thumbs up / thumbs down – dec 22, 2006 drug-eluting stents and occluded arteries eric j topol md...

Thumbs up / Thumbs down – Dec 22, 2006

Drug-eluting stentsand occluded arteries

Eric J Topol MDDirector, Scripps Translational Science InstituteChief Academic Officer, Scripps HealthProfessor of Translational Genomics, TSRISenior Consultant, Division of Cardiovascular Diseases, Scripps ClinicLa Jolla, CA

Robert M Califf MDProfessor of MedicineVice Chancellor for Clinical ResearchDirector, Duke Clinical Research InstituteDuke University Medical CenterDurham, NC


Drug-eluting stents

The dominant form of therapy in interventional cardiology

Drug-eluting stents have led to a dramatic reduction in restenosis rates

Potential risk: Stent thrombosis

In response to discussion at the European Society of Cardiology, the FDA held a hearing• To understand whether the signal is real• If it is, to determine what to do about it

Califf


Two-day FDA meeting

As many as 40 different presentations of data from around the world

Day 1

• On-label indications for drug-eluting stents, which are fairly restrictive

Day 2

• Off-label indications, which are the dominant uses

• ~60%–70% of drug-eluting stents are used for off-label indications

Topol


Day 1

Individualized data from all the Taxus and Cypher randomized trials• Risk of late thrombosis was offset by protection

from death and MI early on

If drug-eluting stents are used on-label with on-label antiplatelet medication, the risk of late stent thrombosis was mitigated by some of the protective aspects• For the low-risk population included in randomized

trials, the overall data looked favorable

Topol


Risk vs benefit

Drug-eluting stents are very useful • Studied in very well done randomized trials for

particular types of patients

The risk of late thrombosis isn't large relative to the benefit • We need to determine who is at risk and what

can be done to prevent it

Were these people on clopidogrel longer than the recommended on-label duration?

Califf


Real-world antiplatelet therapy

Most of the patients adhered to the recommendation in the randomized trials

• Six months of clopidogrel for Taxus stents, three months for Cypher stents

Is that representative of the way antiplatelet therapies are used in the real world?

Topol


Restenosis is not benignConvincing data showed that restenosis inside drug-eluting stents is not as benign as many of us thought

The reason the risk of late thrombosis is neutralized is probably because the risk of in-stent restenosis is not as benign as thought

• In-stent restenosis is much more common with bare-metal stents

I think the antiplatelet therapy limited to three to six months is not representative of real-world practice

Topol


Duration of antiplatelet therapy

How long will you leave your on-label patients on clopidogrel?

Califf


No data for on- or off-label patients

The bleeding risk of patients must be considered

If someone has panvascular disease or worrisome coronary anatomy, there might be reasons to use more than three to six months of antiplatelet therapy in an on-label situation

The AHA/ACC recommends dual antiplatelet therapy for one year after a drug-eluting stent, regardless of label

"I don't know where that came from because I'm not aware of any data to substantiate that."

Topol


Revisiting CREDO

CREDO showed that one year was superior to one month of clopidogrel plus aspirin for bare-metal stents

The superiority had little to do with the stent• It had to do with protection from MI (coming from

nontarget vessels) and stroke

The same results were seen in CHARISMA• Patients with coronary disease who got dual

antiplatelet therapy were protected from death, MI, and stroke

Topol


The art of medicine

You might want to continue dual antiplatelet therapy for even longer than one year

You have to look at the individual patient

• Bleeds can be very serious

"There's still room for the art of medicine, that's why I don't like guidelines."

Topol


The trouble with guidelines

There's room to individualize medicine • That's why a doctor and patient need to

determine what's right for that individual

"It's about the bleeding hazard, it's about the panvascular atherosclerotic burden, the LV function—if this vessel were to thrombose, how much of a risk is it to this patient? There are no guidelines that are going to take all those things into account."

Topol


Duke study

Off-label use of drug-eluting stents is more controversial

Study from Duke University just published • Real-world, all comers • Drug-eluting and bare-metal stents • Varying durations of antiplatelet therapy

Results suggest that the best possible outcome was in patients who received drug-eluting stents and long-term dual antiplatelet therapy

Topol

Eisenstein EL et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA; published online before print December 5, 2006.


Swedish registry

There was a very significant risk (~0.6%) of late thrombosis that appeared to be continuous over time

Because drug-eluting stents are not the predominant stent used in Sweden, data were available from both types of stents

"That data from Sweden had significance, especially in terms of raising concern."

Topol


Other data presented

There were many other sets of data presented

BASKET-LATE trial

• The only randomized trial of off-label patients to suggest concern for late thrombosis

Editorial published within a week of the FDA meeting

Topol

Harrington RA et al. Late ischemic events after clopidogrel cessation following drug-eluting stenting. Should we be worried? J Am Coll Cardiol 2006; 48:2592-2594.


The DEcIDE Network

We had a contract with the Agency for Healthcare Research and Quality

• Determine what to do about in-stent restenosis

We used our database to look at issues concerning modern revascularization therapy

Califf


Replication of Swedish results

An all-comers analysis (not randomized) showed that drug-eluting stents look better than bare-metal stents in the early phase for death and MI

There's a hazard after about nine to 12 months that doesn't ever diminish • When you compare drug-eluting and bare-

metal stents, the excess risk of having an event at 18 months and one day is about the same as at 12 months and one day

Califf


No difference

When you average the early benefit and the late detriment over two years, there's no significant difference• There is a worrisome trajectory

Best outcome: Drug-eluting-stent patients who stayed on clopidogrel

Worst outcome: Drug-eluting-stent patients who stopped clopidogrel

Intermediate outcome: Bare-metal-stent patients, whether on clopidogrel or not

Califf


BASKET-LATE

BASKET-LATE randomized to type of stent and then stopped clopidogrel in everyone

The results looked like the bare-metal and the drug-eluting stent arms of our study in which patients were not taking clopidogrel

Califf


Time-oriented analysis

The Swedish registry is a common database with long-term follow-up that includes almost every stent put in in Sweden

Drug-eluting stents look better early on but the curves slip and the excess hazard doesn't change after that

In the all-comers situation, does the risk keep expanding or stay flat?

What is the right direction for clopidogrel?

Califf


Inadequate antiplatelet therapy?

The Swedish data looked more worrisome • In the Swedish registry, duration of

clopidogrel was limited• In the Duke study, the best arm was

clopidogrel for two years

BASKET LATE, a small randomized trial, and the Duke study corroborated these results• The hazard with drug-eluting stents seems

to be related to the limited duration of clopidogrel

Topol


Restrict use of drug-eluting stents

"We are left with the sense that, until these matters are worked out, the interventional cardiology community should be a little more restrictive or judicious about the use of drug-eluting stents in a population of patients where the risk/benefit evidence is incomplete and at least somewhat concerning."

Topol


Patient compliance

Up to 20% of people are not going to take their clopidogrel

• Because of an upcoming surgical procedure

• Because of social circumstances

"I see no excuse for putting a drug-eluting stent in a person like that, and I think it has to be stopped."

Califf


Unforeseen surgery

The problem arises when surgery is unforeseen

When you know a patient is not going to be compliant or has an upcoming major operation, it's straightforward

Topol


The gray zone

We have a large gray zone in terms of stent selection

It might not ever get sorted out with the current stents • Maybe new technology will take care of the

problem

Do you agree with Renu Virmani, that this is a predictable issue that should have been better looked at because people knew in advance that it was going to be a problem?

Califf


Biologic mechanisms?

I think that there is a biology that leads to incomplete endothelialization • However, for some patients, the stent

might not have been put in properly

The bulk of patients who have stent thrombosis might be poor endothelializers or have more active platelet reactivity• The true biologic mechanisms in such

patients have not yet been worked out

Topol


Defining who is at risk

More than one million people each year in the US get stents

If we could define who was really at risk, then probably only a very limited number of patients would require dual antiplatelet therapy for multiple years

Topol


Did the FDA make a difference?

The FDA deserves credit for having gathered, from all over the world, virtually every group doing research to come in for two days and review all the data

"Will the cardiologists take any heed of this and be a little more judicious? I doubt it. I suspect it won't change practice patterns very much."

Topol


Getting the data we need

We need a national system of data collection about drugs and devices

We need to do much simpler and more frequent randomized trials

Until we get a national system, we're going to continue to get fragmented one-off studies• All the world's experts can't figure out

exactly what these data mean

Califf


Two approaches

We need a very large randomized trial comparing long-duration clopidogrel with on-label use (up to six months)

We need to get the DNA from hundreds of patients who have had late stent thrombosis and who are still alive

• That would provide insight about predisposing factors

Topol


The value of DNA testing?

"My prediction is that won't be very helpful, but I'd be in favor of doing it. I would like to be proven wrong on that because, if you could predict who is at risk, it would change the treatment to being very targeted to those people."

Califf


The value of DNA testing

"I say that if we could get those hundreds of patients who had late stent thrombosis together, it would be extremely helpful and informative."

Topol


Two thumbs up

Some of the Fellows at Duke are working right now on just what you described

Two thumbs up for the FDA

A neutral rating for the clinical-practice community and the industry

Califf


The Occluded Artery Trial (OAT)

NIH-sponsored major trial to address whether or not to open up an occluded infarct-related artery a month after an MI event

Results suggest that patients who had their infarct-related artery opened had more events and did not benefit

Topol

Hochman JS, et al. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006; 355:2395-2407.


OAT population

The goal was to find people who had an occluded artery three to 28 days after an MI• People with left main or three-vessel

disease or angina at rest or who were hemodynamically unstable (very highest-risk people) were excluded

Researchers attempted to simulate the run-of-the-mill patient who comes in with a relatively uncomplicated infarct and then three days later in the cath lab it is discovered that an artery is occluded

Califf


OAT resultsOAT randomized 2166 patients

Primary end point (composite of death, MI, and heart failure)• 17% of PCI patients vs 15.6% of medically

treated patients

Death (4-year total) • 9.1% of PCI patients vs 9.4% of medically

treated patients

Nonfatal infarction • 6.9% of PCI patients vs 5% of medically

treated patients

Califf


Total Occlusion Studyof Canada (TOSCA)-2

Angiographic study looking at left ventricular (LV) function and volumes

In the group randomized to opening with PCI

• Very small changes in LV volumes

• No big change in LV function in the group randomized to opening with PCI

Califf

Dzavik V, et al. Randomized trial of percutaneous coronary intervention for subacute infarct-related coronary artery occlusion to achieve long-term patency and improve ventricular function. The Total Occlusion Study of Canada (TOSCA)-2 trial. Circulation 2006; 114:2449-2557.


Another humiliating defeat

The medical-treatment group did pretty well

• We really should try to get the right vascular and metabolic protective agents on board in people who have recently had an MI

Califf


No functional assessment

If someone has an occluded artery, wouldn't they have a functional assessment if they had provocable ischemia?

• In TOSCA-2, they didn't have to

Topol


TOSCA-2 still inclusive

Correct, although people who did have a functional assessment, unless it was profound ischemia, were still randomized, so some of those patients were included

Califf


Real-world patients

You would like to think that, in practice, the patients with provocable ischemia would have been segmented

• Opening up the artery on pure anatomical grounds is very tenuous

TOSCA-2 had a very protracted recruitment period and was a struggle to complete

Topol


A period of American failures

Just over 400 patients randomized in the US

• Took longer than in the rest of the world

Many of our prestigious centers felt they already knew the answer

• Intervention was mandated in these patients to save their lives, and they couldn't possibly be randomized

Califf


The rest of the world answered the question

That gives an out to American practitioners who believe that there is something magic about American medicine

"It's concerning in the overall trend that we're increasingly outsourcing our clinical research, leaving us in a position of not knowing if the results apply to our own circumstances."

Califf


Homegrown data

Are data from outside the US not as good as US data?

Topol


The data can be as good

Whether it's applicable to US practice depends on a number of factors• If the data are from a center that gives

good medical therapy, where the technology and practice patterns are similar, then they can be as good

• If the data are from a place that gives very different medical therapy, has different follow-up, a patient population that might be dependent on the trial to get regular medical care, then they might not be as good

Califf


US bias

Overall bias in the US

• The question of whether to open up an artery was considered to be resolved, even though it had never been adequately addressed before OAT

Most of the sites participating in OAT had a relatively comparable level of quality of care

Topol


Every study should be looked at individually

The Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) study in China

• A great study for China, but I'm not sure that the results can be applied to American practice

Some American physicians will likely say that OAT doesn't apply because the patients weren't representative of American practice

Califf


US attitude

"I think there's a bit too much of this 'doing-it-better-in-the-US' attitude, which is unfounded."

There are no data indicating that treatment in the US is associated with better outcomes

Topol


There are things we're not better at

We should cooperate with the rest of the world • Coronary disease doesn't know the

difference between a Frenchman and an American

"We need to hold up our end of the bargain and develop systems that do clinical research more effectively, which we're failing at right now."

Califf


The reason for randomized trials

The OAT results came as a surprise

"I guess that's why you do randomized trials."

Topol


Opening an artery

Why does opening a closed infarct vessel, opened for only anatomic reasons, potentially hurt people? • It certainly didn't help anybody in OAT

overall

Is that because you embolize the clot and atheromatous material? • So you can't recruit collaterals when you

need to • It basically shuts down the collateral

network

Topol


Reasons for unexpected results

The effects on myocardial healing and electrical stability were much less than hoped for

In TOSCA, the most seriously damaged people were excluded, so the effect seen was quite small

Electrical instability is a whole different issue with the widespread use of beta blockers and ACE inhibitors

• The risk of sudden death in such populations has dramatically gone down

Many of the old observational studies indicated that the greatest benefit was prevention of sudden death

Califf


Contributing factor

Beta blockers have preempted the need to open up arteries

"Unfortunately, we don't do a very good job of preventing the destruction of the collateral circuitry."

Topol

Hillis LD and Lange RA. Myocardial infarction and the open-artery hypothesis. N Engl J Med 2006; 355:2475-2477.


Two sides of the coinThere are two areas of damage • That done during the procedure • The set of factors that change the

distribution of blood flow over time in the myocardium

We can now grow collateral vessels using growth factors

It is possible for an artery that was previously feeding a dead zone to provide key blood nutrition to other areas through collateral flow to those areas as they become stenosed or occluded

Califf


Clinical trials do surprise

The first trial we did, the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) trial, had some similarities to the OAT trial

We were sure that opening the artery after thrombolysis would improve the outcome of patients

That's probably what makes clinical trials still fun to do, even after all these years

Califf


Will it change practice?

Ideally in practice, there's a functional assessment• If that had been done in OAT, a lot of patients

would not have been subjected to potential PCI

Doing PCI postinfarct on pure anatomic grounds is a strategy that needs to be challenged

I give OAT two thumbs up

Topol


Two thumbs up for OAT

"I agree; two thumbs up and an extra pat on the back for perseverance against the odds."

Califf


SHOCK and OAT

"Those are the special Hochman trials, like SHOCK and OAT. Anyone who can lead trials like that, my hat's off to them. They're very difficult to execute."

Topol

thumbs up / thumbs down – dec 22, 2006 drug-eluting stents and occluded arteries eric j topol md...

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