novel antithrombotic agents in acute coronary syndromes: better or worse tha n p2y12 inhibitors

Novel antithrombotic agents in acute coronary syndromes: better or worse than P2Y12

inhibitors

Giuseppe Biondi Zoccai

Sapienza Università di [email protected]

Learning goals

State-of-the-art antithrombotic therapy in acutecoronary syndromes (ACS):• The past: aspirin, clopidogrel, and warfarin• The present: prasugrel and ticagrelor• The future: atopaxar, vorapaxar, cangrelor,

apixaban, dabigatran, and rivaroxaban

The platelet: our common foe<- Aspirin

<-

<-

PAR inhibitors

<-

P2Y12inhibitors

<-Anticoagulants

IIb/IIIainhibitors

Jackson et al, Nat Rev Drug Discov 2003

The past

Aspirin• Oral drug• Irreversibly inactivates

cyclooxygenase• Inhibits production of

thromboxane A2 (TXA)• Limits TXA-mediated platelet

activation and aggregation• Does not impact on other

activation pathways and has variable response

• Oral drug• Irreversibly inactivates

cyclooxygenase• Inhibits production of

thromboxane A2 (TXA)• Limits TXA-mediated platelet

activation and aggregation• Does not impact on other

activation pathways and has variable response

Aspirin

Clopidogrel• Oral drug• Irreversibly inactivates the

P2Y12 platelet receptor for ADP

• Limits P2Y12-mediated platelet activation and aggregation

• Does not impact on other activation pathways and has variable response

Warfarin

• Oral anticoagulant• Inhibits the synthesis of

factors II, VII, IX, and X, as well as protein C, S, and

• Has very limited therapeutic index and requires frequent monitoring and adjustments

The WOEST trialDe

ath,

MI,

stro

ke, T

VR, o

r ST

(%)

Dewilde et al, Lancet 2013

The WOEST trial

Dewilde et al, Lancet 2013

The present

Prasugrel• Oral drug• Irreversibly inactivates the

P2Y12 platelet receptor for ADP (more potently and predictably than clopidogrel)

• Limits P2Y12-mediated platelet activation and aggregation

• Does not impact on other activation pathways

The TRITON-TIMI 38 trial

Wiviott et al, New Engl J Med 2008

Cardiovascular death, MI or stroke

Non-CABG-related TIMI major bleeding

The TRILOGY ACS trial

Wiviott et al, Circulation 2008

Endp

oint

(%)

HR=0.91 (0.79-1.05), p=0.21

CV death, MI, or stroke

Ticagrelor

• Oral drug• Reversibly antagonizes the

P2Y12 platelet receptor for ADP

• Thus limits P2Y12-mediated platelet activation and aggregation


The PLATO trialVascular death, MI or stroke Major bleeding

Months Months

Wallentin et al, New Engl J Med 2009

Benefits across the board

Wallentin et al, New Engl J Med 2009

All patients*Ticagrelor(n=9,333)

Clopidogrel(n=9,291)

HR for (95% CI) p value

Primary objective, n (%) CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001

Secondary objectives, n (%) Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Myocardial infarction CV death Stroke

901 (10.2)

1,290 (14.6)

504 (5.8)353 (4.0)125 (1.5)

1,065 (12.3)

1,456 (16.7)

593 (6.9)442 (5.1)106 (1.3)

0.84 (0.77–0.92)

0.88 (0.81–0.95)

0.84 (0.75–0.95) 0.79 (0.69–0.91)1.17 (0.91–1.52)

<0.001

<0.001

0.005 0.001 0.22

Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001

Adjusted indirect comparison

Biondi-Zoccai et al, Int J Cardiol 2011

The future

Atopaxar

• Oral drug• Reversibly inhibits the

protease-activated receptor (PAR)-1 which binds thrombin on platelets

• Thus limits thrombin-mediated platelet activation and aggregation

The LANCELOT-ACS trial

O’Donoghue et al, Circulation 2011

The LANCELOT trial

Wiviott et al, Circulation 2011

Vorapaxar

• Oral drug• Reversibly inhibits the

protease-activated receptor (PAR)-1 which binds thrombin on platelets

• Thus limits thrombin-mediated platelet activation and aggregation

The TRACER trialCardiovascular death, MI or stroke GUSTO moderate/severe bleeding

Months Months

Tricoci et al, New Engl J Med 2012

Cangrelor

• IV drug• Reversibly antagonizes

the P2Y12 platelet receptor for ADP

• Thus limits P2Y12-mediated platelet activation and aggregation


The CHAMPION PHOENIX trialSt

ent t

hrom

bosis

(%)

Bhatt et al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)

The CHAMPION PHOENIX trial

Bhatt et al, New Engl J Med 2013 (57% CSA, 25% NSTEACS, 18% STEMI)

Apixaban

• Oral anticoagulant• Factor Xa inhibitor• Favorable risk-benefit

profile already established in atrial fibrillation and deep vein thrombosis-pulmonary embolism

The APPRAISE-2 trial

Alexander et al, New Engl J Med 2011

81% on DAPT

The APPRAISE-2 trial

Alexander et al, New Engl J Med 2011

Dabigatran• Oral anticoagulant• Direct thrombin

inhibitor • Favorable risk-benefit


The RE-DEEM trial

Oldgren et al, Eur Heart J 2011

99.2% on DAPT

The RE-DEEM trial

Oldgren et al, Eur Heart J 2011

Rivaroxaban

• Oral anticoagulant• Factor Xa inhibitor• Favorable risk-benefit


The ATLAS ACS 2-TIMI 51 trial

Mega et al, New Engl J Med 2012

93% on DAPT

The ATLAS ACS 2-TIMI 51 trial

Mega et al, New Engl J Med 2012

Take home messages• Antithrombotic management of ACS will resemble in a

few years the treatment of hypertension, with many available drugs and dozens of possible cocktails.

• Aspirin remains the background therapy of choice for its cost-effectiveness (and potential antineoplastic effects).

• Clopidogrel continues to be useful in those at low thrombotic risk or high bleeding risk.

• Prasugrel and ticagrelor are useful in all those without high bleeding risk, especially if at high thrombotic risk.

Take home messages• Atopaxar, vorapaxar and cangrelor may have some favorable

features in carefully selected patients, but the evidence base is still incomplete.

• Apixaban and dabigatran do not seem beneficial on top of dual antiplatelet therapy.

• Conversely, rivaroxaban may appear beneficial even within a triple therapy regimen, as long as bleeding risk is not high, with a 2.5 mg bid regimen possibly reducing mortality.

• Only further trials will clarify whether a WOEST-like dual-agent new-generation P2Y12-factor Xa inhibitor combo (e.g. ticagrelor plus rivaroxaban) may be the best possible option.

Many thanks for your attention

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novel antithrombotic agents in acute coronary syndromes: better or worse tha n p2y12 inhibitors

Documents

acutecoronary syndromes

acs patients

acute coronary syndromes

novel antithrombotic

art antithrombotic therapy

ticagrelorthe future

warfarinthe present

rivaroxabanthe platelet