thumbs up/thumbs down – may 2002 direct coronary intervention for mi direct coronary intervention...

Thumbs up/Thumbs down – May 2002

Direct coronary intervention for MI

Direct coronary intervention for ST-elevation MI

Eric J Topol MDProvost and Chief Academic OfficerChairman, Department of Cardiovascular MedicineThe Cleveland Clinic FoundationCleveland, Ohio

Robert M Califf MDProfessor of MedicineAssociate Vice Chancellor for Clinical ResearchDirector, Duke Clinical Research InstituteDuke University Medical CenterDurham, North Carolina



DANAMI-2 and C-PORT

DANAMI-2

•DANish Multicenter Trial in Acute Myocardial Infarction 2

C-PORT•Atlantic Cardiovascular Patient

Outcomes Research Team



DANAMI-2: Setup

1572 patients randomized to fibrinolysis (100 mg front loaded tPA) or PCI + stent

Primary endpoint: Death, reinfarction, or disabling stroke in 30 days

5 PCI centers and 24 referral hospitals which served 62% of Danish population

Patients arriving at a referral center who were randomized to PCI were transferred to the nearest PCI center



DANAMI-2: Stratification

Patients arriving at referral hospitals:

• 1100 planned/1129 enrolled

• Received either tPA or ambulance transfer to PCI center for PCI

Patients arriving at PCI centers:

• 800 planned/443 enrolled

• Received either tPA or PCI



DANAMI-2: Pre-treatment

Inclusion criteria:

• ST-elevation 4 mm

• Symptoms 12 hrs at randomization

• Transfer time of 3 hrs

Few complications in transport



DANAMI-2: Time to treatmentTime to hospital:

• < 1-hr transport by ambulance from referral center to PCI center

• 120 minutes from onset of symptoms to hospital

• Door-to-needle time < 1 hr

• Door-to-balloon time did not differ much between patients arriving at referral hospitals or PCI centers



ACC 2002

DANAMI-2: Events by hospital type

0%

2%

4%

6%

8%

10%

12%

14%

16%

Combined Referral hospital PCI center

PCI Fibrinolysis

p=0.0003 p=0.002

p=0.048

8.0

13.7

8.5

14.2

6.7

12.3



ACC 2002

DANAMI-2: Event rate

0%

2%

4%

6%

8%

10%

12%

14%

Combined Reinfarction Stroke Death

PCI Fibrinolysis

p=0.0003

p<0.0001

p=0.15

p=0.358.0

13.7

1.6

6.3

1.12.0

6.67.6



C-PORT: Setup

451 AMI patients randomized to tPA (n=226) or primary PCI (n=225)

Primary endpoint: Death, reinfarction, and stroke in 6 months; median hospital length of stay

11 community hospitals without on-site cardiac surgery were turned into PCI centers

Door-to-balloon time: 101 minutes



C-PORT: Original plan

Trial was planned with 2550 patients but was stopped in June 1999 due to poor funding

"So it's almost 3 years before the trial findings are seeing the

light of day."

Topol



Aversano T et al. JAMA 2002;287:1943-51

C-PORT: Combined endpoint

0%2%4%6%8%

10%12%14%16%18%20%

6 weeks 6 months

PCI Fibrinolysis

p=0.03 p=0.03

10.7

17.7

12.4

19.9



C-PORT: Interpretation

The trial data get more weight when put in context with DANAMI-2

"The big problem of course is how do you interpret this in terms of 'are there new recommendations for practice'?"

I don't know if C-PORT and DANAMI-2 justify making lytic therapy an obsolete strategy

Topol



Effects on mortality

"In fact there's never been, and there still is not, one single trial that shows survival improvement. And that's been our standard in acute MI."

Topol

Some of the 21 studies Cannon cites did not show superiority, somewhere along the way he's not counting right



Issues with the PCI trials

There are problems with the PCI trials •Lytic trials of over 200 000 patients•These PCI trials are open trials, not

blinded•There are less than 10 000 patients in

these randomized PCI trials•DANAMI-2 had only 2.5% rate of rescue

PCI and a high ST-segment elevation entry criteria

Topol



Counterarguments

"Let me respond to the whole barrage of fibrinolytic propaganda."

•There is a trend in most of these trials

•We can't blind PCI (How to do device trials in acute MI is a general issue that needs to be discussed)

Califf



Small inferior MI

"Would I rather expose that person to a cardiac cath (which they are probably are going to need anyway) or to a 1-2% risk of intracranial hemorrhage?"

Califf

"I don't know it gets up that high unless you're talking about greater than age 75."

Topol



Refuting PCI for everyone"I want to cut through the

hyperbole about PCI for everyone and every hospital now should be made into a PCI center. I don't think that the data necessarily support that."

"I think PCI is superior to lytics -- in the right place at the right time."

Topol



Refuting PCI for everyone"I'm just trying to fast-forward to

St Elsewhere hospital with an operator that's never done a PCI who takes these trials and says, 'You know what? I'm going to start doing angioplasty in acute MI because these trials support that.' "

Topol



Ideals and reality"I think you would agree with me that the ideal now would be if you could organize hospitals into MI centers and have an efficient, effective transportation system where patients could get to the right place at the right time."

Califf

"Well that sounds really good, but you know what? In reality it's not going to work so easily."

Califf



A force fit

"I would like to know that it works; that you can really do streamlined transfer of patients, that you can really get operator proficiency before we adapt cities around our country into a forced fit."

Topol

Cannot throw out the current therapy on just these trials, it is premature



"I'd hate to see these two trials reshape public health policy on acute MI."

Topol

These trials are best-case scenarios: not enough rescue angioplasty was done in DANAMI-2 and C-PORT is an aborted trial

Reshaping policy



DANAMI-2 site

DANAMI-2: 12-hour window

0%2%4%6%8%

10%12%14%16%18%20%

Pri

mary

end p

oin

t

0-1.5 >1.5-2.5 >2.5-4 >4-12

Time to randomization (hours)

PCI Fibrinolysis



Door-to-balloon time

Intuitively, the shorter the door-to-balloon time, the better

• Ideally, I would want it between 60-90 minutes.

•Even 2 hours is too long

• I would take lytics within 45 minutes of hitting the ER over direct PCI in 2 hours without question

Topol



One size does not fit all

You can't make blanket statements about what to do in all MIs •A patient with anterior MI aged <75,

little risk of ICH – I would be comfortable using a GUSTO V-type regimen

• In a patient with a high risk for ICH it would make sense to accept a longer transport time to get direct PCI

Topol



Hub-and-spoke model

All evidence points to an advantage in creating MI centers with experienced personnel

Califf

But the delays in transfer are so long that you cannot abandon lytics

Topol



Time to PCI

The door-to-balloon time should be as short as possible

•DANAMI doesn't have enough data to support 3 hours as acceptable

•That transfer time was used to prepare the cath-team in the PCI center to receive the patient

"I don't know that our system, in most places, is so well conditioned like that."

Topol



Unskilled practitioners

"This whole idea […] that coronary intervention is so safe now with stents, IIb/IIIa inhibitors, and other adjunctive therapy that we don't need bypass surgery backup? I think this is overstepping the data we have available today?"

Topol

Many cardiologists in the US don't haveadequate volume in elective PCI, let alone AMI



Adequate proficiency in PCI

Must exceed the AHA/ACC minimums

•>100 interventions per year

•> 25 acute interventions per year

"Those are so remarkably low threshold to me for this sort of decision."

Topol



Community MI centers

A community would be well-served to centralize its MI care if it could assure efficient transfer from outlying hospitals

•Califf: Up to 3 hrs would be acceptable

•Topol: 1.5-hour limit to mechanical reperfusion – 3 hrs only if you also give lytics during the wait



Next trials

The next set of trials that should be done is to randomize patients who will be transported to either get chemical reperfusion en route or not

Califf

Is the difference between the "bland" infarct from coronary intervention vs the hemorrhagic infarct from the drugs important in the end result?

Topol



Pitfalls

"There's some real pitfalls of these two trials. That unless you tune into the details you might just dismiss lytics which have, I would say, an exceptional track record of having gone through rigorous trials and large numbers of patients."

Topol



When to move on

"I'm a big fan of lytics as you know, and both of us have spent a good part of our careers developing them, but I would also say at some point if something better comes along you've gotta give it up."

Califf



Mandated health strategy

"When you roll out a strategy all across the country and you start to make that a mandate and its really a contrived sort of thing without the data to back it up […] I think there's a lot of uncertainties here."

Topol

We must beware of overextrapolation from the results



Establishing standards

Communities who do want to implement this direct-PCI strategy

•Should have good records of actual transport times

•The outside limit of time delay is still unclear and needs to be determined



0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

Death inDANAMI-2

Mortality benefit

Is this 1% absolute benefit in PCI not about salvage? Is it just patency that's important?

Topol

After 3 hours after symptoms, the wavefront may well be done. So beyond 3 hours it may be just a question of the open artery

Califf



Device approval

What should the criteria be for approving a device for AMI?

The FDA and device community have rejected a randomized mortality trial as being unfeasible

Califf



"The only problem they had is they were too good, it may not be generalizable to most countries and communities."

Califf

Califf: 2 thumbs up for DANAMI-2



Califf: 1 up/1 down for C-PORT

"It was an innovative study but it obviously didn't achieve its objective in terms of enrollment and left a lot of questions unanswered."

Califf



Topol: 1 up/1 down for C-PORT

"By not having done the experiment as planned it suffers from some concerns about the conclusions."

Topol



Topol: 2 thumbs up for DANAMI-2

"I wish they had been more permissive with rescue intervention […] But to do that in only 2.5% of patients seemed like it loaded the deck unnecessarily for the mechanical strategy."

Topol



Califf: Final thoughts

"It's a topic we shouldn't get complacent about. It's still the leading cause of death in the developed world and something that every percent reduction in mortality is very important."

Califf

thumbs up/thumbs down – may 2002 direct coronary intervention for mi direct coronary intervention...

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