Alexopoulos

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, %

Control

VASP-guided

p

68 ±11 −

69 ±10

0.4

38 ±14*

*<0.001

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

400

PRU value

Persistently high reactivity @ 30 days: 62% vs 40%, p<0.001

300

200 100 0

N=1105 N=1013 N=940

Post-PCI 30 d ITT population

6 mo

N=1109 N=1012 N=944

Post-PCI 30 d

6 mo

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

Circulation 2009;119;2854-2857

Study flow chart Patients post PCI with Platelet Reactivity Assessment N=210 PRUâ&#x2030;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&#x20AC;&#x2DC;prasugrel resistanceâ&#x20AC;&#x2122;. (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

HTPR rates

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&#x20AC;&#x2122;s exact test).

JACC 2010

Efficacy Outcomes in Relation to CYP2C19 Genetics

0.3

0.5

Ticagrelor better

1.0

2.0

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

210 R

93 R

5 nR

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

140 carriers

Step 3 Clopidogrel 150 Step 3* Prasugrel N=98

Step 4 Phenotyping n=210 73 nR Step 5 Prasugrel n=51 650 R

137 R

49 R

2 nR

93 R

5 nR

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&#x20AC;&#x201C;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.

THERAPEUTIC WINDOW

Total R= 860 1000 pts with ACS post PCI

Step 1 Contra to prasugrel?

No N=700

Yes N=300

prasugrel

clopidogrel

665 R

35 nR

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)

Prasugrel

60-­‐mg loading dose 10-­‐mg daily up to 6 months.

Clopidogrel

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