Pharmacologic Options in the Invasive Management of Acute Coronary Syndrome

Pharmacologic Options in the Invasive

Management of Acute Coronary Syndrome

Ross J. Goodfellow, DO FACC FSCAIHealth First Medical Group

Cape Canaveral Hospital/Holmes Regional Medical Center

Cocoa Beach & Melbourne, Florida

Disclosures

•Speaker•Astra Zeneca•Zoll Medical

Acute Coronary Syndrome(UA, NSTEMI, STEMI)

•2014•Majority of patients undergo invasive

strategy (cardiac cath within 24-48 hrs)•FRISC-II, RITA, ICTUS•Meta-analysis demonstrated 19%

RRR in CV Death or MI in patients managed with early invasive strategy

Risk Stratification:TIMI Risk Score

•Age 65 or older•3 or more CAD risk factors•DM, Smoking, HTN, HDL<40mg/dl, FamHx of

premature CAD•Known CAD•ASA use in past 7 days•2 or more anginal episodes in 24 hours•ST changes > 0.5mV•Positive cardiac biomarkers

ACS Pharmacology:Invasive Strategy

•Decrease myocardial demand/increase supply

•Beta Blockers, Nitrates, Calcium Channel Blockers

•Analgesics

•Morphine

•Oral Antiplatelet Agents

•ASA, Clopidogrel, Prasugrel, Ticagrelor

•Intravenous Antiplatelet Agents

•IIb/IIIa Antagonists (Abciximab, Eptifibitide, Tirofiban)

•Anticoagulants

•Heparin, Bivalirudin, LMWH (Enoxaparin, Dalteparin)

8

Vessel Injury

Sites of action of antiplatelet and anticoagulant medications1

Platelet activation

Platelet aggregation

Fibrinogen

Fibrin

Thrombin

Plasma clotting factors

Prothrombin

Tissue factor

Collagen

ADP/TXA2mediated platelet adhesion

1. Monroe DM et al. Arterioscler Thromb Vasc Biol 2002;22:1381-9

Please see important safety information and bleeding definitions on slides 64 and 65. Please see accompanying full Prescribing Information.

Aspirin and Thienopyridines

ANGIOMAXGP IIb/IIIa inhibitors

AT

FactorXa

AT

HeparinLMWH

•Meta-analysis of all trials demonstrates a 10% reduction in death or MI with enoxaparin over UFH

•No significant differences in major bleedings

•Meta-analysis included conservatively managed patients

•Largest trial of invasively treated patients (SYNERGY) showed increased bleeding with enoxaparin

Enoxaparin v. UFH

Oral Antiplatelet Agents•ADP-P2Y12 interaction

•Amplifies platelet activation•P2Y12 receptor antagonists•Thienopyridines•Ticlopidine•Clopidogrel (PLAVIX)•Prasugrel (EFFIENT)

•CPTP (Cyclopentyltriazolopyrimidine)•Ticagrelor (BRILINTA)

CURE Trial•Unstable angina/NSTEMI•ASA + Clopidogrel (300mg load/75mgqd) v.

ASA alone•N=12,562•20% RRR in CV Death, MI, and Stroke in

Clopidogrel group•Driven by decreased nonfatal MI

•PCI-CURE•Clopidogrel pre-treatment (6 days) pre-PCI

associated with 31% RRR in primary endpoint

PCI-CURE

•Rationale•Attempt to address high on-

treatment platelet reactivity seen in 10-30% pts.

•Double-dose clopidogrel load/maintenance dose x 7 days v. standard dose in ACS pts.•2 x 2 design also assessing ASA dose

CURRENT-OASIS 7

Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCIASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

Median duration of therapy - 12 months

N= 13,600

Wiviott SD et al AHJ 152: 627,2006

Enrollment Criteria•Inclusion Criteria

Planned PCI for :Mod-High Risk UA/NSTEMI (TRS > 3)

STEMI: < 14 days (ischemia or Rx strategy)STEMI: Primary PCI

•Major Exclusion Criteria:–Severe comorbidity

–Increased bleeding risk–Prior hemorrhagic stroke or any stroke < 3 mos

–Any thienopyridine within 5 days–No exclusion for advanced age or renal function

KnownAnatomy

Wiviott SD et al AHJ 152: 627,2006

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

HR 0.80P=0.0003

HR 0.77P=0.0001

Days

Prim

ary

Endp

oint

(%) 12.1

(781)

9.9 (643)

Primary EndpointCV Death,MI,Stroke

NNT= 46

ITT= 13,608

LTFU = 14 (0.1%)

Wiviott SD et al NEJM 357: 2001, 2007

Components of EndpointsClopidogrel HRPrasugrel

12.1 0.819.9

2.4 0.892.1

9.5 0.767.3

1.0 1.021.0

uTVR

Nonfatal Stroke

Nonfatal MI

CV Death

CV Death, MI, Stroke

0.5 1 2

3.7 0.662.5

Prasugrel Better Clopidogrel Better

All Cause Mortality3.2 0.953.0

Stent Thrombosis

2.4 0.481.1

HR Wiviott SD et al NEJM 357: 2001, 2007

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

Endp

oint

(%)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Efficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167Wiviott SD et al NEJM 357: 2001, 2007

TIMI Major Bleeds

Life Threaten-ing

Nonfatal Fatal ICH0.0

0.8

1.5

2.3

3.0

1.8

0.9 0.9

0.10.3

2.4

1.41.1

0.4 0.3

Bleeding EventsSafety Cohort

(N=13,457)

% E

vent

s

ARD 0.6%HR 1.32P=0.03

NNH=167

ClopidogrelPrasugrel

ARD 0.5%HR 1.52P=0.01

ARD 0.2%P=0.23

ARD 0%P=0.74

ARD 0.3%P=0.002

ICH in Pts w Prior Stroke/TIA

(N=518)Clop 0 (0) % Pras 6 (2.3)% (P=0.02)


Net Clinical BenefitDeath, MI, Stroke,

Major Bleed (non CABG)

0

5

10

15

0 30 60 90 180 270 360 450Days

Endp

oint

(%)

HR 0.87P=0.004

13.9

12.2

Prasugrel

ClopidogrelITT= 13,608

-28

-19

-9

0

9

-23

6

Events per 1000 pts

MI

Major Bleed

(non CABG)

+ All Cause

MortalityClop 3.2%Pras 3.0 %

P=0.64


B

OVERALL

No GPIGPI

DESBMS

DMNo DM

>7565-74

<65

FemaleMale

STEMIUA/NSTEMI

0.5 1 2Prasugrel Better Clopidogrel BetterHR

Age

Reduction in risk (%)18

211225146

143020182116

19

21

Pinter = NS

CV Death, MI, StrokeMajor Subgroups

CrCl > 60CrCl < 60 14

20


Net Clinical BenefitBleeding Risk Subgroups

OVERALL

>=60 kg

< 60 kg

< 75

>=75

No

Yes

0.5 1 2

Prior Stroke / TIA

Age

Wgt

Risk (%)+ 54-16

-1

-16

+3

-14

-13

Prasugrel Better Clopidogrel BetterHR

Pint = 0.006

Pint = 0.18

Pint = 0.36

Post-hoc analysis


August 30, 2009 at 08.00 CET

Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

OH

OH

O

OH

N

F

S

NH

NN

NN

F

• Direct acting – Not a prodrug; does not require metabolic activation– Rapid onset of inhibitory effect on the P2Y12 receptor– Greater inhibition of platelet aggregation than clopidogrel• Reversibly bound– Degree of inhibition reflects plasma concentration– Faster offset of effect than clopidogrel – Functional recovery of all circulating platelets

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major

bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading

dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose,

then90 mg bid maintenance;

(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)

Clopidogrel-treated or -naive;randomised within 24 hours of index event

(N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke)

No. at risk

ClopidogrelTicagrelor

9,2919,333

8,5218,628

8,3628,460

8,124

Days after randomisation

6,7436,743

5,0965,161

4,0474,147

0 60

120

180

240

300

360

1211109876543210

13

Cum

ulat

ive

incid

ence

(%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Hierarchical testing major efficacy endpoints

All patients*Ticagrelor(n=9,333)

Clopidogrel(n=9,291)

HR for (95% CI) p value†

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

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

901 (10.2)

1,290 (14.6)

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

1,065 (12.3)

1,456 (16.7)

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

0.84 (0.77–0.92)

0.88 (0.81–0.95)

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

<0.001

<0.001

0.005 0.001 0.22

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

The percentages are K-M estimates of the rate of the endpoint at 12 months.

No. at risk


9,2919,333

8,5608,678

8,4058,520

8,177


6,7036,796

5,1365,210

4,1094,191

0 60

120

180

240

300

360

6

5

4

3

2

1

0

7

Cum

ulat

ive

incid

ence

(%)

Clopidogrel

Ticagrelor

5.8

6.9

8,279

HR 0.84 (95% CI 0.75–0.95), p=0.005

0 60

120

180

240

300

360

6

4

3

2

1

0

Clopidogrel

Ticagrelor

4.0

5.1

HR 0.79 (95% CI 0.69–0.91), p=0.001

7

5

9,2919,333

8,8658,294

8,7808,822

8,589


70797119

5,4415,482

4,3644,4198,626

Myocardial infarction

Cardiovascular death

Cum

ulat

ive

incid

ence

(%)

Secondary efficacy endpoints over time

Stent thrombosis

Ticagrelor(n=5,640)

Clopidogrel (n=5,649)

HR (95% CI) p value

Stent thrombosis, n (%)

Definite

Probable or definite

Possible, probable, definite

71 (1.3)

118 (2.1)

155 (2.8)

106 (1.9)

158 (2.8)

202 (3.6)

0.67 (0.50–0.91)

0.75 (0.59–0.95)

0.77 (0.62–0.95)

0.009

0.02

0.01

(evaluated in patients with any stent during the study)

*Time-at-risk is calculated from first stent insertion in the study or date of randomisation

Time to major bleeding – primary safety event

No. at risk


9,1869,235

7,3057,246

6,9306,826

6,670

Days from first IP dose

5,2095,129

3,8413,783

3,4793,433

0 60

120

180

240

300

360

10

5

0

15

Clopidogrel

Ticagrelor 11.2

0

11.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434K-

M e

stim

ated

rate

(% p

er y

ear)

Total major bleeding

NS

NS

NS

NS

NS

0

K-M

est

imat

ed ra

te (%

per

yea

r)

PLATO major bleeding

12345678

910

1211

13

TIMI major bleeding

Red cell transfusion*

PLATO life-threatening/

fatal bleeding

Fatal bleeding

Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; *Proportion of patients (%); NS = not significant

11.611.2

7.9 7.7

8.9 8.9

5.8 5.8

0.3 0.3

TicagrelorClopidogrel

Non-CABG and CABG-related major bleeding

p=0.026

p=0.025

NS

NS

9K-

M e

stim

ated

rate

(%

per

yea

r)

Non-CABGPLATO major

bleeding

8

7

6

5

4

3

2

1

0 Non-CABGTIMI major bleeding

CABGPLATO major

bleeding

CABG TIMI major bleeding

4.5

3.8

2.8

2.2

7.47.9

5.35.8

TicagrelorClopidogrel

Holter monitoring & Bradycardia related events

Holter monitoring at first weekTicagrelor(n=1,451)

Clopidogrel(n=1,415) p value

Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, %

5.82.0

3.61.2

0.010.10

Holter monitoring at 30 daysTicagrelor(n= 985)

Clopidogrel(n=1,006) p value

Ventricular pauses ≥3 seconds, % Ventricular pauses ≥5 seconds, %

2.10.8

1.70.6

0.520.60

Bradycardia-related event, %

Ticagrelor(n=9,235)

Clopidogrel(n=9,186)

p value Pacemaker Insertion Syncope Bradycardia Heart block

0.91.14.40.7

0.90.84.00.7

0.870.080.211.00

Other findings

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186) p value*

Dyspnoea, %

Any

With discontinuation of study treatment13.8

0.9

7.8

0.1<0.001

<0.001

Neoplasms arising during treatment, %

Any

Malignant

Benign

1.4

1.2

0.2

1.7

1.3

0.4

0.17

0.69

0.02

*p values were calculated using Fischer’s exact test

Conclusions

• Reversible, more intense P2Y12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non-ST-elevation ACS provides – Reduction in myocardial infarction and stent thrombosis– Reduction in cardiovascular and total mortality– No change in the overall risk of major bleeding

Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of ischaemic events, stent

thrombosis and death in the acute and long-term treatment of patients with ACS

•Inhibit >80% of platelet aggregration•Early studies demonstrated short and long

term event reduction in ACS patients compared with heparin alone•Driven by reduction in peri-procedural MI•Increased bleeding

•Recent Trials•ISAR-REACT 2, EARLY ACS, ACUITY

IIb/IIIa Antagonists

4711

Moderate-and high-Risk ACS

(n=13,819)

ACUITY Study Design – First Randomization

Angi

ogra

phy

with

in

72h

Aspirin in allclopidogrel;dosing and

timingper local practice

UFH/Enox+ GP

IIb/IIIa(n=4,603)Bivalirudin

+ GP IIb/IIIa

(n=4,604)Bivalirudi

nAlone†

(n=4,612)

R*

*Stratified by pre-angiography thienopyridine use or administration†ANGIOMAX alone (with GP IIb/IIIa inhibition reserved for severe breakthrough ischemia and procedural complications during PCI)The safety and effectiveness of ANGIOMAX have not been established in patients with acute coronary syndromes (ACS) who are

not undergoing PTCA or PCI.Stone GW et al. N Engl J Med. 2006;355:2203-2216

Moderate- and high-risk unstable angina or NSTEMI undergoing an early invasive strategy (N=13,819)

Medicalmanagemen

t

PCI

CABG

4812

Overall ACUITY Management Strategy (N=13,819)

56.4%

11.1%

32.5%

CABG (n=1,539)

Medical Rx (n=4,491)

PCI (n=7,789)

UFH/Enox + GP IIb/IIIaN = 2,561

Bivalirudin + GP IIb/IIIaN = 2,609

Bivalirudin aloneN = 2,619

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

4916

Primary Results – 30 Days

UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

0%

20%

13%

8% 7%

15%

9%8%

12%9%

4%

UFH/Enox+GP IIb/IIIa (N=2561)Bivalirudin+GP IIb/IIIa (N=2609)Bivalirudin alone (N=2619)

30 d

ay e

vent

s (%

)

Stone GW et al. Lancet. 2007;369:907-919.Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information

P=.10 P=.057

P=.16 P=.45 P=.32 P<.001

5019

0 31 62 92 123 154 185 215 246 277 308 338 369 4000.0

1.0

2.0

3.0

Mor

talit

y (%

)

Days from Randomization

Early and Late MortalityUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

30-dayEstimate

P(log rank)

0.9%0.451.2%0.631.1%

—Estimate

P(log rank)

3.1%0.702.4%0.482.2%

1-year

—

p=0.78

Data on file, The Medicines Company, Parsippany, NJ.Please refer to important ANGIOMAX safety information on slide 28 and see full Prescribing Information

Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…

Primary PCICABG

– Medical Rx

–

UFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)

Bivalirudin monotherapy(± provisional GP IIb/IIIa)

Aspirin, thienopyridine R

1:1

3006 pts eligible for stent randomization R

3:1

Bare metal EXPRESS stent

Paclitaxel-eluting TAXUS stent

Clinical FU at 30 days, 6 months, 1 year, and then

yearly through 3 years; angio FU at 13 monthsStone, GW N Engl J Med 2008;358:2218-

30.

Harmonizing Outcomes with Revascularization and Stents in AMI

R 1:1

Randomized

* Biomarkers WNL and no DS >50% by core lab determination (30 day FU only)

1-Year FU Eligible

3-Year FU

• • • Withdrew • • •

• • • Lost to FU • • •

2646

2253

3602 pts with STEMI

• • • Not true MI* • • •

28

29

1-Year FU

UFH + GP IIb/IIIaN=1802

BivalirudinN=1800

N=1628 N=1634

N=1774

N=1771

N=1702 N=1696• • • Withdrew • •

•• • • Lost to FU • •

•

1757

1844

Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

3-Year Major Bleeding (non-CABG)*

* Intracranial, intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion

12

0

4

6

8

10

0.64 (0.51, 0.80)

2

0

12 15 18 21 24 27 30 33 36

P=0.0001

3-yr HR (95%CI)

6.9%

10.5%

Maj

or B

leed

ing

(%)

Months

3 6 9

Bivalirudin alone (n=1800)Heparin + GPIIb/IIIa (n=1802)

9.4%

6.0%


3-Year Cardiac Mortality'

5.1%

Time in MonthsTime in Months


Car

diac

Mor

talit

y (%

)

P=0.001

3-yr HR (95%CI)0.56 (0.40, 0.80)

2.9%

0 12 15 18 21 24 27 30 33 36

Months3 6 9

0

1

6

5

4

3

2

3.8%

2.1%


3-Year Reinfarction


6.2%

8.2%

Rei

nfar

ctio

n (%

)

0123456789

10

P=0.04

3-yr HR (95%CI)0.76 (0.59, 0.99)

0 12 15 18 21 24 27 30 33 36Months

3 6 9

4.4%3.6%


Conclusions: Pharmacology Randomization

●In this large-scale, prospective, randomized trial of pts with STEMI undergoing primary PCI, the initial treatment with bivalirudin alone compared to heparin plus GPIIb/IIIa inhibitors at 3 years resulted in:

– A significant 36% reduction in major bleeding and a significant 24% reduction in reinfarction, with non significantly different rates of stent thrombosis, TVR and stroke

– A significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality, the latter representing 18 lives saved per 1000 patients treated with bivalirudin (NNT = 54 to save 1 life)


Other Issues to Consider...

•Timing of intervention•Emergent v. Urgent (24-48

hours)•Access site•Femoral, Radial, Brachial•Closure device•Maintaining access vessel

patency (upper extremity)

My preferences•Emergency PCI (STEMI, Unstable NSTEMI)•Patient on antiplatelet therapy•Bivalirudin (or UFH)•Reload in ED (Ticagrelor 180mg)•IIb/IIIa antag as “bailout”

•Patient antiplatelet naive•Bivalirudin/UFH•Lower threshold to use IIb/IIIa antagonist•Oral antiplatelet on table (Ticagrelor)

My preferences (Cont’d)

•Delayed angiography/PCI•Bivalirudin/UFH•IIb/IIIa antagonists if markedly

rising enzymes•Ticagrelor, Clopidogrel

The Future...•CANGRELOR•BRIDGE Trial

•Cangrelor “bridging” decreased platelet reactivity in patients with prior stents scheduled for CABG

•CHAMPION-PHOENIX Trial•Cangrelor v. Clopidogrel in PCI patients

•Early results show decreased ischemic events at 48 hours in cangrelor group v. clopidogrel

•Platelet function assays to guide antiplatelet Rx

•Pharmacogenomic Studies, etc.

QUESTIONS?

THE END

Pharmacologic Options in the Invasive Management of Acute Coronary Syndrome

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