Loading Dose Of Clopidogrel Research Articles

Simultaneous Carotid Artery Stenting and Coronary Artery Bypass Grafting in Urgent Patients: A Single Center Experience

Background: Coexisting coronary artery disease and critical carotid stenosis present challenges in revascularization, particularly in urgent cases requiring surgery. Combining carotid artery stenting (CAS) with coronary artery bypass grafting (CABG) has gained popularity. Methods: This study analyzed 36 patients who underwent simultaneous CAS and CABG from 2014 to 2024. CAS was performed first, with the patient awake for real-time neurocognitive assessment. A clopidogrel loading dose was administered three hours post-surgery. From postoperative day 1, dual antiplatelet therapy was initiated. Results: The median age was 72 years (64–77) and 22.2% were females. The median EuroSCORE II was 2.80 (2.06–3.58). Nine patients (25%) underwent associated procedures. The median cardiopulmonary bypass and cross-clamp times were 66 (54–89) and 51 (41–72) minutes. We observed no in-hospital mortality and no postoperative stroke. The median postoperative bleeding in 24 h was 500 mL and only one (2.8%) patient needed resternotomy for bleeding. The median ventilation time was 9 h (6–12). The median intensive care unit and postoperative length of stay were 2 (2–4) days and 8 (7–11) days, respectively. The median follow-up time was 6 years. Survival at 1, 5, and 10 years was 93.7%, 81.5%, and 60.2%, respectively, while freedom from PTCA/PCI at 1, 5, and 10 years was 100%, 96.7%, and 87.5%, respectively. Conclusions: Simultaneous CAS and CABG is a safe and effective procedure with low in-hospital mortality and morbidity. Our protocol carries a low risk of perioperative stroke. Antiplatelet therapy administration on the day of surgery does not increase the risk of postoperative bleeding.

TICA-CLOP STUDY: Ticagrelor Versus Clopidogrel in Acute Moderate and Moderate-to-Severe Ischemic Stroke, a Randomized Controlled Multi-Center Trial.

Many studies evaluated the efficacy and safety of ticagrelor versus clopidogrel in patients with ischemic stroke; none of these trials included North African participants, and all of these trials comprised only participants who experienced transient ischemic attack (TIA) or minor stroke. We compared the efficacy and safety of ticagrelor versus clopidogrel in patients with first-ever noncardioembolic moderate or moderate-to-severe ischemic stroke. Our trial involved 900 first-ever noncardioembolic patients with acute ischemic stroke (AIS) who randomly received either loading and maintenance doses of ticagrelor or clopidogrel within the first 24 h of stroke onset. We involved 900 patients in the intention-to-treat analysis. A total of 39 (8.7%) patients in ticagrelor arm and 62 (13.8%) in clopidogrel arm experienced a new stroke [hazard ratio (HR) 0.46; 95% confidence interval (CI) 0.34-0.83; P value = 0.006]. A total of 57 (12.7%) patients in ticagrelor group and 80 (17.8%) patients in clopidogrel group experienced composite of new stroke, myocardial infarction (MI), or death due to vascular insults (HR 0.51; 95% CI 0.43-0.82; P value = 0.004). Participants who received ticagrelor experienced less frequent unfavorable outcomes. We found no significant variation between our study's two arms concerning the hemorrhagic and non-hemorrhagic complications. Patients with noncardioembolic moderate or moderate-to-severe ischemic stroke who received ticagrelor within the first 24 h after ischemic stroke had better clinical outcomes based on recurrent stroke rates and unfavorable modified Rankin Scale (mRS) rates compared with those who received clopidogrel. There were no significant variations between ticagrelor and clopidogrel regarding hemorrhagic and non-hemorrhagic complications. ClinicalTrials.gov identifier number NCT05553613.

Comparison of 600 mg VS 300 mg clopidogrel loading dose for patients with ischemic heart disease: a meta-analysis of randomized controlled trials

Abstract Background While a 600-mg loading dose (LD) of clopidogrel has demonstrated superior inhibition of platelet function compared to 300-mg LD, the clinical evidence supporting this superiority is limited. The debate centers on whether a higher clopidogrel LD regimen in primary percutaneous coronary intervention outperforms the standard 300 mg LD, with potential benefits being more pronounced in higher-risk patients. Balancing enhanced platelet inhibition to reduce ischemic events against the associated risk of increased bleeding remains a critical consideration in determining the optimal loading dose of clopidogrel for patients with ischemic heart disease. Purpose The objective of this meta-analysis is to validate current randomized trials that investigate the efficacy and safety of two clopidogrel loading regimens (600 mg vs 300 mg) in patients with ischemic heart disease treated with primary percutaneous coronary intervention. Method A systematic literature search for randomized controlled trials was performed comparing 600 mg with 300 mg LD of clopidogrel using PubMed, MEDLINE, Embase, Cochrane, Clinicaltrials.gov. and Herdin PH. Studies included those between 2010 - 2023 involving human subjects. The primary efficacy endpoint was a 1-month rate of major adverse cardiac event (MACE) and the primary safety outcome was bleeding adverse effects. Result Nine randomized control studies involving 29,827 patients were included in the efficacy analysis. Mean duration of follow-up was 30 days. Only 8 studies were eligible for safety analysis. Compared with standard LD clopidogrel, high LD significantly reduced incidence of overall MACE (OR:0.82, 95% CI:0.74-0.91, p=0.0002), nonfatal myocardial infarction (OR:0.56; 95% CI:0.32-0.99, p = 0.15) and target vessel revascularization (OR 0.63; 95% CI 0.41 to 0.95, p = 0.03 ), without significant difference in terms of cardiac death (OR:0.89; 95% CI:0.76-1.04, p=0.15) and stroke (OR 0.92; 95% CI 0.67 to 1.26, p = 0.61). However, major bleeding risk was higher in the 600 mg LD (1.9%; 261/13288) compared with 300 mg LD (2.4%; 328/13242) [OR:1.27; 95% CI:1.08-1.49, p=0.005] without significant difference in minor bleeding (OR:1.05; 95% CI:0.94-1.17, p=0.35). Conclusion The administration of 600 mg of clopidogrel LD reduces the overall risk of MACE with an associated increased risk of major bleeding in patients with ischemic heart disease undergoing primary percutaneous coronary intervention.MACE OUTCOMES

Ticagrelor versus Clopidogrel in Prevention of No Reflow after 1ry PCI in Diabetic Patients with STEMI

Abstract Background Adequacy of coronary flow can be judged upon using several methods like TIMI Grade and myocardial blush grade. No-reflow phenomenon, defined as incomplete reperfusion at the microvascular level despite adequate patency of the occluded artery, remains an important limitation of primary percutaneous intervention in STEMI patients nowadays. We aim in this study to investigate the relationship between the antiplatelet loading dose whether to be Ticagrelor or Clopidogrel and post intervention coronary flow, bleeding risk in these patients. Aim of the Work To compare between the effects of preoperative loading dose of Ticagrelor and clopidogrel in Diabetic STEMI patients undergoing primary percutaneous coronary intervention regarding prevention of no reflow, Instent thrombosis and short term bleeding risk. Myocardial reperfusion was judged upon using TIMI Grade and myocardial blush grade. Patients and Methods a single center prospective randomized controlled trial based at the coronary care units in Ain shams university hospitals. The study included Three hundred Diabetic patients presenting to Ain shams university hospitals diagnosed with STEMI in the ER fulfilling the inclusion criteria were randomized to receive Ticagrelor (150 patients) or receiving clopidogrel (150 patients) Results As regard TIMI flow there was statistically highly significant highly significant difference between two studied groups with P value 0.000 where in group A 64 % of patients developed TIMI III flow, 22.7 % with TIMI II flow, 12.7% with TIMI I and 0.7% with TIMI 0 While in group B 86% of patients developed TIMI III flow, 9.3% of them developed TIMI II, 3.3 % developed TIMI I flow and 1.3 % developed TIMI 0. As regard MBG there was statistically highly significant difference between two groups with P value 0.00 where in group A where percentage of patients with MBG grades 0,1,2 and 3 were 4%, 16 %,18 % and 62 % respectively while in group B percentage of patients with MBG grades 0,1,2 and 3 were 1.3 %, 3.3 %, 9.3 % and 86 % respectively. As regard echo EF, there was statistically significant difference between two groups with P value 0.036 where mean EF in patients with group A was 40.50 ± 7.93 while the mean EF in patients with group B was 42.55 ± 8.88 . Conclusion Ticagrelor loading before primary PCI resulted in improved post-procedural TIMI flow. It also increased the post-procedural MBG. This resulted in a significant increase in the number of patients having more post-procedural Ejection fraction as measured by modified Simpson’s method. However, it did not decrease incidence of in-hospital MACE. Also there was no significant increase in risk of major nor minor bleeding in both young and elderly patients.

Ticagrelor versus Clopidogrel in Prevention of No Reflow after 1ry PCI in Diabetic Patients with STEMI

Abstract Background Adequacy of coronary flow can be judged upon using several methods like TIMI Grade and myocardial blush grade. No-reflow phenomenon, defined as incomplete reperfusion at the microvascular level despite adequate patency of the occluded artery, remains an important limitation of primary percutaneous intervention in STEMI patients nowadays. We aim in this study to investigate the relationship between the antiplatelet loading dose whether to be Ticagrelor or Clopidogrel and post intervention coronary flow, bleeding risk in these patients. Aim of the Work To compare between the effects of preoperative loading dose of Ticagrelor and clopidogrel in Diabetic STEMI patients undergoing primary percutaneous coronary intervention regarding prevention of no reflow, Instent thrombosis and short term bleeding risk. Myocardial reperfusion was judged upon using TIMI Grade and myocardial blush grade. Patients and Methods a single center prospective randomized controlled trial based at the coronary care units in Ain shams university hospitals. The study included Three hundred Diabetic patients presenting to Ain shams university hospitals diagnosed with STEMI in the ER fulfilling the inclusion criteria were randomized to receive Ticagrelor (150 patients) or receiving clopidogrel (150 patients) Results As regard TIMI flow there was statistically highly significant highly significant difference between two studied groups with P value 0.000 where in group A 64 % of patients developed TIMI III flow, 22.7 % with TIMI II flow, 12.7% with TIMI I and 0.7% with TIMI 0 While in group B 86% of patients developed TIMI III flow, 9.3% of them developed TIMI II, 3.3 % developed TIMI I flow and 1.3 % developed TIMI 0. As regard MBG there was statistically highly significant difference between two groups with P value 0.00 where in group A where percentage of patients with MBG grades 0,1,2 and 3 were 4%, 16 %,18 % and 62 % respectively while in group B percentage of patients with MBG grades 0,1,2 and 3 were 1.3 %, 3.3 %, 9.3 % and 86 % respectively. As regard echo EF, there was statistically significant difference between two groups with P value 0.036 where mean EF in patients with group A was 40.50 ± 7.93 while the mean EF in patients with group B was 42.55 ± 8.88 . Conclusion Ticagrelor loading before primary PCI resulted in improved post-procedural TIMI flow. It also increased the post-procedural MBG. This resulted in a significant increase in the number of patients having more post-procedural Ejection fraction as measured by modified Simpson’s method. However, it did not decrease incidence of in-hospital MACE. Also there was no significant increase in risk of major nor minor bleeding in both young and elderly patients.

Abstract WP150: Correlation Between CYP2C19 Genotype and Platelet Reactivity Units in Patients Receiving Clopidogrel After Acute Ischemic Stroke

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard of care for secondary prevention in non-cardioembolic minor acute ischemic stroke (AIS) and high-risk transient ischemic attack (TIA). However, clopidogrel is a prodrug metabolized to its active form by the CYP2C19 enzyme and therefore has decreased efficacy in patients with at least one loss-of-function (LOF) allele in the CYP2C19 gene that encodes the enzyme. The use of ticagrelor over clopidogrel for DAPT improves outcomes in CYP2C19 LOF carriers; however, CYP2C19 genotyping is not currently standard practice in the cerebrovascular population. P2Y12 assays that measure P2Y12 receptor-mediated platelet aggregation in platelet reactivity units (PRUs) are more widely accessible, but it is unclear if this assay correlates with CYP2C19 genotype in this population. Therefore, we aimed to investigate the correlation between CYP2C19 genotype and PRUs to evaluate PRUs as a potential surrogate biomarker for identifying suboptimal clopidogrel response. We hypothesized that PRUs would be increased in CYP2C19 LOF carriers compared to non-carriers due to the reduced bioactivation of clopidogrel in patients with decreased CYP2C19 enzymatic function. This prospective, observational study enrolled patients > 18 years of age presenting with minor AIS or high-risk TIA and discharged from University of Virginia Health on DAPT for secondary stroke prevention. A whole blood sample for P2Y12 assay and CYP2C19 genotyping was obtained at least 12 hours after a 300 milligram clopidogrel loading dose. The primary outcome was the correlation between PRUs and CYP2C19 LOF allele carrier status. Of 35 patients genotyped, 27 (77%) subjects self-reported European ancestry, 7 (20%) African ancestry, and 1 (3%) Asian ancestry. Six participants (17%) were found to be LOF carriers. LOF carriers had significantly increased PRUs compared to non-carriers (mean difference +103.7; 95% CI +30.71 to +176.1; p<0.01), indicating diminished pharmacodynamic response to clopidogrel. This suggests that measurement of PRUs via an accessible and established P2Y12 assay may be a viable surrogate biomarker for identifying suboptimal clopidogrel response in the cerebrovascular population.

Possible clinical and radiological predictors of haemorrhagic transformation in acute stroke patients undergoing dual antiplatelet therapy: a clinical study.

The predictors of intracranial haemorrhagic transformation (HT) in acute ischaemic stroke (AIS) patients undergoing dual antiplatelet therapy (DAPT) are not well known. The aim of this study is to identify the possible clinical and radiological predictors of HT in patients, irrespective of clinical indication for this treatment. This study is a monocentric cohort retrospective study. We enrolled consecutive AIS patients, from our prospective register, admitted to Stroke Unit between June 2021 and June 2023 undergoing DAPT with Acetylsalicylic Acid and Clopidogrel within 72 h from symptoms onset. According to current guidelines, DAPT indication was for patients with a minor stroke, symptomatic intracranial artery stenosis and carotid angioplasty stenting. We collected clinical, demographical and radiological data. We used ABC/2 method to measure stroke volume in magnetic resonance imaging (MRI)/Diffusion-weighted imaging (DWI) sequences performed within 48 h. The primary outcome was the presence of HT at non-contrast brain computed tomography, performed 7 days after commencing DAPT. One hundred ninety-four patients were included. Twenty-eight (14.4%) presented HT. Higher NIH Stroke Scale (NIHSS) and MRI/DWI lesion volume related to increased risk of HT (p < 0.001). Reperfusion therapy and mechanical thrombectomy (MT), stent placement and a loading dose (LD) of dual antiplatelet or Clopidogrel were associated with a higher occurrence of HT (p < 0.05). Furthermore, we individuated an NIHSS cut-off value >4 (area under the curve (AUC) 0.80, sensitivity 0.82, specificity 0.65) and a volume cut-off value >8.2 ml (AUC 0.82, sensitivity 0.79, specificity 0.80) associated with an increased risk of HT (respectively, adjusted odds ratio (adj. OR) 6.5, confidence interval (CI) 1.3-32.7, p = 0.024 and adj. OR 11.0, CI 3.1-39.2, p < 0.001). In clinical practice, MT treatment, antiplatelet LD administration, stent placement and clinical severity may relate to a higher risk of HT in patients with AIS and DAPT in the acute phase. In particular, we found that lesion volume cut-off could help to identify patients at greater risk of HT, regardless of the indication for DAPT.

Thromboelastography with Platelet Mapping to Optimize Surgical Timing in Coronary Artery Bypass Grafting Patients on P2Y12 Receptor Blockers Therapy.

An increasing number of patients attending coronary artery bypass grafting (CABG) receive preoperative antiplatelet drugs (acetylsalicylic acid, clopidogrel, prasugrel, ticagrelor). The optimal assessment of preoperative platelet function is the aim of this study for a shorter surgical timing in patients undergoing elective coronary artery bypass grafting. This study was performed on patients presenting for first-time isolated CABG on therapy with an P2Y12 receptor blockers loading dose (clopidogrel [300 mg] or prasugrel [60 mg] or ticagrelor [180 mg]) or P2Y12 receptor blockers maintenance therapy at least for five days (clopidogrel [75 mg once daily], prasugrel [10 mg once daily], ticagrelor [90 mg twice daily]). All patients received simultaneously acetylsalicylate acid (100 mg daily). Exclusion criterion was emergency CABG regardless of preoperative antiplatelet and anticoagulant therapy. All patients' data were recorded in an Excel® file and analyzed using RStudio® software. Forty-eight consecutive adult patients presenting for CABG were enrolled. Preoperative thromboelastography-platelet mapping showed platelet resistance to P2Y12 blockers receptor - 25% for clopidogrel (6/24), 33% for ticagrelor (6/18), 33% for prasugrel (2/6), and this data was useful to obtain a shorter CABG waiting time in comparison with current guidelines (2.7 vs. five days for clopidogrel, 2.5 vs. five days for ticagrelor, 3.3 vs. seven days for prasugrel). Preoperative thromboelastography-platelet mapping is helpful to detect harmful P2Y12 receptor blockers resistance and to minimize CABG waiting time avoiding unnecessary and life-threatening delays.

Platelet reactivity and activated clotting time predict haemorrhagic site complications in patients with chronic coronary syndromes undergoing percutaneous coronary intervention

Abstract Background/Introduction Same-day discharge has become a standard of care for patients with chronic coronary syndromes (CCS) treated with ad hoc percutaneous coronary interventions (PCI). QuickClot Radial kaolin-based haemostatic device may shorten haemostasis time and reduce the incidence of vascular site complications. Besides unfractionated heparin (UFH) and aspirin (ASA), an ad hoc procedure demands a loading dose of clopidogrel. Dynamic changes in platelets and thrombotic activity may influence the outcomes at vascular sites. Rapid "point-of-care" testing measures the effects of anticoagulation but the optimal threshold during and after PCI still requires further research. Purpose We investigated the effect of a standard dose of UFH and a loading dose of clopidogrel measured with point-of-care devices: Hemochron activated clotting time device (ACT), VerifyNow P2Y12 test on on-site outcomes. Methods We conducted a prospective, observational study of consecutive patients with CCS who qualified for ad hoc PCI. Patients were on chronic ASA therapy, received 100 IU/kg UFH, and a 600 mg loading dose of clopidogrel. ACT was measured before and 10 min, 2 h, and 6 h after the administration of UFH and clopidogrel, respectively, and the VerifyNow P2Y12 test measured after 2 and 6 h. A QuickClot haemostatic pad with gradually released compression for up to 2 h was used in all patients. Ultrasonographic assessment of artery diameter and patency was performed before and 6 h after the procedure. Bleeding (BARC criteria) or local haematoma (EASY scale) were observed regularly until hospital discharge. Results Forty patients were enrolled in the study. The mean±SD age was 68.8±8.8 years, 30 (75%) patients were men, 13 (35%) had diabetes, 38 (95%) hypertension, 16 (40%) previous myocardial infarction, and 15 (37,5%) were active smokers. Patients received a median [interquartile range (IQR)] 8000 [7000-9000] IU of UFH and 600 mg of clopidogrel. All of the radial arteries remained patent during observation; local bleeding (BARC 2) was observed in 11 (27,5%) and haematomas (EASY 1 and 2) in 11 (27,5%) patients. Patients with bleeding had lower platelet activity measured with platelet reactivity units (PRU) after 2 h (122.5± 51 vs 158.7± 43, p= 0.04) and higher ACT (s) (216.9 ±40 vs. 184.6±28 s, p=0.006). An ACT &amp;gt;196 s, measured 2 h after the procedure, predicted the occurrence of bleeding or haematoma (AUC 0.72; 95%CI 0.56-0.85, p=0.008). Conclusion Lower platelet activity and higher ACT after PCI were associated with higher risk of haemorrhagic site complications. "Point-of-care" measures post PCI in CCS patients may be clinically applicable.

Ticagrelor or Clopidogrel to reduce ischemic events after Percutaneous Coronary Intervention in chronic coronary syndrome in clopidogrel naive patient: the ALPHEUS Naive sub-study

Abstract Background The ALPHEUS trial showed a similar rate of type 4 myocardial infarction (MI) or major myocardial injury in elective PCI treated by clopidogrel or ticagrelor. Whether clopidogrel therapy at baseline might have affected these results is unknown. Purpose We evaluated the impact of ticagrelor versus clopidogrel loading dose in clopidogrel naïve patients as compared to patients already treated by clopidogrel in this pre-specified analysis. Methods We divided 1882 randomized patients with complete data on baseline clopidogrel into 2 groups according to presence of clopidogrel therapy &amp;gt; 7 days (long term clopidogrel = Clopi+) or its absence (clopidogrel naïve = Clopi-). The primary endpoint was the rate of PCI-related MI and myocardial injury as defined by the 3rd and 4th universal definition of MI evaluated within 48 h of PCI (or hospital discharge if earlier) and major and minor bleeding. Angiographic complications evaluated by the core laboratory (coronary slow flow, no flow, dissection, and thrombus) were also compared. Event rates were compared and the interaction of the allocated treatment in the randomized groups was evaluated. Results 1077 patients (57.2%) were Clopi- and 805 patients were Clopi+. Patients in the Clopi- group were less frequently male (78.0% vs 81.9%, p= 0.04) with less often dyslipidemia (57.8% vs 65.6%, p&amp;lt; 0.001) and peripheral artery disease (11.1% vs 14.4%, p= 0.03) and had less acute coronary syndrome in the last 12 months (3.4% vs 8.7% p= 0.002). The primary endpoint was less frequent in Clopi- as compared to tClopi+ (32.8% vs 40%, OR =0.73, CI [0.60-0.88], p=0.001). This difference was mainly driven by a lower rate of major myocardial injury 24.% vs 31.6% while the rate of type 4a MI and stent thrombosis were similar (8.4% vs 8.2%) and (0.4% vs 0.2%) respectively. Angiographic complication rate was similar in the Clopi- and the Clopi+ groups (14.6% vs 12.9%) OR=1.15 CI [0.88-1.5], p=0.31. Major bleedings were infrequent in the trial. (0.1% vs 0%), and minor bleeding did not differ significantly between Clopi- and Clopi+ patients (7.0% vs 4.8% OR=1.47, CI [0.99-2.19], p=0.06). At 30 days, no difference in any outcomes were reported between the two groups. Alike for the main trial results, in the Clopi- group, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis, p for interaction was 0.83. Conclusions Periprocedural MI and procedural angiographic complications were less frequent in clopidogrel naïve patients as compared to patients already on clopidogrel therapy, and not influenced by the potency of the P2Y12 inhibitor’s loading dose prior to PCI. These results globally suggest no benefit of a long term clopidogrel pretreatment in patients receiving a loading dose of P2Y12 in the 24 hours prior to PCI in chronic coronary syndrome undergoing elective PCI and support the use of clopidogrel as the standard of care.

Efficacy of Treatment with and without Initial Clopidogrel Loading in Branch Atheromatous Disease.

Objective Despite aggressive therapeutic interventions during the acute phase of branch atheromatous disease (BAD)-type cerebral infarction, many patients, even those with a mild condition at the onset, experience neurological deterioration after hospitalization and develop serious deficits. We compared the therapeutic efficacy of multiple antithrombotic therapies for BAD between patients who received a clopidogrel loading dose (loading group; LG) and those without loading (non-loading group; NLG). Patients Between January 2019 and May 2022, patients with BAD-type cerebral infarction in the lenticulostriate artery admitted within 24 h of the onset were recruited. This study included 95 consecutive patients who received combination argatroban and dual antiplatelet therapy (aspirin and clopidogrel). Methods Patients were classified into the LG and NLG according to whether or not a loading dose of clopidogrel (300 mg) had been administered on admission. Changes in neurological severity [National Institutes of Health Stroke Scale (NIHSS) score] during the acute phase were retrospectively evaluated. Results There were 34 (36%) and 61 (64%) patients in the LG and NLG, respectively. On admission, the median NIHSS score was similar between the groups [LG: 2.5 (2-4) vs. NLG: 3 (2-4), p=0.771]. At 48 h following admission, the median NIHSS scores were 1 (0.25-4), and 2 (1-5) in the LG and NLG, respectively (p=0.045). Early neurological deterioration (END; defined as worsening of the NIHSS score by ≥4 points at 48 h after admission) occurred in 3% of LG and 20% of NLG patients (p=0.028). Conclusion Administration of a clopidogrel loading dose with combination antithrombotic therapy for BAD reduced END.

Platelet glycoprotein IIb/IIIa inhibitor tirofiban in clopidogrel-naïve patients undergoing elective percutaneous coronary intervention.

The safety of administration of tirofiban, aplatelet glycoprotein IIb/IIIa inhibitor, followed by aclopidogrel loading dose in clopidogrel-naïve patients undergoing ad-hoc percutaneous coronary intervention (PCI) is not yet clear. In aretrospective observational cohort analysis, clopidogrel-naïve patients undergoing ad-hoc PCI who received ahigh-dose bolus of tirofiban (25 μg/kg) followed by a600-mg clopidogrel loading dose (group1) were compared with patients undergoing elective PCI who were pretreated with clopidogrel (group2), between September 2014 and October 2021. The primary outcome was major adverse cardiovascular events (MACE) defined as the composite of death, myocardial infarction, stroke, target-lesion revascularisation and bleeding at 30days. Secondary outcomes were MACE at 7days and individual components of the primary outcome at 7and 30days. Atotal of 1404 patients were included: 432 (31%) in group1 and 972 (69%) in group2. Median age was 69years, and 28% were female. At 7‑day follow-up, MACE occurred in 1.4% in group1 versus 3.0% in group2 (p = 0.08). 30-day MACE were observed in 1.9% in group1 and 4.2% in group2 (p = 0.03). Secondary outcomes were comparable between the groups. Cox regression analysis, corrected for baseline differences, revealed no significant difference in the primary outcome (hazard ratio:1.8; 95% confidence interval: 0.8-3.9). Ad-hoc PCI in clopidogrel-naïve patients who were treated with high-dose bolus of tirofiban followed by aclopidogrel loading dose immediately after the procedure appeared to be safe.

Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists.

Background: The P2Y12 receptor antagonist selatogrel is being developed for subcutaneous self-administration with a ready-to-use autoinjector at the onset of acute myocardial infarction (AMI) symptoms. The unique pharmacological profile of selatogrel (fast, potent, and short-acting) can bridge the time gap between the onset of AMI and first medical care. A clinical Phase 1 study showed a time-dependent pharmacodynamic interaction between selatogrel and loading doses of clopidogrel and prasugrel. As treatment switching is a common clinical practice, the assessment of subsequent switching from a clopidogrel loading dose to the first maintenance dose of oral P2Y12 receptor antagonists is highly relevant. Objectives: Model-based predictions of inhibition of platelet aggregation (IPA) for the drugs triggering pharmacodynamic interactions were to be derived to support clinical guidance on the transition from selatogrel to oral P2Y12 receptor antagonists. Methods: Scenarios with selatogrel 16 mg administration or placebo followed by a clopidogrel loading dose and, in turn, prasugrel or ticagrelor maintenance doses at different times of administration were studied. Population pharmacokinetic/pharmacodynamic modeling and simulations of different treatment scenarios were used to derive quantitative estimates for IPA over time. Results: Following selatogrel/placebo and a clopidogrel loading dose, maintenance treatment with ticagrelor or a prasugrel loading dose followed by maintenance treatment quickly achieved sustained IPA levels above 80%. Prior to maintenance treatment, a short time span from 18 to 24 h was identified where IPA levels were predicted to be lower with selatogrel than with placebo if clopidogrel was administered 12 h after selatogrel or placebo. Predicted IPA levels reached with placebo alone and a clopidogrel loading dose at 4 h were consistently lower than with selatogrel administration, followed by a clopidogrel loading dose at 12 h. If a clopidogrel loading dose is administered at 12 h, selatogrel maintains higher IPA levels up to 16 h. IPA levels are subsequently lower than on the placebo until the administration of the first maintenance dose. Conclusions: Model-based predictions informed the transition from selatogrel subcutaneous administration to oral P2Y12 therapy. The application of modeling techniques illustrates the value of employing pharmacokinetic and pharmacodynamic modeling for the simulation of various clinical scenarios of switching therapies.

ДЕТЕРМИНАНТЫ ВЫСОКОЙ И НИЗКОЙ ОСТАТОЧНОЙ РЕАКТИВНОСТИ ТРОМБОЦИТОВ ПРИ ПРИЕМЕ КЛОПИДОГРЕЛА В 1-2 СУТКИ ИНФАРКТА МИОКАРДА

The aim of the study was to determine the clinical and laboratory factors that determine high and low platelet reactivity in patients taking clopidogrel on day 1-2 of myocardial infarction (MI). Material and Methods. A total of 405 patients (322 men and 83 women) with MI aged 31 to 74 years were examined. Group 1 included patients with low residual platelet reactivity (LRPR) – 89 people, group 2 consisted of patients with optimal platelet reactivity (OPR) – 223 people, group 3 was composed of patients with high residual platelet reactivity (HRPR) – 93 people. Platelet aggregation was assessed on a Multiplate impedance aggregometer (Germany) with several aggregation inducers. A blood test and a study of morphometric parameters of platelets were performed by the cytoflow method on an automated hematology analyzer Sysmex XS-500i (Japan). The study of the level of soluble CD40 ligand (sСD40L) and sP-selectin was performed in 140 patients, von Willebrand factor (VWF) and endothelin-1 were assessed in 150 people on the enzyme immunoassay analyzer Sunrise (TECAN, Austria) using Fine Biotech kits (China). All studies were performed upon admission to the hospital on day 1-2 of MI (at least 12 hours after the administration of a loading dose of clopidogrel). Results. A one-way linear regression analysis identified the following factors that independently affect the value of the ADP-test: age (β=-0.21, 95% CI: -0.42 – -0.0095; p=0.04); total cholesterol (β=1.4, 95% CI: 0.26–2.56; p=0.04); white blood cell count (β= 0.57, 95% CI: 0.003–1.14; p=0.049); hemoglobin (β=-0.16, 95% CI: -0.27 – -0.044; p=0.0067); platelet count (β=1.4, 95% CI: 0.26 – 2.56; p=0.04); PCT (β=76.8, 95% CI: 41.5 – 112.1; p=0.000024); TRAP-test (β=0.4, 95% CI: 0.33–0.46; p&lt;0.000001); CD40L (β=0.044, 95% CI: 0.013–0.074; p=0.005); sP-selectin (β=2.3, 95% CI: 0.63 – 3.97; p=0.007); VWF (β=0.06, 95% CI: 0.016 – 0.11; p=0.0085). To determine the probability of HRPR developing a binary logistic regression model was constructed based on the observational data of a sample of 398 patients, which included the following indicators: age, white blood cell count, mean platelet volume (MPV) and platelet distribution width (PDW) values, results of TRAP-test and the level of creatinine. At the probability cut-off p=0.4746, the sensitivity of the constructed model was 74.2%, specificity - 74.1%, classification accuracy – 74.1%, the area under the ROC-curve – 0.795 (CI: 0.745 – 0.844). To determine the probability of developing LRPR, a binary logistic regression model was constructed based on the observational data of 143 patients, which included the following indicators: the number of leukocytes, MPV and TRAP-test values, fibrinogen and VWF levels. With a probability cut-off p=0.5589, the sensitivity of this model was 84.6%, specificity – 77.8%, classification accuracy – 79.0%, the area under the ROC-curve – 0.826 (CI: 0.747 – 0.905). Conclusion. On days 1-2 of MI, 22% of patients with an excessive response to clopidogrel and 23% with an insufficient response to clopidogrel were identified. The determinants of HRPR are age, white blood cell count, MPV, PDW, TRAP-test and creatinine levels. The determinants of LRPR are white blood cell count, MPV values, spontaneous platelet aggregation, detected by the TRAP-test, the level of fibrinogen and VWF.

The impact of smoking status on clopidogrel responsiveness in patients with coronary artery disease who undergo percutaneous coronary intervention

Background: Previous studies have pointed out the disproportionate action of clopidogrel in inhibiting platelet aggregation due to smoking more than ten cigarettes per a day. This study was designed to examine whether smoking enhances clopidogrel responsiveness in patients who are clinically diagnosed with coronary artery disease (CAD), following percutaneous coronary intervention (PCI). Methods: A total of 324 IHD participants were enrolled in a case-control study. Platelet function test was performed to all participants two hours before PCI procedure to measure clopidogrel response. Participants were then categorized into a non-responder group (case group n = 111) and responder group (control group n = 213). Each group was subdivided into a smoker group and a non-smoker group. All participants received clopidogrel loading dose equivalent to 600 mg and scheduled for elective PCI. Participants’ age, gender, family history of chronic illnesses was recorded in this study. Results: Smoking participants displayed a significant higher level of hemoglobin as compared to the non-smoking participants among the responder and the non-responder study groups (14.6±0.55 vs. 13.12±0.38, P &lt; 0.029; 14.3±0.31 versus 12.96±0.39, P &lt; 0.033) but lower AUC level (17±9 vs. 45±6, P &lt; 0.005; 62±3 vs. 95±7, P &lt; 0.008). Additionally, smoking intensity enhanced clopidogrel responsiveness by odd’s ratio 0.4213 at 95% C.I. (0.259 - 0.684), P &lt; 0.0002. Conclusions: Current smokers had a good response to clopidogrel therapy which exerted a beneficial effect when undergoing PCI as compared to non-smokers. The marked difference in AUC between smokers and non-smokers could be related to the variance in hemoglobin level. The smokers’ paradox needs further justification to confirm this concept.

#4878 STUDYING THE EFFECTIVENESS OF PRASUGREL AND CLOPIDOGEL IN PATIENTS WITH CHRONIC LOWER LIMB ISCHEMIA WITH STAGE 2 CKD

Abstract Background and Aims To compare the clinical and rheological efficacy of prasugrel and clopidogrel in patients with chronic lower limb ischemia with stage 2 chronic kidney disease. According to statistics, in Europe, peripheral arterial disease is common in more than 40 million Europeans. According to the developed tactics, not only stroke should be recognized as a serious, life-threatening condition, but other peripheral vascular diseases can lead to disability and death. Methods The study included 101 patients with critical lower limb ischemia of atherosclerotic origin. The mean age of the patients was 51.51±8.33 years. As a control group, 20 healthy volunteers (mean age 53.90 ± 9.05 years) were examined without signs of pathology of the cardiovascular system, including those of a vegetative nature. All patients included in the study were hospitalized in the Department of Interventional Cardiology of the Republican Specialized Scientific and Practical Center for Therapy and Medical Rehabilitation, Tashkent city. Results In 94 patients (93.07%), CLCI was accompanied by hemodynamically significant multifocal atherosclerotic lesions. The first place in frequency of combined lesions was occupied by the coronary vessels, the second place - by the arteries of the brachiocephalic basin. 82 patients (81.19%) had previously suffered arterial occlusion, also most often in the form of acute myocardial infarction, somewhat less often - acute cerebrovascular accident. 47 patients (46.53%) underwent revascularization earlier, mainly coronary artery stenting, coronary artery bypass grafting, carotid endarterectomy. 8 patients (7.92%) underwent revascularization of the contralateral leg. The study studied spontaneous (SAT) and ADP-induced platelet aggregation. In the CG, SAT was noted only in 50% of cases and in all patients of the CLCI group. After comparing the results in the groups of patients with CLCI and representatives of the CG, in whom SAT was noted, it was found that both the rate and degree of SAT in the group of patients were significantly higher than in healthy individuals (2.95±0.59% versus 0.55± 0.21% and 6.05±1.54% versus 1.24±0.21%, respectively, p&amp;lt;0.001 significance of the intergroup difference of both parameters). All patients due to CINC underwent endovascular revascularization of the affected leg. After the procedure, patients were prescribed an antiplatelet agent at a maintenance dose (prasugrel 10 mg/day, clopidogrel 75 mg/day). After 3 months, a control examination was carried out, during which the dynamics of platelet aggregation activity was studied. It was found that the indicators of CAT and ADP induced aggregation decreased by 22-37%. During the test, patients with resistance to antiplatelet agents were identified - in whom the decrease in the degree of ADP5 induced aggregation was less than 20%. Such resistance was found in 19 patients: 1 patient in the prasugrel group (1.69%) and 18 patients in the clopidogrel group (42.86%, chi square = 27.00, p&amp;lt;0.001). Isolation of patients with normal and reduced response to the loading dose of clopidogrel revealed some differences (Table 3.3). So, already initially in this group of patients, the degree of ADP5-induced aggregation was lower than in the group of patients with an antiplatelet response of more than 20%. After the application of a loading dose of clopidogrel, differences in relative dynamics were noted only in terms of the degree of ADP%-induced aggregation (p&amp;lt;0.001). Conclusions Thus, the present study revealed that in patients with CLCI, there is a significant activation of CAT and an increase in the aggregation response to the introduction of high doses of the inducer of ADP5 aggregation. The loading dose of antiplatelet agents contributed to a significant decrease in platelet aggregation activity after 2 hours with a large effect of prasugrel. Chronic antiplatelet therapy led to a decrease in the rate and degree of aggregation, both spontaneous and ADP-induced, a decrease in the endogenous ADP release response, also with a great effect in patients taking prasugrel.

COMPARISON OF LOADING DOSE OF CLOPIDOGREL WITH TICAGRELOR IN ELDERLY PATIENTS UNDERGOING PCI IN STABLE ISCHEMIC HEART DISEASE

This study aimed to compare the efficacy and safety of loading doses of clopidogrel with ticagrelor in elderly patients undergoing PCI in SIHD. Methods: A randomized controlled trial was conducted at Saidu Group of Teaching Hospitals from January 2019 to January 2020. 600 patients aged 65 years or older with SIHD who underwent PCI were randomized to receive either a loading dose of clopidogrel 600mg or ticagrelor 180mg. The primary endpoint was a composite of death, myocardial infarction, stent thrombosis, or stroke at 30 days post-PCI.Results: The incidence of the primary endpoint was similar in both groups (8.3% in the clopidogrel group vs. 8.2% in the ticagrelor group, P=0.95). There were no significant differences in the rates of individual components of the primary endpoint between the two groups. Bleeding events were also similar in both groups (4.8% in the clopidogrel group vs. 4.7% in the ticagrelor group, P=0.95). However, ticagrelor was associated with a significantly higher incidence of dyspnea (9.8% vs. 2.3%, P&lt;0.001).Conclusion: In elderly patients undergoing PCI for SIHD, a loading dose of clopidogrel was found to be non-inferior to ticagrelor in terms of the composite endpoint of death, myocardial infarction, stent thrombosis, or stroke at 30 days post-PCI.

Acute loading dose of antiplanets before Stent-assisted repair of cerebral aneurysm associated with reduced ischemic events and good outcomes (P8-5.016)

<h3>Objective:</h3> Objective is to evaluate if loading doses of aspirin and clopidogrel (LDAC) reduces TEE without increased intracranial hemorrhage (IH) and improves outcomes in SARIA. <h3>Background:</h3> There are no universal antiplatelets regimens to prevent Thromboemboembolic event (TEE) in stent-assisted repair of intracranial aneurysms (SARIA). Antiplatelets effects are highest in first 4 hours. <h3>Design/Methods:</h3> Consecutive patients underwent SARIA with LDAC; aspirin 324 mg (4 baby aspirin) and clopidogrel 300 mg in 2 to 4 hours before procedure were enrolled from 2011 to 2022. Outcome was measured using modified Rankin Scale (mRS) score. <h3>Results:</h3> 112 patients with mean age of 53 ± 13 underwent SARIA (7 ruptured and 55 symptomatic). Aneurysms are; Right internal carotid artery (ICA) 27, left ICA 35, middle cerebral artery 25, basilar artery 19 and anterior communicating artery 6. There are no intra-operative ruptures. Small left subarachnoid hemorrhage developed on a right MCA aneurysm on day 3, which resolved spontaneously. Stent thrombosis in one; resolved with intraarterial integrilin with no stroke. Clinical TEE were observed in 2 cases (1.8%); first event was in a 42 years old woman with a giant right ICA giant aneurysm and achieved mRS 1. Second event was visual distortion and diplopia in a 66 years old woman with basilar artery aneurysm and achieved mRS1. Ruptured and symptomatic were repaired and no subarachnoid hemorrhages during follow-up. Immediate complete and near complete obliteration of aneurysm was observed in 72% and subtotal in 28%. There was no mortality or permanent disability in our series. 90 days mRankins 0 and 1 was observed in 98 (92.5%), mRS 2 in 7(6.6%) at baseline and mRS 3 in 2 (1.9%), which sustained in 12 months. <h3>Conclusions:</h3> LDAC in SARIA is associated with reduced TEE without increased IH and good outcome. LDAP may be an option in SARIA to prevent TEE. Further studies are required. <b>Disclosure:</b> Dr. Lodi has nothing to disclose.

The impact of smoking status on clopidogrel responsiveness in patients with coronary artery disease who undergo percutaneous coronary intervention

Background: Previous studies have pointed out the disproportionate action of clopidogrel in inhibiting platelet aggregation due to smoking more than ten cigarettes per a day. This study was designed to examine whether smoking enhances clopidogrel responsiveness in patients who are clinically diagnosed with coronary artery disease (CAD), following percutaneous coronary intervention (PCI). Methods: A total of 324 IHD participants were enrolled in a case-control study. Platelet function test was performed to all participants two hours before PCI procedure to measure clopidogrel response. Participants were then categorized into a non-responder group (case group n = 111) and responder group (control group n = 213). Each group was subdivided into a smoker group and a non-smoker group. All participants received clopidogrel loading dose equivalent to 600 mg and scheduled for elective PCI. Participants’ age, gender, family history of chronic illnesses was recorded in this study. Results: Smoking participants displayed a significant higher level of hemoglobin as compared to the non-smoking participants among the responder and the non-responder study groups (14.6±0.55 vs. 13.12±0.38, P &lt; 0.029; 14.3±0.31 versus 12.96±0.39, P &lt; 0.033) but lower AUC level (17±9 vs. 45±6, P &lt; 0.005; 62±3 vs. 95±7, P &lt; 0.008). Additionally, smoking intensity enhanced clopidogrel responsiveness by odd’s ratio 0.4213 at 95% C.I. (0.259 - 0.684), P &lt; 0.0002. Conclusions: Current smokers had a good response to clopidogrel therapy which exerted a beneficial effect when undergoing PCI as compared to non-smokers. The marked difference in AUC between smokers and non-smokers could be related to the variance in hemoglobin level. The smokers’ paradox needs further justification to confirm this concept.

Predictors of Acute Stent Thrombosis After Primary Percutaneous Coronary Intervention

OBJECTIVES To identify the specific predictors of acute stent thrombosis in patients after primary percutaneous coronary intervention.METHODOLOGY This retrospective study was carried out at the Department of Cardiology Hayatabad Medical Complex Peshawar from 1st January to 30th June 2022. All consecutive patients with an angiographically confirmed stent thrombosis were enrolled. Patients gave informed consent for the inclusion of data in this registry. Stent thrombosis was categorized according to the timing of the event as acute (occurrence within the first 24 hours after the index procedure).RESULTSA total of 400 patients were included in the study. Age ranged between 35-70 years, with a mean age of 52.5. There were 260(65%) males and 140(35%) females, with male to female ratio of 1.8:1. All patients underwent primary PCI with stent implantation. According to the elapsed time since stent implantation, 42(10.5%) patients presented with acute stent thrombosis after primary percutaneous coronary intervention. The mean time to develop acute stent thrombosis after primary PCI was ±4.5 hours (range 3-6 hours). In most STEMI patients, 340(85%) received a loading dose of clopidogrel at the time of the index PCI. In 23(54.7%) patients, acute stent thrombosis occurred within 6 hours, 10(23.8%) within 12 hours, 6(14.2%) within 18 hours and 3(7.1%) after clopidogrel loading.CONCLUSIONInadequate stent expansion or mal-opposition, diabetes mellitus, chronic kidney disease, and female gender were the strong predictors of acute stent thrombosis.