Gilles Montalescot, MD, PhD


July 29, 2014

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Preloading: It's Different in NSTEMI

Hello. I am Gilles Montalescot, Professor of Cardiology at Hôpital la Pitié-Salpêtrière in Paris, and I am here at EuroPCR in Paris, where we had some interesting presentations on adjunctive pharmacology in acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI).

We had several presentations about pretreatment and loading in patients when they need to go to the catheterization laboratory for coronary angiography first, and often for a PCI. The first point was this debate that we have on pretreatment differences in ST-segment elevation myocardial infarction (STEMI) vs non-STEMI (NSTEMI). It is probably different if we look at the totality of data. The data support pretreatment for STEMI patients undergoing primary PCI, even with clopidogrel. The data look good. We have positive data, although in a limited number of studies, and even the only randomized study that we have with clopidogrel, CIPAMI,[1] is negative, statistically speaking. When we look at clinical events numerically, they all go into the right direction, with a drug that is not very potent and is not very rapidly active.

We need more data in STEMI, and we will get more. At the next meeting of the European Society of Cardiology, we will present the results of the ATLANTIC study,[2] which is all about pretreatment in STEMI patients undergoing primary PCI, this time with ticagrelor. In one arm, it is early treatment; the other arm is late treatment in the cath lab. We will have something to show for pretreatment with a P2Y12 receptor antagonist in STEMI patients.

NSTEMI Options

In NSTEMI, it is more complex. The data on clopidogrel are not very good. We still see a trend toward a reduction of ischemic events, but we also see an excess of major bleeding. It is kind of a difficult balance to determine when it is actually effective. We have seen randomized studies with clearly negative results: PRAGUE-8[3] in stable patients; ARMYDA-5[4] also in stable patients, but lots of ACS, and it was negative. You may remember the CREDO trial,[5] which also had a number of patients with ACS, and for this question, it was negative. The randomized studies are not very good in NSTEMI for the question of pretreatment with clopidogrel.

Now we have a new study which has been published: the ACCOAST study[6] of prasugrel pretreatment, and the results were negative. There was no benefit in terms of ischemic events with pretreatment, and there were a lot of bleeding complications in these patients -- all of them going to the cath lab for a coronary angiogram.

At this meeting, we presented some PCI data -- this is the ideal group of patients to study, those undergoing PCI after ACS. It is a retrospective analysis[7] because we only knew whether they had PCI after it was finished, when they went out of the lab. In this population, we had the same findings: excessive bleeding complications; no real benefit with respect to ischemic events; and the thrombus burden, which was a first prognosis marker for these patients. The drug, when given early as a pretreatment, had absolutely no impact on thrombus burden.

 What About Bivalirudin?

That is what we have for pretreatment here. We have heard some news about bivalirudin as anticoagulation in primary PCI. We all know the HORIZONS-AMI[8] results. We know the EUROMAX study,[9] which showed a reduction of the primary endpoint combining death and major bleeding. It was all driven by the reduction of major bleeding, with no impact on death, and there was still an excess of stent thrombosis as also observed in HORIZONS-AMI.

Now we had HEAT-PPCI,[10] which is a study that compared bivalirudin with unfractionated heparin. This was unlike EUROMAX, where glycoprotein IIb/IIIa inhibitors were advocated in the control arm, and unlike HORIZONS-AMI, where it was mandatory to use glycoprotein IIb/IIIa inhibitors in the control arm. This was a head-to-head comparison between bivalirudin and heparin, and although this study is not yet published, it is not in favor of bivalirudin [Editor's Note: HEAT-PPCI has been published since this commentary was recorded]. We see an excess of ischemic events. We do not see a real benefit. There is no impact on deaths. Globally, it is not a good message for bivalirudin.

Altogether, we have 4 randomized studies in STEMI patients -- HORIZONS-AMI, EUROMAX, HEAT-PPCI, and BRAVE-4.[11] When we analyzed all the data together, there was no difference in death and no difference in major bleeding. The only thing that came out as significant is the excess of stent thrombosis. So it is a little bit disappointing for bivalirudin, and we will see whether there are new drugs for the future to replace this type of intravenous agent. We need intravenous agents in the cath lab.

Platelet Response Testing Not Dead Yet

Is there a place for testing of antiplatelet therapy? We have had 2 large studies -- GRAVITAS[12] and ARCTIC[13] -- looking at such testing, and they were negative, not favoring the measurement of the antiplatelet effect to adjust therapy, but it is not finished. One study is still ongoing and recruiting patients: the ANTARCTIC study.[14] This is a randomized study in the elderly using prasugrel, and this is the big difference. The other 2 studies were performed with clopidogrel. Now it is prasugrel, and the dose is adjusted according to the response as measured with VerifyNow. So, you can increase the dose, but you can also switch a patient to clopidogrel if the response is too high to prasugrel 5 mg. This is an ongoing topic, and we will get more information.

Desperately Seeking Intravenous Agents

What can we expect for the future? What about cangrelor, for example? We have positive data from CHAMPION PHOENIX.[15] The drug is being evaluated now by the authorities. We do not have an intravenous drug available for the patients who need this type of drug because they are intubated, on a ventilator, and cannot swallow pills, or they vomit pills after they swallow them. These are all circumstances where we would need an intravenous agent. It is still being evaluated. It is probably not easy, because the results were good, but mostly on soft endpoints: for example, no difference in mortality. We need to wait and see whether this drug is going to be approved.

We probably also need new anticoagulants, and we will get one in Europe which is rivaroxaban, an oral factor Xa inhibitor for secondary prevention. As you may remember, we had a reduction of mortality with this agent in the ATLAS study.[16] Probably for the high-risk patients, it would make sense to use this drug. In some of our patients (large anterior MI, for example) who are exposed to heart failure, thrombosis, and arrhythmias, it would make sense to have anticoagulation in these patients for the long-term follow up.

For intravenous anticoagulants, we are almost back to unfractionated heparin with the failure of otamixaban[17] and bivalirudin in the recent trials. We are left with intravenous unfractionated heparin. Many of us also use intravenous enoxaparin, which is an alternative to unfractionated heparin, because of the positive data from the ATOLL study.[18] Clearly, this is a field where we would like to see new agents to be used in emergency situations or in the cath lab.

This is about what we have seen here at EuroPCR. Thank you for looking at this program, and see you soon.


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