Cangrelor dose titration using platelet function testing during cerebrovascular stent placement

BackgroundOptimal antiplatelet inhibition is vital during cerebrovascular stenting procedures, yet no standardized recommendation exists for antithrombotic therapy in these scenarios. Cangrelor is an intravenous P2Y12 inhibitor with a favorable pharmacokinetic profile for use during neuroendovascular stenting.MethodsA retrospective review of all neuroendovascular patients who underwent stenting between 1 January 2019 and 22 March 2020 and were treated with cangrelor was conducted. Thirty-seven patients met inclusion criteria.ResultsAll patients were administered a bolus of 5 mcg/kg of cangrelor followed by a maintenance infusion. Antiplatelet effects of cangrelor were monitored using platelet reactivity units (PRU). Based on the initial PRU, seven patients’ doses were adjusted with subsequent PRUs in or near the goal range of 50–150. One patient experienced an acute intraprocedural occlusion likely related to a subtherapeutic PRU which subsequently resolved with cangrelor dose adjustment and intra-arterial tirofiban administration, and one patient experienced a post-procedure stent occlusion which required a thrombectomy and intra-arterial tirofiban administration. No hemorrhagic complications occurred.DiscussionCangrelor utilization during neuroendovascular stenting with maintenance doses of <2 mcg/kg/min with dose adjustments based on platelet function testing has not been previously described. Cangrelor presents many advantages compared to standard therapy in patients undergoing stent placement related to its pharmacokinetic profile, rapid onset of action, ease of transition to oral P2Y₁₂ antiplatelet agents, and measurability.ConclusionCangrelor is a promising alternative to currently available therapies, especially in patients with a high hemorrhagic risk.     

Prostacyclin receptor stimulation facilitates detection of human platelet P2Y12 receptor inhibition by the PFA-100® system

The rationale for monitoring platelet inhibition by thienopyridines for the identification of patients at risk for future recurrent arterial thrombosis or ischemic events is intensively discussed, as well as which monitoring systems are appropriate, robust and reliable. Flow cytometric measurement of phosphorylated VASP (vasodilator-stimulated phosphoprotein), expressed as platelet reactivity index (PRI), is presently “the gold standard method” for evaluating P2Y₁₂ receptor inhibition. The PFA-100® system, a commercially available and clinically widely used platelet test system, is based on a different principle, not that of VASP phosphorylation. The aim of the present study was to compare the two methods and evaluate whether the conventional PFA-100® collagen/ADP cartridge could be pharmacologically improved to enable its routine clinical use for detection of platelet P2Y₁₂ receptor inhibition. The effects of increasing concentrations of the competitive P2Y₁₂ receptor antagonist cangrelor (AR-C69931MX) and the time-dependent effects of a single oral loading dose of clopidogrel (600 mg) were analysed with human whole blood. P2Y₁₂ receptor inhibition was measured by the VASP/PRI assay and the PFA-100® collagen/ADP cartridge system, with and without preincubation with the prostacyclin analog iloprost (Ilomedin®). In vitro addition of iloprost (0.5 nM) enabled PFA-100® collagen/ADP cartridge system detection of P2Y₁₂ receptor inhibition in whole blood by cangrelor in vitro or by clopidogrel treatment of volunteers. The addition of a prostacyclin analog facilitates PFA-100® collagen/ADP system detection of P2Y₁₂ receptor inhibition, achieving a sensitivity similar to that of the VASP/PRI reference method. Future studies should now evaluate whether this modified PFA-100® system, like the VASP assay, is a reliable test system for monitoring P2Y₁₂ receptor inhibition under clinical conditions.     

Squalene synthase inhibitors

Hypercholesterolaemia (defined as elevated levels [> 200 mg/dl] of plasma total cholesterol [TC]) is a significant risk factor for the development of atherosclerosis. The discovery and development of new hypocholesterolaemic agents has been a high priority for both pharmaceutical and academic researchers because of the devastating nature of the illness and the potentially huge patient population. Until recently, therapies for the treatment of hypercholesterolaemia suffered from a poor side-effect profile and lingering concerns over long-term toxicity. All of this changed with the introduction of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (HMGRIs), the most effective therapy to date in terms of lipid-lowering and side-effect profile. These compounds inhibit the enzyme, HMG CoA reductase, in the rate-limiting step of cholesterol biosynthesis and this results in significant decreases of plasma cholesterol at relatively low doses of HMGRI. The success of these agents has stimulated the search for other inhibitors of the multistep cholesterol biosynthetic pathway. Probably the most desirable enzyme to inhibit in this pathway is squalene synthase (SS). This is the only enzyme in the whole pathway that is solely committed to the synthesis of the sterol nucleus of cholesterol, and therefore inhibition would not affect the biosynthesis of other biologically important molecules. It is hoped that this would lead to an even better side-effect profile than the HMGRIs. Researchers have used substrate-based drug design, natural product screening and archival screening in their efforts to discover novel squalene synthase inhibitors. Whether the efficacy and safety of these agents in man will be superior to currently available therapies remains to be determined.     

Emerging antithrombotic drugs for acute coronary syndrome

Introduction: Acute coronary syndrome (ACS) encompasses acute myocardial infarction (MI) and unstable angina. Activation of platelets and coagulation cascade plays a central role in the development of ACS. Over the past decade, there have been substantial improvements in the strategies for secondary prevention of ACS, including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor. However, therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable.

Areas covered: This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents; cangrelor (an intravenous P2Y12 receptor antagonist), vorapaxar (protease-activated receptor-1 inhibitor) and rivaroxaban (an oral factor Xa inhibitor).

Expert opinion: Cangrelor appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed. Vorapaxar in addition to standard oral antiplatelet therapy was effective in patients with prior MI, but was not safe in patients with a prior stroke. Low dose rivaroxaban decreased cardiovascular events and mortality in patients post-ACS compared to placebo, although bleeding was increased.     

Outcomes With Cangrelor Versus Clopidogrel on a Background of Bivalirudin: Insights From the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI])

ObjectivesThe aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.BackgroundCangrelor is a potent intravenous P2Y₁₂ inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.MethodsIn the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.ResultsAt 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non–ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).ConclusionsCangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.     

Cangrelor in patients undergoing cardiac surgery: the BRIDGE study

The benefit of long-term dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes, drug-eluting stents and those at high risk for thromboembolic events has been well established in a number of well-designed randomized controlled studies. Current research in this area has focused on the development of novel antiplatelet agents for clinical use. The BRIDGE trial evaluated the use of cangrelor as a bridge to coronary artery bypass graft surgery in patients receiving extended DAPT. The BRIDGE trial results confirm the efficacy and safety of cangrelor in this population. This study is novel as it attempts to address the lapse in thienopyridine therapy required for many surgical and invasive procedures. The future of antiplatelet agents, particularly cangrelor, must also focus on bridging for high-risk patients undergoing noncoronary artery bypass graft surgical procedures. Overall, the BRIDGE trial represents a significant advance for patients appropriate for long-term DAPT.     

Use of Cangrelor as a Bridge to Left Ventricular Assist Device Implantation in a Patient with a Recent Drug-Eluting Stent Who Developed Acute Tirofiban-Related Thrombocytopenia

Current guidelines emphasize the need for at least 6–12 months of oral dual antiplatelet therapy consisting of aspirin and a P2Y12 inhibitor following drug-eluting coronary artery stent implantation. In patients with recently implanted coronary artery stents who require urgent cardiac or noncardiac surgery, the benefits of maintaining oral dual antiplatelet therapy must be carefully weighed against the risks of excessive bleeding, and current practice is largely guided by individual surgeon preferences. When the effects of a second oral antiplatelet agent are undesirable during the perioperative period, the use of a short-acting intravenous antiplatelet agent as “bridge” therapy that can be discontinued shortly before surgery is associated with a reduced occurrence of adverse clinical events in patients with recently implanted coronary stents requiring urgent coronary artery bypass graft surgery. Cangrelor is an intravenous adenosine triphosphate analog P2Y12 receptor antagonist with a short plasma half-life that has been used off label in patients with recent coronary stents as a bridge to invasive procedures with excessive bleeding risk. To our knowledge, this is the first case report to demonstrate the safe and effective use of cangrelor as a bridge to left ventricular assist device implantation in a patient with a recently implanted drug-eluting coronary artery stent who developed acute thrombocytopenia following reexposure to tirofiban, a glycoprotein IIb/IIIa inhibitor.     

Novel use of cangrelor in pediatrics: A pilot cohort study demonstrating use in ventricular assist devices

Thromboembolic events and bleeding are major sources of morbidity among pediatric patients supported on a ventricular assist device (VAD). Pharmacokinetics and pharmacodynamics of enteral antiplatelet agents are affected and variable due to erratic enteral absorption in end‐stage heart failure and VAD circulation. Additionally, 20%‐40% of the population are poor metabolizers of clopidogrel, a prodrug, making cangrelor an alternative when antiplatelet therapy is crucial. Cangrelor has been used effectively and safely for short durations in adults during percutaneous coronary interventions, but the use of cangrelor is still under investigation in pediatrics. This case series utilized cangrelor, a novel short‐acting, reversible, intravenous P2Y₁₂ platelet inhibitor in managing pediatric patients supported with a VAD. We performed a retrospective, single‐center review of patients admitted to a tertiary medical center with end‐stage heart failure requiring mechanical circulatory support and concomitant cangrelor administration between January 2019 and March 2020. Platelet function testing, cangrelor dose, bleeding complications, thromboembolic events, and frequency of circuit interventions during the use of cangrelor were recorded. Optimal platelet reactivity, defined as P2Y₁₂ < 180 platelet reaction units (PRU), was measured with serial point‐of‐care testing (VerifyNow). Seven patients, median age of 4.9 years, met the above criteria. Three patients had a diagnosis of complex congenital heart disease. Four patients had dilated or restrictive cardiomyopathy. All patients were on continuous flow VADs. The median VAD duration was 84.5 days (IQR 61.5‐103). The median duration on cangrelor was 43 days (IQR 8‐70). The median cangrelor dose to reach the therapeutic threshold was 0.75 μg/kg/min with the mean P2Y₁₂, while on cangrelor of 164.75 PRU. Bleeding complications included mild gastrointestinal bleeding and hematuria. There was one patient with pump thrombosis requiring intervention. There were no cerebrovascular events while on cangrelor. We report the first successful long‐term use of cangrelor in pediatric patients. The reversibility and short half‐life of cangrelor make it a feasible antiplatelet agent in selected patients. This data supports the use of cangrelor in children as a viable antiplatelet option; with minimal bleeding complications and no cerebrovascular events demonstrated in this cohort.