Marijan Pašalić

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.

Venovenous extracorporeal membrane oxygenation in a patient with acute respiratory distress syndrome caused by drowning

Case report: 32-year-old male patient with no prior medical history presented to our Emergency Department following drowning and a successful resuscitation. He was found submerged in the pool just a couple of minutes after being seen conscious and swimming. Lifeguard on duty pulled him out of the pool and started cardiopulmonary resuscitation. Upon the arrival of Emergency Medical Service, patient had a pulse and was breathing spontaneously, but was exhibiting grand mal seizures and not recovering consciousness. In the emergency department he was put on mechanical ventilation (MV) due to global RF and in the Coronary Care Unit therapeutic hypothermia (TH) was started. Urgent diagnostics was performed and no signs of stroke, coronary artery disease, pulmonary embolism or significant electrolyte imbalance were detected. 12-lead ECG and echocardiography showed no abnormal findings despite severe respiratory acidosis. Due to signs of ARDS (Figure 1) and worsening RF in Marijan Pašalić*, Boško Skorić, Maja Čikeš, Daniel Lovrić, Jana Ljubas Maček, Hrvoje Jurin, Jure Samardžić, Joško Bulum, Davor Miličić

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.

The change in pulmonary vascular resistance after left ventricular assist device implantation - the predictive role of platelets revisited

E-mail: marijan.pasalic@yahoo.com Purpose: While analyzing the group of patients implanted with a left ventricular assist device (LVAD) at our institution to verify which of the preand postoperative factors constitute the optimal survival outcome predictors, we determined a significant increase in postoperative pulmonary vascular resistance (PVR) values in the expired patients1. The aim of this study was to further analyze the data in order to determine which of the preoperative factors were related to the aforementioned increase in postoperative PVR values. Methods: For the 20 patients (18 M, 2 F; mean age 58.7±8.3 years) that have been implanted with an LVAD in our institution during the past 2 years, preimplantation echocardiography, right heart catheterization (RHC) and laboratory data were collected and compared according to the values of the postimplantation PVR. The groups were compared by using the adequate statistical test (t-test, Mann Whitney U test, statistical significance set at 0.05). Correlation analysis and linear regression were performed. Results: Among the 20 patients, 14 had postoperative RHC data and 4 of them were proven to have elevated PVR values (>2.4 WU). When comparing the pts. with elevated to those with normal PVR values, no significant difference was found neither in the RV function (FAC 33±7% vs 22±12%, TAPSE 1,0±0,7 cm vs 1.6±0.5 cm, NS), nor in the RV and LV dimensions (RVIDd 34±9 mm vs 35±12 mm, LVIDd 65±10 mm vs 73±9 mm). The borderline significance was found in the left ventricular EF (28±3% vs 19±8%, p=0.06) and the degree of the MR (median values 1 vs 2, p=0.05). The preoperative RHC parameters were not found to be predictive of changes in postoperative PVR (preoperative PVR 4,2±3,4 vs 3,4±1,5 WU, C.I. 1,8±0,7 vs 1,9±0,4 L/min/m, TPG 14±11 vs 13±4 mmHg and RVSWI 11,4±2,2 vs 8,9±2,1, NS). As for the laboratory values, only the platelet count significantly differed between the groups (128 ±73 vs 246±65 E3/mm, p<0.05). The correlation analysis showed a strong negative correlation between the platelet count and postoperative PVR values (r=-0,761, p<0.01). The linear regression verified the following relationship between the variables PVR=6,247-0,017xPLT, p<0.01). Conclusion: These preliminary data show that the platelet count is a significant predictor of the postoperative PVR values in patients with an LVAD (a previously shown survival predictor1). Further investigation will be conducted to explain the role of platelets in the etiology of PVR in our group of pts.