Miroslav Krpan

CYP2C19*2 genotype influence in acute coronary syndrome patients undergoing serial clopidogrel dose tailoring based on platelet function testing: Analysis from randomized controlled trial NCT02096419.

Aspirin and a P2Y12 inhibitor administration are crucial in acute coronary syndrome (ACS) and percutaneous coronary intervention. ADP- induced high on-treatment platelet reactivity (HTPR) increases the rate of adverse ischemic events and whether it is a modifiable risk factor for future events is not clear. CYP2C19 enzyme plays a significant role in clopidogrel bioactivation and its polymorphism can cause clopidogrel pharmacodynamic effect reduction. Earlier, we performed a clopidogrel dose tailoring trial based on serial platelet function testing (PFT) using Multiplate® electrode aggregometry during 12 months to maintain optimal platelet reactivity (PR) in ACS patients presenting with HTPR. Patients were randomly assigned to an interventional group taking up to two additional 600 mg loading doses and a range of 75-300 mg maintenance dose, and a control group on standard clopidogrel maintenance dose. Patients in the interventional group maintained better PR during follow-up and had better outcome. In this exploratory analysis we sought to evaluate the effect of CYP2C19*2 genotype on PR levels in both groups of patients during the initial trial. There were no differences in PR between CYP2C19*2 carriers and non-carriers in the interventional group (p=0.187) while CYP2C19*2 carriers had significantly higher PR compared to non-carriers in the control group (p<0.05). Adjusting clopidogrel dose after PFT to reach and maintain optimal PR might overcome unfavorable genotype in ACS patients initially presenting with HTPR. This implies that strategies of antiplatelet therapy tailoring studies should be focused on maintaining optimal PR phenotype, rather than adjusting P2Y12 inhibition based on genotype to improve outcomes.

Clopidogrel dose adjustment in acute coronary syndrome and initial high on-treatment platelet reactivity – can we overcome reduced activity of isoenzyme CYP2C19?

Uvodd: Velika interindividualna varijabilnost antitrombocitnog ucinka klopidogrela posljedica je vise uzroka i pod utjecajem je klinickih, stanicnih i genetickih cimbenika. Nedovoljno je istražena promjena antiagregacijskog ucinka klopidogrela kod pojedinog bolesnika tijekom uzimanja lijeka. U inicijalnoj studiji randomizirali smo 87 bolesnika s akutnim koronarnim sindromom (AKS) i visokom ostatnom reaktivnosti trombocita (RT) nakon PCI u skupinu kojoj ce se serijski prilagođavati doza klopidogrela prema RT (43 bolesnika) i skupinu lijecenu standardnim dozama klopidogrela (44 bolesnika) te pokazali da su u intervencijskoj skupini kontrola RT-a i ishodi bolesnika bili bolji nakon 12 mjeseci. Cilj ovog istraživanja je analizirati intraindividualne promjene vrijednosti RT-a u obje skupine ispitanika. Metode: Analizirani su podatci o RT tijekom 12 mjeseci pracenja – 1., 2., 3., 7. i 30. dan te 2., 3., 6., 9. i 12. mjesec od PCI. Također, analizirani su rasponi RT za svakog bolesnika te promjene statusa RT (hiporeaktor-normoreaktor) uz klopidogrel. Za analizu broja promjene statusa u obzir su uzeti bolesnici kojima su ucinjena sva predviđena mjerenja tijekom 12 mjeseci - 39 bolesnika iz kontrolne (88, 6%) te 37 bolesnika iz intervencijske skupine (86, 0%). Rezultati: Prosjecni raspon RT kod svakog bolesnika u ispitivanoj skupini je iznosio 50 U (SD ± 17, 47), a u kontolnoj skupini 53, 46 U (SD ± 16, 71). Inhibicija trombocita je uglavnom bila nekonzistentna u odnosu na granicu vrijednosti RT koja oznacava oslabljeni ucinak lijeka jer je 64, 8% u ispitivanoj i 48, 7% bolesnika u kontrolnoj skupini promijenio status reaktora na klopidogrel najmanje tri puta tijekom 12 mjeseci. Prosjecno su bolesnici u ispitivanoj skupini status mijenjali 3, 11 puta (raspon 0-6), a u kontrolnoj 2, 15 puta (raspon 0-6). Zakljucak: Intraindividualna varijacija antitrombocitnog ucinka klopidogrela tijekom 12 mjeseci uzimanja lijeka nakon AKS-a je znacajna. Potrebna su daljnja istraživanja ovoga fenomena.