heartbeat – wcc 2006 world congress of cardiology 2006 christopher cannon md staff cardiologist...

Heartbeat – WCC 2006

World Congress of Cardiology 2006

Christopher Cannon MDStaff CardiologistBrigham and Women's Hospital,Boston, MA

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical Center, New York, NY

James Ferguson MDAssociate Director, CardiologyTexas Heart Institute, Houston, TX


History of stents

Early 1990s: Bare-metal stents were first used

2003: Cypher (sirolimus-eluting) stent introduced in the US

2004: Taxus (paclitaxel) stent introduced

There are currently ~6 million people with drug-eluting stents

Average costs:• Drug-eluting stent: >$2000• Bare-metal stent: $800

Fuster


Risk of thrombosis

Some studies have found that thrombosis can occur with drug-eluting stents at one year, at two years, at three years . . .

Are the data supporting this strong?

Fuster


Stents and thrombosis

Stent thrombosis is a pretty catastrophic event

•Associated with Q-wave MI in about two thirds of patients

•Associated with a 30% to 40% mortality risk

Stenting in patients with stable or unstable angina can create worse problems

Cannon


Issues surrounding drug-eluting stents

The interventional cardiology community has enthusiastically embraced drug-eluting stents because they deal with restenosis

In the US, probably in excess of 80% of stents used are drug-eluting stents

Two controversies have brought this issue to a head• The long-term implications of drug-eluting stents • The use of drug-eluting stents in the

stable angina population

Ferguson


Stent thrombosis

Total rate of stent thrombosis with coated stents over a period of six months is ~1.3% •Not much different from bare-metal stents

Mortality and MI at 36 months •Not much difference between drug-eluting and bare-metal stents

Fuster


SIRIUS: 5-year follow-up

533 patients received sirolimus-eluting stents, 525 patients received bare-metal stents

Incidence rate of stent thrombosis: 0.8% in each group at five years

Fuster


RAVEL: 5-year follow-up

Incidence of thrombosis was practically zero

Freedom from death and MI

•81.1% with sirolimus-eluting stents vs 89.5% with bare-metal stents

One of the critical questions was how long these patients actually took clopidogrel

Serruys PW. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain. Fuster


TAXUS II: 4-year follow-up

No significant difference in terms of events

Not much thrombosis

Colombo AA. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain. Presentation 4864. Fuster


Reason to worry?

These are relatively small numbers of patients and selected clinical trials

Drug-eluting stents are being widely used outside the confines of the rigid inclusion criteria that applied in clinical trials

Reports of isolated cases of subacute stent thrombosis late in patients is worrisome

Ferguson


Looking for answers

Are mega-studies—the meta-analyses and the registries—going to provide the answers?

Fuster


More use, more risk

"As things have progressed, we've gotten more and more adventurous and have been able to do interventions in sicker and sicker patients."

With more use, the absolute risk of stent thrombosis rises

Cannon


BASKET-LATE

Patients were randomized on a 111 strategy

Compared bare-metal stents with sirolimus-eluting and paclitaxel-eluting stents

After six months, all the patients who were free of any events were followed for 18 months

Pfisterer ME. American College of Cardiology Annual Scientific Session 2006; March 14, 2006; Atlanta GA. Fuster


BASKET-LATE: Troublesome results

The composite of death and MI at 18 months was significantly different

•4.9% for both drug-eluting stents combined vs 1.3% for metal-stent group

Incidence of stent thrombosis

•2.6% for drug-eluting stents vs 1.3% for metal stents

Fuster


BASKET-LATE: Entire population

The entire BASKET population (826 patients) was followed for 18 months

No significant difference in death and MI

•7.5% for bare-metal stents and 8.4% for drug-eluting stents

In the original BASKET trial, clopidogrel was not given beyond a few months

Fuster


Strength of BASKET

"The strength of this study was that they had a very strict timing of clopidogrel, where everyone got exactly six months."

In other trials, a duration was recommended but not necessarily followed

That made it a very clean experiment of what stopping clopidogrel does to the early thrombosis risk

Cannon


BASKET-LATE: Not a clopidogrel trial

In BASKET-LATE, people had to be event free at six months, excluding those who develop restenosis in the first six months

BASKET-LATE compared drug-eluting stents with bare-metal stents, not six-month clopidogrel vs clopidogrel of longer duration

The results have been interpreted by some to mean that clopidogrel should be given for a year or forever

Ferguson


BASKET-LATE: Sorting out the data

How do the clopidogrel issues relate to drug-eluting stents?

Are there differences between the drug-eluting stents?

A subanalysis of BASKET-LATE looking at bypass grafts and small vessels suggested that, in that population, there was demonstrable benefit of drug-eluting stents

Ferguson


A registry study

Of 8146 patients registered, there were 152 instances of stent thrombosis

• Incidence rate of 1.3 per 100 patient-years

Rates of stent thrombosis •1.2% at 30 days•1.7% at 1 year•2.3% at 2 years•2.9% at 3 years

A cumulative increase of 0.6% per year

Wenaweser P. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Presentation 1012. Fuster


Questions about the registry

Did all the patients have angiography?

Is this a selective group?

What was the rate for bare-metal stents?

Fuster


Ongoing and constant risk

"The demonstration of an ongoing and pretty constant risk is the sobering component of this."

With drug-eluting stents, we need to worry about the long term, not just the first six months after placement

Cannon


The question of clopidogrel

In this registry study, 51% of patients were taking only aspirin; 23% were taking neither aspirin nor clopidogrel

Incident rate of thromboembolism with a mechanical heart valve

•Without anticoagulants: ~3% per year

•With anticoagulants: 1% per year

Fuster


Stent thrombosis: A new problem?

We don't have the data from bare-metal stents to know whether this is a problem that we just didn't recognize before

After stenting, three to six months of combination therapy (aspirin+clopidogrel) is just not enough

The data suggest an ongoing risk of stent thrombosis; however, the rate is relatively low

Ferguson


Evaluating stent thrombosis

We don't often have angiographic confirmation of an occlusive thrombus

A lot of trials have had to infer, from clinical events or higher rates of mortality or death/MI, that there might be a thrombotic problem

We don't yet understand the physiology of what is going on

Ferguson


Drug-eluting stents and thrombosis

Stent thrombosis is more likely to happen with drug-eluting stents

The coating and potentially the polymers are designed to prevent healing, so the stent is exposed for a much longer period of time

As interventionalists and cardiologists, we need to make it very clear to primary-care physicians that longer-duration dual-antiplatelet therapy is needed

Cannon


CHARISMA

High-risk patients, the majority with coronary artery disease

The incidence of stroke and major hemorrhage were exactly the same with aspirin alone and aspirin+clopidogrel

The incidence of the medium type of hemorrhage was slightly different between aspirin alone and aspirin+clopidogrel

If I were going to get a drug-eluting stent tomorrow, I would take aspirin+clopidogrel forever

Fuster


Risk of long-term clopidogrel

I would also take aspirin+clopidogrel forever

In the broader set of patients, the risk of longer-term antiplatelet therapy has to be considered

We must recognize that long-term antiplatelet therapy goes along with drug-eluting stents

Cannon


Ongoing clopidogrel: The down side

I would take clopidogrel for an absolute minimum of one year and, if I could afford it, would continue to take it

The difficulty is that you cannot infinitely defer elective surgical procedures

•Some of the procedures that really should be done might be deferred or might not be done at all because of concerns about continued aspirin+clopidogrel therapy

Ferguson


Elective surgery and ongoing therapy

When patients with mechanical heart valves undergo elective surgery, they might be off Coumadin for 10 days

The overall incidence of events in that window is very low

The only thing we don't know is whether this is a rebound phenomenon

Fuster


Reality vs perception

The risk associated with discontinuing clopidogrel for some brief finite period of time is very small

The perception in the practicing world is that if clopidogrel is stopped, the patient is going to subacutely thrombose the next day

We have to better define what the risks are

If we really think there is a risk, maybe we can develop some sort of bridging strategy with shorter-acting agents

A risk of 0.6% per year is not very high; one has to balance the reality of caring for patients in the real world

Ferguson


Understanding the biology

For me, right now, the minimum duration for clopidogrel after a drug-eluting stent is one year

•After that, the pluses and minuses of continuing therapy can be examined

We need to better define which patients are at risk

We need to identify the patients in whom endothelialization is inadequate

When we better understand the biology,we might be able to develop markers to identify these patients

Ferguson


Safety of drug-eluting stents: A meta-analysis

A meta-analysis of randomized trials of sirolimus- and paclitaxel-eluting stents

With sirolimus-eluting stents, overall adverse events were significant

•6.3% with sirolimus-eluting stents vs 3.9% with bare-metal stents

Difference between paclitaxel-eluting stents and bare-metal stents was not quite significant

Camenzind E. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Hotline I. Fuster


Different meta-analysis, different findings

A meta-analysis with 17 randomized controlled trials with the sirolimus- and paclitaxel-eluting stents

There was no significant difference at all, except there might have been a slight increase in mortality with the sirolimus-eluting stent that was not cardiac in origin

Nordmann AJ. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Hotline I. Fuster


The value of meta-analyses

Original studies are often too small, but here we have two meta-analysis with the same type of patients coming up with different results

Fuster


The value of peer review

Anything presented and not published is preliminary

"The key to a meta-analysis, other than doing the statistics properly, is making sure that you've identified all appropriate studies to be included and then keeping them in the analysis."

The peer-review process ensures that appropriate studies weren't excluded, so that you have the totality of the evidence

Cannon


Larger newer studies needed

A lot of issues are arising now because we're using these devices in higher-risk lesions

Cannon


The mechanisms

Across the board, the chance of developing thrombosis is less with clopidogrel

If the diameter of the vessel stented is more than 2.5 to 3 mm, the chance of thrombosis is higher

Surfaces tend to endothelialize much later, and not completely, with drug-eluting than with bare-metal stents

Maybe we were much more conservative with bare-metal stents

Fuster


Endothelialization

It seems unlikely, in very late stent thrombosis (two and three years out), that the stents still have not endothelialized

Ferguson


Vessel size

All things being equal, larger vessels should be less likely to clot

Could it be exposure to the compound, or could it be that there's a larger area that has to endothelialize?

Quality vs quantity

•The endothelium might be in place but it might not be functioning as well as it should be

Ferguson


Higher-risk patients

The early clinical trials, for which we have long-term follow-up data, did not include very-high-risk patients

In the real world, drug-eluting stents have been used in increasingly high-risk patients

Maybe we are now seeing some selection bias in terms of how these stents are being used

If the endothelium is part of the problem, then the problem may be worse in diabetics, who have the equivalent of endotheliopathy

The problems are going to become more evident as drug-eluting stents are used in higher-risk patients

Ferguson


Theoretically . . .

Is the endothelium really a problem?

Fuster


Assessing endothelialization

In patients who've died, there's no endothelium•Stents are designed to prevent healing, so that's not

that much of a surprise

How can we figure out who has endothelialized and who has not?

With advanced and targeted imaging, we might be able to develop tests for this

•Patients could be imaged after 18 to 24 months to determine whether the stent has endothelialized and whether it is safe to discontinue antiplatelet therapy

Cannon


Progenitor cells

It is becoming clear that bone-marrow cells are critical in healing the endothelial surfaces

In the future, maybe we'll be able to stimulate bone-marrow cells to encourage healing

Fuster


Bioabsorbable stents

This is part of the impetus that has sparked interest in bioabsorbable stents

If there is a long-term thrombotic issue, we need to be smarter about how we deliver the drugs and over what period of time

Maybe a device that disappears after some period of time is the answer

Cannon


FREEDOM

Patients with multivessel coronary disease are randomized to coronary artery bypass surgery or drug-eluting stents

•Close to 3000 patients enrolled

Currently, the recommendation is to use clopidogrel across the board for at least one year

We are waiting to hear from the FDA and other groups that are looking at this before we make any changes to this recommendation

Fuster


Collecting data

Is it difficult to get data from industry to complete meta-analyses?

Fuster


Collaboration: To everyone's benefit

In general, it's the same whether it's an academic group or industry

The stent makers probably recognize that it will improve the safety of their devices

• It's in their interest to help sort out what the issues are and how to fix them

Collaboration wasn't an issue in the Cholesterol Treatment Trial or with COX-2 inhibitors (a contentious area)

Cannon


Going backward?

Are we going back to bypass surgery for the stable angina patient or to bare-metal stents (with all the restenosis issues)?

Fuster


A legitimate question

"We have embraced enthusiastically (and in some circumstances unquestioningly) the benefits associated with aggressive revascularization strategies, particularly in so-called stable patients."

In the interventional world, it's very hard to overcome the oculostenotic reflex of "see a lesion, treat a lesion"

We have aggressive revascularization strategies and conservative revascularization strategies

•For stable angina, the best course of action remains unresolved

Ferguson


Not black and white

There are good reasons for revascularization

•When large amounts of territory are at risk

•When silent angina or other risk factors are present

•When someone absolutely has to have their coronaries fixed

There are a lot of other cases that fall in the gray area

Ferguson


Short- vs long-term data

So many advances have occurred in cardiology over the past 20 years, but our data are basically short term

For example, everything is fantastic in the prevention of restenosis in the relatively short term, and then all of a sudden we see a problem

Are the long-term data going to give us a different picture of things?

Fuster


Safety is paramount

Matching the observation period with how drugs or devices are used is important

In the post-Vioxx era, safety is paramount with any new intervention

Unfortunately, currently, what happens in modest-sized trials gets adopted widely; we then have to circle back to look at safety data for unstudied populations

Regulatory agencies are beginning to see the value of large safety-type analyses

Cannon


The CAD patient today

I would think twice before putting in a drug-eluting stent in a coronary-artery-disease patient who has

•A large artery•Very severe disease•A history of bleeding

If a drug-eluting stent is appropriate for the patient, I would use it and then clopidogrel for an indefinite period of time, until we know more

Fuster


Good news and bad news

Drug-eluting stents reduce restenosis

The elimination of potential restenosis must be weighed against the possibility of lifetime combination therapy (aspirin+clopidogrel)

There is a population of patients who will no doubt benefit from lifelong combination therapy, but we are not able to identify this group

Committing everybody with a drug-eluting stent to lifelong clopidogrel+aspirin is not the answer

I hope we will develop imaging, biomarkers,or some sort of indicators to identify who will benefit from prolonged therapy

Ferguson


There are risks with everything

The vast majority of people should continue to get drug-eluting stents, but we have to be more diligent in making sure that they get the follow-up therapy

In discharge notes and in cath-lab reports here at Brigham and Women's Hospital, we're very explicit about not stopping clopidogrel

Given this ongoing 0.6% per year, my current thinking is clopidogrel for at least two years, to be revised when we get more data from other registries

Cannon


Summary of the WCC

The World Congress of Cardiology 2006 was very successful, although there were no real breakthroughs

Currently, the science of the cardiovascular system is advancing step by step

At the WCC, our knowledge of cardiovascular disease just moved half an inch forward

Fuster

heartbeat – wcc 2006 world congress of cardiology 2006 christopher cannon md staff cardiologist...

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