Antithrombotic and Antiplatelat Strategy in ACS

Emir Fazlibegović,FESC SKB Mostar , Bosnia and Herzegovina

7 th Joint Bosnia Herzegovina and Turkish Cardiology Meeting

May 25-27,2012 Sarajevo,Bosnia and Herzegovina

“These data, together with a major and statistically significant decrease in systolic blood pressure, measured in all streptokinase patients, are compatible with the hypothesis that streptokinase improves cardiac function after acute myocardial infarction by decreasing total peripheral resistance” NEJM 1979;301:797-802

Various and Very Different Thrombotic Situations

Venous thrombosis: fibrin rich thrombus – Important thrombus burden – VTE –

Afib

–

Mechanical heart valves

Arterial thrombosis: platelet rich thrombus – Modest thrombus burden – Acute coronary syndromes (STEMI,NSTEMI,NAP) – PCI / Stent implantation – CVD – PAD

ACS with persistent ST-segment elevation ACS without persistent ST-segment elevation Adapted from Michael Davies Adapted from Michael Davies CK- MB or Troponin Troponin elevated or not

108

Antiplatelet Therapy in ACS

ASA ASA + Clopidogrel ASA + Prasugrel - 22% - 20% - 19% Reduction in Ischemic Events 0 Placebo + 60% APTC Single Antiplatelet Rx + 38% CURE Dual Antiplatelet Rx + 32% Increase in Major Bleeds TRITON-TIMI 38 Higher IPA

Predictors of Bleeding

• – – – – – – – – Baseline characteristics Age Sex Body weight Chronic kidney disease Diabetes Anemia History of bleeding … Invasive approach Excessive dosing of antithrombotic drugs Combination of antithrombotic agents

A novel score (HAS-BLED) to assess one-year risk of major bleeding in AF : The Euro Heart Survey

R Pisters Chest 2010 DOI 10.1378/chest.10-0134

Balancing Safety and Efficacy

High risk of ischemic events “Sweet spot” High risk of bleeding events

Inhibition of platelet aggregation Ischemic risk Bleeding risk

Ferreiro & Angiolillo. Thromb Haemost 2010

Targets for Antithrombotic Agents

Tissue factor Collagen Aspirin Direct Xa inhib Fondaparinux LMWH Heparin AT AT Bivalirudin Hirudin Plasma clotting cascade Prothrombin Factor Xa Thrombin ADP Thromboxane A 2 Clopidogrel Prasugrel Ticagrelor Conformational activation of GPIIb/IIIa TRA GPIIb/IIIa inhibitors Platelet aggregation Fibrinogen Fibrin Dabigatran Thrombus

Parenteral anticoagulants

Drug Indication Heparins and derivatives UFH LMWH

Inpatient treatment of:  ACS  Elective PCI  AF with embolization  DVT and PE  Clot prevention in arterial and cardiac surgery  Prophylaxis and treatment of peripheral arterial embolism  As UFH

Mechanism of action

 Indirect FXa and thrombin inhibition via AT

Fondaparinux Direct thrombin inhibitors (DTIs) Bivalirudin Hirudin

 VTE prevention and treatment  ACS  HIT; alternative to heparin in PCI; ACS  As UFH, but FXa inhibition >> thrombin inhibition   Indirect FXa inhibition via AT No direct thrombin inhibition  Covalently bind and inactivate fibrin and/or active thrombin binding sites AT, antithrombin; DVT, deep vein thrombosis; FXa, Factor Xa; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary interventions; PE, pulmonary embolism; VTE, venous thromboembolism

Recent and emerging anticoagulants

Thrombin inhibitors – Direct, oral Ximelagatran Dabigatran Factor Xa inhibitors – Indirect, parenteral Fondaparinux Idraparinux/biotinylated – Direct, oral Rivaroxaban Apixaban Others

OASIS-5 Fewer Bleedings = Fewer Deaths

Bleeding Reduced by 50% Deaths Reduced by 17% HR: 0.52 95% CI: 0.44-0.61 p<0.001

Yusuf S, Mehta S, et al. OASIS-5 Investigators NEJM 2006

ACS PCI / Stent

Current Standard of care

Anticoagulation Antiplatelet Agents

UFH LMWHs Fondaparinux* Bivalirudin ASA Clopidogrel GPIIb/IIIa inhibitors * with bolus of UFH in case of PCI

New strategies with new AC drugs

Heparin(s) Fondaparinux Initial overlap between two standard Tx AVK Switch from standard Tx to new oral agent Heparin(s) Fondaparinux Dabigatran One agent with dose modification for LT prevention Apixaban, Rivaroxaban

PRIMARY EFFICACY ENDPOINTS: 2.5 mg PO BID In Patients Treated with ASA + Thienopyridine

12% CV Death / MI / Stroke* HR 0.85

Placebo mITT p=0.039

5% 10.4% 9.0% ITT p=0.011

Cardiovascular Death HR 0.62

mITT p<0.001

ITT p<0.001

Placebo 5% All Cause Death HR 0.64

Placebo 4.2% mITT p<0.001

ITT p<0.001

2.5% 4.5% 2.7% 0 Rivaroxaban 2.5 mg BID

NNT = 71

12 Months 24 0 Rivaroxaban 2.5 mg BID

NNT = 59

12 Months 24 0 Rivaroxaban 2.5 mg BID

NNT = 56

12 Months 24

*: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat.

STENT THROMBOSIS* ARC Definite, Probable, Possible Placebo

2 Yr KM Estimate

2.9% 2.3% HR 0.69 (0.51- 0.93) Rivaroxaban (both doses) mITT p = 0.016

ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012

ITT p = 0.008

Months After Randomization

* End point events are as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

TREATMENT-EMERGENT FATAL BLEEDS AND ICH

1.2

1

p=NS for Riva vs Placebo p=0.009 Riva Vs Placebo Placebo 2.5 mg Rivaroxaban 5.0 mg Rivaroxaban

0.8

0.7

0.6

p=0.044 for 2.5 mg vs 5.0 mg

0.4

0.4

0.4

p=NS for Riva vs Placebo

0.2

0.2

0.1

* 0.2

0.1

0.1

0.2

0

n=9 n=6 n=15 n=5 n=14 n=18 n=4 n=5 n=8 Fatal ICH Fatal ICH *Among patients treated with aspirin + thienopyridine, there was an increase in fatal bleeding among patients treated with 5.0 mg of Rivaroxaban (15/5110) vs 2.5 mg of Rivaroxaban (5/5115) (p=0.02)

Phase A = 547

Study Design

Recent (



7 days) Acute Coronary Syndrome

plus at least one additional risk factor

Placebo

n=184

Phase A 1:1:1 Apixaban 2.5 mg BID

n=179

Apixaban 10 mg QD

n=184

Interim analysis (DSMB review)

Phase B = 1168 Phase B 3:1:1:2:2

•

Randomized, double blind.

•

Study drug for 6 months.

•

Aspirin



165 mg/d.

•

Clopidogrel per MD discretion (stratified randomization)

Discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapy

Total = 1715 Placebo

n=427

Apixaban 2.5 mg BID

n=138

Apixaban 10 mg QD

n=134

Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH) Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic stroke

NO STRATUM 1 ASA Alone N=761

STUDY DESIGN

Recent ACS Patients Stabilized 1-7 Days Post-Index Event MD Decision to Treat with Clopidogrel N = 3,491 Aspirin 75-100 mg YES STRATUM 2 ASA + Clop.

N=2,730 PLACEBO N=253 5 mg (77) 10 mg (98) 20 mg (78) RIVA QD N=254 5 mg (77) 10 mg (99) 20 mg (78) RIVA BID N=254 2.5 mg (77) 5 mg (97) 10 mg (80) PLACEBO N=907 5 mg (74) 10 mg (428) 15 mg (178) 20 mg (227) RIVA QD N=912 5 mg (78) 10 mg (430) 15 mg (178) 20 mg (226) RIVA BID N=911 2.5 mg (76) 5 mg (430) 7.5 mg (178) 10 mg (227) Treat for 6 Months

Gibson CM, AHA 2008

Rivaroxaban: a novel oral, direct Factor Xa inhibitor Once daily Predictable pharmacokinetics and pharmacodynamics High oral bioavailability Rapid onset of action Fixed dose No requirement for coagulation monitoring

O N O O N O H N O S Cl

Rivaroxaban Rivaroxaban binds directly to the active site of Factor Xa (K i 0.4 nM) Roehrig

et al.

2005; Perzborn

et al

. 2005; Kubitza

et al

. 2005; 2006; 2007

N ~3,500 NO Recent acute coronary syndrome patients Stabilized 1 –7 days post-index event

MD decision to treat with clopidogrel

STRATUM 1 *Dose levels 5, 10 and 20 mg Aspirin 75 –100 mg YES STRATUM 2

Placebo Rivaroxaban once daily 3 dose levels* Rivaroxaban twice daily 3 dose levels* Placebo

Treat for 6 months

Primary endpoint: TIMI significant bleeding Rivaroxaban once daily 3 dose levels* Rivaroxaban twice daily 3 dose levels*

New Antiplatelet Agents

Clopidogrel new regimen Prasugrel Ticagrelor

Risk of Infarction and Dabigatran

Uchino Arch Intern Medicine 2012

Drug/

Trial

Comparison of Efficacy and Safety Endpoints at Study End in Recent Major Antiplatelet Trials

Comparator D+MI+S Death Bleeding (non CABG)

Ticagrelor

Plato

Prasugrel

Triton

Clopidogrel High LD

Current Current PCI

Clopidogrel Clopidogrel Clopidogrel Clopidogrel -16% -19% NS -14% -16% NS NS NS +27% +32% +24% +31%

Primary Endpoint: CV Death, MI, Stent Thrombosis

JAMA. 2011;305(11):1097-1105

Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel and vitamin K antagonists

New Parenteral Anticoagulants under Investigation

         Idrabiotaparinux, ultra-low-molecular-weight heparins, re-engineered UFH [M118]), Direct FIIa inhibitors , flovagatran sodium, pegmusirudin, NU172, HD1 22), Direct FXIa inhibitors (BMS-262084, antisense oligonucleotides targeting FXIa, clavatadine), FIXa inhibitors (RB-006), FVIIIa inhibitors (TB-402), FVIIa/tissue factor inhibitors (tifacogin, NAPc2, PCI-27483, BMS 593214), FVa inhibitors (drotrecogin alpha activated, ART-123) Dual thrombin/FXa inhibitors (EP217609, tanogitran).

M118: Rationally engineered heparin

Xa and IIa binding sites on each chain – First LMWH with significant IIa activity – Constant Xa/IIa ratio over time – Presence of IIa activity allow for point-of-care anticoagulant monitoring Reduced polydispersity – More predictable PK – Contributes to protamine neutralization Unnecessary sequences eliminated/more accessible Xa/IIa sites – Reduced PF4 binding sites (potentially reduced HIT) – Contributes to TFPI release IV and SC administration

Pentasaccharid e AT-III Binding Sequence Thrombin Binding Sequence

Semuloparin for Thromboprophylaxis in Patients Receiving Chemotherapy for Cancer SAVE-ONCO Trial

In total 8 ongoing trials with Semuloparin

Agnelli N Engl J Med 2012;366:601-9.

Take-home messages

 Cardiology is a complex discipline. Try to keep it simple  Standard of care is going to change dramatically  New antiplatelet agents have already changed the standard of care. Ticagrelor has the potential to replace clopidogrel in all forms of ACS  New oral anticoagulants have the potential to revolutionize the treatment of VTE, AF and ACS. Rivaroxaban has the potential to cover all indications

Take-home messages-STEMI

All patients with ST-elevation myocardial infarction (STEMI) should receive anticoagulation, irrespective of the reperfusion strategy, anticoagulant therapy should be given as soon as possible after diagnosis. All patients with STEMI should receive dual antiplatelet therapy.

Take-home messages

The choice of anticoagulant agent depends upon the treatment strategy for each patient (unfractionated heparin [UFH], low molecular weight heparin, bivalirudin, or fondaparinux) For all patients treated with primary PCI, we recommend anticoagulant therapy (

Grade 1B

).

Take-home messages

We recommend either bivalirudin (with provisional glycoprotein [GP] IIb/IIIa inhibitor in cases of ischemic complications or large thrombus burden) or UFH (and planned GP IIb/IIIa inhibitor) in preference to fondaparinux (

Grade 1B

). We suggest bivalirudin (with provisional GP IIb/IIIa inhibitor) in preference to UFH (with planned GP IIb/IIIa inhibitor) (

Grade 2B

).

Take-home messages

For patients treated with fibrinolytic therapy, we suggest anticoagulant therapy (

Grade 2B

). For patients not at high risk of bleeding, we suggest using enoxaparin as opposed to UFH, fondaparinux, or bivalirudin For those patients in whom PCI is possible or likely after fibrinolytic therapy, UFH a reasonable choice.

Take-home messages

For patients at high risk of a bleeding complication and who are not likely to require PCI, we suggest fondaparinux as opposed to enoxaparin or UFH (

Gr. 2C

). For patients not treated with reperfusion therapy, we suggest anticoagulant therapy with enoxaparin, UFH, or fondaparinux, as opposed to no anticoagulant therapy, as soon as possible after presentation (

Gr.2B

).

Take-home messages-NSTEMI

Anticoagulant therapy with either bivalirudin, fondaparinux, unfractionated heparin (UFH), or enoxaparin prevents thrombus related ischemic events in patients with NSTE ACS(UAP+NSTEMI).

We recommend anticoagulant therapy for all patients (

Grade 1A

).

Take-home messages

For patients managed with an early invasive strategy (angiography within 4 to 48 h), we recommend bivalirudin, fondaparinux, or UFH as opposed to enoxaparin (

Grade 1A

).

The choice between bivalirudin, fondaparinux, or UFH should be made based on issues of cost and local practice

Take-home messages

For patients who will be referred to the catheterization laboratory within four hours (usually due to patient instability for reasons such as refractory angina, heart failure, arrhythmia, or hemodynamic instability), we recommend UFH or bivalirudin as opposed to fondaparinux or enoxaparin (

Grade 1B

).

Take-home messages

For patients in whom a conservative (non invasive) strategy is planned, we recommend either fondaparinux or enoxaparin in preference to either unfractionated heparin or bivalirudin (

Grade 1B

).

The choice between fondaparinux and enoxaparin should be guided by issues of cost and local practice. For patients at higher risk of bleeding, we suggest fondaparinux (

Grade 2B

).

Aspirin

1.Aspirin block

the enzyme cyclooxigenase that mediates the first step in the biosynthesis of prostaglandins and thromboxanes from arachidonic acid.Thromboxane A2 is a potent stimulator of platelat aggregation.

Aspirin

ISIS-2 (17,187 pat.)-23% reduction Mt(with STK 42%) and The Antithrombotic Trialists Collaboration (200,000 pat.) 30% reduction nonfatal MI,nonfatal ICV or Mt CURRENT and OASIS 7 trial recommend 75-162mg dose with lower risk of gastrointestinal bleeding compared with higher dose 300-325mg.

P2Y12 - receptor blockers

The platelet P2Y12 receptor blockers

clopidogrel, ticlopidin, ticagrelor and prasugrel block the binding of ADP to a specific platelat receptor P2Y12,thereby inhibiting activation of the GP Iib/IIIa complex and platelat agregation. Most evidence shows that the antiplatelet benefits of these agents are additive to those of aspirin, irrespective of whether the patient receives fibrinolytic therapy,PCI or no reperfusion.

P2Y12 - receptor blockers

In most cases of STEMI, this drugs should be started immediately and continued for up to one year.

COMMIT/CCS-2(45,582 pat.) and CLARITY-TIMI 28 trials showed clear evidence of benefit from early adminsitration of clopidogrel in patients also treated with aspirin and fibrinolytic therapy.

P2Y12 - receptor blockers

PCI-CLARITY subset trial in CLARITY TIMI 28(1863 pat.)showed a significant reduction Mt,IM or ICV in 30 d folow-up after PCI.

PCI-CURE,CREDO and CURE trials in NSTE ACS with clopidogrel 9-12 months was evidence of increasing benefit.

P2Y12 - receptor blockers

CAPRIE trial was evidence a possible benefit from clopidogrel for longer than one year in patients with atherosclerosis (not limited to MI).

P2Y12 - receptor blockers

HORIZONS AMI and OASIS 7 trials (25,086 pat.) with

600mg

loading dose clopidogrel on day and

150mg

/6 day and 75mg after to compare with

300mg

loading+

75mg

werw noted: -significantly reduced the rate of the primary outcome (3,9:4,5%), the secundary outcome (17,263 pt)1,6:2,3% -Major bleeding (2,5:2%) and 1,6:1,1%(PCI subgroup)

P2Y12 - receptor blockers

TRITON-TIMI 38 trial (13,608 pat with PCI in ACS) and 3534 with STEMI and 2438 pat with STEMI+PCI primary and 1096 pat with STEMI+PCI(38h post MI)

prasugrel

(60mg loading dose+10mg/day):

clopidogrel

(300mg loading dose+75mg/day) the median duration of therapy was 14,5 months

P2Y12 - receptor blockers

-the primary efficacy endpoint Mt,nonfatal MI,nonfatal ICV occurred significantly less often in pat. Treated with prasugrel (15 months follow-up) 10:12,4% -The rate of definite or probable stent thrombosis was significantly reduced in the prasugrel group (1,6:2,8%) -There was no significant difference in the rate of major bleeding

Ticagrelor

Her binds with P2Y12 receptors is reversibly with a more rapid action than clopidogrel and to more intense platelat inhibition.

PLATO trial (18,000 pat. with ACS) -the primary end point (MI,ICV and Mt) occurred less often with ticagrelor compared to clopidogrel(9,4:10,8%)

Ticagrelor

TRITON-TIMI and PLATO trials The risk of CABG related major bleeding was significantly increased with prasugrel(13,4:3,2%) but not ticagrelor (7,4:7,9%) compared to clopidogrel.

ACUITY and CURE trials in subgroup analyses patients with CABG and who received clopidogrel had a lower rate of adverse outcomes.

Non-bleeding adverse effects of P2Y12 receptor blocker:

-neutropenia and -thrombotic thrombocytopenia purpura/hemolytic uremic syndrome -TTP HUS ( with ticlopidine) -hypersensitivity (with clopidogrel)

The management strategy

-for patients treated with medical therapy (no revascularisatin), we prefer ticagrelor to clopidogrel (prasugrel has not been studied in these patients) -for patients managed with primary PCI, we prefer either ticagrelor or prasugrel to clopidogrel.When clopidogrel is chosen, we suggest treating patients not at high risk fo bleeding for one week with a higher maintenance dose of clopidogrel (150mg) when clopidogrel is chosen. After one week the maintenance dose of clopidogrel is 75mg daily.

The management strategy

For patients managed with fibrinolytic therapy, we recommend clopidogrel rather than prasugrel or ticagrelor, as these latter two have not been tested in this setting.

There are no data regarding safety and bleeding risk with prasugrel or ticagrelor combined with fibrinolytic therapy. If a STEMI patient treated with fibrinolytic therapy is later referred for PCI,use of prasugrel is reasonable; in the TRITON-TIMI 38 trial, prasugrel led to better outcomes than clopidogrel.

The management strategy

The maintenance doses are clopidogrel 75mg/daily, prasugrel 10mg/daily and ticagrelor 90mg/twice daily.

-We recommend that dual antiplatelet therapy be continued for at least one year.

Glycoprotein IIb/IIIa inhibitors

(abciximab,tirofiban,eptifibatide) inhibits only one of several important patways to platelet activation and agregation.

-a meta-analysis of over 27,000 patients(11 trials) found that abciximab compared to placebo, significatntly lowered the rate of death at 30 days(2,4:3,4%)

Glycoprotein IIb/IIIa inhibitors

-tirofiban to compared with placebo significantly reduced tha rate of major adverse cardiovascular events (Mt,MI,urgent CABG)at 30 days (5,8:8,6%) -BRAVE-3 trial (800 patients with acute STEMI)and who were treated with 600mg of clopidogrel were randomly assigned to either abciximab or placebo in the emergency room or intensive care unit before primary PCI and found there was no significant difference between the two groups in pšrimary and secundary end point(Mt,MI,ICV,urgent ACBP)