New Drug Of The Year: LCZ696 from Novartis
Old Drug of the Year: Ezetimibe
Not-So-Funny Drug of the Year: Ivabradine
Epinephrine has been a cornerstone of therapy during cardiac resuscitation after cardiac arrest because of its well-established ability to stimulate the heart and increase the probability of a return of spontaneous circulation (ROSC). In recent years, however, concerns have been raised that people treated with epinephrine may have worse neurological outcomes following their resuscitation.
In a study published in the Journal of the American College of Cardiology, French researchers analyzed data from more than 1,500 patients who were successfully resuscitated after an out-of-hospital cardiac arrest and were subsequently treated at a large hospital in Paris….
On Thursday the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 in favor of approval for Daiichi Sankyo’s edoxaban(Savaysa), but the outcome will likely result in a drug that will be on the market but that few physicians will prescribe until further studies are performed.
Drones have been used to kill people in war zones and to spy on people. Now a sharp young graduate student in the Netherlands has come up with an innovative new use for drones that could one day help save thousands of lives.
The FDA’s Circulatory System Devices advisory panel gave an extremely cautious endorsement on Wednesday to Boston Scientific’s Watchman device, a novel catheter-delivered left atrial appendage closure device for people with atrial fibrillation. They signaled that although they thought the device should be made available they also thought that there should be significant restrictions on its use.
On Wednesday Boston Scientific’s Watchman device will once again appear before the FDA’s Circulatory System Devices advisory panel. The Watchman is a novel catheter-delivered left atrial appendage closure device which is intended to be used in place of chronic warfarin therapy to lower the risk of stroke in people with atrial fibrillation. It has been under development for more than a decade and its approval has twice been postponed by the FDA. Briefing documents released ahead of Wednesday’s panel suggest that the third time may not be the charm for Watchman, though close FDA watchers believe the device may ultimately squeak through.
An interventional cardiologist– the cardiologists who put in stents and usually treat heart attack patients in the first few hours– asked an electrophysiologist– the cardiologists who treat arrhythmias– whether wearable defibrillators should be used post-MI. Here’s what that electrophysiologist, Edward J. Schloss, the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH, replied. It is a good example of how sometimes a procedure or a therapy that seems, intuitively, to be worthwhile and beneficial, may actually not be beneficial at all. Here’s his response, which he originally posted on Twitter:
The controversial drug ivabradine just got a little more controversial. The drug, which is marketed by Servier under the brand names of Corlentor and Procoralan, is available in Europe and elsewhere and is used for the treatment of heart failure and stable angina. The drug is not available in the US, but it is under development by Amgen for a heart failure indication.
Now a very large new study presented at the European Society of Cardiology meeting in Barcelona and published simultaneously in the New England Journal of Medicine has found no evidence of benefit in a stable angina population and found more adverse events associated with the drug and even suggested the likelihood of harm in a very large and important trial subgroup. The findings have resulted in an investigation by the European Medicines Agency, placing a cloud over the future status of the drug.
Investigators of the much-anticipated and controversial SIGNIFY trial have told the European Society of Cardiology leadership that they will not participate in a previously scheduled press conference on Sunday at the society’s main meeting in Barcelona. But they say they will present the main results of their trial at a Hot Line session later in the afternoon.
According to the ESC, the SIGNIFY investigators, who include Kim Fox, Ian Ford, Philippe Gabriel Steg, Jean-Claude Tardif, Michal Tendera, and Roberto Ferrari, told the ESC leadership that regulators at the European Medicines Authority (EMA) had told the investigators that because they (the investigators) were scheduled to appear before the EMA they should not discuss or comment on their trial outside the official presentation at the ESC conference.
Acute use of the popular macrolide antibiotic clarithromycin has been linked to a small but significant increase in cardiac death. In a report in the BMJ, researchers in Denmark analyzed the effects over a 14-year period of the acute use of penicillin V, roxithromycin, and clarithromycin.
Earlier research raised concerns that marcrolide antibiotics in general, and erythromycin and azithromycin in particular, might prolong the QT interval and increase the risk for fatal arrhythmias.
In the new study, clarithromycin was associated with a significant increase in the rate of sudden cardiac death compared with the other two antibiotics…
Digoxin is one of the oldest drugs in the cardiovascular arsenal, derived from the foxglove plant and first described in the 18th century by William Withering. It is frequently used in patients with heart failure (HF) and with atrial fibrillation (AF). The few trials supporting its use were performed in HF patients before newer treatments arrived. There have been no good trials in AF.
The growing popularity of marathons and other extreme sports has sparked worries about the potential dangers of these activities. The popular press and medical research have both focused on the risk of cardiac arrest and other heart rhythm problems. But that concern may be misdirected. A new study from Israel published in the Journal of the American College of Cardiology finds that a much more serious danger may be heat stroke, which is defined as a core body temperature above 104 or 105 degrees associated with multiorgan dysfunction.
Once again dabigatran (Pradaxa) has raised the wrath of the critics. Several articles and an editorial published today in The BMJ raise more questions and concerns about the drug, which is the first of the new oral anticoagulants. Relying on new evidence along with previously disclosed data, Deborah Cohen, the investigations editor for The BMJ, casts doubt on the reliability of the data supporting the drug as well as the behavior and decisions of regulatory authorities, trial investigators, and employees of Boehringer Ingelheim, the drug’s manufacturer.
The first real details about the much-anticipated novel new heart failure drug from Novartis will kick off this year’s Hot Line sessions at the annual meeting of the European Society of Cardiology in Barcelona, Spain. The meeting runs from August 30 until September 3.
As I have previously reported, the PARADIGM-HF trial was stopped because of a highly statistically significant reduction in cardiovascular mortality in patients taking LCZ696 (a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor) instead of the current gold standard of treatment, an ACE inhibitor….
Here is the complete list of Hot Line trials:
Boston Scientific hopes the third time will be the charm. The company disclosed on Tuesday yet another obstacle in the path to approval for its novel Watchman left atrial appendage closure device for the prevention of stroke in patients with atrial fibrillation. Although it has already been before two FDA advisory panels, the company said that it had been informed by the FDA that it will need to undergo yet another advisory panel before gaining approval.
ICDs are routinely implanted in heart failure patients with ejection fractions (EFs) of 35% and lower to prevent sudden cardiac death. However, the benefits in patients at the higher end of the spectrum– between 30% and 35%– have not been well demonstrated in clinical trials, since few patients in this range have been enrolled in clinical trials.
In recent years there has been an explosion of interest in atrial fibrillation (AF), the most common heart rhythm disorder. Although it is sometimes thought to be relatively benign, AF increases the risk of stroke if untreated. Even if treated, it can be the source of significant discomfort and can contribute to additional complications, especially when accompanied by other cardiovascular conditions. Now a new study published in Circulation finds that hospitalizations for AF are on the increase, and this may have important implications for the delivery and economics of health care in the coming years.
Researchers analyzed data from nearly 4,000,000 hospitalizations in which AF was the primary discharge diagnosis from the years 2000 through 2010. Here are some of their key findings:
In recent years researchers have developed a more complicated view of the relationship of health and exercise. Although observational studies have consistently shown that some physical activity is better than none, studies that have drilled deeper into the data suggest that these health benefits may be curtailed in people who exercise very frequently or very intensely. Now two new studies from Europe, published in the journal Heart, offer new support for these observations.
In the latest development in its ongoing review of the new oral anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim), the FDA today offered largely reassuring news about the sometimes controversial drug. The FDA study of 134,000 Medicare patients found that dabigatran was associated with a reduced risk for ischemic stroke, bleeding in the brain, and death, compared to warfarin. But the study also found that, dabigatran was associated with an increased risk for major gastrointestinal bleeding. There was no difference between the drugs in the risk of MI.
When cardiologists implant defibrillators in patients at high risk of dying from a heart rhythm disorder they nearly always perform a defibrillation test in which they induce a lethal arrhythmia, ventricular fibrillation, to make sure the device accurately detects the arrhythmia and terminates it with an appropriate shock. But routine defibrillation testing has never been shown to be safe or necessary. In recent years some experts have maintained that routine defibrillation testing may not be necessary.
Now a new study, presented yesterday at the Heart Rhythm Society meeting in San Francisco, offers evidence that although routine testing is generally safe it may increase complications without producing any improvement in outcomes.
MADIT-CRT was an influential trial that showed a reduction in heart failure complications — but not mortality — when cardiac resynchronization therapy (CRT) was added to an implantable defibrillator in patients with mild heart failure who also had left bundle-branch block (LBBB). Patients in the trial were followed for 2.4 years, raising questions about the long-term effects of CRT. Now, a second look at 854 patients who participated in a follow-up study, presented at the American College of Cardiology and published in the New England Journal of Medicine, suggests that over the long term, CRT may save lives in this population. MADIT-CRT was sponsored by Boston Scientific.
MADIT-CRT Long-Term Follow-Up Shows Survival Benefit with CRT-D
A new guideline for atrial fibrillation (AF) was released on Friday by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. Among other features, the 2014 Guideline for the Management of Patients With Atrial Fibrillation incorporates important new information about the new oral anticoagulants and catheter ablation for the treatment of AF symptoms.
Editor’s Note: The following guest post is published with the permission of its author, Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.
by Edward J. Schloss, MD
On March 24, St. Jude Medical announced the global launch of the Optisure family of ICD leads. It’s been a while since a new ICD lead was launched, and I’m probably not the only one who was caught by surprise. I’d like to explore why this approval is important for the ICD community. First, a brief history of ICD leads from St. Jude.
FROM RIATA TO DURATA
St. Jude Medical developed its own line of ICD leads after it purchased the former ICD vendor Ventritex in 1996. The first-generation Riata lead, approved in 2001, was succeeded by the Riata ST line in 2006. These leads were distinguished, in part, by their thin diameter, permitting implantation through a 7 Fr introducer sheath. In that era, implanting physicians’ interest in a thin lead was very strong. Even the high-profile failure of the 7 Fr Medtronic Fidelis ICD lead didn’t seem to dampen that enthusiasm.
Both of St. Jude’s Riata lead families later developed problems. Reports of subacute perforation soon after implant in the Riata ST line arose in the late 2000s. A year or two later, the internal core structure of both the Riata and Riata ST leads was discovered to break down in 25% and 10%, respectively, of these leads, as evident on fluoroscopic evaluation — a process called externalization. This problem, along with noted increased electrical failures of this lead, prompted an FDA class I recall of both product lines in December 2011, in addition to intense scrutiny and discussion in the lay press, investor press, blogosphere, and academic literature.
By the time the Riata and Riata ST leads were recalled, St. Jude had already gotten approval and marketed the successors: Riata ST Optim and, later, the Durata lead. Both these leads shared design similarities with the Riata ST lead, but additional modifications were intended to prevent the failures that the predecessor lines had exhibited. To mitigate the perforation risk specifically, changes in the Durata lead were intended to minimize tip pressure to the myocardium. And both new leads had a new insulator wrapping around the silicon core from Riata ST. This Optim insulation, shown to be more resistant to abrasion, has apparently been successful at preventing the fluoroscopic externalization that had occurred with the earlier leads.
The failure of the Riata leads has been shown to be time-dependent, so the device community has expressed some concern about Durata’s future performance. In addition, FDA has continued to apply pressure, with a January 2013 warning letter about this lead, specifically noting problems detected during a California plant inspection. Early active registry studies of Durata have been highly favorable, but a limited number of Durata problems have been discussed in case reports. Noted ICD critic Dr. Robert Hauser has also reported on a series of Durata failures from the FDA MAUDE database.
INSIDE THE DURATA
The Durata and Riata ST may share some failure mechanisms. In particular, the Swerdlow case report revealed inside–out abrasion under the distal shocking coil, resulting in a short between that coil and the ring-electrode cable, and consequent oversensing. Swerdlow and the Hauser MAUDE study have suggested that a similar form of insulation failure at the proximal shocking electrode could result in failure to defibrillate. (Because Durata and Riata ST have essentially the same internal design and materials at the level of the shocking coils, it is possible that this failure mechanism will occur with the newer leads.)
Moreover, Swerdlow found evidence of disruption of the Optim layer, which he hypothesized was due to Optim degradation, possibly related to hydrolysis of the polymer and cyclical stresses during the 4 years of lead service. The long-term biostability of Optim is critical, because without the Optim layer, the Durata leads are quite similar to Riata ST.
St. Jude has staunchly defended Durata, citing the favorable active registry data and additional testing in a large bibliography on its website. The company’s independent engineering analysis concluded that Swerdlow’s lead was damaged externally as a result of the extraction tools, not Optim degradation (counter to Swerdlow’s assertion).
THE BASICS ABOUT OPTISURE
St. Jude released Optisure this week, its first new ICD lead line since Durata. The product literature describes Optisure as “providing an additional system enhancement for addressing lead complications and improving system reliability.” The company says the slightly thicker 8 Fr lead is “for physicians who prefer a larger lead diameter.”
According to St. Jude, Optisure is built on the basic design of Durata with these additional modifications:
FDA filings show Optisure was submitted for approval as a PMA (pre-market approval) supplement on 10/24/12 and approved for release on 02/21/14. The filing links back to the original PMA for the Ventritex TVL lead issued in 1996. It does not appear that a human clinical trial was performed, as is common in PMA supplement approvals.
MY ANALYSIS OF OPTISURE
I’m happy that ICD companies continue to pursue process improvement. If we ever reach the point when we think we have a lead that is “good enough,” that will be really unfortunate. I’ve continued to have some concerns about Durata. ICD lead failures in the Riata lines have not become evident until 4 years of use, and we are only recently accumulating large numbers of Durata leads that have been implanted that long. Fortunately, Optisure’s design attempts to directly address two of the feared possible failure mechanisms of the Durata lead.
First, the increased Optim thickness in the proximal lead is likely to diminish the can/lead abrasion in the pocket, and perhaps in areas of cyclical stress. I find it really ironic and satisfying to read that St. Jude is promoting Optisure “for physicians who prefer a larger lead diameter.” Back in 2010, when I criticized thin ICD leads in an HRS debate, I had a hard time getting people to agree with me. Now, going thicker is a marketing strategy. Times really have changed.
Second, the Optim layer under the proximal shocking coil should help to prevent internal shorts that could cause lead failure. This type of short, if it involves the distal high voltage cable, is especially worrisome, as it may manifest only at the time of clinical or induced ventricular fibrillation. I fear that proximal coil HV shorting may be responsible for many of the Riata and Durata lead failures and deaths documented in MAUDE database entries, such as those published by Hauser (as well as this more recent report). Having a layer of Optim between the silicone core and the SVC shocking coil should help to prevent this shorting, just as it has prevented externalization. Unfortunately, this mitigation will not change the likelihood of shorting under the RV coil (as in Swerdlow’s case) but should help overall lead reliability. St. Jude seems to feel the same way, citing Optisure’s design as an “enhancement for addressing lead complications and improving system reliability.”
WHAT’S NEXT FOR ICDs?
Getting a pacemaker or ICD lead designed, approved, and built is an enormous undertaking. The process has only become more difficult because of increasing regulatory barriers. The formerly common process of PMA supplement approval has come under greater scrutiny. ICD and LV leads that formerly might have been approved under PMA supplement now require large U.S. trials. The trials’ costs, coupled with the fear of another Fidelis or Riata debacle, appear to have stifled lead innovation. Given the development of two new of leadless pacemakers (now being implanted in Europe) and the U.S.-approved subcutaneous ICD, we may be at the beginning of the end of the era of transvenous cardiac leads.
I have to agree with Zheng and Redberg that the PMA supplement process for medical device approval is problematic. The fact that leads from Riata to Optisure were approved on the basis of a dissimilar lead developed by a different company nearly 20 years ago should be ample evidence of this argument. Should Riata leads have gone through a clinical trial? Answering yes may seem logical. The unfortunate reality, however, is that no pre-market clinical trial would have picked up this lead’s late and novel failure mechanism. Even today, I would argue that careful industry engineering and close post-market scrutiny (including FDA-mandated registries) are doing far more to help our ICD patients than any pre-market trial ever could.
Nevertheless, it is critical to improve existing products, especially ICD leads. Most of us agree these are the “weak link in the chain.” I fear that a more highly regulated environment is having the paradoxically adverse effect of forcing us to settle with what we already have. That’s why I tweeted on March 24 that the quick approval of Optisure “both surprises and pleases me.” I wonder if this lead would even have been developed if it had been forced through a long, expensive clinical trial. Would that outcome have been a good thing?
Anticoagulation is a cornerstone of therapy for atrial fibrillation because it lowers the heightened risk for stroke in this population. People with chronic kidney disease are also at increased risk for stroke, but the benefits of anticoagulation are less clear in this group, and anticoagulation is used less often in AF patients who have CKD. Now, a large observational study offers some reassurance that anticoagulation in AF patients with CKD may be beneficial.
Researchers in Sweden analyzed data from more than 24,000 survivors of acute myocardial infarction who had AF….
The FDA has granted marketing approval for the Thermocool Smarttouch ablation catheter for use in patients with drug-resistant paroxysmal atrial fibrillation (AF), sustained monomorphic ischemic ventricular tachycardia and Type I atrial flutter. The device is manufactured by Biosense Webster, a Johnson & Johnson company.