Lower Ticagrelor Dosing in the Dual Antiplatelet Regimen for Neurointerventional Procedures

IntroductionThromboembolic events are among the most critical complications in neuroendovascular procedures, and dual antiplatelet therapy (DAPT) can reduce them. The effects of using aspirin and clopidogrel in the DAPT are...

Endovascular treatment of intracranial aneurysms carries the risk of perioperative thromboembolism and bleeding, and the optimal prophylactic antiplatelet strategy remains unclear. This study aimed to evaluate the efficacy and safety of prophylactic tirofiban administration compared with oral dual antiplatelet (DAP) therapy. We searched PubMed, EMBASE, Cochrane Library, Web of Science, and Chinese National Knowledge Infrastructure databases for relevant studies up to August 2, 2023. All data analyses were conducted using RevMan 5.4 and Stata 14.0. Eight randomized controlled trials with a total of 806 participants receiving endovascular treatment of intracranial aneurysms were included. The results indicated that prophylactic monotherapy with tirofiban was associated with significantly higher rate of good clinical outcome (risk ratio [RR]: 1.15, 95% confidence interval [CI]: 1.03-1.28, P = .01). It also reduced the incidence of thromboembolic (RR: 0.44, 95% CI: 0.26-0.74, P = .002) and hemorrhagic (RR: 0.47, 95% CI: 0.24-0.91, P = .03) events. Subgroup analyses further revealed the benefits of prophylactic tirofiban in combination with DAP therapy in reducing the incidence of hemorrhagic events, with a trend of reducing thromboembolic events. Meanwhile, prophylactic monotherapy with tirofiban reduced the incidence of thromboembolic events without increasing the incidence of hemorrhagic events. Sensitivity analyses demonstrated the robustness of all pooled results, but it was not possible to remove the negative impact of publication bias on the pooled results. These findings support the prophylactic administration of tirofiban to patients undergoing endovascular treatment of intracranial aneurysms, as it was associated with a significantly lower incidence of thromboembolic events without increasing the risk of hemorrhagic events. More studies are needed to determine differences between prophylactic monotherapy with tirofiban and prophylactic tirofiban in combination with DAP therapy.

The optimal anti-thrombotic therapy to prevent recurrent ischemic events in patients with acute coronary syndrome and coronary artery ectasia (CAE) remains unclear. To assess the efficacy and safety of antiplatelet plus anticoagulant therapy versus dual antiplatelet therapy in patients with acute coronary syndromes and coronary artery ectasia. OVER-TIME is an investigator initiated, exploratory, open label, single center, randomized clinical trial comparing dual antiplatelet therapy (acetyl-salicylic acid plus a P2Y12 inhibitor) with the combination of an antiplatelet monotherapy (a P2Y12 inhibitor) plus a low dose anticoagulant (rivaroxaban, 15mg oral dose) for the prevention of recurrent ischemic events among patients with CAE. We aim to enroll approximately 60 patients with CAE and acute coronary syndromes. After recruitment, patients are randomized to (a) standard of care (dual antiplatelet regimen) or (b) the combination of antiplatelet monotherapy and low dose anticoagulant. Patients will be followed for at least 12 months. The OVER-TIME study aims to assess the efficacy of the regimen in prevention of major cardiovascular events and its security in bleeding events in acute coronary syndromes among patients with CAE. Expected results and conclusions: OVER-TIME is the first randomized controlled trial to assess different antithrombotic strategies in patients with CAE and acute coronary syndrome, and its results will offer preliminary data for the prevention of major cardiovascular events and bleeding events in this group of patients. NCT05233124 (ClinicalTrials.gov), date of registration: February 10, 2022.

BackgroundMultiple scores have been proposed to stratify bleeding risk, but their value to guide dual antiplatelet therapy duration has never been appraised. We compared the performance of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HAS‐BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) scores in 1946 patients recruited in the Prolonging Dual Antiplatelet Treatment After Grading Stent‐Induced Intimal Hyperplasia Study (PRODIGY) and assessed hemorrhagic and ischemic events in the 24‐ and 6‐month dual antiplatelet therapy groups.Methods and ResultsBleeding score performance was assessed with a Cox regression model and C statistics. Discriminative and reclassification power was assessed with net reclassification improvement and integrated discrimination improvement. The C statistic was similar between the CRUSADE score (area under the curve 0.71) and ACUITY (area under the curve 0.68), and higher than HAS−BLED (area under the curve 0.63). CRUSADE, but not ACUITY, improved reclassification (net reclassification index 0.39, P=0.005) and discrimination (integrated discrimination improvement index 0.0083, P=0.021) of major bleeding compared with HAS‐BLED. Major bleeding and transfusions were higher in the 24‐ versus 6‐month dual antiplatelet therapy groups in patients with a CRUSADE score >40 (hazard ratio for bleeding 2.69, P=0.035; hazard ratio for transfusions 4.65, P=0.009) but not in those with CRUSADE score ≤40 (hazard ratio for bleeding 1.50, P=0.25; hazard ratio for transfusions 1.37, P=0.44), with positive interaction (P int=0.05 and P int=0.01, respectively). The number of patients with high CRUSADE scores needed to treat for harm for major bleeding and transfusion were 17 and 15, respectively, with 24‐month rather than 6‐month dual antiplatelet therapy; corresponding figures in the overall population were 67 and 71, respectively.ConclusionsOur analysis suggests that the CRUSADE score predicts major bleeding similarly to ACUITY and better than HAS BLED in an all‐comer population with percutaneous coronary intervention and potentially identifies patients at higher risk of hemorrhagic complications when treated with a long‐term dual antiplatelet therapy regimen.Clinical Trial Registration URL: http://clinicaltrials.gov. Unique identifier: NCT00611286.

Introduction: Data on P2Y12 inhibitor (single agent) use in percutaneous coronary intervention (PCI) is sparse. Hypothesis: Long term outcomes in patients undergoing PCI with only P2Y12 inhibitors vs. dual antiplatelet therapy (DAPT). Methods: We used PCI registry of Guthrie clinic system from the year 2001 to 2012. We identified patients discharged only on P2Y12 inhibitors (Plavix, Ticagrelor, Prasugrel) due to aspirin allergy. We created propensity score using patient demographics (age, gender), risk factors (hypertension, diabetes, hyperlipidemia etc.), medications detail (statin, B blocker etc.) and catheterization detail (vessel involved, type of stent and culprit vessel etc.) for patients discharged only on P2Y12 inhibitors vs DAPT. Propensity score match (1:100) analysis was conducted using greedy’s method for adjusting confounders. The primary outcome was MACE(myocardial infarction(MI), stroke, death, coronary artery occlusion) up to 8 years and secondary outcomes were death and recurrent myocardial infarction(MI) up to 8 years. Sensitivity analysis was done using Cox-proportional hazard regression. Results: 7742 patients with successful intervention were identified during the study period. Out of which, 43(0.65%) had aspirin allergy and received only P2Y12 inhibitor. Hyperlipidemia (78.8%), hypertension (72.8%), obesity (48.7%) and diabetes (31.6%) were most common risk factors. >90% patients were on optimum medical treatment. 59% of patients received drug-eluting stent/s and 17.5% patients underwent multivessel PCI. Right coronary artery(37.6%) and left anterior descending artery(35.8%) were commonest culprit vessels. Median follow up period was 1828 days (~ 5 years). After adjusting with propensity score match, primary outcome (HR:1.73, 95% CI: 1.17-2.67, p-0.005) and secondary outcomes (MI: HR: 2.46, 95% CI:1.28-4.51, p-0.005), (death: HR:1.85, 95% CI:1.09-2.23, p-0.023) were higher in patients discharged only on P2Y12 inhibitors. Sensitivity analysis showed similar results. Conclusions: Only P2Y12 inhibitor was inferior to DAPT in patients undergoing PCI. Future clinical trials will be needed to reinforce our findings.

Benefit of Long-Term Dual Anti-Platelet Therapy in Patients Treated With Drug-Eluting Stents: From the NHLBI Dynamic Registry

Objective: To test the optimal strategy of dual antiplatelet therapy (DAPT) after implantation of drug-eluting stents (DESs) according to specific DAPT time and subsequent monotherapy. Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, and Web of Science to identify randomized controlled trials (RCTs). Six DAPT strategies were compared: 1-month DAPT followed by P2Y12 inhibitor monotherapy, 3-month DAPT followed by P2Y12 inhibitor monotherapy, 3-month DAPT followed by aspirin monotherapy, 6-month DAPT followed by aspirin monotherapy, 12-month DAPT, and >12-month DAPT. Pooled odd ratios (ORs) with 95% credible intervals (CrIs) were calculated to summarize the effect of each strategy tested. Results: We identified 24 RCTs containing 81,405 patients. In comparison with 12-month DAPT, 3-month DAPT followed by P2Y12 inhibitor monotherapy reduced net clinical events (OR: 0.72; CrI: 0.55–0.94). Major bleeding (OR: 0.57; CrI: 0.34–1.00) was marginally decreased without impact on ischemic events (OR: 0.93; CrI: 0.68–1.29). Moreover, the benefits of 3-month DAPT (P2Y12 inhibitor) were consistent for male patients with acute coronary disease, young age, complex lesion, single-vessel disease, low body mass index, and without diabetes. Although >12-month DAPT was associated with a lower risk of myocardial infarction (OR: 0.67; CrI: 0.51–0.93), the risk of major bleeding (OR: 1.70; CrI: 1.10–2.70) was increased. Conclusion: Among patients treated with DESs, 3-month DAPT followed by P2Y12 inhibitor monotherapy may be the optimal antiplatelet strategy, while DAPT beyond 1 year reduces myocardial infarction at the expense of increased major bleeding.

Background and ImportanceIn the absence of complications, the European Society of Cardiology and American Heart Association guidelines recommend ticagrelor and prasugrel over clopidogrel in dual antiplatelet therapy (DAPT) following percutaneous...

Dual antiplatelet therapy (DAPT) associating aspirin+clopidogrel is commonly utilized in neurovascular interventions despite unpredictable clopidogrel efficacy with 4% to 50% of patients considered nonresponders. Ticagrelor is an antiplatelet agent with low resistance rates but unknown efficacy and safety in neurovascular patients. To evaluate frequency of ischemic and hemorrhagic events in patients treated with aspirin and ticagrelor when associated with perioperative heparin bolus for unruptured aneurysms treated with intracranial stents. One hundred fifty-four consecutive patients with unruptured intracranial aneurysms treated by stent procedures (113=flow diverter stent [FDS], 41=stent-assisted coiling) were retrospectively analyzed. All patients received aspirin and ticagrelor without platelet function testing. Patients were separated in 2 groups following perioperative heparin dose: group I=70 U/kg; group II=50 U/kg. FDS versus stent-assisted coiling procedures were also separately analyzed. Nine patients (5.8%) presented symptomatic neurological complications poststenting (3 ischemic, 6 hemorrhagic): 8 patients received 70 U/kg of heparin (11.1%) and 1 patient received 50 U/kg (1.2%; P<.009). Four patients died (2.6%) during the 3-mo follow-up period-all deaths were correlated to intracranial hemorrhage: 3 at group I and 1 at group II (P<.251). No difference in complications or death was observed considering separately FDS and stent-assisted coiling procedures. This study did not find more neurological complications than in previous neurointerventional reports using DAPT with aspirin+ticagrelor or aspirin+clopidogrel. Overall number of neurological complications was lower when a lower dose of heparin was administered. Neurovascular studies comparing clopidogrel to ticagrelor and different doses of heparin are necessary to demonstrate which association is more efficient with lower complication rates.

Dual antiplatelet therapy with a P2Y12 inhibitor (e.g., clopidogrel and ticagrelor) and aspirin is recommended for at least one year after percutaneous coronary intervention (PCI) to prevent further myocardial infarction and stent thrombosis as the major adverse effects of PCI. This randomized clinical trial was conducted from October 2022 to March 2023. Patients who had undergone elective PCI were included in the study. Patients were randomized into two different groups. One group took ASA 80 mg and clopidogrel 75 mg once daily, while the other took ASA 80 mg once daily and ticagrelor 90 mg twice daily. After six months of close follow-up, patients were asked to score their dyspnea on a 10-point Likert scale. They were also asked about dyspnea on exertion, paroxysmal nocturnal dyspnea (PND), bleeding, and the occurrence of major adverse cardiovascular events (MACEs). 223 patients were allocated to the clopidogrel group and 214 to the ticagrelor group. In the ticagrelor group, 95 patients (44.3%) reported dyspnea at rest, compared with only 44 patients (19.7%) in the clopidogrel group (P < 0.001). MACEs occurred in 7 patients (2.8%) in the ticagrelor group, compared with 16 (7.6%) in the clopidogrel group (P = 0.031). Eight patients (3.8%) reported bleeding with ticagrelor, as did seven (3.2%) with clopidogrel (P = 0.799). New-onset dyspnea was recorded more frequently with ticagrelor than clopidogrel, yet fewer MACEs occurred with ticagrelor (ClinicalTrials.gov number: NCT05858918).

Highlight: Dual antiplatelet is the gold standard for endovascular treatment of wide-neck aneurysms. The role of dual antiplatelet is to prevent stent thrombosis after treatment. The thrombosis rate reported during stent-assisted coiling is quite high. ABSTRACT Stent-assisted coiling (SAC) in wide-neck aneurysm treatment is associated with antiplatelet use. Dual antiplatelet therapy (DAPT) has been the gold standard for protecting against thrombosis events and is widely accepted for endovascular embolization treatment with a stent-assisted or flow diverter. Some patients experience vascular events due to the reduced efficacy of antiplatelet agents despite taking DAPT. The reported thrombosis rates during stent-assisted coiling embolization range from 2% to 20%. Thromboembolic complications, such as in-stent thrombosis, can manifest in 4.6% of cases. The correlation between platelet reactivity during treatment and bleeding events remains unclear. However, the association between High Residual Platelet Reactivity (HRPR) or hyporesponsiveness and ischemic events is well established. Based on various laboratory definitions, hyperresponsiveness in patients with clopidogrel occurs in about 14–30% of patients due to major and minor bleeding. Therefore, the optimization of antiplatelet therapy has developed significantly in the neurointerventional community.

Short-term (≤6 months) dual antiplatelet therapy (DAPT) and DAPT de-escalation become attractive for patients with acute coronary syndrome. A systemic search identified randomized controlled trials that included patients with acute coronary syndrome treated using (1) standard DAPT (12 months) with clopidogrel, prasugrel (standard/low dose), or ticagrelor; (2) extended DAPT (≥18 months); (3) short-term DAPT (≤6 months) followed by P2Y12 inhibitor or aspirin; (4) 12-month DAPT with unguided de-escalation from potent P2Y12 inhibitors to low-dose potent P2Y12 inhibitor or clopidogrel at 1 month; and (5) guided selection DAPT with genotype or platelet function tests. The primary efficacy outcome (major adverse cardiovascular events) was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major or minor bleeding. This meta-analysis included 32 randomized controlled trials with 103 497 patients. While there were no differences in efficacy between short, unguided de-escalation and guided selection strategies, unguided de-escalation was associated with reduced risk of major adverse cardiovascular events compared with standard DAPT with clopidogrel or ticagrelor (hazard ratio [95% CI], 0.67 [0.49-0.93] and 0.68 [0.50-0.93]). Both short DAPT followed by P2Y12 inhibitor and unguided de-escalation were associated with reduced risks in safety compared with other strategies, including guided selection (hazard ratio [95% CI], 0.66 [0.47-0.93] and 0.48 [0.33-0.71]). Short DAPT followed by a P2Y12 inhibitor was associated with reduced risk of major bleeding and all-cause death compared with standard, extended DAPT (eg, versus DAPT with clopidogrel; hazard ratio [95% CI], 0.64 [0.42-0.97] and 0.60 [0.44-0.82]). By rankogram, unguided de-escalation strategy was the safest and most effective strategy in reducing major adverse cardiovascular events and major or minor bleeding while short DAPT followed by P2Y12 inhibitor was ranked the best for major bleeding and all-cause death. In patients with acute coronary syndrome, unguided de-escalation was associated with the lowest risk of major adverse cardiovascular events and major or minor bleeding outcomes, while short DAPT followed by P2Y12 inhibitor was associated with the lowest risk of major bleeding and all-cause death.

BackgroundCurrent guidelines recommend potent P2Y12 inhibitors for patients after acute coronary syndrome. However, the data on the efficacy and safety of potent P2Y12 inhibitors in elderly Asian populations was limited. We aimed to investigate the major adverse cardiovascular events (MACE), bleeding events, and net adverse clinical events (NACE) with ticagrelor and clopidogrel in Taiwanese patients aged 65 and older after acute myocardial infarction (AMI).MethodsThis retrospective population-based cohort study was conducted using data from the National Health Insurance Research Database. The AMI patients aged ≥65 years who underwent percutaneous coronary intervention (PCI) and survived after 1 month were included. The patients were separated into 2 cohorts depending on the type of dual antiplatelet therapy (DAPT) they received: ticagrelor plus aspirin (T + A) or clopidogrel plus aspirin (C + A). We used inverse probability of treatment weighting to balance the difference between these 2 study groups. The outcome included all-cause mortality, MACE (cardiovascular death, nonfatal ischemic stroke, and nonfatal myocardial infarction), intracerebral hemorrhage, major bleeding, and NACE which is composed of cardiovascular death, ischemic and hemorrhagic events. The follow-up period was up to 12 months.ResultsFrom 2013 to 2017, a total of 14,715 patients who met the eligibility criteria were separated into 2 groups: 5,051 for T + A and 9,664 for C + A. Compared to patients with C + A, patients who received T + A had a lower risk of cardiovascular death and all-cause death, with an adjusted HR of 0.57 [95% confidence interval (CI), 0.38–0.85, p = 0.006] and 0.58 (95% CI 0.45–0.74, p < 0.001), respectively. No differences were found in MACE, intracranial and major bleeding between the 2 groups. In addition, the patients with T + A had a lower risk of NACE with an adjusted HR of 0.86 (95% CI 0.74–1.00, p = 0.045)ConclusionAmong elderly AMI patients receiving DAPT after successful PCI, ticagrelor was a more favorable P2Y12 inhibitor than clopidogrel because of lowering the risk of death and NACE without increasing the risk of severe bleeding. Ticagrelor is an effective and safe P2Y12 inhibitor in Asian elderly survivors after PCI.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): The study project was financially supported by a non-conditional grant by Astrazeneca. Background/Introduction Premature cessation of dual antiplatelet therapy (DAPT) after acute coronary syndrome (ACS) has been associated with increased risk of major adverse cardiovascular events (MACE) Purpose To assess the relationship between premature DAPT discontinuation versus therapy continuation and outcomes in ACS patients discharged on ticagrelor or clopidogrel. Methods Prospective, observational, multicentre all-comers registry of ACS patients who were intended to receive 12-month DAPT with ticagrelor or clopidogrel. Adherence was defined by the medication possession ratio metric (MPA, proportion of days of medication supply within a time interval). Categories for DAPT cessation included: physician-recommended discontinuation, brief interruption (invasive procedures), or disruption due to non-compliance or because of bleeding. Fully-adjusted Cox models with time-varying covariates to account for informative censoring, were used to examine the effect of DAPT cessation on MACE (a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, definite stent thrombosis, or target-lesion revascularization). Moderation analysis was also performed to assess for potential exposure-adherence interaction. Results Among 2070 patients included (mean age 63 years, 73% men), 150 (7.3%) prematurely discontinued DAPT, median (IQR) 214 (101-236) days. Significantly more clopidogrel than ticagrelor users discontinued medication (9.5% vs 5%, respectively; P = .001), though timing of cessation was similar in both groups. At 1 year, MPR was slightly higher, but not significantly different, in the clopidogrel group than in the ticagrelor group (70±30 vs 64±29; P = .06). Overall, physician-guided discontinuation and bleeding were the main reasons for DAPT cessation. These were observed with a similar rate in both groups, while non-compliant disruption was more common among ticagrelor- than clopidogrel-treated patients (8% vs 2%, respectively; P for trend .04). After adjustments, DAPT cessation was associated with significantly increased risk of MACE (adjusted HR 2.94; 95% CI 1.82 – 4.74; P &amp;lt; .0001), regardless of the P2Y12 inhibitor (P interaction = 0.665). Non-compliance related cessation resulted in higher risk of MACE (HR 6.04, 95%CI 2.15 – 16.95; P = .001). Conclusion(s) Overall, approximately 7% of patients discontinued DAPT. Early cessation of either ticagrelor- or clopidogrel-based DAPT portended to a near 3-fold increased risk of MACE. Disruption due to non-compliance resulted in higher risk for ischemic events. These data warrant efforts to focus on patient education in subgroups at high risk of non-compliance.

Short-term use of dual antiplatelet therapy (DAPT) is superior to single antiplatelet therapy (SAPT) for early outcomes in acuteischemic stroke (AIS). However, the long-term effects of SAPT and DAPT remain unclear. This study aimed to evaluate long-term effects of DAPT and SAPT on clinical outcomes in patients with AIS. A retrospective cohort study was conducted at three tertiary hospitals in Saudi Arabia, including 912 patients with AIS who received either DAPT (aspirin plus clopidogrel) or SAPT (aspirin or clopidogrel alone). The primary outcome was the incidence of net adverse clinical and cerebral events (NACCEs), which was defined as the incidence of any hemorrhagic transformation within 30days, or stroke recurrence and/or all-cause mortality within 12months of the index stroke. Of 4043 screened patients, 912 met the inclusion criteria, with a mean age of 65.47years. Among them, 582 patients (63.8%) received DAPT. In the treatment selection model, patients with a more severe stroke presentation had lower odds of receiving DAPT. Over the 12-month period, there was no significant difference in the incidence of NACCEs between the DAPT and SAPT groups (p = 0.946). Additionally, the DAPT group showed a higher rate of stroke recurrence within the first 50days post stroke. In contrast, the SAPT group had higher hemorrhagic transformation and mortality. However, none of these associations were statistically significant (p = 0.1075, 0.0865, and 0.3121, respectively). In the adjusted Cox models, DAPT was not independently associated with stroke recurrence, hemorrhagic transformation, all-cause mortality, or the composite NACCE endpoint (p > 0.05). The addition of a second antiplatelet agent did not significantly reduce the long-term risk of stroke recurrence or mortality in patients with AIS over a 12-month period. Further studies are needed to assess long-term benefits and risks of DAPT in different stroke subpopulations.