2. 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
3. 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
6. 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
7.
8. Adjunctive Antithrombotic Therapy to Support PCI After
Fibrinolytic Therapy
(ACC/AHA)
Antiplatelet therapy
After 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
9. • 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
11. • For UA/NSTEMI patients
Initial conservative (i.e., noninvasive) strategy
Clopidogrel or ticagrelor (loading dose followed by daily maintenance
dose) plus aspirin and anticoagulant therapy as soon as possible after
admission and administered for up to 12 months . (Level of Evidence: I
B)
The duration and maintenance dose of P2Y12 receptor inhibitor
therapy 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 given
for at least 12 months. (I B)
b. If the risk of morbidity because of bleeding outweighs the
anticipated benefits afforded by P2Y12 receptor inhibitor therapy,
earlier discontinuation should be considered. (Level of Evidence: C)
13. SUMMARY OF TRIALS OF
CARDIOVASCULAR PREVENTION
ASCET Patients with documented
stable coronary heart
disease.
clopidogrel 75 mg once daily
for two years
Versus 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
atherosclerotic
manifestations (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)
14. 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 CV
causes 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)
15. SUMMARY OF TRIALS OF AF
ACTIVE W , 2006 Clopidogrel (75 mg per day)
plus aspirin
(75-100 mg per day)
versus
oral 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 75-100
mg daily
versus
aspirin 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.
16. SUMMARY OF TRIALS OF ACS
COMMIT ,
2005
clopidogrel 75 mg daily
versus
Placebo
Aspirin 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 -
+aspirin
75-325 mg)
versus
placebo (+ aspirin 75-325 mg)
in pts of NSTE-ACS
In patients with acute coronary syndrome
receiving aspirin, a strategy of clopidogrel
pretreatment followed by long-term therapy
is beneficial in reducing major cardiovascular
events, compared with placebo.
CLARITY-TIMI
28 , 2005
clopidogrel (300-mg loading
dose, followed
by 75 mg once daily)
versus
placebo
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.
17. SUMMARY OF TRIALS OF ACS
CURE , 2001 clopidogrel 300 mg
immediately, followed
by 75 mg once daily +
aspirin for 3 to 12
months
versus
Aspirin (+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 clopidogrel
versus
Standard-dose
clopidogrel
In patients undergoing PCI for acute coronary
syndromes, a 7-day double-dose clopidogrel
regimen 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 clopidogrel
regimen can be considered for all patients with
acute coronary syndromes treated with an early
invasive strategy and intended early PCI.
18. SUMMARY OF TRIALS OF STENT
GRAVITAS ,
2011
High-dose clopidogrel
(600-mg initial
dose, 150 mg daily
thereafter for 6 months)
versus
regular 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 100
mg qD
versus
Ticlopidine 250 mg BID x4
wks Aspirin 100 mg qd
After the placement of coronary-artery
stents in unselected patients, antiplatelet
therapy with aspirin and clopidogrel seems
to be comparably safe and effective as
aspirin and ticlopidine. Noncardiac events
were significantly reduced with clopidogrel.
19. SUMMARY OF TRIALS OF STENT
CLASSICS , 2000 Clopidogrel 300mg x1, 75
mg qD x4 wks
Aspirin 325 mg qD
versus
Ticlopidine 250 mg BID x4
wks Aspirin
325 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 qD
versus
Ticlopidine + Aspirin 325
mg qD
Clopidogrel is better tolerated than ticlopidine
during 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, clopidogrel
confers similar protection as ticlopidine against
subacute stent thrombosis and major adverse
cardiac events.
20. SUMMARY OF TRIALS OF STENT
Piamsomboon ,
2001
Clopidogrel 300 mg x1, 75
mg qD x4 wks
Aspirin 300 mg BID x4 wks,
300 mg qD
versus
Ticlopidine 250 mg po BID
x4 wks
Aspirin 300 mg BID x4 wks,
300 mg qD
Clopidogrel plus aspirin is an effective
coronary stenting regimen comparable to
ticlopidine plus aspirin.
21. SUMMARY OF TRIALS OF CABG
CASCADE , 2009 aspirin 162 mg plus
clopidogrel 75 mg
daily for 1 year
versus
aspirin 162 mg plus
placebo daily
compared with aspirin
monotherapy, the
combination of aspirin
plus clopidogrel did not
significantly reduce the
process of SVG intimal
hyperplasia 1 year after
coronary artery bypass
grafting.
23. • CLopidogrel as Adjunctive ReperfusIon TherapY
–
Thrombolysis In Myocardial Infarction (CLARITY
TIMI 28) TRIAL
24. Hypothesis
•The addition of clopidogrel to standard
fibrinolytic regimens that include aspirin would:
• Improve infarct-related artery patency
• Decrease ischemic complications
25. Study Design
Double-blind, randomized, placebo-controlled trial in
3491 patients, age 18-75 yrs with STEMI < 12 hours
Fibrinolytic, ASA, Heparin
Clopidogrel
300 mg + 75 mg qd
Coronary Angiogram
(2-8 days)
Primary endpoint:
Occluded
artery (TIMI Flow
Grade 0/1)
or D/MI by time
of angio
randomize
Placebo
Study
Drug
30-day clinical follow-up
Open-label
clopidogrel
per MD in
both groups
26. Clopidogrel in STEMI : RESULTS
36%
P<0.0001
15.0
21.7
25
20
15
10
5
0
Occluded Artery or Death/MI (%)
Clopidogrel Placebo
Placebo
Sabatine MS et al. NEJM 2005; 352: 1179
20%
Odds Ratio 0.80
(95% CI 0.65-0.97)
P=0.026
days
CV Death, MI, or Urg Revasc (%)
0 5 10 15
Clopidogrel
0 5 10 15 20 25 30
27. Summary
•In patients with STEMI 75 yrs, receiving a standard fibrinolytic
regimen, 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
28. •Conclusion
•Clopidogrel offers an effective, simple,
inexpensive, and safe means by which to
improve infarct-related artery patency and
reduce ischemic complications.
30. 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
32. 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
35. 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
36. Primary End Point - MI/Stroke/CV
Death
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
Cumulative Hazard Rate
Clopidogrel
+ ASA*
Placebo
+ ASA*
3 6 9
Months of Follow-Up
11.4%
9.3%
20% RRR
P < 0.001
N = 12,562
0 12
37. 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.
38. 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)
41. 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
42. Study Design
CURE PCI-CURE
Randomize
N=2,658 NSTEMI patients undergoing PCI
Pretreatment(for 6 days)
PCI
PLACEBO
+ ASA
CLOPIDOGREL
+ ASA
30 d. post PCI
End of follow-up:
12 months
Open-label thienopyridine(4weeks)
N = 1345
N = 1313
Pretreatment (for 6 days)
PCI-Open-
label thienopyridine
43. 30 Day Results ( Primary end point)
Composite of cardiovascular death, MI, or urgent revascularization
0 5 10 15 20 25 30
Days of follow-up
0.08
0.06
0.04
0.02
0.0
30% RRR
P = 0.03
N = 2658
Cumulative Hazard Rate
6.4
%
4.5
%
Clopidogrel
+ ASA*
Placebo
+ ASA*
44. Composite of cardiovascular death or MI from randomization to end of follow-up
0.15
0.10
0.05
0.0
0 100 200 300 400
Days of follow-up
12.6%
8.8%
31% RRR
P = 0.002
N = 2658
Clopidogrel
+ ASA*
Placebo
+ ASA*
Cumulative Hazard Rate
Overall Long-Term Results
45. † 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
46. Conclusions
– There was an increase in minor bleeding, but was no
significant difference in major or life-threatening
bleeding between the two treatment groups
48. 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 clopidogrel
300 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
49. 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
50. Overall Study Design
Placebo Arm Clopidogrel Arm
PCI 28 Days
Pretreatment(3-24hrs prior to
PCI)
LD Clopidogrel 300
mg
Placebo #
Clopidogrel#
Clopidogrel #
R
Clopidogrel*
Placebo*
12 Months
51. 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.
52. 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
54. 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
57. Clopidogrel for High
Atherothrombotic Risk and
Ischemic Stabilization,
Management and Avoidance
(CHARISMA) TRIAL
58. CHARISMA trial design
Clopidogrel
75 mg/day
(n=7802
Placebo
1 tablet/day
(n=7801)
Low-dose ASA 75-162 mg/day
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
(n=15 603)
3-month Visits every 6 months
visit
59. Patients aged ≥45 years
with
at least one of the following:
Inclusion criteria
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
62. 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).
63. 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.
64. Antiplatelet Therapy for Reduction of
Myocardial Damage During Angioplasty
Study (ARMYDA-2) Trial
65. 255 patients with stable coronary artery disease or
High Loading Dose clopidogrel
600 mg Pre-PCI
n=126
ARMYDA-2 Trial
Standard Loading Dose clopidogrel
300 mg Pre-PCI
n=129
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
67. 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 .
68. ARMYDA (Antiplatelet therapy for Reduction of MYocardial
Damage 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”
69. 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
70. • Five hundred and three patients on >10 days
clopidogrel therapy (41% with non-ST-segment
elevation acute coronary syndrome,
ACS) randomly received 600 mg clopidogrel
loading 4-8 h before PCI (n = 252) or placebo
(n = 251).
71. 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
72. RESULT
Group Clopidogrel
reload (%)
Placebo
(%)
OR (95% CI) p
All patients 6.7 8.8 0.75 (0.37–1.52) 0.50
Stable
7.0 3.9 1.84 (0.60–5.88) 0.36
patients
ACS
patients
6.4 16.3 0.34 (0.32–0.90) 0.033
73. CONCLUSIONS
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
74. 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”
75. 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
76. 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.
77. 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
78. 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.
79. 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.
80. ARMYDA - 150
• High versus standard clopidogrel
maintenance 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.
81. CONCLUSIONS:
For patients undergoing percutaneous coronary
intervention, the 150-mg/day clopidogrel maintenance
dose is associated with stronger platelet inhibition,
improvement of endothelial function, and reduction of
inflammation, compared with the currently
recommended 75-mg/day regimen; those effects might
have a role in the clinical benefit observed with
clopidogrel and may provide the rationale for using the
higher maintenance regimen in selected patients.
82. ARMYDA-8-RELOAD-ACS TRIAL
Efficacy of Clopidogrel Reloading in Patients With
Acute Coronary Syndrome Undergoing Percutaneous
Coronary Intervention During Chronic Clopidogrel
Therapy (from the Antiplatelet therapy
for Reduction of MYocardial Damage during
Angioplasty [ARMYDA-8 RELOAD-ACS] Trial)
83. •Whether an additional clopidogrel load in
patients receiving chronic clopidogrel
therapy and undergoing percutaneous
coronary intervention (PCI) for acute
coronary syndrome (ACS) is associated
with clinical benefit has not been well
characterized.
84. 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).
85. 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.
86. CURRENT- OASIS- 7
•Current oasis-7: A 2x2 factorial
randomized trial of optimal clopidogrel
and aspirin dosing in patients with ACS
undergoing an early invasive strategy with
intent for PCI.
89. • No significant difference in efficacy or bleeding between ASA
300-325mg and ASA 75-100mg
90.
91. Primary Results of The Gauging
Responsiveness with A VerifyNow
Assay - Impact on Thrombosis And
Safety Trial
GRAVITAS
AHA 2010
92. 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.
93. 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
94. Elective or Urgent PCI with DES*
VerifyNow P2Y12 Test 12-24 hours post-PCI
Standard-Dose Clopidogrel†
clopidogrel 75-mg daily X 6 months
High-Dose Clopidogrel†
clopidogrel 600-mg, then
clopidogrel 150-mg daily X 6 months
PRU ≥ 230
R
GRAVITAS Study Design
Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo
Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo
Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months
*Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs
†placebo-controlled
All patients received aspirin (81-162mg daily)
95. GRAVITAS Patient Flow
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
96. 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.
97. 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.
98. 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
99. New Oral Antiplatelet Drugs
Adenosine Diphosphate-Receptor Antagonists
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
* Not approved by FDA
100. 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
101. • 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.
102. 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
103. CONCLUSION
• In patients who have an ACS with or without
ST segment elevation, treatment with
ticagrelor as compared to clopidogrel
significantly 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.
