Preventing Thrombosis in ACS: Five Things That Every Interventional

Cardiologist Should Know CME

Freek W. A. Verheugt, MD; Stefan K. James, MD, PhD; Robert F. Storey, MD

CME Released: 01/27/2015 ; Valid for credit through 01/27/2016

Freek W. A. Verheugt, MD: Hi, I am Freek Verheugt, Professor of Cardiology in the Department of Cardiology
at the Heart Center in Amsterdam, The Netherlands. With me is Dr Stefan James, Senior Consultant
Cardiologist and Associate Professor at Uppsala University in Sweden. Also with me is Dr Robert Storey,
Professor of Cardiology in the Department of Cardiovascular Science at the University of Sheffield in the United
Kingdom. Welcome.

Slide 1.
Please try to answer these questions.

Educational Impact Challenge

Assess your clinical knowledge by completing this brief survey. Answering these questions again after the
activity will allow you to see what you learned and to compare your answers with those of your peers.

Different scores can be used for risk assessment in patients experiencing an acute coronary
syndrome (ACS). Which of the following statements is accurate? (7/9/15)
Scores are recommended only for patients with non-ST-segment elevation (NSTE)-ACS
Only the GRACE (Global Registry of Acute Coronary Events) risk score is recommended by the
European Society of Cardiology (ESC)
Only the CRUSADE risk score is recommended by the ESC
Assessment of the ischemic and bleeding risk is recommended (*)
Given the data from recent trials and the European guidelines on the management of patients with
ACS, what assumption do you consider true? (24/8/15)
Long-term dual antiplatelet treatment is recommended over a 12-month period
After coronary artery bypass graft surgery (CABG), patients should receive aspirin monotherapy
After percutaneous coronary intervention (PCI), patients should receive dual antiplatelet
treatment over a 1-month period
 In medically treated patients, dual antiplatelet treatment is not recommended (*)
In a patient experiencing a NSTE-ACS, how do you manage the antiplatelet treatment before
surgery if the patient is referred for CABG? (31/8/15)
Clopidogrel is never stopped before surgery
Aspirin should be stopped before surgery
Stopping prasugrel 7 days before surgery is recommended (*)
Stopping ticagrelor 7 days before surgery is recommended
How confident do you feel in your ability to choose an antiplatelet treatment in patients experiencing
an ACS?
1 Very confident
2
3
4
5 Not at all confident
Approximately how many patients with ACS do you see in a week?
0
1-10
11-20
21-40
>40

Slide 2.
In this program, we will review the current European Society of Cardiology (ESC) guidelines for the acute use
of antithrombotic therapy in the setting of acute coronary syndrome (ACS). We will evaluate clinical trial
evidence, demonstrating the benefit or risk of various antithrombotics in combination during the prehospital
phase of ACS. Finally, we will discuss the recommendations and clinical trial data regarding the postdischarge
use of antithrombotics in patients who have presented with an ACS.

Stefan, can you tell us more about the use of risk certification in patients who present with an ACS?
Stefan K. James, MD, PhD: Thank you Freek. It is an important question because a large number of patients
present with chest pain and we need to select the right ones for invasive therapy and for medications. We also
need to understand their future risks. Many different risk scores have been developed.

Slide 3.
Primarily, the ESC guidelines recommend the GRACE (Global Registry of Acute Coronary Events) risk score
because it has been around for a long time. It has been validated for short-term outcome, long-term outcome,
and in different populations with ACS. The GRACE risk score has also been used to evaluate the benefit of
therapies and to select patients undergoing catheterization and other procedures.

It includes the clinical variables, is very easy to use, and can be downloaded to a phone or as an app. It gives a
risk score number, but also provides an actual risk of myocardial infarction (MI) and death.

Slide 4.
The GRACE risk score is useful, but like all scores, it has limitations. It contains some modifiable risk factors,
but some that are not modifiable. One of these is age, which is a very important risk factor. Many clinicians do
not use these score instruments formally, but it is important to educate physicians to use them because they
add important information to our decisions.

Dr Verheugt: The decision is also whether or not the patient should have an invasive strategy. Can you go into
more detail on this subject?

Dr James: A few factors are more important than others. I want to point out troponin, which is a very important
risk factor because it verifies that the patient has the right diagnosis. If patients do not have troponin elevation,
they are likely to have another diagnosis; the higher the levels of troponin, the more effective the invasive
therapy.
Slide 5.
Dr Verheugt: Troponin elevation has prognostic consequences.

Dr James: Troponin elevation is a very strong prognostic indicator in the first place, and is similar to ST
depressions. The level of ST depression is a very important prognostic indicator.

As almost all patients are undergoing catheterization early, we have learned that troponin is no longer very
important for the prediction of future events after percutaneous coronary intervention (PCI). The extent of
severity of coronary disease at the angiography is important for the future prognosis.

In a recent analysis that we carried out, troponin was not found to be a significant predictor of outcome after
PCI was performed.

Dr Verheugt: However, before going to the cath...

Dr James: Beforehand, it is a very important one, but afterwards, other prognostic indicators such as heart
failure are even stronger.

Dr Verheugt: Is there also a timing consequence with the troponins? If a patient has high troponin, should they
go to the cath lab earlier compared with a patient with low troponin, who can wait over the weekend? Can you
tell us more about that?

Dr James: What we have developed and proposed in the ESC guidelines is that patient risk is assessed prior
to selecting early or late cath. The recent guidelines suggest that a patient should go to the cath lab early if a
typical rise in troponins or ST depressions is observed mainly because this prevents reinfarctions.

Slide 6.
This is not really logical and cannot be proven, but it prevents reinfarctions. If you are going to cath anyway, it is
also more efficient to go early as it reduces the risk of bleeding and the duration of stay in hospital, which is
worthwhile.

Slide 7.
Robert F. Storey, MD: I suppose the risk score is a triage device when there is restricted access to the cath
lab, and a guide for which patients should go early when there are limitations. In centers where there is no
restriction in terms of access to the cath lab and all patients can have early invasive strategy, then it becomes
less important and more guided by troponin levels for diagnosis.

Dr Verheugt: Most patients worldwide go to centers without a cath lab, making it very important to consider the
timing of the invasive study. Rob, what about the timing of antithrombotic therapy in these patients who present
with chest pain suggestive of ACS?

Slide 8.
Dr Storey: I think this is a really interesting and hotly debated topic because we have two potential strategies in
terms of when to initiate P2Y12 inhibitors. The current ESC guidelines recommend initiating them as soon as
the diagnosis is made in non-ST-segment elevation (NSTE)-ACS. Then, we have data from ACCOAST (A
Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST-elevation Myocardial Infarction) suggesting
that this strategy may increase bleeding without helping efficacy compared with loading after coronary
angiography.

Given this finding from ACCOAST and some of the other analyses and clopidogrel studies, it is important to
understand the potential limitations of a double-blind study in terms of interrogating this question. It is not just
when you initiate the P2Y12 inhibitor. It is all the adjunctive therapy, such as the anticoagulant therapy
particularly, and also the strategy that when you get to PCI as to what adjunctive therapy you employ. That is
difficult to incorporate into a double-blind study.
For example, in my center, we pretreat with ticagrelor as first-line therapy for non-ST-segment elevation
myocardial infarction (NSTEMI), but we do not use therapeutic doses of heparin or enoxaparin to bridge to
cath. If the patient is not going straight away, we will use fondaparinux, which is a much safer combination with
potent P2Y12 inhibition.

In ACCOAST, that was hardly used in the study. The therapeutic dosing of anticoagulant was the more popular
strategy. That does not go with pretreatment, and is not part of the ESC guidelines, which favor fondaparinux.

Giving a therapeutic dose of heparin or enoxaparin may be suitable if the patient is not getting a P2Y12
inhibitor. The double-blind strategy is not helpful when looking at adjunctive therapy. If someone is pretreated
with ticagrelor, I would certainly favor a radial approach to angiography and PCI to avoid the bleeding.

Dr Verheugt: What do you use as initial therapy in your ER for a patient who presents with chest pain very
suggestive of ACS given the electrocardiogram (ECG) and symptoms? What antithrombotic therapy is used
before getting the troponin results and before deciding whether to use an invasive strategy early, later, or not at
all?

Slide 9.
Dr Storey: The patient would get aspirin. Then you have time to look at the results. If a patient has ischemic
ECG changes, that may be sufficient to warrant initiating a P2Y12 inhibitor at that stage, as long as there is no
evidence of active bleeding or other contraindications. Otherwise, you can wait for the troponin results because
that is another clinical problem.

Dr Verheugt: What would do regarding the anticoagulant? Would you also wait for the patient's troponin
results?

Dr Storey: Again, if you have confirmed the diagnosis of NSTE-ACS, this may require waiting for the troponin
results, and also, perhaps the full blood count to ensure the patient is not iron deficient or anemic, for example,
or if there is evidence of bleeding. The clinical trials do not tell us that we should be initiating these drugs before
we fully assess the patient and have made the diagnosis.

Dr Verheugt: Except for aspirin.

Dr Storey: Apart from aspirin, which is a relatively weak antithrombotic, but effective as monotherapy in NSTE.

Dr Verheugt: Then, later on, you decide which P2Y12 blocker to start with and which anticoagulant to use.

Dr Storey: That is right, but if you are going to pretreat with a potent P2Y12 inhibitor such as ticagrelor, then do
not also use therapeutic doses of anticoagulation. Fondaparinux is favored. If the patient is going straight to the
cath lab, then it is probably not necessary.
Dr Verheugt: No, then you give heparin. This is very clear.

Stefan, when there is an invasive strategy, and the interventionalist and the attending cardiologist decide that
this patient should not have a PCI, but should have coronary artery bypass graft surgery (CABG) because of
severe triple vessel disease or main stem lesions, what kind of antithrombotic sets should be used? Should we
change what we started with, should we add something, or should we stop something with regard to antiplatelet
and anticoagulant therapy?

Slide 10.
Dr James: That is a very important question. In my experience, and considering data from the literature and
trials, the proportion of patients with ACS, NSTE-ACS primarily, who require a CABG is slightly less than 10%,
which is a fair proportion of the population. There are no trials that have addressed antithrombotic therapy in
CABG patients only, but they have been included in the large pharma trials. If a CABG is needed in a patient
with NSTE-ACS, it is not needed acutely most of the time. It is usually possible to wait one to three days.

Dr Verheugt: The surgeons want it too, right?

Slide 11.
Dr James: Yes, it is very interesting and important that the PLATO (Platelet Inhibition and Patient Outcomes)
study showed that antithrombotic therapy with a potent agent like ticagrelor was very effective in the CABG
population. In fact, it was in the CABG population that we found the greatest reduction in mortality, without a
great excess in bleeding using this potent agent. We also learned from the protocol and from experience that if
you stop therapy at least two days before a planned surgery, it is safe to undergo a CABG with ticagrelor on
board. Prasugrel must be stopped earlier because it lasts longer and has a longer onset of action.

Dr Verheugt: I think most interventionalists use prasugrel only when they have put a stent in a patient, as
pointed out by Rob.
Slide 12.
Let us consider a patient who comes in with an ACS. Going to the cath lab was decided, so the patient goes on
aspirin and ticagrelor. The patient still has heparin on board. How long do you continue with the P2Y12 blocker
before the actual surgery? How many days do you stop the P2Y12 blocker? How do you bridge if you bridge?

Slide 13.
Dr James: Here, there is a difference between the label and the ESC guidelines. On the label, it says that you
should stop ticagrelor five days prior to surgery, but the ESC guidelines say it should be stopped at least two
days based on the data.

The label is more concerned about bleeding.

Dr Storey: There is a recent ESC position paper on this topic.

We proposed following the regulatory guidelines; stopping 5 days before, but with the option of using platelet
function testing to shorten the duration. One has to be cautious about taking the patient to surgery too soon
because we know that P2Y12 inhibition generally is associated with bleeding and may increase mortality risk
related to bypass surgery.

Given the ACCOAST data, with pretreatment showing this excess of CABG-related bleeding, you should really
be stopping the drug well before surgery, at least 5 days in the case of prasugrel. The recommendation is 7
days actually. Not taking the patient to surgery too soon is important because bleeding does lead to mortality.

In PLATO, we saw this remarkable mortality reduction with ticagrelor compared with clopidogrel. A hypothesis
is that some of that reduction may be related to adenosine reuptake inhibition with ticagrelor, which may have
beneficial effects that offset some of the problems related to bleeding.
Slide 14.
Dr Verheugt: Would you advise bridging? For instance, are you suggesting that we should bridge those
patients with an IV platelet inhibitor? What is your opinion?

Slide 15.
Dr James: I do not think there is a lot of data to support a default strategy of bridging. That is also the reason
that I would be more prone to not delay surgery for 5 days, but rather cut it slightly shorter. You reduce the need
for bridging.

Dr Verheugt: Yes, but in a stable patient...

Slide 16.
Dr James: In very high-risk patients, I would consider some type of bridging for patients with recurrent
symptoms.

Dr Verheugt: Yes, if such patients should have surgery as soon as possible, which bridging strategy would you
advise?
Dr Storey: I do not really have an optimal bridging strategy. The options are GP2b3a inhibitors, but we know
that they are associated with an increased risk of major bleeding. It is not ideal. Low-molecular-weight heparins
are another option, but again, good evidence for their use is lacking.

In the position paper, we suggested bridging particularly for those with high ischemic risk, but low bleeding risk;
for example, critical left main stem lesion. That is when you may want to bridge to surgery or to take them
slightly earlier with a platelet-function-guided strategy.

Dr Verheugt: Anything about cangrelor? It is not available yet, but if it became available, would that be a
bridging strategy you would like to adopt?

Dr James: Theoretically, it is an ideal substance because you can turn it on and off quickly. It makes a lot of
sense to use it when it becomes available.

Dr Verheugt: We have to wait for approval of the agent, if it is approved.

Dr James: If I can add to your question, for ST-segment elevation myocardial infarction (STEMI) it is different.
In reality, at least in my country and in my clinical experience, acute CABG is extremely infrequent for STEMI
patients. There are only a handful of cases in the country per year that go to acute surgery.

Dr Verheugt: In general, my experience is that the patients do well if urgent surgery is needed.

Dr James: I hardly see any need actually. I think surgery for acute STEMI is not a good indication.

Dr Verheugt: As routine, of course.

Dr James: Yes, you should treat the lesion with PCI and then do the surgery if necessary.

Dr Verheugt: That will fix it. I would like to discuss the issue of patients who do not to go to the cath lab straight
away. They may be sent later for many reasons, including ongoing diagnostic discussions or frailty. How should
we manage such patients who are diagnosed with ACS, but who will not go to the cath lab. Should we treat
them with aspirin?

Slide 17.
Dr Storey: Absolutely, yes.

Dr Verheugt: Since you are not going to the cath lab, you will not stent this patient in the upcoming weeks. Is it
useful to start the P2Y12 blocker in such patients?
Dr Storey: If they have elevated high sensitivity troponin levels, and you are confirming a diagnosis of
NSTEMI, then ticagrelor, unless contraindicated, is the most effective drug.

Dr Verheugt: Yes, as we have seen.

Dr Storey: It is a good match in terms of anticoagulant. There is some uncertainty, but as I mentioned before,
fondaparinux is favorable combined with a potent P2Y12 inhibitor and aspirin.

Slide 18.
Dr Verheugt: Prasugrel has been tested as well in this situation. I do not think we have very good results there.
It was rather flat.

Slide 19.
Dr Storey: TRILOGY (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute
Coronary Syndromes) was neutral, showing no benefit with prasugrel compared with clopidogrel overall in
medically managed patients. There is some uncertainty about those with angiographically proven coronary
artery disease.
Slide 20.
Dr Verheugt: Then you need an invasive strategy for diagnosis, right?

Dr Storey: That is right and curious considering prasugrel is associated with more effective P2Y12 inhibition
than clopidogrel.

Dr Verheugt: Absolutely, but initially the design of the TRILOGY trial was meant to randomize patients within
24 hours. The inclusion was so slow that it was then extended up to a week. This resulted in 4 days of waiting
time before patients were randomized to the active platelet blocker prasugrel. In my view, that was one of the
reasons that the trial started too late this effective agent with regard to platelet inhibition. Then, neutral results
were obtained because most of the thrombotic events occur in the first few days, in NSTEMI cases at least.

Dr Storey: You have to look at the risk characteristics. Certainly, for those with low risk characteristics, many of
the events occur early on. Those with diabetes, renal failure, and the elderly experience this progressively
accumulating incidence of events over a year and beyond. In the high-risk subgroups, you might expect that a
more effective antiplatelet strategy would be efficacious. It is surprising that despite roughly 6% mortality, there
was no difference.

Slide 21.
Dr James: Those findings were very consistent in the PLATO trial and showed that it is important to treat the
inpatients who intended for a noninvasive strategy and also those who were, in fact, not treated invasively.

Dr Verheugt: The big difference is that ticagrelor was given very early and worked very well in patients who
were not going to the cath lab initially, as well as in those who did not see the cath lab at all. I saw your recent
paper in the European Heart Journal, but I think timing is very important. If you wait four days for an effective,
strong P2Y12 blocker, most of your potential benefit is already gone.

Dr James: Yes, you can see the diverging event curves in this high-risk population. They continue to diverge
throughout the duration of follow-up. It appears to be effectively preventing late events as well.
Slide 22.
Dr Verheugt: This makes ticagrelor a good drug to use for all patients immediately, even before you decide to
go to the cath lab.

Dr Storey: The difference between ticagrelor and other drugs such as thienopyridines in medically managed
patients raises the hypothesis that this is due to some off-target effect of ticagrelor. This is most likely related to
adenosine reuptake inhibition, which is seen in vivo with ticagrelor therapy. We need to see what further trials
show us, but that is currently a very strong hypothesis.

Slide 23.
Dr Verheugt: The number needing treatment in that population that never went to the cath lab was indeed very
low, only 50 to save one life. Mortality benefit, even without an intervention was clearly shown by ticagrelor over
clopidogrel. It is a very important finding. I think that it is a universal P2Y12 blocker in ACS when given very
early.

Now, the patients have been taken care of; they either did or did not go to the cath lab. What is the optimal
postdischarge antithrombotic strategy in patients who survive their ACS? Even in the case of a STEMI, what is
the optimal antithrombotic strategy? First, Rob, what is your opinion?
Slide 24.
Dr Storey: Obviously, we are waiting for trial results to guide us on this matter. At the moment, the ESC
guidelines propose one year of dual antiplatelet therapy following NSTE-ACS and STEMI. That strategy seems
appropriate on the basis of current evidence. However, we know that there are high-risk patients who continue
to accrue events beyond one year at a substantial rate. Therefore, you could argue that an arbitrary threshold
of one year to stop dual antiplatelet therapy does not make clinical sense.

That is why we need these studies. DAPT (Dual Antiplatelet Therapy) will look at post-PCI patients.

Slide 25.
PEGASUS (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor
Compared to Placebo on a Background of Aspirin) will look at patients beyond one-year post-infarct to see
whether ticagrelor as dual therapy is more effective than aspirin. These further studies will show us the
optimum duration particularly in those high-risk patients. Is it long-term in those who are high risk?

Dr Verheugt: What about the patients who did not go to the cath lab? Worldwide, a large group of patients do
not undergo an angiographic strategy. Do you think they also need long-term dual antiplatelet therapy for at
least a year?

Slide 26.
Dr Storey: I think so. These medically managed patients, such as the elderly with renal failure, are often at the
highest risk and have a very high event rate. They probably need potent antiplatelet therapy of some type for
the long-term. Whether dual therapy is appropriate or whether a more potent single agent, such as ticagrelor as
a monotherapy, is more effective will be determined by other studies that will guide us as to what is a better
strategy.

Dr Verheugt: Rob, thank you. What about management of patients who had CABG?
Slide 27.
Dr Storey: This is a really interesting question. The ESC guidelines on NSTE-ACS recommend restarting dual
antiplatelet therapy, ie, including the P2Y12 inhibitor, as soon as it is considered safe after CABG. In PLATO,
the recommendation was to restart ticagrelor after surgery, although there was some variability. We observed a
profound mortality reduction with ticagrelor compared with clopidogrel.

In the patients who underwent CABG, there is obviously concern about graft occlusion, and we know that
aspirin is very weak. Patients in the post-bypass situation may get increased platelet turnover, and some may
have a reduced effect of aspirin. It makes a lot of sense, but I think we will have more data to support the
strategy of restarting with the P2Y12 inhibitor early.

Dr Verheugt: In fact, in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, this was
also done and was successful, but many surgeons and physicians forget this. They think that the patient had
surgery, so aspirin will be effective.

The last point is the duration of dual antiplatelet therapy generally in patients who have survived their ACS. Is it
better to get stented, surgery, or medical therapy? What is the optimal duration of dual antiplatelet therapy
before we switch back to aspirin? Stefan, what do you think?

Slide 28.
Dr James: That is a very complex and difficult question because there is a lot more we need to learn about
this. There is certainly a high remaining risk of long-term ischemic events. There is a need to suppress that risk
with effective antiplatelet or anticoagulative therapy. The optimal duration is still included in many ongoing trials
as we do not know the ideal length of time. In the current guidelines, we do recommend continuing with aspirin.
In addition to aspirin, we do not yet know whether it should be a combination of a dual antiplatelet therapy, a
potent P2Y12 inhibitor, or a monotherapy with a P2Y12 inhibitor, a combination of aspirin and a weak, low-dose
anticoagulant, or different combinations of these therapies. We need to learn a lot more.
Dr Verheugt: Rob, what do you think?

Dr Storey: I think we need more evidence. Studies will give us some more guidance on the value of restarting
a P2Y12 inhibitor after bypass surgery. Let us see what emerges from these further studies. For the moment,
the guidelines support restarting P2Y12 early after surgery and continuing it for up to one year, like the other
patients.

Dr Verheugt: Thank you both for this interesting conversation about the risk stratification in ACS, the beginning
of antithrombotic therapy, and the ending of dual antiplatelet therapy after ACS.

Thank you very much for viewing this conversation.

Slide 29.
This transcript has been edited for style and clarity.

Educational Impact Challenge

What did you learn from this activity? Please click on the "Continue" button to proceed to a brief survey to see
how your knowledge improved after the education. You can also see how your answers compare with those of
your peers.

Educational Impact Challenge

Different scores can be used for risk assessment in patients experiencing an acute coronary
syndrome (ACS). Which of the following statements is accurate? (7/9/15)
Scores are recommended only for patients with non-ST-segment elevation (NSTE)-ACS
Only the GRACE (Global Registry of Acute Coronary Events) risk score is recommended by the
European Society of Cardiology (ESC)
Only the CRUSADE risk score is recommended by the ESC
Assessment of the ischemic and bleeding risk is recommended (*)
Given the data from recent trials and the European guidelines on the management of patients with
ACS, what assumption do you consider true? (24/8/15)
Long-term dual antiplatelet treatment is recommended over a 12-month period
After coronary artery bypass graft surgery (CABG), patients should receive aspirin monotherapy
 After percutaneous coronary intervention (PCI), patients should receive dual antiplatelet
treatment over a 1-month period
In medically treated patients, dual antiplatelet treatment is not recommended (*)
In a patient experiencing a NSTE-ACS, how do you manage the antiplatelet treatment before
surgery if the patient is referred for CABG? (31/8/15)
Clopidogrel is never stopped before surgery
Aspirin should be stopped before surgery
Stopping prasugrel 7 days before surgery is recommended (*)
Stopping ticagrelor 7 days before surgery is recommended
How confident do you feel in your ability to choose an antiplatelet treatment in patients experiencing
an ACS?
1 Very confident
2
3
4
5 Not at all confident
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