Controversies in PCI A young cardiologist s perspective Antiplatelet Tx, PLT function monitoring should be mandatory CONTRA M. Valgimigli, MD, PhD Ferrara, Italy Euro-PCR Session @ ESC August 30th 2010, Brussels Room Zone A
Potential Conflicts of Interests I am not sure I can still be considered a young interventional cardiologist. I am a believer that personalised medicine may be the FUTURE!!..NOT the PRESENT..
Tailored Anti-PLT Tx?... Still the land of confusion!
Issues in Monitoring and Reacting to PLT Function Methodological Issues Logistic Issues Cultural Issues Economical/Reimbursement Issues
What to measure and how to measure? Platelet Aggregation Light transmittance aggregometry Impedance platelet aggregation Flow Cytometry GPIIb/IIIa receptor activation P-selectin expression Monocyte-platelet aggregates Vasodilator-associated stimulated phosphoprotein (VASP) Point-of-care Ultegra rapid platelet function analyzer (VerifyNow) Multiplate Platelet function analyzer (PFA-100) Thromboelastagraph (TEG) Plateletworks Cone and plate(let) analyzer (IMPACT) Gene sequence variations
Bland Altman analysis of agreement to assess how closely two measurements are related to each other, with limits of agreement depicting the range of variability in agreement between the two measures. Kappa Statistics 0-2: poor agreement 2-4: fair agreement 4-6: moderate agreement 6-8: substantial agreement 8-1: perfect agreement Lordkipanidzé M et al. Eur Heart J 2008;29:2877-2885
Clopidogrel response: head-to-head comparison of different platelet assays to identify clopidogrel non responder patients after coronary stenting 70 consecutive patients taking 150 mg clopidogrel Clopidogrel response was assessed with ADP-induced aggregation (ADP-Ag) (non response if >70%), Platelet reactivity index VASP (PRI VASP) (non response if >50%) and Verify Now Point-of-care assay (VN) (non response if PRU > 240 AU). Indeed, our results demonstrated a poor agreement between different platelet assays and suggested that identification of clopidogrel non responders is test-dependent Cuisset T et al Arch Cardiovasc Dis. 2010 Jan;103(1):39-45
Results of each PLT Function test cannot be expended to others They measure different things and express the results in a NON interchangeable way For each test the whole sequence of evidence has to be accrued: Results of a Test Prognostic Implications Reaction LTA VeriftNow Multiplate VASP PFA-100 IMPROVE PROGNOSIS
+600 mg +600 mg +600 mg Am J Cardiol 2009;103:5 10
Trial Design Aspirin and/or Clopidogrel Poor Responders via VerifyNow Aspirin + Clopidogrel UFH or Bivalirudin Tirofiban* Bail-out Placebo 1:1 Double Blind Placebo Bail-out Tirofiban Blood sampling: Hb, PLT, Tp; CK-MB mass @ 6, 12, 18 or 24 hrs Clinical F-UP: 30-d, 4, 8 and 12 months *: 25 g/kg in 3 mins, followed by an 14-24 hour infusion at 0.15 g/kg/min
Primary Endpoint Tp >3 ULN w/in 48 hs Placebo Tirofiban P=0.009 for superiority 50 45 40 35 30 25 20 RRR: 42% 95%CI: 61-12 35.1% 20.4% 15 10 5 0 Valgimgli et al, Circulation 2009
1-Year Outcome 100 Peri-MI CK-MB3X Death, MI, Stroke Free Survival 100 90 80 70 60 Peri-MI Trop3X Tirofiban Placebo P=0.01 Death, MI, Stroke Free Survival 95 90 85 80 Tirofiban Placebo 0 50 100 150 200 250 300 350 400 450 Days 0 50 100 150 200 250 300 350 400 450 Days
Landmark 3-400 Days No Long-term effect 00 Tirofiban 90 Death, MI, Stroke Free Survival 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 Placebo P=NS 50 100 150 200 250 300 350 400 450 Days 10 8 6 4 2 0 Tirofiban Placebo
CADP Closure Time (seconds) P2Y12 Reaction Units PLT reactivity as a function of 135 STEMI patients-pfa-100 Time 175 r=0.66 vs T1 r=0.65 vs T2 r=0.62 vs T3 r=0.54 vs T2 r=0.51 vs T3 r=0.64 vs T3 N=323 PCI patients 150 On Treatment PLT P2Y12 Units 125 100 300 Median 25%-75% 75 50 25 78±11 (80) p<0.01 vs T1, T2, T3 102±14 (101) p<0.01 vs T2, T3 118±20 (116) p=0.08 vs T3 121±18 (121) 200 P<0.02 0 T0 T1 T2 T3 100 ROC Cut-offs per MACE prediction PRUp BASE PRUp 5M PRUp 30G 72 s 92 s 99 s Campo G, Valgimigli M. et al Thrombosis Heamostasis 2008
% Aggregation -ADP 10 Ng/ml PLT reactivity increases during Common Cold 18 healthy subjects with viral upper respiratory tract infection (URTI) pts with URTI Controls CRP TNF-a 50 P<0.001 30 40 25 30 20 20 15 10 10 P<0.01 5 0 During Cold 6 ws After 0 During Cold 6 ws After Keutz RP, Blood Coagul Fibrinolysis. 2007 Dec;18(8):713-8
Lost in Translation?? Is all this worth the hassle? On Tx residual PLT Reactivity Short-Term Prognosis 5-10% Medium-Term Prognosis Assessment Therapeutic Response 100% 25% 25% Poor Responders Hyper Responders Responders with Events Responders w/out Events
Therapeutic Window? 2,533 pts undergoing PCI after 600 mg Clopidogrel Sibbing et al JACC 2010 Sibbing et al J Thromb Haemost 2010
0.0 0.05 0.10 0.15 0.20 Therapeutic Dilemma: What to do in clopidogrel hyper-responders? CV Death/MI Stent Placebo Evidence that decreasing Clopidogrel MD in hyper-responders you will reduce Bleeding-w/out increasing ischemia Clopidogrel RRR: 27% (95% CI; 0.56-0.95) P=.02 0 100 200 Days of Follow-up 300 Mehta SR, et al. J Am Coll Cardiol. 2003;41:45A.
Cytochrome P-450 Polymorphisms and Response to Clopidogrel SNP *2 accounts for 12% of clopidogrel response variability* Mega, New Eng J Med 2009 *: Sculdiner AR, JAMA 09; 302: 849
let s try. Male, 31 year old, Anterior STEMI Thrombectomy BMS 3.5*15, NC 4.0 @20 atm Nanosphere *2 (+/-) VerifyNow: PRUp 124; 27% Multiplate: AUC 213
Oooops 4 days later while the patient was still in H, Chest pain and recurrent ST Genotype more than Phenotype may have triggered a protective response
Time for a Reality Check! Patients are Heterogeneous Chest Pain STEMI, NSTEACS, UA Elective PCI Chronic Atherosclerotic disease Different age, sex, history Various Treatment Settings Pre-Hospital Emergency Room CCU Cath-Lab Surgical Department/OR Different Professional Figures Emergency Doctors Internists Non-invasive Cardiologists Interventional Cardiologists General Practitioners Surgeons Anaesthetists Diverse Therapeutic Options PCI CABG Medical Tx
Preliminary Conclusions Since we are Cardiologists and not Philosophers, there is no need to monitor PLT function: There are no real practical information beyond prognosis If anything, this may only impact on MI on short term Attempt to modify Tx accordingly may further increase the complexity of our decision making and render Tx even more chaotic
Mr PLT Function Assessment