Anticoagulation Therapy in Percutaneous Coronary...

Anticoagulation Therapyin Percutaneous Coronary Interventions

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Thrombus Formation: Platelet Activation and Blood Coagulation

Coagulationcascade

FactorXa

Thrombin

Fibrinogen

fibrin

Platelets

Thrombin

ADP

Thromboxane

Collagen

Activated Platelet

Platelet Aggregation

GP IIb/IIIa

CLOT

InflammationCellular

proliferation

Hamm CW. et al.ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation:

The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology.(ESC).

Coagulation Processes: Mostly Cell Surface-based

De Caterina R. et al.General mechanisms of coagulation and targets of anticoagulants (Section I).

Position Paper of the ESC Working Group on Thrombosis--Task Force on Anticoagulants in Heart Disease.Thromb Haemost.2013 Apr;109(4):569-79

INITIATION AMPLIFICATION PROPAGATION

Thrombin: Exertion of Multiple Biological Actions

TF/FVIIa

FX FIX

FIXa

FVIIIaFXa

FVa

thrombin inflammationProtein C activationand anticoagulation

FXI activationFXIII activation andfibrin stabilazation

Platelet activationAnti fibrinolysis

FV FVIII

FVa FVIIIa

Fibrinogen Fibrin

Thrombin: Actions on Blood Cells and Blood Vessels

Endothelium

Platelet

MonocyteLymphocyte

SmoothMusclecell

ThrombinCytokinesGrowth factorsAutocoidsProteases

Shape andpermeabilitychanges

Serine protease generated at sites of vascularinjury. Most effective platelet activator (PAR-protease activated receptor). Elicits host ofresponses in vascular endothelium: shape &permeability changes, mobilization of adhesivemolecules to endothelial surface & stimulation ofautocoid (small molecule mediators such asprostaglandins, PAF) & cytokine production.Chemotactic for monocytes. Mitogenic forlymphocytes & mesenchymal cells.

NeutrophilNeutrophil

Coughlin SR.Thrombin signalling and protease-activated receptors.

Nature.2000 Sep 14;407(6801):258-64

Thrombin: the Multi Faceted Enemy Within

In vivo arterial thrombosis involvesplatelet aggregation, tissue factorgeneration and fibrin formation

Falati S. et al.Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse.

Nat Med.2002 Oct;8(10):1175-81

Thrombus Composition in AMI:A Time Dependent Phenomenon

Silvain J. et al.Composition of coronary thrombus in acute myocardial infarction.

J Am Coll Cardiol. 2011 Mar 22;57(12):1359-67

Scanning Electron Micrograph at 3,000 Magnification

Thrombin Generation in ACS and Stable CAD

ACS

Control

CAD

Brummel-Ziedins K. et al.Thrombin generation in acute coronary syndrome and stable coronary artery disease: dependence on plasma factor composition.

J Thromb Haemost. 2008 Jan;6(1):104-10

Thrombin Levels in ACS: 6 Mo. F.U

Merlini PA. et al.Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.

Circulation.1994 Jul;90(1):61-8

atherosclerosis pronecoronary segment

focal plaque formation

vascular remodeling response

Constrictiveremodeling

Compensatoryremodeling

Excessive expansiveremodeling

Flow limitationstable angina

quiescence potential forplaque rupture

High ESS

Subclinical Plaque Ruptureor Intraplaque Hemorrhage

Hypothesis of the Natural History ofVulnerable Plaque and CAD Progression

Low ESS

5-10%

95%

~5%

+

+

Stable CAD

Acute CoronarySyndromes/RapidPlaque Progression

PlaqueErosion

PlaqueRupture

+

Stone PH.TCT 2014

Rationale for antithrombotic therapy during PCI

Tissue Factor

Adhesion Molecules

ThrombinGeneration

PlateletActivation

Vessel Wall Injuryand Inflammation

David J. CohenFellows Course 2015

Mechanical vessel injury in PCI andspontaneous injury in ACS are thrombogenic

Heparins (UFH/LMWH): Mechanism of Action

Heparin/antithrombin (AT) complex inhibits thrombin and Factor XaMust have adequate AT present for anticoagulant effect

Thrombin inhibition requires“bridging” by heparin chain(at least 18 units)

LMWH has greater activityagainst Xa than thrombin

Heparin chains withpentasaccharide sequence(~30%) bind to AT causing aconformational change

Hirsh J. et al.Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.

Chest. 2001 Jan;119(1 Suppl):64S-94S

UFHbound

toAT

Heparin: A Disgusting ProductCombine 5,000 lbs. intestines, 200 gallons water, 10 gallons chloroform, and 5gallons toluene. Hold at 90°F for 17 hours.Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide toadjust pH, and 235 gallons water.Bring to a boil; then filter.Add 200 gallons hot water to filtrate and allowto stand overnight, then skim off the fat.Keep pancreatic extract at 100°F for three days,then bring to boil.Filter solids and assay for heparin content.

G.W. Stone, TCT 2014.Bivalirudin vs. Heparin Monotherapy in STEMI: Debating the merits.

Pharmacological Properties of Current Anticoagulants:UFH

UFHPredictability in pharmacological profile -

Cofactor required +++

Renal clearance -

Non-specific protein binding +++

Platelect activation +++

Rebound of thrombin generation after discontinuation +++

Inhibition of bound thrombin -

Neutralization by platelet factor 4 +++

Inhibition of thrombin generation +

Unfractionated Heparin in PCI: a Meta-Analysis

Chew DP. et al.Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials.

Circulation.2001 Feb 20;103(7):961-6

10.1%11.1%

8.6% 8.9%

6.6%7.5% 7.7%

9.8%

0.15

0.10

0.05

0.00250 300 350 400 450

Minimum ACT at device activation

Probability of 7 Day Death, MI or RevascPr

obab

ility

of d

eath

, MI,

orre

vasc

at 7

-day

s p = 0.001 between 11.1% and 7.7%

Unfractionated Heparin in PCI: a Meta-Analysis

16.9%

12.4%

8.6%9.9%

12.4%13.7%

12.4%

16.9%

Maximum ACT during PCI

0.20 Probability of TIMI major + minor hemorrhage

0.15

0.10

0.05

0.00250 300 350 400 450

Prob

abili

ty o

f maj

or o

r

min

or b

leed

ing

Chew DP. et al.Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials.

Circulation.2001 Feb 20;103(7):961-6

Heparin + GP IIb/IIIa:Efficacy and Bleedingby Tertiles of Maximum ACT

Heparin + GP IIb/IIIa:Efficacy and Bleedingby Tertiles of Maximum ACT

10,0%11,5%

10,3%

0,6% 0,3% 0,4%

6,1%7,3% 7,0%

0,7%1,9% 1,4%

0%

5%

10%

15% placebo

eptifibatide39%39% 37%37%

ACT244 - 292

n=678

ACT244 - 292

n=678

ACT>292n=676

ACT>292n=676

32%32%

ACT292n=676

ACT

Pharmacological Properties of Current Anticoagulants:LMWH

LMWHPredictability in pharmacological profile ++

Cofactor required +++

Renal clearance ++

Non-specific protein binding +

Platelect activation +

Rebound of thrombin generation after discontinuation +

Inhibition of bound thrombin -

Neutralization by platelet factor 4 +

Inhibition of thrombin generation ++

Enoxaparin in PCIsimulated curve

1.0 mg/kg sc steady state + 0.3 mg/kg iv

0.00.20.40.60.81.01.21.41.61.82.0

0 2 4 6 8 10 12 14 16 18 20Time (h)

aXa I

U/m

l

0.3 mg/kg IV at 8 hours or more after lastsc. injection allows “optimal” therapeutic levels

Martin JL. et al.Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention:

The pharmacokinetics of enoxaparin in PCI (PEPCI) study.Catheter Cardiovasc Interv. 2004 Feb;61(2):163-70

Pharmacotherapy Across the Spectrum of CAD/ PCI:Enoxaparin

Ris

k/ (M

orta

lity)

Stableangina

Unstableangina

NSTEMI STEMI

N=18.452Randomized Patients


Study Pts. Comparators Setting Main Results

STEEPLE 3528

IV UFHVs.

IV enoxaparin 0.75 mg/kgVs.

IV enoxaparin 0.5 mg/kgElective PCI

Significant reduction in 48h non–CABG-related bleeding* with Enoxaparin 0.5.

Significant reduction in major bleeding withboth enoxaparin groups.

SYNERGY 10027

IV UFHVs.

Enoxaparin

NSTE-ACS No differences in 30-day death/MI*. No differences in procedural events. Bleeding modestly higher with enoxaparin. Relative advantage of enoxaparin when

therapy crossovers were censored.

ATOLL 910IV UFH

Vs.IV enoxaparin 0.5 mg/kg

STEMI Not significant reduction of 30-day ischemic

outcomes with enoxaparin. No differences in bleeding.

RCT comparing IV enoxaparin vs. UFH

ATOLL Per-Protocol Analysis:Primary End Point/ Main Safety End Point

Collet JP. Et al.A direct comparison of intravenous enoxaparin with unfractionated heparin in primary percutaneous coronary intervention (from the ATOLL trial).

Am J Cardiol. 2013 Nov 1;112(9):1367-72

Pentasaccharide (and Hexadecasaccharide):Fondaparinux anti Fxa

But…Wait! This is an interventional meeting!!!

(Gly)4

Bivalirudin: Bivalent Synthetic Direct Thrombin Inhibitor

Gly-Pro-Arg-Pro(active site binding region)

C-terminal dodecapeptide(exosite 1-binding region)

• Bivalent direct thrombininhibitor

• High specificity andpotency

• Lack of dependence onantithrombin-III

• Effect on clot-bound &free thrombin

• No platelet activation• No inhibition by PF4 and

others• t½ of 25 min

Adapted from:Eric J. Topol, Paul S. Ternstein.

Textbook of Interventional Cardiology, 6th Edition.Elsevier/ Expert Consult.

Pharmacological Properties of Current Anticoagulants:Bivalirudin

BivalirudinPredictability in pharmacological profile +++

Cofactor required -

Renal clearance ++

Non-specific protein binding -

Platelect activation -

Rebound of thrombin generation after discontinuation -

Inhibition of bound thrombin +++

Neutralization by platelet factor 4 +

Inhibition of thrombin generation +++

Pharmacotherapy Across the Spectrum of CAD/ PCI:Bivalirudin

Ris

k/ (M

orta

lity)

Stableangina

Unstableangina

NSTEMI STEMI

N=27.593Randomized Patients


Study Pts. Comparators Setting Main ResultsACUITY(multicenter) 13819

Heparin + GPI Vs.Bivalirudin + GPI Vs.

Bivalirudin

NSTE-ACSPCI 56%

Similar ischemic events. Bleed reduction with bivalirudin monotherapy.

ISAR-REACT 4(multicenter) 1721

UFH + GPI Vs.Bivalirudin

NSTE-ACSPCI 100%⃰

No differences in ischemic events/major bleed. Bleed reduction with bivalirudin.

HORIZONS- AMI(multicenter) 3602

UFH + GPI vs.Bivalirudin (infusion

stopped at the end of PCI)

STEMIP- PPCI

Bleed and mortality reduction with bivalirudin. Similar MACE; acute ST higher with bivalirudin.

EUROMAX(multicenter) 2218

Heparin + optional GPI Vs.Bivalirudin (infusion

prolonged after PCI*)

STEMIP-PCI

Bleed and mortality reduction with bivalirudin. Similar MACE; Acute ST higher with bivalirudin.

BRIGHT(multicenter) 2194

UFH Vs.Bivalirudin Vs.UFH + Tirofiban

STEMINSTEMI

Ischemic events/bleed reduction with bivalirudincompared to both groups.

Bleed reduction with bivalirudin.

HEAT PPCI(single center) 1812

UFH Vs.Bivalirudin (infusion

stopped at the end of PCI)

STEMIP-PCI

Reduction in ischemic events with UFH No difference in bleeding Acute ST higher with bivalirudin.

RCT on Bivalirudin

Historical Trials of Bivalirudin vs. UFH in PCI

Trial ComparatorStrategyIschemicendpoints Bleeding

REPLACE 2 UHP+GPIequivalent

↓↓

ACUITY UHP+GPI equivalent ↓↓

HORIZONS AMI UHP+GPI equivalent ↓↓

ISAR REACT 3 UHP (high dose) equivalent ↓

ISAR REACT 4 UHP+GPI equivalent ↓↓

What about PCI has Changed Over the Last Decade?

Increased use of novel ADP antagonists–More potent and more rapid onset than clopidogrel

Marked decrease in use of GPIs

Development of 2nd and 3rd generation DES–Less thrombogenic than 1st gen DES or BMS

Increased use of transradial PCI

Taken together, these changes have dramatically alteredthe thrombotic and bleeding milieu in the cath lab:

Motivation to reassess antithrombotic therapy!

The Great Debate:UFH vs. Bivalirudin

Bivalirudin vs. Heparin Monotherapy During Primary PCI in STEMI:Three major RCTs

EUROMAX BRIGHT HEAT PPCIN centers 65 82 1N patients 2198 2194 1812-Bivalirudin 1089 735 905-Heparin 460 729 907-Heparin + GPI 649 730 -Heparin mono bolus 60 IU/Kg 100 IU/Kg 70 IU/KgBival. infusion None, low or

High doseMean 4.5 h

Low doseMean 4h -

GPI bailoutBiv. vs UFH 7.9% vs 25.4% 4.4% vs 5.6% 13.5% vs 15.5%

Prasugrel/ Ticagrelor 59% 0% 89%

0,0

2,0

4,0

6,0

8,0

10,0

0 5 10 15 20 25 30

Days from Randomization Date

Even

t Rat

e

Bivalirudin

Heparins with optional GPI 8.4%

Log-rank p = 0.002

Euromax Primary Endpoint:Death or Major Bleed, 30 day

5.1%

Zeymer U. et al.Bivalirudin is superior to heparins alone with bailout GP IIb/IIIa inhibitors in patients with ST-segment elevation myocardial infarction transported

emergently for primary percutaneous coronary intervention: a pre-specified analysis from the EUROMAX trial.Eur Heart J. 2014 Sep 21;35(36):2460-7

Stent thrombosis(ARC definition)

17 (1.6) 6 (0.5) 2.89 (1.14–7.29) 0.02

Definite 17 (1.6) 6 (0.5) 2.89 (1.14–7.29) 0.02Probable 0 (0) 0 (0) – n/aAcute (≤24 hours) 12 (1.1) 2 (0.2) 6.11 (1.37–27.24) 0.007Subacute

(>24 hours to 30 days)5 (0.5) 4 (0.4) 1.27 (0.34–4.73) 0.75

HEAT PPCI:Timing of First MACE Event

Shahzad A. et al.Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI):

an open-label, single centre, randomised controlled trial.Lancet.2014 Nov 22;384(9957):1849-58

Bivalirudin Heparinn % % n

All Events 24 3.4 % v 0.9 % 6

Relative risk = 3.91 (95% CI 1.6 - 9.5) P=0.001

Is HEAT-PPCI an Outlier or an Eye-Opener ?

Meta-analysis of 16 RCTs (n=33,958)comparing bivalirudin vs. heparin-basedanticoagulation for PCI

When pooled results indicated significantheterogeneity, results stratified byindication for PCI (STEMI, NSTEMI,elective) and use of GPIs (planned vs.provisional) in heparin and bivalirudinarms

Cavender MA., Sabatine MS.Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials.

Lancet.2014 Aug 16;384(9943):599-606

Stent Thrombosis: STEMI Trials


Lancet.2014 Aug 16;384(9943):599-606

Bleeding: According to Pattern of GPI Use


Lancet.2014 Aug 16;384(9943):599-606

Findings suggest that reduced bleeding with bivalirudin is directlyrelated to the rate of use of GPI in the comparison group

MACE: All Indications


Lancet.2014 Aug 16;384(9943):599-606

No evidence of between-trial heterogeneity (Q-stat 12.1, p=0.79)Pooled OR 1.09 (95% CI 1.01-1.17) P= 0.0204

Mortality: All Trials


Lancet.2014 Aug 16;384(9943):599-606

No difference in mortality across trialsHORIZONS results appear to be an outlier

What Do the Guidelines Say?Enoxaparin UFH Bivalirudin

Elective PCI (EU 2014) IIa B I B IIa⃰ A

Elective PCI (U.S. 2011) IIb B I C I B

NSTE-ACS (EU 2014) IIa⃰⃰⃰ ⃰ B I C I A

NSTE-ACS (U.S. 2011) IIb B I C I B

STEMI (EU 2014) IIa B I C IIa A

STEMI (U.S. 2013) - - I C I B

B

The Future So Bright:Factor IX Inhibition Aptamers

Aptamers encode their own control agents

Aptamer Control Agent

Woodruff RS., Sullenger BA.Modulation of the Coagulation Cascade Using Aptamers.

Arterioscler Thromb Vasc Biol.2015 Aug 27. pii: ATVBAHA.115.300131. [Epub ahead of print]

pegnivacoginAnticoagulant aptamer

anivamersenActive control agent

Aptamer and Reversal Agent: Mode of Action

ActivatedProtein function

proceeds unimpeeded

InactivatedAptamer with high

specificity and highaffinity selectively

inhibits protein

ActivatedControl agent binds to

aptamer, complex is incapableof inhibiting

target protein andfunction returns to normal

Woodruff RS., Sullenger BA.Modulation of the Coagulation Cascade Using Aptamers.

Arterioscler Thromb Vasc Biol.2015 Aug 27. pii: ATVBAHA.115.300131. [Epub ahead of print]

REG-1 Aptamer Anticoagulant2-Component Controllable Factor IX Inhibitor

Guidelines: or else…Where Is The Knowledge We Have Lost In Information?

2014 ESC/EACTS Guidelines on myocardial revascularization:the Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for

Cardio-Thoracic Surgery (EACTS).Eur J Cardiothorac Surg. 2014 Oct;46(4):517-92

Roughly 5 different antiplatelet drugs × roughly 5 differentanticoagulants × 4 major different clinical settings:

DO THE MATH.!

Balancing Risks and Benefits in ChoosingAdjunct Pharmacological Therapy for PCI

IschemiccomplicationsRecurrent ischemiaMyocardial infarctionIschemia-driven TVRStent thrombosis

HemorrhagicComplicationsAccess site relatedNon-access siteIntracranialGI,GU, otherBlood transfusions

Survival and QOL

Thank you

Months After Randomization

Is there a Need for Ongoing Factor Xa inhibition?

Rivaroxaban(both doses)

HR 0.84(0.74-0.96)ARR 1.7%

mITT p = 0.008ITT p = 0.002

NNT = 59

10.7%

8.9%

Estim

ated

Cum

ulat

ive

Rat

e (%

) Placebo

5113 4307 3470 2664 1831 1079 42110229 8502 6753 5137 3554 2084 831

PlaceboRivaroxaban

2 Yr KM Estimate

No. at Risk

Mega JL. et al.Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLASACS-2-TIMI-51 trial (Anti-Xa Therapy toLower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51).

J Am Coll Cardiol. 2013 May 7;61(18):1853-9

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