Dose Of Prasugrel Research Articles

Clinical and peri procedural outcomes using reduced dose prasugrel vs standard dose ticagrelor in elderly patients of acute coronary syndrome undergoing PCI

Abstract Introduction The novel antiplatelet agent prasugrel is generally not indicated in elderly(>75-years) patients in standard dose(60 mg loading and 10 mg maintenance) however, there is a scarce data on safety and efficacy of reduced dose prasugrel(30 mg loading and 5 mg maintenance dose) among elderly patients undergoing elective PCI. Some previous studies have raised concerns regarding the differences in pharmacodynamic and pharmacokinetic responses to prasugrel in asian ethnicities. The efficacy and safety of reduced dose prasugrel in elderly patients has not been investigated. Therefore, in this study we have compared the efficacy and safety of a reduced dose prasugrel with standard dose ticagrelor in elderly Indian patients undergoing elective PCI for acute coronary syndrome (ACS). Purpose To study the periprocedural and intermediate term clinical outcomes using reduced dose prasugrel versus standard dose ticagrelor in elderly Indian patients of acute coronary syndrome undergoing PCI. Methods This was a single centre, randomised, prospective cohort study. Based on the previous reference studies, at 95% level of significance and 80% of power, the sample size was calculated as 73 in each group. Study was conducted from May 2021 to October 2022 (18 months). Patients >75 years of age with ST-segment–elevation (STE) or Non ST elevation (NSTE) ACS treated with PCI were included. The study was approved by the institutional ethics review board. Participants were assigned to receive a standard dose of ticagrelor (180 mg loading followed by 90 mg twice daily, n=73) or a reduced dose prasugrel (30 mg loading followed by 5 mg once daily, n=73). The primary efficacy end point of the study was a composite of major adverse cardiac events (MACE) including cardiovascular mortality , non fatal MI and stroke. The secondary safety end points were major and minor bleeding events. Patients were followed up at 15 days, 3 months and 6 months. Results The baseline clinical and demographic characteristics were comparable in the both groups. The composite of primary efficacy end points at 6 months occurred significantly more in ticagrelor group vs reduced dose prasugrel group(13.7% vs 4.1% P value=0.05) and composite of secondary safety end point were comparable in both the groups(21.9% vs 16.4% respectively, p=0.44). Dyspnoea was seen more frequently in standard dose ticagrelor group as compared to reduced dose prasugrel group (15.1% vs. 6.8% respectively, p value=0.133). Conclusion The results of our study indicate that the reduced dose prasugrel is safe in elderly patients, has similar bleeding events as compared to standard dose ticagrelor group and is better tolerated. The reduced dose prasugrel is significantly more efficacious as compared to standard dose ticagrelor in elderly patients in terms of reduced MACE events. Although large scale randomized studies may be warranted in such populations to draw a broader conclusion.Baseline characteristicsEnd results

Segmental post-PCI physiological gradients using ultrasonic or optical flow ratio

Abstract Background Segmental pressure gradients post percutaneous coronary intervention (PCI) may detect residual disease and potential targets for optimization. Ultrasonic flow ratio (UFR) or optical flow ratio (OFR) provide simultaneous physiological and morphological data using a single imaging catheter. Notably, both have been validated against wire based FFR Objectives To evaluate the utility of UFR and OFR to identify residual disease post-PCI. Methods The present study is a sub analysis of the ASET (Acetyl Salicylic Elimination Trial) JAPAN pilot study Phase I which showed the feasibility and safety of low dose prasugrel monotherapy following PCI in Japanese patients presenting with chronic coronary syndrome and an anatomical SYNTAX score <23. Patients with complete intra-vascular imaging pullback data were included with UFR/OFR acquired in all patients post-PCI. Quantitative and qualitative assessment of IVUS or OCT pullbacks was performed by automatically delineating vessel, lumen, and stent contours every 0.5 mm using QCU-CMS (version 4.69, Division of Image Processing, Leiden University Medical Centre). UFR or OFR was calculated using the respective IvusPlus or OctPlus software, Pulse Medical, Shanghai, China.(13)(15) All UFR and OFR tracings, and IVUS and OCT pullbacks were analyzed at the CORRIB Core lab, Galway, Ireland by two analysts blinded to clinical and procedural data. Anatomically focal lesions distal and proximal to the stent were evaluated in segments ≥5mm long. UFR/OFR virtual pullback curves were used to calculate intra-stent pressure gradients and physiologically define lesions as focal or diffuse by segmental pressure drops ≥0.05 over lengths <10mm or ≥10mm, respectively. Results The median post-PCI UFR/OFR was 0.93 (0.88-0.96) with 69/195 vessels (35.4%) having a UFR/OFR≤0.90. There were significantly more focal anatomical and physiological lesions proximal and distal to the stent in vessels with a UFR/OFR≤0.90 versus >0.90. In vessels with a UFR/OFR≤0.90 there was moderate agreement (weighted kappa=0.553, p<0.001) between anatomical and physiological focal lesions proximal to the stent, whilst it was fair (weighted kappa=0.219, p=0.002) distally. In-stent gradient had poor discriminative ability to detect significant stent under-expansion. The performance of a proximal or distal virtual FFR gradient to detect proximal or distal anatomically focal disease was good (AUC–0.835 and 0.877, respectively) Conclusions UFR/OFR enables suboptimal vessel physiology post-PCI to be detected and helps identify the precise anatomical location with corroboration from intra-vascular imaging. Adequately powered physiology optimization trials using UFR/OFR will determine the role of combined morphology and physiological evaluation post PCI in improving clinical outcomes.

Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis

Abstract Background Carriers of cytochrome 2C19 (CYP2C19) loss of function (LoF) alleles treated with clopidogrel have impaired drug metabolism resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored. Purpose To assess the comparative effects of different alternative antiplatelet agents in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI). Methods Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing PCI were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios (OR) and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR as defined in each trial. Standard-dose of clopidogrel (75 mg daily) was used as reference treatment. Antiplatelet strategies were ranked according to P-scores, ranging between 0 (poor performance) and 1 (good performance). Results A total of 13 RCTs testing 6 alternative strategies (i.e., clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -128.61; 95% CI -145.09; -111.49) and ticagrelor 90 mg bid (MD -125.61; 95% CI -170.66; -80.56), followed by prasugrel 5 mg (MD -118.03; 95% CI -143.15; -92.92) and prasugrel 3.75 mg (MD -73.00; 95% CI -108.97; -37.03). High-dose clopidogrel was associated with a modest (MD -32.11; 95% CI -51.33; -12.90) and adjunctive cilostazol with a non-significant (MD -44.11; 95% CI -98.05; -9.82) reduction in PRU compared with standard-dose clopidogrel (Figure 1). Rates of HPR were reduced with all treatments compared with standard-dose clopidogrel. Ranking of treatments for the primary endpoint showed that standard-dose prasugrel ranked as the best treatment (P-score=0.884), followed by ticagrelor (P-score=0.835), low-dose prasugrel (0.767), very-low dose prasugrel (P-score=0.474), cilostazol (P-score=0.306), high-dose clopidogrel (P-score=0.224), and standard-dose clopidogrel (P-score=0.009) (Figure 2). Conclusion Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, followed by reduced-dose of prasugrel, while double-dose clopidogrel and adjunctive cilostazol showed only modest effects. The clinical implications of these pharmacodynamically effective strategies warrant further investigation.

Comparative Efficacy and Safety of Novel Antiplatelets and Standard Therapy in Patients With Coronary Artery Disease.

Coronary artery disease (CAD) is a significant health concern that has affected approximately 110 million people worldwide. CAD is defined as persistent narrowing of the coronary arteries as a result of atherosclerotic plaque build-up. Acute coronary syndrome (ACS), which encompasses ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina, often results from plaque ruptures. Platelets are crucial for atherogenesis, vascular inflammation, and oxidative stress. Antiplatelet therapy aimed at reducing thrombotic events is vital for ACS treatment. Clinical guidelines advise the use of dual antiplatelet therapy (DAPT) that combines aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) in ACS patients undergoing percutaneous intervention (PCI). This study aimed to assess comprehensively the effectiveness and safety of ticagrelor and prasugrel in comparison to clopidogrel in patients with ACS. An extensive literature search was conducted using PubMed, PubMed Central (PMC), ScienceDirect, and EBSCO databases. The search revealed studies that compared ticagrelor and prasugrel to clopidogrel in ACS patients, and we selected these studies based on specific inclusion and exclusion criteria, which included observational studies, clinical trials, literature reviews, and meta-analyses involving adult ACS patients treated with ticagrelor, prasugrel, or clopidogrel. The efficacy outcomes were defined as major adverse cardiovascular events (MACE) and thrombotic events, whereas the safety outcomes were measured by major and minor bleeding and hemorrhagic stroke. After a rigorous quality assessment to minimize bias, 23 studies were selected for analysis. The findings indicated that novel antiplatelets reduced MACE but increased bleeding complications, with ticagrelor consistently associated with dyspnea.In conclusion, novel P2Y12 inhibitors provide cardiovascular benefits but require careful patient selection and monitoring due to gastrointestinal bleeding (GIB) risks. Future research should standardize bleeding definitions and assess long-term outcomes. Ticagrelor and prasugrel may be more effective and safer than clopidogrel in ACS patients. Given the high risk of GIB, especially among older individuals or those with a past stroke, it is advisable to suggest a lower prasugrel dose without raising the bleeding rates. Since fewer patients use the novel antiplatelet regimen compared to clopidogrel, future clinical trials should include a broader patient population and compare these regimens.

Demystifying the Contemporary Role of 12-Month Dual Antiplatelet Therapy After Acute Coronary Syndrome.

For almost two decades, 12-month dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) has been the only class I recommendation on DAPT in American and European guidelines, which has resulted in 12-month durations of DAPT therapy being the most frequently implemented in ACS patients undergoing percutaneous coronary intervention (PCI) across the globe. Twelve-month DAPT was initially grounded in the results of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which, by design, studied DAPT versus no DAPT rather than the optimal DAPT duration. The average DAPT duration in this study was 9 months, not 12 months. Subsequent ACS studies, which were not designed to assess DAPT duration, rather its composition (aspirin with prasugrel or ticagrelor compared with clopidogrel) were further interpreted as supportive evidence for 12-month DAPT duration. In these studies, the median DAPT duration was 9 or 15 months for ticagrelor and prasugrel, respectively. Several subsequent studies questioned the 12-month regimen and suggested that DAPT duration should either be fewer than 12 months in patients at high bleeding risk or more than 12 months in patients at high ischemic risk who can safely tolerate the treatment. Bleeding, rather than ischemic risk assessment, has emerged as a treatment modifier for maximizing the net clinical benefit of DAPT, due to excessive bleeding and no clear benefit of prolonged treatment regimens in high bleeding risk patients. Multiple DAPT de-escalation treatment strategies, including switching from prasugrel or ticagrelor to clopidogrel, reducing the dose of prasugrel or ticagrelor, and shortening DAPT duration while maintaining monotherapy with ticagrelor, have been consistently shown to reduce bleeding without increasing fatal or nonfatal cardiovascular or cerebral ischemic risks compared with 12-month DAPT. However, 12-month DAPT remains the only class-I DAPT recommendation for patients with ACS despite the lack of prospectively established evidence, leading to unnecessary and potentially harmful overtreatment in many patients. It is time for clinical practice and guideline recommendations to be updated to reflect the totality of the evidence regarding the optimal DAPT duration in ACS.

Periprocedural antiplatelet medication assessed by VerifyNow for neuroendovascular treatment: Comparison of prasugrel with clopidogrel

Objective The maintenance dose of prasugrel (PRAS) for neuroendovascular treatment requires much research. We report the antiplatelet effect of PRAS measured by VerifyNow P2Y12 reaction units (PRUs) in patients during the perioperative period of neuroendovascular treatment. Methods Between January 2017 and January 2023, 230 patients who underwent endovascular treatment for unruptured intracranial aneurysms or carotid artery stenosis at our institution were retrospectively identified. Patients received dual antiplatelet therapy with 100 mg aspirin (ASA) and 75 mg clopidogrel (CLP)/day (CLP group, n = 186) or 100 mg ASA and 3.75 mg PRAS/day (PRAS group, n = 44) 2 weeks before the procedures. The PRU value was compared between the CLP and PRAS groups. In the study, we defined 95≦PRU < 208 as the optimal range. Perioperative complications within seven days of surgery were also analyzed. Results The mean value of PRU was significantly low in the PRAS group (179.13 ± 66.03 in CLP vs. 154.75 ± 54.01 in PRAS, p = 0.024). The proportion of the patients who exhibited 95≦PRU < 208 was significantly higher in the PRAS group (55.4% vs. 72.7%, p = 0.036). Ischemic and hemorrhagic complication rates were not significantly different between the CLP and PRAS groups (7.6% vs. 0%, p = 0.076; 4.7% vs. 0%, p = 0.361). The ischemic complication rate was higher in patients with a PRU > 208 than in those with PRU < 208 (12.5% vs. 3.8%, p = 0.044). The hemorrhagic complication rate was not significantly different between the PRU < 95 and 95≦PRU groups (8.4% vs. 3.2%, p = 0.224). Conclusions Maintenance dose PRAS further decreased the PRU value and reached the optimal range in more cases than CLP during the perioperative period of neuroendovascular treatment. Ischemic complications significantly increased in the 208 < PRU group.

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.

Single antiplatelet therapy directly after percutaneous coronary intervention in non-ST-segment elevation acute coronary syndrome patients: the OPTICA study.

Early P2Y12 inhibitor monotherapy has emerged as a promising alternative to 12 months of dual antiplatelet therapy following percutaneous coronary intervention (PCI). In this single-arm pilot study, we evaluated the feasibility and safety of ticagrelor or prasugrel monotherapy directly following PCI in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Patients received a loading dose of ticagrelor or prasugrel before undergoing platelet function testing and subsequent PCI using new-generation drug-eluting stents. The stent result was adjudicated with optical coherence tomography in the first 35 patients. Ticagrelor or prasugrel monotherapy was continued for 12 months. The primary ischaemic endpoint was the composite of all-cause mortality, myocardial infarction, definite or probable stent thrombosis or stroke within 6 months. The primary bleeding endpoint was Bleeding Academic Research Consortium type 2, 3 or 5 bleeding within 6 months. From March 2021 to March 2022, 125 patients were enrolled, of whom 75 ultimately met all in- and exclusion criteria (mean age 64.5 years, 29.3% women). Overall, 70 out of 75 (93.3%) patients were treated with ticagrelor or prasugrel monotherapy directly following PCI. The primary ischaemic endpoint occurred in 3 (4.0%) patients within 6 months. No cases of stent thrombosis or spontaneous myocardial infarction occurred. The primary bleeding endpoint occurred in 7 (9.3%) patients within 6 months. This study provides first-in-human evidence that P2Y12 inhibitor monotherapy directly following PCI for NSTE-ACS is feasible, without any overt safety concerns, and highlights the need for randomised controlled trials comparing direct P2Y12 inhibitor monotherapy with the current standard of care.

Reduced-dose prasugrel monotherapy without aspirin after PCI with the SYNERGY stent in East Asian patients presenting with chronic coronary syndromes or non-ST-elevation acute coronary syndromes: rationale and design of the ASET Japan pilot study

The Acetyl Salicylic Elimination Trial (ASET) Japan pilot study is a multicentre, single-arm, open-label, proof-of-concept study with a stopping rule based on the occurrence of definite stent thrombosis. This study aims to demonstrate the feasibility and safety of low-dose prasugrel monotherapy following percutaneous coronary intervention (PCI) in Japanese patients presenting with chronic coronary syndromes (CCS) or non-ST-elevation acute coronary syndromes (NSTE-ACS). Four hundred patients with a SYNTAX score <23 requiring PCI due to CCS or NSTE-ACS will be screened and considered eligible for the study. The enrolment is planned in two phases: 1) 200 patients presenting with CCS, followed by 2) 200 patients presenting with NSTE-ACS. After optimal PCI with implantation of a SYNERGY (Boston Scientific) stent, patients will be enrolled and loaded with prasugrel 20 mg, followed by a maintenance dose of prasugrel 3.75 mg once daily without aspirin continued for 3 months in Phase 1 (CCS patients), and for 12 months in Phase 2 (NSTE-ACS patients). After these follow-up periods, prasugrel will be replaced by standard antiplatelet therapy according to local practice. The primary endpoint is a composite of cardiac death, target vessel myocardial infarction, or definite stent thrombosis after the index procedure. The primary bleeding endpoint is any Bleeding Academic Research Consortium type 3 or 5 bleeding occurring within 3 months of the index PCI for CCS patients, or 12 months for NSTE-ACS patients. The ASET Japan study is designed to demonstrate the feasibility and safety of reduced-dose prasugrel monotherapy after PCI in East Asian patients with acute and chronic coronary syndromes.

Prasugrel-Based De-Escalation in Patients With Acute Coronary SyndromeAccording to Renal Function.

Patients with coronary artery disease and impaired renal function are at higher risk for both bleeding and ischemic adverse events after percutaneous coronary intervention (PCI). This study assessed the efficacy and safety of a prasugrel-based de-escalation strategy in patients with impaired renal function. We conducted a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS study. Patients with available estimated glomerular filtration rate (eGFR) (n=2,311) were categorized into 3 groups. (high eGFR: >90mL/min; intermediate eGFR: 60 to 90mL/min; and low eGFR:<60mL/min). The end points were bleeding outcomes (Bleeding Academic Research Consortium type 2 or higher), ischemic outcomes (cardiovascular death, myocardial infarction, stent thrombosis, repeated revascularization, and ischemic stroke), and net adverse clinical event (including any clinical event) at 1-year follow-up. Prasugrel de-escalation was beneficial regardless of baseline renal function (P for interaction=0.508). The relative reduction in bleeding risk from prasugrel de-escalation was higher in the low eGFR group than in both the intermediate and high eGFR groups (relative reductions, respectively: 64% (HR: 0.36; 95%CI: 0.15-0.83) vs 50% (HR: 0.50; 95%CI: 0.28-0.90) and 52% (HR: 0.48; 95%CI: 0.21-1.13) (P for interaction=0.646). Ischemic risk from prasgurel de-escalation was not significant in all eGFR groups (HR: 1.18 [95%CI: 0.47-2.98], HR: 0.95 [95%CI: 0.53-1.69], and HR: 0.61 [95%CI: 0.26-1.39]) (P for interaction=0.119). In patients with acute coronary syndrome receiving PCI, prasugrel dose de-escalation was beneficial regardless of the baseline renal function.

Abstract 12333: Therapeutic Window of Low-Dose Prasugrel for Platelet Reactivity in the Chronic Phase of Post-Percutaneous Coronary Intervention: The Chaperon Study

Introduction: There are many reports on the effects of on-treatment platelet reactivity using P2Y 12 reaction units (PRU) on the ischemic or bleeding risk in patients who underwent percutaneous coronary intervention (PCI). However, there was little report including low-dose prasugrel (2.5mg). Hypothesis: We assumed that low-dose prasugrel use may contribute to the effectiveness and safety in the chronic phase of PCI in Japanese patients. Methods: This prospective observational study included 398 patients who underwent PCI between 2017 and 2018 (mean age: 68±11 years, male: 83%). Serial PRU measurements were performed; the baseline was at 6 to 12 months after PCI, and the follow-up was after 6 months later. The PRU was measured by the VerifyNow® P2Y 12 assay, and we assessed the distribution of PRU in each P2Y 12 inhibitor, after defined PRU 86 to 238 as therapeutic window. Results: Among 398 patients, the follow-up PRU was obtained in 360 patients (90%), and 80 patients (22%) were taking prasugrel 2.5mg. The baseline PRUs of clopidogrel 75mg, prasugrel 3.75mg, and prasugrel 2.5mg were 175±64, 147±55, and 154±66, respectively ( p &lt;0.001), and the portions of PRU ≤239 (ischemic risk) were 14.6%, 4.4%, and 9.5%, respectively ( p =0.007). At the time of follow-up, a statistically significant trend of PRU was revealed in 24 patients changed clopidogrel 75mg to prasugrel 2.5mg (baseline vs. follow-up: 183±64 vs. 149±43, p =0.037). Regarding distribution of PRU, prasugrel 2.5mg was less frequent in PRU ≤85 (bleeding risk) compared to prasugrel 3.75mg (7.5% vs. 21.0%, p =0.019). In addition, a multivariable logistic regression analysis revealed that prasugrel 2.5mg use was an independent predictor of therapeutic window (odds ratio: 2.15; 95% confidence intervals: 1.01-4.59, p =0.044). Conclusions: We found prasugrel 2.5mg use after PCI significantly associated with therapeutic window. Thus, we believe low dose prasugrel use may contribute to the future risk reduction after PCI.

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of Prasugrel in Healthy Male Volunteers.

This study evaluated the pharmacokinetics and pharmacodynamics of the antiplatelet agent prasugrel, and explored its optimal dose regimens via modeling and simulation using NONMEM. We measured platelet aggregation and the serial plasma concentrations of the inactive (R-95913) and active metabolites (R-138727) of prasugrel after a single oral dose of 10-60mg in 20 healthy adult male volunteers. A pharmacokinetic model for R-95913 and R-138727, and a pharmacodynamic model between the concentration of R-138727 and maximal platelet aggregation measured by light transmittance were constructed. The predictability of the model for platelet aggregation was evaluated by comparing the model prediction values with the observed ones not used in the construction of the model. Pharmacokinetic data were best described by a 3-compartment models for R-95913, a 1-compartment model for R-138727 with transit compartment model for absorption delay, and first-pass metabolic conversion of R-95913 into R-138727 during absorption. The association-dissociation model between R-138727 and its receptor in platelets was applied for the inhibitory effect of prasugrel on platelet aggregation. Prasugrel rapidly inhibited platelet aggregation after oral administration, with a prolonged duration of action; however, the concentration of the active metabolite decreased rapidly, which may have been due to the slow dissociation rate of R-138727 from its target receptor in platelets. The external validation suggests that our model could be used to individualize prasugrel treatment in various clinical situations. Simulation showed rapid onset of inhibitory effect with great magnitude and consistent inhibition after therapeutic dose of prasugrel.

Changes in Antithrombotic Therapy Over Time and Durability of a Prasugrel WOEST-Like Regimen for Percutaneous Coronary Intervention Patients With Atrial Fibrillation - Post Hoc Analysis of the PENDULUM Mono and PENDULUM Registries.

Background: Previously published randomized atrial fibrillation (AF) percutaneous coronary intervention (PCI) trials have demonstrated the safety and efficacy of a WOEST-like regimen (oral anticoagulant [OAC] plus P2Y12 inhibitor) in patients with AF PCI within 1 year. However, the efficacy of this regimen in real-world practice has not been fully confirmed, especially the efficacy of the WOEST-like regimen using the approved dose of prasugrel in Japan.Methods and Results: This post hoc analysis included 186 and 220 patients from the PENDULUM mono and PENDULUM registries, respectively. Endpoints were the cumulative incidences of clinically relevant bleeding (CRB) and major adverse cardiac and cerebrovascular events (MACCE) at 12 months after PCI. Differences in the enrollment period led to an increase in OAC prescriptions (from 64.7% to 81.2%) and a reduction in the median duration of triple antithrombotic therapy (from 203.0 to 32.0 days) in the PENDULUM vs. PENDULUM mono registries, respectively. After adjustment by the inverse probability of treatment method, in patients with OAC, PENDULUM mono AF significantly reduced CRB without increasing MACCE compared with PENDULUM AF.Conclusions: A WOEST-like regimen with prasugrel may reduce CRB, without increasing MACCE, in Japanese patients with AF and high bleeding risk undergoing PCI.

Differences in Optimal Platelet Reactivity after Potent P2Y12 Inhibitor Treatment in Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention.

Background: East Asian patients receiving treatment with the potent P2Y12 inhibitors prasugrel or ticagrelor experience more potent platelet inhibition than with clopidogrel. Methods: This study investigated differences in OPR rates with reduced doses of prasugrel (n = 38) or ticagrelor (n = 40) for maintenance therapy in 118 Korean ACS patients who had undergone PCI, in comparison to conventional-dose clopidogrel (n = 40). We assessed drug responses at one- and three-months post-PCI with VerifyNow and multiple electrode aggregometry assays. Results: At the one-month period, patients receiving standard-dose prasugrel or ticagrelor had lower platelet reactivity as determined by the three assays than those receiving the conventional dose of clopidogrel (VN: p = 0.000; MEA: p = 0.000; LTA: p = 0.000). At the 3-month point, platelet reactivity was lower in those receiving reduced-dose prasugrel or ticagrelor than the clopidogrel-treated patients (VN: p = 0.000; MEA: p = 0.012; LTA: p = 0.002). Prasugrel resulted in significantly lower platelet inhibition than ticagrelor as determined by VN and LTA (VN: p = 0.000; LTA: p = 0.003). At three months, there was a significant overall difference in OPR among the three groups when measured by VN (p < 0.001), but not when measured by MEA (p = 0.596). OPR in the reduced-dose prasugrel group was not significantly different to the clopidogrel group at three months (VN: p = 0.180; MEA: p = 0.711). OPR in the reduced-dose ticagrelor group was similar to clopidogrel as determined by MEA at three months, but was different when assessed by VN (VN: p = 0.000; MEA: p = 0.540). Compared to standard-dose, the reduced-dose prasugrel OPR rate was significantly increased (VN: p = 0.008; MEA: p = 0.020). Conclusions: OPR values for reduced-dose prasugrel and conventional-dose clopidogrel at three months were similar but higher than for reduced-dose ticagrelor as determined by VN, but no differences were noted by MEA. The MEA assay might have less sensitivity and consistency than the VN assay. Further studies are needed to explore this discrepancy.

A Japanese Dose of Prasugrel versus a Standard Dose of Clopidogrel in Patients with Acute Myocardial Infarction from the K-ACTIVE Registry.

Background: Dual antiplatelet therapy (DAPT) with aspirin plus P2Y12 inhibitor is used as a standard therapy for patients with acute myocardial infarction (AMI) treated with drug-eluting stents (DESs). In Japan, clopidogrel was the major P2Y12 inhibitor used for a decade until the new P2Y12 inhibitor, prasugrel, was introduced. Based on clinical studies considering Japanese features, the set dose for prasugrel was reduced to 20 mg as a loading dose (LD) and 3.75 mg as a maintenance dose (MD); these values are 60 and 10 mg, respectively, globally. Despite this dose discrepancy, little real-world clinical data regarding its efficacy and safety exist. Methods: From the K-ACTIVE registry, based on the DAPT regimen, patients were divided into a prasugrel group and a clopidogrel group. The ischemic event was a composite of cardiovascular death, non-fatal MI, and non-fatal stroke. The bleeding event was type 3 or 5 bleeding based on the Bleeding Academic Research Consortium (BARC) criteria. Results: Substantially more patients were prescribed prasugrel (n = 2786) than clopidogrel (n = 890). Clopidogrel tended to be selected over prasugrel in older patients with numerous comorbidities. Before adjustments were made, the cumulative incidence of ischemic events at 1 year was significantly greater in the clopidogrel group than in the prasugrel group (p = 0.007), while the cumulative incidence of bleeding events at 1 year was comparable between the groups (p = 0.131). After adjustments were made for the age, sex, body weight, creatine level, type of AMI, history of MI, approach site, oral anticoagulation therapy, presence of multivessel disease, Killip classification, and presence of intra-aortic balloon pumping, both ischemic and bleeding events became comparable between the groups. Conclusion: A Japanese dose of prasugrel was commonly used in AMI patients in the real-world database. Both the prasugrel and clopidogrel groups showed comparable rates of 1 year ischemic and bleeding events.

Prasugrel Dose De-escalation Therapy After Complex Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome

De-escalation of dual-antiplatelet therapy through dose reduction of prasugrel improved net adverse clinical events after acute coronary syndrome (ACS), mainly through the reduction of bleeding without an increase in ischemic outcomes. However, whether such benefits are similarly observed in those receiving complex procedures is unknown. To investigate whether the benefits of prasugrel dose de-escalation therapy are maintained in the complex percutaneous coronary intervention (PCI) subgroup. This was a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS trial, a randomized, open-label, adjudicator-blinded, multicenter trial performed at 35 hospitals in South Korea. Study participants included patients with ACS who were receiving PCI. Data were collected from September 30, 2014, to December 18, 2015, and analyzed from September 17, 2020, to June 15, 2021. Patients were randomized to a prasugrel dose de-escalation (5 mg daily) at 1 month post-PCI group or a conventional (10 mg daily) group. Complex PCI was defined as having at least 1 of the following features: 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI, total stent length 60 mm or larger, left main PCI, or heavy calcification. The main analysis end points were MACE (major adverse cardiac event, a composite of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and repeat revascularization) at 1 year for ischemic outcomes, and BARC (Bleeding Academic Research Consortium) class 2 or higher bleeding events at 1 year for bleeding outcomes. Of 2271 patients (mean [SD] age, 58.9 [9.0] years; 2024 [89%] male patients) for whom full procedural data were available, 705 patients received complex PCI, and 1566 patients received noncomplex PCI. Complex PCI was associated with higher rates of ischemic outcomes but not with bleeding outcomes. Prasugrel dose de-escalation did not increase the risk of MACE (hazard ratio [HR], 0.88; 95% CI, 0.47-1.66; P = .70 in complex PCI; HR, 0.81; 95% CI, 0.45-1.46; P = .48 in noncomplex PCI; P for interaction = .84) but decreased BARC class 2 or higher bleeding events (HR, 0.25; 95% CI, 0.10-0.61; P = .002 in complex PCI; HR, 0.62; 95% CI, 0.38-1.00; P = .05 in noncomplex PCI; P for interaction = .08), albeit with wide 95% CIs. In this post hoc analysis of patients with ACS, prasugrel dose de-escalation compared with conventional therapy was not associated with an increased risk of ischemic outcomes but may reduce the risk of minor bleeding events at 1 year, irrespective of PCI complexity. ClinicalTrials.gov Identifier: NCT02193971.

Prasugrel-based De-Escalation of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With STEMI.

De-escalation of dual-antiplatelet therapy through dose reduction of prasugrel improved net adverse clinical events (NACEs) after acute coronary syndrome (ACS), mainly through the reduction of bleeding without an increase in ischemic outcomes. Whether the benefits of de-escalation are sustained in highly thrombotic conditions such as ST-elevation myocardial infarction (STEMI) is unknown. We aimed to assess the efficacy and safety of de-escalation therapy in patients with STEMI or non-ST-segment elevation ACS (NSTE-ACS). This is a pre-specified subgroup analysis of the HOST-REDUCE-POLYTECH-ACS trial. ACS patients were randomized to prasugrel de-escalation (5 mg daily) or conventional dose (10 mg daily) at 1-month post-percutaneous coronary intervention. The primary endpoint was a NACE, defined as a composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, clinically driven revascularization, stroke, and bleeding events of grade ≥2 Bleeding Academic Research Consortium (BARC) criteria at 1 year. Among 2,338 patients included in the randomization, 326 patients were diagnosed with STEMI. In patients with NSTE-ACS, the risk of the primary endpoint was significantly reduced with de-escalation (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.48-0.89; p=0.006 for de-escalation vs. conventional), mainly driven by a reduced bleeding. However, in those with STEMI, there was no difference in the occurrence of the primary outcome (HR, 1.04; 95% CI, 0.48-2.26; p=0.915; p for interaction=0.271). Prasugrel dose de-escalation reduced the rate of NACE and bleeding, without increasing the rate of ischemic events in NSTE-ACS patients but not in STEMI patients.

Incidence of Device-Related Thrombosisin WatchmanPatients Undergoing a Genotype-Guided Antithrombotic Strategy.

This study sought to report the incidence of device-related thrombosis (DRT) and thromboembolic (TE) events when an alternative to clopidogrel is prescribed in loss-of-function (LOF) allele carriers of the cytochrome P450 2C19 (CYP2C19) gene. LOF polymorphisms of the CYP2C19 gene are associated with reduced hepatic bioactivation of clopidogrel. A total of 1,002 Watchman patients were included. Six hundred forty-five patients underwent CYP2C19 genetic testing; among patients with clopidogrel resistance, clopidogrel was replaced by either prasugrel (pilot cohort) or half dose direct oral anticoagulant ([DOAC]/Group 1), both in combination with aspirin. We compared the incidence of DRT/TE events among genotyped patients and a control group which received standard dual antiplatelet therapy (DAPT) (Group 2; n=357). All reported events occurred during a timeframe between 45- and 180-day follow-up transesophageal echocardiograms, when the 2 different antithrombotic strategies (genotype-guided vs standard DAPT) were adopted. In the pilot cohort (n=244), bleeding events occurred in 10.2% of patients who received aspirin plus prasugrel, leading to early discontinuation of the prasugrel-based protocol. DOAC Group 1 patients (n=401), 25.7% were reduced metabolizers, and clopidogrel was replaced by half dose direct oral anticoagulant. DRT was documented in 1 (0.2%) patient of Group 1 and 7 (1.96%) patients of Group 2 (log-rank P =0.021). The composite endpoint of DRT/TE events was significantly loweramong patients receiving a genotype-guided antithrombotic strategy (0.75% vs 3.10%; log-rank P =0.017). In Watchman patients, a genotype-based antithrombotic strategy with aspirin plus half dose DOAC in reduced clopidogrel metabolizers was superior to standard DAPT with respect to DRT/TE events.

B-PO02-157 INCIDENCE OF DEVICE-RELATED THROMBOSIS IN WATCHMAN PATIENTS UNDERGOING A GENOTYPE-GUIDED ANTITHROMBOTIC STRATEGY

Loss of Function (LOF) polymorphisms of cytochrome P450 2C19 (CYP2C19) are associated with reduced hepatic bioactivation of clopidogrel. To report the incidence of device-related thrombosis (DRT) and thromboembolic (TE) events when an alternative to clopidogrel is prescribed in patients with a LOF allele of CYP2C19 gene. Among 1002 Watchman patients, 645 underwent CYP2C19 genetic testing; among patients with clopidogrel resistance, clopidogrel was replaced by either prasugrel (pilot cohort) or half dose novel oral anticoagulant (NOAC; Group 1) both in combination with aspirin. We compared the incidence of DRT/TE events among genotyped patients and a control group which received standard dual antiplatelet therapy (DAPT; Group 2; n=357). All reported events occurred during a timeframe between 45- and 180-day follow-up TEEs, when the genotype-guided or standard DAPT strategies were adopted. In the pilot cohort (n=244), bleeding events occurred in 10.2% of patients receiving prasugrel, leading to discontinuation of the prasugrel-based protocol. Among Group 1 patients (n=401), 25.7% were reduced metabolizers and clopidogrel was replaced with half dose NOAC. DRT was documented in 1 (0.2%) patient of Group 1 and 7 (1.96%) of Group 2 (log-rank p-value=0.021). The composite endpoint of DRT/TE events was significantly lower among patients receiving a genotype-guided strategy (0.75% vs. 3.1%; log-rank p-value=0.017). In Watchman patients, a genotype-based antithrombotic strategy with aspirin plus half dose NOAC in reduced clopidogrel metabolizers was superior to standard DAPT with respect to DRT/TE events.

Clinical validation of AggreGuide A-100 ADP, a novel assay for assessing the antiplatelet effect of oral P2Y12 antagonists

In this prospective, 3-arm, repeated-measure multicenter investigation in 280 patients with cardiovascular risk factors, platelet aggregation was measured with the novel AggreGuide A-100 ADP (A-100 ADP) and VerifyNow (VN)-PRU assays at baseline, and after United States Food and Drug Administration approved loading and 7days maintenance doses of clopidogrel (n = 94), prasugrel (n = 43) or ticagrelor, (n = 143). Based on the predetermined cutoff values of < 4.7 platelet activity index with A-100 ADP assay to indicate antiplatelet response, more than 91% of patients met the criteria following loading and maintenance doses of prasugrel and more than 84% patients met the criteria following loading and maintenance doses of ticagrelor whereas only 32% and 51% of patients met the criteria following loading and maintenance doses of clopidogrel, respectively. The total percent agreement between the A-100 ADP and VN-PRU assays was 89%. The A-100 ADP assay, which includes whole blood in motion, performs comparably to the VN-PRU assay in a study of patients with cardiovascular risk factors treated with P2Y12 inhibitors possessing known differences in antiplatelet potencies. Trial registration ClinicalTrials.gov Identifier: NCT3111420.