Early And Long Term Treatment With Clopidogrel In Coronary Artery Disease ףףףף’ ףףףף ףףףףףף ףףףף ףףף, ףף"ף ףףףףףףף ףףףףף2005
Feb 11, 2016
Early And Long Term Treatment With Clopidogrel In Coronary
Artery Disease
פרופ’ יוסף רוזנמןמכון הלב, בי"ח
וולפסון2005דצמבר
Acute Coronary Syndromes
Acute Coronary Syndrome
No ST Elevation ST Elevation
Unstable Angina Myocardial InfarctionNon Q MI Q wave MI
Non ST Elevation MI
Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.
Initial Treatment Strategy ACS
ST Elevation Non ST Elevation
1. Anti-thrombotic Rx (+ Fibrinolysis)
2. Early / Primary PCI
1. Anti-thrombotic Rx2. Early PCI
Reperfusion and culprit plaque stabilization
The best way to stabilize a culprit plaque is with a stent
Culprit plaque stabilization
Minimize peri-procedural complications (related to the treated plaque)
Thrombosis etc
Stabilize the rest of the non-occlusive narrowings
Prevent progressionPrevent atherothrombosis
1
2
Goals of Peri – PCI Medical Treatment (short and long term)
The Clinical QuestionsCombination Rx. (ASA + Clopidogrel)
When angiography / PCI is planned in a patient already treated with ASA:Is additional pre-treatment with clopidogrel improving outcome (until angiography / PCI, at 1 month – or longer)Is continuation of clopidogrel beyond 1 month improving long-term outcome
1
2
Goals of therapy1. Prevent ischemic events until coronary
angiography / PCI Before plaque stabilization was achieved
2. Prevent PCI / stent related ischemic complications
Clopidogrel before coronary angiography - Patients with ACS 1
Clopidogrel before coronary angiography - Patients with ACS
• ST Elevation–CLARITY
• Non ST Elevation–CURE
1
• ST Elevation–CLARITY
• Non ST Elevation–CURE
1Clopidogrel before coronary
angiography - Patients with ACS
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
Primary Endpoint:Primary Endpoint:Occluded Artery Occluded Artery (or D/MI by time of angio)(or D/MI by time of angio)
15.0
21.7
0
5
10
15
20
25
Occ
lude
d A
rter
y or
Dea
th/M
I (%
)
PlaceboPlaceboClopidogrelClopidogrel
P=0.00000036P=0.00000036
Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)
1.00.4 0.6 0.8 1.2 1.6
ClopidogrelClopidogrelbetterbetter
PlaceboPlacebobetterbetter
n=1752 n=1739
36%Odds Reduction
15.418.6 19.5
23.3
29.333.0
0
5
10
15
20
25
30
35
(%)
ClopidogrelPlacebo
Need for Urgent orAdditional Treatment
21% P=0.01
21% P=0.005
16% P=0.07
Early Angio(w/in 48 hrs)
Urgent Revasc(index hosp)
GP IIb/IIIaif PCI
CV Death, MI, RI CV Death, MI, RI Urg Revasc Urg Revasc
days
Perc
enta
ge w
ith e
ndpo
int (
%)
Perc
enta
ge w
ith e
ndpo
int (
%)
05
1015
0 5 10 15 20 25 30
PlaceboPlacebo
ClopidogrelClopidogrel
Odds Ratio 0.80Odds Ratio 0.80(95% CI 0.65-0.97)(95% CI 0.65-0.97)
P=0.026P=0.026
20%20%
1
CLARITY: Patient Management
Clopidogrel PlaceboParameter (n=1,752) (n=1,739)
Symptom onset to fibrinolytic (hours) 2.7 2.6Fibrinolytic to study drug (minutes) 10 10Median doses of study medication 4 4Angiography performed (%) 94 94Study drug to angiography (hours) 84 84Coronary revascularization (%): 63 63
PCI 57.2 56.6CABG 5.9 6.0
Sabatine M et al. New Engl J Med 2005; 352: 1179–1189.
PCI-CLARITY: MI, Stroke, or CV DeathEvents pre and post PCI
***MI or Stroke
Patie
nts
with
end
poin
t (%
)
0
5
10
15
7.5
12.0 Clopidogrel Pretreatment (n=933)
No Pretreatment (n=930)
41%p=0.001
OverallEvents*
Pre-PCIEvents**
4.06.2
38%p=0.03
3.6
6.2
46%p=0.008
Post-PCIEvents*
M Sabatine, et al. JAMA 2005,
Prehospital Fibrinolysis with Double Antiplatelet Therapy in Acute ST-Elevation Myocardial Infarction:
The Clarity Ambulance SubstudyThe Clarity Ambulance Substudy
Montalescot G. ESC, September 2005
Substudy Sites and Patient Numbers
France: 172 patientsL Soulat: 57Y Lambert: 48F Lapostolle: 28F Thieuleux: 21C Gully: 10D Pollet: 5D Galley: 2L Olliver: 1
UK: 40 patientsJ Adgey: 27J Purvis: 13
Sweden: 5 patientsJ-E Karlsson: 5
217 patients in total
Montalescot G. ESC, September 2005
Angiographic & ECG Parameters: Ambulance vs. Non-Ambulance
TFG 3 64.4 64.4 NS
Complete* ST resolution at ECG
90 min
180 min
47.2
63.2
37.0
52.7
0.02
0.05
*Complete considered to be >70%; ECG=electrocardiogram
p valueEvent rate (%)
Ambulance Non-ambulance
Non-ambulance betterAmbulance better
Odds ratio (95% CI)
0.50 1.0 1.5 2.0 2.5 3.0
Montalescot G. ESC, September 2005
0 0.5 1.0 1.5 2.0
Ambulance
Non-ambulance
Overall
Clopidogrel better Placebo better
Odds ratio (95% CI)
Primary Endpoint of TIMI Flow Grade 0/1, MI or Death
0.60 (0.301.17)
0.64 (0.530.76)
0.65 (0.540.77)
• ST Elevation–CLARITY
• Non ST Elevation–CURE
1Clopidogrel before coronary
angiography - Patients with ACS
Clopidogrel 75mg q.d. + ASA 75-325 mg q.d.*
(6259 patients)
Placebo + ASA 75-325 mg q.d.*(6303 patients)
Day 1
6 m. V
isit
9 m. V
isit
12 m
.
or F
inal
Visit
3 m. V
isit
Disc
harg
e Visi
t
1 m. V
isit
Patients withAcute Coronary
Syndrome
(unstable angina or non-ST-segment
elevation MI)
RR
Plac
ebo
load
ing
dose
R = Randomization* In combination with other standard therapy The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Study DesignStudy Design
3 months double-blind treatment 12 months
Clopidogrel 300 mg loading dose
CURE
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cum
ulat
ive
Haz
ard
Rat
e
Clopidogrel Clopidogrel + ASA*+ ASA*
33 66 99
Placebo Placebo + ASA*+ ASA*
Months of Follow-UpMonths of Follow-Up
11.4%11.4%
9.3%9.3%
20% RRR20% RRRPP < 0.001 < 0.001
N = 12,562N = 12,562
00 1212
* In combination with standard therapy
The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Primary End Point - MI/Stroke/CV DeathPrimary End Point - MI/Stroke/CV DeathCURE
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cum
ulat
ive
Haz
ard
Rat
e
Clopidogrel Clopidogrel + ASA*+ ASA*
1010 2020 3030
Placebo Placebo + ASA*+ ASA*
Days of Follow-UpDays of Follow-Up00
21% RRR21% RRRPP = 0.003 = 0.003
N = 12,562N = 12,562
* In combination with standard therapy
The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
MI/Stroke/CV Death within 30 DaysMI/Stroke/CV Death within 30 DaysCURE
1
2.1%
1.5%
0
0.5
1
1.5
2
2.5
Placebo + aspirin Clopidogrel + aspirin
CV
deat
h, n
onfa
tal M
I,st
roke
or r
efra
ctor
y or
seve
re is
chem
ia
34%
NEJM 2001; 345:495-502
MI/Stroke/CV Death or severe Ischemia at 24 hours
CURE
1
2%
1.1%
0
0.5
1
1.5
2
2.5
Placebo +aspirin
Clopidogrel +aspirin
% p
atie
nts
requ
iring
thro
mbo
lytic
ther
apy 43%
7.2%5.9%
012345678
Placebo +aspirin
Clopidogrel +aspirin
% p
atie
nts
requ
iring
GP
IIb/II
Ia in
hibi
tors
18%
NEJM 2001; 345:495-502
Need for Additional Anti-Thrombotic After Randomization
P< 0.0010.001 P= 0.0030.003
Thrombolysis GP IIb/IIIa Inhibitor
CURE
1
Should clopidogrel be added GP IIb/IIIa Should clopidogrel be added GP IIb/IIIa antagonists as pretreatment before antagonists as pretreatment before coronary angiography (“upstream”) ?coronary angiography (“upstream”) ?
Is there additional benefit to clopidogrel that would justify:
Increased CABG bleedingor alternatively
Need to postpone CABG for 3-5 days
No data in the literature however
Adhesion
The Role of Platelets in Atherothrombosis
Aggregation3
Reproduced with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.
1
Activation2
Conclusions: Early Clopidogrel TherapyConclusions: Early Clopidogrel Therapy
Treatment with clopidogrel is indicated as soon as possible in patients with acute coronary syndrome
ST elevation and non ST elevation
Treatment is effective to reduce ischemic complications
Before coronay angiography During and after PCI
1
Conclusions: Early Clopidogrel TherapyConclusions: Early Clopidogrel Therapy
Loading dose should be 600mg to achieve early optimal antiplatelet effect
?? 300mg in patients after fibrinolytic therapy
It is unclear whether therapy should be added to “upstream” GP IIb/IIIa antagonists
Especially in high risk patients in whom the likelihood for CABG is high
1
Minimize peri-procedural complications (related to the treated plaque)
Thrombosis etc
Stabilize the rest of the non-occlusive narrowings
Prevent progressionPrevent atherothrombosis
1
2
Goals of Peri – PCI Medical Treatment (short and long term)
The Clinical QuestionsCombination Rx. (ASA + Clopidogrel)
When PCI is planned in a patient already treated with ASA:Is additional pre-treatment with clopidogrel improving outcome (until PCI, at 1 month – or longer)Is continuation of clopidogrel beyond 1 month after PCI / stent improving long-term outcome
1
2
Discharge/Post-Discharge Discharge/Post-Discharge Medications - GuidelinesMedications - Guidelines
ASA, if not contraindicatedASA, if not contraindicated
Clopidogrel, when ASA contraindicatedClopidogrel, when ASA contraindicated
Aspirin + Clopidogrel for up to 9 monthsAspirin + Clopidogrel for up to 9 months-blocker, if not contraindicated-blocker, if not contraindicated
Lipid Lipid agents + diet, if LDL >130 mg/dL agents + diet, if LDL >130 mg/dL
ACE Inhibitor: CHF, EF < 40%, DM, or HTNACE Inhibitor: CHF, EF < 40%, DM, or HTN
I IIa IIb III
2
PCI
PLACEBO + ASA *
CLOPIDOGREL+ ASA *
30 days post PCIEnd of follow-upUp to 12 months
after randomization
Open-label thienopyridineOpen-label thienopyridine
PretreatmentOpen-label thienopyridineOpen-label thienopyridine
PretreatmentN = 2,658 patients undergoing PCI
N = 1345
N = 1313
PCI-CURE
Overall Study Design: PCI-CURE
R
Mehta, SR. et al for the CURE Trial Investigators CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
PCI-CURE
Question 1
Question 2
Clo
pido
grel
C
lopi
dogr
el
ArmArm
Plac
ebo
Plac
ebo
ArmArm
PCI*PCI* 28 Days28 Days
Placebo + Placebo + ASAASA†† (325 mg) (325 mg)
Randomization -Randomization -Pre-treatmentPre-treatment
Clopidogrel 300 mgClopidogrel 300 mg+ ASA+ ASA†† (325 mg) (325 mg)
Clopidogrel 75 mg QDClopidogrel 75 mg QD+ ASA+ ASA†† 325 mg QD 325 mg QD
Clopidogrel 75 mg QDClopidogrel 75 mg QD+ ASA+ ASA†† 325 mg QD 325 mg QD
RR
12 Months12 Months
Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al. JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.
Placebo QDPlacebo QD+ ASA+ ASA†† (81-325 mg) QD (81-325 mg) QD
Clopidogrel 75 mg QDClopidogrel 75 mg QD+ ASA+ ASA†† (81-325 mg) QD (81-325 mg) QD
Overall Study Design: CREDO
Question 1 Question 2
1 2
Open labelclopidogrel
continuationcontinuation
Methodological PitfallCan a study with a single randomization
provide an answer to two questions?
Alternatively
Should a second randomization be done in order to answer the second question?
PCI
PLACEBO + ASA *
CLOPIDOGREL+ ASA *
30 days post PCIEnd of follow-upUp to 12 months
after randomization
Open-label thienopyridineOpen-label thienopyridine
PretreatmentOpen-label thienopyridineOpen-label thienopyridine
Pretreatment
N = 1345
N = 1313
PCI-CURE
Study Designsingle randomization
R
Mehta, SR. et al for the CURE Trial Investigators CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
PCI-CURE
Continuation
Continuation
PCI
PLACEBO + ASA *
CLOPIDOGREL+ ASA *
Open-label thienopyridineOpen-label thienopyridine
PretreatmentOpen-label thienopyridineOpen-label thienopyridine
Pretreatment
N = 1345
N = 1313
PCI-CURE
Alternative Study Designtwo randomizations
R1
Mehta, SR. et al for the CURECURE Trial Investigators Trial Investigators. N Engl J Med. 2001;345:494-502.
PCI-CURE
R2
R2
Clop.
Placebo
Continuation
Continuation
Question 22
Is it just methodology?
Can we really expect long term benefit from early antiplatelet therapy?
Adjunct antiplatelet therapy for PCI EPISTENT
– Randomized study designed to determine the effect of treatment with abciximab
TARGET– Randomized study designed to show that tirofiban is not
inferior to abciximab– Post-hoc nonrandomized comparison among those who were
or were not pre-treated with clopidogrel PCI-CURE
– Subgroup of CURE patients who underwent PCI– Randomized comparison of pre-treatment and continued
clopidogrel therapy vs. placebo
4.8
3.9
3
0.91.3
0.8
0
5
1 month 1 month to 1 year
EPISTENTTARGETPCI-CURE
Absolute reduction of Death or MI at 1 month and 1 year
-Abciximab-Early clopidogrel-Early and continued clopidogrel
% re
duct
ion
*
* 6 month data in TARGET
Early and long term reduction of death or MI from antiplatelet therapy in patients with ACS
Long Term Clopidogrel Post PCI
Clinical guidelines: 9 months to 1 year in patients with ACS
However, current data does not fully support this recommendation
What should we do?
2
Comulative event rate in primary prevention stable CAD and ACS
ACS
Stable
Primary
Risk of vascular event after ACSR
isk
of e
vent
Time after ACS
Stable CAD
Commulative risk
Risk per time
Risk of vascular event after ACShigh and low risk
Ris
k of
eve
nt
Time after ACS
High risk
Low risk
Risk of bleeding after initiation of clopidogrel (high and low risk)
Ris
k of
eve
nt
Time after clopidogrel
High risk
Low risk
Fixed, except for the initial few days heparin, catheterization
Risk of event (vascular/bleeding) after ACS and clopidogrel
Ris
k of
eve
nt
Time after ACS3 months ??
vascular
bleeding
Risk of event (vascular/bleeding) after ACS and clopidogrel
Ris
k of
eve
nt
Time after ACS3 months ??
vascular
bleeding
> 1 year
High vascular risk
Risk of event (vascular/bleeding) after ACS and clopidogrel
Ris
k of
eve
nt
Time after ACS3 months ??
vascular
bleeding
< 1 months
High bleeding riske.g. coumadin
Risk of event (vascular/bleeding) after ACS and clopidogrel
Ris
k of
eve
nt
Time after ACS3 months ??
Long term clopidogrel for patients withHigh risk for vascular eventLow bleeding risk
Short term clopidogrel for patients withLow risk for vascular eventHigh bleeding risk
vascular
bleeding
Who is ”High Risk”Patients in whom long term clopidogrel should be considered
The vulnerable patientTIMI risk scoreAspirin FailureOthers
Who is ”High Risk”Patients in whom long term clopidogrel should be considered
The vulnerable patientTIMI risk scoreAspirin FailureOthers
ACS PathophysiologyInflammation, Plaque Rupture, Thrombosis, and MicroembolizationInflammation, Plaque Rupture, Thrombosis, and Microembolization
Quiescent plaqueQuiescent plaque
Plaque formationLipids, other risk factors
InflammationLDL, others, Infection?
Plaque rupture (erosion)? Macrophages, metalloproteinases
ThrombosisPlatelet Activation, Thrombin
Vulnerable plaqueVulnerable plaque
MacrophagesFoam Cells
Collagen platelet activation
TF TF ClottingClotting Cascade Cascade
Lipid core
Metalloproteinases
InflammationInflammation
Courtesy of David Kandzari.
PlaquePlaque ruptureruptureCulprit plaqueCulprit plaque
Platelet-thrombin micro-emboliPlatelet-thrombin micro-emboli
Atherosclerotic Plaques -Terminology
• Culprit– Responsible for the clinical event
• Vulnerable– High risk to become culprit (cause
clinical event)• QuiescentQuiescent (Stable)
– Primary or healed (vulnerable or culprit)
Fuster, V. et al. J Am Coll Cardiol 2005;46:937-954
Coronary Artery Disease: Diffuse disease with a variable mix of stable, vulnerable and culprit plaques
Culprit and healed plaques in a coronary bifurcation
N Engl J Med 2000;343:915-22
Angiograms of 253 patients with acute MIComplex Plaques:
Single: 153 - 60.5%Multiple: 100 – 39.5%
Clinical Outcome at 1 Year –Single vs. Multiple Complex Plaques
Similar results when analysis was restricted to patients with multivessel coronary disease:74.5% of single91.0% of multiple
Characteristics of Carotid Plaques: Patients with Unstable versus Stable Angina
Multivariate analysis: UA and CRP >3 mg/l were independently and strongly associated with complex carotid plaques
Vulnerable Patient – at high risk for vascular event
coronary elsewhere
Who is the vulnerable patient?
Patient with current multiple complex plaques– Coronary, carotid etc
Patient with multiple uncontrolled risk factors– At risk to develop new complex plaques
Vulnerability cutoff value ?
Who is ”High Risk”Patients in whom long term clopidogrel should be considered
The vulnerable patientTIMI risk scoreAspirin FailureOthers
TIMI Risk Score and Outcome
Budaj et al. circulation 2002
Excess major bleeding risk with clopidogrel is independent of the TIMI risk – it is 1%
TIMI Risk Score and Absolute Reduction of death/MI/Stroke with Clopidogrel
0.1
2.1 1.91.3
4.2
7.1
0
2
4
6
8
0-1 2 3 4 5 > 5
TIMI Risk ScoreN= 752 2524 3730 3567 1593 396
Perc
ent r
educ
tion
Major bleeding – 1%
Majority of patients
Who is ”High Risk”Patients in whom long term clopidogrel should be considered
The vulnerable patientTIMI risk scoreAspirin FailureOthers
Aspirin Failure – Patient with acute vascular event (coronary, cerebral)
while being treated with aspirin
Aspirin was not enough to prevent the eventAspirin is ineffective as an antiplatelet
agent – resistance?Aspirin is effective as an antiplatelet agent
but the disease risk is high and there is a need for more aggressive antiplatelet therapy
Aspirin Resistance
Cellular FactorsInsufficient suppression
of COX-1
Overexpression of COX-2 mRNA
Erythrocyte-induced platelet activation
Increased norepinephrine
Generation of 8-iso-PGF2
Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43:1127-1129.
Aspirin Resistance
Genetic Polymorphisms
COX-1GP IIIa receptor
Collagen receptorvWF receptor
Clinical Factors Failure to prescribe
NoncomplianceNonabsorption
Interaction with ibuprofen
Can be intermittent
Unfortunately (surprisingly) there is no subgroup analysis
of CAPRIE or CURE for patients who were on prior aspirin
However
There are other subgroup analyses
10
1234
9
5678
00 6 12 18 24 30 36
9.7%
8.1%
Aspirin
Clopidogrelp = 0.03
Months of Follow-up
43%50
15
5
10
20
25
45
30
35
40
00 6 12 18 24 30 36
Aspirin
Clopidogrel
46.1%
p = 0.001
36.7%
Months of Follow-up
31%
Clopidogrel in patients with prior CABG CAPRIE substudy (N=1480)
Vascular death Combined endpoint: Vascular death, MI, stroke or hospitalization for ischemia or bleeding
Circulation 2001; 103: 363-368
Ringleb, P. A. et al. Stroke 2004;35:528-532
Clopidogrel in patients with history of prior ischemic event - CAPRIE substudy (N=4496)
Overall 12562 9.3 11.4Associated MI 3283 11.3 13.7No associated MI 9279 8.6 10.6Male sex 7726 9.1 11.9Female sex 4836 9.5 10.765 yr old 6354 5.4 7.665 yr old 6208 13.3 15.3ST-segment deviation 6275 11.5 14.3No ST-segment deviation 6287 7.0 8.6Enzymes elevated at entry 3176 10.7 13.0Enzymes not elevated at entry 9386 8.8 10.9Diabetes 2840 14.2 16.7No diabetes 9722 7.9 9.9Low risk 4187 5.1 6.7Intermediate risk 4185 6.5 9.4High risk 4184 16.3 18.0History of revascularization 2246 8.4 14.4No history of revascularization 10316 9.5 10.7Revascularization after randomization 4577 11.5 13.9No revascularization after randomization 7985 8.1 10.0
Placebo + ASA*Characteristic
No. ofPatients
Clopidogrel + ASA*
Percentage of Patients with Event
Placebo BetterClopidogrel BetterRelative Risk (95% CI)
1.21.00.80.60.4* In combination with standard therapy
The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Beneficial Outcomes with Clopidogrel in Various SubgroupsBeneficial Outcomes with Clopidogrel in Various Subgroups
CURE
8.4
14.4
9.510.7
5
10
15
Yes No
ClopidogrelPlacebo
6.0% 1.2%
CURE: Impact of History of Revascularization
Percent of Patients with an Event
History of Revascularization
(N=2246) (N=10316)
Conclusions – early treatmentClopidogrel loading should be given to
patients with ACS (both STE and Non-STE) as soon as possible regardless* of the timing of the planned coronary angiography– * It is still unclear whether treatment can be
postponed when “upstream” GP IIb/IIIa is being used (especially when the likelihood of CABG is high).
• will be clarified by ongoing trial – “early ACS”
Clinical guidelines recommend 9-12 months clopidogrel to all patients with non-STE ACS
Treatment should be definitely continued as long as there is a risk for stent thrombosis– Longer duration
• high risk subset (multiple complex plaques, TIMI risk score >5, continuously elevated CRP?)
• Aspirin failure ?– Shorter duration
• High bleeding risk (e.g. coumadin etc)
Conclusions – long term treatment