Tag Archives: American College of Cardiology

Prevent Atherothrombotic Events? It’s Complicated

When researchers reported earlier this week at the American College of Cardiology’s annual meeting results from the TRA 2P-TIMI 50 trial, which tested a novel anticoagulant drug, vorapaxar, for preventing cardiovascular death, myocardial infarction (MI), and stroke in stable patients with cardiovascular disease, the results showed a questionable balance between benefit and bleeding risk that only looked good if you squinted and confined the analysis to patients with just a history of MI, no history of stroke, a body weight of at least 60 kg, and, ideally, those who were younger than 75 years old. Even within this pared-down universe, experts differed on whether vorapaxar had an unequivocal net benefit after taking into account the bleeding risk it caused.

But if vorapaxar someday gets FDA approval and appears on the U.S. market, physicians will face the tricky calculus of how to use it compared with the other new, potent antithrombotic drugs.

blood clot/courtesy Janice Carr; Public Health Image Library

Looking at vorapaxar’s performance in patients with stable cardiovascular disease, it was hard not to recall last November’s report on the ATLAS ACS 2-TIMI 51 trial, which tested adding a 2.5 mg b.i.d. dosage of another new anticoagulant drug, rivaroxaban, in acute coronary syndrome (ACS) patients also treated with aspirin and clopidogrel. In ATLAS, adding this small dose of rivaroxaban led to benefit and a bleeding risk that was strikingly similar to the pattern seen with vorapaxar in TRA 2P.  Rivaroxaban on top of aspirin and clopidogrel produced an absolute, 1.6% cut in the combined rate of cardiovascular death, MI, or stroke while boosting the rate of major bleeds by an absolute 1.2%, and the rate of intracranial bleeds by 0.2%. The new vorapaxar results showed that in the best-case subgroup, adding the drug to aspirin and clopidogrel cut cardiovascular death, MI, or stroke by an absolute 1.9%, while boosting major bleeds by 1.0% and intracranial hemorrhage by 0.2%.

A big difference in the two analyses was that the benefits and risk seen with 2.5 mg rivaroxaban was in the entire study population of 5,100 patients, with no need to resort to subgroup analyses. The vorapaxar result was in about 9,500 patients, roughly 70% of all patients enrolled in the trial. Another big difference was the major impact of rivaroxaban was on cutting cardiovascular deaths. Vorapaxar’s main effect was to lower nonfatal MIs. It cut cardiovascular deaths too, but not as well as low-dose rivaroxaban.

Many experts whom I spoke with at the meeting seemed confident that low-dose rivaroxaban is on track for FDA approval later this year for treating ACS patients. Whether Merck, the company developing vorapaxar, will seek FDA approval for its drug in stable patients based on the TRA 2P data remains to be seen.

But while rivaroxaban won’t receive labeling for treating non-ACS patients, all that separates an ACS patient and a patient who is stable but with a history of prior MI is time; in fact, just a few weeks or months. The point at which an acute ACS patient becomes a stable, post-MI patient is pretty murky. Would anyone consider treating a stable, post-ACS patient with low-dose rivaroxaban? The labeling probably won’t cover it, but will the temptation be there? And the what-ifs don’t stop there.

Both the low-dose rivaroxaban study and the vorapaxar study used aspirin and clopidogrel as standard, background treatment. But U.S. physicians are increasingly switching from clopidogrel to the newer, more potent antiplatelet drugs already on the market, prasugrel and ticagrelor, several experts told me at ACC. Putting a patient on prasugrel or ticagrelor plus aspirin will likely preclude any thought of also adding rivaroxaban, not to mention vorapaxar. These combinations have not been tested, and given the bleeding risks that these drugs pose individually, the idea of using them in combination is downright scary.

After several years when clopidogrel plus aspirin reigned alone as the top treatment for preventing atherothrombotic events, the last few years brought a flurry of new agents. How these drugs compare and relate to each other, and how they are optimally used alone or in combination, will take several more years to sort out.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Keeping Score on the STS Risk Score

The Society of Thoracic Surgeons has a formula for estimating a patient’s risk of dying following cardiac surgery, the STS Predicted Risk of Mortality score. Some new data reported during the past 2 months suggest that the score doesn’t predict death as well as some experts thought. It looks like when it’s applied to very sick patients, it may produce an overly pessimistic estimate and predict more deaths than patients will actually experience.

"Death's Door" by William Blake; courtesy Wikimedia Commons

A patient’s mortality risk score derives from a list of 30 clinical and demographic inputs, factors like type of surgery, age, sex, hypertension, diabetes, cardiac history, vascular health, hemodynamics, etc. Based on all this, the formula spits out a patient’s probability of dying during the 30 days following the proposed surgery.

The PARTNER trial enrolled patients with severe aortic stenosis to compare a new technique of percutaneous aortic valve replacement with standard open surgical replacement. An initial report on results from the randomized portion of the study occurred last month at the annual meeting of the American College of Cardiology, and some more details on strokes and other neurologic outcomes got reported a few days ago at the American Association for Thoracic Surgery’s annual meeting in Philadelphia.

The patients entered into PARTNER were very, very sick. Their average age was about 83 years, and about 95% had the two highest grades of heart failure, New York Heart Association class III or IV. Their STS risk scores were also high, averaging about 12, which meant these patients had a 12% predicted risk of dying during the 30 days following open surgical replacement of their dysfunctional aortic valve.

These patients “were probably the highest 10% of risk on the STS score,” said Dr. D. Craig Miller, the cardiac surgeon who presented the neurologic data at the AATS meeting. “STS scores have never been validated at this extreme. Never before were enough patients [with scores this high] operated on to validate the STS score ” at this level, Dr. Miller said.

The reality was that the scores broke down. Instead of having a 12% 30-day mortality rate, the patients who underwent open surgery had about an 8% death rate. “We were pleasantly surprised by the low death rates,” at least in comparison to what the STS scores predicted, he said.

The only caveat to this good news was that the less-than-dire outcomes of some patients might have been very specific for the high-level treatment that patients received at the 26 centers that participated in this carefully structured trial. “What would be the results in the real world? That remains unanswered,” Dr. Miller said.

—Mitchel Zoler (on Twitter @mitchelzoler)


Filed under Cardiovascular Medicine, IMNG, Surgery, Thoracic Surgery

Seeing Red: Heart Disease and Women

The Red Dress Campaign has caught women’s attention regarding the very real dangers of cardiovascular disease, but a new study shows they may not be taking the message to heart.

Photo courtesy of The Heart Truth®, NHLBI, NIH

The study, presented at the recent American College of Cardiology meeting, found that the overall incidence of acute MI decreased among 315,246 patients admitted to New Jersey hospitals 1986-2007. The decrease was significant among both men and women, but was more prominent among men.

The incidence of acute MI fell from 598 to 311 per 100,000 men and from 321 to 197 per 100,000 women, according to cardiologist Dr. Liliana Cohen and her colleagues at the Robert Wood Johnson Medical School in New Brunswick, N.J. They also identified a growing gap in the rates of left heart catheterization and percutaneous coronary intervention between men and women.

The rates of catheterization increased fivefold in women and threefold in men over the 22-year study period, but the likelihood of catheterization remained lower for women. Moreover, the difference among male and female cath patients going on to receive PCI increased from 2.2% in 1986 to 9.4% in 2007.

Finally, both in-hospital and 1-year mortality remained higher among women, and failed to show a significant decrease after 2002 – the year the National Heart Lung and Blood Institute launched the Red Dress campaign.

“Although awareness of cardiovascular disease in women has increased in the general population, there has been much less translation of this into clinical practice,” Dr. Cohen told me.

This may be due to women presenting later because they doubt an MI can happen to them or that physicians still are not treating women as aggressively as they treat men, she said. It also may relate to the fact that women have more difficult cardiac anatomy, so that once they receive cardiac cath, PCI remains difficult.

Photo courtesy of The Heart Truth®, NHLBI, NIH

Dr. Cohen suggests that in its next phase, the campaign needs to continue to focus on public health awareness, but also on research into how to translate public awareness into clinical practice by focusing on physicians and into newer techniques of PCI for the smaller blood vessels in women.

Quibble if you will about the generalizability of data from a single state or the potential impact of a single PR campaign, but it’s hard to ignore these disappointing outcomes.

I once heard a bold and blistering guest lecture at a cancer meeting by Nancy Goodman Brinker, founder and CEO of Susan G. Komen for the Cure, who told several thousand — mostly male — oncologists that a survival rate topping 90% for early stage breast cancer simply wasn’t good enough.  Truer words were never spoken.

— Patrice Wendling

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Second-Generation Coronary Stents Come of Age


Slightly more than 3 years ago, in February 2008, the  first of what’s been called the “second generation” of drug-eluting coronary stents received FDA approval to enter the U.S. market. At the annual meeting of the American College of Cardiology,  held earlier this month, this new generation of coronary stents seemed  to fully come of age.

coronary stent image courtesy of Abbott

The second generation has had growing pains. The first approved stent from this generation, Medtronic’s Endeavor  zotarolimus-eluting stent, produced underwhelming restenosis rates compared with the first-generation drug eluting coronary stents, Cypher and Taxus. This became such a problem for Medtronic that at this year’s ACC meeting they unveiled much of their new data on a follow-up zotarolimus-eluting stent, Resolute, that differs from Endeavor  only  by a longer period of drug elution, (6 months) a change that seems to have solved the restenosis problem.   

Soon after Endeavor appeared came another second-generation stent in 2008, an everolimus-eluting device sold by two different companies under two different names because of a complex ownership history, the Xience V and Promus stents, sold by Abbott and Boston Scientific, respectively. These everolimus-eluting stents have done well, and are now the most widely used drug-eluting coronary stents on the U.S. market.

But now there is more to the new generation, with the Resolute stent moving to likely U.S. approval, and with a follow-up to the Xience V and Promus stents, a platinum-containing stent that is otherwise similar to its everolimus-eluting forebears that  may, or may not, have advantages over the Xience V and Promus models. A report  at the ACC meeting presented data on more than 700 patients who received the platinum-containing version of the everolimus-eluting stent.

Interventional cardiologist Gregg W. Stone gushed  over the roughly 3.5% target lesion failure rate seen in this PLATINUM trial, both in patients who received the new stent as well as in those who received the comparator, Xience V/Promus stents, as well as the 3.7% rate seen in noncomplex patients treated with the Resolute stent.

“I think that this generation of drug-eluting stents is clearly different. They are better than the first generation. We’ve seen tremendous progress made,” Dr. Stone said.

His fellow interventionalist, Martin B. Leon, who reported some of the Resolute results, was equally effusive about all four second-generation stents.  “Over many years we have evolved into a state of really excellent PCI outcomes with these new and improved drug-eluting stents. We saw it first with Xience V and Promus, and now with Resolute and the Platinum stents. These results are very hard to beat, and it is difficult to distinguish among these devices” for either safety or efficacy, he said.

Four well-performing, second-generation stents that are difficult to distinguish? The only downside seems to be the inevitable marketing storm, as competing companies try to convince physicians that their second-generation stent stands out from the new-and-improved pack. When marketing mania hits, it will mark these stents as members of a fully mature next  generation.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Cardiologists Challenged

The opening scientific session at the annual American College of Cardiology meeting kicked off with a glitzy video montage that would have made Hollywood proud. I half expected to see a reminder to visit the concession stand crawl across the big screens. But just as the hype was beginning to overwhelm, Dr. James Orbinski rose to deliver the most scorching presidential lecture in memory.

Image courtesy TheSilentPhotographer at en.wikipedia (CC)

The internationally acclaimed physician and humanitarian challenged the audience to get involved in global heath and to tackle issues that most people write off as hopeless causes. He pointed out that the $13,000 price of antiretroviral drugs to combat AIDS was once a virtual death sentence for all but the wealthy.

With vocal outrage from humanitarian groups including Dignitas International, which he cofounded with James Fraser, however, the price tag has dropped to just $64 per year for generic therapies, and somehow, Big Pharma did not collapse, as was prophesied, he said.

Dr. Orbinski didn’t shy away from politics, which at most medical meetings is politely veiled in talk of pending legislation.

As Chief of Mission to Rwanda with Médecins Sans Frontières during the genocide, he recalled a young girl brought to his care who avoided being hacked to death as her mother had been by hiding in a latrine. He scolded France for supplying arms to the Habyarimana regime, and the global compliancy exhibited by countries including the United States despite overwhelming evidence of genocide.

Dr. Orbinski, who collected the Nobel Prize on behalf of MSF for its work in Rwanda, spoke of the need for ongoing research of neglected tropical illnesses and the growing threat that West Nile virus and Dengue fever pose to even the most well-heeled Americans. He spoke about climate change and the political unrest caused by hunger, now experienced by one in seven persons across the globe.

He reminded us that 43 years ago today when Dr. Martin Luther King Jr. was assassinated in Memphis, no one would have dreamed that it was possible for a black man to become president of the United States.

The lecture was nothing like I’ve ever heard before.

Dr. Ralph Brindis

When he finished, the packed ballroom was silent and still. Many rose to give Dr. Orbinski a standing ovation, but some did not. So when outgoing ACC president Dr. Ralph Brindis rose to speak, there was something of a sense of relief in the air. It was short lived.

Dr. Brindis cited the recent ICD-registry study by Dr. Sana Al-Khatib and colleagues that found that 22.5% of 111,707 patients received nonevidence based ICD implantations for the primary indication of sudden cardiac death between January 2006 and June 2009.

Dr. Brindis said he has been disappointed in physician participation with the National Cardiovascular Data Registry, despite its ability to provide greater understanding of physician practice as well as local and national trends in socioeconomic disparity.

“The NCDR data are your clinical data,” said the mild-mannered Dr. Brindis, while pointing his finger squarely at the audience. “You are responsible for the accuracy of the information, and you should strive to take advantage of these reports to discover opportunities to improve the care of your patients.”

This reporter tips her hat to the ACC for selecting New Orleans for its annual meeting and for being bold enough to challenge its members. Thinking outside the box beats Hollywood any day.

—Patrice Wendling from New Orleans

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The Surgery Was a Success, But the Device Died

From the annual meeting of the American College of Cardiology in Atlanta. 

When a medical device tests safe and works well enough to cut patient mortality in half  it usually has a rosy future. But not when the small-company developer falls victim to the recent financial crisis, an economic calamity that led to bankruptcy  more than a year before the promising trial results were known. 

Coapsys device, a cord threaded through the left ventricle and attached to two external pads. (photo by Mitchel Zoler)

The device was called Coapsys, and it had an unusual design: A piece of cord threaded through a patient’s left ventricle and tethered with two pads on either side of the heart (see photo). The idea was that the tension the cord exerted on the pads could reshape an enlarged heart to improve its function and partially correct mitral regurgitation, a leakage of blood through the valve that separates the left atrium from the left ventricle. 

At the American College of Cardiology meeting last week, Dr. Eugene A. Grossi, a cardiothoracic surgeon at New York University, presented results from a multicenter, randomized trial that included 165 patients with enlarged hearts, heart failure, and functional mitral regurgitation. The device was safe, with none of the 81 patients who received it having a peri-operative complication. The device recipients also had significantly fewer adverse events during 3 years of follow-up. And their overall mortality rate was about half that of the 84 control patients, who had conventional surgical treatment of their mitral regurgitation. 

After the company that developed the device and started the trial, Myocor, closed down in late 2008, a viable medical-device company, Edwards Lifesciences purchased the rights for the Coapsys device and all of Myocor’s other intellectual property. But a query today to a spokeswoman for Edwards revealed that the company had no specific, immediate plans for further development of the Coapsys device, or at least no plans that they were willing to reveal. 

Despite Edwards’ suprising lack of enthusiasm, or at least expressed enthusiasm, Dr. Grossi remained optimistic that the new results will not be overlooked. “With something as concrete as a mortality benefit, I think we’ll see a lot of equivalent devices that focus on treating the ventricle and not the mitral valve,” he said. 

—Mitchel Zoler (on Twitter @mitchelzoler) 

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Never On Sunday

Photo by Bruce Jancin

From the annual scientific session of the American College of Cardiology, Atlanta

If you’re going to have a heart attack, it remains an excellent idea to arrange it for a weekday.

The “weekend effect”–worse outcomes for myocardial infarction patients admitted on Saturday or Sunday–remains operative across the U.S. despite numerous advances in acute cardiac care in recent years, according to a large national study.

The problem, according to Dr. Abhishek Deshmukh, appears to be that fewer of these treatment advances are brought to bear urgently on weekends because of diminished staffing and, in some hospitals, restricted cardiac catheterization lab hours.

He analyzed more than 287,000 MIs included in the 2007 National Inpatient Sample database and found the in-hospital mortality rate for patients admitted on weekends was 7.6% as compared to 6.4% for weekday admissions. After adjustment for hospital characteristics and disease severity, MI patients admitted on weekends had a 23% greater risk of in-hospital death. They also had greater average lengths of stay, got fewer revascularization procedures, and waited almost half-a-day longer for them.

Nevertheless, if chest pain arises on a weekend it remains critical to seek immediate medical care. Waiting it out until Monday is a very bad idea, stressed Dr. Deshmukh, an internal medicine resident at the Medical College of Wisconsin, Milwaukee.

—Bruce Jancin

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Thinking Outside of Clopidogrel’s Black Box

From the annual meeting of the American College of Cardiology in Atlanta 

image courtesy of Flickr user jmcraftworks

The black box warning that the FDA slapped onto its labeling for the antiplatelet drug clopidogrel (Plavix) on March 12 became the talk of the American College of Cardiology’s annual meeting when it started a couple of days later. It also abruptly changed medicine’s antiplatelet playing field. 

Cardiologists, as well as primary care physicians, prescribe clopidogrel, often with aspirin, to many patients with coronary disease to help keep blood clots from forming inside their arteries. 

The FDA said it decided to impose the boxed warning because anywhere from 2%-14% of people are “poor metabolizers” of clopidogrel, which makes them unable to effectively convert it into its active form. In other words, when a poor metabolizer receives clopidogrel it’s as if the drug were never administered, because the person cannot change the drug to make it active. 

The implications of the FDA’s action were clear to many physicians at the ACC meeting. They now had three options for dealing with patients who needed antiplatelet therapy. They could: 

1. Treat patients with clopidogrel and then test their platelets’ reactivity to see if it had been properly blunted by clopidogrel treatment. If not, switch to a different drug. 

2. Test each patient before starting clopidogrel to see if they carried a mutation in one or both of their genes for the liver enzyme (cytochrome P2C19) responsible for producing the active metabolite of clopidogrel. If they carried a mutation, switch to a different drug. 

3. Skip either test and jump straight to an alternative drug. The most obvious alternative right now is prasugrel (Effient), an agent that’s very similar to cloipidogrel except it does not require enzymatic activation. 

What the FDA’s action precluded was maintaining the status quo. By adding the black box warning to clopidogrel last week, the FDA eliminated prescribing clopidogrel blindly as standard of care. 

—Mitchel Zoler (on Twitter @mitchelzoler) 

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Hey, AMA: Deal or No Deal?

From a press briefing at the U.S. Capitol with AARP, the American Medical Association, the Military Officers Association of America, and Sen. Debbie Stabenow.

Sen. Debbie Stabenow (D-Mich.) held a press briefing Tuesday morning designed to get the word out that she was ready to end what has now become an annual “Kabuki dance” as she put it — the congressional scrambling each year to restore cuts to physicians’ Medicare pay required by the “sustainable growth rate” formula. Why Kabuki? Because, she said, everyone knows that the cuts will never happen, and yet Congress goes through the high drama of pretending that it needs the revenue from the fee reductions, but then votes at the last minute to give physicians their money.

A Fine October Day At the Capitol/Photo by A. Ault

A Fine October Day at the Capitol/Photo by A. Ault

But, in a time when the President has promised that he won’t sign any bill that adds to the deficit and when Congress is supposed to be operating under rules that require a dollar savings for every dollar spent, reporters wanted to know — why was Sen. Stabenow making a $250 billion (over 10 years) promise to the American Medical Association?

The Hill has been rife with rumors that the Michigan Senator’s bill was a quid pro quo, buying off the AMA’s support for health reform. (Yes, other physician groups are supporting the SGR fix, including the American College of Cardiology, but the AMA still has powerful political cachet in the capital.)

First, a reporter asked if passage of the Stabenow bill would mean that the AMA would support the Democrats’ health reform bill.  AMA President  James Rohack deftly deflected and noted that the SGR fix predated any discussion of health reform.  The AMA is committed to the bill because it solves a problem that’s been around at least 7 years, Dr. Rohack said.

Yeah, but does it guarantee that AMA will support the health reform bill?

“The AMA has been supporting health system reform for a long time,” demurred Dr. Rohack.

OK, but does passage of the SGR fix mean that the AMA would support the Senate reform bill?

“We haven’t seen the bill,” said the AMA president.

In the hall outside the briefing, reporters tried again.  So are rumors of a deal just that?

The AMA is focusing on a problem that predates health reform, replied Dr. Rohack.

But there are reports that you promised Harry Reid a deal. “We’ve been working on this issue a long time,” said Dr. Rohack, who now appeared to have been replaced by a robot.

But did you cut a deal with Sen. (Harry) Reid to support this deal?

An aide pulled Dr. Rohack away from the huddle. “Saved by the bell,” quipped a reporter.

Meanwhile, on the Senate floor, GOP Sen. Bob Corker (Tenn.) flat out accused the Democrats of having bought off the AMA, labeling it a “sinister act.”

For her part, Sen. Stabenow stood her ground that there were no politics involved. “I just want to get this fixed and stop pretending we are somehow paying for this by moving every year this cut into the future.”

So what do you think? Did the AMA cut a deal?

— Alicia Ault (on Twitter @aliciaault)

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A Good Meeting

from the annual congress of the European Society of Cardiology in Barcelona

I often hear program committee chairs from major medical meetings say that they have no idea what will be presented in late-breaker meeting reports, and generally I have no reason to doubt this. I can certainly buy that everyone is ignorant of the results when late-breaker sessions get put together and schedules arranged.

This element of serendipity makes what happened at this year’s ESC meeting especially remarkable. Two very important, practice-changing reports came back-to-back during the late breaker session last Sunday morning, August 30 (a session that the ESC calls a Hot Line).

photo by Mitchel Zoler

photo by Mitchel Zoler

First came the PLATO report on an 18,000-patient study that established the safety and efficacy of ticagrelar, a new anti-platelet drug that may largely replace clopidogrel (Plavix) and rival prasugrel (Effient) when it gets to market. Immediately following came the RE-LY study, also involving 18,000 patients and showing that the new anticoagulant drug dabigatran was safer and more effective than  the longtime mainstay warfarin.

In addition to these two blockbusters the meeting had a good share of other important, practice-changing reports on its undercard.

In the cardiovascular disease world three annual meetings dominate the landscape: the American Heart Assoc. Scientific Sessions in November, the American College of Cardiology Annual Scientific Sessions in March, and the ESC in late August/early September.  For most of the many years that I’ve covered these, the ESC was a solid meeting but clearly the lesser of the three.

Not so this year. It was a landmark meeting that will long be rembered for RE-LY, for PLATO,  and many other reports.

—Mitchel Zoler at 2 PM on Sept. 2 in Barcelona (on Twitter @mitchelzoler)

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