Platelet P2Y12 Receptor Antagonist Research Articles

A-149 Performance Characteristics of VerifyNow PRU and ARU Tests During a Clinical Method Verification Exercise

Abstract Background Dual antiplatelet therapy with aspirin and a platelet P2Y12 receptor antagonist is indicated for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary intervention procedure. Two different assays are available in the VerifyNow Test device for monitoring the anti-platelet therapy response. The aspirin assay (ARU Test) utilizes arachidonic acid as an agonist and is sensitive to acyl salicylic acid. The P2Y12 assay (PRU test) is sensitive to thienopyridines (such as clopidogrel, prasugrel, ticagrelor) and uses adenosine diphosphate (ADP) as an agonist. The PRU test is a non-waived test and ARU test is a waived test. A comprehensive method performance verification is required for the PRU test. We evaluated performance characteristics of the VerifyNow PRU Test and ARU Test for clinical use. Methods The standard precision and accuracy study using two levels (low and high) of quality control materials were performed (N = 10) for both the assays. Alternative qualitative method comparison was carried out (N = 49) using the VerifyNow PRU Test in a reference lab and in-house. The in-house inter-instrument comparisons were carried out (N = 42). The blood samples were obtained from patients taking P2Y12 inhibitors and from normal donors not on any drugs. The results of the PRU Test are expressed in P2YI2 reaction units (PRU). The VerifyNow-Aspirin assay results are expressed as aspirin reaction units (ARU). The statistical analysis to evaluate performance characteristics was carried out using the EP Evaluator. Results The VerifyNow device 1561 precision characteristics for low QC (Obs Mean = 1.5 PRU (N = 10), SD = 0.2; 95% CI for Obs Mean 1.0 to 2.0 PRU) and high QC (Obs Mean = 258.3 PRU (N = 10), SD = 8.2; 95% CI for Obs Mean 252.4 to 264.2 PRU) were within acceptable performance limits. The CV for high QC was 3.2%. The ARU test also demonstrated high precision for two levels (Low QC Obs Mean = 350ARU (N = 10), SD = 0.0); High QC Obs Mean = 583.3 (N = 10), SD = 7.2; 95% CI for Obs Mean = 578.1–588.5) with a CV of 1.2%. The PRU Test Method PRU 1561 In House vs Ref Method Verify Now PRU Test (N = 49) demonstrated overall agreement of 93.9% with positive agreement (intended use population on drugs, N = 27) of 92% and negative agreement (normal non-drug group, N = 22) of 95.8% (Cohen’s Kappa = 87.8%; Kappa >75% indicates “"high” agreement). The McNemar Test for Symmetry passed (P > 0.999, Fisher’s Exact test) in this qualitative method comparison. A value of P < 0.05 would suggest the methods are significantly different. The other in-house instrument 1562 also demonstrated comparable or better performance characteristics. Conclusion It is important to confirm the medical decision limit for the intended use population and determine acceptance criteria while considering biologic variability. However, the reference range verifications with drug responders and non-responders are not always feasible and cost-effective. Based on the qualitative method comparison in this study, we have transferred the medical decision limits from the peer group. The in-house multi-instrument comparison should be repeated every six months to monitor the performance of the instruments.

Plasma protein signatures for high on-treatment platelet reactivity to aspirin and clopidogrel in peripheral artery disease

BackgroundA significant proportion of patients with peripheral artery disease (PAD) displays a poor response to aspirin and/or the platelet P2Y12 receptor antagonist clopidogrel. This phenomenon is reflected by high on-treatment platelet reactivity (HTPR) in platelet function assays in vitro and is associated with an increased risk of adverse cardiovascular events. ObjectiveThis study aimed to elucidate specific plasma protein signatures associated with HTPR to aspirin and clopidogrel in PAD patients. Methods and resultsBased on targeted plasma proteomics, 184 proteins from two cardiovascular Olink panels were measured in 105 PAD patients. VerifyNow ASPI- and P2Y12-test values were transformed to a continuous variable representing HTPR as a spectrum instead of cut-off level-defined HTPR. Using the Boruta random forest algorithm, the importance of 3 plasma proteins for HTPR in the aspirin, six in clopidogrel and 10 in the pooled group (clopidogrel or aspirin) was confirmed. Network analysis demonstrated clusters with CD84, SLAMF7, IL1RN and THBD for clopidogrel and with F2R, SELPLG, HAVCR1, THBD, PECAM1, TNFRSF10B, MERTK and ADM for the pooled group. F2R, TNFRSF10B and ADM were higher expressed in Fontaine III patients compared to Fontaine II, suggesting their relation with PAD severity. ConclusionsA plasma protein signature, including eight targets involved in proatherogenic dysfunction of blood cell-vasculature interaction, coagulation and cell death, is associated with HTPR (aspirin and/or clopidogrel) in PAD. This may serve as important systems-based determinants of poor platelet responsiveness to aspirin and/or clopidogrel in PAD and other cardiovascular diseases and may contribute to identify novel treatment strategies.

Ticagrelor inverse agonist activity at the P2Y12 receptor is non-reversible versus its endogenous agonist adenosine 5´-diphosphate.

Ticagrelor is labelled as a reversible, direct-acting platelet P2Y12 receptor (P2Y12 R) antagonist that is indicated clinically for the prevention of thrombotic events in patients with acute coronary syndrome (ACS). As with many antiplatelet drugs, ticagrelor therapy increases bleeding risk in patients, which may require platelet transfusion in emergency situations. The aim of this study was to further examine the reversibility of ticagrelor at the P2Y12 R. Studies were performed in human platelets, with P2Y12 R-stimulated GTPase activity and platelet aggregation assessed. Cell-based bioluminescence resonance energy transfer (BRET) assays were undertaken to assess G protein-subunit activation downstream of P2Y12 R activation. Initial studies revealed that a range of P2Y12 R ligands, including ticagrelor, displayed inverse agonist activity at P2Y12 R. Only ticagrelor was resistant to washout and, in human platelet and cell-based assays, washing failed to reverse ticagrelor-dependent inhibition of ADP-stimulated P2Y12 R function. The P2Y12 R agonist 2MeSADP, which was also resistant to washout, was able to effectively compete with ticagrelor. In silico docking revealed that ticagrelor and 2MeSADP penetrated more deeply into the orthosteric binding pocket of the P2Y12 R than other P2Y12 R ligands. Ticagrelor binding to P2Y12 R is prolonged and more akin to that of an irreversible antagonist, especially versus the endogenous P2Y12 R agonist ADP. This study highlights the potential clinical need for novel ticagrelor reversal strategies in patients with spontaneous major bleeding, and for bleeding associated with urgent invasive procedures.

Abstract 10874: Predictors of Prehospital Opiate Use in Patients With ST Elevation Myocardial Infarction: Results From a Nationwide Database

Introduction: Opiates are traditionally used in STEMI patients to relieve pain, decrease pulmonary congestion, and anxiety. Yet, according to in vitro measurements, they delay and diminish the effect of all currently used oral platelet P2Y12 receptor antagonists. To be able to draw causal conclusions on the potential effects of opiates on clinical outcomes using real-world registries, the bias in treatment allocation may be minimized by propensity score methods. Therefore, we constructed a simple model of prehospital opiate administration using the database of the National Ambulance Service. Methods: We analyzed data of 10,139 subjects who were diagnosed with STEMI within 24 hours from symptom onset between November 2018 and June 2021. Patients with unsuccessful out-of-hospital CPR were excluded. Opiates were applied in 3,992 cases (39.4%). Besides onset-to-door time and need for CPR due to OHCA, basic demographic data like age and sex were studied as candidate predictors using logistic regression. Non-linearity of the continuous predictors was assessed by restricted cubic splines. Relative importance of the predictors was characterized by the Akaike Information Criterion (AIC). Results: Overall model fit was good: likelihood ratio chi-square=610.40, d.f.=10, p<0.0001. Opiate use was strongly associated with onset-to-door-time (p<0.0001, AIC=333.83) and Wald testing for linearity suggested a non-linear relationship (p<0.0001) with the highest odds at about 120 minutes. Similarly, it was also highly (p<0.0001, AIC=193.78) and non-linearly (p<0.0001) related to age with an inverted U-shaped curve. Moreover, it was negatively dependent on the need for CPR (p=0.0019, AIC=7.64) and unrelated to the sex of the patient (p=0.15, AIC=0.09). Conclusion: Our propensity score model may help to evaluate the role of opiate administration on clinical outcomes of STEMI patients and underscores the importance of non-linear modeling of continuous predictors.

Aspirin or Ticagrelor in Staphylococcus aureus Infective Endocarditis: Where Do We Stand?

Infective endocarditis is a challenging disease with a high mortality and morbidity rate. Antibiotic prophylaxis is currently recommended in high-risk infective endocarditis patients. However, the use of antibiotics faces the challenge of a low efficacy and contributes further to the emerging infection rate by antibiotic-resistant strains, emphasizing the need for new therapeutic strategies. Platelets are essential in the initial phase of infective endocarditis, acting as first-line immune responders. During the first phase of disease, bacteria can interact with platelets and counteract platelet antimicrobial activities. Mechanistic in vitro and animal studies on the effect of aspirin on bacteria-platelet interactions and the prevention of vegetation development showed promising results. However, data from clinical studies on the outcome of infective endocarditis patients who were receiving medically indicated aspirin therapy remain controversial. Therefore, the benefit of antiplatelet agents in infective endocarditis prevention has been questioned. Besides aspirin, it has been discovered that the platelet P2Y12 receptor antagonist ticagrelor has antibacterial properties in addition to its potent antiplatelet activity. Furthermore, a recent study in mice and a case report remarkably indicated the ability of this drug to eradicate Staphylococcus aureus bacteremia. This review will focus on current knowledge on antibacterial activity of ticagrelor, compared to aspirin, pointing out main unanswered questions. The goal is to provide food for thought as to whether a prior ticagrelor therapy might be beneficial for the prevention of infective endocarditis.

Optimal Antiplatelet Therapy After PCI in High-Bleeding-Risk Patients

Several recent randomized trials suggest that abbreviated dual antiplatelet therapy (DAPT; aspirin plus a platelet P2Y12 receptor antagonist) can

Monotherapy with Aspirin vs. Clopidogrel After Coronary Stenting

Dual antiplatelet therapy (DAPT) with aspirin plus a platelet P2Y12 receptor antagonist reduces ischemic complications (including stent thrombosis) in

Ticagrelor: clinical development and future potential.

Platelets participate centrally in atherothrombosis, resulting in vessel occlusion and ischaemia. Consequently, optimisation of antiplatelet regimens has the potential to further reduce the residual burden of morbidity and mortality associated with atherosclerosis. Ticagrelor is a potent oral platelet P2Y12 receptor antagonist that (1) inhibits a central amplification pathway of platelet activation directly as well as via an active metabolite, (2) has a rapid onset and offset of antiplatelet action that remains consistent in the circulation during twice-daily administration and is amenable to reversal, (3) has inverse agonist properties, and (4) demonstrates pleiotropic effects that contribute to anti-thrombotic, anti-inflammatory and vasodilatory properties. These advantageous characteristics of ticagrelor have translated to beneficial clinical outcomes in patients with acute coronary syndromes or ischaemic stroke, during prolonged maintenance therapy in specific high-risk populations, and following percutaneous coronary intervention but not definitively following coronary artery bypass graft surgery or in peripheral artery disease patients. Novel innovative strategies aim to reduce the risk of bleeding during dual antiplatelet therapy via shortening the duration of treatment and replacing the standard-of-care with ticagrelor monotherapy. In cases where aspirin is an essential component in secondary prevention, dose modification when combined with ticagrelor may hypothetically provide desirable clinical outcomes following appropriate clinical assessment as predicted by pharmacological studies. Overall, the future management of acute coronary syndromes could potentially involve the dichotomisation of antithrombotic therapies, whereby only those with high-risk of ischaemia, without a high-risk of bleeding, receive ticagrelor plus very-low-dose aspirin, while ticagrelor monotherapy is administered to the remaining majority.

Implications of the Antiplatelet Therapy Gap Left With Discontinuation of Prasugrel in Canada

BackgroundThe current Canadian Cardiovascular Society antiplatelet therapy guidelines recommend the use of ticagrelor or prasugrel over clopidogrel as first-line platelet P2Y12 receptor antagonists for treatment of moderate- to high-risk acute coronary syndromes. Recently, Effient (prasugrel [Eli Lilly Canada Inc, Toronto, Canada]) was discontinued by its distributor in Canada. MethodsFive members of the Canadian Cardiovascular Society antiplatelet therapy 2018 guidelines committee undertook an independent, evidence-based review to outline patients for whom prasugrel should be the optimal P2Y12 agent and discuss alternative strategies to consider without prasugrel. ResultsSeveral clinical scenarios where prasugrel should be indicated are identified and discussed. Considerations to be undertaken for alternative therapies are summarized, including a review of national and international guidelines for de-escalation of P2Y12 receptor antagonists. ConclusionsThe discontinuation of prasugrel poses a challenge for clinicians. Clinicians must consider key factors in determining the best alternate therapy.

CYP2C19 Polymorphisms and Smoking Status Affects Responsiveness to the Platelet P2Y12 Receptor Antagonist Clopidogrel

CYP2C19 Polymorphisms and Smoking Status Affects Responsiveness to the Platelet P2Y12 Receptor Antagonist Clopidogrel

ANTIPLATELET THERAPY OF ACUTE CORONARY SYNDROME: CURRENT CAPAB ILITIES

Dual antiplatelet therapy (acetylsalicylic acid and platelet P2Y12 receptor antagonist) is a standard component of treatment of any type of acute coronary syndrome, independently of perfusion and the chosen treatment strategy. Due to certain limitations of clopidogrel as the 2nd component of dual antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention, the possibility of using prasugrel or ticagrelor should be considered first. Their effectiveness is higher than clopidogrel’s, as was demonstrated in large clinical trials. As a result, prasugrel and ticagrelor were included in all major international and Russian guidelines on treatment of this category of patients with the same class and level of evidence. Currently, there’re no data from any finished large randomized clinical trials of sufficient statistical power directly comparing the effectiveness and safety of prasugrel and ticagrelor. Therefore, careful analysis of the accumulated data on the safety and effectiveness of each drug including meta-analyses and registries is necessary for providing the best care for every individual patient.

Abstract WP395: Verifynow P2Y12 Assay With Regard to Cytochrome P450 2C19 Polymorphisms and Stroke Recurrence

Background and Purpose: No evidence as yet that clopidogrel resistance (CR) on VerifyNow assay in relation to cytochrome P450 2C19 (CYP2C19) polymorphisms are more clinically informative at predicting recurrent vascular events during follow-up after ischemic stroke (IS). The aim of this study was to perform a subgroup analysis of MESTRO study to explore the relationship between VerifyNow P2Y12 assay with regard to CYP2C19 polymorphisms and stroke recurrence in patients with non-cardiogenic IS and clopidogrel treatment. Methods: The methods of the MAESTRO study have been published previously. For the study, CR was tested by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotype was classified as an ultrarapid metabolizer (UM; *1/*17, *17/*17), extensive metabolizer (EM; *1/*1), intermediate/unknown metabolizer (*1/*2, *1/*3 and *2/*17, *3/*17), or poor metabolizer (PM; *2/*2, *2/*3, *3/*3) based on CYP2C19 genotype status. UM or EM status patients were allocated into the good genotype group for clopidogrel metabolism, and intermediate/unknown metabolizer or PM status patients were allocated into the poor genotype group. Results: Of the 256 patients with clopidogrel treatment, 20 (7.8%) had a recurrent stroke: 15 (75%) experienced an IS and 5 (25%) experienced an ICH. Of the patients with percent inhibition (% INH) ≥40, the risk of recurrent stroke in the good genotype group was 2.2% and was not significantly different from that in the poor genotype group (6.7%) (P=0.400). There was also no significant reduction in the risk of a major vascular event between the groups (2.2% vs 6.7%, P=0.400). Of the patients with % INH <40, there was a trend towards reduction in risk for the recurrent stroke (2.1% vs 8.3%, p=0.142) and a major vascular event (2.1% vs 9.8%, p=0.081) in the good genotype group. Conclusions: Impaired responsiveness to the platelet P2Y12 receptor antagonist clopidogrel alone may not predict stroke recurrence.

The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions.

Scientists and clinicians have been concerned by the lack of a clinically suitable strategy for cardioprotection in patients with acute myocardial infarction despite decades of intensive pre-clinical investigations and a surprising number of clinical trials based on those observations which have uniformly been disappointing. However, it would be a mistake to abandon this search. Rather it would be useful to examine these past efforts and determine reasons for the multiple failures. It appears that earlier clinical trials were often based on results from a single experimental laboratory, thus minimizing the importance of establishing reproducibility in multiple laboratories by multiple scientists and in multiple models. Clinical trials should be discouraged unless robust protection is demonstrated in pre-clinical testing. After approximately 2005 a loading dose of a platelet P2Y12 receptor antagonist became increasingly widespread in patients with acute myocardial infarction prior to revascularization and quickly became standard-of-care. These agents are now thought to be a cause of failure of recent clinical trials since these pleiotropic drugs also happen to be potent postconditioning mimetics. Thus, introduction of an additional cardioprotective strategy such as ischemic postconditioning which uses the same signaling pathway as these P2Y12 antagonists would be redundant and doomed to failure. Additive cardioprotection could be achieved only if the second intervention had a different mechanism of cardioprotection. This concept has been demonstrated in experimental animals. So lack of reproducibility of earlier studies and failure to examine interventions in experimental animals also treated with anti-platelet agents could well explain past failures. These realizations should clear the way for development of interventions which can be translated into successful clinical treatments.

Increased Benefit With Vorapaxar Use in Patients With a History of Myocardial Infarction and Diabetes Mellitus: What the Data Show Us.

Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial metabolic disease mainly characterized by hyperglycemia and insulin resistance. Abnormal platelet reactivity associated with an increased risk of cardiovascular disease (CVD) is also a feature characteristic of patients with T2DM. Dual antiplatelet therapy consisting of aspirin and an adenosine diphosphate platelet P2Y12 receptor antagonist, such as clopidogrel, represents the standard antithrombotic regimen for the secondary prevention of CVD risk in T2DM. However, a high proportion of patients with T2DM exhibit high on-treatment platelet reactivity to aspirin and/or clopidogrel, associated with a greater risk of adverse cardiovascular events compared with nondiabetic patients. Consequently, novel antiplatelet therapeutic approaches may be required in order to avoid such events. Vorapaxar is a novel antiplatelet agent that targets the platelet protease-activated receptor 1 and inhibits thrombin-induced platelet activation. Vorapaxar has been studied in 2 phase III clinical trials and has been approved for use in the secondary prevention of atherothrombotic events in patients with a previous myocardial infarction (MI) or peripheral arterial disease. New data from the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial MI cohort demonstrate that the subgroup of patients with T2DM exhibits increased benefit from vorapaxar use compared with non-T2DM patients. The aim of the present work is to critically review the current knowledge concerning vorapaxar use in patients with T2DM as well as to discuss the possible mechanism(s) underlying vorapaxar's beneficial effect in T2DM.

Cangrelor for the management and prevention of arterial thrombosis

ABSTRACTIntroduction: Despite advances in antiplatelet therapy, the optimum antithrombotic regimen during percutaneous coronary intervention (PCI) remains to be determined. Cangrelor is an intravenous, reversibly-binding platelet P2Y12 receptor antagonist with ultra-rapid onset and offset of action that is approved in Europe and United States for use in patients undergoing PCI. This article describes the background for the development of cangrelor, the biology, pharmacology and clinical evidence supporting its use, and its likely position in the future.Areas covered: The role of the platelet P2Y12 receptor in platelet biology and the implications of this for atherothrombotic disease are described. Currently unmet needs in antithrombotic management during and after PCI are discussed followed by a description of the chemistry, pharmacokinetics and pharmacodynamics of cangrelor, including its interactions with oral thienopyridines. Subsequently, the clinical trial evidence supporting its adoption into clinical practice is reviewed, including the evidence indicating its superiority over a strategy based on clopidogrel treatment alone.Expert commentary: The current status and future potential of cangrelor is discussed, including a view of its place in current clinical practice.

Cangrelor-Mediated Cardioprotection Requires Platelets and Sphingosine Phosphorylation.

In animal models platelet P2Y12 receptor antagonists put the heart into a protected state, not as a result of suppressed thrombosis but rather through protective signaling, similar to that for ischemic postconditioning. While both ischemic postconditioning and the P2Y12 blocker cangrelor protect blood-perfused hearts, only the former protects buffer-perfused hearts indicating that the blocker requires a blood-borne constituent or factor to protect. We used an anti-platelet antibody to make thrombocytopenic rats to test if that factor resides within the platelet. Infarct size was measured in open-chest rats subjected to 30-min ischemia/2-h reperfusion. Infarct size was not different in thrombocytopenic rats showing that preventing aggregation alone is not protective. While ischemic preconditioning could reduce infarct size in thrombocytopenic rats, the P2Y12 inhibitor cangrelor could not, indicating that it protects by interacting with some factor in the platelet. Ischemic preconditioning is known to require phosphorylation of sphingosine. In rats treated with dimethylsphingosine to block sphingosine kinase, cangrelor was no longer protective. Thus cangrelor's protective mechanism appears to also involve sphingosine kinase revealing yet another similarity to conditioning's mechanism.

Transition strategies from cangrelor to oral platelet P2Y12 receptor antagonists.

Cangrelor is the first parenteral antagonist of the platelet P2Y12 receptor. This direct-acting antagonist of the platelet P2Y12 receptor should be considered an adjunct to a percutaneous coronary intervention in patients who have not been adequately pretreated with platelet P2Y12 receptor antagonists at the time of the procedure. The use of cangrelor requires transition to an oral platelet P2Y12 receptor antagonist. Transition strategies have been developed on the basis of pharmacologic characteristics of platelet P2Y12 receptor antagonists, results of pharmacodynamic studies, and results from clinical trials. Cangrelor blocks the binding to the platelet P2Y12 receptor of the active metabolite of the thienopyridines, clopidogrel and prasugrel. The active metabolite of thienopyridines is present in blood for a short interval after administration. For this reason, clopidogrel should be administered after cangrelor is stopped. Prasugrel can be administered at the end of the cangrelor infusion or up to 30 min before cangrelor is stopped. Ticagrelor is also a reversible direct-acting antagonist of the platelet P2Y12 receptor. Because there is no interaction between ticagrelor and cangrelor, ticagrelor can be administered before or during the infusion of cangrelor.

Abstract 10281: Cangrelor’s Anti-Infarct Effect Requires Phosphorylation of Sphingosine in Platelets: The Missing Link

Patients with myocardial infarction routinely receive a platelet P2Y12 receptor antagonist prior to percutaneous coronary intervention. In monkeys, rabbits, and rats P2Y12 antagonists act as potent postconditioning-mimetics. Unlike ischemic postconditioning, however, the P2Y12 antagonist cangrelor could not reduce infarct size in Krebs buffer-perfused hearts. We tested whether platelets were required for protection from cangrelor. Rats were treated with intraperitoneal placebo or anti-rat thrombocyte serum (ARTS), 0.5ml, which decreased platelet counts by at least 96%. After 24h the heart was exposed and left coronary artery occluded for 30min and reperfused for 2h. Risk zone and infarct size were measured. In placebo rats infarct size averaged 45.3±1.2% of risk zone, while an intravenous bolus of cangrelor, 60μg/kg, 10 min before reperfusion followed by infusion of 6μg/kg/min decreased infarction to 25.0±1.8% (p<0.001). ARTS alone had no effect on infarct size (50.5±3.7%). However, ARTS blocked cangrelor’s protective effect (48.4±3.4% infarction). Hence cangrelor’s cardioprotective effect depends on platelets. But how can cangrelor cause platelets to trigger postconditioning’s protective signaling? Activated platelets release sphingosine -1 phosphate (S1P), a known trigger for conditioning. Some of the S1P from platelets comes from a sphingomyelinase that is recruited during activation and catabolizes membrane sphingomyelin to sphingosine (sph) which is quickly phosphorylated by sph kinases. We blocked sph kinase with intravenous N-N-dimethylsphingosine (DMS), 0.33 mg/kg, administered 15 min after coronary occlusion. DMS alone had no effect on infarction (43.8±2.3%). But it abrogated cangrelor’s protective effect (42.8±2.0%). In the presence of cangrelor platelets can’t aggregate and plug vascular defects caused by ischemic injury. We propose that in cangrelor-treated post-ischemic hearts platelets enter the interstitial space early in reperfusion and release S1P when they contact collagen which postconditions the heart and protects against reperfusion injury. Thus blocking aggregation allows platelets to produce a pharmacological trigger of postconditioning that reduces infarction.

The Platelet Function Analyser (PFA)-100 and von Willebrand disease: a story well over 16 years in the making.

The Platelet Function Analyser (PFA)-100 and von Willebrand disease: a story well over 16 years in the making.

IMPACT OF CANGRELOR OVERDOSING ON BLEEDING COMPLICATIONS IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: INSIGHTS FROM THE CHAMPION TRIALS

Overdosing of parenteral antithrombotic therapies can increase the risk of bleeding. Cangrelor is a potent intravenous platelet P2Y12 receptor antagonist with rapid onset and offset of action. In patients undergoing percutaneous coronary interventions (PCI), compared with control, cangrelor (30 µg/kg bolus, followed immediately by a 4 µg/kg per minute infusion for 2–4 h or until the conclusion of the index PCI, whichever was longer) reduces periprocedural thrombotic complications without an increase in major bleeding complications, although minor bleeding is increased. The impact of cangrelor overdosing on bleeding is unknown and represented the aim of this analysis. Patients with cangrelor overdosing were identified among safety population patients enrolled in the CHAMPION program (n = 25,107). Overdose was defined as administration of an excess >20 % of the bolus dose (30 μg/kg) and/or infusion rate (4 μg/kg per min). Bleeding complications were assessed. Among the safety analysis population in the CHAMPION program, 12,565 patients received cangrelor. A total of 36 overdosed cangrelor patients (0.29 %) were identified in this pooled analysis (20 with both bolus and infusion, 5 with bolus only, and 11 with infusion only). In the majority of patients, the dose did not exceed 2.5 times the recommended dose. Bleeding events were balanced between treatment arms and were consistent with those in the overall CHAMPION program. Only one overdosed patient experienced a serious bleed. There was no correlation between bleeding and magnitude of cangrelor overdose. In a large clinical trial program of patients undergoing PCI, cangrelor overdosing was rare and not associated with an increase in bleeding complications, an observation that may be attributed to its very short-half life and rapid offset of action.