CV safety study — not generally an expectation that you’re going to show benefit in all those cases — because people are generally risk averse here. There is a risk, however, to this kind of risk aversion — that is, that you are going to stifle drug development somewhat. How aggressive you are about this will determine how much stifling you do, but there’s no question that if you’ve got to do outcomes study that bounder the risk of CV events in a setting where the CV event rate is low you will have a great deal of trouble doing that, because it will take an enormous trial to get those kind of confidence [boundaries] — so it’s a difficult problem and I think there’s plenty of room for public discussion on the topic of how risk averse you want to be and what are the costs of being as risk averse as you are.”
Here is Krumholz‘s response:
There is confusion about this issue. It is not about the blood pressure reduction hypothesis — but about acknowledging that drugs that lower blood pressure have many effects on the body and the only way to know the net effect on patients is to study the drugs in outcomes trials. Even within a class there may be different net effects on patients. How many times do we need to observe that favorably modifying a risk factor does not always equal favorably modifying risk — even if the risk factor is a strong predictor of outcomes and is part of the mechanism of adverse outcomes — it is not about the risk factor, but about the breadth of effects of the drugs and the need to know the net effect. That being said, there may be circumstances where the uncertainty about the net effect is unavoidable — but it should be a purposeful decision.”
Finally, here is Kaul‘s response:
The guidance calls for a limited general statement regarding stroke, myocardial infarction, and cardiovascular mortality outcome benefit associated with blood-pressure lowering regardless of how it is lowered, followed by a more detailed drug and/or class-specific outcome data or lack thereof. Of the 15 classes of drugs approved for chronic treatment of hypertension, 13 are supported by outcome data. Plus, the link between blood-pressure lowering and CV outcome benefit is more robust and consistent than the relationship between other surrogate endpoints (such as blood-glucose lowering) and CV outcome benefit.
The guidance was developed based on the recommendations of two Cardiorenal advisory committee meetings convened in 2005 and 2006 to discuss class labeling for cardiovascular outcome claims for drugs that are indicated to treat hypertension. It was acknowledged during the panel deliberations that the failure to include information about cardiovascular outcomes in the drug label was contributing to inadequate treatment of hypertension, a significant public health problem. It was the consensus of the committee members that inclusion of CV outcomes claim in the label would serve as a teaching moment for both physicians and patients thereby promoting more adequate treatment of hypertension. Furthermore, the potential to incentivize drug development was viewed as an additional benefit. It is important to keep in mind that over the last two decades the FDA has approved only one new class of antihypertensive drug — aliskiren, a direct renin inhibitor approved in 2007. In contrast, seven new classes of drugs to treat diabetes have been approved by the FDA during this time.
Thus, although this guidance sets a regulatory precedent for extending an outcome claim across a set of pharmacologically distinct drug classes, I think it is quite reasonable and justified.
As to Stockbridge’s statement about the potential of diabetes drug guidance to stifle drug development, it should be noted that the initiation of over a dozen randomized trials enrolling more than 100,000 subjects after the issuance of the 2008 FDA diabetes guidance which calls for outcome data ruling out unacceptable CV risk can hardly be viewed as ‘stifling’ diabetes drug development.”
April 22nd, 2013
The Science of Management and The Art of Medicine
Kenneth John McConnell, PhD and John Ryan, MD
John Ryan interviews K. John McConnell about his research group’s study of standard management practices as they relate to quality of care in hospital cardiac units. The original article appears in JAMA Internal Medicine.
THE STUDY
Investigators used an established approach for assessing management and organizational practices in the manufacturing sector to assess performance at 597 hospital cardiac care units. Eighteen practices were evaluated in 4 domains: standardizing care, tracking key performance indicators, setting targets, and providing incentives to employees. (For a complete list of the 18 practices, click here [JAMA Internal Medicine subscription required].)
Management practices varied widely across institutions. On a 5-point scale where a higher score means better performance, fewer than 20% of cardiac units scored a 4 or a 5 on more than 9 measures. Better management practices were significantly correlated with lower mortality and with process-of-care measures, but not with lower 30-day readmission rates.
THE AUTHOR RESPONDS
John Ryan: Nearly 40% of the hospitals in your study had a mean score of less than 3 across the 18 management practices. Why are hospitals having limited success in following these practices?
John McConnell: In general, the cardiac units were performing better than I had anticipated. The Institute of Medicine reports had been beaten into my head, so I expected that units and hospitals would be doing much less in terms of improving management practices. However, with the scrutiny from Hospital Compare and the guidelines that have been promoted in cardiology, there actually has been a lot of standardization and buy-in for protocols and for modern management approaches. However, we also sensed a lack of awareness about what is possible when the quality of management is truly great.
An interesting aspect of the survey, which we have not yet published, was that at the end of it, we asked managers to rank how well their unit was managed on a scale of 1 to 10, where 10 is the best. Almost everyone gave themselves as an 8 or a 9. So they’ve adopted some good practices, but not all of them are aware how much room there is for improvement.
Ryan: How might institutions go about improving? And what examples of great success did you find?
McConnell: I think our study’s framework is a good one for measuring how well managed a hospital unit is. However, the study does not demonstrate how to move from a hospital from a score of 2 to a 5, nor does it address the science of organizational change. Improvements are still ongoing, and there is an effort to see what the practices can be when at the highest level.
That said, we could hear the excitement and engagement over the phone when we talked to nurse managers in units that had taken their management systems to a very high level. They had a tangible sense of the systems and organizational tools that empower nurses — it really gave them a sense of agency and effectiveness in patient care. Those interviews stood out because they could almost anticipate the management questions we were going to ask. With very little prompting, they would describe in detail the systems they had in place for avoiding errors, setting targets, and monitoring progress.
The majority of hospitals in our study had moved toward standardization (including, for example, standardized admission order sets), but relatively few had a process for monitoring how often the standardized policies and protocols were being followed. Similarly, many hospitals had some way of analyzing medical errors or near misses after they happened, but few had prospective policies to catch errors in advance. As an example of the latter, one hospital we studied had something called “Safety Fridays,” which involved a walk-through to determine what could go wrong — and where — before it happened.
Ryan: You found that 20% of hospitals rewarded employees the same way regardless of performance, which you characterized as a practice that can be improved. Why is this an undesirable practice, and how would you change it?
McConnell: Some of that may be influenced by nursing unions, which sometimes establish pay based on seniority rather than on how you’re doing in the position. Also, for some hospitals, once they hire someone, it can be extremely difficult to remove the person for underperformance. That type of job security can be attractive if you’re an employee, but it is probably not how you want to structure incentives if your aim is to deliver the best possible patient care. Overall, we would like to see the ability to reward or motivate better performance, along with the flexibility to re-train or remove underperformers.
Ryan: What about people who say that this kind of approach is not appropriate for medical care and that we need to retain physician autonomy?
McConnell: Thomas Lee has a nice summary of the approach that Geisinger took with their CABG practice, specifically noting that the standardization and protocols they developed were not “cookbook medicine” and that practitioners have leeway to deviate from the protocols. However, when they do deviate, they need to explain why. So there is a balance between the older “artisan” type of work versus complete standardization and automation. Too much of the former and you get unwanted variations; too much of the latter and you’re ignoring clinical nuance. Optimally we would like to have standardized practice, but there should be room for physicians to deviate from it when appropriate.
Share your observations about improving management practices in healthcare settings. How much enthusiasm for — and resistance to — improvement efforts exist at your institution?
April 18th, 2013
Educating House Staff on Appropriate Use of Echoes
Rory B Weiner, MD, Rajan Sacha Bhatia, MD/MBA and John Ryan, MD
CardioExchange invited R. Sacha Bhatia and Rory B. Weiner to discuss their paper in JACC: Cardiac Imaging (free full text) on an educational intervention to reduce the rate of inappropriate transthoracic echocardiography (TTE) ordered by house staff at Massachusetts General Hospital. They found that a program consisting of (1) a lecture based on the 2011 appropriate use criteria, (2) a pocket card that described the criteria in the context of common clinical scenarios, and (3) twice-monthly e-mail feedback on the appropriateness of orders resulted in a 26% reduction in TTEs compared with the control period. During the intervention period, the proportion of TTEs deemed inappropriate dropped from 13% to 5%. The appropriate use criteria for echoes were updated just this week.
Dr. Ryan: Why did you develop this educational intervention?
Drs. Bhatia and Weiner: This intervention was developed as an effort to improve utilization of echocardiography at our institution. Analysis of TTE utilization patterns at our hospital showed patterns similar to national trends, with an inappropriate rate of ~15% on the inpatient medical service. In addition to aiming to reduce the inappropriate rate, the goal was to generally educate house staff on the Appropriate Use Criteria (AUC).
Dr. Ryan: How did you develop the intervention?
Drs. Bhatia and Weiner: A key step prior to developing the intervention was analysis of ordering patterns for TTE at MGH. We identified several clinical situations which accounted for the majority of inappropriate TTEs on the medical service. The 2 most common situations included TTEs that related to endocarditis and lightheadedness. These clinical situations are therefore the focus of the pocket card (Figure 1 in the paper) that was distributed to the medical residents. Valve disease and heart failure, also common indications for inappropriate TTE, were highlighted on the back of the pocket card. The AUC is a large, comprehensive document and we believed that focusing on the most common inappropriate clinical situations would be more likely to make a difference than would trying to be exhaustive.
We feel that the feedback was a key component of our intervention, and indeed, previous studies support the concept that feedback can facilitate the success of interventions aimed at improving physician ordering.
Dr. Ryan: Do you think what you did is scalable and can be replicated throughout an entire hospital or health care system?
Drs. Bhatia and Weiner: We believe that the educational and feedback intervention utilized in our study can be used as a template for other institutions seeking to incorporate appropriate use criteria (for echocardiography or for other cardiovascular technologies) into their daily ordering practices. Knowledge of baseline local ordering patterns is essential to developing such interventions. However, the components of the intervention (lecture, pocket card, and email feedback) can be easily adopted by others. The classification of TTEs and subsequent generation of the feedback can be time-consuming when done manually, but if the process were automated through integration of ordering software with the electronic medical record, this type of intervention could be done on a large scale.
Dr. Ryan: Should we integrate this approach into every institution?
Drs. Bhatia and Weiner: Tracking appropriateness of orders is now a requirement for accreditation for echo labs. The next logical step is using this information to improve ordering practices. Further study is required to analyze the impact of approaches such as ours on patient outcomes and healthcare spending. In addition, the use of this kind of program in other settings (i.e., community clinics or with attending level physicians) requires study. Intuitively, however, such interventions empower physicians to take responsibility for improving utilization of diagnostic testing and preserve the privilege of physician self-regulation.
April 17th, 2013
Cardio Oncology: Counseling Women on The Cardiovascular Risks of Radiation Therapy
John Ryan, MD
This post is the second in a series inspired largely by the recent publication of the study Risk of Ischemic Heart Disease in Women after Radiotherapy for Breast Cancer in the New England Journal of Medicine. Our participants included invited study authors Candace Correa and Kazem Rahimi; author of an accompanying editorial, Javid J. Moslehi; and Jerry Walker, who has appointments in both the Division of Cardiology and the Department of Radiology at the University of Utah School of Medicine, to discuss this important topic. John Ryan moderated. See the previous post
Dr. Ryan: When radiation-therapy is being initiated do you feel that women should be counseled about the cardiovascular risks and what would you tell them?
Dr. Rahimi: Yes, I think that such counseling should be the standard of care (and I believe this is already the case in most oncology departments). Prior to our study it was difficult to have an informed discussion about absolute risks (and benefits) of radiotherapy with patients. Now, doctors can clearly say: without radiotherapy you have a x% chance of suffering a major cardiac event over the next y years. Undergoing radiotherapy would expose your heart to irradiation by z%. This is expected to increase your risk of suffering a major cardiac event from a% to b%. The conversation would then continue by explaining the expected benefits of radiotherapy for prevention of cancer-related events.
Dr. Walker: I think we live in an age in which patients expect to be told what the risks and benefits are for any given treatment. Certainly, a patient who is treated for cancer wants the treatment that will result in the best chance of cure. They will need to know that there might be side effects to the treatments offered. I think we as physicians can help them balance these risks and actually help them plan for the possible outcome of a coronary event. I believe that this gives patients an important sense of control over their situation.
Dr. Correa: The most important thing to remember is that radiotherapy significantly reduces the risk of breast cancer recurrence and increases breast cancer specific survival for many patients. However, women should be counseled about the potential cardiovascular risks of radiotherapy. I tell my patients that there was an elevated risk of developing heart disease after breast cancer radiotherapy using older techniques, and there may be a smaller elevated risk with modern radiotherapy. One of the key findings of the NEJM paper is that the risk of developing heart disease is a function of the dose of radiation that the heart receives. With modern radiotherapy we can employ specialized techniques to reduce incidental irradiation of the heart and thereby reduce this risk. Before the NEJM study we did not have a good idea of what dose limits to use for incidental cardiac irradiation and now we have at least a rough idea of safer cardiac doses.
Dr. Moslehi: The Darby paper suggests that women with risk factors for ischemic cardiac disease or women with a history of ischemic cardiac disease are especially susceptible to an ischemic cardiac event. Therefore, these women should be under the care of a cardiologist at the time of initiation of breast cancer therapy and radiation.
April 16th, 2013
Blood Sample Mismatch Leads ‘Anguished’ Authors to Retract Three Lipitor Papers
Larry Husten, PHD
Three substudies of the influential TNT (Treating to New Targets) trial have been retracted after the sponsor of the trial, Pfizer, discovered that blood samples from the study had been matched to the wrong participants.
The main results of TNT, published in 2005 in the New England Journal of Medicine, had a major impact on clinical practice and statin prescription patterns. The trial supported the increasingly aggressive use of statins and helped to solidify the enormous commercial success of atorvastatin (Lipitor, Pfizer).
The 3 newly retracted substudies do not appear to affect the main finding of TNT. Two papers were published in the Journal of the American College of Cardiology. The third was published in the American Heart Journal. (The AHJ retraction notice has not yet been published, but the editors have confirmed the retraction.) Here are the 3 retracted articles:
Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial: A Nested Case-Control Study
Roeland Huijgen, MD; S. Matthijs Boekholdt, MD, PhD; Benoit J. Arsenault, PhD; Weihang Bao, PhD; Jean-Michel Davaine, MD; Fatiha Tabet, PhD; Francine Petrides, BSc; Kerry-Anne Rye, PhD; David A. DeMicco, PharmD; Philip J. Barter, MD, PhD; John J.P. Kastelein, MD, PhD; Gilles Lambert, PhD
J Am Coll Cardiol. 2012;59(20):1778-1784. doi:10.1016/j.jacc.2011.12.043
Prediction of Cardiovascular Events in Statin-Treated Stable Coronary Patients by Lipid and Nonlipid Biomarkers
Benoit J. Arsenault, PhD; Philip Barter, MD, PhD; David A. DeMicco, PharmD; Weihang Bao, PhD; Gregory M. Preston, PhD; John C. LaRosa, MD; Scott M. Grundy, MD, PhD; Prakash Deedwania, MD, PhD; Heiner Greten, MD; Nanette K. Wenger, MD; James Shepherd, MD; David D. Waters, MD; John J.P. Kastelein, MD, PhD
J Am Coll Cardiol. 2011;57(1):63-69. doi:10.1016/j.jacc.2010.06.052
Vitamin D levels do not predict cardiovascular events in statin-treated patients with stable coronary disease
Vera Bittner, MD, MSPH, Nanette K. Wenger, MD, David D. Waters, MD, David A. DeMicco, PharmD, Michael Messig, PhD, John C. LaRosa, MD
American Heart Journal, Volume 164, Issue 3 , Pages 387-393, September 2012
Here is the main text of the retraction:
The main findings of the TNT Trial were published in 2005 (1). Since that time, members of the Steering Committee and other investigators have published 32 papers based upon additional analyses of TNT. The data for these papers were derived from analyses of the TNT clinical database, managed by Pfizer. The clinical database has been crosschecked many times and the data in it is valid. During the trial, blood samples were drawn from the patients at regular intervals for subsequent analysis. We performed a nested case-control study that included 507 patients who experienced a CV event and 1,020 control patients in the main biomarker analysis, and 496 patients who experienced a CV event and 1,117 control patients in the PCSK9 analysis. The biomarker database was separate from the clinical database. An anonymization code was run in 2007 to link patients from one database to the other.
In late 2012, the TNT frozen blood samples were integrated into a large automated biobank that includes samples from other Pfizer trials. At that time discrepancies were noted among the samples, indicating that an error had occurred when the samples were anonymized in 2007. Further investigation revealed that the code created to manually anonymize the data was accidentally run twice. During the first run, anonymized subject identifiers were successfully assigned to both biosamples and clinical data. However, after this first run had passed quality control checks, the anonymization code was re-run inadvertently, replacing the first correct set of identifiers with a random and incorrect set. We do not understand how or why the code was re-run. The study team, who were blinded as to patient identity, thus reported on mismatched clinical and biomarker data. The investigators of the biomarkers study were puzzled that none of the 18 biomarkers were predictive of cardiovascular events. However we were reassured because on-treatment LDL-cholesterol, HDL-cholesterol and triglyceride levels were all strongly predictive of events, and we reported this in the paper. These lipid levels were part of the clinical database, and thus were not subject to the error that occurred with the biomarkers. In the PCSK9 analysis, PCSK9 levels were predictive of events in the atorvastatin 10-mg group (p = 0.039) but not in the 80-mg group. This finding, which we now realize is totally spurious, was not unexpected and raised no red flags. Similarly, the failure of vitamin D levels to predict events, as reported in the AHJ paper, was not surprising.
Since the error was discovered, we have created a new anonymized clinical and biomarker database by restoring the original set of anonymized identifiers. We are currently reanalyzing the data according to our original study plans. However, the nested case-control feature of the original study design has been lost because the patient selection for biomarker sampling was random. Only approximately one tenth of patients now had an event, compared to one third in the original study design. Thus, the power to detect a difference in the level of a biomarker between patients with and without events has been attenuated.
All authors of these manuscripts are anguished to have made this mistake and publishing incorrect information.
TNT investigator John Kastelein, an author of two of the papers, told Retraction Watch:
Since the retraction was the result of a sample mix up and the results of our analysis were negative with regards to the predictive ability of the biomarkers in question, I, in fact, do hope that with the corrected sample labels and a new analysis we will be able to make better sense of the data.
Hat tip: Marilyn Mann
April 16th, 2013
Small Study Links Left Anterior Fascicular Block to AF and CHF
Larry Husten, PHD
In people without known cardiovascular (CV) disease the presence of left anterior fascicular block (LAFB) has not been thought to indicate increased risk. Now a research letter published in JAMA finds evidence that elderly people with LAFB are more likely to die and to develop atrial fibrillation (AF) and congestive heart failure (CHF) than people without LAFB.
The authors speculated that LAFB may be a marker for left heart fibrosis, which is a substrate of AF and CHF. They then examined the long-term outcomes of 1,664 participants without overt CV disease enrolled in the Cardiovascular Health Study (CHS). Of these, 39 patients had LAFB at baseline. After a median followup of 15.7 years and adjustment for baseline differences and risk factors, the LAFB patients had significantly increased risk for AF (HR 1.89, CI 1.11-3.24, p = .02), CHF (HR 2.43, CI 1.44-4.12, p = .001) and death (HR, 1.57, CI 1.08-2.26, p = .02). The authors ruled out progression of conduction disease as a cause because none of the LAFB patients went on to develop LBBB and after 10 years only two required a pacemaker.
The authors concluded that “LAFB may be a clinically relevant marker of an individual’s propensity to left heart fibrosis.” They acknowledged that “it remains possible that LAFB is simply a marker of undetected underlying hypertension or coronary disease.”
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