Interviewed by Steven Greer, MD
Does stenting alleviate angina? William Boden, MD discusses the quality of life subanalysis of the COURAGE trial. Dr. Boden was the principal investigator of COURAGE.
Cardiac surgery, Cardiology, Cardiology/interventional, Cardiology/medicine, Internal medicine, NEJM, Univ Buffalo | apples49 | 
March 9, 2012 5:10 pm | 
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The Healthcare Channel
April 5, 2011
Edwards Lifesciences (EW) makes the new minimally invasive implanted aortic valve called the Sapien. It is more advanced in the regulatory pathway than Medtronic is with their CoreValve device. This new class of medical device promises to change the way that millions of people receive treatment for aortic stenosis. (Note: transcatheter aortic valve implantation (TAVI) is not the best term since the valves can be implanted using a trocar in the chest and entering the apex of the heart).
With few publicly traded medical device companies making investors any money, the several-hundred-percent ($20 to $88) improvement in Edwards Lifesciences (EW) has earned a loyal following from Wall Street analysts and investors. The bad economy and fewer insured patients are financially crippling most medical centers. With the safety troubles surrounding drug eluting coronary stents and recent SYNTAX studies showing that CABG is superior to stents in complex disease, the hospitals are also eager for a new effective therapy, such as percutaneous heart valves, to keep the cath labs busy.
Politically, the medical device industry is now a top priority for President Obama, his FDA’s CDRH, and with the Republican Speaker of the House. The high unemployment rate and potential jobs created by the medical device industry are allowing the critics of slow FDA approval of medical devices to have the upper hand in the constant battle with the safety-minded.
All of this could create a perfect storm that might lead to one of the biggest safety disasters in the history of medical devices. The first generation of percutaneous aortic valves have serious design flaws leading to much higher stroke rates than the traditional open-heart surgery. Also, higher complication rates with the femoral artery were seen, but Wall Street and some cardiologists seem dismissive of these problems.
The PARTNER A trial was designed to test whether the percutaneous catheter-loaded valve was non-inferior to traditional open-heart surgery. The study succeeded in showing non-inferiority at 1-year (catheter valve cohort was 24.2% vs. 26.8% in the surgical group (p-value 0.001), and the catheter cohort actually had a lower mortality at the 30-day mark than the open-heart patients (catheter valve 3.4% vs. open-heart-surgery-valve 6.5%, p=0.07). However, the large-French profile of the catheter-loaded valves releasing atherosclerotic debris from the aortic arch and the balloon dilation of the calcified native valve caused a 100% increase in stroke (catheter valve 8.3% vs. open-heart-surgery 4.3%; statistically significance p=0.04). In addition, the major vascular complications caused by the large diameter catheter fitting into the small leg arteries were much more common (11.3% v 3.5%; p<0.01).
For other medical device trials, stroke rates like those have been “show stoppers”. Carotid artery stenting, for example, has never been widely adopted given that Medicare is yet to reimburse for the procedure due to the increased stroke rate in the stented patients compared to traditional surgery. In the elderly sick population studied in the PARTNER trials, the higher stroke rates are being dismissed by most Wall Street analysts and doctors participating in the trials.
Wells Fargo analyst Larry Biegelsen (Outperform rating) wrote ” In our view, the most important outcome from the trial was the numerically lower rate of mortality and major stroke at 1 year for TAVI versus SAVR (26.5% vs. 28.0; p=NS) because this indicates that the slightly higher rate of stroke with TAVI does not lead to poorer overall outcomes for TAVI. We think this will be an important driver for patients to select TAVI over SAVR given the faster recovery time with TAVI (time in the ICU was 5 days with SAVR vs. 3 days with TAVI). We think it’s important to highlight that the TAVI results should improve over time because the trial used a first generation device and 19 of the 26 centers had no prior TAVI experience whereas the surgeons in the trial were probably the best and most experienced in the US and Canada.”
Merrill Lynch analyst Bob Hopkins (Neutral rating) wrote, “The one point of controversy related to relative stroke rates (major stroke rate in the TAVI arm was 2x the surgical group – 5.1% versus 2.4% p value .07). Stroke risk may have an impact on the initial pace of uptake in the high risk surgical patient population studied in PARTNER A, but we see the issue as temporary with no long term implications on the TAVI market opportunity as the absolute stroke rates were low, there was no difference in mortality or mortality plus stroke and there are solid reasons to believe the TAVI stroke rate will fall over time and good reasons to believe the surgical stroke rate will rise as we discuss below.”
Michael Crawford, MD, chief of clinical cardiology at University of California, San Francisco, told the WSJ, “It will definitely change the practice for this disease. As good as surgery is, patients don’t want it.”
Craig R. Smith, MD, who presented the results at the ACC said in a statement reported by Medpage Today, “(TAVI) is the most exciting new treatment for aortic stenosis in the past two to three decades.” Smith is the chief of the Division of Cardiothoracic Surgery at New York-Presbyterian Hospital/Columbia University Medical Center and the study’s co-principal investigator. Columbia is also the home of Marty Leon, pioneer of the Edwards valve.
However, some doctors were concerned by the latest PARTNER A data. In the cardiology blog, CardioExchange (part of the NEJM), Dr. Richard Lange wrote, “TAVI was associated with a higher incidence of stroke, vascular complications, and perivalvular leak, with no mortality or clinical benefit. Yet the lead investigator touts TAVI as an “excellent alternative” to AVR because it was associated with less atrial fibrillation and bleeding. This is an interesting conclusion, since most physicians and patients are more concerned about periprocedural stroke and vascular complications than atrial fibrillation or transfusions. In “high-risk” patients eligible for AVR, is TAVI really a PARTNER or a blind date (“Thanks, but no thanks”)? “
It is important to remember that the PARTNER trials tested a very small subset of patients deemed to be poor surgical candidates. Conclusions cannot be extrapolated to the entire population of aortic stenosis. If the new catheter-based valves were approved, they would certainly be used off-label in patients less sick, just as drug eluting stents (DES) are now used in patients types not tested in pivotal trials. With this real-world usage fueled by financial invectives to doctors and hospitals, what would be the actual increase in strokes seen around the world?
Wall Street financial models forecast more than 300,000 total cases to treat aortic stenosis by the year 2020 with 200,000 being performed by the new catheter-based techniques. The stroke rates seen in PARTNER trials were from the most skilled hands in special cardiac hospitals. Assuming that the lesser trained doctors can somehow perform the procedures as well, at a total stroke rate of more than 8%, that translates into 16,000 strokes in very sick patients. With a 100% delta in the Kaplan curves, that means approximately 8,000 strokes per year would be attributable to the new valves, with no offsetting clinical benefit in mortality.
The other important consideration is the extremely short follow up in the PARTNER trials. Traditional prosthetic heart valves undergo the longest follow up, most extreme scrutiny, of any medical device before The FDA grants approval, and for good reason. If an aortic or mitral valve fails, rapid death ensues, as seen in the Bjork-Shiley debacles decades ago.
Cardiologists, in stark contrast to cardiac surgeons, are accustomed to having new stents and devices approved with only one year of follow up data. One year proved to be woefully inadequate for drug eluting stents. It was only after 12-months that the insidious deadly problem of late stent thrombosis began to rear its ugly head.
Prior to the Johnson and Johnson Cypher drug eluting stent being approved, Marty Leon displayed a slide at his TCT cardiology meeting that showed the Nike swoosh logo, and beneath it read “Just Stent It”, implying that all coronary artery disease should be treated by stents rather than CABG surgery. The interventional cardiology community was drunken with excitement. Coupled with a rare Medicare reimbursement decision even prior to an FDA approval, drug eluting stents proceeded to be used massively in off-label indications. Virtually all coronary interventions resulted in an expensive, untested, drug eluting stent. It was only after millions of patients were stented that the late stent thrombosis safety problem became known. Along with the SYNTAX and COURAGE trials that showed no benefit from DES over medical therapy or CABG, the usage of DES decreased, but only after millions of patients were harmed.
History seems to be repeating itself, but in a more dangerous way. The same clinical investigators have pioneered the catheter-based aortic valves. The same alliance of industry, medical societies, and academic thought leaders, is trying yet again to have a new cardiac device rapidly approved with short follow up data. This time, the consequences of failure are even more deadly.
Cardiac surgery, Cardiology, Cardiology/interventional, FDA, Late Breaking Data, Medical Devices, Neurology, Op-Ed, Policy, UCSF, Univ Buffalo | apples49 | April 5, 2011 10:30 am | Comments (0)
February 27, 2010
Two major studies were reported this week testing different procedures to prevent stroke: carotid endarterectomy (CEA) and carotid artery stenting (CAS). The CREST study received most of the headlines as a “long –awaited” study that finally vindicated stenting as being as safe as the open-incision neck surgery. The primary endpoint was a composite of: “any stroke, MI, or death within 30 days plus subsequent ipsilateral stroke”. In both the CAS and CEA groups, this composite endpoint was statistically equivalent. However, the pure stroke component was 78% greater for the stent cohort (4.1% v 2.3%), consistent with previous studies. Conversely, the MI component was 110% greater in the CEA group (2.3% v 1.1%).
The other major study released this week was the ICSS from Europe. These data were just from an interim analysis. Therefore, it received less press coverage. In contrast to the CREST study, the primary endpoint in the ICSS was a single clinical outcome of “serious” stroke, which is more clinically relevant. In the stent group, all forms of stroke were 88% greater (7.7% v 4.1%) in the stent group.
Most carotid stenting trials recognize the difference between small brain infarcts from emboli released during the procedure and “serious” strokes caused years later unrelated to the type of preventive procedure. In both the CREST and ICSS trial, the minor strokes caused by the procedure were nearly twice as common with stents. A subset of ICSS patient underwent MRI-imaging and three times the number of stent patients revealed small brain infarcts than the CEA group.
What is a “minor stroke”? A good example was seen in the world of sport a few years ago. The famous New England Patriot All-Pro linebacker Tedy Bruschi suffered a short-term “mild” stroke that forced him to retire. He was partially paralyzed on an entire side of his body.
Proponents of the CREST trial who believe that carotid stenting is a valid alternative to CEA surgery point out that the periprocedural heart attack (MI) rate offsets the risk of minor stroke. However, as was seen recently with Vice President Dick Cheney, modern “heart attacks” are often small infarcts diagnosed only by enzyme elevations. It is unknown at this time how many of the MI’s seen in the CEA group were true Q-wave serious “heart attacks” and how many were “Dick Cheney” attacks.
The HCC interviewed one of the investigators of the CREST trial, Dr. Nick Hopkins, about the issues raised above. Dr. Hopkins is Chairman of Neurosurgery and Professor of Radiology at the University at Buffalo, State University of New York. Regarding the rationale for using a composite endpoint in CREST rather than a single clinical endpoint as in the ICSS, he replied, “Stroke alone ignores one of the most common and important complications of CEA surgery: MI. The composite endpoint is the only “all in” way to evaluate these procedures so clinicians can make intelligent judgments….Doctors will now better understand the risks and benefits of both procedures for each patient so they can make the right choice for each individual. ICSS has many issues and is an interim analysis only.”
Dr. Hopkins declined to comment on the merits of ICSS using the single parameter of “serious” stroke as the primary endpoint. In previous interviews, Drs. Sanjay Kaul, Gordon Guyatt, and Nortin Hadler have explained how composite endpoints can lead to misleading outcomes favoring the drug or device under study.
Critics of the ICSS trial that showed much higher rates of MRI-image-verified new brain infarct lesions and clinically diagnosed stroke point out that the CREST trial used a single type of Abbott device. They also claim that the CREST trial doctors were better trained (see also Dr. White’s comments). Dr. Hopkins wrote, “Credentialing was significantly less rigorous in ICSS than in CREST. “Experienced” interventionalists only had to have done 10 CAS procedures to begin randomization…Telltale numbers…64 CAS procedures were aborted (8%) whereas only 2 CEA’s were aborted…and Experienced centers fared less well than supervised centers. In ICSS two centers were removed from the study but not until they randomized 11 patients resulting in 5 disabling/ fatal strokes. This might suggest CAS operators were overall on an earlier learning curve compared to CREST where we required committee review of data and if that looked good, 20 lead in cases prior to randomization and formal didactic and observational training before randomization.”
One could argue, however, that the ICSS mirrors the real world better than CREST and would likely be what the U.S. would see once Medicare began to reimburse for carotid stenting and let the Genie out of the bottle. Thousands of doctors with little to no experience at carotid stenting and neurovascular anatomy, using numerous different makes and models of stents and filters, would begin stenting millions of patients. The ICSS outcomes are precisely what CMS (Medicare) is hesitant to unleash with a national coverage decision.
The full data from CREST need to be evaluated before the medical community, FDA, and CMS officials can properly weigh the pros and cons of carotid stenting versus CEA surgery. If the MI’s seen in CREST were of the mild enzyme elevation variety, then the temporary paralysis and neurocognitive disability caused more commonly by stenting will not be warranted. On the other hand, permanent vocal cord damage from laryngeal nerve damage and serious Q-wave MI’s during CEA surgery would support stenting.
Cardiology/interventional, Late Breaking Data, NEJM, Neurosurgery, Univ Buffalo | apples49 | October 20, 2010 9:17 am | Comments (2)
May 15, 2008 Wall Street Journal, Scott Hensley
Stent Skeptic Blasts JNJ
“When your arteries narrow, so does your life,” says a TV ad from Johnson & Johnson. “It’s time to open it up.”
Cue the kaleidoscopic image of the company’s Cypher drug-coated stent. And then come the shots of remarkably buff people, presumably with Cypher stents, doing things we couldn’t even dream of trying in our relatively healthy state, like swimming long distance in open water under a cloudy, threatening sky.
Enter William Boden, stent skeptic at the University at Buffalo Schools of Medicine and Public Health, who trashes the Cypher TV ad campaign in the New England Journal of Medicine. Boden, lead author of a commentary in the journal, asks if the direct-to-consumer advertising for Cypher crosses the line in consumer health education.
He pretty much answers his own question: “A device is being promoted to millions of people who are ill equipped to make judgments about the complex therapeutic issues that even specialists continue to debate.” TV ads give safety issues short shrift compared with print, and the images and text in the 60-second spot play up the benefits. He goes on to ask the FDA to investigate whether Cypher ad met the basic requirements for “nondeceptive” drug advertising.
For its part, J&J told the Health Blog in a statement:
The content, messaging and fair balance of the ads were reviewed with the U.S. Food and Drug Administration prior to airing. The fair balance information was appropriate for a television ad and directed the viewer to other sources of more detailed information, including their doctors and a more extensive Patient Information statement that was also reviewed with FDA.
Recall that Boden helped fuel the recent debate about the use of drug-coated stents with results from the Courage trial, which showed that patients with stable heart disease could do just as well on drug therapy alone as stents combined with drugs.
And late last year, he told the New York Times that the Cypher ad was “deplorable” and might be a sign of desperation for J&J. For more from Boden, see the video interview courtesy of the HealthCare Channel.
If you haven’t seen the Cypher ad lately, it’s because you don’t live in Baltimore. J&J has discontinued the spot nationally, but keeps it running in Charm City, “a test market for a market strategy we’re assessing,” a company spokesman wrote us. You can still see the Cypher ad online here.
Cardiology, Cardiology/interventional, Cardiology/medicine, Univ Buffalo, WSJ.com coverage | apples49 | January 24, 2010 2:31 am | Comments (0)
