Negative Impact of ST-Segment Elevation Myocardial Infarction and Morphine Dose on Ticagrelor Uptake and Pharmacodynamics: A Population PK/PD Analysis of Pooled Individual Participant Data.

BACKGROUND: Ticagrelor is widely used in patients with stable and acute coronary artery disease. Understanding the factors that influence its pharmacokinetics (PK) and pharmacodynamics (PD) could improve therapeutic outcomes. We therefore performed a pooled population PK/PD analysis using individual patient data from two studies. We focused on the impact of morphine administration and ST-segment elevation myocardial infarction (STEMI) on the risk of high platelet reactivity (HPR) and dyspnea. METHODS: A parent-metabolite population PK/PD model was developed based on data from 63 STEMI, 50 non-STEMI, and 25 chronic coronary syndrome (CCS) patients. Simulations were then run to evaluate the risk of non-response and adverse events associated with the identified variability factors. RESULTS: The final PK model consisted of first-order absorption with transit compartments, distribution with two compartments for ticagrelor and one compartment for AR-C124910XX (active metabolite of ticagrelor), and linear elimination for both drugs. The final PK/PD model was an indirect turnover model with production inhibition. Morphine dose and STEMI, independently, had a significant negative effect on the absorption rate (reduction of log([Formula: see text]) by 0.21×morphine dose (mg) and by 2.37 in STEMI patients, both p < 0.001), and the presence of STEMI significantly impacted both efficacy and potency (both p < 0.001). The simulations run with the validated model showed a high rate of non-response in patients with those covariates (RR 1.19 for morphine, 4.11 for STEMI and 5.73 for morphine and STEMI, all three p < 0.001). By increasing ticagrelor dosage, the negative morphine effect was reversible in patients without STEMI and just limited in patients with STEMI. CONCLUSION: The developed population PK/PD model confirmed the negative impact of morphine administration and presence of STEMI on ticagrelor PK and antiplatelet effect. Increasing ticagrelor doses seems effective in morphine users without STEMI, whereas the STEMI effect is not entirely reversible.

Surgical Outcome Risk Tool (SORT) to predict 30-day postoperative mortality in a mixed surgical population in Swedish tertiary hospitals.

BACKGROUND: The Surgical Outcome Risk Tool (SORT) was derived and validated in the UK to improve preoperative prediction of postoperative risk. The aim of this study was to validate the SORT in a European mixed-case surgical population outside of the UK. METHODS: The study included patients aged at least 18 years with ASA Physical Status (ASA-PS) grades I-V who underwent non-cardiac surgery at four tertiary hospitals in Sweden between November 2015 and February 2016. Exclusion criteria were surgery under local anaesthesia and missing data on the SORT predictors (ASA-PS, surgical urgency, high-risk surgery, surgical severity, malignancy, age over 65 years). The outcome was 30-day mortality. Discrimination and calibration of the SORT were assessed using area under the receiver operating curve (AUROC) statistics and calibration plots. A sensitivity analysis was done in a high-risk subgroup (ASA-PS III or higher; surgical complexity major to Xmajor according to the SORT; gastrointestinal, orthopaedic, urogenital/obstetric surgery; and age at least 18 years). RESULTS: The validation cohort included 17 965 patients; median age was 58 (i.q.r. 40-70) years, 43.2 per cent were men, and the mortality rate at 30 days was 1.6 per cent. The SORT had excellent discrimination, with an AUROC of 0.91 (95 per cent c.i. 0.89 to 0.92), and good calibration. The high-risk subgroup (1807 patients) had a 30-day mortality rate of 5.6 per cent; in the sensitivity analysis, the SORT had good discrimination, with an AUROC of 0.79 (0.74 to 0.83), and calibration remained good. CONCLUSION: The estimates of the original the SORT for prediction of 30-day mortality were valid and reliable in a mixed-case surgical population in a non-UK European setting.

Elimination of CO2 insufflation-induced hypercapnia in open heart surgery using an additional venous reservoir.

OBJECTIVES: Carbon dioxide (CO2) gas insufflation is used for continuous de-airing during open heart surgery. The aim was to evaluate if an additional separate venous reservoir eliminates CO2 insufflation-induced hypercapnia and keeps sweep gas flow of the oxygenator constant. METHODS: A separate reservoir was used during cardiopulmonary bypass in addition to a standard venous reservoir. The additional reservoir received drained blood and CO2 gas continuously via a suction drain (1 l/min) and handheld suction devices from the surgical wound. CO2 gas was insufflated via a gas diffuser in the open wound at 10 l/min. In a cross-over design for each patient, gas and blood were either continuously drained from the additional to the standard venous reservoir or not. CO2 pressure in arterial blood (PaCO2) was measured after adjustment of sweep gas flow as necessary and after steady state of PaCO2 was observed. Mean values for each setup (median 4 times) for each patient were analysed with Wilcoxon rank-sum test. RESULTS: Ten adult patients undergoing open aortic valve replacement were included. Median PaCO2 did not differ between setups (5.41; 5.29-5.57, interquartile range vs 5.41; 5.24-5.58, P = 0.92), whereas sweep gas flow (l/min) was lower (2.58; 2.50-3.16 vs 4.42; 4.0-5.40, P = 0.002) when CO2 gas was not drained from the additional to the standard reservoir. CONCLUSIONS: An additional venous reservoir for the evacuation of blood from the open surgical wound eliminates CO2 insufflation-induced hypercapnia in open heart surgery keeping PaCO2 and sweep gas flow constant. This prevents possible CO2-induced hyperperfusion of the brain and decreases the risk of cerebral particulate embolization during CO2 insufflation for de-airing in open heart surgery. CLINICAL TRIAL REGISTRATION: NCT04202575. IRB APPROVAL DAT AND NUMBER: 2018-07-13 and 2018/1091-31.

Platelet function analysed by ROTEM platelet in cardiac surgery after cardiopulmonary bypass and platelet transfusion.

OBJECTIVES: The aim of this study was to investigate whether ROTEM platelet can provide additional information to the traditional ROTEM analysis to guide treatment with platelet transfusions in cardiac surgery and to identify factors triggering platelet administration. BACKGROUND: Platelets play a crucial role in coagulation and haemostasis after cardiac surgery. Excessive bleeding after cardiopulmonary bypass usually requires transfusions of blood products, including platelets. The ROTEM platelet is a novel point-of-care analysis for whole blood. MATERIALS AND METHODS: We included 23 patients scheduled for complex cardiac surgery. ROTEM (in-tem, ex-tem), ROTEM platelet (ARA-tem, ADP-tem and TRAP-tem) and platelet count were analysed before induction of anaesthesia (T0), after cardiopulmonary bypass and protamine reversal (T1) and after platelet transfusion (T2, n = 10). RESULTS: ROTEM and ROTEM platelet tests were all significantly reduced between T0 and T1. ROTEM parameters improved significantly after platelet transfusion. Regarding ROTEM platelet, only TRAP-tem increased between T1 and T2 (P = .008). Factors triggering platelet transfusion were long duration of surgery and time on cardiopulmonary bypass. CONCLUSION: ROTEM platelet with thrombin activation, TRAP-tem, improved significantly, indicating that platelet transfusion may reverse cardiopulmonary bypass-induced platelet dysfunction. Further studies are needed to evaluate whether TRAP-tem can be a valuable analysis regarding indications for transfusion of platelets after extensive cardiac surgery.

Assessment of platelet function after discontinuation of ticagrelor.

BACKGROUND: Patients presenting with acute coronary syndromes (ACS) are often treated by percutaneous coronary intervention (PCI) with insertion of coronary artery stents and a majority receive dual antiplatelet therapy (DAPT), usually a combination of a COX-1 inhibitor (aspirin) and a P2Y12 inhibitor (eg ticagrelor). Not seldom the question arises as to when DAPT should be discontinued prior to interventional surgery. This study was done with the primary aim of investigating thrombocyte function immediately prior to and after discontinuation of ticagrelor. MATERIALS AND METHODS: In this prospective, longitudinal, observational study including 24 patients, venous blood was obtained from patients on day 0, before stopping maintenance dose of 90 mg ticagrelor twice daily, and then on days 1, 3, 5, and 8, after discontinuation. Samples were analyzed using Multiplate® and VerifyNow® . RESULTS: Prior to urgent surgery platelet aggregation >30 aggregation units (Multiplate® ) and >208 P2Y12 reaction units (VerifyNow® ) have been shown to correlate with reduced risk of peri- and postoperative bleeding risk. On day 3 after ticagrelor discontinuation, 100% (P = .016) and 67% (P=<.001) of patients had reached these levels on Multiplate® and VerifyNow® , respectively. On day 5, the corresponding figures were 100% (P = .016) and 78% (P=<.001). CONCLUSION: Discontinuation of ticagrelor for 3 days resulted in return of adequate platelet function in all patients on Multiplate® and in a majority of patients on VerifyNow® , indicating a lower bleeding risk. A bedside test for platelet function may be considered if time to anticipated surgery is less than 5 days after ticagrelor discontinuation.

Bleeding in Patients Treated With Ticagrelor or Clopidogrel Before Coronary Artery Bypass Grafting.

BACKGROUND: We evaluated perioperative bleeding after coronary artery bypass grafting (CABG) in patients preoperatively treated with ticagrelor or clopidogrel, stratified by discontinuation of these P2Y12 inhibitors. METHODS: All patients from the prospective, European Multicenter Registry on Coronary Artery Bypass Grafting (E-CABG) treated with ticagrelor or clopidogrel undergoing isolated primary CABG were eligible. The primary outcome measure was severe or massive bleeding defined according to the Universal Definition of Perioperative Bleeding, stratified by P2Y12 inhibitor discontinuation. Secondary outcome measures included four additional definitions of major bleeding. Propensity score matching was performed to adjust for differences in preoperative and perioperative covariates. RESULTS: Of 2,311 patients who were included, 1,293 (55.9%) received clopidogrel and 1,018 (44.1%) ticagrelor preoperatively. Mean time between discontinuation and the operation was 4.5 ± 3.2 days for clopidogrel and 4.9 ± 3.0 days for ticagrelor. In the propensity score-matched cohort, ticagrelor-treated patients had a higher incidence of major bleeding according to Universal Definition of Perioperative Bleeding when ticagrelor was discontinued 0 to 2 days compared with 3 days before the operation (16.0% vs 2.7%, p = 0.003). Clopidogrel-treated patients had a higher incidence of major bleeding according to the Universal Definition of Perioperative Bleeding when clopidogrel was discontinued 0 to 3 days compared with 4 to 5 days before the operation (15.6% vs 8.3%, p = 0.031). CONCLUSIONS: In patients receiving ticagrelor 2 days before CABG and in those receiving clopidogrel 3 days before CABG, there was an increased rate of severe bleeding. Postponing nonemergent CABG for at least 3 days after discontinuation of ticagrelor and 4 days after clopidogrel should be considered.

Calculation Algorithm Reduces Protamine Doses Without Increasing Blood Loss or the Transfusion Rate in Cardiac Surgery: Results of a Randomized Controlled Trial.

OBJECTIVES: The aim of the study was to investigate whether the HeProCalc algorithm affects heparin and protamine dosage, postoperative blood loss, and transfusion rate. DESIGN: Randomized controlled trial. SETTING: University hospital. PARTICIPANTS: The study comprised 210 cardiac surgery patients undergoing cardiac surgery with cardiopulmonary bypass. Twenty patients were excluded because of re-exploration for localized surgical bleeding (n = 9), violation of protocol (n = 2), aprotinin use (n = 3 and nadir body temperature <32°C (n = 6). INTERVENTIONS: Study participants were randomly assigned to either traditional heparin and protamine dosage based on body weight only (control group) or dosage based on the HeProCalc algorithm (intervention group). MEASUREMENTS AND MAIN RESULTS: The initial median heparin dose was 32,500 IU (interquartile range [IQR] 30,000-35,000) in the intervention group compared with 35,000 IU (IQR 30,000-37,500) (p = 0.025) in the control group. The total heparin dose in the intervention group was 40,000 IU (IQR 32,500-47,500) compared with 42,500 IU (IQR 35,000-50,000) in the control group (p = 0.685). The total protamine dose was 210 mg (IQR 190-240) in the intervention group compared with 350 mg (IQR 300-380) (p < 0.001) in the control group. The ratio of total protamine to initial dose of heparin in the intervention group was 0.62 compared with 1.0 (p < 0.001). The amount of chest tube bleeding after 12 postoperative hours was 320 mL (IQR 250-460) in the intervention group compared with 350 mL (IQR 250-450) (p = 0.754) in the control group. Neither the transfusion rate nor postoperative blood loss differed significantly between the 2 groups. CONCLUSION: Use of the HeProCalc algorithm reduced protamine dosage and the protamine/heparin ratio after cardiopulmonary bypass compared with conventional dosage based on weight without significant effect on postoperative blood loss or the transfusion rate.

Venoarterial extracorporeal membrane oxygenation for postcardiotomy shock: Risk factors for mortality.

OBJECTIVES: Refractory postcardiotomy cardiogenic shock is associated with a high mortality, and venoarterial extracorporeal membrane oxygenation can offer acute cardiopulmonary life support. The aim of this study was to identify pre-venoarterial extracorporeal membrane oxygenation risk factors of 90-day mortality. METHODS: We retrospectively analyzed 105 consecutive patients supported with venoarterial extracorporeal membrane oxygenation due to refractory postcardiotomy cardiogenic shock. The association between preimplant variables and all-cause mortality at 90 days was analyzed with univariable and multivariable logistic regression. RESULTS: Main surgical subgroups were single noncoronary artery bypass grafting (29%), isolated coronary artery bypass grafting (20%), and 2 and 3 concomitant surgical procedures (31% and 20%, respectively). The median age of patients was 62 years (interquartile range, 52-68 years), and 76% were men. Cardiopulmonary resuscitation was performed in 30% of patients before venoarterial extracorporeal membrane oxygenation initiation. The median duration of venoarterial extracorporeal membrane oxygenation was 7 days (interquartile range, 3-14). The 90-day overall mortality was 57%, and in-hospital mortality was 56%. Forty-seven percent of patients died on venoarterial extracorporeal membrane oxygenation, 51% of patients were successfully weaned, 1% of patients were bridged to heart transplantation, and 1% of patients were bridged to left ventricular assist device. Multivariable logistic regression analysis identified arterial lactate (odds ratio per unit, 1.22; 95% confidence interval, 1.07-14.0; P = .004) and ischemic heart disease (odds ratio, 7.87; 95% confidence interval, 2.55-24.3; P < .001) as independent risk factors of 90-day mortality. CONCLUSIONS: In patients with postcardiotomy cardiogenic shock, ischemic heart disease and level of arterial lactate before venoarterial extracorporeal membrane oxygenation initiation were identified as independent pre-venoarterial extracorporeal membrane oxygenation risk factors of 90-day mortality. These risk factors are easily available for pre-venoarterial extracorporeal membrane oxygenation risk prediction and may improve patient selection for this resource-intensive therapy.

Ticagrelor pharmacokinetics and pharmacodynamics in patients with NSTEMI after a 180-mg loading dose.

The pharmacokinetics after a 180-mg loading dose (LD) of ticagrelor has not been thoroughly investigated in NSTEMI patients. We aimed to compare the ticagrelor uptake and on-treatment platelet reactivity between non-ST-segment elevation myocardial infarction (NSTEMI) patients and a control group of patients with stable coronary artery disease (SCAD) undergoing elective percutaneous coronary intervention. We performed an observational, prospective, single-center study including 40 NSTEMI patients and 20 SCAD controls. Key exclusion criteria included ongoing opioid treatment. Both groups received a 180-mg ticagrelor LD, and blood samples were taken pre-dose and 1, 2, 3, 4, 5, and 6 hours post-LD. Plasma concentrations of ticagrelor and its active metabolite AR-C124910XX were determined by validated methods. Platelet aggregation was tested using ADP-induced multiple electrode aggregometry. The primary endpoint was the time to maximal ticagrelor concentration (Tmax). Clinical trial registration identifier number: NCT02292277. None of the pharmacokinetic variables differed significantly between the groups, including the Tmax of ticagrelor (2.0h [1.0-3.0] versus 2.0h [2.0-3.0], p = 0.393) and the active metabolite AR-C124910XX (3.0 [2.0-4.0] versus 3.0 [2.5-4.0], p = 0.289). High on-treatment platelet reactivity (HPR) was defined as > 46 aggregation units and was at one hour seen in 15% of the NSTEMI patients versus 10% of the controls (p = 1.0). At two hours post the 180-mg ticagrelor LD, 3% of the NSTEMI patients had HPR compared with none of the controls (p = 1.0). In conclusion, the uptake of ticagrelor was not significantly slower in NSTEMI patients not receiving opioids compared with the SCAD controls, leading to adequate onset of platelet inhibition in both groups.

Correlation between point-of-care platelet function testing and bleeding after coronary angiography according to two different definitions for bleeding.

Platelet function testing could be useful when assessing the risk for bleeding during treatment with antiplatelet drugs. This has been indicated in several studies, including the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding (ARMYDA-BLEEDS) study, which demonstrated that testing with a point-of-care assay correlated with bleeding events after percutaneous coronary intervention. To standardize bleeding definitions, the Bleeding Academic Research Consortium (BARC) published a consensus report, which is in need of data-driven validation. Hence, the investigators conducted an observational, prospective, single-center study of 474 patients receiving clopidogrel and aspirin who underwent coronary angiography with or without percutaneous coronary intervention from October 2006 to May 2011. Platelet reactivity was measured with adenosine diphosphate-induced single-platelet function testing (Plateletworks) at the start of coronary angiography. The primary end point was the 30-day incidence of bleeding as defined by BARC and ARMYDA-BLEEDS. The aim of the present study was to investigate the relation between on-treatment platelet reactivity and the 30-day incidence of bleeding complications according to the BARC and ARMYDA-BLEEDS definitions. Patients in the first platelet aggregation quartile had a higher frequency of type 2 or higher BARC bleeding and ARMYDA-BLEEDS-defined bleeding <30 days after coronary angiography compared with the fourth quartile (16.9% vs 6.7%, p = 0.014, and 8.5% vs 1.7%, p = 0.016, respectively) and the third quartile (16.9% vs 7.7%, p = 0.031, and 8.5% vs 2.6%, p = 0.048, respectively). In conclusion, patients with low on-treatment platelet reactivity at the time of intervention had a significantly higher incidence of bleeding according to the BARC and ARMYDA-BLEEDS definitions <30 days after coronary angiography with or without percutaneous coronary intervention.

Point-of-care testing of clopidogrel-mediated platelet inhibition and risk for cardiovascular events after coronary angiography with or without percutaneous coronary intervention.

High-on-treatment platelet reactivity (HPR) during antiplatelet treatment with clopidogrel is associated with increased risk for adverse cardiovascular events after percutaneous coronary intervention (PCI). Recent studies have indicated that the point-of-care platelet function test Plateletworks can predict such events. The objectives were to investigate the incidence of HPR, to identify correlating variables, and to assess if platelet function testing could predict adverse cardiovascular events. Observational, prospective, single-center study of 491 patients on clopidogrel and aspirin who underwent coronary angiography with or without PCI between October 2006 and May 2011. Platelet reactivity was measured with adenosine diphosphate-induced single-platelet function testing (Plateletworks). A cutoff of 82.3% aggregation was established and used to define HPR. Patients were followed for 3 months, and the primary end-point was myocardial infarction. Secondary end-points included stent thrombosis, death, rehospitalization, and a composite of myocardial infarction, death, and stent thrombosis. One hundred and ninety-six of the 491 patients had HPR. This group had a higher BMI (P < 0.001), and had more often received their clopidogrel loading dose within 6-24 h before coronary angiography (P = 0.001). At 3 months follow-up, the event rates of myocardial infarction and rehospitalization, respectively, were higher in HPR patients [5.1 vs. 1.7%, odds ratio (OR) 3.12, 95% confidence interval (CI) 1.05-9.27, P = 0.03; and 23.0 vs. 14.2%, OR 1.80, CI 1.13-2.86, P = 0.01, respectively]. Testing with Plateletworks identified patients at increased risk of myocardial infarction and rehospitalization within 3 months after coronary angiography with or without PCI.

Adenosine diphosphate-induced single-platelet count aggregation and bleeding in clopidogrel-treated patients undergoing coronary artery bypass grafting.

OBJECTIVES: To investigate the association between adenosine diphosphate (ADP)-induced platelet aggregation measured by single-platelet count testing and postoperative blood loss in clopidogrel-treated patients with acute coronary syndromes undergoing coronary artery bypass grafting (CABG). DESIGN: Prospective observational study. SETTING: Clinical study in one cardiac surgery center. PARTICIPANTS: Eighty-eight patients treated with clopidogrel (300-600 mg loading dose followed by 75 mg daily) within 7 days before CABG. INTERVENTIONS: Platelet function was assessed preoperatively by single-platelet count ADP-induced platelet aggregation. Postoperative blood loss and transfusion requirements were recorded. MEASUREMENTS AND MAIN RESULTS: There was no significant association between ADP-induced platelet aggregation and blood loss 12 hours postoperatively (estimate -7.51; 95% confidence interval [CI]: -16.9-1.9; p = 0.12). ADP-induced platelet aggregation was associated significantly with the number of platelet concentrates administered within 24 hours after surgery (incidence rate ratio [IRR] 0.95; 95% CI: 0.92-0.98; p<0.01), but not to the number of packed red blood cells (IRR 0.98; 95% CI: 0.95-1.01; p = 0.14). CONCLUSIONS: Preoperative ADP-induced platelet aggregation measured by single-platelet count testing in clopidogrel-treated patients with acute coronary syndromes undergoing CABG was not associated with postoperative blood loss or packed red blood cells transfused, but was associated significantly with number of platelet concentrates administered during the initial 24 postoperative hours.