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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

John Greenwood and colleagues compared the diagnostic accuracy of CMR and SPECT in 752 patients with suspected CHD. All the patients also underwent invasive x-ray angiography. The investigators calculated the sensitivity, specificity, positive predictive value (PPV), and the negative predictive value (NPV) of the two tests.
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Ray of Light for the Physician Payment Sunshine Act 1

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

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

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

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

IHD Mortality and Adjusted Hazard Ratios (AHR):
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22 Years Later, Study Shows Life-Prolonging Effect of Antihypertensive Therapy 2

After more than 20 years the benefits of antihypertensive therapy are still evident, according to a new paper published in JAMA. John Kostis and colleagues performed a 22-year followup study on patients enrolled between 1985 and 1988 in the Systolic Hypertension in the Elderly Program (SHEP) trial.

In 1991 SHEP found that low-dose chlorthalidone in 4,736 elderly patients with isolated systolic hypertension reduced the incidence of stroke and major cardiovascular events at 5 years. Now, with 22 years of followup data, the SHEP investigators report that patients who received active treatment during the trial had a significant gain in life expectancy. Each month of active treatment resulted in roughly about one day extra in life expectancy.

Life-expectancy gain:
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ALTITUDE Study of Aliskiren Terminated Early by Novartis 2

Novartis announced today the early termination of the ALTITUDE trial, which was testing the effect of the direct renin inhibitor aliskiren (Rasilez, Tekturna) in type 2 diabetics at high risk for cardiovascular and renal events. The action was based on the recommendation of the independent Data Monitoring Committee (DMC), after it found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after 18-24 months. Patients in ALTITUDE were randomized to receive aliskiren or placebo in addition to an ACE inhibitor or an angiotensin receptor blocker (ARB).

The company is also recommending that physicians not prescribe drugs containing aliskiren with either an ACE inhibitor or an ARB. Patients who are already taking a combination pill should be switched to an alternative anti-hypertensive regimen, according to the company.

The action represents a major setback for a drug that had once been thought to have blockbuster potential. Novartis said it was immediately ceasing all promotion of products containing aliskiren and was talking with health authorities about the implications of the findings.
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More Uncertainty About Vitamin D Supplements Reply

Although many experts believe that vitamin D deficiency may play a significant role in cardiovascular disease, there is little evidence to support the use of vitamin D supplements for the prevention of cardiovascular disease. In a narrative review published in Annals of Internal Medicine, Cora McGreevy and David Williams write that the few available studies have been inconclusive and difficult to interpret. More and bigger studies are needed to test the possible beneficial effects of vitamin D supplements, they write.

A second publication in Annals presents an updated meta-analysis of studies of vitamins D and calcium supplements for fracture and cancer protection. The results will inform forthcoming draft recommendations from the USPSTF. Analysis of data from 19 trials and 28 observational studies found that for fracture prevention vitamin D alone was not effective, but that the combination of vitamin D and calcium supplements was effective in older patients. The evidence for vitamin D in cancer prevention is inconclusive, write the authors. An additional area of concern is the proper dosing of vitamin D, since too much vitamin D may cause renal and urinary tract stones.

FDA Adds New Warnings to Dronedarone (Multaq) Label 1

In an updated  safety communication the FDA announced it was adding new warnings  to the dronedarone (Multaq, Sanofi) label. Based on results from the PALLAS trial, which was discontinued early due to safety concerns, the drug label will now warn:

Healthcare professionals should not prescribe Multaq to patients with AF who cannot or will not be converted into normal sinus rhythm (permanent AF), because Multaq doubles the rate of cardiovascular death, stroke, and heart failure in such patients.

In addition, the label will state that people taking dronedarone should have an ECG every 3 months. Dronedarone should be stopped if a patient is found to be in AF or, if clinically indicated, the patient should undergo cardioversion.

The FDA also performed a new analysis of the ATHENA trial, which included only patients with non-permanent AF, and which formed the basis for the drug’s approval and labeling. The analysis reaffirmed the benefits of dronedarone in ATHENA, finding that dronedarone caused a reduction in hospitalizations and was not associated with an increased risk of cardiovascular death, stroke or heart failure.

Click here for previous coverage of Multaq on CardioBrief.
Click here to read the FDA communication…

The Good, the Bad, and the Ugly: AHA Releases Update of Heart and Stroke Statistics Reply

Once again, statistics on the cardiovascular health of the United States portray a complicated picture of improvement and decline. On the one hand, deaths from cardiovascular disease continue to decline. On the other hand, ominous trends, many stemming from the increase in obesity, suggest that the good news may not last much longer. The full picture is contained in the American Heart Associations Heart Disease and Stroke Statistics– 2012 Update,  published  in Circulation.

Here are a few key items from the update:
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Investigation in Poldermans Case Expands to Leiden University Medical Center 1

The investigation in the Dutch scientific misconduct case has now spread to the Leiden University Medical Center, according to media reports in the Netherlands. The case first came to public attention last month when the Erasmus Medical Center in Rotterdam fired  prominent cardiovascular researcher Don Poldermans. (Click here for previous CardioBrief coverage of the case.)

A spokesman for LUMC told the Dutch media that the investigation is specifically looking at “a professor who has published frequently” with Poldermans [according to Google Translate], but it may also investigate other Leiden scientists. No names have so far been publicly mentioned, though CardioBrief has identified a prominent academic cardiologist at LUMC who has published more than 350 papers with Poldermans.

Study Examines New-Onset Atrial Fibrillation After TAVI Reply

The broad enthusiasm for TAVI (transcatheter aortic valve implantation) as it enters the marketplace has been partially offset by concerns about an increased risk of stroke associated with the procedure. The role of one major cause of stroke, atrial fibrillation (AF), has not been the subject of close scrutiny. Now a new study from Quebec published in the Journal of the American College of Cardiology provides new information about the rate of new-onset AF following TAVI.
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Meta-analysis Finds No Danger for PCI Performed at Centers Without Surgical Backup 1

On-site surgical backup for PCI has long been mandated by guidelines, though its necessity in the modern era has been questioned, and the most recent PCI guidelines published last month lack a specific recommendation about surgical backup. Now a large new meta-analysis published in JAMA suggests that the PCI performed without surgical backup may be safe.

Examining data from 40 studies, Mandeep Singh and colleagues found no significant differences in in-hospital mortality or emergency CABG between centers with or without on-site surgery:
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Large Analysis Confirms Safety of ADHD Medications Reply

The cardiovascular safety of ADHD (attention-deficit/hyperactivity disorder) drugs has been uncertain. Now a large new study published online in JAMA provides reassurance that the drugs are safe.

Laurel Habel and colleagues analyzed data from more than 440,000 adults, including 150,359 users of ADHD medications and matched nonusers and found “no evidence of an increased risk of MI, SCD, or stroke associated with current use compared with nonuse or remote use of ADHD medications.” Even in a worst-case scenario, the absolute increase in risk is quite small, the authors said.
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From the Archives: Understanding Risk: Tricky Business 3

Note to readers: The attached article (click on the image to download the PDF) about understanding risk was originally published in the Harvard Health Letter in 1994. I recently stumbled across it in my archives and thought some readers here might enjoy it. Although it is directed at a consumer and not a professional audience, I think it’s very important for all of us to consider how we think about risk and communicate our understanding to others.

Sometimes our lack of progress can be disheartening, as evidenced by the brief mention in the story of cell phones and brain cancer. The one obvious mistake in the piece is the paragraph on estrogen. The general concept is still correct, but clearly the benefits of estrogen did not turn out as we thought back in the nineties. In a way, though, this illustrates the larger point of the piece, which is that understanding risk is a tricky business.

Click to view the entire article.

FDA Advisory Panel Votes Against Implantable CardioMEMS HF Pressure Measurement System Reply

Members of the FDA Circulatory System Devices Panel today recommended against approval of the implantable CardioMEMS HF Pressure Measurement System. Although panel members agreed that the device was safe by a 9-1 vote, they voted 7-3 that the device had not been shown to be effective and 6-4 that the benefits did not outweigh the risks.

Panel discussion focused on the CHAMPION trial. In an extraordinary addendum to its main review of the trial, the FDA reviewers raised serious concerns that “the conduct of the trial may have biased the study results.” An audit of the trial by FDA inspectors determined that the sponsor or the principal investigators “routinely contacted investigational sites and made specific therapeutic recommendations for some Treatment Group study subjects.”

As previously reported here and here, Wells Fargo analyst Larry Biegelsen was the first to uncover the news that the FDA would raise serious questions about the CHAMPION trial at the advisory panel. These initial charges were dismissed by Jay Yadav, the cardiologist who founded the company, but the concerns about CHAMPION now appear to be valid.


Oops, She Did It Again! FDA Disinvites Another Advisor 2

Today an FDA advisory panel will meet to review the safety of oral contraceptives that contain drospirenone. One person who will not be voting on the panel is Sidney Wolfe, the well known consumer advocate and pharma critic. Wolfe was originally listed as a panel member, but then, only 2 days before the meeting, he was removed from the panel by none other than Janet Woodcock, the imperious director of the FDA’s  Center for Drug Evaluation and Research (CDER). Her reason: Wolfe had an intellectual conflict of interest because he had already said the drug should not be used in his Worst Pills newsletter and website.

After some back and forth, as detailed here, Wolfe will end up taking part in the proceedings, but he will not be able to vote. There are a lot of different issues involved here, many quite complex. But there’s one aspect of the issue that strikes me as quite simple: Woodcock and the FDA had absolutely no justification for removing Wolfe from the panel so shortly before the scheduled meeting. Any concerns about Wolfe should have been thoroughly reviewed and discussed long before, when the FDA first began to assemble the panel. Wolfe is an extremely public figure (some might argue too public), so it would not have been hard to determine if his previous statements made him ineligible to participate.
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CV Risk of Prostate Cancer Therapy Underappreciated Reply

Androgen suppression therapy (AST) for prostate cancer may be a serious risk factor for cardiovascular (CV) disease, according to a Viewpoint published online in Heart. The scope of the problem is widely underappreciated and is rarely considered in clinical practice, write Liam Bourke and colleagues. The subject was also the topic of a 2010 scientific statement from the American Heart Association, the American Cancer Society, and the American Urological Association.

For every 1000 men treated for 5 years with AST the authors estimate there will be an excess 315 incident cases of coronary heart disease, 360 cases of diabetes, 28 MIs, and 42 strokes.

“The current status quo of no action is, in our view, unsatisfactory for the patient and unlikely to be cost effective,” the authors write. “There is a need to investigate integration of AST specific CVD risk augmentation strategies into standard clinical care.” Cancer nurse specialists, they suggest, are a “potentially cost efficient, efficacious resource to manage CVD risk in these men.”
Click here to read the press release from Heart…

FDA Undertakes Safety Review of Dabigatran (Pradaxa) Reply

The FDA announced today that it was initiating a safety review of  dabigatran (Pradaxa, Boehringer Ingelheim). The review was prompted by reports of serious bleeding events in people taking the drug.

Bleeding complications, the FDA acknowledges, are a “a well-recognized complication of all anticoagulant therapies.” The FDA said it was “working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected.”

The FDA noted that it is difficult to compare bleeding complications with dabigatran and with warfarin, since complications associated with the older warfarin may be less likely to provoke an adverse event report.
Click here to read the FDA Safety Communication…

Change in Fitness More Important Than BMI Over Time Reply

Experts have been debating the relative role of obesity and fitness in cardiovascular risk. Now a new report from the Aerobics Center Longitudinal Study published in Circulation finds that maintaining or improving fitness significantly lowers CV risk irrespective of changes in BMI.

Duck-chul Lee and colleagues followed 14,435 men for 11.4 years. Compared with people whose fitness deteriorated over time, people with stable fitness or improved fitness had significantly lower rates of all-cause and CV mortality. Here are the hazard ratios and 95% confidence intervals, after multivariate adjustment:
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