REVIEW ON TRIALS OF CLOPIDOGREL

Richa Sharma

ABOUT CLOPIDOGREL

An inhibitor of platelet ADP receptor P2Y12

Irreversibly inhibit the binding of ADP to the

P2Y12 receptor

Prevent the transformation & activation of

the GpIIb/IIIa receptor

PHARMACOKINETICS & DOSAGES

Inactive prodrug; requires in vivo oxidation by hepatic &/or intestinal cyp 3A4 & 2C19

Onset of action: within hours

Steady state: b/w 3-7 days

300 mg LD: within 4-6 hours

600 mg LD: within 2 hours

Cessation for 5 days is recommended prior to CABG

GUIDELINES

Maintenance doses and duration of therapy

ASPIRIN: 81- to 325-mg daily maintenance dose (indefinite)* I A ● 81 mg daily is the preferred maintenance dose* IIa B

DES placed: Continue therapy for 1 y with:● Clopidogrel: 75 mg daily I B ● Prasugrel: 10 mg daily I B ● Ticagrelor: 90 mg twice a day* I B

BMS† placed: Continue therapy for 1 y with:● Clopidogrel: 75 mg daily I B ● Prasugrel: 10 mg daily I B ● Ticagrelor: 90 mg twice a day* I B

DES placed:● Clopidogrel, prasugrel, or ticagrelor* continued beyond 1 y IIb C ● Patients with STEMI with prior stroke or TIA: prasugrel III: Harm B

Adjunctive Antithrombotic Therapy to Support PCI After Fibrinolytic Therapy

(ACC/AHA)Antiplatelet therapyAfter PCI, aspirin should be continued indefinitely (81-325mg).

P2Y12 receptor inhibitors• Loading doses• For patients who received a loading dose of clopidogrel with fibrinolytic

therapy: Continue clopidogrel 75 mg daily without an additional loading dose I C

• For patients who have not received a loading dose of clopidogrel:● If PCI is performed within 24 h of fibrinolytic therapy: clopidogrel 300-mg loading dose before or at the time of PCI I C ● If PCI is performed 24 h after fibrinolytic therapy: clopidogrel 600-mg loading dose before or at the time of PCI I C ● If PCI is performed 24 h after treatment with a fibrin-specific agent or 48 h after a non–fibrin-specific agent: prasugrel 60 mg at the time of PCI IIa B • For patients with prior stroke/TIA: prasugrel III

• Maintenance doses and duration of therapy

• DES placed: Continue therapy for at least 1 y with:

• ● Clopidogrel: 75 mg daily I C

• ● Prasugrel: 10 mg daily IIa B

• BMS* placed: Continue therapy for at least 30 d and up to 1 y with:

• ● Clopidogrel: 75 mg daily I C

• ● Prasugrel: 10 mg daily IIa B

Recommandations of Antiplatelet agents in ACS/NSTEMI undergoing PCI (2014 ACC/AHA GUIDELINES)

• For UA/NSTEMI patients

Initial conservative (i.e., noninvasive) strategy

Clopidogrel or ticagrelor (loading dose followed by daily maintenancedose) plus aspirin and anticoagulant therapy as soon as possible afteradmission and administered for up to 12 months . (Level of Evidence: IB)

The duration and maintenance dose of P2Y12 receptor inhibitortherapy should be as follows:

a. In UA/NSTEMI patients undergoing PCI, either clopidogrel 75 mg daily, prasugrel* 10 mg daily , ticagrelor 90 mg twice daily should be givenfor at least 12 months. (I B)

b. If the risk of morbidity because of bleeding outweighs theanticipated benefits afforded by P2Y12 receptor inhibitor therapy,earlier discontinuation should be considered. (Level of Evidence: C)

REVIEW OF TRIALS OF CLOPIDOGREL

SUMMARY OF TRIALS OF CARDIOVASCULAR PREVENTION

ASCET Patients with documented stable coronary heart disease.clopidogrel 75 mg once daily for two yearsVersus Aspirin 160 mg once daily for two years

No difference in the composite endpoint of stroke,USA,MI and death between the two groups

CAPRIE study, 1996 Clopidogrel 75 mg/d for a minimum of one year and a maximum of 3 years compared with Aspirin 325 mg/d in patients with atheroscleroticmanifestations (ischemic stroke, recent MI,PAD)

Clopidogrel therapy resulted in a relative risk reduction of 8.7% (CI 0.3-16.5%) compared with aspirin therapy (p = 0.043). Gastrointestinal hemorrhages occurred in 1.99% of patients treated with clopidogrel and 2.66% of patients treated with aspirin (p < 0.002)

SUMMARY OF TRIALS OF CARDIOVASCULAR PREVENTION

CHARISMA study, 2006 Clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) compared with placebo plus low-dose aspirin

The combination was not significantly more effective than aspirin alone in reducing the rate of MI, stroke, or death from CVcauses among patients with stable CV disease or multiple CV risk factors. The risk of moderate bleeding was increased. There was a potential benefit in symptomatic patients (those with established vascular disease)

SUMMARY OF TRIALS OF AF

ACTIVE W , 2006 Clopidogrel (75 mg per day) plus aspirin(75-100 mg per day)versusoral anticoagulation therapy

Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy

ACTIVE A , 2009 clopidogrel 75 mg daily + aspirin 75-100mg dailyversusaspirin 75-100 mg daily alone

In patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events (stroke,MI,non-cns embolism), especially stroke, but increased the risk of major hemorrhage.

SUMMARY OF TRIALS OF ACSCOMMIT , 2005

clopidogrel 75 mg dailyversusPlaceboAspirin 162mg given in both the arms

In a wide range of patients with acute MI, adding clopidogrel 75 mg daily to aspirin and other standard treatments (such as fibrinolytic therapy) safely reduces mortality and major vascular events in hospital, and should be considered routinely.

CURE (PCI sub study) ,2001

pretreatment with clopidogrel -+aspirin75-325 mg)versusplacebo (+ aspirin 75-325 mg) in pts of NSTE-ACS

In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrelpretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo.

CLARITY-TIMI 28 , 2005

clopidogrel (300-mg loading dose, followedby 75 mg once daily)versusplacebo

In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.

SUMMARY OF TRIALS OF ACSCURE , 2001 clopidogrel 300 mg

immediately, followed by 75 mg once daily + aspirin for 3 to 12 monthsversusAspirin (+placebo)NSTEMI

The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel.

CURRENT OASIS 7, 2010

Double-dose clopidogrelversusStandard-dose clopidogrel

In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrelregimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrelregimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI.

SUMMARY OF TRIALS OF STENT

GRAVITAS , 2011

High-dose clopidogrel(600-mg initialdose, 150 mg daily thereafter for 6 months)versusregular clopidogrel dose (75mg daily for 6 months)

Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis.

Mller , 2000 Clopidogrel 75 mg qD x4 wks Aspirin 100mg qDversusTiclopidine 250 mg BID x4 wks Aspirin 100 mg qd

After the placement of coronary-artery stents in unselected patients, antiplatelettherapy with aspirin and clopidogrel seems to be comparably safe and effective as aspirin and ticlopidine. Noncardiac events were significantly reduced with clopidogrel.

SUMMARY OF TRIALS OF STENTCLASSICS , 2000 Clopidogrel 300mg x1, 75

mg qD x4 wksAspirin 325 mg qDversusTiclopidine 250 mg BID x4 wks Aspirin325 mg qD

The safety/tolerability of clopidogrel (plus aspirin) is superior to that of ticlopidine (plus aspirin) (P=0.005). The 300-mg loading dose was well tolerated, notably with no increased risk of bleeding. Secondary end point data are consistent with the hypothesis that clopidogrel and ticlopidine have comparable efficacy with regard to cardiac events after successful stenting.

TOPPS , 2001 (Ticlid or Plavix post stent trial)

Clopidogrel + Aspirin 325 mg qDversusTiclopidine + Aspirin 325 mg qD

Clopidogrel is better tolerated than ticlopidineduring a 2-week regimen after intracoronary stent implantation. Combining either thienopyridine with an intravenous platelet IIb/IIIa inhibitor appears to be safe. When applied to a broad spectrum of patients receiving stent implantation, clopidogrelconfers similar protection as ticlopidine against subacute stent thrombosis and major adverse cardiac events.

SUMMARY OF TRIALS OF STENTPiamsomboon , 2001

Clopidogrel 300 mg x1, 75 mg qD x4 wksAspirin 300 mg BID x4 wks, 300 mg qDversusTiclopidine 250 mg po BID x4 wksAspirin 300 mg BID x4 wks, 300 mg qD

Clopidogrel plus aspirin is an effective coronary stenting regimen comparable to ticlopidine plus aspirin.

SUMMARY OF TRIALS OF CABG

CASCADE , 2009 aspirin 162 mg plus clopidogrel 75 mgdaily for 1 yearversusaspirin 162 mg plus placebo daily

compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimalhyperplasia 1 year after coronary artery bypass grafting.

TRIALS OF CLOPIDOGREL IN

STEMI

• CLopidogrel as Adjunctive ReperfusIon TherapY–Thrombolysis In Myocardial Infarction (CLARITY TIMI 28) TRIAL

Hypothesis

•The addition of clopidogrel to standard fibrinolytic regimens that include aspirin would:

• Improve infarct-related artery patency

• Decrease ischemic complications

Study Design

Fibrinolytic, ASA, Heparin

Clopidogrel300 mg + 75 mg qd

Coronary Angiogram(2-8 days)

Primary endpoint:Occludedartery (TIMI Flow Grade 0/1)or D/MI by timeof angio

randomize

Placebo

Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours

StudyDrug

30-day clinical follow-up

Open-labelclopidogrelper MD in

both groups

Clopidogrel in STEMI : RESULTS

15.0

21.7

0

5

10

15

20

25

Occlu

ded

Art

ery

or

Death

/MI

(%

)

PlaceboClopidogrel

36% P<0.0001

Sabatine MS et al. NEJM 2005; 352: 1179

days

CV

De

ath

, MI,

or

Urg

Rev

asc

(%)

05

10

15

0 5 10 15 20 25 30

Placebo

Clopidogrel

Odds Ratio 0.80(95% CI 0.65-0.97)

P=0.026

20%

Summary•In patients with STEMI 75 yrs, receiving a standard fibrinolyticregimen, a loading dose of 300 mg of clopidogrel followed by 75 mg daily resulted in:

• 36% reduction in the odds of an occluded infarct-related artery, or death/MI by angio (NNT = 16)

• Highly consistent benefit across all major subgroups

• 20% reduction in CV death, MI, or recurrent ischemia leading to urgent revasc through 30 days (NNT = 36)

• No excess in TIMI major or minor bleeding (including in those undergoing CABG) or in ICH

•Conclusion

•Clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve infarct-related artery patency and

reduce ischemic complications.

CLOPIDOGREL AND METOPROLOL IN MI

TRIAL (COMMIT)

Study design

Treatment Clopidogrel 75 mg OD vs placebo (aspirin 162 mg daily in both groups)

Inclusion Suspected acute MI (ST change or LBBB) within 24 h of symptom onset

Exclusion Primary PCI or high risk of bleeding

1 Outcomes Death , re-MI, or stroke up to four weeks in hospital (or prior to discharge

Mean treatment + follow-up = 16 days

COMMIT: Clopidogrel (75 mg qd) in STEMI

9% relative risk reduction (P=.002)

Placebo+ASA(10.1%)(2311 events)

Clopidogrel+ASA(2125 events) (9.3%)

Days

De

ath

, MI,

Str

oke

(%

)

9

8

7

6

5

4

3

2

1

00

Mo

rtal

ity

(%)

Days

Placebo+ASA (8.1%) (1846 deaths)

Clopidogrel+ASA(7.5%)(1728 deaths)

7% relative risk reduction (P=.03)

7

6

5

4

3

2

1

07 14 21 28 0 7 14 21 28

COMMIT Collaborative Group. Lancet. 2005;366:1607.

45,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)

COMMIT: Conclusions

• Adding 75 mg daily CLOPIDOGREL to aspirin in acute MI prevents ~10 major vascular events per 1000 treated

• No excess of cerebral, fatal or transfused bleeds (even with fibrinolytic therapy and in older people)

• Each million MI patients treated for ~2 weeks would avoid 5000 deaths and 5000 non-fatal events

TRIALS IN NSTEMI/USA

Clopidogrel in Unstable Angina to prevent Recurrent

Events (CURE) TRIAL

Study Design

AIM: to assess the efficacy of clopidogrel in

reducing the risk of ischaemic stroke, MI or

vascular death

Participants: pts(n= 12,562) with recent

ischaemic stroke, recent MI or symptomatic

PAD

Drug: clopidogrel (300 mg LD f/b 75 mg

OD)

Follow up: 1-3 years

Primary End Point - MI/Stroke/CV Death

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Cu

mu

lati

ve

Ha

za

rd R

ate

Clopidogrel

+ ASA*

3 6 9

Placebo

+ ASA*

Months of Follow-Up

11.4%

9.3%

20% RRR

P < 0.001

N = 12,562

0 12

Conclusions• In the CURE study of 12,562 patients with ACS without ST-

segment elevation:

– clopidogrel demonstrated a 20% RRR in MI, stroke or cardiovascular death with long-term use. (P <0.001)

– the Kaplan-Meier curves began to diverge within hours and continued to diverge over the course of 12 months.

– clopidogrel also demonstrated a 14% RRR in MI, stroke, cardiovascular death or refractory ischemia. (P <0.001)

• Clopidogrel in addition to aspirin demonstrated an early effect (within hours) and sustained long-term benefit throughout the entire study period of 12 months.

Conclusions• Minor bleeding was increased, but there was no

increase in life-threatening bleeds (including

intracranial bleeds) but with sig. increase in major

bleed

• 18% Relative Risk Reduction in heart failure

(P = 0.03)

• Significant reductions in the reported use of:

• IV GP IIb/IIIa inhibitor: 18% (P = 0.003)

• thrombolytics: 43% (P < 0.001)

TRIALS IN PCI

PCI – CURE TRIAL

Objective

–To test the hypothesis that pre-treatment with clopidogrel in addition to aspirin and other standard therapy would be more effective than aspirin and standard therapy alone in preventing major ischemic events within the first 30 days after PCI

–To determine if long-term treatment (up to 1 year) with clopidogrel in addition to aspirin and other standard therapy after PCI would provide additional clinical benefit

Study Design

RandomizePCI

PLACEBO+ ASA

CLOPIDOGREL+ ASA

30 d. post PCIEnd of follow-up:

12 months

Open-label thienopyridine(4weeks)

Pretreatment (for 6 days)

Pretreatment(for 6 days)

N=2,658 NSTEMI patients undergoing PCI

N = 1345

N = 1313

CURE PCI-CURE

PCI-

Open-label thienopyridine

30 Day Results ( Primary end point)

0 5 10 15 20 25 30

Days of follow-up

0.0

0.02

0.04

0.06

0.08

30% RRRP = 0.03

N = 2658

Cu

mu

lati

ve H

azar

d R

ate 6.4

%

4.5

%Clopidogrel

+ ASA*

Placebo + ASA*

Composite of cardiovascular death, MI, or urgent revascularization

0.15

0.10

0.05

0.0

0 100 200 300 400

Days of follow-up

12.6%

8.8%

31% RRRP = 0.002N = 2658

Clopidogrel+ ASA*

Placebo+ ASA*

Cu

mu

lati

ve H

azar

d R

ate

Composite of cardiovascular death or MI from randomization to end of follow-up

Overall Long-Term Results

† Up to 12 months

Conclusions

• For the composite of MI or cardiovascular death in the 2658 patients who underwent PCI in the CURE trial:– clopidogrel plus aspirin demonstrated a 31% RRR from

randomization to the end of follow-up (P = 0.002)

– clopidogrel plus aspirin demonstrated a 25% RRR in the composite of MI or cardiovascular death with long-term use† from PCI to end of follow-up (P = 0.04)

– clopidogrel in addition to aspirin and other standard therapy provides early beneficial effects and sustained long-term†

benefit in ACS patients requiring PCI

Conclusions

– There was an increase in minor bleeding, but was no

significant difference in major or life-threatening

bleeding between the two treatment groups

CLOPIDOGREL FOR THE REDUCTION OF

EVENTS DURING OBSERVATION (CREDO) TRIAL

Objective

–To evaluate the long term efficacy of prolonged (1 year) therapy with clopidogrel 75mg vs placebo in patients on top of standard therapy (including ASA)

–To evaluate the effect of pretreatment with a clopidogrel300 mg loading dose on the composite of death (all-cause), MI (Q- or non-Q-wave), or TVR at Day 28, in patients who underwent PCI

–To evaluate the safety of clopidogrel, specifically the frequency of major bleeding events and early discontinuation of study drug

1 Year Endpoint

–First occurrence of any component up to 1 year of the cluster of:

• Death, MI, or stroke

28 Day Endpoint

–First occurrence of any component up to 28 days of the cluster of:

• Death, MI, or urgent TVR

Overall Study Design C

lop

idogre

l Arm

Pla

ceb

o A

rm

PCI 28 Days

Placebo #

Pretreatment(3-24hrs prior to

PCI)

LD Clopidogrel 300

mg

Clopidogrel #

Clopidogrel#

R

Clopidogrel*

Placebo*

12 Months

General Conclusions

• Long-term results at 1 year demonstrate a 27 % RRR (p=0.02) in

the combined endpoint of MI, stroke, and death.

• The results indicate an increased benefit of pretreatment with

clopidogrel as early as possible prior to PCI.

• The important RRR (37.4 %RRR, p=0.04) between 29-days and 1

year highlights the value of for long-term protection (up to 1 year)

with Clopidogrel.

• The benefit was consistent through all patient subgroups evaluated

and independent of the background therapy, with a favorable safety

profile.

Overall Safety Outcomes: Conclusions

• No fatal bleeds or intracranial hemorrhages were observed

• When Clopidogrel was continued for a full year there was no statistically significant increase in major bleeding (8.8% vs. 6.7 %, p=0.07), and minor bleedings rates were approximately equal

• Approximately 2/3 of all major bleeds occurred in patients undergoing CABG:

–CABG patients in both groups experienced a high incidence of major bleeds

CLOPIDOGREL VERSUS ASPIRIN IN PATIENTS AT RISK FOR ISCHAEMIC

EVENTS (CAPRIE) TRIAL

Design• Objective: to compare the efficacy and safety of

clopidogrel 75 mg with active control – ASA 325 mg

• Double-blind, randomized, prospective trial

• Multicenter (384 centers in 16 countries)

• Follow-up of 19,185 patients from 1 to 3 years with:

– Ischemic atherothrombotic stroke

– Myocardial infarction (MI)

– Peripheral arterial disease

• Combined primary endpoint: cluster of ischemic stroke, MI, and vascular death

Cumulative Event Rate

(Myocardial Infarction, Ischemic Stroke or Vascular

Death)

Months of follow-up

8.7%*

Overallrelative

riskreduction

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

Cu

mu

lati

ve

even

t ra

te (

%)

ASA

p = 0.043, n = 19,185

Clopidogrel

Reduction of Myocardial Infarction

Months of follow-up

0

1

2

3

4

5

0 3 6 9 12 15 18 21 24 27 30 33 36

Cu

mu

lati

ve

even

t ra

te (

%)

p = 0.008, n = 19,185

ASA 3.6%

Clopidogrel 2.9%

Clopidogrel

ASA 19.2%*

Relativerisk

reduction

Clopidogrel for High Atherothrombotic Risk and

Ischemic Stabilization, Management and Avoidance

(CHARISMA) TRIAL

CHARISMA trial design

Clopidogrel 75 mg/day(n=7802

Placebo 1 tablet/day (n=7801)

1-month

visit

Final visit (fixed study end date)(28 months)

Patients age ≥45 years at high risk for atherothrombotic events

R Double-blind treatment up to 1040 primary

efficacy events*

Low-dose ASA 75-162 mg/day

Low-dose ASA 75-162 mg/day

(n=15 603)

Visits every 6 months3-month

visit

Patients aged ≥45 years

with

at least one of the following:

1A) Documented coronary disease

and/or

1B) Documented cerebrovascular disease

and/or

1C) Documented symptomatic PAD

and/or

2) Two major or one major and two minor or three minor risk factors

With written informed consent

Without exclusion criteria

Inclusion criteria

Primary Efficacy Outcome (MI, Stroke, or CV Death)†C

um

ula

tiv

e ev

ent

rate

(%

)

0

2

4

6

8

Months since randomization

0 6 12 18 24 30

Placebo + ASA

7.3%

Clopidogrel + ASA

6.8%

RRR: 7.1% [95% CI: -4.5%, 17.5%]

p=0.22

Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)†

Placebo + ASA

17.9%

Clopidogrel + ASA

16.7%

RRR: 7.7% [95% CI: 0.5%, 14.4%]

p = 0.04

Cu

mu

lati

ve

even

t ra

te (

%)

0

5

10

15

20

Months since randomization§0 6 12 18 24 30

Conclusions

•7.1% RRR for the primary endpoint in the

overall population (p = 0.22).

•7.7% RRR for the secondary endpoint which

included hospitalizations (p =0.04).

Conclusions

In patients with multiple risk factors, without clearly

documented CV disease, dual antiplatelet therapy was not

beneficial excess in CV mortality as well as an increase in

bleeding.

In patients with documented CV disease (CAD, CVD, or PAD)

long-term clopidogrel plus ASA resulted in a significant 12.5%

RRR in MI/stroke/CV death with no significant increase in

severe bleeding compared to ASA alone.

Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty

Study (ARMYDA-2) Trial

High Loading Dose clopidogrel600 mg Pre-PCI

n=126

ARMYDA-2 Trial

Standard Loading Dose clopidogrel300 mg Pre-PCI

n=129

255 patients with stable coronary artery disease or

non-ST-elevation ACS prior to PCI

Excluding those with Primary intervention for AMI, baseline levels CK-MB > upper normal limit,

contraindications to antithrombotic/antiplatelet therapy, high risk bleeding, CABG in past 3 mos, or

clopidogrel treatment within 10 days of randomization

23% female, mean age 64 years

13% received IIb/IIa inhibitors and 20% drug-eluting stents

RESULTSPrimary end-point

P=0.041

4%

12%

0

3

6

9

12

15

mg 600

mg 300

Summary

Among patients with stable CAD or NSTE- ACS about to undergo PCI

with stenting there was a significant decrease in the primary

composite endpoint of in those who received the higher (600mg)

dose of clopidogrel .

The secondary composite endpoint (peak value of cardiac markers

Trop I,CKMB,Myoglobin taken at 8 and 24 hrs) was also lower in the

high-dose clopidogrel group.

There was no increase in the risk of major bleeding or transfusion in

the high-dose clopidogrel group.

This was the first randomized trial comparing high-dose clopidogrel

to standard dose clopidogrel .

ARMYDA (Antiplatelet therapy for Reduction of MYocardialDamage during Angioplasty) study group

Prospective, multicenter, randomized, double blind trial investigating influence on PCI outcome of additional 600 mg clopidogrel load

in patients on chronic therapy - “ARMYDA 4 -Reload”

GOAL OF THE STUDY

To evaluate safety and effectiveness of a

strategy of 600 mg clopidogrel reload in

patients undergoing PCI on chronic

clopidogrel therapy, and to evaluate

difference in outcome in patients with ACS

vs stable angina

• Five hundred and three patients on >10 days clopidogrel therapy (41% with non-ST-segment elevation acute coronary syndrome, ACS) randomly received 600 mg clopidogrelloading 4-8 h before PCI (n = 252) or placebo (n = 251).

STUDY ENDPOINTS

Primary endpoint

30-day incidence of death, MI, TVR

Secondary endpoints

Post-procedural increase of markers of myocardial injury above UNL

(CK-MB, troponin I, myoglobin)

Occurrence of any vascular/bleeding complications

“Point of care” evaluation of platelet reactivity at different time points

in the two arms

Group Clopidogrel reload (%)

Placebo (%)

OR (95% CI) p

All patients 6.7 8.8 0.75 (0.37–1.52) 0.50

Stable patients

7.0 3.9 1.84 (0.60–5.88) 0.36

ACS patients

6.4 16.3 0.34 (0.32–0.90) 0.033

RESULT

The ARMYDA-Reload trial indicates that a significant proportion of

patients undergoing PCI are on chronic clopidogrel therapy

Patients with stable angina who are already taking clopidogrel can safely

undergo PCI without need of further reload

In patients with ACS, a 600 mg reload strategy can significantly improve

outcome

No major bleeding, and no increased bleeding risk are observed in the

“reload” approach in either stable or ACS patients

CONCLUSIONS

ARMYDA-5 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study

Prospective, multicenter, randomized trial investigating influence on outcome of in-lab 600 mg

clopidogrel loading vs 6-hour pre-PCI treatment – “ARMYDA-Preload”

GOAL OF THE STUDY

To evaluate safety and effectiveness of a strategy of 600 mg clopidogrel load given in the cath-lab, at the time of PCI, after diagnostic coronary angiography

CONCLUSIONS

ARMYDA-5 indicates that 600 mg “in lab” clopidogrel load pre-

PCI does not have unfavorable influence on outcome (vs 6 hrs

preload).

Differences in platelet reactivity by aggregometry (at PCI and

at 2 hrs) do not translate into different event rates in the

“upstream” vs the in-lab strategy.

No bleeding differences and no major bleedings were

observed in the 2 arms.

The in-lab strategy may obviate the need of preloading before

knowing patients’ anatomy: thus, when indicated, in-lab 600

mg clopidogrel administration can be a safe and effective

alternative to pretreatment given several hours pre-PCI.

ARMYDA 6 MI

• Outcome comparison of 600- and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results from the ARMYDA-6 MI

METHODS

A total of 201 patients undergoing primary PCI for STEMI randomly received a 600-mg (n = 103) or 300-mg (n = 98) clopidogrel loading dose before the procedure.

The primary endpoint was the evaluation of the infarct size, defined as the area under the curve of cardiac markers.

CONCLUSIONS:

In STEMI patients, pre-treatment with a 600-mg clopidogrel loading dose before primary PCI was associated with a reduction of the infarct size compared with a 300-mg loading dose, as well as with improvement of angiographic results, residual cardiac function, and 30-day major adverse cardiovascular events;

Further studies are warranted to evaluate impact of such strategy on survival.

ARMYDA - 150

• High versus standard clopidogrelmaintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation results of the ARMYDA-150 mg (antiplatelet therapy for reduction of myocardial damage during angioplasty) randomized study.

CONCLUSIONS:

For patients undergoing percutaneous coronaryintervention, the 150-mg/day clopidogrel maintenancedose is associated with stronger platelet inhibition,improvement of endothelial function, and reduction ofinflammation, compared with the currentlyrecommended 75-mg/day regimen; those effects mighthave a role in the clinical benefit observed withclopidogrel and may provide the rationale for using thehigher maintenance regimen in selected patients.

ARMYDA-8-RELOAD-ACS TRIAL

Efficacy of Clopidogrel Reloading in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention During Chronic ClopidogrelTherapy (from the Antiplatelet therapyfor Reduction of MYocardial Damage during Angioplasty [ARMYDA-8 RELOAD-ACS] Trial)

•Whether an additional clopidogrel load in patients receiving chronic clopidogreltherapy and undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) is associated with clinical benefit has not been well characterized.

AIM

• To evaluate, in a randomized protocol, the safety and effectiveness of clopidogrel reload for patients with ACS undergoing PCI in the background of chronic clopidogrel therapy.

• A total of 242 patients with non ST-segment elevation ACS with >10 days of clopidogrel therapy randomly received a 600-mg loading dose of clopidogrel 4 to 8 hours before PCI (n [ 122) or placebo (n [ 120).

• The primary end point was the 30-day incidence of major adverse cardiac events (death, myocardial infarction, target vessel revascularization).

CONCLUSION

•The results from the Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty (ARMYDA-8 RELOAD-ACS) trial have shown a significant clinical benefit from reloading patients with ACS receiving chronic clopidogrel therapy before PCI.

CURRENT- OASIS- 7

•Current oasis-7: A 2x2 factorial randomized trial of optimal clopidogreland aspirin dosing in patients with ACS undergoing an early invasive strategy with intent for PCI.

25,087 patients

• No significant difference in efficacy or bleeding between ASA

300-325mg and ASA 75-100mg

Primary Results of The Gauging

Responsiveness with A VerifyNow

Assay - Impact on Thrombosis And

Safety Trial

GRAVITAS

AHA 2010

Point-of-Care Platelet Function Testing: Current Status

• At least 7 studies involving more than

3,000 patients have concluded that high

residual (on-clopidogrel) platelet reactivity

measured by the VerifyNow P2Y12 test is

associated with poor clinical outcomes after

PCI.

• A treatment strategy for patients with high

residual platelet reactivity has not been

tested in a large, randomized, clinical trial.

GRAVITAS: Primary Hypothesis

• . High-dose clopidogrel for 6 months is

superior to standard-dose clopidogrel

for the prevention of adverse CV

events after PCI in patients with high

residual reactivity

Standard-Dose Clopidogrel†

clopidogrel 75-mg daily X 6 months

High-Dose Clopidogrel†

clopidogrel 600-mg, thenclopidogrel 150-mg daily X 6 months

Elective or Urgent PCI with DES*

VerifyNow P2Y12 Test 12-24 hours post-PCI

PRU ≥ 230

R

GRAVITAS Study Design

†placebo-controlled

Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 moKey Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 moPharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months

All patients received aspirin (81-162mg daily)

*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs

5429 patients screened with VerifyNow P2Y12 12-24 hours post-PCI

2214 (41%) with high residual

platelet reactivity

(PRU ≥ 230)

3215 (59%) without high

residual platelet reactivity

(PRU < 230)

Clopidogrel

High Dose

N=1109

Clopidogrel

Standard Dose

N=1105

GRAVITAS Patient Flow

GRAVITAS: Summary

• Compared with standard-dose therapy, high-dose

clopidogrel achieved a modest

pharmacodynamic effect in patients with high

residual reactivity.

• In patients with high residual reactivity measured

after PCI, 6-months of high-dose clopidogrel did

not reduce the rate of cardiovascular death, non-

fatal MI, or stent thrombosis and did not increase

GUSTO severe or moderate bleeding.

GRAVITAS does not support a

treatment strategy of high-dose

clopidogrel in patients with high

residual reactivity identified by a

single platelet function test after PCI.

Issues with Clopidogrel

• Onset: 4-6 hours (after loading dose with 8 x maintenance dose)

• Offset: 5-7 days

• Variable response: 25-30% of patients achieve less than 25% inhibition of platelet activity

• Must undergo 2 step metabolism (CYP3A4 mediated) to active agent

• Binds irreversibly to P2Y12 receptor

• Postulated but unproven interaction with PPIs.

Gurbel, PA, et al, Circulation 2003; 107:2908-2913;

Laine L, Hennekens CH: Am J Gastro. Published online 11/13/09

New Oral Antiplatelet Drugs

Prasugrel– Thienopyridine

– More rapid onset of action

than clopidogrel

– Irreversible inhibitor of the

P2Y12 receptor

Ticagrelor *– Cyclo-pentyl-triazo-

pyrimidine (CPTP)

– More rapid onset of action

than clopidogrel

– Reversible inhibitor of the

P2Y12 receptor

Adenosine Diphosphate-Receptor Antagonists

* Not approved by FDA

Triton-TIMI 38

• Evaluation of Prasugrel vs Clopidogrel in

ACS patiets

• 13,608 patients with moderate to high-risk

acute coronary syndromes with scheduled

PCI

• Randomized to prasugrel (60 mg loading

dose and a 10 mg daily maintenance dose)

or clopidogrel (300 mg loading dose and a 75

mg daily maintenance dose) for 6-15 months.

Triton –TIMI Investigators. NEJM; 357: 2001 2015

• CONCLUSIONS

In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.

PLATO Ticagrelor vs Clopidogrel in Patients with Acute

Coronary Syndromes

• 18,624 patients with acute coronary

syndromes

• Randomization:

– Ticagrelor 180 mg loading dose, 90mg BID

– Clopidogrel 300-600 mg loading dose, 75 mg

QD

• All patients received ASA 75-325 mg

Wallentin, L et al NEJM 2009; 361: 1045-1057

CONCLUSION

• In patients who have an ACS with or without ST segment elevation, treatment with ticagrelor as compared to clopidogrelsignificantly reduced the rate of death from vascular causes myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding.

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