Two FDA Officials Quarrel Over Safety Of Angiotensin Receptor Blockers 1

Two FDA officials are quarreling in public about their different views about the safety of angiotensin-receptor blockers (ARBs), according to a story by Thomas Burton in Friday’s Wall Street Journal.

One official, Thomas Marciniak, contends that ARBs may increase the risk of cancer. Marciniak has been a vocal critic of FDA’s efforts to assess drug  safety. In the past he has raised questions about other major drugs, including prasugrel, rosiglitazone, and rivaroxaban. But Marciniak’s boss, Ellis Unger, who is the acting director of the office of new drugs, told the WSJ  that Marciniak’s concerns are a “diversion.”

Click here to read the full story on Forbes.

 

English: Logo of the .

 

 

Advertisements

Large Meta-Analysis Quantifies Risk Of NSAIDs And Coxibs Reply

Findings from a very large meta-analysis of clinical trials of NSAIDs may now allow physicians to quantify the cardiovascular and gastrointestinal risks associated with these drugs. The results of the Coxib and traditional NSAID Trialists’ (CNT) Collaboration, employing data from more than 350,000 randomized patients, have now been published in the Lancet.

Here are some of the key findings:

Click here to read the full post on Forbes.

English: Sintofarm

Independent Re-Adjudication Of RECORD Confirms Safety Of Rosiglitazone Reply

An independent re-adjudication of the RECORD trial has confirmed the original findings of the trial, that rosiglitazone d0es not increase cardiovascular risk. But critics of the trial and the drug are unlikely to be appeased by the new result.

The re-adjudication of RECORD will be the subject of an extraordinary two-day FDA advisory committee meeting next week on June 5 and 6. GlaxoSmithKline posted a summary of the results (PDF) on its website last October, but its presence was not generally known until the publication of an article in BioCentury on Tuesday.

The FDA also required GSK to commission the independent re-adjudication of RECORD that has now resides on the GSK website. The re-adjudciation was performed by the Duke Clinical Research Institute. According to BioCentury, “GSK said it does not typically publicize data put on its clinical trial registry and added that the Duke researchers are planning to submit the data for publication.”

Here is the conclusion of the DCRI re-adjudciation:

Click here to read the full post on Forbes.

 

 

Interpretations Differ Over Study Of Coenzyme Q10 In Heart Failure Reply

Coenzyme Q10 (CoQ10) may be beneficial in heart failure, according to the results of the Q-SYMBIO study presented this past weekend at the Heart Failure 2013 meeting in Lisbon, Portugal. But the results should be viewed with a critical eye, say experts.

Click here to read the full post on Forbes, including a comment from Milton Packer.

 

Candidate Therapeutic Target For Pulmonary Arterial Hypertension Identified Reply

I don’t normally write about pre-clinical research but my friend and CardioExchange colleague John Ryan has been on a tear lately (he even won a Young Investigator award from the AHA last year) with some fascinating and potentially important research. Briefly, and, I hope, not too simply, Ryan’s research may have uncovered a key mechanism underlying the pathogenesis of pulmonary arterial hypertension. And, if the research holds up, it may offer a new therapeutic target for this rare but deadly disease, for which there are no good therapies available.

Ryan

Ryan’s research was performed in Stephen Archer’s lab while he was a cardiology fellow at the University of Chicago. (Ryan is now on the faculty at the University of Utah and Archer has moved to Queen’s University in Ontario.) The research has focused on the previously unappreciated role of mitochondria in pulmonary artery smooth muscle cells (PASMCs). Ryan and colleagues found that proliferation of PASMCs– a key contributor to the pulmonary vascular obstruction that is the hallmark of PAH– requires mitochondrial division in order to occur, since the daughter cells will each require mitochondria. They  identified a protein, called DRP1, that leads to mitochondrial division (fission). They then tested a DRP1 inhibitor, called Mdlv-1, that prevented PASMC proliferation in rodent models and in cultured human cells.

“Pathological rates of mitochondrial fission in PAH may present an ‘Achilles heel’ for these fast-growing cells,” the investigators wrote last year. “Inhibiting mitochondrial fission constitutes a novel therapeutic strategy in PAH.”

In a recent paper, Ryan and colleagues looked at the effects of another protein, MFN2, and its impact on mitochondria in female rats with PAH and in female patients with PAH. They found that MFN2, which promotes mitochondrial fusion (the opposite of division), had antiproliferative effects on PASMCs in rodents and in humans and caused regression of PAH in rodent models of the disease.

It should be emphasized that there is a long way to go before we know if this early work fulfills its promise. It’s also possible that this research may have implications beyond PAH, since this pathway seems to have a general antiproliferative effect in vascular beds, according to Archer. But whatever the ultimate outcome of this research, I feel confident that we are looking at the early stage of a promising career.

 

Rivaroxaban Gains Approval In Europe For ACS Indication Reply

Rivaroxaban (Xarelto, Bayer) has been approved in Europe for the prevention of atherothrombotic events (cardiovascular death, myocardial infarction or stroke) following an acute coronary syndrome (ACS). The drug was approved at a dose of 2.5 mg twice-daily and should be used in combination with standard antiplatelet therapy. Rivaroxaban is now the only oral anticoagulant to receive an ACS indication.

The approval is based on data from the pivotal ATLAS ACS 2-TIMI 51 trial. In the United States, where Xarelto is marketed by Johnson & Johnson, the FDA has twice rejected an ACS indication for rivaroxaban.

The new indication joins the already-approved indications for higher doses of rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery, for the treatment of, (and prevention of recurrent) DVT and PE, and for stroke prevention in patients with atrial fibrillation.

“We know that thrombin levels remain elevated long after an ACS event, leaving patients at risk. In the ATLAS ACS 2-TIMI 51 study, we’ve shown that treating these patients with a low dose of rivaroxaban in combination with standard antiplatelet therapy targets both pathways of clot formation providing more complete long-term protection, including significant reduction in mortality risk,” said C. Michael Gibson, the Principal Investigator of the ATLAS ACS2-TIMI 51 trial, in a Bayer press release. “This approval marks an important shift in the way we deliver protection to patients who are at risk of a secondary atherothrombotic event.”

 

Spinning RECORD: Battle Over Rosiglitazone Heats Up Two Weeks Before Crucial FDA Meeting 1

Battle lines are being drawn two weeks before a highly unusual two-day FDA advisory committee meeting to discuss the contentious diabetes drug rosiglitazone (Avandia, GlaxoSmithKline). This will be the second time an FDA panel has wrestled with the fate of the drug and expectations have been that the discussion will once again be heated.

But at least one source of fierce criticism won’t be participating in the panel. Steve Nissen, who originally raised concerns about the drug and who has remained the most consistent critic of the drug, will not participate in the deliberations or present to the committee. Early on Thursday Nissen contributed a blog post on Forbes accusing the FDA of stacking the committee in favor of rosiglitazone. The FDA leadership, he says, is trying to use the meeting to “whitewash” its reputation:

GlaxoSmithKline said that “many inaccuracies exist in Dr. Nissen’s commentary and need to be addressed.” The company specifically denied the multitude of reports over the years that it had suppressed negative data about rosiglitazone over the years. The GSK response offers one potentially very important piece of news. The main focus of the June 5-6 hearing will be the re-adjudication of the RECORD trial performed by the Duke Clinical Research Institute. No public disclosure of the results of the re-adjudication have been made, and in the normal course of events the details of the re-adjudication, along with the rest of the committee’s briefing documents, would appear two days before the start of the hearing on the FDA website. But FDA staff, advisory panel members, and the drug sponsor (GSK) have almost certainly already seen the re-adjudication. In its statement, GSK flatly states that the re-adjudication confirms the safety of rosiglitazone:

The RECORD study is the largest clinical trial designed to evaluate the cardiovascular safety of Avandia. The study conclusions have now been confirmed through a re-examination by one of the leading independent institutions in the country (Duke Clinical Research Institute). In the accepted hierarchy of evidence generation, the results of a randomized, controlled clinical trial usually take precedence over other forms of evidence such as meta-analysis and observational studies. Despite some limitations of trial design, including the open label nature of the study, RECORD remains the only randomized trial of cardiovascular outcomes for Avandia at this time. The confirmation of the RECORD results by the independent re-examination support a positive risk/benefit profile for Avandia for the treatment of type 2 diabetes in appropriate patients.

It remains to be seen whether this is more RECORD spinning or an accurate summary of the Duke re-adjudication.

Click here to read the full story on Forbes.

 

Deutsch: Tonabnehmer eines Plattenspielers

 

Novartis Acknowledges Employees Participated In ‘Independent’ Trials Reply

Novartis has acknowledged that employees of the company participated in five “independent” investigator-initiated post-registration trials without disclosing their relationship to the company. The company said that a broader “comprehensive investigation with independent third party experts is ongoing” but that it has “provided an update” to Japanese medical societies and to the principal investigators of the five trials.

The new statement from Novartis admits that “one of our former employees [presumably Shirahashi] had varying levels of involvement in five investigator initiated valsartan trials in Japan.” The statement also disclosed that “a second former employee (who reported to the first former employee) had involvement which was limited to one of these trials.” Novartis said that independent investigation is continuing but that so far there has been no indication of a “specific company strategy to integrate the first former employee into the five valsartan investigator initiated trials.” However, the investigation has revealed

that some of this former employee’s superiors in Japan knew of his participation in these trials and were supportive of him in these activities. They believed that employees of a business that had academic titles could perform clinical research support as academics, without any conflict of interest issues arising. In addition, there is no indication that any of his supervisors knew or approved of the incomplete disclosure of his affiliation in the published papers for these studies.

Click here to read the full story on Forbes.

 

İsviçre Basel'deki Novartis binası

 

 

Small Study Suggests Statins May Blunt Benefits Of Exercise 1

A small study is raising big questions about whether statins may blunt the beneficial effects of exercise. The study has been published online in the Journal of the American College of Cardiology and was the subject of a New York Times blog today.

The authors concluded: “Given the strong independent cardio-protective effects of increasing cardiorespiratory fitness or lowering LDL, the benefits and risks of each should be carefully considered when choosing treatment modalities.”

Click here to read the full story on Forbes.

 

John Thyfault

 

Athletes With Defibrillators Don’t Need To Quit Sports Reply

Although the American College of Cardiology and the European Society of Cardiology now advise people with ICDs not to participate in vigorous sports, a new study offers strong support for people with ICDs who want to take part in sports. Although a large number of people with ICDs are elderly heart failure patients who are unlikely to want to participate in sports, ICDs are also implanted in young and otherwise healthy people with genetic diseases that leave them at high risk for lethal arrhythmias.

Now findings from the ICD Sports Safety Registry, published in Circulation, provide vital new information about this important topic. The registry, which was performed with the assistance of patient advocacy groups, included 372 ICD patients between 10 and 60 years of age who participated in sports more vigorous than golf or bowling. The most common reasons for having an ICD among people in the registry were long-QT syndrome in 73 people, hypertrophic cardiomyopathy in 63 people, and arrhythmogenic right ventricular cardiomyopathy in 55. 60 subjects were college age or younger who took part in competitive sports.

Click here to read the full post on Forbes.

 

HOLLAND, MI - MARCH 7:  Fennville High School ...

 

European Medicines Agency Starts Review of Combined Use Of Drugs That Block The Renin-Angiotensin System 1

The European Medicines Agency said last week that it was initiating a review of the combined use of agents that block the renin-angiotensin system (RAS). The three classes of RAS-blocking drugs (ACE inhibitors, ARBs, and direct renin inhibitors) are used to treat hypertension and congestive heart failure.

The EMA said that the review was being performed to address concerns that combined RAS-blocking drugs could increase the risk for hyperkalemia, hypotension, and kidney failure when compared with a single agent.  A recent meta-analysis of 33 clinical studies published in the British Medical Journal concluded that “although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events… The risk to benefit ratio argues against the use of dual therapy.”

Franz Messerli, senior author of the BMJ meta-analysis, applauded the EMA action and said that “as usual the FDA is dragging its feet.”

Click here to read the full story on Forbes.

 

 

 

Similar Cardiovascular Risk Observed With COPD Drugs Reply

A large observational study has found no difference in the increased risk for cardiovascular disease between the two main classes of drugs used in the first-line treatment of chronic obstructive pulmonary disease (COPD). LABAs (long-acting inhaled beta-agonists) and LAMAs (long-acting muscarinic antagonists) have a variety of beneficial effects in COPD patients, but evidence has been building that these agents may produce a small but significant increase in cardiovascular risk.

In a new study published online in JAMA Internal Medicine, Andrea Gershon and colleagues analyzed data from nearly 200,000 elderly COPD patients from Ontario, Canada. 28% of the group had a cardiovascular event.

Click here to read the full post on Forbes.

 

Instagram for Heart Attacks: iPhone App Speeds ECG Transmission To Hospital Reply

In the crucial early stages of a possible heart attack, EMTs on the scene now rely on slow and unreliable proprietary technology to transmit vital ECG data to physicians at a hospital for evaluation. But a new iPhone app using standard cell phone networks may help speed the process and, ultimately,  cut delays in treatment for heart attack patients.

In a presentation earlier today at the American Heart Association’s Quality of Care and Outcomes Research Scientific Sessions 2013 meeting in Baltimore, faculty and students at the University of Virginia designed an iPhone app to overcome some of the limitations of the current system. The iPhone app takes a photo of the ECG, reduces its size, and transmits the image over a standard cell phone network to a secure server. The image can then be viewed at the receiving hospital by physicians qualified to read an ECG.

Click here to read the full post on Forbes.

Opening Screen of the iPhone App

Salt Report From IOM Sparks Much Heat, Only A Little Light Reply

An Institute of Medicine report on salt earlier this week sparked a lot of controversy. The report concludes that there’s no evidence to support current efforts to lower salt consumption to less than 2,300 mg/day. Unfortunately, the press coverage offered little insight into the science behind the issue. On the Knight Science Journalism Tracker blog, Faye Flam deftly uncovers the almost universal shallow coverage in the media.

The one exception, the one story worth reading that “dug into the science,” according to Flam, is Gina Kolata’s story in the New York Times:

Click here to read the full post on Forbes.

 

English: A close up of salt crystals.

Study Questions Role Of Dual-Chamber ICDs For Primary Prevention Reply

Dual-chamber ICDs are implanted in a majority of primary prevention patients without a pacing indication who receive an ICD. Although there are a number of theoretical advantages with dual-chamber devices, these devices are more likely to cause complications. Although CMS requires providers to justify the medical necessity of dual-chamber devices, current guidelines from the AHA/ACC and HRS do not specify a single-chamber device.

In a new study published in JAMA, Pamela Peterson and colleagues analyzed data from 32,000 primary prevention patients without a pacing indication who were enrolled in the National Cardiovascular Data Registry (NCDR). 38% received a single-chamber device and 62% received a dual-chamber device. At 1 year there wereno significant differences in mortality, all-cause hospitalization, or heart failure hospitalization between the two groups. However, patients in the dual-chamber group had a higher risk of complications, including a highly significant increase in the 90 day risk of mechanical complications requiring reoperation (1.43% in the single-chamber group versus 2.02% in the dual-chamber group, p < 0.001). A very similar pattern emerged when the investigators performed an analysis that matched patients in the two groups with a propensity model. The analysis suggested “that the choice of a dual-chamber device is relatively random with respect to patient characteristics.

Click here to read the full story on Forbes.

 

 

Novel Leadless Pacemaker Makes Debut At HRS 2013 Reply

First results in human patients of a novel leadless pacemaker were presented last week at the HRS meeting in Denver by Vivek Reddy.  Pacemaker leads are the most common source of complications associated with pacemakers today. The self-contained device is delivered via catheter to the right ventricle, to which it is attached with a fixation mechanism.  The device is manufactured by Nanostim, Inc, a small company which is being acquired by St. Jude Medical.

Click here to read the full story on Forbes.

 

 

Leadless

 

Our Limitless Capacity For Self-Deception 10

I want to share with my readers a recent post and accompanying comment published on CardioExchange. The original post is by Eric Lindley, a cardiology fellow at the University of Utah:

Journal X: Not so Subtle Marketing Messages

I was the rare resident who thought that conflict of interest issues in medicine were a bit overblown. I did not find (or ignored) the evidence that pharma played a role in prescribing habits very persuasive, at least not when it came to my personal prescribing habits. I was not alone among the house staff, however, in appreciating an occasional “free” lunch, and the much rarer sponsored dinners at places I couldn’t afford as a physician-in-training.

Now I’m a fellow, and my attitudes about the pervasiveness of pharma influence have changed. Am I older and wiser? I’d like to think so. But I owe most of my conversion to the fresh perspective of my three-year-old daughter. She refers to most things by their color, including a majority of my medical journals. For instance, my JACC journals: blue for the mother journal, red for heart failure, green for interventions, etc. But then she started calling the original JACC the “X” journal. When I asked her why, she pointed to the “X” in Xarelto (rivaroxaban). I realized that every issue of JACC is covered front to back with the “X”. The message was subliminal to me, but quite obvious to her.

How do you think all of our pharma marketing looks with naive eyes?

This post prompted the following response from Siqin Ye, a cardiology fellow at Columbia University:

A story that I heard at ACC a few years ago goes something like this:

In a roomful of interventional cardiologists, the speaker asks, “How many of you have ever put in a stent that was unnecessary?”

Two or three hands went up.

The speaker then asks, “How many of you have seen someone in this room put in a stent that was unnecessary?”

About half the room raised their hands.

I think there is something similar with respect to our attitude towards pharma ads and gifts. I know plenty of residents and fellows who firmly believe that ads and dinners do not affect their personal practice patterns. Whether or not this is true for any given individual, the fact that pharma continue to spend so much on these activities suggest that as a whole, we are probably more susceptible than we believe.

 Thanks to Drs. Lindley and Ye for permission to reprint their words.

 

Suspicions Raised About Another Japanese Cardiovascular Researcher Reply

Significant questions about research misconduct have been raised about a prominent Japanese cardiovascular researcher, Issei Komuro.

Last year a Nature paper on which Komuro served as a co-author was corrected because “several images were mistakenly switched or duplicated during preparation of the artwork.” The Nature correction states that the “corrections do not alter any of the conclusions” of the paper. Now, however, a Japanese blog, entitled Issei Komuro – image manipulation –, raises questions about 13 additional papers. The papers were all published in well-known journals, including a second Nature paper, Nature Medicine, and 4 separate papers in Circulation. On many of the papers Komuro served as the senior author.

Click here to read the full post on Forbes.

 

 

Encouraging 4 Year Results For Watchman Device In AF Patients Reply

Encouraging long-term results from the PROTECT AF trial comparing the Watchman left atrial appendage closure device to warfarin in atrial fibrillation patients were presented yesterday at the Heart Rhythm Society meeting in Denver.

Previously, the main results of the trial, published in the Lancet, demonstrated that the Watchman was noninferior to warfarin, but the total number of events in the trial was small. In addition, there were more safety problems, as might be expected, in the early days after implantation. The FDA required the company to perform a confirmatory trial. That trial, PREVAIL, has been the subject of considerable controversy. Now, long term followup of PROTECT AF may help better understand the risks and benefits of the device.

Vivek Reddy presented 4 year followup results from PROTECT AF. The primary efficacy endpoint– the combined rate of all stroke, cardiovascular or unexplained death and systemic embolism– occurred in  2.3% of the device group versus 3.8% of the warfarin group (RR 0.60, CI 0.41-1.05).

Click here to read the full story on Forbes.

 

 

 

Bruise Control: Continued Warfarin Beats Heparin Bridging During Device Implantation 1

Many patients receiving an ICD or a pacemaker are already receiving oral anticoagulants. Current guidelines recommend replacement of the oral anticoagulant with the temporary use of heparin as a bridging strategy. Now a new study, BRUISE CONTROL (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial), offers convincing evidence that this strategy is not beneficial and, in fact, results in an increase in device-pocket hematoma. Results of the trial were presented today at the Heart Rhythm Society meeting in Denver and published simultaneously in the New England Journal of Medicine.

A group of mostly Canadian investigators randomized 681 patients undergoing ICD or pacemaker implantation with an annual risk for thromboembolic events greater than 5% to either heparin bridging or continued warfarin. The trial was terminated early after a prespecified interim analysis by the data and safety monitoring board. The primary outcome — clinically significant device-pocket hematoma, which the investigators defined as a hematoma that led to prolonged hospitalization, interruption of anticoagulation, or hematoma evacuation — was significantly reduced in the continued-warfarin group, as were all three components of the endpoint:

Primary outcome: 3.5% with continued warfarin versus 16% with heparin bridging (RR 0.19, CI 0.10-0.36, p<0.001).

Click here to read the full story on Forbes.

 

Another Disappointing Study For Fish Oil Supplements 3

Another large study has failed to find any benefits  for  fish oil supplements. The Italian Risk and Prevention Study, published in the New England Journal of Medicine, enrolled 12,513 people who had not had a myocardial infarction but had evidence of atherosclerosis or had multiple cardiovascular risk factors. The patients were randomized to either a fish oil supplement (1 gram daily of n-3 fatty acids) or placebo.

After 5 years of followup, the primary endpoint– the time to death from cardiovascular causes or admission to the hospital for cardiovascular causes– had occurred in 11.7% of the fish oil group versus 11.9% of the placebo group (adjusted hazard ratio 0.97, CI 0.88-1.08, p=0.58). There were no significant differences in any of the prespecified secondary endpoints.

Click here to read the full post on Forbes, including comments from James Stein and Dariush Mozaffarian

A typical softgel

Longer Detection Time Helps Prevent Unnecessary ICD Shocks Reply

Increasing the detection intervals in ICD programming can reduce the number of unnecessary or inappropriate shocks, according to results of the ADVANCE III study published in JAMA.

A group of Italian investigators randomized 1,902 patients receiving an ICD to programming with either long- or standard-detection intervals. After 12 months of followup, patients in the long-detection group had a significant reduction in the primary endpoint, which was the total number of antitachycardia pacing episodes and shocks:

Click here to read the full story on Forbes.

 

Burton Sobel, Towering Cardiologist, Dead At 75 Reply

Burton Sobel, a towering scientist and cardiologist, died at home on May 3 at the age of 75. Sobel had been treated in the past for prostate cancer and had suffered a recurrence, but it is not known if this was the immediate cause of his death.

Sobel was among the most powerful and influential cardiologists in the 1980s when he played a key early role in the development of fibrinolysis and the first major biotechnology product, TPA. From his perch as the chief of cardiology at Washington University in Saint Louis and as the editor of Circulation, Sobel was a member of a small group of cardiologists who set the agenda for cardiology and moved the field forward. The group, which also included James Willerson, Myron Weisfeldt, and Eugene Braunwald, was “innovative” and “visionary,” said Allan Jaffe, who worked closely with Sobel at Washington University for many years. “It was a very exciting time in cardiology,” he said.

Click here to read the full post on Forbes.

 

 

Metaanalysis Finds Same Day Discharge For Low Risk PCI May Be Feasible Reply

Although elective PCI for most low risk patients is extremely safe, overnight observation is still standard practice in the US, largely due to the lack of evidence demonstrating that same-day discharge is safe. Now a new metaanalysis, published online in the Journal of the American College of Cardiology, provides support for same-day discharge in carefully selected low-risk patients.

Click here to read the full post on Forbes.

LONDON, ENGLAND - OCTOBER 13:  Two NHS staff w...

 

 

 

 

 

 

 

FDA Approves Combination Of Ezetimibe And Atorvastatin Reply

The FDA has approved a new combination drug from Merck for lowering cholesterol. The drug, which will carry the brand name of Liptruzet, is a combination of two previously approved cholesterol-lowering drugs, ezetimibe and atorvastatin.

Merck said the new drug (pronounced “LIP-true-zett”) would be commercially available starting next week. Liptruzet will be available as a once-daily tablet combining 10 mg of ezetimibe with either 10, 20, 40, or 80 mg of atorvastatin. In clinical trials Liptruzet lowered LDL cholesterol from 53% to 61%, depending on dosage.

Click here to read the full post on Forbes.