Oral antiplatelets in ACS PCI: Are we barking up the wrong tree? · 2016-12-20 · 20-Dec-16 Nick Curzen 1. I don’t think that the evidence supports a wholesale shift away from

20 December 2016

Nick Curzen BM(Hons) PhD FRCP

Professor of Interventional Cardiology Southampton University Hospitals NHS Trust/University of Southampton

Oral antiplatelets in ACS PCI: Are we barking up the wrong tree?

20 December 2016

20-Dec-16 Nick Curzen

1. I don’t think that the evidence supports a wholesale shift away from clopidogrel as the default P2Y12 inhibitor

2. I’m not sure that aspirin is absolutely necessary if the patient is on a P2Y12 inhibitor

Barking up the wrong tree?

20 December 2016

20/12/2016 22:47

GP IIb/IIIa inhibitors & antagonists

GP IIb/IIIA receptor complex

Fibrinogen binding

AGGREGATION

Serotonin

Collagen Thrombin Vasopressin

Thromboxane PAF

Epinephrine ADP

ACTIVATION

Clopidogrel Ticlopidine Prasugrel Ticagrelor

Aspirin

20 December 2016

In routine clinical practice we all tend to blindly do the same for all our patients...

20 December 2016

Individual Response

Standard Dose Aspirin

Standard Dose Clopidogrel

PCI ACS Patient

Enzyme Rise/MI

Stent Thrombosis

Aspirin

Has become a default component of care in coronary disease & PCI... A concept that is unchallenged

Around for over 100 years...



Why Evolve to Dual Antiplatelet Therapy?



20/12/2016 22:47

Why Evolve to Dual Antiplatelet Therapy?

The Current Culture is.. We play 2 Upfront!

•Aspirin is the first name on the team sheet

•P2Y12 inhibitors are never sure of their place


CLOPIDOGREL: Does it have an image problem?

What is wrong with Clopidogrel?

Do we need a different anti-platelet?


In the context of ACS/PPCI, what is it that we wish for with a “better” P2Y12 inhibitor?

20 December 2016

What would be better about a “better” P2Y12 inhibitor?

Act more quickly? Be “more powerful”?

Improve PPCI outcome? Reduce ST rate?




So: we are aware of the problem of clopidogrel resistance,

we are wary of it, but we don’t really understand it

20-Dec-16

The Changing Face of Anti-platelet Therapy in ACS

Nick Curzen

0

10

20

30

40

50

60

70

80

90

100

pre 2hr 6hr 24hr

%C

In

Platelets 2007

If we had known about these patients... Could we have tailored their therapy & reduced ST risk?




Prasugrel: Why might it be better?






It’s more potent, with more rapid onset of action

SO......

It’s obvious that we should use prasugrel instead of clopidogrel in PPCI?



20 December 2016


CV death+MI+stroke



So....

Prasugrel is better than clopidogrel for PCI in ACS & should be used for nearly all patients instead?

20 December 2016

“If you want to leave Vegas with a small fortune....... Make sure you arrive there with large one”

20 December 2016





Weaknesses of the TRITON Study

No clopidogrel pre-loading!



Lancet 2009

20 December 2016




20 December 2016




BLEEDING risk

20 December 2016

Weaknesses of the TRITON Study


This isn’t just procedural bleeding either- quite the reverse!!

Shorten the duration of prasugrel?

You could eliminate most of the excess of bleeding You would lose a lot of efficacy


20 December 2016




BLEEDING risk

20 December 2016

JACC 2011

20 December 2016


What about Ticagrelor?

20 December 2016




BLEEDING risk




20 December 2016




BLEEDING risk

20 December 2016

Too good to be true?

20 December 2016

Let’s not kid ourselves: bleeding is important!!!



10% of both groups had CABG....... So 90% didn’t!!


Fatal/Life-threatening= MAJOR Bleeding

ICH >5 g/dL Haemoglobin >4 unit transfusion Hypotension requiring pressors or surgery Tamponade Hypovolaemic shock



10% of both groups had CABG....... So 90% didn’t!!

20 December 2016




BLEEDING risk



Circulation 2010 N=7544


P=0.07

P=0.07

20 December 2016




BLEEDING risk


Clopidogrel is :

Effective as an antiplatelet in the vast majority of patients

Safer than prasugrel & ticagrelor ... Lower major bleeding risk

Cheaper

So... In my view:

But we need to know which patients are not responding to clopidogrel So we need a quick & easy near patient test to assess response Then, if we identify non-responders, we can tailor their therapy


Assuming that we do need aspirin + AN Other drug..... (An assumption without basis?) What would be the ideal, safest & cheapest strategy for the second antiplatelet?

ACS Patient has PCI

Near patient test Response to aspirin & clopidogrel

Continue aspirin & clopidogrel

Change to prasugrel or ticagrelor

Near patient test to confirm response

Adequate response

Inadequate response

Individual Response

Standard Dose Aspirin

Standard Dose Clopidogrel

PCI Patient

Enzyme Rise/MI

Stent Thrombosis

✘

✘

Platelets 2011;22:210-16

Platelets 2007;18:497-505

Validation of short TEG

Platelets 2006;17:385-92.


The Wessex Cardiac Unit Clopidogrel Resistance in

Stent Thrombosis (CREST) Registry

Nalyaka Sambu, Alison Calver, Simon Corbett, Huon Gray, Iain Simpson and Nick Curzen

Southampton University Hospital, UK

http://www.tctmd.com/expert-presentations/table-2.html?product_id=5695&title=Impact of Distal Embolization After Intervention in Atherosclerotic and Thrombotic Lesions&sort_key=5&large_image_p=1

Patient admitted with definite ST

Referred to CREST Registry prior to discharge

CREST team arrange for an appropriately timed platelet function test

Platelet reactivity and response to APT is measured using Short TEG

Report and clinical recommendation issued to consultant

Follow up testing arranged as appropriate

Treatment modification: clopidogrel (n=19)

% c

lott

ing

in

hib

itio

n

-40

-20

0

20

40

60

80

100

clopidogrel 75mg

clopidogrel 150mg

prasugrel ticagrelor





So you can personalise medicine in the field of antiplatelets...

But you need to test their phenotypic response to do so!




Indulgent Speculation

SO: The Evolution of DAPT is Clear...?

•Aspirin is the first name on the team sheet

•P2Y12 inhibitors are never sure of their place


But.... How do we know that this is right?


Aspirin may actually be harmful in combination with a P2Y12 inhibitor

0

200

400

600

800

1000

1200

AU

C1

5

ADP Channel

AA Channel

P re P os t P re P os t

C lopidogrel

Volunteers on no med until 600mg clopidogrel

Patients on maintenance aspirin until 600mg clopidogrel

Platelets 2009


0

200

400

600

800

1000

1200

Ch

an

ge

in

AU

C

ADP Channel

AA Channel

P re P os t P re P os t

C lopidogrel

J Thromb Haemos 2010


Heart 2010


What we have (ie clopidogrel) may be better then the “better” alternatives?

Are we seduced by new fancy drugs when the evidence doesn’t stack up?

20 December 2016

Why is prasugrel used for PPCI in so many UK centres?

How on earth can the combination of prasugrel + bivalirudin be justified????

20 December 2016

The event rate is still high... We haven’t got there yet!!!


Clopidogrel works in most patients There is no evidence of benefit of prasugrel or ticagrelor in PPCI Clopidogrel is safer and cheaper than prasugrel and ticagrelor Is the interventional mindset obsessed with new technologies?

Tailored therapy is the way forward Aspirin may be the wrong tree to bark up?

20 December 2016

Acknowledgements

Nalyaka Sambu

Alex Hobson

Interventional Colleagues in Soton

Catheter Lab team in Soton

Documents

Oral antiplatelets in ACS PCI: Are we barking up the wrong tree? · 2016-12-20 · 20-Dec-16 Nick Curzen 1. I don’t think that the evidence supports a wholesale shift away from