Discontinuation Of Ticagrelor Research Articles

Absolute Thrombocytopenia with Ticagrelor

The most prevalent ticagrelor adverse effects are bleeding, dyspnea, bradycardia, and, in rare cases, thrombotic thrombocytopenic purpura. Although extremely rare, ticagrelor can cause absolute or profound thrombocytopenia. We present a case of total thrombocytopenia caused by ticagrelor after 4 days of treatment. A male in his 60 s with hypertension, type 2 diabetes mellitus, and dyslipidemia presented with chest pain. A 12-lead electrocardiogram showed sinus rhythm at 80 beats per min, ST-segment elevation, Q waves, and ST depression in V4-V6, indicating inferolateral myocardial infarction. Patient received thrombolytics with prompt administration of aspirin and ticagrelor. Baseline platelet count was 138 × 109/L. A subsequent angiography was performed 10 h later that revealed multivessel disease and the patient deemed a candidate for coronary artery bypass surgery. About 72 h after presentation, he had hematuria and his platelet count dropped to 23 109/L. On repeat testing, a complete blood count indicated platelet counts of 23 × 109 and 9 × 109/µL. A peripheral smear revealed no signs of platelet clumping or schistocytes. As a result, ticagrelor and aspirin were promptly stopped. Six platelet units were transfused. Prior to discharge, the platelet count hit the 50 s and then recovered to baseline. Clopidogrel and aspirin were prescribed for the patient. On outpatient follow-up, no thrombocytopenia was observed. In addition to our patient, we came across two patients in the literature who developed profound thrombocytopenia after being treated with ticagrelor. The timing of ticagrelor-induced thrombocytopenia varied and all patients were treated with platelets transfusion and discontinuation of ticagrelor. No thrombocytopenia was seen thereafter. In conclusion, thrombocytopenia with ticagrelor should be considered when other potential causes of thrombocytopenia have been ruled out.

Refractory drug-induced systemic small-vessel vasculitis with two varied extracutaneous manifestations: a case report and review of the literature

BackgroundClopidogrel and ticagrelor are rarely reported to cause vasculitis via drug hypersensitivity reaction, largely mediated by T cells and immunoglobulin E (IgE). Despite therapeutic advances, the etiology of refractory vasculitides remains incompletely understood. Recently, (non)immunological mechanisms bypassing T cells and IgE have been proposed to explain resistance to standard immunosuppressants. Herein, we report a case of refractory drug-induced systemic small-vessel vasculitis with varied extracutaneous manifestations and incorporate multiple sources of data to provide detailed accounts of complex (non)immunological phenomena involved in this case. Study objectives are to provide an insight about rare presentations of commonly used drugs, upgrade the pathophysiological concepts of drug-induced vasculitis, raise need for further investigation to define causes and risk factors for refractory vasculitis, and discuss most of the current knowledge suggesting novel therapeutic approaches to treat this vasculitis. To our knowledge, this is the first case of the two flares of systemic small-vessel vasculitis in a single patient in response to clopidogrel and ticagrelor exposure, respectively. However, this report is limited by attribution/observer bias.Case presentationWe herein report a 24-year-old Caucasian male student with a medical history of mild seasonal allergic rhinoconjunctivitis, tension-type headaches, posttraumatic arterial stenosis, and previous exposure to ibuprofen, acetylsalicylic acid, and mRNA coronavirus disease 2019 (COVID-19) vaccine who suffered largely from acute urticaria and dyspnea after 20 days of acetylsalicylic acid and clopidogrel introduction. A skin punch biopsy confirmed leukocytoclastic vasculitis. Serologic antibody testing, complement analysis, microbiologic testing, and cancer biomarkers revealed no abnormalities. Regarding the patient’s medical history, both acetylsalicylic acid and clopidogrel were exchanged for ticagrelor. Furthermore, the addition of naproxen, cyclosporine, bilastine, prednisolone, and montelukast resulted in complete recovery. After 7 days, diarrhea and hematuria occurred. Urinalysis and computed tomography showed reversible proteinuria with gross hematuria and hypodense changes in kidney medulla, respectively, associated with discontinuation of ticagrelor and naproxen. In addition, the patient recovered completely without any immunosuppression up-titration.ConclusionsThis case highlights the role of clopidogrel and ticagrelor as possible triggering agents for systemic small-vessel vasculitis and offers an insight into novel therapeutic strategies for refractory vasculitides. Further research is needed to build on the findings of a current report.

Dyspnea-Related Ticagrelor Discontinuation After Percutaneous Coronary Intervention

BackgroundNearly 20% of patients on ticagrelor experience dyspnea, which may lead to treatment discontinuation in up to one-third of cases. ObjectivesThe authors sought to evaluate the incidence, predictors, and outcomes of dyspnea-related ticagrelor discontinuation after percutaneous coronary intervention (PCI). MethodsIn the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, after 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The occurrence of dyspnea associated with ticagrelor discontinuation was evaluated among all patients enrolled in the trial. A landmark analysis was performed at 3 months after PCI, that is, the time of randomization. Predictors of dyspnea-related ticagrelor discontinuation were obtained from multivariable Cox regression with stepwise selection of candidate variables. ResultsThe incidence of dyspnea-related ticagrelor discontinuation was 6.4% and 9.1% at 3 and 15 months after PCI, respectively. Independent predictors included Asian race (lower risk), smoking, prior PCI, hypercholesterolemia, prior coronary artery bypass, peripheral artery disease, obesity, and older age. Among 179 patients who discontinued ticagrelor because of dyspnea after randomization, ticagrelor monotherapy was not associated with a higher risk of subsequent ischemic events (composite of all-cause death, myocardial infarction, or stroke) compared with ticagrelor plus aspirin (5.0% vs 7.1%; P = 0.566). ConclusionsIn the TWILIGHT trial, dyspnea-related ticagrelor discontinuation occurred in almost 1 in 10 patients and tended to occur earlier rather than late after PCI. Several demographic and clinical conditions predicted its occurrence, and their assessment may help identify subjects at risk for therapy nonadherence.

Cost-Effectiveness and Budget Impact of a Novel Antithrombotic Drug Removal System to Reduce Bleeding Risk in Patients on Preoperative Ticagrelor Undergoing Cardiac Surgery.

Antithrombotic drugs, including the P2Y12 inhibitor ticagrelor, increase the risk of perioperative bleeding in patients requiring urgent cardiac surgery. Perioperative bleeding can lead to increased mortality and prolong intensive care unit and hospital stays. A novel sorbent-filled hemoperfusion cartridge that intraoperatively removes ticagrelor via hemoadsorption can reduce the risk of perioperative bleeding. We estimated the cost-effectiveness and budget impact of using this device versus standard practices to reduce the risk of perioperative bleeding during and after coronary artery bypass grafting from the US healthcare sector perspective. We used a Markov model to analyze the cost-effectiveness and budget impact of the hemoadsorption device in three cohorts: (1) surgery within 1 day from last ticagrelor dose; (2) surgery between 1 and 2 days from last ticagrelor dose; and (3) a combined cohort. The model analyzed costs and quality-adjusted life years (QALYs). Results were interpreted as both incremental cost-effectiveness ratios and net monetary benefits (NMBs) at a cost-effectiveness threshold of $100,000/QALY. We analyzed parameter uncertainty using deterministic and probabilistic sensitivity analyses. The hemoadsorption device was dominant for each cohort. Patients with less than 1 day of washout in the device arm gained 0.017 QALYs at a savings of $1748(USD), for an NMB of $3434. In patients with 1-2 days of washout, the device arm yielded 0.014 QALYs and a cost savings of $151, for an NMB of $1575. In the combined cohort, device gained 0.016 QALYs and a savings of $950 for an NMB of $2505. Per-member-per-month cost savings associated with device was estimated to be $0.02 for a one-million-member health plan. This model found the hemoadsorption device to provide better clinical and economic outcomes compared with the standard of care in patients who required surgery within 2 days of ticagrelor discontinuation. Given the increasing use of ticagrelor in patients with acute coronary syndrome, incorporating this novel device may represent an important part of any bundle to save costs and reduce harm.

Preoperative treatment with clopidogrel and ticagrelor on bleeding complications in off-pump coronary artery bypass grafting

BackgroundDual antiplatelet therapy (DAPT) consisting of acetylsalicylic acid and clopidogrel or ticagrelor increased bleeding complications in patients undergoing coronary artery bypass grafting (CABG). We aimed to compare the bleeding risks between patients treated with clopidogrel and ticagrelor preoperatively and investigate the influence of discontinuation of clopidogrel and ticagrelor on bleeding risk in off-pump CABG (OPCABG). MethodsWe conducted a retrospective analysis of patients with DAPT who underwent OPCABG. The propensity score matching was performed given the baseline differences between clopidogrel- and ticagrelor-treated patients. Bleeding was assessed by chest tube drainage volume and universal definition of perioperative bleeding. ResultsThis study included 836 patients. Five hundred and fifty patients were treated with clopidogrel and 286 patients treated with ticagrelor before surgery. After matching, 275 patients treated with clopidogrel and 275 patients with ticagrelor were included. There were no significant differences in bleeding between clopidogrel and ticagrelor group. Patients who discontinued clopidogrel before surgery <3 d had a higher risk of severe perioperative bleeding compared with those who discontinued ≥5 d (16.4 % vs. 5.0 %, P = 0.045). By contrast, the risk of severe perioperative bleeding was comparable among patients who discontinued ticagrelor for <3 d, ≥3–5 d and ≥5 d preoperatively (16.2 % vs. 9.1 % vs. 10.1 %, P = 0.317). The multivariable analysis confirmed that time since discontinuation (<3 d vs. ≥5 d: OR = 2.732, 95 % CI: 1.332–5.605, P = 0.006) but not the types of P2Y12 receptor antagonist was an independent predictor for severe perioperative bleeding. ConclusionsThere were no significant differences in severe perioperative bleeding between clopidogrel and ticagrelor groups. Discontinuation of clopidogrel <3 d before OPCABG increased the risk of severe perioperative bleeding.

Impact of Ticagrelor Versus Clopidogrel on Bleeding Outcomes of Isolated Coronary Artery Bypass Grafting

BackgroundIncreased bleeding risks have been documented in patients exposed to P2Y12 inhibitors within 5 days of coronary artery bypass surgery (CABG). This study aimed to determine the relative CABG bleeding risks of clopidogrel versus ticagrelor exposure and the proper time course of ticagrelor discontinuation prior to surgery. MethodsClinical outcomes were assessed in 2075 isolated CABG patients, including 375 who had received P2Y12 inhibitors within 5 days of surgery (155 clopidogrel, 213 ticagrelor, 7 prasugrel). BARC-4 CABG bleeding complications and perioperative blood product usage were assessed in propensity-matched P2Y12-inhibited and non-P2Y12-inhibited cohorts. ResultsP2Y12-inhibited patients (n = 375) in comparison to matched non-P2Y12-inhibited patients (n = 1138) had higher rates of re-operation for bleeding (3.8 % vs 1.3 %, p = 0.003), postoperative red blood cell transfusion ≥5 units (5.7 % vs 2.7 %, p = 0.007), and intraoperative and postoperative blood product utilization (42.3 % vs 27.1 %, p < 0.001; 41.8 % vs 32.2 %, p < 0.001, respectively). Univariate predictors of BARC-4 bleeding included clopidogrel (OR: 2.145, 95 % CI: 1.131–4.067, p = 0.019) and ticagrelor discontinued within 3 days of surgery (OR: 2.153, 95 % CI: 1.003–4.169, p = 0.049). Multivariate logistic regression demonstrated that only clopidogrel exposure was an independent BARC-4 bleeding predictor (OR: 1.850, 95 % CI: 1.007–3.398, p = 0.048). Unadjusted ticagrelor patients with drug discontinuation 4–5 days prior to CABG only demonstrated higher rates of perioperative platelet transfusion, without additional signs of excessive bleeding. ConclusionsClopidogrel exposure within 5 days of CABG is an independent predictor of BARC-4 bleeding, whereas major ticagrelor bleeding effects are confined to drug exposure within 3 days of surgery.

Ticagrelor Induced Diffuse Alveolar Hemorrhage - A Case Report

Drug-induced Alveolar Hemorrhage is a rare cause of Diffuse Alveolar Hemorrhage (DAH). It requires to be considered in the differential diagnosis among patients presenting with DAH and prompt management, including the need for mechanical ventilation in severe cases. Here we present a case of severe DAH following percutaneous coronary intervention and Ticagrelor therapy that responded well to discontinuation of Ticagrelor.

Effect of discontinuation of ticagrelor and switching-over to other P2Y12 agents in patients with acute coronary syndrome: a single-center real-world experience from India

BackgroundDual antiplatelet therapy is the current standard of care after acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). We intended to study the pattern of use of ticagrelor in patients with acute coronary syndrome undergoing PCI and the effect of switching over to other P2Y12 receptor inhibition on clinical outcomes.ResultsAll patients aged > 18 years who had been admitted with acute coronary syndrome and had been provided ticagrelor as the second antiplatelet agent were included as study participants. The primary outcome of the study was the composite outcome of death, recurrent myocardial infarctions, re-intervention, and major bleeding. We studied 321 patients (54 female patients, 16.82%). The mean age of the patients was 56.65 ± 11.01 years. Ticagrelor was stopped in 76.7% on follow-up. It was stopped in 6.3%, 13.5%, 13.1%, 21.9%, and 45.1% of patients during the first month but after discharge, between first and third months, between 3 and 6 months, between 6 and 12 months, and after 12 months, respectively. In the majority of patients, ticagrelor was replaced by clopidogrel (97.9%). It was stopped according to the physician’s discretion in 79.3% of patients, whereas it was the cost of the drug that made the patient to get swapped to another agent in 18.6%. No difference in the primary composite outcome was observed between the groups where ticagrelor was continued post 12 months and ticagrelor was continued and ticagrelor was switched-over to another agent. Similarly, no difference in death, recurrent myocardial infarctions, re-interventions, or major bleeding manifestations was observed between the two groups.ConclusionIn patients with acute coronary syndrome who undergo PCI, we observed that early discontinuation of ticagrelor and switching over to other P2Y12 inhibitors after discharge did not affect clinical outcomes.

255. Ticagrelor Aids Platelet-Mediated Clearance in a Refractory Staphylococcus aureus Endovascular Infection with Septic Emboli

BackgroundThe pore-forming alpha-toxin produced by Staphylococcus aureus (SA) decreases the viability and increases the clearance of platelets, a critical element of innate immune defense in endovascular infection. Our group recently identified that ticagrelor (TICA) blocks alpha-toxin-induced platelet clearance, protecting mice in a lethal systemic SA infection model. Here, we describe a case report in which TICA, added to antimicrobial therapy of a persistent methicillin-susceptible SA (MSSA) bacteremia associated with a septic aortic thrombus, resulted in immediate bacteremia clearance. We further explore TICA synergy with antibiotics and human platelets in vitro.MethodsAntibiotic susceptibility of an MSSA strain from a patient treated with TICA for refractory bacteremia was tested by MIC and checkerboard assays in MHB or RPMI at standard (105 CFU/mL) or high (107 CFU/mL) inocula using TICA, ertapenem (ETP), cefazolin (CZ), or nafcillin (NAF) alone vs. ETP+CZ ± TICA. Killing assays with human platelets ± TICA against SA were also performed.ResultsSA bacteremia secondary to a septic aortic thrombus (>4 mm) with multiple secondary pyogenic foci refractory to standard CZ and subsequent salvage CZ+ETP for 5 days rapidly cleared within 24 h after the addition of TICA. Thrombocytopenia resolved concurrently. Discontinuation of TICA on day 12 led to rebound thrombocytopenia, and TICA was restarted, once again resulting in resolution of thrombocytopenia. TICA alone lacked in vitro activity against SA, nor was TICA synergistic with ETP+CZ. In contrast, addition of a physiological achievable concentration of TICA dramatically sensitized SA to human platelet killing (p< 0.001) in vitro.Figure 1 Figure 2 Figure 3 ConclusionIn a complex case of aortic plaque rupture with septic thrombus, multiple septic emboli, and refractory MSSA bacteremia, addition of TICA to antimicrobial therapy yielded unanticipated immediate clinical and microbiological success. The profound therapeutic effect of TICA in vivo was corroborated by the enhanced staphylocidal activity of human platelets in vitro in the presence of physiological concentrations of the antiplatelet agent. TICA warrants further study as adjunctive treatment of refractory SA bacteremia due to a primary endovascular focus when thrombocytopenia is present.Disclosures Victor Nizet, MD, Centauri Therapeutics (Advisor or Review Panel member)Cidara Therapeutics (Advisor or Review Panel member)InhibRx (Advisor or Review Panel member)Roche Pharmaceutical (Advisor or Review Panel member)

Real-world safety and efficacy of ticagrelor in patients with ST segment elevation myocardial infarction at Assiut University Heart Hospital

Objectives: The new generation antiplatelets are generally recommended by the current US and European guidelines. This article aimed to address the efficacy and safety of using ticagrelor in patients with ST-elevated acute coronary syndromes.Methods: This was a prospective observational study on 120 patients admitted to the Cardiology Care Unit of Assiut University Hospital with ST-segment elevation acute coronary syndrome, who were admitted for urgent revascularization and received aspirin and the P2Y12 antagonist ticagrelor. The patients were followed for three months between May 2018 and September 2019. The primary efficacy end point was the incidence of major adverse cardiovascular events (MACE).Results: At three months, the primary efficacy endpoint, a composite of cardiovascular death, myocardial infarction, or stroke - occurred in 11/120 (9.2%) patients. The primary safety endpoint, the incidence of major bleeding, was observed in two patients (1.7%) with no fatal bleedings. Minor and minimal bleeding occurred in 2.5% and 20.8% of patients, respectively. Other efficacy endpoints were myocardial infarction 4.2% and stent thrombosis (1.7%). Severe dyspnea found in 5.0% of patients and led to 1.7% ticagrelor discontinuation. Multivariate regression analysis revealed no association between bleeding and patients’ age, sex nor IV administration of glycoprotein IIb/IIIa inhibitor. Conclusion: The MACE with ticagrelor was higher than previously reported in most studies. Dyspnea rate was higher and more pronounced than bleeding rate. The majority of bleeding cases were minimal with no fatal major bleeding and no bleeding led to comorbidity.

Reacción de hipersensibilidad a ticagrelor

El ticagrelor es un medicamento antiagregante plaquetario utilizado como prevención secundaria en pacientes con síndrome coronario agudo. Dentro de las reacciones adversas reportadas secundarias a su administración se encuentran hemorragias, cefalea, disnea, epistaxis, pausas ventriculares o bradicardia, hiperuricemia y elevación de la creatinina. No obstante, las reacciones de hipersensibilidad han sido raras. Presentamos un paciente masculino de 63 años con infarto agudo del miocardio, elevación de ST y documentándose en cateterismo cardíaco ectasia y enfermedad de flujos lentos. Requirió terapia de antiagregación dual con ácido acetilsalicílico (ASA) y ticagrelor, con posterior urticaria de origen medicamentoso según concepto de dermatología. Se manejó con esteroide tópico, antihistamínico oral y retiro de ticagrelor. Se considera un caso raro de reacción al antiagregante plaquetario descrito.

Preoperative Management of Antiplatelet Agents for CABG Surgery Patients: A Prospective Cohort Study Focused on P2Y12 Inhibitors

Dual antiplatelet therapy (DAPT) using aspirin and ticlopidine, a thienopyridine P2Y12 inhibitor, was introduced, decreasing the rate of stent thrombosis to about 1%. Continuation of dual antiplatelet therapy (DAPT) until Coronary artery bypass graft (CABG) increases the risk of excessive perioperative bleeding, transfusions, and re-exploration for bleeding as shown in RCTs observational studies and metanalyses. Therefore, it is recommended that the P2Y12 inhibitor should be discontinued whenever possible before elective CABG. For clopidogrel, it was shown in the CABG sub-study of the CURE trial that discontinuation ≥ 5 days before CABG did not increase the risk of bleeding complications. For prasugrel, a longer time interval (7 days) is recommended due to the longer offset time compared to clopidogrel. In a single institution Dutch registry encompassing 705 consecutive patients who underwent isolated on-pump CABG, ticagrelor discontinuation > 72 h and clopidogrel discontinuation > 120 h before surgery were not associated with an increased risk of bleeding-related complications. Prospective data were collected on 150 consecutive patients who were admitted with ACS (Acute coronary syndrome) for CABG from 1st October 2017 onwards. Elective admissions for CABG were excluded. There was a significant delay in between stopping and the day of Surgery in multiple patients. There were 25 patients who were admitted with ACS for CABG and they were without clopidogrel for more than 10 days, 20 patients stayed without Ticagrelor preoperatively. From this study, it was evident that the guideline was partially met. Appropriate stopping of P2Y12 inhibitors should be considered before surgery according to the guidelines to achieve successful perioperative haemostasis.

Assessment of platelet function after discontinuation of ticagrelor.

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. In this prospective, longitudinal, observational study including 24 patients, venous blood was obtained from patients on day 0, before stopping maintenance dose of 90mg ticagrelor twice daily, and then on days 1, 3, 5, and 8, after discontinuation. Samples were analyzed using Multiplate® and VerifyNow® . 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). Discontinuation of ticagrelor for 3days 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 5days after ticagrelor discontinuation.

P328Is there evidence of a rebound increase in platelet aggregation following withdrawal of Aspirin or Ticagrelor in patients who have previously undergone PCI and coronary stenting?

Abstract Introduction In patients treated with coronary stents previous studies have demonstrated an increased risk of acute coronary syndrome in after discontinuation of clopidogrel. In this study, we recruited patients already randomised in the GLOBAL LEADERS study allocated to discontinue aspirin treatment, while remaining on ticagrelor, 1 month after coronary stenting (Ticag MonoRx group) and a control group discontinuing ticagrelor at 6–12 months while remaining on aspirin (ASA MonoRx group). Both groups underwent platelet studies at day 0, prior to discontinuation of aspirin or ticagrelor and then on day 2, 7 and 14 day post cessation with multiple electrode aggregometry. Purpose This study was designed to look for evidence of a rebound increase in platelet aggregation in response to collagen after withdrawal of either aspirin or ticagrelor in patients who have been treated with both drugs after PCI with DES implantation. We needed a sample size of 26 patients in each group for 90% power to detect a mean change in platelet aggregation of 100 AU/min with an alpha of 0.05. The primary outcome measure was change in platelet aggregation in response to collagen between baseline and day 2, day 7 and day 14 following cessation of DAPT. A rebound effect was defined as a &gt;10% increase in collagen induced platelet aggregation on either day 2 or day 7 compared to day 14 post discontinuation of either aspirin or ticagrelor. Methods Patients provided written informed consent and underwent MEA using arachidonic acid (AA), adenosine diphosphate (ADP), thrombin receptor activator peptide (TRAP) and collagen in prespecified concentrations timed at 30 mins post phlebotomy. Results were calculated from the area under the curve and expressed as as whole number aggregation units (AU). Inbuilt QC analysis was used to determine the need for repeat assays. Results Collagen induced platelet aggregation was similar in both groups at day 0 (37 AU vs 34 AU; p=0.687) and at day 2 (55 AU vs 40 AU; p=0.12). By day 7, patients on ticagrelor monotherapy had higher collagen induced platelet aggregation (78 AU vs 37 AU; p=0.0001) and this difference was maintained at 14 days (80 AU vs 43 AU; p=0.0001). In patients, assigned to ticagrelor monotherapy after 1 month of DAPT, AA induced platelet aggregation progressively increased from day 0 to day 14. In the patients discontinuing ticagrelor and continuing on aspirin monotherapy, ADP induced platelet aggregation increased from day 0 to day 14. Rebound was seen in 6/17 (35%) patients in the ticagrelor monotherapy group versus 8/17 (47%) patients in the aspirin monotherapy group (p=0.728) with a mean peak of 21 AU (SD 6) and 10 AU (SD 6) respectively above baseline readings, p=0.003. There was no difference in TRAP induced aggregation at any time point. Figure 1 Conclusions Ticagrelor monotherapy was associated with higher collagen induced platelet aggregation than aspirin monotherapy at both 7 and 14 days post cessation of DAPT. Acknowledgement/Funding British Heart Foundation Project Grant PG/14/97/31263, AstraZeneca UK Limited

COST-EFFECTIVENESS OF SHORTER DURATIONS OF TICAGRELOR-BASED DUAL ANTIPLATELET THERAPY FOLLOWING MYOCARDIAL INFARCTION

Real-world persistence with ticagrelor-based dual antiplatelet therapy (DAPT) following an acute coronary syndrome is lower that of other P2Y12-receptor inhibitors. However, it is not known whether higher than expected rates of patient discontinuation of ticagrelor-DAPT warrants specific intervention. We therefore developed a cost-effectiveness decision analytic model to gauge the clinical impact of shorter durations of ticagrelor-DAPT. Decision trees were created to compare 3, 6, 9, and 12 months of ticagrelor-DAPT to a 12-month regimen of generic clopidogrel-DAPT for patients with myocardial infarction. Clinical outcome probabilities at three-month intervals were generated by estimating the lifetables from relevant landmark clinical trials (PLATO and CURE) and using Dirichlet probability distributions for multiple outcomes. Following ticagrelor discontinuation, patients were assumed to persist with aspirin monotherapy. Clinical outcomes considered in the model included cardiovascular death, myocardial infarction, and major bleeding. Stroke outcomes were not considered as there was no difference in this outcome in the trials. Cost data were derived from a combination of the medical literature and the Régie de l’Assurance-Maladie du Québec medication formulary and is expressed in 2018 Canadian dollars ($CAN). Quality of life weights were derived from the literature. We present our initial analysis of cost-effectiveness at one year (TABLE). Using a willingness-to-pay threshold of $50,000 per quality-adjusted life year (QALY), three months of ticagrelor-DAPT was cost-effective compared to 12 months of clopidogrel-DAPT at one year ($43,496/QALY), 57% probability of cost-effectiveness). Longer regimens of ticagrelor-DAPT were not cost-effective at one year, but are anticipated to be more attractive over a lifetime time horizon. Both cost and effectiveness projections are in line with prior cost-effectiveness models of ticagrelor-DAPT for acute coronary syndromes. Sensitivity analyses showed that the cost-effectiveness of ticagrelor-DAPT was sensitive to both the financial and quality of life costs of major bleeding and myocardial infarction. This analysis shows that even just 3 months of ticagrelor-DAPT is likely to be cost-effective compared to 12 months of clopidogrel-DAPT. As such, we conclude that clinicians should continue to preferentially prescribe ticagrelor-DAPT in appropriate patients and that no specific intervention is warranted at a provincial policy level to improve persistence rates with ticagrelor therapy following myocardial infarction.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

TCT-411 Predictors for Early Discontinuation of Ticagrelor in Patients With Acute Coronary Syndrome

TCT-411 Predictors for Early Discontinuation of Ticagrelor in Patients With Acute Coronary Syndrome

Incidence, predictors, and prognosis of premature discontinuation or switch of prasugrel or ticagrelor: the ATLANTIS - SWITCH study

Aim of the present study was to investigate the frequency and predictors of premature discontinuation or switch of ADP receptor blockers and its association with serious adverse events. For this purpose 571 consecutive ACS patients receiving ticagrelor (n = 258, 45%) or prasugrel (n = 313, 55%) undergoing PCI were enrolled in this prospective, observational, multicenter ATLANTIS-SWITCH substudy. Predictors of premature discontinuation or switch of antiplatelet therapy and their association with major adverse cardiovascular events and TIMI bleeding events were evaluated. Premature stop/switch was found in 72 (12.6%) patients: 34 (5.9%) stopped and 38 (6.7%) switched the ADP blocker. Ticagrelor treated patients were significantly more likely to stop/switch therapy as compared to prasugrel (15.9% vs. 9.2%, p = 0.016). We identified 4 independent predictors for stop/switch of ADP blocker: major surgery, need for oral anticoagulation (OAC), TIMI major bleeding and drug intolerance. TIMI major bleeding was a driver of stop/switch actions and occurred in 4.3% vs 0.2% in patients with vs without stop/switch (p = 0.001). The majority of stop/switch actions (75%) were physicians driven decisions. Importantly, stop/switch of therapy was not associated with increased risk of MACE (p = 0.936). In conclusion premature switch/stop of ADP blockers appears to be safe when mainly driven by physician’s decision and clinical indication.

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

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. 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. 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). 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.

Discontinuation of dual antiplatelet therapy and bleeding in intensive care in patients undergoing urgent coronary artery bypass grafting: a retrospective analysis.

Our goal was to evaluate the impact of the discontinuation times of dual antiplatelet therapy with clopidogrel, prasugrel or ticagrelor on postoperative bleeding rates and the use of blood products in patients undergoing isolated urgent coronary artery bypass grafting (CABG). We retrospectively analysed 334 patients with acute coronary syndrome undergoing urgent CABG at the University Hospital Basel. A total of 262 patients continued to take dual antiplatelet therapy during the surgery (72 received clopidogrel; 68, prasugrel; and 122, ticagrelor). They were stratified by the discontinuation time of dual antiplatelet therapy (<24 h, 24-48 h, 48-72 h and >72 h). Seventy-two patients taking acetylsalicylic acid (ASA) as monotherapy served as a comparison group. Median postsurgical bleeding rates were significantly higher with ticagrelor if it was discontinued <24 h [1220 ml, interquartile range (IQR) 978-1520 ml; P < 0.001], 24-48 h (1200 ml, IQR 800-1550 ml; P < 0.001) and 48-72 h (1100 ml, IQR 845-1245 ml; P = 0.036) but not if discontinued >72 h (700 ml, IQR 520-825 ml; P = 0.22) and with prasugrel if discontinued <24 h (1320 ml, IQR 900-1950 ml; P < 0.001) but not if discontinued 24-48 h (1050 ml, IQR 638-1438 ml; P = 0.089) or >72 h (750 ml, IQR 488-1040; P = 0.63) compared to ASA monotherapy (800 ml, IQR 593-1043 ml). The postsurgical use of blood products compared to ASA monotherapy (0, IQR 0-2 units) was significantly higher with ticagrelor and prasugrel if discontinued <24 h (2.5 units, IQR 0-6; P < 0.001 and 2 units, IQR 1-6; P < 0.001, respectively). Discontinuation of ticagrelor and prasugrel for more than 72 h before urgent CABG was not associated with higher bleeding rates compared to treatment with ASA monotherapy. In contrast, discontinuation for less than 24 h was associated with higher use of blood products. For ticagrelor, this study supports evidence and recent guidelines proposing a shorter discontinuation time of 3 days and raises the question of whether the same could be true for prasugrel.

The association between a three-day ticagrelor discontinuation and perioperative bleeding complications.

Dual antiplatelet therapy at the time of cardiac surgery is associated with excessive perioperative bleeding. International guidelines, therefore, recommended discontinuing oral adenosine diphosphate receptor antagonists prior to non-emergency surgery. In this study, we analysed whether a 3-day ticagrelor discontinuation was sufficient to avoid major bleeding complications. This study is a retrospective cohort analysis of 3377 patients undergoing coronary artery bypass or single-valve surgery from January 2013 to September 2017. Patients exposed to ticagrelor prior to surgery were compared with control patients exposed to aspirin only. Outcome measures included transfusion requirements, bleeding volumes, the need for re-exploration and the composite outcome major bleeding complication. Data were retrieved from the the Western Denmark Heart Registry. During the study period, 101 patients were preoperatively exposed to ticagrelor, whereas 3276 patients were exposed to aspirin only. Propensity-score matching resulted in 90 pairs of patients. Overall, ticagrelor exposure was associated with a greater risk of major bleeding complications compared with control patients [31 vs 12%, relative risk 2.6, 95% confidence interval (CI) 1.4-4.8]. While ticagrelor exposure within 0-72 h before surgery (n = 42) was associated with a substantially increased risk of major bleeding complications (48 vs 10%, relative risk 5.0, 95% CI 1.9-13.4), ticagrelor exposure 72-120 h before surgery (n = 48) showed no statistically significant association (17 vs 15%, relative risk 1.1, 95% CI 0.4-2.9). In our historical cohort, ticagrelor exposure 0-72 h prior to cardiac surgery was associated with an increased risk of major bleeding complications. On the other hand, ticagrelor exposure 72-120 h prior to surgery was not associated with a clinically relevant increase in major bleeding complications.