Overcoming clopidogrel resistance

Dimitrios Alexopoulos, MD, FESC, FACCPatras University Hospital

1.7.2011

Price, Circ 2009

Mega, JAMA Nov 2010

Hochholzer JACC 2010

v.Beckerath N et al, EHJ 2008

Doubling the maintenance dose of clopidogrel.

Angiollilo AJC 2008 Aleil JACCInterv 2008

LOW RESPONDERS TO CLOPIDOGREL 75 MG

Mean ±SD Control VASP-guided p

VASP after first LD, % 68 ±11 69 ±10 0.4VASP after adjustment, % − 38 ±14* *<0.001

Bonello et al. J Am Coll Cardiol 2008

MACE: CV death, MI, revascularization

Log rank p =0.007

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.

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

500

400

300

200

100

0

PRU value

Post-PCI

High-Dose

30 d 6 mo Post-PCI 30 d 6 mo

Standard-Dose

N=1013 N=940N=1105 N=1012 N=944N=1109

P = 0.98P < 0.001

ITT population

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

Secondary Comparison: High vs. Not High Reactivity

Observed event rates are listed. P value by log-rank test.

Wiviott SD et al, Circulation 2007

Prasugrel compared to standard or high dose of Clopidogrel

Circulation 2009;119;2854-2857

Study flow chart Patients post PCI with Platelet Reactivity

Assessment N=210

PRU≥235 N=71 (33.8%)

Clopidogrel 150mg/d N=35Side effects N=2, low compliance N=1Complete Day 30 data N=32

Prasugrel 10mg/d N=32Side effects N=0, lost follow-up N=5Complete Day 60 data N=27

Prasugrel 10mg/d N=36Side effects N=0, low compliance N=4Complete Day 30 data N=32

Clopidogrel 150mg/d N=32Side effects N=1, lost follow-up N=5Complete Day 60 data N=26

Randomized N=71

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-of-function 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 ‘prasugrel resistance’.

(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, Prescott’s exact test).

JACC 2010

L Wallentin. Lancet 2010

Ticagrelor better

1.0 2.00.3 0.5

Clopidogrel better

Efficacy Outcomes in Relation to CYP2C19 Genetics

Step 1Phenotyping n=1000

350 nR

1000 pts with ACS post PCI

650 R 210 R

140 nR

Step 2Clopidogrel 150

Step 3Phenotyping n=350

Step 4Prasugrel N=98

93 R 5 nR

Total R=953Phenotyping

Step 1Phenotyping n=1000

350 nR

1000 pts with ACS post PCI

650 R

Step 2Genotyping n=350

Step 3*Prasugrel N=98

93 R 5 nR

Total R=929Phenotyping n=1210

140 carriers210 noncarriers

Step 3Clopidogrel 150

Step 4Phenotyping n=210

137 R

73 nR

Step 5Prasugrel n=51

49 R 2 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 –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

Step 1Contra to prasugrel?

NoN=700

YesN=300

1000 pts with ACS post PCI

prasugrel clopidogrel

665 R 35 nR 195 R 105 nR

Total R= 860

TRIGGER-­‐PCITes$ng  Platelet  Reac$vity  In  Pa$ents  Undergoing  Elec$ve  Stent  Placement  on  

Clopidogrel  to  Guide  Alterna$ve  Therapy  With  Prasugrel  

ClinicalTrials.gov Identifier: NCT00910299

July  2009  –  April  2011

CAD+PCI  with  implanta?on  ≥1  DESClopidogrel  600-­‐mg  loading  dose  (≤24  h)Aspirin  ≥  250-­‐mg  (≤24  h)

VerifyNow  P2Y12  reac?on  units  >  208  (2-­‐7  h)

Prasugrel60-­‐mg  loading  dose10-­‐mg  daily  up  to  6  months.

Clopidogrel75-­‐mg  daily  up  to  6  months.

Primary  Endpoint:  The  ?me  to  first  occurrence  of  heart  aWack  or  cardiovascular  deathSecondary  Endpoint:The  ?me  to  first  occurrence  of  stent  thrombosis,  all-­‐cause  death  or  MI

Enrolled  pts:  426

This  study  has  been  terminated  due  to  the  low  rate  of  primary  endpoint  events