2015 Pharmacy - ProCEs3.proce.com/res/pdf/CHS/CHS2015SepHandout.pdf · 2016. 7. 19. ·...

Medication Use in Preparation and Procedure: Stress Testing and Coronary AngioplastyCHS Pharmacy Education Series

ProCE, Inc.www.ProCE.com 1

2015 Pharmacy Education Series

September 16, 2015Medication Use in Preparation and Procedure:p

Stress Testing and Coronary Angioplasty

Featured Speaker:

Jeffrey J. Popma, MDDirector, Interventional Cardiology Clinical ServicesBeth Israel Deaconess Medical CenterProfessor of MedicineHarvard Medical School 1

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September 16, 2015Medication Use in Preparation and Procedure:

Stress Testing and Coronary Angioplasty

Featured Speaker:

Jeffrey J. Popma, MDDirector, Interventional Cardiology Clinical ServicesBeth Israel Deaconess Medical Center

6

It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Popma is a Consultant/Speaker for Abbott and Boston Scientific; has received Grant/Research Support from Abbott, Boston Scientific, Direct Flow Medical, and Medtronic; is a Non‐Vested Equity Stock Shareholder in Direct Flow Medical.

Please note: The opinions expressed in this activity should not be construed as those of the CME/CE provider. The information and views are those of the faculty through clinical practice and knowledge of the professional literature. Portions of this activity may include unlabeled indications. Use of drugs and devices outside of labeling should be considered experimental and participants are advised to consult prescribing information and professional literature.

Professor of MedicineHarvard Medical School



CE Activity Information & Accreditation

ProCE, Inc. (Pharmacist CE)

– 2.0 contact hours

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American Academy of Family Physicians (Physician CME)

– 2.0 contact hours (application pending)

7

Funding:This activity is self‐funded through CHSPSC.

2015 Update In Interventional Cardiology:

Ischemia Detection and Cost-Effective Antithrombotic Agents

Jeffrey J. Popma, MDDirector, Interventional Cardiology

Clinical ServicesBeth Israel Deaconess Medical Center

Professor of MedicineHarvard Medical School

8

Harvard Medical SchoolBoston, MA



Conflict of Interest StatementConflict of Interest Statement

Within Within the the past 24 monthspast 24 months, I , I have have had a financial had a financial interest/interest/arrangement arrangement or affiliation with the or affiliation with the organization(s) listed below.organization(s) listed below.

Company Relationship

Medtronic Institutional Grants

Boston Scientific Institutional Grants; Medical Advisory Board

Abbott Institutional Grants; Medical Advisory Board

9

Direct Flow Medical Institutional Grants, Consultant, Nonvested Equity

Tendyne Institutional Grants

CardiAQ Institutional Grants

• Identify the advantages and disadvantages of exercise versus drug induced hyperemia in stress testing

• Outline the pro and cons of the medications used in stress

ObjectivesObjectives

testing; including, dosing, administration, side effects and cost considerations

• Describe anticoagulant/antiplatelet medication strategies in PCI

• Explain the history and current dosing recommendations for tirofiban in PCI

10

for tirofiban in PCI

• Discuss clinical outcomes literature using the high dose bolus strategy for tirofiban compared to alternatives

• Discuss the literature related to medication selection in the cath lab



But first, let’s review the complexities of But first, let’s review the complexities of managing patients with ischemic heart managing patients with ischemic heart disease in 2015 disease in 2015 –– it has changed it has changed alotalot

•• Historic Notes Historic Notes Humble BeginningsHumble Beginnings

•• Importance of Ischemia DetectionImportance of Ischemia Detection

•• Appropriate Use CriteriaAppropriate Use Criteria

•• Incredible Marketing CompetitionIncredible Marketing Competition

11

•• Incredible Marketing CompetitionIncredible Marketing Competition

•• Mandate for Cost Effective Decision MakingMandate for Cost Effective Decision Making

Dr. Andreas Dr. Andreas GruentzigGruentzig in 1977in 1977

12



Humble Beginnings of PCI Humble Beginnings of PCI 38 38 Years AgoYears Ago

13GruntzigGruntzig

A.B. A.B. -- 38 year old man with angina38 year old man with angina

14



Original catheterization laboratory

Source DocumentationSource Documentation

laboratoryrecord of the first successful PTCA procedureUniversitatpital ZurichSeptember 16, 1977Compliment of E

15

Compliment of E. Schneider, M.D.

30 Year 30 Year University University Hospital, Hospital, Zurich Sept, 2007Zurich Sept, 2007

16



“Percutaneous Coronary Intervention” now “Percutaneous Coronary Intervention” now comprises all of the following:comprises all of the following:

Dates TechniqueDates Technique

1977-1991 Balloon angioplasty

1991-1994 Directional atherectomy, rotational atherectomy, laser angioplasty

1994 2003 B t l t t

17

1994-2003 Bare metal stents

2003-2015 Drug eluting stents

DES in 2006DES in 2006 -“a million

ticking time bombs”

18



A Changing Healthcare A Changing Healthcare EnvironmentEnvironment

Primarily related to inappropriate

19

inappropriate assessment of lesion severity in elective PCI

• 71 year old man• Vague and

i i t t i

71 71 year old man with year old man with inconsistent chest paininconsistent chest pain

inconsistent angina with exertion

• No episodes of pain at rest or without exertion

• Moderate anterior defect on sestamibiscanning at 7 minutes

20

scanning at 7 minutes• Single vessel coronary

artery disease by cath

PCI? Or No PCI?



Predicting Vulnerable Plaque

21

Untimely suddencardiac death at 58

Ischemic CAD

“Russert had earlier been diagnosed with asymptomatic coronary artery disease, but it was well-controlled with medication and exercise, and he had performed well on a stress test in late April. An

22

autopsy showed that he had an enlarged heart and an acute occlusion of the left anterior descending artery.”



The COURAGE Has Changed How We Practice . . . .

23Boden WE et al N Engl J Med 2007;356:1503-16

Survival Free of Death from Any Cause Survival Free of Death from Any Cause and Myocardial Infarctionand Myocardial Infarction

1.0 Optimal Medical Therapy (OMT)

0 0

0.5

0.6

0.7

0.8

0.9

PCI + OMT Hazard ratio: 1.0595% CI (0.87-1.27)P = 0.62

24

Number at Risk

Medical Therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Years0 1 2 3 4 5 6

0.0

7

Boden WE et al N Engl J Med 2007;356:1503-16



The presence of documented ischemia was a critical determinant of outcome in COURAGE

25

• Evaluated patients with pre- and post-MPS (6-18 months)

• Determined percent ischemic myocardium

• >5% reduction in amount of ischemic myocardium

Shaw, LJ Circulation 2008;117:1283-1291

COURAGE Nuclear SubstudyCOURAGE Nuclear Substudy

•• The average decrease in % ischemic The average decrease in % ischemic myocardium was greater among PCImyocardium was greater among PCI--OMT OMT patients then among OMT alone patients (patients then among OMT alone patients (--2 7% vs2 7% vs --0 5% p=0 0001)0 5% p=0 0001)2.7% vs. 2.7% vs. --0.5%, p=0.0001)0.5%, p=0.0001)

•• More PCIMore PCI--OMT patients achieved significant OMT patients achieved significant ischemia reduction (33% vs. 19%, p=0.0004). ischemia reduction (33% vs. 19%, p=0.0004).

•• This difference was more pronounced This difference was more pronounced among patients who had moderate/severe among patients who had moderate/severe ischemia at baselineischemia at baseline

26

ischemia at baseline. ischemia at baseline.

•• Nearly twice as many OMTNearly twice as many OMT--PCI patients had PCI patients had ““no ischemiano ischemia”” at followat follow--up.up.




COURAGE: Relationship Between Residual Ischemia on MPS and Outcome

27


IInternational nternational SStudy tudy CComparing omparing HHealth ealth EEffectiveness with ffectiveness with MMedical and edical and

IInvasive nvasive AApproachespproaches

• Patients with ≥ moderate ischemia randomly assigned to “cath+revasc” or “no cath” after CTA excludes left main disease

28

• Submitted February 2010 -> Funded 2011

• Judith Hochman, NYU PI

• Recruitment Ongoing



Our focus has changed for the

management of patients with stable

coronary artery disease – demonstration

of ischemia is of paramount importance

d i t l t f ti

29

and an integral part of our practice

guidelines

• PCI has been designated the most overused medical procedure by AARP

The result has been . . . .The result has been . . . .

p y

• Catheterization laboratory volumes fell by 20-30% -- now stabilized with a 1-5% increase

• Increased use of ‘”in-lab” stress testing using FFR

30

FFR

• Patients now come to the cath lab with an exercise test – when applicable









31




83 yo active physicianStandard ETT showed 1.5 mm horizontal ST depression in the inferior leads but atypical symptoms

Repeated nuclear imaging study to 8.2 mins on Br ce protocol

32

mins on Bruce protocol to MHR 140 (100% predicted) and BP 160 systolic



What did walking stress What did walking stress exercise accomplish?exercise accomplish?

G d d i i h t t• Graded increase in heart rate

• Graded increase in blood pressure

• Graded Increase in cardiac contractility

• Graded increase in coronary flow

33

• Differential blood flow away from areas with coronary stenoses > 50%

Yet one third to one half of all Yet one third to one half of all stress tests are performedstress tests are performedstress tests are performed stress tests are performed

using pharmacologic agentsusing pharmacologic agents

When should they be When should they be

34

performed?performed?



The ACC appropriateness utilization criteria (AUC) recommend that pharmacologic stress testing is instituted when contraindications to routine exercise stress exist or when the patient is unable to exercise because of debilitating conditions

• Elderly patients with decreased functional capacityElderly patients with decreased functional capacity

• Patients with chronic debilitation and possible CAD

• Younger patients with functional impairment due to injury, arthritis, orthopedic problems, peripheral neuropathy, myopathies, or peripheral vascular disease, in which a maximal heart rate is not easily achieved with routine

35

maximal heart rate is not easily achieved with routine exercise stress testing

• Other cases, including patients taking beta-blockers or other negative chronotropic agents that would inhibit the ability to achieve an adequate heart response to exercise

Agents Vasodilator Chronotrope Ionotrope

Vasodilators

Pharmacologic Stress AgentsPharmacologic Stress Agents

Vasodilators

Dipyridamole +++ -- --

Adenosine +++ -- --

Regadenoson +++ -- --

Ionotropes

36

p

Dobutamine --- ++ +++

Enoximone --- ++ +++



DipyridamoleDipyridamole

Mechanism: Dipyridamole is an indirect coronary vasodilator that works by increasing intravascular adenosine levels. This occurs by the inhibition of intracellular reuptake and deamination of adenosine. However, the increase in coronary blood flow induced by dipyridamole is less predictable than that of adenosine.

In one comparative study of dipyridamole and adenosine, 66% of patients (10 of 15) receiving dipyridamole versus 80% of

37

of patients (10 of 15) receiving dipyridamole versus 80% of patients (12 of 15) receiving adenosine had a maximal hyperemic response. However, this difference may not be apparent clinically.

Source: Medscape

DipyridamoleDipyridamoleIndications:

• Patients taking beta-blockers or other negative chronotropicagents that would inhibit the ability to achieve an adequateagents that would inhibit the ability to achieve an adequate heart rate response to exercise are also appropriate candidates for vasodilator stress.

• Patients with left bundle branch block or a ventricular pacemaker (particularly those with severely diseased AV nodes or status post-AV node

38

Dosage:

Dipyridamole IV infusion 0.56 mg/kg intravenously over a 4-minute period (142 mcg / kg / min) followed by dye

Source: Medscape



DipyridamoleDipyridamoleAbsolute Contraindications:

• Patients with active bronchospasm or patients being treated for reactive airway disease should not be administeredfor reactive airway disease should not be administered dipyridamole because this can lead to prolonged bronchospasm

• Patients with more than first-degree heart block (without a ventricular demand pacemaker) should not undergo dipyridamole infusion because this may lead to worsening f th h t bl k

39

of the heart block.

• Patients with an SBP of less than 90 mm Hg should not undergo dipyridamole stress testing because of the potential for further lowering of the blood pressure.

Source: Medscape

AdenosineAdenosineMechanism: Once transported across cell membranes, adenosine interacts and activates the A1 and A2 cell surface receptors In the vascular smooth muscles adenosinereceptors. In the vascular smooth muscles, adenosine primarily acts by activation of the A2 receptor, which stimulates adenylate cyclase, leading to an increase in cyclic adenosine monophosphate (cAMP) production. Increased cAMP levels inhibit calcium uptake by the sarcolemma, causing smooth muscle relaxation and vasodilation. In cases of severe vessel stenosis or total occlusions with

40

compensatory collateral circulation, a decrease in coronary blood flow may occur in the diseased coronary artery, thus inducing ischemia via a coronary steal phenomenon. This regional flow abnormality also induces a perfusion defect during radionuclide imaging.Source: Medscape



AdenosineAdenosineIndications:

• Patients taking beta-blockers or other negative chronotropict th t ld i hibit th bilit t hi d tagents that would inhibit the ability to achieve an adequate

heart rate

• Patients with left bundle branch block or ventricular pacemaker should undergo pharmacologic vasodilator stress because exercise stress often produces a false-positive perfusion defect in the interventricular septum.

41

Dosage

• Adenosine IV 140 mcg/kg/min infusion for 6 minutes; radiopharmaceutical dye initiated at midpoint of this infusion

Source: Medscape

AdenosineAdenosineAbsolute Contraindications:

• Patients with active bronchospasm or patients being treatedPatients with active bronchospasm or patients being treated for reactive airway disease

• Patients with more than first-degree heart block (without a ventricular-demand pacemaker) should not undergo adenosine infusion because this may lead to worsening of the heart block.

• Patients with an SBP less than 90 mm Hg should not

42

gundergo adenosine stress testing because of the potential for further lowering of the blood pressure.

• Patients using dipyridamole or methylxanthines (eg, caffeine and aminophylline)

Source: Medscape



Mechanism:

LexiScan (regadenoson)

• A coronary vasodilator; an A2A adenosine receptor agonist

• Increases coronary blood flow

- Low affinity agonist for the A2A adenosine receptor with 10-fold lower affinity for the A1 adenosine receptor

W k ffi it f th A2B d A3 d i t

43

- Weak affinity for the A2B and A3 adenosine receptors

Source: Medscape

Indications:

• Patients taking beta-blockers or other negative chronotropic


agents that would inhibit the ability to achieve an adequate heart rate response to exercise are also appropriate candidates for vasodilator stress.

• Patients with left bundle branch block or a ventricular pacemaker (particularly those with severely diseased AV nodes or status post-AV node

44

p

Dosage

• Regadenoson IV injection (0.4 mg) over 10- 30 seconds followed by saline flush and radiopharmaceutical dye

Source: Medscape



Absolute Contraindications:

• Patients with active bronchospasm or patients being treated for reactive airway disease should not be administered


for reactive airway disease should not be administered dipyridamole because this can lead to prolonged bronchospasm

• Patients with more than first-degree heart block (without a ventricular demand pacemaker) should not undergo dipyridamole infusion because this may lead to worsening f th h t bl k

45

of the heart block.

• Patients with an SBP of less than 90 mm Hg should not undergo dipyridamole stress testing because of the potential for further lowering of the blood pressure.

Source: Medscape

Dosage and Side EffectsDosage and Side Effects

46

Adapted from Hinkle et al. http://pharmacyce.unm.edu/nuclear_program/freelessonfiles/Vol13Lesson2.pdf



Administration Time

• 140mcg/kg/min over 6 minutes• The radionuclide is injected at midpoint (3 Adenosine j p (

minutes of the infusion)Adenosine

• 0.14mg/kg/min for 4 minutes• Following the dipyridamole infusion, inject the

radionuclide within 5 minutesDipyridamole

47

• 0.4mg (5ml) over ~10 seconds and then followed by a 5ml saline flush

• Wait 10-20 seconds then administer the radionuclide

Regadenoson

• J Med Econ. 2013;16:449-460.

Published Evidence

ADVANCE-MPI 1 ADVANCE-MPI 2

• Adenosine vs. regadenoson

• SPECT MPI to detect reversible perfusion defects

• 1 231 patients

• Adenosine vs. regadenoson

• SPECT MPI to detect reversible perfusion defects

• 787 patients1,231 patients• Non-inferior agreement

rates• Tolerability focus

787 patients• Non-inferior efficacy• Tolerability focus

48



Stop infusion earlier if: • Systolic blood pressure less than 80 mm Hg

S t ti i t t d d

For all three agents

• Symptomatic, persistent second-degree or complete heart block

• Wheezing

• Persistent chest pain or ST depression

• Signs of poor perfusion (pallor, cyanosis, cold

49

skin)

• Technical problems with the monitoring equipment

• Patients’ request

Urgent / Emergent Use (for severe or i t t d ti )persistent adverse reactions):

Aminophylline 50-100 mg (range: 50-250 mg) by slow intravenous injection over 30-60

50

seconds



5454--yy--o. man, PTCA prox LAD 8 years ago,o. man, PTCA prox LAD 8 years ago,stable angina, occluded distal LCxstable angina, occluded distal LCx

4848--yy--o. man, aborted sudden death,o. man, aborted sudden death,No other stenosis at angioNo other stenosis at angio

FFR can provide some answers

AdenosineAdenosine AdenosineAdenosine

51

John McB. Hodgson, M.D.

•• Intermediate stenosisIntermediate stenosis

•• MildMild--toto--moderate stenosismoderate stenosis

•• Non flow limiting stenosisNon flow limiting stenosis

•• Non significant stenosisNon significant stenosis

•• Gross irregularityGross irregularity

•• ......

AngiographistAngiographist’’s glossarys glossaryFFR = 50 / 90 = 0.55FFR = 90 / 93 = 0.97

The most commonly used The most commonly used agent for intracoronary agent for intracoronary

vasodilation is:vasodilation is:vasodilation is: vasodilation is:

Adenosine, 140 mcg/kg/min Adenosine, 140 mcg/kg/min infusion for 2infusion for 2--4 minutes 4 minutes

52

monitoring BP for a 10% drop monitoring BP for a 10% drop in blood pressurein blood pressure



Lesions warranting Lesions warranting PCI identifiedPCI identified

PCI performed onPCI performed onPCI performed on PCI performed on

FFRFFR--GuidedGuided AngioAngio--GuidedGuided

FAME: Flow FAME: Flow Chart (N=1005)Chart (N=1005)

PCI performed onPCI performed onindicated lesionsindicated lesionsRandomizedRandomized

indicated lesions indicated lesions only if FFR ≤0.80only if FFR ≤0.80

Composite of death, Composite of death, MI and repeat revasc.MI and repeat revasc.

(MACE) at 1 year (MACE) at 1 year

Primary EndpointPrimary Endpoint

53

Individual rates of death, MI, Individual rates of death, MI, and repeat revasc., MACE, and repeat revasc., MACE,

and functional status at 2 yearsand functional status at 2 years

Key Secondary EndpointsKey Secondary Endpoints

FAME: 2 FAME: 2 Year Survival Free of MACEYear Survival Free of MACE

FFRFFR--GuidedGuided

AngioAngio--GuidedGuided

730 days730 days

54

4.5%4.5%



An FFR > 0.080 was highly An FFR > 0.080 was highly predictive of the absence ofpredictive of the absence ofpredictive of the absence of predictive of the absence of clinical events for two years.clinical events for two years.

Now used in 10Now used in 10--20% of cases 20% of cases

55

with stable anginawith stable angina

Physiologic Measures in Intermediate Lesions

56

FFR Preferred over Doppler

Kushner et al JACC 2009;54;2205-2241



HeartFlowHeartFlow –– CT CT -- FFRFFR

57

Computational Flow DynamicsUsed to Determine FFR

Single study for Structure and Function

Guidelines Provide a Road Map for TherapyGuidelines Provide a Road Map for Therapy

58

Levine Circulation. 2011;124:e574-e651



Guidelines Provide a Road Map for TherapyGuidelines Provide a Road Map for Therapy

59Jneid H et al Circulation on-line August 14, 2012

ACC-AHA Levels Of Recommendation

Class

Level of Evidence

60Wright et al; JACC. 2011;57;1920-1959 Levine Circulation. 2011;124:e574-e651



2011 PCI Guidelines2011 PCI Guidelines

FFR has been incorporated into PCI Guidelines

61

Are Guidelines Sufficient (or Useful)?

Nearly 50% of our guidelines are based on “expert opinion” rather than “clinical trial evidence”

62Tricoci et al JAMA 2009 301:831-841



2012 ACC-SCAI Appropriateness Criteria

63Patel et al JACC 2012 on line

Coronary revascularization is appropriate

Definition Used for Analysis

Coronary revascularization is appropriate when the expected benefits in terms of survival and health outcomes (symptoms, functional status, and/or quality of life) exceed the expected negative

f th d

64

consequences of the procedure

Patel et al JACC 2009 53 (February): 530-553



Appropriateness Criteria

Stable Angina and Asymptomatic Coronary Artery

Disease

65Patel et al JACC 2009 53 (February): 530-553

Appropriateness: Low Risk Stable CAD




Appropriateness: Intermediate Risk Stable CAD


Appropriateness: High Risk Stable CAD




European Guidelines: Indications for RevascularizationEuropean Guidelines: Indications for Revascularization

The ESC GuidelinesThe ESC Guidelines have supported the use of revascularization in those patients with a substantial portion of

69Wijns et al EHJ 2010

myocardium (> 10%) at risk







70






Role of the GP IIb/IIIa Receptorclopidogrel, prasugrel, ticagrelor, cangrelor

ASA

UFH, LMWH, bivalirudin

AGGRASTAT inhibits the final step in platelet aggregation

71

GP IIb/IIIa inhibitor Class Overview

Product information presented in this table is not necessarily indicative of clinical efficacy, safety or improved treatment outcomes. Aggrastat and Integrilin (eptifibatide) have not been compared in head-to-head clinical trials. Please refer to Prescribing Information for each product.

72



Frequency of Vulnerable Plaques

• 65% of patients with CAD risk factors have evidence for at least one thin-capped fib hfibroatheroma

• 25% of patients dying of noncardiacdisease without prior history of ACS have evidence of previous plaque rupture

Cheruvu PK, Finn AV, Gardner C, et al. Frequency and distribution of thin-cap fibroatheroma and ruptured plaques in human coronary arteries: a pathologic study. J Am Coll Cardiol 2007;50: 940-9.

73

There are a myriad of decisions to make in patients who present with acute coronary syndromes!

Early Invasive

vs. Selective Invasive

Which Anticoag lant?What

NSTEMI

Invasive Anticoagulant?•LMWH•UFH•DTI

Which Antiplatelet?

•Clopidogrel•Prasugrel•Ticagrelor

•GPI

600 mg vs. 300 mg

Clopidogrel?

What Dose of ASA?

Start Meds

Upstream vs. In

Cath Lab?Bolus only

GPI, Duration of infusion?

IC or IV?

What if Pt.

needs a CABG?

LMWH=Low Molecular Weight HeparinUFH= Unfractionated HeparinDTI= Direct Thrombin Inhibitor



PRISM-PLUS: CLINICAL OUTCOMES

• ≈ 1500 patients randomized trial with low dose tirofiban and heparin versuslow dose tirofiban and heparin versus heparin alone

• Early 48 hour ischemic endpoint

• Used for a labeled indication for unstable angina

FOR INTERNAL EDUCATION PURPOSES ONLY – NOT TO BE DISTRIBUTED

75

• Similar studies with abxicimab and later with eptifibatide were less beneficial with 30 day outcomes

PRISM-PLUS: clinical outcomes

20

Heparin (n = 797) Tirofiban (n = 773)

P=0 01 P=0 006 P=0 03 P=0 06

Pat

ient

s (%

)

2.6

8.3

11.9

15.3

0 9

4.9

8.7

12.3

5

10

15

20 P=0.01 P=0.006 P=0.03 P=0.06

0.90

48 hours 7 days 30 days 6 months

Death/MI

PRISM PLUS Investigators N Engl J Med 1998;338:1488-97

Confidential76



PRISM-PLUS: safety outcomes

Placebo (n = 797) Tirofiban (n = 773)

P=NS

Pat

ient

s (%

)

0 8

8

2.8

0 8 0 31.4

10.5

4

1.90 52

4

6

8

10

12 P=0.23 P=0.21 P=0.44P=0.07

0.8 0.8 0.3 0.50

TIMI major bleeding

TIMI minor bleeding

Transfusions Platelets ≤90,000mm3

Platelets ≤50,000mm3

PRISM PLUS Investigators N Engl J Med 1998;338:1488-97

Confidential77

• Early studies were all performed with balloon angioplasty

GPIIbGPIIb--IIIaIIIa and PCI in the 1990sand PCI in the 1990s

Why So Popular?Why So Popular?

• Unfractionated heparin was the sole agent for PCI

• Abciximab superior to unfractionated heparin

- 10,000 U UFH and 1,000 U/hr infusion

- Less elevation of 3x CPK-MB

- At a substantial cost of bleeding

78

At a substantial cost of bleeding

• Eptifibatide – low dose – borderline IMPACT Trials

• Tirofiban – low dose – negative Restore Trial

• TARGET Trial – superiority for abciximab v v. tirofiban



Adequate Platelet Inhibition Reduces MACE

14.416

485 patients undergoing PCI receiving a GP IIb/IIIa inhibitor

P=0.006

6.4

4

8

12

% M

AC

E

*

0< 95% ≥ 95%

MACE = Major Adverse Cardiac Events

% Platelet Inhibition at 10 minutes

Steinhubl et al. Circulation 2001;103:2572-8 79

Mechanism of Action

AGGRASTAT is a reversible antagonist of fibrinogen that binds to the GP IIb/IIIa receptor, thereby blocking the final common pathway to platelet aggregation.

Competitive removal of already bound fibrinogen results in p y gdisaggregation of newly formed thrombus.

Platelet inhibition is reversible following cessation of the infusion. AGGRASTAT has a half-life of approximately 2 hours.

Confidential

80Goto et al. J Am Coll Cardiol 2004;44:316-23



Why a Dose Evolution?

10 mcg/kg bolus used in TARGET provided 61-66% IPA* at 15-45 minutes vs. 90-94% IPA with Reopro (abciximab)

The degree of early platelet inhibition induced by the 10 mcg/kg bolus g y p y g gwas not optimal in TARGET and was never FDA approved

Therefore, new bolus dosing finding studies were conducted to obtain optimal early platelet inhibition →

25 mcg/kg bolus at the time of PCI provides > 90% IPA*

within 10 minutes

FDA approved in October 2013

Kabbani et al. Am J Cardiol 2002;89:647-50Schneider et al. Am J Cardiol 2002;90:1421-3

*Inhibition of platelet aggregation, measured by Turbidometric aggregation in response to 20 µM ADP

81

Bare metal stents improved outcomes by reducing the

GPIIbGPIIb--IIIaIIIa in the late 1990sin the late 1990s

Enter Bare Metal Stents . . . ..Enter Bare Metal Stents . . . ..

• Bare metal stents improved outcomes by reducing the need for emergency surgery

• Eptfibatide – double bolus – higher infusion – lower heparin dose

• Tirofiban – higher bolus dose

More emphasis on bleeding with combination

82

• More emphasis on bleeding with combination unfractionated heparin and GPIIb-IIIa inhibitors

• Aspirin and clopidogrel became standard in the post-procedural period



Anticoagulant choicesAnticoagulant choices

Unfractionated heparin

LMW Heparin

83

BivalirudinFondaparinux

• As a selective anti-thrombin agent the story was

Early 2000sEarly 2000s

Enter Enter BivalirudinBivalirudin ……

As a selective anti thrombin agent, the story was compelling to use bivaluridin to replace heparin

• Another unrecognized effect was to use bivalirudin in acute coronary syndromes

• Focused on “Acuity Bleeding” endpoints

• New terminology of “Net Clinical Benefit”

84

New terminology of Net Clinical Benefit

• Bivaludin was the agent of choice in stable and unstable coronary syndromes due to reduced bleeding and no increase in clinical events



ACUITY: BivalirudinACUITY: BivalirudinMajor Bleeding EndpointMajor Bleeding Endpoint

15 Estimate P (log rank)

5 7%UFH/enoxaparin + GPI (N=4603)

UFH/enoxaparin + GPI vs bivalirudin + GPI vs bivalirudin alone

5

10

Cu

mu

lati

ve E

ven

ts (

%) 5.7%UFH/enoxaparin + GPI (N=4603)

Bivalirudin + GPI (N=4604) 0.415.3%Bivalirudin alone (N=4612) <0.00013.1%

–

85

Stone GW, et al. N Engl J Med. 2006;355:2203-2216.

0

0 5 10 15 20 25 30 35

Days from Randomization

Tremendous Clinical Trial Data with Tremendous Clinical Trial Data with BivalirduinBivalirduin

86



Tremendous Clinical Trial Data with Tremendous Clinical Trial Data with BivalirduinBivalirduin

87

Cavender, M. and Sabatine, M. Lancet 2014;384:599-606

Acute stent thrombosis with bivalirudinwas attributed to shorter infusion and lower dose

CONCLUSIONS: In patients with an acute coronary syndrome the rates of major

88

CONCLUSIONS: In patients with an acute coronary syndrome, the rates of major adverse cardiovascular events and net adverse clinical events were not significantly lower with bivalirudin than with unfractionated heparin. The rate of the composite of urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events was not significantly lower with a post-PCI bivalirudininfusion than with no post-PCI infusion. (Funded by the Medicines Company and Terumo Medical; MATRIX ClinicalTrials.gov number, NCT01433627.)

Valgimigli N Engl J Med 2015;373:997-1009



• As with any novel agent that has a 15

Bivaluridin Today

year history – the use of bivalirudinundergoes constant challenges

- In STEMI – HEAT-PCI- In elective cases – perceived less

bleeding with radial approach

89

bleeding with radial approach- More emphasis on cost saving

• Stable angina:

• No pre treatment with P2Y12 agents

General themes

• No pre-treatment with P2Y12 agents due to potential need for bypass surgery

• Radial v. femoral approach

• Bivalirudin v unfractionated heparin

90

• Bivalirudin v. unfractionated heparin

• Addition of eptifibatide v. tirofiban in the setting of complex morphology



• Unstable angina-NSTEMI

• ? pre treatment with P2Y12 agents

General themes

• ? pre-treatment with P2Y12 agents due to potential need for bypass surgery


• Bivalirudin v unfractionated heparin

91



• STEMI

P t t t ith P2Y12 t d

General themes

• Pre-treatment with P2Y12 agents due to infrequent need for bypass surgery



92




New P2Y12 InhibitorsNew P2Y12 Inhibitors

Replacements to Replacements to clopidogrelclopidogrel

• Prasugrel

• Ticagrelor

• Cangrelor

93

g

15

HR 0.81Clopidogrel

12.1

138events

N=18,000

5

10

(0.73-0.90)P=0.0004

Prasugrel

En

dp

oin

t (%

)

12.1

9.9

CV Death / MI / Stroke

NNT = 46

0

5

0 30 60 90 180 270 360 450

Days

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.8

2.4

35events TIMI Major

NonCABG Bleeds

NNH = 167

Wiviott et al NEJM 2007 94



TRITON‐TIMI 38: Stent Thrombosis(ARC Definite + Probable)

3

Clopidogrel2.4(142)

Any Stent at Index PCIN=12,844

1

2

HR 0.48Prasugrel

1.1 (68)

nd

Po

int

(%)

Days

00 30 60 90 180 270 360 450

0 8P<.0001

NNT=77

En

Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.95

TRITON‐TIMI 38: Net Clinical BenefitBleeding Risk Subgroups

Post‐hoc analysis

No

YesPriorStroke / TIA

Risk (%)+ 37

16

< 60 kg

< 75

≥ 75

NoStroke / TIA

Age

Wgt

-16

-1

-16

+3

Pint = .006

Pint = .18

96

OVERALL

≥ 60 kg

0.5 1 2

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = .36

Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.



6

7Clopidogrel

5.8

6.9

6

7

Myocardial infarction Cardiovascular death

Ticagrelor: PLATO

5

4

3

2

1

Cu

mu

lati

ve in

cid

ence

(%

) Ticagrelor

HR 0.84 (95% CI 0.75–0.95), p=0.005

4

3

2

1

Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79 (95% CI 0.69–0.91), p=0.001

5

um

ula

tive

inci

den

ce (

%)

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,560

8,678

8,405

8,520

8,177

Days after randomisation

6,703

6,796

5,136

5,210

4,109

4,191

0 60 120 180 240 300 360

0

C

8,279

HR 0.84 (95% CI 0.75 0.95), p 0.005

0 60 120 180 240 300 360

0HR 0.79 (95% CI 0.69 0.91), p 0.001

9,291

9,333

8,865

8,294

8,780

8,822

8,589

Days after randomisation

7079

7119

5,441

5,482

4,364

4,4198,626

Cu

N Engl J Med. 2009 Sep 10;361(11):1045-57. Epub 2009 Aug 30.97

GPIIb/IIIa Antagonists in ACS:30‐Day Death/MI in ACS

11.8%12Percent Death/MI

Odds Ratio 0.91P 0 015

Placebo (N=13,105)

10.8%10

8

6

4

P=0.015

Major Bleeding – 2.4% GPIIb/IIIa’s

1.4% Placebo

Boersma E, et al. Lancet 2002;359:189-198

GPIIb/IIIa antagonist (N= 18,297)

0 7 14 21 28

2

0

Days

98



Troponin (‐) Patients Probably Don’t Benefit from IV Antiplatelet Agents (GPI)

Death or MI by 30 Days (%)25 Placebo

GP IIb/IIIa Antagonist19.6

5.8

13.0

4.3

19.0

11.0

4.9 4.9

10.3

5.2 5.7

9.6

5

10

15

20

GP IIb/IIIa Antagonist

0

CAPTURE1 PRISM2 PARAGON B 3Troponin + Troponin - Troponin + Troponin - Troponin + Troponin -

1. Hamm CW, et al. N Eng J Med. 1999;340:1623-1699.2. Heeschen C, et al. Lancet. 1999; 354:1757-1762.3. Newby LK, et al. Circulation. 2001;103:2891-2896.

99

CHAMPION PHOENIX Study Design

Cangrelor2 bolus & infusion (30ug/kg; 4ug/kg/min)

Clopidogrel600 mg oralCHAMPION PHOENIX

N = 10,900 MITT

SA/ NSTE-ACS/ STEMI

Patients requiring PCI1

P2Y12 inhibitor naïve

OR Placebo3 oral (right before PCI or right after, per physicia

Placebo2 bolus & infusion Placebo oral

PCI ~30’

OR Clopidogrel3 (600 mg or 300 mg oral, per physician)

Rand

1 2 to 4 hours0

p g ( g g , p p y )

1Randomization occurred once suitability for PCI was confirmed either by angiography or STEMI diagnosis.Double blind study medication was administered as soon as possible following randomization.

2Study drug Infusion (cangrelor or matching placebo) was continued for 2-4 hours at the discretion of the treating physician. At the end of the infusion patients received a loading dose of clopidogrel or matching placebo and were transitioned to maintenance clopidogrel therapy.

3Clopidogrel loading dose (or matching placebo) was administered as directed by the investigator. At the time of patient randomization, a clopidogrel loading dose of 600 mg or 300 mg was specified by the investigator.

MITT=modified intent-to-treat; NSTE-ACS=non-ST-elevation acute coronary syndrome; PCI=percutaneous coronary intervention; SA=stable angina; STEMI=ST-elevation MI.

Bhatt DL et al. N. Engl. J. Med. 2013; 368: 1303-13 100



Primary Efficacy Outcomes at 48 Hours, MITTCangrelor(N=5472)

Clopidogrel(N=5470)

OR (95% CI) P-value

Primary Analysis Adjusted1y y j

Death/MI/IDR/ST257/5470

(4.7%)322/5469

(5.9%)0.78

(0.66, 0.93)0.005

Secondary Efficacy Outcomes at 48 Hours, MITTStent thrombosis (keysecondary endpoint)

46/5470 (0.8%)

74/5469 (1.4%)

0.62 (0.43,0.90)

0.01

MI 207/5470 (3.8) 255/5469 (4.7) 0.80 (0.67,0.97) 0.02

1. The logistic model was adjusted for baseline status and clopidogrel dose. P value of 0.006 shown on the KM curve is log rank p value.

MI 207/5470 (3.8) 255/5469 (4.7) 0.80 (0.67,0.97) 0.02

Q-wave MI 11/5470 (0.2) 18/5469 (0.3) 0.61 (0.29,1.29) 0.19

IDR 28/5470 (0.5) 38/5469 ( 0.7) 0.74 (0.45,1.20) 0.22

Death 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52,1.92) >0.99

CV Death 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52,1.92) >0.99

Bhatt DL et al. N. Engl. J. Med. 2013; 368: 1303-13 101

Delay of Onset from Oral Agents in STEMI Patients

95100

Ticagrelor Prasugrel

Both ticagrelor and prasugrel exhibit an initial delay in the onset of antiplatelet effects in STEMI patients

76.284.3

95

48.3

8590.3

82.5

30405060708090

100

% I

nh

ibit

ion

0

11.7

00

1020

1 hour 2 hours 6 hours 24 hours Day 5Post Randomization

Alexopoulos D, et al. Circ Cardiovasc Interv. 2012;5:797-804 102



FABOLUS PRO Trial

100 STEMI patients undergoing percutaneous coronary intervention

Valgimigli M, et al. J Am Coll Cardiol Intv 2012;5:268-277103







104






AGGRASTAT History

Merck launches Aggrastat

• PRISM & PRISM-PLUS

TARGET misses primary endpoint (10 µg/kg bolus)

• Incorrect bolus doseM k h l

Aggrastat high-dose bolus (HDB) regimen approved in Europe

Aggrastat HDB FDA approved in

United States (25 µg/kg bolus)

1998 2000 2010

2013

• Loading Infusion Regimen

Rapid ACS adoption

• Merck halts promotion in US

TENACITY study d

(25 µg/kg bolus)

Aggrastat HDB receives

(25 µg/kg bolus)

Aggrastat HDB d f STEMI*

1998-2000 2004 2011 2013

Rapid ACS adoptionAggrastat becomes

most used small molecule GPI

announced (25 µg/kg bolus)

Later put on hold due to financial reasons

Class I recommendation in ACC/AHA/SCAI guidelines

All 3 GPIs given equal recommendation

approved for STEMI* in Europe

GPIs not approved for STEMI in US

* Use of GP IIb/IIIa Inhibitors in STEMI not approved by FDA. Please refer to products’ full prescribing information.

Aggrastat HDB continues to be the most-used GPI worldwide

105

Prescribing Information

Indication

AGGRASTAT is indicated to reduce the rate of thrombotic cardiovascular events (combined endpoint of death, myocardial infarction, or refractory ischemia/repeat cardiac procedure) in patients with non-ST elevation acute coronary syndrome (NSTE-ACS).

Dosage and Administration

High-Dose Bolus (HDB) Regimen

Administered intravenously: 25 µg/kg within 5 minutes and thenAdministered intravenously: 25 µg/kg within 5 minutes and then 0.15 µg/kg/min for up to 18 hours (no minimum specified)

In patients with CrCl ≤60 mL/min, use the full bolus and halve the maintenance infusion.

106



Prescribing Information

Contraindications

Known hypersensitivity to any component of AGGRASTAT

History of thrombocytopenia with prior exposure to AGGRASTAT

Active internal bleeding, or history of bleeding diathesis, major surgical procedure or severe physical trauma within previous month

Warnings and Precautions

AGGRASTAT can cause serious bleeding (If bleeding cannot be controlled discontinue AGGRASTAT)

May lead to thrombocytopenia (discontinue AGGRASTAT andMay lead to thrombocytopenia (discontinue AGGRASTAT and heparin)

Adverse Reactions

Bleeding is the most commonly reported adverse reaction

107







108






Abciximab (n=42) Double-Bolus eptifibatide (n=34) HDB Tirofiban (n=38)

Platelet inhibition with HDB Tirofiban

114 ACS patients undergoing PCI

86

9295

70

80

90

100

elet

Inhi

bitio

n (%

)

mol

/L A

DP

(P

PA

CK

)

PAI ≥ 95%

P<0.001

2944

68

P=0.02**

60

70

Platelet Aggregation Inhibition (PAI) at 10 min

Pla

te20

µm

Danzi et al. J Cardiol 2006;97:489-93

Percent patients achieving ≥95% PAI at 10 min

109

HDB tirofiban* (n = 30)Double-Bolus eptifibatide* (n = 30)

Platelet Inhibition with HDB Tirofiban

120 ACS patients undergoing high-risk, elective PCI

Percent patients achieving

96.194.2

92.9

86.190

100P < 0.001P = 0.003

elet

Inhi

bitio

n (%

)

mol

/L A

DP

(P

PA

CK

)

PAI ≥ 95%

73.3

40 0

≥95% PAI at 10 min

P < 0.001* **

8010 min 6-8 h

Time since treatment initiated

Mardikar et al. Am Heart J 2007;154:344e1-344e5

Pla

te20

µm 40.0

Tirofiban Eptifibatide10 min

* 600 mg of Clopidogrel administered immediately prior to PCI

110



HDB Tirofiban Double-Bolus Eptifibatide

Study Control 1º EP Study Control 1º EPR

OM

E

MI

ON-TIME 2(n=1,398)

heparinP2Y12

PreRXdeath, MI, uTVR

EVA-AMI(n=427)

abciximab STR ≥ 70%

MULTI-STRATEGY

(n=745)abciximab STR ≥ 50%

ASSIST(n=400)

heparinP2Y12

PreRX

death, MI,recurrent ischemia

FATAabciximab STR ≥ 70%

AC

UT

E C

OR

ON

AR

Y S

YN

DR

ST

EM

(n=692)abciximab STR ≥ 70%

TEDA(n=660)

heparin w/ provisional Tirofiban

(43%)

MACE

STRATEGY(n=175)

abciximab w/ bare-metal

stent

death, MI, stroke,binary restenosis

EM

I

ADVANCE(n=202)

heparin P2Y12

PreRX

death, MI, uTVR,bailout

EARLY-ACS

(n 9 492)

heparin w/ provisional

eptifibatide (16%)

P2Y12

PreRXdeath, MI, uTVR,

bailout

GREEN – met primary endpointRED – missed primary endpoint

UA

/NS

TE (n=9,492) eptifibatide (16%)

PROTECT-TIMI-30(n=857)

bivalirudincoronary flow

reserve

EL

EC

TIV

E

3T/2R(n=263)

heparin w/ASA and/or

P2Y12

resistance

P2Y12

PreRXperiprocedural MI

ESPRIT(n=2,064)

heparindeath, MI, uTVR,

bailout

BRIEF-PCI(n=624)

eptifibatide(18-hr infusion)

Periproceduralmyonecrosis

Use of GP IIb/IIIa Inhibitors in STEMI not approved by FDA. Please refer to product’s full prescribing information. Confidential

111

ACUITY Substudy: Pre-Specified Study Design

4,323 patients presenting with UA/NSTEMI randomly assigned to receive Heparin or Bivalirudin

and a GP IIb/IIIa Inhibitor prior to angiography

Oral ASA (300-325 mg) or IV ASA (250-500 mg)Recommended Clopidogrel Loading (300 or 600 mg) ithin 2 ho rs of PCI

Tirofiban (n=1,493)Administered at time of randomization

(12–18 h infusion post-PCI)Heparin or Bivalirudin

Open-Label, Physician Assigned GPI

Recommended Clopidogrel Loading (300 or 600 mg) within 2 hours of PCI

Eptifibatide (n=2,830)Administered at time of randomization

(12–18 h infusion post-PCI)Heparin or Bivalirudin

Primary endpoints:MACE, NACE, and non-CABG Major Bleeding at 30 days

p

Coronary angiography within 72 hContinued Medical Management, PCI, or CABG at discretion of physician

Confidential112

Heparin or Bivalirudin

Nazif et al. Am Heart J 2014:167:43-50



7 6

10

Eptifibatide (n=2,830) Tirofiban (n=1,493)

ACUITY substudy: clinical events (unadjusted)

7.6

5.86.1

3.6

0

5

P = 0.002

Eve

nts

(%)

P = 0.06

0Death/MI/TVR

(MACE)Myocardial Infarction

30 days

Nazif TM, et al. Am Heart J 2014:167:43-50 113

27.7

25

30

Eptifibatide (n=2,830) Tirofiban (n=1,493)

ACUITY substudy: safety events (unadjusted)

12.6

6.5

10.6

5.8

18.8

0

5

10

15

20

25

N Cli i l O N CABG N CABG Mi

P < 0.001

Eve

nts

(%)

P = 0.06 P = 0.39

Net Clinical Outcomes (NACE)

Non-CABG Major Bleeding

Non-CABG Minor Bleeding

30 days

Nazif TM, et al. Am Heart J 2014:167:43-50

Protocol defined bleeding

114



ACUITY substudy: 30-day events (adjusted analysis)

Composite ischemia 0.76

Odds Ratio[95% Confidence Interval]

p=0.19

Major bleeding

Death/MI 0.76

0.76

p=0.25

p=0.20

0.25 0.75 1.25 1.75

Net clinical outcomes

Favors Tirofiban (n=1,493)

Favors Eptifibatide (n=2,830)

0.78p=0.14

Nazif et al. Am Heart J 2014:167:43-50 115

HDB Tirofiban in High-Risk ACS: On-TIME 2

Open-label phaseJune 2004 to June 2006

n = 414 STEMI

ASA (500 mg iv)

Double-blind phaseJune 2006 to November 2007

n = 984 STEMI

HDB tirofiban (n=709) placebo/no tirofiban (n=689)

1:1 Randomization

ASA (500 mg iv)Clopidogrel (600 mg Loading Dose)

All patients pretreated

Pre-hospital study drug administrationMedian pretreatment duration = 55 min

116

HDB tirofiban (n=709)602 primary PCI

536 coronary stentPost-PCI infusion: 18 h

UFH 5000 U bolus (ACT > 200 s)

placebo/no tirofiban (n=689)601 primary PCI

537 coronary stentPost-PCI infusion: 18 h

UFH 5000 U bolus (ACT > 200 s)

Primary endpoint (30 days): composite of death, MI, uTVR

Ten Berg J, et al. J Am Coll Cardiol 2010;55:2446-2455



On-TIME 2: Clinical outcomes at 30 days

15

Placebo/No Tirofiban (n = 662) HDB tirofiban (n = 677)

32.6% RRRP =0.043

46.3% RRRP =0.051

78.6% RRRP =0.031

57.1% RRRP =0.008

Pat

ient

s (%

)

8.6

4.1

1.4

4.25.8

2.20.3

1.8

0

5

10

117Ten Berg J, et al. J Am Coll Cardiol 2010;55:2446-2455

0Death/MI/uTVR

(Primary)Death Stroke Urgent TVR

(PCI)

30 days

On-TIME 2: Safety outcomes

15


31.0% RRRP =0.024

Pat

ient

s (%

)

11.6

2.94.4

8

3.4

5.9

0

5

10 P =0.206P =0.580


*Net clinical outcome: composite of death, MI, uTVR, stroke or major bleeding

0Net clinical outcome* TIMI major bleeding TIMI minor bleeding

30 days



On-TIME 2: 1-year mortality outcomes

10

Placebo/No Tirofiban (n = 656 / pPCI = 586 )

HDB tirofiban (n = 670 / pPCI = 583)

36.2% RRRP =0.08

56.4% RRRP =0.007

Pat

ient

s (%

) 5.8 5.5

3.72.4

0

5


0All patients Primary PCI patients

1-year mortality

On-TIME 2: Stent Thrombosis

10


59.6% RRRP =0.006

93.3% RRRP <0.001

13.6% RRRP =0.67

Pat

ient

s (%

)

5.2

32.22.1

0.2

1.9

0

5

0Early (0-30 days) Acute (0-24 h) Subacute (24 h - 30

days)

Stent thrombosis (ARC defined)

Heestermans AACM, et al. J Thromb Haemost 2009;7:1612-8120



MULTISTRATEGY Study Design

745 patients presenting with STEMI or new LBBB

1:1:1:1 Randomization prior to

ASA (160-325 mg or 250 mg iv) & Clopidogrel (300 mg / 75 mg)

Study drug administered at first medical contact before sheath

HDB tirofiban Post-PCI infusion: 18 to 24 h

UFH 40 – 70 U/kg (ACT > 200 s)

abciximab Post-PCI infusion: 12 h

UFH 40 - 70 U/kg (ACT > 200 s)

pangiography, open-label

medical contact, before sheath insertion during angiography

Uncoated Stent(N=186)

Sirolimus-eluting (N=186)

Uncoated Stent(N=186)

Sirolimus-eluting (N=187)

182 received PCI 183 received PCI 180 received PCI 184 received PCI

Drug comparison primary endpoint (non-inferiority margin of 9%):≥50% ST-segment elevation resolution at 90 min post-intervention

182 received PCIDrug comparison (n=184)Stent comparison (n=186)




Stent comparison primary endpoint (superiority):Composite of death, MI, uTVR within 8 months

Confidential121

Valgimigli et al. J Am Med Assoc 2008;299:1788-99

MULTISTRATEGY Clinical Outcomes at 30 days

8

abciximab (n = 372) HDB tirofiban (n = 372)

Pat

ient

s (%

)

4.33.8

2.2

4 3.8

2.4

0

2

4

6P =0.81P =0.98

P =0.85

0Death/MI/uTVR Death/MI Definite or probable

stent thrombosis

30 days

Confidential122




MULTISTRATEGY Safety Outcomes

10


P =0.40P =0.4480.0% RRR

P =0.004

Pat

ient

s (%

)

1.6

6.2

4

2.4

4.8

0.8

0

2

4

6

8

*0

TIMI major bleeding TIMI minor bleeding Severe or moderate thrombocytopenia

30 days

Confidential123


MULTISTRATEGY Mortality at 3 years

15


Pat

ient

s (%

)

7.86.56.7

4.8

0

5

10

P =0.34P =0.56

0Mortality (all-cause) Mortality (cardiovascular)

3 years

Valgimigli et al. / Int J Cardiol 2013;165:134-41

Confidential124



Meta-Analysis: HDB tirofiban vs. abciximab

8

Abciximab (n=1,105)

HDB Tirofiban (n=1,108)

Pat

ient

s (%

)

1.8

4.1

1.3

3.5

0

4P =0.38

P =0.54

0Death Death/MI

30 days

Valgimigli et al. Eur Heart J 2010:31:35-49

Confidential125

The HDB is not the regimen that was used in studies that established effectiveness of Aggrastat. See full PI for information on those studies. Some of the patient populations were outside of the approved patient populations. This meta-analysis does not imply comparable efficacy, safety or product interchangeability.

Meta-Analysis: HDB tirofiban vs. abciximab

10.0

Abciximab (n=1,105)

HDB Tirofiban (n = 1,108)

Pat

ient

s (%

)

1.5

5.8

1.71.6

3.9

0.50 0

5.0

P =0.74 P =0.004P =0.03

0.0TIMI major bleeding TIMI minor bleeding Thrombocytopenia

Valgimigli et al. Eur Heart J 2010;31:35-49 Valgimigli et al. Expert Opin Drug Saf 2010;9:801-19

Confidential126

The HDB is not the regimen that was used in studies that established effectiveness of Aggrastat. See full PI for information on those studies. Some of the patient populations were outside of the approved patient populations. This meta-analysis does not imply comparable efficacy, safety or product interchangeability.



Platelet inhibition with tirofiban HDB regimen (ADP)

FABOLUS PRO Trial100 STEMI patients undergoing percutaneous coronary intervention

ADP Induced Platelet Aggregation

Confidential

127Valgimigli et al. J Am Coll Cardiol Intv 2012;5:268-77


gg g

Platelet inhibition with tirofiban HDB regimen (TRAP)

FABOLUS PRO Trial100 STEMI patients undergoing percutaneous coronary intervention

TRAP Induced Platelet Aggregation

Confidential

128Valgimigli et al. J Am Coll Cardiol Intv 2012;5:268-77










129




2014 ACC/AHA NSTE-ACS: GP IIb/IIIa Inhibitors

Recommendations Special Considerations COR LOE

IV Antiplatelet Therapy in Patients with Definite or Likely NSTE-ACS

GP IIb/IIIa inhibitor in patients treated ith l i i t t d P f d tiwith an early invasive strategy and

DAPT with intermediate/high-risk features (e.g., positive troponin)

Preferred options areTirofiban or Eptifibatide

IIb B

IV Antiplatelet Therapy in Patients with NSTE-ACS undergoing PCI

At time of PCI, GP IIb/IIIa inhibitor in patients with high-risk features (e.g.,elevated troponin) not adequately pretreated with clopidogrel or ticagrelor

High-Dose Bolus Tirofiban, Double-Bolus Eptifibatide, or abciximab

I A

Amsterdam et al. J Am Coll Cardiol 2014;64:2645-87

Confidential130

p p g g

At time of PCI, GP IIb/IIIa inhibitor in patients with high-risk features (e.g.,elevated troponin) treated with UFH and adequately pretreated with clopidogrel


IIa B



2014 ACC/AHA NSTE-ACS: GP IIb/IIIa Inhibitors

Recommendations Special Considerations COR LOE

IV Antiplatelet Therapy in Patients with Definite or Likely NSTE-ACS

GP IIb/IIIa inhibitor in patients treated ith l i i t t d P f d tiwith an early invasive strategy and

DAPT with intermediate/high-risk features (e.g., positive troponin)

Preferred options areTirofiban or Eptifibatide

IIb B

IV Antiplatelet Therapy in Patients with NSTE-ACS undergoing PCI

At time of PCI, GP IIb/IIIa inhibitor in patients with high-risk features (e.g.,elevated troponin) not adequately pretreated with clopidogrel or ticagrelor


I A

Amsterdam EA, et al. 2014 ACC/AHA Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014 Sep 18;pii:S0735-1097(14)06278-0.DOI:10.1016/j.jacc.2014.09.016. [Epub ahead of print] Confidential

131

p p g g

At time of PCI, GP IIb/IIIa inhibitor in patients with high-risk features (e.g.,elevated troponin) treated with UFH and adequately pretreated with clopidogrel


IIa B

2011 ACC/AHA/SCAI PCI Guideline Recommendations

Patients undergoing PCI

Clopidogrel pre-treatment Patient

Abciximab0.25mg/kg bolus

+ 0.125 µg/kg/min

Eptifibatide2x180µg/kg bolus + 2.0 µg/kg/min

Tirofiban25µg/kg bolus

+ 0.15 µg/kg/min

NO

SIHD CLASS IIa(level of evidence: B)

UA/NSTEMI CLASS I(level of evidence: A)

STEMI* CLASS IIa(level of evidence: A)

SIHD CLASS IIb

YES

SIHD(level of evidence: B)

UA/NSTEMI CLASS IIa(level of evidence: B)

STEMI* CLASS IIa(level of evidence: C)

Levine GN, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. Circulation 2011, 124:e574-e651


132



History

• 47-year-old woman with no prior cardiac history

• 2 weeks of intermittent chest discomfort that began with "head cold" and l i t d ith i t itt t b t l h t th t t nasal associated with intermittent substernal chest pressure that seem to

happen only with exertion, albeit minimal exertion

• Associated shortness of breath requiring her to stop to catch her breath. Most recent episode of chest pain night prior to admission, developed nausea, 2 episodes of non bloody, non bilious emesis, left with arm cramping sensation.

• Symptoms resolved with rest after approximately 10 minutes.

• Because of these symptoms, patient called her PCP's office who instructed her to report to ED for further evaluation

133

On arrival to BIDMC-Needham ED

• VS: HR 110, 180/108, 22 100% on RA.

• Troponin negative < 0.010.

• HCG negative.

• Echo: mild hypokinesis in the mid to distal anterior septum.

134



Presenting EKG in BIDMC-Needham

Patient Pain Free

135

Diagnosis, Prognosis, Risk Stratification

• Diagnosis: Non-cardiac? stable angina? NSTE-ACS? STEMI?S

• Risk Category: High? Intermediate? Low? (TIMI, GRACE)

• Invasive or Ischemia guided (conservative) strategy?

136



+39 +10 +24 +25 +25 +0 +28 +0 = 151

Assessing Risk

• Grace risk model: 151 points corresponding to an in-hospital mortality 3.9-5.4%o a y 3 9 5 %

• TIMI: risk score = 1: 4.7% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization (ST deviations on ECG)

Th TIMI i k i d t i d b th f th f 7 The TIMI risk score is determined by the sum of the presence of 7 variables at admission; 1 point is given for each of the following variables: ≥ 65 y of age; ≥ 3 risk factors for CAD; prior coronary stenosis ≥ 50%; ST deviation on ECG; ≥ 2 anginal events in prior 24 h; use of aspirin in prior 7 d; and elevated cardiac biomarkers

138



Initial Medical Management

139



DAPT and Anticoagulant Therapy

2014 Recommendation• Class I

– An urgent/immediate invasive strategy is indicated in patients with NSTE-ACS who have refractory angina or hemodynamic or electrical instabilityhemodynamic or electrical instability

– An early invasive strategy is indicated in initially stabilized patients with NSTE- ACS who have an elevated risk for clinical event

• Class IIa

– It is reasonable to choose an early invasive strategy over a delayed invasive strategy for initially stabilized high-risk patients with NSTE-ACS.

For those not at high/intermediate risk, a delayed invasive approach is reasonable 142



Procedural Details

• Aspirin 325 mg orally without clopdigrel

• Discussion with patient and family early invasive strategy to understand coronary anatomy and exclude disease

• Right radial approach with unfractionated heparin, 5000U

143

Presentation as Unstable (Accelerated) Angina

Cardiac Cath

144




Cardiac Cath

145


Cardiac Cath

146




Cardiac Cath

147


Cardiac Cath

148




Cardiac Cath

149


Cardiac Cath

150



Decision Tree

• Is this surgical disease?

• What anticoagulants should be given?What anticoagulants should be given?

• What antiplatelet therapy is best?

151

CABG vs. PCI : Considerations

• Extent / complexity of CAD; completeness of revascularizatione ascu a a o

• Short-term risk and long-term durability of PCI

• Operative mortality (STS score)

• Diabetes mellitus; CKD; LV systolic dysfunction; previous CABG; ability to tolerate and comply with DAPT

• In patients with NSTE-ACS, PCI of a culprit unprotected left main coronary artery lesion is an option if the patient is not a candidate for CABG

152



Non-culprit lesion revascularization

• Class IIb

– A strategy of multivessel PCI, in contrast to culprit l i l PCI f th l il l i b bl lesion−only PCI of the culpril lesion, may be reasonable in patients undergoing coronary revascularization as part of treatment for NSTE-ACS (330, 359- 364). (Level of Evidence: B)

Al h h PCI f l i l i i d d i • Although PCI of a nonculprit lesion is not advocated in patients with STEMI, there is less agreement on whether nonculprit lesions should undergo intervention at the time of culprit-lesion PCI for NSTE-ACS.

153

• Most reports, but not all comparing culprit lesion−only PCI with multivessel PCI (e.g., PCI of multiple vessels performed at the same time) in patients with NSTE ACS did

Non-culprit lesion revascularization

performed at the same time) in patients with NSTE-ACS did not find an increased risk of MACE with multivessel PCI and found a reduction in the need for repeat revascularization

• However, the data consist predominantly of post hoc analysis of nonrandomized data with variable duration of follow-up

– This question has not been resolved and is an area of current investigation.

154



Procedural Details

• Discussion with patient and family of PCI v. CABG – strong patient preference for PCI

Additi f ti fib i ti i ti f l ft th • Addition of tirofiban in anticipation of prasugrel after the procedure

DES Choice

• LAD – 3.0 mm x 22 mm Resolute – post dilation 3.25 mm

• LCx – 4.0 mm x 18 mm Resolute – 3.5 mm x 12 mm with post-dilation with 3.75 mm balloon

155

Multivessel PCI

Cardiac Cath

156



Multivessel PCI

Cardiac Cath

157

Multivessel PCI

Cardiac Cath

158



Multivessel PCI

Cardiac Cath

159

PCI—Antiplatelet and Anticoagulant Therapy

• Class I

– In patients with NSTE-ACS and high-risk features (e.g., elevated troponin) not adequately pretreated with clopidogrel or ticagrelor, it is useful to administer a GP IIb/IIIa inhibitor at the time of PCI

– In patients receiving a stent (bare-metal stent or drug-eluting stent [DES]) during PCI for NSTE- ACS, P2Y12 inhibitor therapy should be given for at least 12 months

• Class IIb

– Continuation of DAPT beyond 12 months may be considered in patients undergoing stent implantation. (Level of Evidence: C)

160



DAPT Trial

• Dual Antiplatelet Therapy

– benefits of 12 vs 30 months of DAPT for preventing IST and MACCE; (composite of death, heart attack or stroke) in subjects undergoing DES PCI(composite of death, heart attack or stroke) in subjects undergoing DES PCI

– relative reductions of 71% in stent thrombosis and 29% in major adverse cardiovascular and cerebrovascular events by continuing a thienopyridine plus aspirin for 30 months compared with aspirin alone after 12 months

– IST (0.4% vs 1.4%, hazard ratio 0.29, P < 0.001)

– MACCE (4.3% vs 5.9%, hazard ratio 0.71, P < 0.001)

d i b d ti i di l i f ti (2 1% 4 1% h d ti 0 47 driven by a reduction in myocardial infarction (2.1% vs 4.1%, hazard ratio 0.47, P < 0.001)

– Non-stent thrombosis-related myocardial infarction comprised 55% of the treatment benefit (1.8% vs 2.9%, hazard ratio 0.59, P < 0.001).

– Incidence of stroke was similar between the two treatment arms (0.8% vs 0.9%, P = 0.32). 161

Summary

• 47-year-old woman with no prior cardiac history presents with atypical chest pain but objective evidence of ischemia by EKG and

h diechocardiogram

• Discordance between TIMI Risk Score and GRACE score, underscoring the importance of using both scores for risk stratification

• Urgent angiography demonstrated two vessel coronary artery disease –immediate PCI with complete revascularization of LAD and LCx

P t PCI ti t i d l t l t t i l di • Post-PCI, patient received prasugrel to lower recurrent events, including stent thrombosis

• Long-term duration of benefit now established with DAPT, but influence of third generation DES less certain

162



GP IIb/IIIa Pricing History

250%

300%Accumulation of Unit Price Increases

1999 - 2015

100%

150%

200%

0%

50%

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

Feb 2015 Medi-Span PriceRx.Does not imply comparable efficacy, safety or product interchangeability.

163

164



GP IIb/IIIa Drug Utilization Treatment Costs

WACWAC

$1,801.48

$2,000Integrilin: 2x180 µg/kg bolus + 2.0 µg/kg/min | Aggrastat: 25 µg/kg bolus + 0.15 µg/kg/min

$811.40

$1,306.44

$247.29

$517.81

$765.10

$0

$500

$1,000

$1,500

$03-hr Infusion (90kg) 12-hr Infusion (90kg) 18-hr Infusion (90kg)

Required Units:

Confidential165

Based on WAC pricing as of June 2015. Cost of heparin has not been included. Cost comparisons do not imply comparable efficacy, safety or product interchangeability. Aggrastat and Integrilin (eptifibatide) have not been compared in head-to-head clinical trials. Please refer to prescribing information for approved indications for all products.

WAC

Reopro: 0.25 mg/kg bolus + 0.125 µg/kg/min | Aggrastat: 25 µg/kg bolus + 0.15 µg/kg/min

WAC

$3,407.40$3,000

GP IIb/IIIa Drug Utilization Treatment Costs

$517.81

$

$1,000

$2,000

$ ,

Required Units:

Confidential166

Based on WAC pricing as of June 2015. Cost of heparin has not been included. Cost comparisons do not imply comparable efficacy, safety or product interchangeability. Please refer to prescribing information for approved indications for all products.

$012-hr Infusion (90 kg patient)



SCAI Appropriate Use ToolkitSCAI Appropriate Use Toolkit

167http://nacs.scai-qit.org/#


168http://nacs.scai-qit.org/#




169


170



• RADIAL FIRST for stable and unstable angina, STEMI – fellows and attendings proficient

BIDMC Management StrategyBIDMC Management Strategy

• Variable P2Y12 loading for stable CAD; Ticagrelolpreferred agent for NSTEMI and STEMI in ED

• Unfractionated heparin used for radial access

• Tirofiban added to unfractionated heparin in approximately 50% of cases

171

approximately 50% of cases

• Prolonged infusion for thrombus or reduced flow only

• Interventional cardiology has transitioned over the past 10 years . . .

SummarySummary

- High penetration of drug eluting stents

- Radial penetration > 25%

- Ischemia guided intervention (from stress tests)

- More frequent use of UFH

172

- Cost saving decision making within the cardiac catheterization laboratory



Questions?Questions?

173

U d t C tU d t C t PhPhUpdate on Current Update on Current Pharmacy Pharmacy Initiatives and StrategiesInitiatives and Strategies

175

Trent A. Beach, PharmD, MBA, MHA, BCPS, FASHP, FACHE

Corporate Director, Clinical Pharmacy

Community Health System Professional Services Corporation



176

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