February 2010 Archives:

February 19 » Plavix After Stents: How Long?

February 16 » Stents Downgraded by Wall Street Journal: If Only It Were That Simple

February 12 » Clinton and Eisenhower: Presidents, Hearts, Stents and 55 Years

February 11 » IVUS vs. FFR -- Boston Style

February 9 » Volcano Has AAA Week: Accused, Approved and Acquired

February 7 » Herbal Supplements vs. Heart Drugs: Controversy Re-ignited

February 5 » Patent Spending

February 19, 2010 -- 6:35pm EST

Plavix After Stents: How Long?
I recently interviewed Dr. Eric Topol for Angioplasty.Org about current efforts to determine the optimal duration of dual antiplatelet therapy (a.k.a. DAPT or clopidogrel plus aspirin) after drug-eluting stent placement. My first question was what had we learned about this issue since the 2006 FDA stent safety hearings? And his answer was "Unfortunately, we don't know anything more...".

Sort of shocking. A major study was supposed to come out of those hearings, but the DAPT study just began recruiting last summer and won't be completed for four years. This massive study, sponsored by all the major stent makers, as well as the manufacturers of antiplatelet meds, will enroll 20,000 patients and test them at 12 and 30 months to determine the rates of MACCE (death, heart attack and stroke) stent thrombosis and major bleeding complications. It will be performed with all drug-eluting stent brands and will not compare one to another. What will this teach us? Dr. Topol has an opinion about the DAPT study:

Dr. Topol (who, by the way, was an invited panel member at those 2006 FDA hearings) is currently Director of the Scripps Translational Science Institute (STSI) where he is conducting research on the genomics of coronary artery disease. The bottom line is that all patients are not the same -- and they respond to antiplatelet therapy differently. So Dr. Topol believes that the "one-size-fits-all" concept of thrombosis prevention just doesn't apply.

Another concept is that all drug-eluting stents aren't the same. Because of the metal structure, polymer coating or drug itself, each device has different characteristics and different healing properties. This was seen clearly in the ODESSA trial, where Dr. Giulio Guagliumi used OCT intravascular imaging to measure stent coverage at six months. He found significant incomplete coverage in the CYPHER and TAXUS stents, but complete healing in the ENDEAVOR.

As a result of these findings and other clinical data, two trials, involving only Medtronic's ENDEAVOR stent, are currently starting up: SEASIDE, which Dr. Topol is involved in, will measure the outcomes of patients who receive and only get six months of DAPT; and OPTIMIZE, being conducted in Brazil by Dr. Fausto Feres, which is stopping DAPT at three months.

Rather than testing if DAPT is more effective at longer durations, such as 12 and 30 months, these studies are testing to see if it is just as effective at shorter periods, when used with a DES that has a greater healing profile, like the ENDEAVOR. The advantages of a shorter DAPT duration are several:

• less risk of bleeding complications (inherent in the use of antiplatelet drugs);
• less cost (Plavix costs $4/day -- the difference of a year or two is significant -- newer antiplatelet drugs like prasugrel cost even more);
• less problems deferring surgery (in order to perform surgery of any sort, for example knee replacement, etc., antiplatelet therapy must be stopped).

The short back story here is that when drug-eluting stents first came on the market in 2003-2004, the FDA recommended six months of DAPT to keep the blood from clotting in and around the stent (a.k.a. stent thrombosis). Within a couple of years, reports surfaced about a small number of patients who suffered late stent thrombosis (six months or more after stenting). A flurry of concern arose and the 2006 FDA stent safety hearings resulted in recommendations to extend DAPT to 12 months or more -- the current guidelines. But, as Dr. David Kandzari, co-principal investigator for the SEASIDE trial told Angioplasty.Org:

Dr. Kandzari explores this issue in detail in his Viewpoint article in December's JACC: Interventions, "Identifying the 'Optimal' Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Revascularization"

For more information, read my interview with Dr. Topol and keep up with the latest news in our StentCenter.

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February 16, 2010 -- 10:55pm EST

Stents Downgraded by Wall Street Journal: If Only It Were That Simple
A broad-based critique, claiming overuse of heart stents and angioplasty, was published as a major feature in Thursday's Wall Street Journal. Clocking in at just under 2,000 words, Keith J. Winstein's article, "A Simple Health-Care Fix Fizzles Out", time-travels back three years to look at the COURAGE trial and how it has affected (or not) the treatment of patients with "stable coronary artery disease". (For a refresher on COURAGE, read Angioplasty.Org's 2007 report).

The main thesis of Winstein's piece is that the use of stents, after an initial drop of 13% right after COURAGE was published, is now back to pre-COURAGE levels. With the subtitle, "Why Health Policies Can Fail to Keep Up With Key Medical Findings", the WSJ article questions this rebound in stent use, which it characterizes as a "lucrative treatment" that can be "ineffective" and "unnecessary", and discusses the resistance to the COURAGE results from both the interventional cardiology community and the medical device manufacturers. (Gee...and I always thought the WSJ was a "friend" to business and industry.) The article also discusses how reimbursement policies currently favor stenting over medical therapy.

WSJ Simplifies Study Results by Ignoring Key Issues
Although the impact of the article may have been lessened somewhat when Bill Clinton was treated successfully with two stents only hours after the WSJ hit the street, there's no question that the COURAGE study (along with other similar trials, such as the recent BARI 2D) raises important issues, but the WSJ piece leaves out some important points and, well, here's a sample of the opening graphs:

The words that jump out at me are "simple" and "straightforward" -- because the diagnosis and treatment of coronary artery disease are neither. It may be comforting to view medicine through the eyes of an engineer or programmer, where you define a problem, create a fix, test it and implement it. But figuring out how to diagnose and treat a specific patient involves juggling multiple moving targets while keeping on top of the latest research, findings and available tools: it's what good doctors do.

Also Winstein's choice of the phrase "no additional benefit" is not accurate. The COURAGE study concluded that the addition of stenting "did not reduce the risk of death, myocardial infarction, or other major cardiovascular events." In fact, the Quality of Life portion of COURAGE showed that patients who received stents felt better (less pain) than the patients on OMT. That would definitely be a "benefit".

So here are a few facts and findings that may mess up this "simple concept" and show it to be a bit less than straightforward:

Comparison About More Than Just Drugs vs. Stents
COURAGE was not simply about "generic drug cocktails" vs. stents; it was about Optimal Medical Therapy (OMT) alone vs. OMT with the addition of stents. OMT is defined as a combination of "intensive medical therapy, a reduction of risk factors, and lifestyle intervention (diet, regular exercise, and smoking cessation)." Patients on OMT took 8-10 or more pills daily. They also were counseled about lifestyle changes, given support to lose weight, to exercise, to stop smoking -- none of these changes, as many of us know, are easy to accomplish; These patients got a type of personalized care that unfortunately is not readily available to many. In the "real world" studies have shown 40-50% compliance with diet, exercise, etc. -- in COURAGE compliance was boosted to 80-90% -- but can this be extrapolated to real-life? If insurers actually paid for these types of full-blown support services for weight-loss, exercise and smoking cessation (and they should!) -- what would that additional cost be for all "stable" heart patients?

1/3rd of Patients Given "Drugs Only" Switched to Stents
While it is true that there were no statistically significant differences between the two groups in terms of death and heart attack, fully 1/3 of the patients who started with medical therapy crossed-over to stenting, mainly for symptom relief (the BARI 2D trial experienced a similar cross-over rate of over 40%). In other words, someone thought stenting was beneficial!

Study included only Bare Metal Stents
Drug-eluting stents were not even approved until the final 6 months of COURAGE, so less than 3% of patients received them; 97% received the older bare metal variety. Drug-eluting stents significantly reduce restenosis (reblocking of the artery). Studies have shown that about 1/3 of the time, restenosis manifests as a heart attack. So would the results of COURAGE have favored stenting if drug-eluting stents were used?

Very Limited Patient Selection -- 90% of Candidates Rejected
90% of the patients initially screened for COURAGE were not enrolled in the trial (i.e. they did not fit the study's definitions of "stable angina"). A 90% exclusion rate is fairly high and critics of COURAGE point to this to show that the patient population was not what cardiologists encounter in their day-to-day practice.

Pre-Testing No Simple Solution Either
The WSJ article also makes a case for more pre-testing of patients before a stent is decided upon. According to the AHA/ACC/SCAI Guidelines, this is the way it's s'posed to be. But studies have shown that up to 50% of patients getting a diagnostic angiogram have not had a nuclear stress test. There are reasons. Because of previous diagnostics and/or clear symptoms, there may be no question that the patient has coronary artery disease (Bill Clinton did not need to undergo a stress test last week). Another confounder is that nuclear stress tests show a relatively large number of false positives or equivocal results, so those patients are sent to the cath lab for a diagnostic angiogram -- yet 37% of patients who get diagnostic caths show no coronary artery disease. And the scenario of someone dying of a heart attack the day after a negative stress test is oft-quoted (the tragic case of Tim Russert, for example). Moreover, many imaging experts believe that Cardiac CT is a better, more accurate test for the presence of coronary artery disease -- yet its use is being restricted by insurers and Medicare as being overused (not true) and unsafe (also not true -- properly done, the radiation from a Cardiac CT scan is less than that from a standard nuclear stress test). The testing/decision tree for patients with chest pain definitely needs updating.

Guidelines Plus Individualized Medicine -- More Effective than One Size Fits All!
Certainly, some sort of decision-making, and discussion with the patient, before choosing stenting as the treatment is essential. And treatment with medical therapy and lifestyle change should be the first line. These are the guidelines agreed upon by the professional cardiology societies.

What we really need is better patient and professional education, and a system that supports patient self-care, which might increase implementation of these guidelines. But making that happen is a hard sell -- probably because it doesn't immediately make or save anyone money (take it from those of us in the education business!).

The take-away from COURAGE is that, in this very specific low risk patient population, stenting can be safely deferred, to see if OMT can provide a less invasive, less costly benefit.

The downside for patients, however, is if insurers take some of these concepts and use them to deny care. In an interesting experiment, Blue Cross/Blue Shield in some parts of New York is requiring "stable patients" to do 12 weeks of medical therapy before they will cover a stent procedure. I only wonder if the type of COURAGE-level support will be there for them. I also wonder how the type of patient that would be in the COURAGE cross-over-to-stenting group will fare. Will they have to suffer angina for weeks before their procedure can be covered by insurance?

Finally, there is a strong movement in medicine today towards individualized treatment. As more is learned of genetic markers, cytochromes, etc. it may be that "one size fits all" treatment will disappear. This concept has been discussed at length by many cardiologists, most directly by Dr. Eric Topol regarding optimal duration of antiplatelet therapy. (Read his exclusive interview on Angioplasty.Org)

So the fear of using results from a study of a very particular hand-picked although large patient population to mandate (and possibly limit) care for a broad population of heart patients, is a bit disconcerting.

Remember too that in all of this, we are only discussing those patients with "chronic stable angina", a condition which itself many have trouble defining. Not in dispute are patients with more serious coronary artery disease, especially those in the midst of a heart attack. They are, without any question, best served by reopening the arteries, whether via bypass surgery or angioplasty.

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February 12, 2010 -- 4:30pm EST

Clinton and Eisenhower: Presidents, Hearts, Stents and 55 Years
It's a holiday concurrence: Valentine's Day and President's Day and American Heart Month -- and former President Bill Clinton who got his heart fixed six years ago and just got a "tune-up", is already back home. He was having discomfort, so yesterday morning he saw his cardiologist, he was wheeled into the cath lab -- an hour later he had two stents opening up one of his original coronary arteries (not one of the bypass grafts which had closed completely) and this morning, less than 24 hours later, he was at home in Chappaqua and no doubt already on the phone and back to work. His prognosis: excellent -- this incident should not affect or hinder him in any way.

Whatever your take on comparative effectiveness research, whether too many stents are used, etc., you have to admit it's pretty amazing. The advances made in diagnosis, bypass surgery and interventional catheter-based techniques have revolutionized the treatment of coronary artery disease. Especially when you look back at how this illness used to be treated (or not).

Dr. William W. O'Neill, Professor & Executive Dean for Clinical Affairs, University of Miami, Division of Cardiology has a favorite lecture that he gives on this topic. He goes back to 1955 and describes how then President Eisenhower's chest pains were first diagnosed as gastric upset and finally almost a day later an EKG showed he was in the midst of a massive heart attack. But there was nothing any doctor could do then, except give Ike morphine for the pain. The heart attack had to play itself out, Ike's heart muscle was damaged and he was in the hospital for 7 weeks. He didn't return to work for 3 months. (for you young folk, our Vice President at the time was Richard Nixon!). Ike did continue as President and, in fact, was re-elected to a second term (after all, he was THE hero of WWII). But without question, his ability to lead a fully active life was significantly compromised and ultimately, in 1967, he succumbed to heart disease. (A print version of Dr. O'Neill's lecture can be found here, pages 2-3)

The take-away from Bill Clinton's episode is that even though his quadruple bypass surgery was successful, the natural history of coronary artery disease is that it will progress. Surgery, angioplasty, stents, medicine -- none of these are cures, but they are interventions in this progression. Along with the medications, exercise, diet and smoking cessation, the natural history can be slowed down. Clinton, having experienced this pain previously, knew it was significant and did precisely the right thing: he saw his cardiologist.

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February 11, 2010 -- 8:00pm EST

IVUS vs. FFR -- Boston Style
Earlier today I was doing research for an article about stents for our site, Angioplasty.Org. I Googled "Fractional Flow Reserve FFR" and the sponsored link at the top of the page, titled "IVUS vs. FFR", caught my eye -- mainly because IVUS and FFR are two completely different modalities and doing a "versus" with them is oh so apples and oranges. Anyway, I was curious and clicked through to advertiser Boston Scientific's web page about how IVUS is so much better (10 times better even) than FFR.

So what's wrong with this picture?

Well...FFR measures intracoronary blood pressure across a blockage. A blockage may look significant on an angiogram, but 1/3 of the time (according to the FAME study) it isn't "flow-limiting"-- and probably doesn't need to be opened up and stented. Working this way is called FFR-guided PCI (i.e. angioplasty and stenting). It improves outcomes and saves money. In fact the recently issued AHA/ACC/SCAI Guidelines Update just raised the level of evidence for use of FFR to "A", stating that FFR "can be useful to determine whether PCI of a specific coronary lesion is warranted."

IVUS (IntraVascular UltraSound) is an imaging modality and it doesn't measure blood pressures. It allows the cardiologist to see (and measure quite accurately) the diameter of the artery, the size of the blockage, the length of the diseased portion. In newer sophisticated systems, something called Virtual Histology™ can even differentiate the type of plaque, including so-called "vulnerable plaque" that may be more prone to causing a heart attack. IVUS is a great tool, kind of like having a ruler inside the artery, but the revelations of the FAME study could not have been made using IVUS.

In fact the two tools can work very well together: FFR-guided PCI refines the decision-making process of whether or not to stent; IVUS refines the mechanical stenting process of placing and inflating the device optimally. Ideally, both can be used to improve the outcomes of PCI procedures. It's not either/or: IVUS helps you do a better job when you stent people; FFR helps you avoid stenting people unnecessarily.

So why is Boston Scientific demeaning the value of Fractional Flow Reserve? Possibly because there are only two manufacturers of this technology, and they're not one of them. St. Jude is one, as a result of their acquisition of Swedish firm Radi; Volcano is the other. Volcano is also Boston Scientific's only competitor in the IVUS field -- and they offer a system that integrates both FFR and IVUS.

The ad suddenly made sense.

As for my search for information on FFR, I ran into a familiar situation. The first two hits were articles I had already written on the subject!

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February 9, 2010 -- 11:50pm EST

Volcano Has AAA Week: Accused, Approved and Acquired
Volcano Corporation (Nasdaq: VOLC) has had a pretty interesting week. Last Thursday was the low point: a 13 person jury in Massachusetts Superior Court found Volcano and its subsidiary Axsun liable for a number of contractual breaches against LightLab Imaging, Inc. These all grew out of Volcano's purchase of Axsun, a company that had exclusive contracts with LightLab, Volcano's main competitor in the Optical Coherence Tomography (OCT) field. The court has set March 22 as the start of the damages assessment phase.

But today, Volcano made two more positive announcements. The FDA has approved Volcano's latest IVUS catheter, the Eagle Eye® Platinum. It represents the latest refinement in intravascular ultrasound imaging (see picture above) -- a modality which has been shown to improve stent placement and sizing. And also today, Volcano announced that it has acquired the Xtract™ Thrombus Aspiration Catheter from Lumen Biomedical. This device is sort of a vacuum cleaner, used before angioplasty and stenting during a heart attack to remove the blood clot that stops the blood flow. Thrombus aspiration has been shown to significantly improve patient outcomes.

Looking at these new developments, and given that Volcano's pipeline includes forward-looking IVUS and other future therapeutic modalities, it's clear that the company is compiling an armamentarium of both imaging and treatment devices, all for delivery with the same console in the cath lab: a variation on "see one, do one".

(Volcano's stock closed at $19.84 today, up 33% from a year ago.)

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February 7, 2010 -- 11:10pm EST

Herbal Supplements vs. Heart Drugs: Controversy Re-ignited
An article, that should be of special concern to stent and angioplasty patients, appears in the current Journal of the American College of Cardiology (JACC). This "state-of-the-art paper" from the Mayo Clinic, titled "Use of Herbal Products and Potential Interactions in Patients With Cardiovascular Diseases", has rekindled the herb vs. pill battle and raised the ire of the alternative medicine community. Specifically, the Council for Responsible Nutrition (CRN), a trade association representing the dietary supplement industry, has responded quite pointedly to the paper, stating:

The JACC article details the significant amounts of money ($34.4 billion) expended annually in the U.S. on Complementary and Alternative Medicine (CAM). The authors calculate over $5 billion is spent out-of-pocket on herbal supplements alone. Yes, that's $5 billion -- the total worldwide market for drug-eluting stents -- perhaps executives at Medtronic or Boston Scientific might be thinking, "maybe we're in the wrong business".

In any case, the JACC paper details a number of herbs, natural substances and preparations that have an impact on the cardiovascular system -- from helping lower high blood pressure by dilating arteries, to increased antiplatelet effects to keep blood from clotting. These all sound like useful and good qualities. But, as the authors point out, problems may occur, as in "too much of a good thing".

The CAM forces are unhappy with what they claim is the implication that herbal and natural supplements are unsafe. But I think this misses the major point of the paper. Quite the opposite, the paper details the ways in which herbal supplements are powerful medicines.

If, for example, you have had a stent implanted and are on dual antiplatelet therapy (aspirin and clopidogrel) to keep from developing dangerous blood clots in the stent, you may think it would be a good idea to also take Ginkgo for "cardiovascular health" to keep the blood even more slippery. Yet Ginkgo intensifies the antiplatelet drugs to the point where bleeding complications may arise and may cause internal hematoma or hemorrhage. So it's not that ginkgo is unsafe -- it's that it has a very definite effect.

And so with other supplements that affect the cardiovascular system. Some covered in the JACC article are: St. John's wort, motherwort, ginseng, garlic, grapefruit juice, hawthorn, saw palmetto, danshen, echinacea, tetrandrine, aconite, yohimbine, gynura, licorice, and black cohosh.

The important point of this paper is that patients and physicians should be talking to each other about alternative supplements, and making sure they are taken into account when drawing up a medical management plan -- to ensure there are no interactions or unwanted enhanced effects.

To rebut the implication that physicians currently do not query patients about herbal supplements, CRN has published the results of a survey, showing that, in fact, patients and cardiologists DO discuss them to a high degree.

I wonder if that is really the norm and would welcome comments.

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February 5, 2010 -- 8:40pm EST

Patent Spending
Big money surrounding legal issues for cars and stents this week. But most of us have only heard about the car part: Toyota, that is. Current estimates of Toyota's cost to make good on its brake problems run anywhere from one to two billion dollars! And the company's fortunes have been raked over the headlines in mythic proportions, such as "fall from grace" and "payback for stealing fire from the gods".

But no such hyperbole for this week's stent news. Instead, on Monday, Boston Scientific announced (rather quietly) that, rather than go to jury trial later this month on patent disputes with Johnson & Johnson / Cordis that date back to 2003, they've decided to just settle everything -- for a mere $1.725 billion!

Consider that this price tag is the same quantum as Toyota's hit, and consider that, as the Wall Street Journal points out, not only is this amount almost double J&J's total 2009 sales of drug-eluting stents, it may eclipse Boston's as well. So one might wonder why, other than a few scattered articles in the business press, there's been so little publicity regarding this major concession. After all, these disputes have been in the courts for years, and many millions already have been spent on lawyers' fees, etc.

One can only assume that Boston Scientific foresaw a worse outcome from a jury trial and so, decided on the option of settlement. Perhaps the company saw the futility of trying to challenge the original stent patents of Palmaz and Gray, patents that time and again have been upheld. But a worse outcome than $1.725 billion?

Julio Palmaz, inventor of the original stent design, told me recently that, if you wanted to be an inventor, you'd better be prepared to spend a lot of time in court. Over the past two decades, Palmaz spent years sitting in courtrooms all over the world. In fact, he sold his patents to J&J in 1998 partly to eliminate the suspicion of personal gain when he testified on behalf of his invention. As he told the New York Times in a 2007 profile:

Ray Elliott, Boston's new CEO, stated that the company settled to "mitigate risk" and to resolve "major litigation without exposing Boston Scientific to the uncertainties of a jury trial and a potential damages award that was impossible to predict." But the price tag is very high and a stock analyst, quoted in Tuesday's WSJ, opined, "We think most investors will be surprised and concerned," by the new deal.

As for Dr. Palmaz, he will no doubt be relieved at being able to spend February and March elsewhere.

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