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PERIPROCEDURAL PHARMACOTHERAPHY IN PRIMARY ANGIOPLASTY

SM AshrafPROFESSOR

MD DM FSCAI FESC FACCSahakarana Hrudayalaya

Pariyaram Medical College Hospital

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Causes of death worldwide

*Population: Age ≥60 years; CHD is the second leading cause of death in persons 15-59 years.

Deaths (2002)*

Mackay J, et al. Deaths from coronary heart disease. In: The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004:46-49.

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CHD and mortality inhigh-, middle- and low-income countries

[WHO 2008:A][WHO 2008:A]World Health Organization. The top 10 causes of death, Fact sheet Number 310. November 2008.

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Essential Principals in STEMI Interventions

1. To balance Ischemia and Bleeding2. Control | Speed | Urgency

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Five Best Strategies to PAMI Success

Improving Procedure

• 1. Culprit Lesion Identification & Parameters of success

• 2. Standardized techniques

• 3. Understanding thrombus dynamics/ Selective strategy for thrombus management

• 4. Intracoronary Vasodilators

• 5. Better anti-coagulant & anti platelet drugs

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Unfractionated Heparin

Indirect thrombin inhibitor (does not inhibit clot-bound thrombin)

Nonspecific binding to:― Plasma proteins ― Endothelial cells

(variable anticoagulation level)

Inhibited by platelet factor 4 ― reduced effect in ACS

Causes platelet aggregation

Risk of HIT

Disadvantages Multiple sites of action in

coagulation cascade (IIa,Xa)

Long history of successful clinical use

Readily monitored by aPTT and ACT

Very inexpensive

Advantages

Hirsh J, et al. Circulation. 2001;103:2994-3018

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Advantages of LMWH vs UFH

• No platelet activation

• Inhibits von Willebrand factor release

• Augments TFPI release

• Inhibits thrombin generation

• No rebound hypercoagulability

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Bivalirudin Bivalirudin

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Bivalirudin overcomes the risks and limitations of heparin

ACT= activated clotting time; IV=intravenous.1. Bivalirudin Prescribing Information. The Medicines Company; Parsippany, NJ, December 6, 2005.2. Bates SM et al. J Invasive Cardiol. 2000;12(suppl F):27F-32F. 3. Mehta S et al. Cath Lab Digest. 2004;12:1-4. 4. Minutello RM et al. Poster abstract 340. Presented at: 15th Transcatheter Cardiovascular Therapeutics Meeting; Washington, DC; 2003. 5. Schussler JM et al. Am J Cardiol. 2004;94:1417-1419. 6. Xiao Z et al. Circulation. 1998;97:251-256.

Antithrombotic feature

Bivalirudin

Heparin Benefits

100% bioavailable

Provides a predictable dose response; no continuous ACT monitoring required1

IV, 25-minute half-life Enables fast-on, fast-off activity1

Does not require antithrombin as a binding cofactor

Inhibits thrombin directly, and effectively inactivates clot-bound thrombin2

Binds reversibly to thrombin Thrombin is able to resume normal

hemostatic functions1,3

Sheath removal* 2 hours after discontinuation in most patients

Reduces access-site bleeding complications and time spent in the recovery area after PCI3-5

No heparin/PF4 cross-reactivity No risk of HIT/HITTS1

Does not activate platelets Does not promote platelet activation

or aggregation6

*Sheath removal has not been studied in dialysis-dependent patients treated with Bivalirudin. Follow standard hospital protocol for this population.1

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Return to Hemostasis - Safety Advantage

• Bivalirudin is cleaved by thrombin, allowing thrombin to quickly recover hemostatic activity upon discontinuation of Bivalirudin.2

• The natural reversibility and the short, 25-minute half-life may explain the significantly lower bleeding rates seen in clinical trials.3

• When heparin dissociates from cells/proteins, there can be an anticoagulant effect even when it is not needed. This may explain the prolonged bleeding risk after discontinuation of heparin.1

1. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S.2. Weitz JI et al. Thromb Res. 2002;106:V275-V284.3. Bivalirudin (bivalirudin) [prescribing information]; December 6, 2005.

Why Bivalirudin ?Why Bivalirudin ?

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Rationale on extended infusionRationale on extended infusion

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Anticoagulants: Overview

• Established anticoagulants used in patients with ACS:– Heparin (inhibits thrombin by accelerating

activity of antithrombin III)[Hirsch 1995]

• Low molecular weight heparins; unfractionated heparin

• Bivalurudin- Direct thrombin Inhibitor

– Fondaparinux* (binds reversibly to antithrombin, potentiating its neutralising effect on factor Xa)[Garcia 2012]

*Not approved for the treatment of ACS; †Approved in Europe for the treatment of patients with ACS; ‡Phase III study terminated due to increased risk of bleeding in the absence of counterbalancing reduction in ischaemic events.ACS, acute coronary syndromes.Ansell J, et al. Chest 2008;133:160S–198S; Garcia D, et al. Chest 2012;141:e24S–e43S; Hamm CW, et al. Eur Heart J 2011;32:2999–3054; Hirsch J, et al. Chest 1995;108(Suppl. 4):258S–275S; Steg G, et al. Eur Heart J 2012;33:2569–2619. ACS: Acute Coronary Syndrome

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Role of New oral anticoagulants in the treatment of patients with ACS

• New oral anticoagulants were developed to improve CV clinical management limited by the disadvantages of traditional agents[Eikelboom 2010]

• Rivaroxaban, apixaban, and dabigatran target factor Xa or thrombin, key enzymes in the coagulation pathway[Eikelboom 2010; PRADAXA 2013]

• Only rivaroxaban 2.5 mg is approved for use in patients with ACS in Europe[XARELTO® 2013]

– A Phase III study with apixaban was terminated early due to increased bleeding events with no concurrent reduction in CV events[Alexander 2011]

– It is currently unknown whether a Phase III trial will be initiated with dabigatran

• Given the potential for a higher risk of bleeding, triple therapy with the newer P2Y12 inhibitors plus a new oral anticoagulant in patients with ACS is still controversial

ACS, acute coronary syndromes; CV, cardiovascular.Alexander J, et al. N Engl J Med 2011;365:699–708; Eikelboom J, Weitz J. Circulation 2010;121:1523–1532; PRADAXA® [Prescribing information] 2013;XARELTO® [Summary of product characteristics] Berlin, Germany. Bayer 2013.

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Recommended use of anticoagulants in STEMI- ACS

Class I, LOE A–C•In STEMI patients:

– Must be implemented in addition to antiplatelet therapy in patients with clear indication for anticoagulation†

LOE, level of evidence; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention;STEMI, ST-segment elevation myocardial infarction; UA, unstable angina; UFH, unfractionated heparin.Hamm CW, et al. Eur Heart J 2011;32:2999–3054; Jneid H, et al. Circulation 2012;126:875–910; O’Gara PT, et al. Circulation 2013;127:e362–e425; Steg G, et al. Eur Heart J 2012;33:2569–2619.

Class I, LOE C•In STEMI patients:

– UFH or Bivalirudin is recommended in those undergoing PCI ACC/AHA

ESC

21Storey RF Curr Pharm Des 2006;12:1255–1259

Targets for platelet inhibition

ThromboxaneA

2

5HT

P2Y12

ADP ADPADP

5HT

PLATELET

ACTIVATION

P2Y15HT2A

PAR-1

PAR-4

Densegranule

Thrombingeneration

Shapechange

IIb

3

IIb

3

Fibrinogen

IIb

3

Aggregation

AmplificationAmplification

Alphagranule

Coagulation factorsInflammatory mediators

TP

Coagulation

GPVI

Collagen

ATPATP

P2X1

ASPIRIN

x TICLOPIDINECLOPIDOGRELPRASUGREL

ACTIVE METABOLITE

x TICAGRELOR CANGRELORELINOGREL

GP IIb/IIIa ANTAGONISTS

x

VORAPAXARVORAPAXARE5555

xx

HEPARINSFONDAPARINUX

BIVALIRUDINRIVAROXABAN

APIXABANDABIGATRAN Thrombinx

GP, glycoprotein; PAR, protease-activated receptor; TP, thromboxane A2 / prostaglandin

H2

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CPTP

CPTP•Ticagrelor

ATP Analogues•Cangrelor•Elinogrel

Theinopyridines•Ticlopidine•Clopidogrel•Prasugrel

Ant platelet's: Overview

P2Y12 Receptor Antagonists

Reversible Irreversible

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 Clinical Pharmacology Clopidogrel Prasugrel Ticagrelor

Chemical Class Thienopyridine Thienopyridine Cyclopentatyltriazolopyrimidine

Reversible inhibition of P2Y12

receptorNo No Yes

Pro drug Yes Yes No

Mean IPA at 30 min 8 % 31% 41 %

Mean IPA at 2 Hours 38 % 64% 89 %

Variability with CYP2C19 Yes No No

Comparison of P2Y12 Blockers

Chin CT, et al. Am Heart J 2010;160:16–22; Montalescot G, et al. Lancet 2009;373:723–731;Roe MT, et al. N Engl J Med2012;367:1297–1309.Gurbel PA, et al. JAMA 2012;308:1785–1794.Gurbel PA et al. Thromb Haemost. 2012;108:12–20.Wiviott SD, et al. Circulation. 2007;116:2923-2932.Thomas J, et al. European Heart Journal (2006) 27, 1166–1173.

IPA: Inhibition of Platelet Activation

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Prasugrel comes with increased bleeding tendency in specific sub groups

Beneficial more in PCI pts STEMI Diabetes Stent Thrombosis

Black Box Warning of increased risk if severe bleedDose Adjustment required in < 60 kg, >75 yearsCI in stroke/ TIACABG: d/c atleast 7d

Effient PI; NEJM 357: 2001-2015, 2007

Overall ↑ in TIMI Major Bleed

Subgroup Analysis

> 75 yrs

<60 kg

h/o stroke/ TIA

TIA – Transient ischemic attack ; STEMI : ST Elevation Myocardial Infarction ; TIMI: Thrombolytic in Myocardial Infarction

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Inhibition of platelet reactivity

Gurbel PA, et al. Circulation. 2009;120:2577-2585.

IPA, inhibition of platelet activity

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GP IIb/IIIa Inhibitors in Acute MI

• Key questions regarding new adjuvant therapies– Can we improve reperfusion times?– Can we improve flow after reperfusion?– Can we limit infarct size and thus

complications?

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GP IIb/IIIa Inhibitors in Acute MI

• Why a GP IIb/IIIa inhibitor could work– Early potent antiplatelet therapy– Adjunctive use in PCI improves

outcomes– May improve flow– Relatively safe to use

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12

4.6

10.5

5

14.7

7.3 74.6

10.5

4.5

0

10

20

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Rapport ISAR 2 Admiral Cadillac ACE

No Abciximab

Abciximab

%

GP IIb/IIIa in Acute MI

Abciximab PCI in Acute MI TrialsAbciximab PCI in Acute MI Trials30 Day Endpoint (D, Re-MI, Urg TVR)30 Day Endpoint (D, Re-MI, Urg TVR)

p=0.023

p<0.05p=0.005

PTCAPTCAN = 483N = 483

StentStentN = 401N = 401

StentStentN = 301N = 301

PTCA or StentPTCA or StentN = 2082N = 2082

StentStentN = 400N = 400

p=0.038

p=0.01

30

% p

late

let i

nh

ibiti

on

0

20

40

60

80

100

Baseline Post Bolus 20 min 40 min EOC

TIGER-PATIGER-PAPlatelet Substudy – Platelet Substudy –

TIROFIBAN IN CATH LABTIROFIBAN IN CATH LAB

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From: The Evolving Role of Glycoprotein IIb/IIIa Inhibitors in the Setting of Percutaneous Coronary Intervention: Strategies to Minimize Bleeding Risk and Optimize Outcomes

J Am Coll Cardiol Intv. 2010;3(12):1209-1219. doi:10.1016/j.jcin.2010.09.015

Recommended Strategy of GPI Use in Patients Undergoing PCI and Routinely Treated With Stenting and Thienopyridines

Flow chart of the recommended strategy for glycoprotein IIb/IIIa inhibitor use in patients undergoing percutaneous coronary intervention and who are routinely treated with stenting and thienopyridines. *Non–ST-segment elevation myocardial infarction (18). #The presence of 1 and particularly 2 or more of the following factors is associated with an increased bleeding risk: age > 75 years, female, chronic kidney disease stage 3 or worse, baseline anemia, history of prior bleeding, cardiogenic shock, or class IV heart failure. Also, adjust unfractionated heparin dose during percutaneous coronary intervention: use a starting bolus dose of ≤50 U/kg and achieve a target activated clotting time of low 200 s. †The need for a short infusion after percutaneous coronary intervention (≤2 h) depends on the timing of thienopyridine load. Adjust infusion dose to renal function. GPI = glycoprotein IIb/IIIa inhibitor(s); PCI = percutaneous coronary intervention; thieno = thienopyridine.

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Guidelines : ESC 2014 - STEMI

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Impact of Therapies on Outcomes in Impact of Therapies on Outcomes in PPCIPPCI

Bleeding/ Access and non access site

bleeding

Ischemic events:MI/CKMB↑/StrokeStent Thrombosis

EFFICACY SAFETY

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Relevance of bleeding as a clinical endpoint in contemporary PCI

• Availability of potent antithrombotic therapy including– ASA– P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor)– heparin– GP IIb/IIIa inhibitors– direct thrombin inhibitors

• Has led to a reduction in ischemic events• But is associated with an increased risk of

bleeding• The increase in bleeding is associated with

worse clinical outcome

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Hypothetical Mechanisms associating Bleeding to Mortality

Steg P G et al. Eur Heart J 2011;32:1854-1864

36Steg P G et al. Eur Heart J 2011;32:1854-1864

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How can Bleeding Increase Short and Long Term Mortality ?

• Hemodynamic compromise

• Hyper adrenergic state

• Transfusion induced micro circulatory disorder, NO depletion, immunological effects.

• Inflammatory response.

• Discontinuation of antiplatelet & antithrombotic regimens

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SUMMERY- PHARMACOTHERAPY IN STEMI INTERVENTIONS

• Optimal thrombus management is critical for STEMI Interventions

• With D2B<90 min, a fast acting OAP is mandatory – the role of Clopidogrel in these circumstances is fraught with issues of effectiveness from delayed onset of action

• Intravenous GP2b/3a is a non-ideal option

• Balancing Bleeding & Ischemic Benefits is Crucial in PPCI.

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THANK YOU