Clopidogrel resistance


Published on

  • Be the first to comment

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • Platelets are anucleate cells that lack genomic DNA but contain megakaryocyte-derived mRNA. Initial tethering of platelets at sites of vascular injury is mediated by glycoprotein Ib/V/IX. All of the above agonists will ultimately activate α IIb β 3 (or GP2b3a).
  • Because most agonists can act synergistically in platelet aggregregation, the signalling pathway of platelet is nonlinear and quite complicated. In addition, activated platelets themselves rapidly secrete additional agonists.  Difficult to measure function.
  • Adenosine diphosphate (ADP) and the P2Y12 receptor. Activation of the P2Y12 receptor by ADP liberates the Gi protein subunits Gi and B. Gi inhibits adenylyl cyclase (AC) decreasing platelet cyclic adenosine monophosphate (cAMP) levels with the consequent reduction in protein kinase (PKA) phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P). This results in a decrease in VASP-P inhibition of glycoprotein IIb/IIIa (GP IIb/IIIa), with the consequent GP IIb/IIIa activation and resultant platelet aggregation. Subunit B activates phosphoinositol 3-kinase (PI 3K) and phosphotyrosine kinases (Pt K) linked to GP IIb/IIIa activation and platelet dense granule secretion. PLC: phospholipase C; ATP: adenosine triphosphate.
  • Clopidogrel mechanism of action. Clopidogrel is a prodrug that needs to be metabolised by hepatic cytochrome P 450 3A4 (CYP 3A4) to an active compound that specifically and irreversibly targets the platelet P2Y12 receptor. Cyclic adenosine monophosphate (cAMP) elevating agents prostaglandin E1 (PGE1), nitric oxide (NO), prostacyclin (PGI2), increase phosphorylation of VASP (VASP-P) with the consequent inhibition of GP IIb/IIIa and resultant inhibition of platelet aggregation. AC: adenylyl cyclase; PKA: protein kinase; ATP: adenosine triphosphate; ADP: adenosine diphosphate.
  • Definition of clopidogrel response. Platelet response to clopidogrel was defined as hyporesponders (two standard deviations below the mean), hyper-responders (two standard deviations above the mean), and the rest individuals were defined as standard responders. In this study, 26 subjects ( 4.8 %) experienced almost no measurable change in aggregation (2 standard deviation reductions in aggregation from the mean); they were considered to be hyporesponders . We conducted secondary post-hoc analyses of a dataset consisting of volunteers (n 94) and patients after coronary stenting (n 405), with heart failure (n 25), and after stroke (n 20). Platelet function before and after clopidogrel therapy was analyzed in all 544 individuals by conventional aggregometry. the mean change in aggregation from baseline after the initiation of clopidogrel therapy was 41.9%, with a SD of 20.8%. Distribution of changes in 5 mol of adenosine diphosphate (ADP)-induced platelet aggregation in 544 patients after receiving clopidogrel therapy. Negative changes in aggregation values represent aggregation values after the administration of clopidogrel that were higher than the baseline readings.
  • Platelet aggregation (5 and 20 mol/L ADP), the activation of glycoprotein IIb/IIIa (PAC-1 antibody), and the expression of P-selectin were measured in patients undergoing elective coronary stenting (n96) at baseline and at 2 hours, 24 hours, 5 days, and 30 days after stenting. All patients received aspirin (325 mg). Clopidogrel (300 mg) was administered in the catheterization laboratory and followed by 75 mg daily.
  • The antiplatelet effect of clopidogrel was studied prospectively in 60 consecutive patients who underwent primary angioplasty (percutaneous coronary intervention [PCI]) with stenting for acute ST-segment– elevation myocardial infarction ( STEMI ) to determine whether variability in response to clopidogrel affects clinical outcomes. Patients were stratified into 4 quartiles according to the percentage reduction of ADP-induced platelet aggregation. Although patients in the first quartile were resistant to the effects of clopidogrel (ADP-induced platelet aggregation at day 6, 1038% of baseline), ADP-induced aggregation was reduced to 693%, 587%, and 3312% of baseline, respectively, in patients in quartiles 2 through 4 ( P 0.01 for all). In addition, epinephrine-induced platelet aggregation and platelet aggregation under flow conditions, assessed by the cone-and-plate(let) analyzer method, were reduced significantly less in the first quartile than in quartiles 2 through 4. Whereas 40% of patients in the first quartile sustained a recurrent cardiovascular event during a 6-month follow-up, only 1 patient (6.7%) in the second quartile and none in the third and fourth quartiles suffered a cardiovascular event ( P 0.007). All patients received 300 mg of chewable aspirin on admission and 200 mg/d thereafter throughout the study period. Heparin was administered during the procedure but was discouraged after the procedure. Eptifibatide was administered for a mean of 142 hours. Clopidogrel was administered as a loading dose of 300 mg on completion of the PCI, followed by doses of 75 mg/d for 3 months.
  • Emphasize STEMI patients! smoking seemed to enhance the clopidogrel antiplatelet effect with a consistent gradual increase of the number of cigarette smokers from the first to the fourth quartile, opposing the possibility of this being a chance finding. Aside from smoking, no other baseline characteristic predicted the response to clopidogrel.
  • Emphasize NSTEMI patients! 12 ischemic events occurred at 1-month follow-up, of which 9 occurred in the highest aggregation quartile and 3 in the second highest quartile. We prospectively studied the platelet response to both clopidogrel and aspirin in 106 NSTE ACS consecutive patients undergoing percutaneous coronary intervention (PCI) with stenting. A single post-treatment blood sample was obtained just before PCI and analyzed by platelet aggregometry using both ADP and arachidonic acid (AA) as agonists to explore the responses to clopidogrel and aspirin, respectively. Patients were divided into quartiles according to the ADP or AA induced maximal intensity of platelet aggregation. Patients of the highest quartile (quartile 4) were defined as the low-responders. Results: Twelve recurrent cardiovascular (CV) events occurred during the 1-month follow-up. Clinical outcome was significantly associated with platelet response to clopidogrel [Quartile 4 vs. 1, 2, 3: OR (95% CI) 22.4 (4.6–109)]. Low platelet response to aspirin was significantly correlated with clopidogrel low response (P ¼ 0.003) but contributed less to CV events [OR (95%CI): 5.76 (1.54–35.61)]. Conclusions: A post-treatment ADP-induced platelet aggregation performed just before PCI identifies low responders to dual antiplatelet therapy with an increased risk of recurrent CV events.
  • Largest study so far. EXCELSIOR Our study included 802 consecutive patients undergoing elective coronary stent placement . Before PCI, patients received a loading dose of 600 mg clopidogrel followed by 75 mg daily. Primary end point was the 30-day composite of death, myocardial infarction, and target lesion revascularization (major adverse cardiac events [MACE]). Platelet aggregation was assessed immediately before PCI by optical aggregometry (5 mol/l adenosine diphosphate). RESULTS During 30-day follow-up, 15 patients (1.9%) incurred MACE (3 deaths, 8 myocardial infarctions, 8 target lesion revascularizations). Quartiles of platelet aggregation were 4%, 4% to 14%, 15% to 32%, and 32%. Thirty-day MACE differed significantly (p 0.034) between quartiles of platelet aggregation. It was 0.5% in the first quartile, 0.5% in the second, 3.1% in the third, and 3.5% in the fourth. Platelet aggregation above the median carried a 6.7-fold risk (95% confidence interval 1.52 to 29.41; p 0.003) of 30-day MACE. Multivariable logistic regression analysis, including pertinent covariables, confirmed platelet aggregation as a significant independent predictor of 30-day MACE (adjusted odds ratio per 10% increase in platelet aggregation 1.32, 95% confidence interval 1.04 to 1.61; p 0.026). The observed variability in residual platelet aggregation immediately before PCI depends by 30% on the interindividual variability in platelet function even before the initiation of clopidogrel and by just above 50% on the variability in platelet responses to clopidogrel loading. An adequate delay from loading is critical to the clopidogrel effect at the time of PCI: the proportion of patients with suboptimal inhibition of platelet aggregation during PCI (i.e., platelet aggregation above median of entire cohort) varied considerably with time after loading, from 66.5% in those undergoing catheterization within 2 h after loading to 41.8% in those with a longer delay.
  • Elective PCI patients (n 150) who received aspirin for 1 week but not clopidogrel were included. All patients received bivalirudin during PCI. Blood samples were drawn at baseline and 20 to 24 h after a 300-mg clopidogrel dose. Aspirin resistance was defined by 2 of 3 criteria: rapid platelet function analyzer-ASA score 550, 5 mol/l adenosine diphosphate (ADP)-induced aggregation 70%, and 0.5 mg/ml arachidonic acid-induced aggregation 20%. Clopidogrel resistance was defined as baseline minus post-treatment aggregation 10% in response to 5 and 20 mol/l ADP. RESULTS Nineteen (12.7%) patients were resistant to aspirin and 36 (24%) to clopidogrel. Nine (47.4%) of the aspirin-resistant patients were also clopidogrel resistant. Aspirin-resistant patients were more likely to be women and have diabetes than were aspirin-sensitive patients. They also had lower response to clopidogrel, assessed by platelet aggregation and activation markers (flow cytometry-determined PAC-1 binding and P-selectin expression). Elevation of creatine kinase-myocardial band after stenting occurred more frequently in aspirin-resistant versus aspirin-sensitive patients (38.9% vs. 18.3%; p 0.04) and in clopidogrel-resistant versus clopidogrel-sensitive patients (32.4% vs. 17.3%; p 0.06).
  • Baltimore, Maryland We investigated whether patients who suffered subacute stent thrombosis (SAT) have higher post-treatment reactivity than those who do not encounter stent thrombosis. BACKGROUND High post-treatment platelet reactivity has been reported after coronary stenting after clopidogrel therapy and may be an important factor in the occurrence of SAT. METHODS We identified patients with SAT treated at two tertiary care centers over a 1.5-year period. Light transmittance aggregation induced by adenosine diphosphate (ADP) and arachidonic acid, total and activated glycoprotein (GP) IIb/IIIa after stimulation with ADP, and vasodilatorstimulated phosphoprotein phosphorylation levels to measure P2Y12 receptor inhibition were determined (n 20) and compared with an age-matched group of patients without SAT (n 100). High post-treatment platelet reactivity was defined as 75th percentile ADPinduced aggregation in the group without SAT. RESULTS The SAT patients had higher mean platelet reactivity than those without SAT by all measurements (p 0.05): 49 4% versus 33 2% for 5 mol/l ADP-induced aggregation and 65 3% versus 51 2% for 20 mol/l ADP-induced aggregation (p 0.001), 69 5% versus 46 9% for P2Y12 reactivity ratio (p 0.03), and 138 19 mean fluorescence intensity (MFI) versus 42 4 MFI for stimulated GP IIb/IIIa expression (p 0.001). Of patients with SAT, 60% had high platelet reactivity. Problems : more DES in no SAT and Non-SAT patients were enrolled and studied prospectively, whereas patients with SAT were identified retrospectively and subsequently studied. The analyses of platelet reactivity conducted at different intervals from the index procedure might affect the results.
  • Now possible causes and management of plavix resistance
  • Adminster ADP look at plt aggrgation . More specific way to assess ADP re is vasp
  • Depends on reagent
  • A lot of patient did not respond to plavix
  • ADP induced aggregation
  • Isolated pats with resistance.Higher dose is better, but with incorporating technology to individualize plavix dose
  • Talked about hight resistsnce how about other agents..
  • Delete Baseline
  • Bleeding not significant
  • Summary of management of clopidogrel resistance: Correct clinical modifiable factors (insulin resistance, compliance) Avoid drug interactions (statins and PPIs) Higher dose of Clopidogrel (600 vs 300 mg) Individualized dosing based on level of resistance using biochemical measure. Using other ADP receptor antagonists such as pragrel, AZD.. Addition of other antiplatelet agents (cilastozol, direct thrombin inhibitors, ...)
  • Plavix resistsnce is not fully reflected in guidline.. The only thingg
  • Clopidogrel resistance

    1. 1. “Clopidigrel resistance” and management strategies
    2. 2. Overview• Physiology of platelet function and clopidogrel pharmacology• Definition of clopidogrel resistance• Clinical significance• Potential mechanisms of resistance• Laboratory tests• Prevention and treatment
    3. 3. Platelet physiology• Platelets circulate for about 10 days• Platelet activation:
    4. 4. Activators of plateletsX Drugs 2008; 68 (12): 1647-1664
    5. 5. ADP mediated plt activation VASP Heart, Lung and Circulation 2007;16:S17–S28
    6. 6. Clopidogrel• Clopidogrel is a thienopyridine pro-drug, which is converted to its active metabolite by several enzymes of the P450 family, including CYP3A4 and CYP2C19• The active metabolite combines irreversibly with the platelet membrane P2Y12 ADP receptor, thereby inhibiting this pathway of platelet activation, but leaving the P2Y1 ADP receptor unaffected JACC Vol. 49, No. 14, 2007
    7. 7. ADP-mediated plt activation 15% 85% Heart, Lung and Circulation 2007;16:S17–S28
    8. 8. Defining resistance Clopidogrel resistanceBiochemical Clinical
    9. 9. Clopidogrel resistance (biochemical)• There is marked inter-individual variability in platelet inhibition after clopidogrel ingestion.• Hyporesponders (two standard deviations below the mean) 5% J. Am. Coll. Cardiol. 2005;45;246-251
    10. 10. Clopidogrel resistance (biochemical)• Resistance: as baseline 63% 31% aggregation (%) minus post-treatment aggregation (%) ≤ 10% by 5 mol/L ADP. 31% 15% Circulation. 2003;107:2908-2913.
    11. 11. Defining resistance• Clinical vs Biochemical.• Clinical resistance: In its broadest sense, it refers to the continued occurrence of ischemic events despite adequate anti-platelet therapy and compliance.• there is no current definition which unifies the biochemical and clinical expression of failed treatment.• Rather than attempting to characterize patients as simply resistant or sensitive to a medication, however, therapeutic resistance is more likely a continuous variable similar to blood pressure.• Disregarding existing uncertainty, the reported rate of Clipidogrel resistance ranges from 5-25%.
    12. 12. Clinical significance of clopidogrel resistance • Post-stent ischemic events and peri- procedural myocardial infarction. • Stent thrombosis
    13. 13. J Am Coll Cardiol 2005; 46:1827–32
    14. 14. Etiology
    15. 15. In summary so far …• There is a wide inter-individual variation in platelet response to clopidogrel when measured biochemically.• Low responders will suffer more stent thrombosis and MACE post stenting.• Possible aetiologies for clopidogrel resistant include patients’ clinical factors and variations in pharmaco-kinetics and –dynamics.
    16. 16. Laboratory tests• Light transmittance aggregometry is the current gold standard for determining platelet function.• VASP phosphorylation analysis• Platelet function analyzer• Verifynow rapid platelet function assay
    17. 17. Pros - Cons
    18. 18. Management... Prevention...
    19. 19. Loading dose…• Loading doses of clopidogrel of 300 to 600 mg reach near steady-state levels of platelet aggregation by 4 to 24 hours.• Daily dosing with 75 mg daily without a preload results in steady-state levels within 4 to 7 days.
    20. 20. ARMYDA-2•255 patients with NSTEMI/UA•Death, peri-procedural MI•PCI 4-8h•Endpoint: 300mg 12%, 600mg  4%Circulation 2005;111;2099-2106
    21. 21. Platelet aggregation –Higher dose of clopidogrel •292 patients with NSEMI •All CV events, death •Platelet aggregation •PCI 12h •Endpoint: •300mg: 12% •600mg:5%JACC Vol. 48, No. 7, 2006
    22. 22. ISAR-CHOICE •60 patients with Stable Angina •Platelet aggregation prior to administration and 20, 40, 60, 120, and 240 minutes after elective PCI 12hCirculation 2005;112;2946-2950
    23. 23. Reload prn... VASP guided group Control group•NSTEMI/UA•VASP index>50% 24h after 600mgFor control or till <50% for VASP guided group.•CV events: 10% vs 0% JACC Vol. 51, No. 14, 2008
    24. 24. Reload chronic therapy• ARMYDA-RELOAD ACC 2008:• randomized 436 patients on chronic (>10 days) clopidogrel therapy who presented with stable angina or NSTEMI and going for PCI to reload 600mg vs placebo 30-day MACE :• (7% vs. 9%, p=0.70) overall• (7% vs. 18%, p=0.035) for NSTEMI• (8% vs. 4%, p=0.23) stable angina
    25. 25. Prasugrel•13608 patients with moderate to high risk ACS•Mortality ,CV events NEJM november 15, 2007
    26. 26. Cilostazol JACC Vol. 46, No. 10, 2005
    27. 27. P2Y12 ADP receptor antagonists990 patients with NSTEMI J. Am. Coll. Cardiol. 2007;50;1844-1851;
    28. 28. Summary1)Correct clinically modifiable factors (insulin resistance, compliance)2)Avoid drug interactions (statins and PPIs)3)Higher dose of Clopidogrel (600 vs 300 mg)4)Individualized dosing based on level of resistance using biochemical measures.5)Using other ADP receptor antagonists such as prasugrel, AZD6140..6)Addition of other anti-platelet agents (cilostazol, direct thrombin inhibitors, ...)
    29. 29. Class IIb: In pts in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating left main, or last patent vessel), platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated. (Level of Evidence:Level of Evidence C: Consensus opinion of experts, case studies, or standard-of-care.
    30. 30. Thanks