Overcoming clopidogrel resistance
Dimitrios Alexopoulos, MD, FESC, FACC Patras University Hospital 1.7.2011
Price, Circ 2009
Mega, JAMA Nov 2010
Hochholzer JACC 2010
Doubling the maintenance dose of clopidogrel.
v.Beckerath N et al, EHJ 2008
LOW RESPONDERS TO CLOPIDOGREL 75 MG
Angiollilo AJC 2008
Aleil JACCInterv 2008
Step-wise reloading increased % Inhibition and % responders After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target. Mean ±SD VASP after first LD, % VASP after adjustment, %
68 ±11 −
Log rank p =0.007
MACE: CV death, MI, revascularization
Bonello et al. J Am Coll Cardiol 2008
Barker et al JACCInterv 2010
Primary Endpoint: CV Death, MI, Stent Thrombosis
Observed event rates are listed; P value by log rank test.
Pharmacodynamics: Effect of SD vs HD Clopidogrel Standard-Dose 500
P = 0.98
High-Dose P < 0.001
Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001
200 100 0
N=1105 N=1013 N=940
Post-PCI 30 d ITT population
N=1109 N=1012 N=944
Post-PCI 30 d
Secondary Comparison: High vs. Not High Reactivity
Observed event rates are listed. P value by log-rank test.
Prasugrel compared to standard or high dose of Clopidogrel
Wiviott SD et al, Circulation 2007
Study flow chart Patients post PCI with Platelet Reactivity Assessment N=210 PRUâ‰Ľ235 N=71 (33.8%) Randomized N=71 Clopidogrel 150mg/d N=35 Side effects N=2, low compliance N=1 Complete Day 30 data N=32
Prasugrel 10mg/d N=36 Side effects N=0, low compliance N=4 Complete Day 30 data N=32
Clopidogrel 150mg/d N=32 Side effects N=1, lost follow-up N=5 Complete Day 60 data N=26
Prasugrel 10mg/d N=32 Side effects N=0, lost follow-up N=5 Complete Day 60 data N=27
Platelet reactivity by treatment sequence
Patients individual PR values against the HTPR threshold.
Platelet reactivity by treatment sequence in non carriers and carriers of the CYP2C19*2 allele
Conclusions 1. In patients with HTPR post PCI, prasugrel is more effective compared to high clopidogrel in reducing platelet reactivity. 2. This effect is more prominent in patients carrying at least one loss-offunction CYP2C19*2 allele.
Conclusions 3. In high risk individuals like clopidogrel resistant patients post PCI genotyping for the CYP2C19*2 allele seems to be helpful for selection between clopidogrel maintenance dose doubling and prasugrel administration.
Antiplatelet effects of prasugrel vs double clopidogrel in patients on hemodialysis
STUDY FLOW CHART
(i) increasing the dosage of clopidogrel to 150 mg in HD patients with HTPR is highly ineffective in reducing PR. (ii) Prasugrel 10 mg instead, is much more effective in this population, although a sizable proportion (19%) demonstrates â€˜prasugrel resistanceâ€™. (iii) The well known CYP2C19*2 loss of function allele may not have a central role in determining HTPR in HD patients. (iv) The rate of HTPR may be particularly high in such patients, although its determination was not the primary aim of the study.
Prasugrel 10 mg/d vs Clopidogrel 150mg/d in patients with stable CAD and on-clopidogrel HPR
ClinicalTrials.gov ID: NCT01304472
Study flow chart
PR by treatment sequence.
Data for the pre- and post-crossover periods (presented as LS estimates with 95% CI)
PR at the end of the two treatment periods
12/26 (46.2%) and 3/26 (11.5%) remained poor responders to clopidogrel 150mg/d and prasugrel 10mg/d respectively (p=0.003, Prescottâ€™s exact test).
Efficacy Outcomes in Relation to CYP2C19 Genetics
Clopidogrel better L Wallentin. Lancet 2010
Total R=953 Phenotyping
1000 pts with ACS post PCI Step 1 Phenotyping n=1000 350 nR Step 2 Clopidogrel 150 Step 3 Phenotyping n=350 140 nR Step 4 Prasugrel N=98 650 R
1000 pts with ACS post PCI
Total R=929 Phenotyping n=1210
Step 1 Phenotyping n=1000 350 nR Step 2 Genotyping n=350 210 noncarriers
Step 3 Clopidogrel 150 Step 3* Prasugrel N=98
Step 4 Phenotyping n=210 73 nR Step 5 Prasugrel n=51 650 R
Based upon our current knowledge, genotyping may be useful in antiplatelet treatment choice post PCI if clopidogrel, but not prasugrel or ticagrelor, use is considered. Even if genetic tests are successfully developed, genotyping alone cannot be regarded as a substitute for platelet function testing in identifying clopidogrel nonresponders and platelet reactivity assessment appears complementary or even mandatory â€“if carriage is identified. The exact role of CYP2C19*2 genotyping into clinical practice post PCI should be elucidated by appropriately designed prospective clinical trials.
Total R= 860 1000 pts with ACS post PCI
Step 1 Contra to prasugrel?
195 R 105 nR
TRIGGER-‐PCI Tes$ng Platelet Reac$vity In Pa$ents Undergoing Elec$ve Stent Placement on Clopidogrel to Guide Alterna$ve Therapy With Prasugrel Enrolled pts: 426
July 2009 – April 2011
CAD+PCI with implanta?on ≥1 DES Clopidogrel 600-‐mg loading dose (≤24 h) Aspirin ≥ 250-‐mg (≤24 h) VerifyNow P2Y12 reac?on units > 208 (2-‐7 h)
60-‐mg loading dose 10-‐mg daily up to 6 months.
75-‐mg daily up to 6 months.
Primary Endpoint: The ?me to ﬁrst occurrence of heart aWack or cardiovascular death Secondary Endpoint:The ?me to ﬁrst occurrence of stent thrombosis, all-‐cause death or MI
This study has been terminated due to the low rate of primary endpoint events ClinicalTrials.gov Identifier: NCT00910299