New Approaches to, andIndications for, Antiplatelet Therapy

Kenneth A. Bauer, MDProfessor of Medicine, Harvard Medical School

Chief, Hematology Section, VA Boston Healthcare System

Director, Thrombosis Clinical Research,

Beth Israel Deaconess Medical Center

DisclosuresConsultant

Bayer HealthcareJanssen PharmaceuticalsBristol Myers SquibbPfizerBoehringer IngelheimInstrumentation Laboratory

Acknowledgement

Deepak Bhatt, MD

Atherothrombosis:Clinical Manifestations

Stroke/TIA

Carotid artery disease

Renal artery stenosis

Peripheral arterial diseaseAcute limb ischemiaClaudicationEndovascular stentingPeripheral bypass

Acute coronary syndromes– STEMI– NSTEMI– Unstable anginaStable CADAngioplastyBare metal stentDrug eluting stentCABG

Abdominal aortic aneurysm (AAA)

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261

Platelet and Thrombus Formation:Vascular Injury

Desai NR, Bhatt DL. JACC Intervention 2010

Antiplatelet Agents

Mechanism Of Aspirin In Reducing Risks Of Cardiovascular Disease

Aspirin irreversibly acetylates the active site of cyclooxygenase (COX-1 and COX-2), which is required for the production of thromboxane A2 by platelets, which promotes platelet aggregation.

Efficacy of Aspirin at Various Doses in Reducing Vascular Events in High-Risk Patients

Vascular events included nonfatal MI, nonfatalstroke, and death from vascular causes.

Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.

0.5 1.0 1.5 2.0

500-1500 34 19

160-325 19 26

75-150 12 32

<75 3 13

Any aspirin 65 23

Antiplatelet Better

Antiplatelet Worse

Aspirin (mg daily) Odds Ratio

0

No. of Trials

% Odds Reduction

Treatment effect P<.0001

Effect of Antiplatelet Therapy in Reducing Vascular Events in Diabetic Patients

Antiplatelet Trialists Collaboration BMJ 1994

Benefit/1000 pts (SD): 36 (3) 38 (12)2P: <0.00001 <0.002

No Diabetes Diabetes

Adj

uste

d (%

) of p

ts (+

1 SD

)w

ith v

ascu

lar

even

ts

0

10

20

30 ControlAntiplatelet therapy

ADP ReceptorsReceptorsubtype

Molecularstructure

Intrinsicion channel

GPCRGq

GPCRGi

Secondarymessenger

system[Na+/Ca2+]i PLC/IP3

[Ca2+]i

AC[cAMP]

Functionalresponse

Shape changeaggregation

Shape change transient aggregation

Sustained aggregation

secretion

G protein G protein

P2Y1

Clopidogrel

P2Y12 Activemetabolite

Bhatt DL et al. Nat Rev Drug Discov. 2003;2:15-28.

P2X1

Ticlopidine

Thienopyridine derivative: converted to active metabolites by liver cytochrome P450 isozymes

Irreversible P2Y12 receptor inhibitorLabeled indication: To reduce the risk of recurrent

stroke in patients who have had a stroke or a TIADosage: 250 mg bidIn combination with aspirin, demonstrated to be more

effective than anticoagulation (heparin/warfarin) in the prevention of stent thrombosis

Replaced by clopidogrel due to hematologic side effects:Neutropenia (2%)Thrombotic thrombocytopenic purpura (TTP)

CAPRIE: Superior Efficacy of Clopidogrel versus ASA

*MI, ischemic stroke or vascular death†Intent-to-treat analysis (n=19,185)

CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36Months of follow-up

Cum

ulat

ive

even

t rat

e* (%

)

ASA

Clopidogrel

8.7%† RRR (p=0.043)

20

Patients with recent ischemic stroke, recent MI or symptomatic PAD

CAPRIE: Clopidogrel Provided Amplified Benefit in Patients with Diabetes

Bhatt DL et al. Am J Cardiol 2002; 90: 625628.

*MI, stroke, vascular death or rehospitalization for ischemic events/bleeding†Number of events prevented per 1000 patients per year compared with ASA

ASAClopidogrel

12.7%

17.7%

21.5%

11.8%15.6%

17.7%

0

5

10

15

20

25

Patients without diabetes (n=15,233)

Patients with diabetes (n=3866)

Patients treated with insulin (n=1134)

Even

t rat

e*/y

ear (

%)

9†

21†

38†

p=0.096

p=0.042

p=0.106

Dual Antiplatelet Therapy

Clopidogrel adds to the benefit of aspirin in some circumstances (coronary artery disease).

Benefits and risks:Aspirin + Clopidogrel

Issues with ClopidogrelClopidogrel versus PrasugrelClopidogrel versus Ticagrelor

Cangrelor (investigational) – P2Y12 receptor antagonist

Aspirin + Dipyrimadole (Aggrenox) – sustained releaseASA (25 mg bid)/dipyrimadole (200 mg bid)Approved indication: ischemic stroke or TIA

Issues with ClopidogrelIrreversible P2Y12 receptor: dosage 75 mg qdPharmacokinetics: Oral absorption 1 h, t1/2 8 hOnset: 4-6 hours (after loading dose)Offset: 5-7 daysVariable response: 25-30% of patients achieve

less than 25% inhibition of platelet activityUndergoes 2 step metabolism (CYP3A4/2C19

mediated) to active agent (genetic variability)Potential drug interaction (e.g., PPIs)

CURE: Primary Efficacy Results(MI/Stroke/CV Death)

Randomized trial in acute MI

Yusuf S et al. N Engl J Med 2001; 345: 494–502.

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 3 6 9 12

Months of follow-up

Cum

ulat

ive

Haz

ard

Rat

e Placebo*

(n = 6,303)

Clopidogrel*(n = 6,259)

20% Relativerisk reduction

p = 0.00009

N=12,562

*On top of standard therapy (including ASA)

CURE: Clopidogrel in Patients with ACS and Diabetes

*Number of events prevented/1,000 patients treated/9 months†On top of standard therapy (including ASA)

Myocardial Infarction, Stroke, or Vascular Death

No previous diabetesn = 9,721

Diabetesn = 2,840

18

Cum

ulat

ive

even

t rat

e (%

)

9.9%

16.7%

7.9%

14.2%

Placebo†

Clopidogrel†

2

4

6

8

10

12

14

16

20*

25*

Yusuf S et al. N Engl J Med 2001; 345: 494–502.

CHARISMAA randomized, double-blind placebo controlled trial of

15,603 patients (79% ) with established CVD and 21% with multiple risk factors designed to test whether clopidogrel should be continued beyond 1 year in addition to aspirin.

All patients received daily aspirin (75-162 mg) and were randomized to daily clopidogrel (75 mg) or placebo

Clopidogrel patients had an event rate of 6.8% and placebo patients had an event rate of 7.3%.

CHARISMA demonstrated no significant benefit long term when clopidogrel is added to aspirin.

Rates of severe bleeding were similar, but clopidogrel patients experienced significantly higher rates of moderate bleeding.

Bhatt DL, et al; N Engl J Med. 2006. 54: 1706-1717

CHARISMA: Proportion of Diabetic Patients in Subgroups

Diabetics

42%Diabetics

31%Diabetics

83%

Non Diabetics

58%

Non Diabetics

17%

Non Diabetics

69%

Overall population

Secondary prevention

Primary prevention

N=15,613 N=12,153 N=3,284

Population RR (95% CI) p value

Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046(n=12,153)

Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20 (n=3,284)

Overall Population† 0.93 (0.83, 1.05) 0.22 (n=15,603)

Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category

0.6 0.8 1.41.2Clopidogrel + ASA

BetterPlacebo + ASA

Better

1.60.4

* A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-specified subgroups of patients† 166 patients did not meet any of the main inclusion criteria

Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

Overall populationN=15,603

Secondary preventionN=12,152

Primary preventionN=3,284

Non Diabetics

N=9,047

Diabetics

N=6,556

Non Diabetics

N=8,380

Diabetics

N=3,773

Non Diabetics

N=569

Diabetics

N=2,715

Primary Efficacy – Diabetics vs Non Diabetics

Placebo + ASA Clopidogrel + ASA

0%

2%

4%

6%

8%

10%

6.7%

5.87%

8.24% 8.17%

6.73%

5.89%

10.04%9.23%

6.98%5.97%

5.14%

6.69%

p-value for interaction: 0.283 p-value for interaction: 0.923 p-value for interaction: 0.255

Mechanism of Action of Prasugrel

Bhatt DL. N Engl J Med 2009.

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 et al. NEJM 2007.

Stent Thrombosis(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

Endp

oint

(%)

Any Stent at Index PCIN= 12,844

Wiviott SD et al NEJM 2007. Slide courtesy of Dr. Elliott Antman

1.8

0.9 0.9

0.1 0.3

2.4

1.41.1

0.4 0.3

0

2

4

TIMI MajorBleeds

LifeThreatening

Nonfatal Fatal ICH

Bleeding Events - Safety 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)

Slide courtesy of Dr. Elliott Antman

Diabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

Endp

oint

(%)

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = ２１

N=314617.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.62.5

Wiviott et al. Circulation 2008.

Mechanism of Action of Ticagrelor(a cyclopentyl triazolopyrimidine)

Bhatt DL. Nature Reviews Cardiology. 2009;6:737-38.

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

13C

umul

ativ

e in

cide

nce

(%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

Wallentin L, et al. N Engl J Med. 2009.

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

6

5

4

3

2

1

0

7

Cum

ulat

ive

inci

denc

e (%

)

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

9,291

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

Myocardial infarction Cardiovascular death

Cum

ulat

ive

inci

denc

e (%

)

Secondary Efficacy Endpoints

Wallentin L, et al. N Engl J Med. 2009.

Ticagrelor in Patients with Diabetes Mellitus PLATO Study

James S et al. EHJ 2010.

CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Platelet Inhibition and Patient Outcomes; TRITON-TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction.Ferreiro JL, Angiolillo DJ. Circulation 2011. 123:798-813.

Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials

TRITON-TIMI 38 17.0 12.2 0.70 (0.58 – 0.85)

PLATO 16.2 14.1 0.88 (0.76 – 1.03)

CURRENT OASIS 7 5.6 4.9 0.87 (0.66 – 1.15)(PCI Cohort)

Study % of Events Hazard Ratio (95% confidence interval)Standard New Drug/Approach

New Drug/ApproachBetter

Standard ClopidogrelBetter

0 0.5 1 1.5

DUAL ANTIPLATELET THERAPY AND INCREASED RISKS OF BLEEDING

In a meta-analysis of 18 randomized trials which included 129,314 patients

Those assigned to dual antiplatelet therapy have about a 50% increase in risk of major bleeding compared with those given single agent therapy

The magnitude of this excess risk is about as high as the approximately 60% increase observed in the trials comparing single antiplatelet agents to placebo

These excess risks of major bleeding should be considered in relation to the benefits on occlusive CVD events in choosing the optimal antiplatelet strategy, especially for long-term treatment of patients with prior events or those at high risk of developing CVD.

Fund Clin Pharm 2008; 22:315-321

Conclusions

Increased platelet activation/aggregation in diabetic patient

contributes to their increased rate of ischemic events

Clear role for aspirin in secondary prevention, ? “primary” prevention

Dual antiplatelet therapy indicated for at least 1 year after ACS or PCI

More potent P2Y12 receptor antagonists likely of greater benefit in

diabetics, if bleeding risk not too high