Boston Scientific May Face A Tough FDA Panel Reply

On Wednesday the FDA’s Circulatory System Devices Panel will once again review Boston Scientific’s Watchman left atrial appendage closure device for the prevention of stroke in atrial fibrillation patients (click here for the meeting materials). The panel will be the latest chapter in the long and contentious story of the Watchman. In 2010 the FDA issued a complete response letter and earlier this year a scandal broke out when the American College of Cardiology cancelled a prestigious late-breaking clinical trial presentation of the PREVAIL trial after the company broke an embargo by giving trial results to investors.

Wells Fargo analyst Lawrence Biegelsen predicts that the panel will be “contentious” but that ultimately the device will be approved next year. Although the trial missed one of its three c0-primary endpoints, the FDA reviewers emphasis on “the totality of the data” suggests a more benign FDA perspective, he writes.

One knowledgeable observer, Sanjay Kaul, who has served on several FDA panels, thinks the panel will indeed be contentious….

Click here to read the full post on Forbes.

 

Sanjay Kaul
Sanjay Kaul

 

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European Air Pollution Standards May Need To Be Strengthened Reply

A large new analysis published in the Lancet has found a strong association between long-term exposure to air pollution and the risk of dying. The results suggest that European standards for air quality may need to be strengthened.

The European Study of Cohorts for Air Pollution Effects (ESCAPE) analyzed data from 22 European  studies, including 367,251 participants followed for an average of 13.9 years. Nearly 30,000 deaths from natural causes occurred during followup. ESCAPE is the first large multi center study to examine long-term exposure to air pollution and mortality across many different European settings….

Click here to read the full story on Forbes.

 

Red Desert

 

Why Is Actelion Suppressing Phase III Data? 2

I highly recommend a terrific article by Ian Parker in this week’s New Yorker about Merck’s efforts to develop a novel insomnia drug, suvorexant. Normally I don’t write about non-cardiology topics but I want here to call attention to one small, almost tangential detail buried in the middle of the story. It’s not about the Merck drug but about another orexin antagonist from Actelion, almorexant:

“At the time, Jed Black, the Stanford sleep specialist, was on a two-year leave of absence, working full time on almorexant, the rival drug made by Actelion. Phase III trials of the drug were under way. This work has not been published, and Black cannot discuss it, although he recently described almorexant as having ‘an absolutely remarkable profile’ that was likely to outperform zolpidem in sleep maintenance.

But, in early 2011, Actelion announced that it was halting the drug’s development, because of an undisclosed possible safety issue. Merck’s scientists speculated about the nature of the concerns, and feared for the future of suvorexant. Black said that the problem was ‘straightforward,’ but that Actelion had decided to pause and take its time. ‘I don’t think almorexant needs re-tinkering at the molecular level,’ he said, implying a problem of drug delivery. Black, who is back at Stanford, suspects that almorexant will be launched, and is certain that such drugs will eventually become dominant. (GlaxoSmithKline recently published results, from Phase II studies, of its own orexin antagonist.)”

The time frame is not entirely clear, but it appears that Actelion has been actively suppressing phase III data about almorexant for several years at least.

Click here to read the full post on Forbes.

 

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Large Study Finds Favorable Risk-Benefit Profile For The New Anticoagulants Reply

A very large new meta-analysis finds a favorable risk-benefit for the new oral anticoagulant drugs in the setting of atrial fibrillation. The findings, published online in the Lancet, were remarkably consistent for all four of the new agents which have been fighting to replace warfarin, which was the only oral anticoagulant available for decades until the arrival of the new agents. Although warfarin is inexpensive, it has numerous interactions with other drugs and foods and requires regular monitoring and dose adjustments. The new agents can be taken once or twice a day and do not require dose changes.

Christian Ruff and colleagues combined data from the nearly 72,000 patients randomized in the four large mega-trials: RE-LY, which studied dabigatran (Pradaxa, Boehringer-Ingelheim); ROCKET AF, which studied rivaroxaban (Xarelto, Johnson & Johnson); ARISTOTLE, which studied apixaban (Eliquis, Pfizer and BristolMyers Squibb); and ENGAGE-AF-TIMI 48, which studied edoxaban (Daiichi Sankyo).

Click here to read the full post on Forbes.

Can Personalized Medicine And An Adaptive Trial Design Salvage This Hard Luck Drug? Reply

Arca Biopharma today announced that it had received FDA clearance to start a phase 2B/3 trial of its novel beta-blocker, Gencaro (bucindolol) for the prevention of atrial fibrillation in patients with heart failure. The GENETIC-AF trial has all the hallmarks of the modern era: the drug will only be tested in patients with a genetic variation that the company believes may predict a positive response to the drug. And the trial will be one of the first to utilize the much-discussed “adaptive” trial design, starting as a phase 2B study and then possibly expanding to a phase 3 study after an interim analysis of the trial data.

But if GENETIC-AF represents the very model of a modern drug, it also serves as a good example of the pitfalls of drug development. Because this drug has been around for a very long time and has had a very troubled history.

Click here to read the full story on Forbes.

 

Michael Bristow, Arca Biopharma President and CEO

 

Stents Lose In Comparisons With Surgery And Medical Therapy Reply

Despite the enormous increase in the use of stents in recent decades, there is little or no good evidence comparing their use to the alternatives of CABG surgery or optimal medical therapy in patients also eligible for these strategies. Now two new meta-analyses published in JAMA Internal Medicine provide new evidence that the alternatives to PCI remain attractive and that some of the growth in PCI may have been unwarranted.

Click here to read the full post on Forbes.

 

New Guideline Recommends Conservative Treatment for Heart Patients with Anemia Reply

The American College of Physicians (ACP) is recommending more conservative use of transfusions and erythropoiesis-stimulating agents (ESAs) in anemia patients with heart disease. But the authors of the new clinical practice guidelines, published in the Annals of Internal Medicine, acknowledge that the evidence base is too flimsy to support firm conclusions.

“Overall,” wrote the authors, “despite the epidemiologic and biologically plausible association of anemia with poor outcomes, we did not find consistent evidence that anemia correction improves outcomes in patients with heart disease…” The poor outcomes of heart patients with anemia have prompted aggressive treatment strategies, but “it is unclear whether these strategies improve outcomes.”

Click here to read the full post on Forbes.

 

Physicians Report Alarming Increase In LVAD Pump Thrombosis Reply

Physicians from three top institutions report an abrupt and highly troubling increase over the last two years in the incidence of pump thrombosis in patients who have received the HeartMate II left ventricular assist device (LVAD) manufactured by Thoractec.

The current investigation, published online in the New England Journal of Medicine, was initially prompted by an observed increase in pump thrombosis at the Cleveland Clinic. This first led to an analysis performed by INTERMACS (the Interagency Registry for Mechanically Assisted Circulatory Support) which found an increase from 2% before May 2011 to 5% afterwards. But, write the NEJM authors, there is reason to believe the INTERMACS analysis may have underestimated the rate of pump thrombosis. (The INTERMACS data, along with other papers about the problem, have been published in a special issue of the Journal of Heart and Lung Transplantation.)

The new paper is based on pooled data from 895 patient who received the HeartMate II LVAD at the Cleveland Clinic,  Barnes-Jewish Hospital, and the Duke University Medical Center . The authors report that after March 2011 the incidence of confirmed pump thrombosis within three months of implantation increased from 2.2% to 8.4% by January 2013.

Click here to read the full story on Forbes.

HeartMate II

Little Difference In Chest Pain Between Men And Women 1

In recent years the medical community has grown increasingly concerned that women with heart attacks may be less likely to receive prompt and effective treatment. The difference between the sexes in the presentation of symptoms is thought to be a major barrier to better treatment for women. But now a new study published in JAMA Internal Medicine finds that a key aspect of these differences– the description of chest pain in the emergency department– may not play as big a role as previously suspected.

Click here to read the full post on Forbes.

 

JAMA Int Med

FDA Removes Restrictions On Avandia Reply

In a remarkable climax to a long-running drama, the FDA today lifted major restrictions on rosiglitazone (Avandia, GlaxoSmithKline). The drug has been the subject of  intense criticism and controversy since the 2007 publication of the famous Nissen meta-analsysis that first raised the possibility that the blockbuster diabetes drug might increase the risk of heart attack and cardiovascular death.

The FDA said its actions were “consistent with the recommendations of expert advisory committees.” In June of this year an FDA panel reviewed re-adjudicated data from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial and concluded that the trial had not found an elevated risk of heart attack or death associated with rosiglitazone.

Click here to read the full post on Forbes.

 

FDA Spanks 23andMe, Grants Breakthrough Status To Factor Xa Inhibitor, and Approves Promus Premier Stent Reply

It was a busy morning at the FDA. Three new FDA actions may be of considerable interest in the cardiology universe:

FDA Halts 23andMe Personal Genome Test– The FDA sent a scathing letter to 23andMe ordering the company to stop selling its Personal Genome Service (PGS) test.   The FDA highlighted two cardiology-related uses of PGS as “particularly concerning,” including drug responses involving warfarin sensitivity and clopidogrel response.

FDA Grants Breakthrough Status To Factor Xa Inhibitor Antidote–

 …

FDA Approves Promus Premier Everolimus-Eluting Platinum Chromium Coronary Stent System–

Click here to read the full story on Forbes.

 

 Image representing 23andMe as depicted in Crun...

Image representing Portola Pharmaceuticals as ...

Slouching Toward Phase 3: Progress Report On New Cholesterol Drugs At The AHA Reply

The American Heart Association meeting in Dallas this year brought new phase 2 data about several promising new cholesterol drugs. But before jumping on any bandwagons it would be good to remember that even for the drugs most far along in development we still haven’t seen any phase 3 data. In addition, it bears repeating that the FDA may well be raising the entry bar for new cholesterol medications. As I wrote not too long ago, there is a good chance that the FDA will require completed outcomes studies for new cholesterol drugs. There’s good reason to be interested in these drugs but any predictions at this point would be hopelessly speculative.

One Year Results For Amgen’s PCSK-9 Inhibitor 

HDL Drug From CSL Limited

Esperion’s Novel Agent

Click here to read the full story on Forbes.

Go Nuts! Consumption of Nuts Linked to Mortality Benefit Reply

Nut consumption has long been linked to healthy lifestyles. Now, a study in the New England Journal of Medicine extends the finding and demonstrates a strong association with improved mortality.

Ying Bao and colleagues examined data from nearly 120,000 people enrolled in the Nurses’ Health Study and the Health Professionals Follow-up Study to assess the relationship of nut consumption and mortality. With over 3 million person-years of follow-up, the investigators found a strong inverse correlation between the frequency of nut consumption and mortality, after adjusting for other risk factors.

Here are the hazards ratio for death based on frequency of nut consumption (compared to no consumption):

Click here to read the full story on Forbes.

English: a walnut and a walnut core

 

TACT Principal Investigator Reflects On A Long And Contentious Journey Reply

In a fascinating and important blog post, Gervasio Lamas offers a deeply personal perspective on the long and contentious journey of the Trial to Assess Chelation Therapy (TACT), for which he was the principal investigator.

gervasio-lamasHere are a few quotes from his post, but I can’t urge you strongly enough to read the entire post over on CardioExchange. (Click here for my brief summary of TACT.)

Changing minds is difficult. Unexpected results meet resistance. Out of the mainstream research is subject to heavy criticism. I guess I knew all these truisms when we embarked on the Trial to Assess Chelation Therapy (TACT). Still, I thought we were answering an important clinical question.

To say that this trial was controversial is an understatement. I had previously worked peacefully in other clinical trials, worrying about enrollment, about the DSMB, and about interpretation of data. Not so, here. In retrospect, I had always thought that the adversaries to this study would be the chelation practitioners. After all, they were using an unproven therapy. Why would they want us to show it did not work?

The opposite was true. The chelation practitioners and their main professional organization, the American College for Advancement in Medicine, helped us at every turn. They felt they were doing good, and that bringing chelation to the crucible of a clinical trial would lead to many more patients being helped.

In fact, the principal obstructionists were groups of self-appointed anti-chelation “experts”, who had never administered chelation, had never designed or run clinical trials, but who knew how to make noise and recruit media to their dubious cause – that scientific thought should not be brought to bear on the question of whether chelation was safe and effective.

The gist of the objections to the trial, once legitimate methodological concerns were addressed, was an outcry that, because cardiologists believed that EDTA was quackery, the study had to be negative. Therefore we had done something wrong. Just imagine if this had been stem cells or a new anti-platelet: Kudos all the way, right? Humble chelation got heckles and hecklers. I told my dean at Columbia that people were very upset because they did not like the results. He said “That’s why you do research.”

So now what? Do we recommend chelation? This is where the cautious scientist has to take control. We reported a subgroup, and we have been fooled by subgroups before, so more research has to take place before all of us can jump on this bandwagon.

 

New Anticoagulant From Daiichi Sankyo Works Well In AF Patients Reply

Edoxaban, a direct oral factor Xa inhibitor under development by Daiichi Sankyo, is the latest in the series of new oral anticoagulants seeking to take over the troubled role of warfarin in clinical practice. The results of ENGAGE-AF-TIMI 48 were presented at the American Heart Association meeting in Dallas and published simultaneously in the New England Journal of Medicine. The results of the trial were promising, but edoxaban may have a hard time finding its footing as the fourth new oral anticoagulant to enter the market, following dabigatran (Pradaxa), Boehringer Ingelheim; rivaroxaban (Xarelto), Johnson & Johnson; and apixaban (Eliquis), Pfizer and Bristol-Myers Squibb.

In the trial, more than 21,000 patients with moderate-to-high-risk AF were randomized to one of two regimens of edoxaban or warfarin. Both high-dose and low-dose edoxaban were found to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. Here are the on-treatment annual rates of stroke or systemic embolism:

Click here to read the full post on Forbes.

 

TACT Substudy Suggests Possible Strong Benefit for Chelation in Diabetics Reply

One year ago the results of the TACT trial were published in JAMA, sparking an enormous controversy over the propriety of publishing a trial suggesting that chelation therapy might be beneficial in people with cardiovascular disease. Chelation therapy has long been a staple of alternative medicine, but until the publication of TACT it had received no credit whatsoever in mainstream medicine. TACT was supported by the NIH as part of an initiaitve to test the scientific basis of alternative medical therapies.

The JAMA paper reported positive results for the prespecified subgroup of patients who had diabetes at the start of the trial. Now a new paper, presented at the American Heart Association Scientific Sessions and published online in Circulation: Cardiovascular Quality and Outcomes, focuses on this important subgroup, and provides even stronger evidence for a possible benefit for chelation in patients with diabetes. The authors speculate that ethylene diamine tetra-acetic acid (EDTA) chelation might have an effect on metal-catalyzed oxidation reactions in the development of advanced glycation end-products, which appear to play a central role in diabetic complications.

The primary endpoint of the main trial – the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina – was significantly lowered from 30% in the placebo group to 26% in the chelation group (HR 0.82, 0.69-0.99, p=0.035).

Click here to read the full post on Forbes.

 

No Evidence That Statins Impact Cognitive Function Reply

In 2012 the FDA revised the label of statins to include a warning about reports that the drugs had been linked to memory loss or confusion. The FDA action appeared to be based largely on case reports. Despite concerns about this topic that have appeared sporadically in recent years, no high-quality review of the topic has appeared until now. In a paper published in Annals of Internal Medicine, Karl Richardson and colleagues report on a systematic review of the literature to assess the effect of statins on cognitive function.

The authors reviewed 25 trials, including randomized, controlled trials and cohort, case-control, and cross-sectional studies, that evaluated cognition in patients taking statins.

Their review found little evidence to support any adverse effect on cognitive function:

Click here t read the full story on Forbes.

 

No Evidence That Statins Impact Cognitive Function Reply

In 2012 the FDA revised the label of statins to include a warning about reports that the drugs had been linked to memory loss or confusion. The FDA action appeared to be based largely on case reports. Despite concerns about this topic that have appeared sporadically in recent years, no high-quality review of the topic has appeared until now. In a paper published in Annals of Internal Medicine, Karl Richardson and colleagues report on a systematic review of the literature to assess the effect of statins on cognitive function.

The authors reviewed 25 trials, including randomized, controlled trials and cohort, case-control, and cross-sectional studies, that evaluated cognition in patients taking statins.

Their review found little evidence to support any adverse effect on cognitive function:

“… low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance in procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment, nor any change in cognitive performance related to global cognitive performance scores, executive function, declarative memory, processing speed, or visuoperception.”

In a second analysis of the FDA post-marketing surveillance databases, the investigators found similar reporting rates for cognitive-related adverse events for statins and two other widely used drugs, losartan and clopidogrel.

The reviewers noted, however, that much of the data were not high quality and, in particular, there was a sparsity of data for high-dose statins, which are increasingly used.

They concluded that the available evidence does not support concerns linking statin use to cognitive impairment. “Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition.”

 

No Value For Renal-Artery Stenting In CORAL Reply

Previous small studies have failed to find any benefit associated with renal-artery stenting, but the trials have been small and were not powered for clinical outcomes. Now, the CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) trial, presented at the American Heart Association meeting and published simultaneously in the New England Journal of Medicine, offers strong and persuasive evidence that renal-artery stenting is not beneficial.

A total of 947 patients with renal-artery stenosis and either systolic hypertension, despite taking two or more antihypertensive agents, or chronic kidney disease were randomized to medical therapy plus stenting or medical therapy alone. There were no significant differences after 43 months in the primary composite endpoint of cardiovascular and renal events (death from cardiovascular or renal causes, MI, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy):

Click here to read the full post on Forbes.

 

Controversy Erupts Over Accuracy Of Cardiovascular Risk Calculator For Guidelines Reply

In the face of a highly critical story in the New York Times by Gina Kolata about the new cardiovascular guidelines, authors of the guidelines and leaders of the American Heart Association and the American College of Cardiology defended the value and integrity of the guidelines.

The Times story claims that the cardiovascular risk calculator used to assess individual risk in the new guidelines is deeply flawed. “In a major embarrassment to the health groups, the calculator appears to greatly overestimate risk, so much so that it could mistakenly suggest that millions more people are candidates for statin drugs.” The story quotes former ACC president Steve Nissen: “It’s stunning. We need a pause to further evaluate this approach before it is implemented on a widespread basis.”

But the guideline authors and AHA/ACC officials strenuously defended the guideline at a news conference Monday morning at the American Heart Association meeting in Dallas. They said  the new risk calculator is far superior to previous efforts, incorporating far more data that now includes stroke assessment and for the first time provides specific predictions for African Americans.

The assembled officials rejected any call to delay implantation of the guidelines, but one author, Donald Lloyd-Jones said that “over time we will modify the risk scores so that they get better and better.”

“We think we’ve done our due diligence,” said AHA president Mariell Jessup. “We have faith and trust in the people who developed the guidelines.”

Click here to read the full story on Forbes.

 

Press Conference

Replacement Versus Repair for Mitral Valve Regurgitation Reply

Surgery is thought to be life-saving for people who have ischemic mitral regurgitation, but it is unknown whether surgical repair or surgical replacement of the mitral valve is the better procedure. Repair is thought to result in fewer preoperative deaths and replacement is thought to have better long-term outcomes with a reduced incidence of recurrent mitral regurgitation. In recent years, many surgeons have grown to favor repair. Currently about two-thirds of patients in the US undergo a repair operation.

In a trial presented at the American Heart Association meeting in Dallas and published simultaneously in the New England Journal of Medicinemembers of the Cardiothoracic Surgical Trials Network randomized 251 patients with severe ischemic mitral regurgitation to either repair or replacement.

At one year there was no difference in the primary end point, left ventricular end-systolic volume index, between the two groups. 

Click here to read the full post on Forbes.

 

Hypertension Treatment Flowchart Fills in for Missing Guideline Reply

When the AHA and the ACC released four updated clinical guidelines earlier this week, a fifth document, the hypertension guideline, was conspicuous by its absence. According to the AHA and the ACC, the authors of the hypertension document have chosen to publish it independently. (No word has yet emerged about their reasons for doing so or when the document will be published.) In response, the AHA and the ACC announced that they would publish full hypertension guidelines in 2014, but in the meantime would publish a brief interim document. Now the two organizations, in conjunction with the Centers for Disease Control, have published a scientific advisory on the AHA and the ACC websites.

Click here to read the full story on Forbes.

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The Fate Of New Cholesterol Drugs Depends On IMPROVE-IT Reply

Prospects for the highly anticipated new class of cholesterol-lowering drugs, the PCSK9 inhibitors, took a wild roller coaster ride this week. The publication of new lipid guidelines by the American Heart Association and the American College of Cardiology led many observers to think that the promising new drugs under development by Regeneron (in partnership with Sanofi), Amgen, and Pfizer might suffer significant delays.

The guidelines delivered a strong statement questioning the increasingly controversial theory that LDL lowering by itself is beneficial. “We found that non-statin therapies really didn’t provide an acceptable risk reduction benefit compared to their potential for adverse effects in the routine prevention of heart attack and stroke,” said the co-chair of the guideline. This led many observers to think that the FDA would likely require the developers of PCSK9 inhibitors to complete cardiovascular outcome trials before getting US approval. This decision would delay approval for several years.

Then, on Thursday, the companies developing PCSK9 inhibitors received some apparent good news. Bloomberg News reported that an FDA official said that the drugs “will only have to meet the U.S. Food and Drug Administration’s existing standards for clearance, including whether they cut cholesterol and reduce blood pressure or inflammation.”

But then the FDA added one other very important caveat. Here’s how they phrased it to me:

Click here to read the full post on Forbes.

 

After Long Wait, Updated US Cardiovascular Guidelines Now Emphasize Risk Instead Of Targets 1

Updated cardiovascular health guidelines were released today by  the American Heart Association (AHA) and the American College of Cardiology (ACC). The guidelines are designed to provide primary care physicians with evidence-based expert guidance on cholesterol, obesity, risk assessment, and healthy lifestyle.

The new guidelines reinforce many of the same messages from previous guidelines, but also represent a sharp change in philosophy. That change is most evident in the new lipid guidelines, in which the focus has shifted away from setting numerical targets for cholesterol levels in favor of treatment decisions based on individual risk status.

“This guideline represents a departure from previous guidelines because it doesn’t focus on specific target levels of low-density lipoprotein cholesterol, commonly known as LDL, or ‘bad cholesterol,’ although the definition of optimal LDL cholesterol has not changed,” said Neil J. Stone, chair of the lipid expert panel that wrote the new guideline. “Instead, it focuses on defining groups for whom LDL lowering is proven to be most beneficial.”

The long-awaited and often controversial guidelines are the successors to the extremely influential NHLBI guidelines, including the Adult Treatment Panel (ATP) series of guidelines that brought cholesterol to the consciousness of millions of people. Earlier this year the NHLBI announced that it would no longer issue guidelines but would, instead, provide support for guidelines produced by other organizations. Following the NHLBI announcement, the AHA and the ACC said that they would take over publication of the guidelines.

Statins Indicated for Four Broad Groups

Click here to read the full post on Forbes.

Guideline Maze

Original illustration by Max Husten

 

Promising GSK Heart Drug Misses Primary Endpoint In 15,000 Patient Trial Reply

GlaxoSmithKline announced today that the first of two large pivotal phase 3 trials with a new drug, darapladib, had failed to meet its primary endpoint. Full results of the trial will be presented at a scientific meeting.

The STABILITY trial (STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY) tested the effect of darapladib, an investigational Lp-PLA2 inhibitor, in more than 15,000 patients with chronic coronary heart disease. GSK reported a nonsignificant 6% relative risk reduction associated with the use of darapladib in the time to first occurrence of any major adverse cardiovascular event (the composite of heart attack, stroke, and cardiovascular death).

Click here to read the full post on Forbes.