Prasugrel Loading Dose Research Articles

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.

Impact of diabetes mellitus on the pharmacodynamic effects of prasugrel and ticagrelor after switching from clopidogrel in patients with coronary artery disease

Switching P2Y12 inhibitors is common in clinical practice. However, data on the pharmacodynamic (PD) effects of switching in clinical settings characterized by high platelet reactivity, such as diabetes mellitus (DM), are limited. This is a post-hoc analysis from a prospective, randomized, open-label study conducted in coronary artery disease patients comparing the PD effects of loading dose (LD) and maintenance dose regimens of prasugrel vs ticagrelor according to DM status. A total of 110 patients were enrolled: 42 (38%) with DM and 68 (62%) without DM. All patients were on maintenance dual antiplatelet therapy with aspirin and clopidogrel. PD assessments were performed using whole blood vasodilator-stimulated phosphoprotein (VASP), with results quantified by the platelet reactivity index (PRI), VerifyNow P2Y12 (VN-P2Y12) with results reported as P2Y12 reaction units(PRU), and light transmittance aggregometry(LTA) following 20 and 5µM adenosine diphosphate stimuli with results reported as maximum platelet aggregation (MPA). PD assessments were performed at baseline (while on clopidogrel), 30min after LD, 2h after LD, and 1week after LD. Overall, platelet reactivity was higher in DM than in non-DM patients while on clopidogrel therapy. After switching to either prasugrel or ticagrelor, platelet reactivity dropped but remained significantly higher among patients with DM at 30min with all tests (VN-PRU p < 0.01, MPA 20µM p < 0.01, VASP-PRI p = 0.02) and at 2h with VN-PRU (p < 0.01) and LTA-MPA 20µM (p < 0.01) but not with VASP-PRI (p = 0.19). There were no significant differences between prasugrel and ticagrelor both among patients with or without DM, except for lower LTA-MPA 20 at 30min (p < 0.01) among non-DM patients treated with prasugrel. Patients with DM treated with clopidogrel have higher platelet reactivity compared to patients without DM. Although platelet reactivity markedly reduces to a similar extent after switching to prasugrel or ticagrelor, patients with DM persist with increased platelet reactivity compared to patients without DM.Study registration: ClinicalTrials.gov identifier: NCT01852175.

Clinical Efficacy and Safety of Reduced-Dose Prasugrel versus Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis of randomized controlled trials (RCTs) compared the clinical efficacy and safety of reduced-dose prasugrel (loading dose: 20 mg; daily maintenance dose: 3.75 mg) and clopidogrel in patients undergoing percutaneous coronary intervention (PCI). PubMed, Embase, and the Cochrane Library database were searched for relevant articles from inception to March 8, 2021. Only RCTs that compared the clinical efficacy and safety of reduced-dose prasugrel and clopidogrel treatment in adult patients undergoing PCI were included. The primary outcome was the risk of major cardiovascular events (MACEs). Four RCTs involving 2464 patients were included. The overall risk of MACEs was 8.3% (102/1235) in the study group (reduced-dose prasugrel) and 9.8% (121/1229) in the control group (clopidogrel). No significant difference was observed in the risk of MACEs between the study and control groups (risk ratio: 0.84, 95% confidence interval: 0.65-1.08, I 2 = 0%). In addition, cardiovascular-related death, all-cause death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and stent thrombosis did not differ significantly between the two groups. Apart from a higher risk of minor bleeding in the study group, reduced-dose prasugrel had a similar bleeding risk to clopidogrel. The clinical efficacy of reduced-dose prasugrel is comparable to that of clopidogrel; however, the risk of minor bleeding should be considered when prescribing this regimen for patients undergoing PCI.

Dual Antiplatelet Therapy with 3rd Generation P2Y12 Inhibitors in STEMI Patients: Impact of Body Mass Index on Loading Dose-Response.

This study aims to assess the association between body mass index (BMI) and platelet reactivity in STEMI patients treated with oral 3rd generation P2Y12 inhibitors. Overall, 429 STEMI patients were enrolled in this study. Patients were divided into two groups according to BMI (BMI < 25 vs ≥ 25kg/m2). A propensity score matching (1:1) was performed to balance potential confounders in patient baseline characteristics. Platelet reactivity was assessed by VerifyNow at baseline and after 3rd generation P2Y12 inhibitor (ticagrelor or prasugrel) loading dose (LD). Blood samples were obtained at baseline (T0), 1h (T1), 2h (T2), 4-6h (T3), and 8-12h (T4) after the LD. High on-treatment platelet reactivity (HTPR) was defined as a platelet reactivity unit value ≥ 208 units. After propensity score matching, patients with BMI ≥ 25 had similar values of baseline platelet reactivity, while they had higher level of platelet reactivity at 1 and 2h after the LD and higher rate of HRPT. Furthermore, multivariate analysis demonstrated that BMI ≥ 25 was an independent predictor of HTPR at 2h (OR 2.01, p = .009). Conversely, starting from 4h after the LD, platelet reactivity values and HRPT rates were comparable among the two study groups. A BMI ≥ 25kg/m2 is associated with delayed pharmacodynamic response to oral 3rd generation P2Y12 inhibitor LD, and it is a strong predictor of HTPR in STEMI patients treated by dual antiplatelet therapy with ticagrelor or prasugrel.

Predictors of In-Hospital De-Escalation of P2Y12 Inhibitors to Clopidogrel in Patients With Acute Myocardial Infarction Treated With Percutaneous Coronary Intervention

BackgroundTicagrelor or prasugrel are recommended to reduce ischemic events in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). However, in clinical practice, patients are often switched from a potent P2Y12 inhibitor to clopidogrel prior to or at discharge (‘de-escalation’). We sought to assess the incidence and predictors of de-escalation. MethodsConsecutive patients who received either a ticagrelor or prasugrel loading dose for AMI PCI at two tertiary centers between Jan 2015–Mar 2019 who survived to discharge were included. Data were obtained from the electronic health record and institutional NCDR CathPCI data. Patients who were de-escalated to clopidogrel were compared with those who remained on potent P2Y12 inhibitors through the time of discharge. ResultsOf the1818 patients in the cohort, 1146 (63%) were de-escalated. Patients in the de-escalation group were older, more often Black, had lower prevalence of co-morbidities, less often had private insurance, and had less complex PCI. After adjustment, older age remained positively associated (OR 1.2, CI 1.08–1.34, p = .001) and Caucasian race (OR 0.5, CI 0.33–0.77, p = .002), prior MI (OR 0.7, CI 0.5–0.97, p = .032), bifurcation lesion (OR 0.71, CI 0.53–0.95, p = .019), and greater number of stents (OR 0.82, CI 0.75–0.91, p = .0001) were negatively associated with de-escalation. In de-escalated patients, the rationale was not documented in 75.9% of cases. ConclusionsDe-escalation occurred frequently in patients with AMI and was associated with both non-clinical and clinical factors. Medical decision making was poorly documented and represent an area for improvement.

211 Impact of smoking habits on baseline and on-treatment platelet reactivity in STEMI patients treated with third generation P2Y12

Abstract Aims Smoking habit is a well-known risk factor for cardiovascular disease. High on-treatment platelet reactivity has been associated with high risk of ischaemic events in STEMI patients. The relationship between platelet reactivity and smoking habit was investigated only in few studies, and the impact of smoke on platelet reactivity in STEMI patients treated with 3rd generation P2Y12 inhibitor is still lacking. This study aim to assess the impact of smoking habits on baseline and on-treatment platelet reactivity in STEMI patients treated with 3rd generation P2Y12 inhibitor. Methods Overall, 429 STEMI patients were enrolled in this study. Patients were divided into two groups according to smoking habit. Platelet reactivity was assessed by VerifyNow at baseline and after 3rd generation P2Y12 inhibitor (ticagrelor or prasugrel) loading dose (LD). Blood samples were obtained at baseline (T0), and after 1 h (T1), 2 h (T2), 4w6 h (T3) and 8–12 h (T4) after LD. Results The mean age of the enrolled population was 62 ± 12 and male rate was 75%. Patients with smoking habit were younger (75.8% vs. 38.9%, P &amp;lt; 0.001 for age &amp;lt;65 years), with higher prevalence of family history of CAD, while with a lower rate hypertension (43.4% vs. 65.9%, P &amp;lt; 0.001) and previous myocardial infarction (5.3% vs. 11.4%, P = 0.022). Smoker patients had lower platelet reactivity either at baseline [T0: 249 (205–285) vs. 284 (230–324), P &amp;lt; 0.001] or at 2 h after the LD [T2: 107 (18–279) vs. 136 (51–260), P = 0.003]. Similarly, Smoker patients experienced a lower rate of in-hospital composite adverse event of death, Re-infarction, stroke or acute kidney injury (1.6% vs. 12.4%; P≤0.001). Multivariate analysis demonstrated that left ventricular ejection fraction at admission (OR = 0.916, 95% CI 0.865–0.969; P = 0.002), and platelet reactivity at baseline (OR = 1.013, 95% CI 1.002–1.024; P = 0.024) were independent predictors of in-hospital composite adverse event. Conclusions Smoker status is associated with lower platelet reactivity either at baseline or after LD and with a better short-term prognosis in STEMI patients treated by dual antiplatelet therapy with ticagrelor or prasugrel.

205 Dual antiplatelet therapy with third generation P2Y12 inhibitors in STEMI patients: impact of body mass index on high on-treatment platelet reactivity

Abstract Aims High on-treatment platelet reactivity (HTPR) has been associated with high risk of ischaemic events in STEMI patients. Body mass index (BMI) and specifically overweight and obesity are risk factors for increased platelet reactivity in different series of patients; however, data regarding their relationship with pharmacodynamic response to oral 3rd generation P2Y12 inhibitors is still lacking. This study aims to assess the association between BMI and HTPR in STEMI patients treated with oral 3rd generation P2Y12 inhibitors. Methods Overall, 429 STEMI patients were enrolled in this study. Patients were divided into two groups according to BMI (BMI &amp;lt;25 vs. ≥25 kg/m2). A propensity score matching (1:1) was performed to balance potential confounders in baseline patients characteristics. Platelet reactivity was assessed by VerifyNow at baseline and after 3rd generation P2Y12 inhibitor (ticagrelor or prasugrel) loading dose (LD). Blood samples were obtained at baseline (T0), 1 h (T1), 2 h (T2), 4–6 h (T3) and 8–12 h (T4) after the LD. HTPR was defined as a platelet reactivity unit values ≥ 208 units. Results Mean age was 62 ± 12 years, and males were 75%. Patients with a BMI ≥25 were younger (61 ± 12 vs. 64 ± 11, P= 0.006), with a higher prevalence of male gender (78% vs. 68%, P = 0.035), and they were less frequently treated with morphine before PCI (30% vs. 42%; P=0.018). After propensity score matching, patients with BMI ≥25 had similar values of baseline platelet reactivity [T0: 308 (285–342) vs. 300 (281–330), P= 0.396], while they had higher level of platelet reactivity at 1 and 2 h after the LD [T1: 285 (200–308) vs. 265 (196–320), P= 0.047; T2: 241 (87–305) vs. 200 (56–256), P= 0.004] and higher rate of HRPT [T1: (66% vs. 47%, P= 0.004); T2: (40% vs. 24%, P= 0.006)]. Furthermore, multivariable analysis demonstrated that BMI ≥25 was an independent predictor of HTPR at 2 h (OR 2.01, 95% CI 1.18–3.42; P=0.009). Conversely, starting from 4 h after the LD, platelet reactivity values [T3: 68 (7–173) vs. 15 (6–71), P = 0.76; T4: 38 (4–104) vs. 44 (4–82), P=0.958] and HRPT rates (T3: 13% vs. 10%, P = 0.595; T4: 1% vs. 1%, P= 0.320) were comparable among the two study groups. Conclusions A BMI ≥25 kg/m2 is associated with decelerated pharmacodynamic response to oral 3rd generation P2Y12 inhibitors LD, and it is a strong predictor of HRPT in STEMI patients treated by dual antiplatelet therapy with ticagrelor or prasugrel.

Not-high before-treatment platelet reactivity in patients with STEMI:prevalence, clinical characteristics, response to therapy and outcomes

Abstract Background Platelet reactivity (PR) has been indicated as a pathophysiological key element for ST-Elevation Myocardial Infarction (STEMI) development. In STEMI patients, PR following pharmacological treatment has been extensively studied with focus on patients with on-treatment high platelet reactivity (HPR). Patients with before-treatment not-high platelet reactivity (NHPR) have been poorly studied so far. Purpose Aim of the study is to investigate the prevalence, clinical characteristics, response to therapy and outcomes of baseline prior to treatment NHPR among patients with STEMI undergoing primary PCI. Methods We analysed the data from 358 STEMI patients with assessment of PR by VerifyNowbefore P2Y12 inhibitor loading dose (LD). All patients received a P2Y12 inhibitor (ticagrelor or prasugrel) LDafter baseline PR assessment. Blood samples were obtained at baseline (T0), and after 1 hour (T1), 2 hours (T2), 4–6 hours (T3) and 8–12 hours (T4) after LD. HPR was defined as Platelet Reactivity Unit values ≥208, while patients with values &amp;lt;208 at baseline were defined as having NHPR. Results Overall, 20% patients had NHPR. Patients with before-treatment NHPR values were more frequently young, of male gender and more frequently smokers (p=0.005), overweight or obese (p=0.009), affected by dyslipidemia (p=0.03) and with a family history of coronary artery disease (p=0.04). Age and male gender resulted both independent predictors of NHPR, even after propensity score adjustment. The percentage of inhibition of PR after ticagrelor or prasugrel LD was similar between HPR and NHPR patients at each time point (figure 1) and residual PR was constantly lower in patients with before-treatment PRU &amp;lt;208 from baseline to 8–12 hours from LD (figure 2). However, patients with HPR showed worse in-hospital clinical outcomes, and the composite adverse outcome endpoint of death, reinfarction, stroke, acute kidney injury or heart failure was significantly higher (10.0% vs 1.4%; p=0.017) as compared with the NHPR group. Conclusions A significant proportion of patients presenting with STEMI has a baseline NHPR; they are predominantly young males with a high-risk cardiovascular profile. NHPR is associated with better in-hospital outcomes as compare with patients with HPR. Further studies are needed to better understand the underlying pathophysiology in order to find out potential personalized treatments in this setting. Funding Acknowledgement Type of funding sources: None.

Dual antiplatelet therapy with 3rd generation P2Y12 inhibitors in STEMI patients: impact of Body Mass Index on high on-treatment platelet reactivity

Abstract Background High on-treatment platelet reactivity (HTPR) has been associated with high risk of ischemic events in STEMI patients. Body mass index (BMI) and specifically overweight and obesity are risk factors for increased platelet reactivity in different series of patients, however data regarding their relationship with pharmacodynamic response to oral 3rd generation P2Y12 inhibitors is still lacking. Purpose This study aims to assess the association between BMI and HTPR in STEMI patients treated with oral 3rd generation P2Y12 inhibitors. Methods Overall, 429 STEMI were enrolled in this study. Patients were divided into two groups according to BMI (BMI &amp;lt;25; BMI ≥25). A propensity score matching (1:1) was performed to balance potential confounders in baseline study characteristics. Platelet reactivity was assessed by VerifyNow at baseline and after 3rd generation P2Y12 inhibitor (ticagrelor or prasugrel) loading dose (LD). Blood samples were obtained at baseline (T0), 1 hour (T1), 2 hours (T2), 4–6 hours (T3) and 8–12 hours (T4) after the LD. HTPR was defined with a platelet reactivity unit values ≥208 units. Results The mean age of the enrolled population was 62±12 and male rate was 75%. Patients with a BMI ≥25 were younger (61±12 Vs 64±11, p=0.006), with a higher prevalence of male gender (78% vs 68%, p=0.035), and hypertension (56% vs 46%, p=0.072), and they were less frequently treated with pre-PCI mophine use (30% Vs 42%; p=0.018). After propensity score matching (Table), patients with BMI ≥25 had similar values of baseline platelet reactivity [T0: 308 (285–342) vs 300 (281–330), p=0.396), while they had higher level of platelet reactivity at 1 and 2 hours after the LD [T1: 285 (200–308) vs 265 (196–320), p=0.047); T2: 241 (87–305) vs 200 (56–256), p=0.004)] and higher rate of HRPT [T1: (66% vs 47%, p=0.004); T2: (40% vs 24%, p=0.006)]. Furthermore, multivariable analysis demonstrated that BMI ≥25 was an independent predictor of HTPR at 2h (OR 2.01, 95% CI 1.18–3.42; p=0.009). Conversely, starting from 4 hour after the LD, platelet reactivity values [T3: 68 (7–173) vs 15 (6–71), p=0.76); T4: 38 (4–104) vs 44 (4–82), p=0.958)] and HRPT rates (T3: 13% vs 10%, p=0.595; T4: 1% vs 1%, p=0.320) were comparable among the study groups. Conclusions A BMI ≥25 is associated with decelerated pharmacodynamic response to oral 3rd generation P2Y12 inhibitors LD and resulted a strong predictor of HRPT in STEMI patients treated by dual antiplatelet therapy with ticagrelor or prasugrel. Funding Acknowledgement Type of funding sources: None. Table, panel ATable, panel B

Impact of smoking habit on baseline and on-treatment platelet reactivity in STEMI patients treated with 3rd generation P2Y12

Abstract Background Smoking habit is a well known risk factor for cardiovascular disease. High on-treatment platelet reactivity has been associated with high risk of ischemic events in STEMI patients. The relationship between platelet reactivity and smoking habit was investigated only in few studies, and the impact of smoke on platelet reactivity in STEMI patients treated with 3rd generation P2Y12 inhibitor is still lacking. Purpose This study aim to assess the impact of smoking habits on baseline and on-treatment platelet reactivity in STEMI patients treated with 3rd generation P2Y12 inhibitor. Methods Overall, 429 STEMI patients were enrolled in this study. Patients were divided into two groups according to smoking habit. Platelet reactivity was assessed by VerifyNow at baseline and after 3rd generation P2Y12 inhibitor (ticagrelor or prasugrel) loading dose (LD). Blood samples were obtained at baseline (T0), and after 1 hour (T1), 2 hours (T2), 4–6 hours (T3) and 8–12 hours (T4) after LD. Results The mean age of the enrolled population was 62±12 and male rate was 75%. Patients with smoking habit were younger (75.8% vs 38.9%, p&amp;lt;0.001 for age &amp;lt;65 years), with higher prevalence of family history of CAD, while with a lower rate hypertension (43.4% vs 65.9%, p&amp;lt;0.001) and previous myocardial infarction (5.3% vs 11.4%, p=0.022) (Table). Smoker patients had lower platelet reactivity either at baseline [T0: 249 (205–285) vs 284 (230–324), p&amp;lt;0.001] or at 2 hours after the LD [T2: 107 (18–279) vs 136 (51–260), p=0.003] (Table). Similarly, Smoker patients experienced a lower rate of in-hospital composite adverse event of death, reinfarction, stroke or acute kidney injury (1.6% vs 12.4%; p≤0.001) (Table). Multivariate analysis demonstrated that left ventricular ejection fraction at admission (OR= 0.916, 95% CI 0.865–0.969; p=0.002), and platelet reactivity at baseline (OR= 1.013, 95% CI 1.002–1.024; p=0.024) were independent predictors of in-hospital composite adverse event. Conclusions Smoker status is associated with lower platelet reactivity either at baseline or after LD and with a better short-term prognosis in STEMI patients treated by dual antiplatelet therapy with ticagrelor or prasugrel. Funding Acknowledgement Type of funding sources: None.

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.

Pharmacokinetic/pharmacodynamic modeling of drug interactions at the P2Y12 receptor between selatogrel and oral P2Y12 antagonists.

Selatogrel is a potent and reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients with suspected acute myocardial infarction. After single‐dose emergency treatment with selatogrel, patients are switched to long‐term treatment with oral P2Y12 receptor antagonists. Selatogrel shows rapid onset and offset of inhibition of platelet aggregation (IPA) to overcome the critical initial time after acute myocardial infarction. Long‐term benefit is provided by oral P2Y12 receptor antagonists such as clopidogrel, prasugrel, and ticagrelor. A population pharmacokinetic (PK)/pharmacodynamic (PD) model based on data from 545 subjects in 4 phase I and 2 phase II studies well described the effect of selatogrel on IPA alone and in combination with clopidogrel, prasugrel, and ticagrelor. The PK of selatogrel were described by a three‐compartment model. The PD model included a receptor‐pool compartment to which all drugs can bind concurrently, reversibly or irreversibly, depending on their mode of action. Furthermore, ticagrelor and its active metabolite can bind to the selatogrel‐receptor complex allosterically, releasing selatogrel from the binding site. The model provided a framework for predicting the effect on IPA of selatogrel followed by reversibly and irreversibly binding oral P2Y12 receptor antagonists for sustained effects. Determining the timepoint for switching from emergency to maintenance treatment is critical to achieve sufficient IPA at all times. Simulations based on the interaction model showed that loading doses of clopidogrel and prasugrel administered 15 h and 4.5 h after selatogrel, respectively, provide sustained IPA with clinically negligible drug interaction. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Selatogrel is a potent reversible P2Y12 receptor antagonist developed for subcutaneous self‐administration by patients in case of suspected acute myocardial infarction. Transition to oral P2Y12 receptor antagonists without drug interaction and sufficient inhibition of platelet aggregation must be assured at all times. WHAT QUESTION DID THIS STUDY ADDRESS? The pharmacokinetic/pharmacodynamic model semimechanistically describes the effect of selatogrel on platelet inhibition alone and in combination with the oral P2Y12 receptor antagonists clopidogrel, prasugrel, and ticagrelor. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Model‐based simulations showed that loading doses of clopidogrel and prasugrel can be administered from 15 h and 4.5 h after selatogrel, respectively. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? These results support guiding the clinical transition from selatogrel emergency treatment to oral maintenance therapy in a safe and efficacious way.

Not-high before-treatment platelet reactivity in patients with STEMI: prevalence, clinical characteristics, response to therapy and outcomes

Platelet reactivity (PR) has been indicated as a pathophysiological key element for ST-Elevation Myocardial Infarction (STEMI) development. Patients with not-high before-treatment platelet reactivity (NHPR) have been poorly studied so far. The aim of this study is to investigate the prevalence, clinical characteristics, response to therapy and outcomes of baseline prior to treatment NHPR among patients with STEMI undergoing primary PCI. We analyzed the data from 358 STEMI patients with assessment of PR by VerifyNow before P2Y12 inhibitor loading dose (LD). Blood samples were obtained at baseline, and after 1 hour, 2 hours, 4–6 hours and 8–12 hours after LD. High platelet reactivity (HPR) was defined as Platelet Reactivity Unit values ≥208, while patients with values <208 at baseline were defined as having NHPR. Overall, 20% patients had NHPR. Age and male gender both resulted independent predictors of NHPR, even after propensity score adjustment. The percentage of inhibition of PR after ticagrelor or prasugrel LD was similar between HPR and NHPR patients at each time point. However, patients with HPR showed worse in-hospital clinical outcomes, and the composite adverse outcome endpoint of death, reinfarction, stroke, acute kidney injury or heart failure was significantly higher (10.0% vs 1.4%; p = .017) as compared with the NHPR group. In conclusion, a significant proportion of patients presenting with STEMI has a baseline NHPR that is associated with better in-hospital outcomes as compared with patients with HPR. Further studies are needed to better elucidate the potential therapeutic implications of NHPR in terms of secondary prevention.

Use of the VerifyNow point of care assay to assess the pharmacodynamic effects of loading and maintenance dose regimens of prasugrel and ticagrelor

Prasugrel and ticagrelor are potent oral platelet P2Y12 inhibitors and are recommended over clopidogrel in patients with acute coronary syndrome (ACS). Oral platelet P2Y12 inhibitors are characterized by varying degrees of pharmacodynamic response profiles as assessed by a variety of commercially available assays. Because of its ease of use, rapid turnaround times and ability to provide results specific to P2Y12 inhibitory effects, VerifyNow has emerged as one of the most commonly utilized platelet function assays. However, reference ranges with VerifyNow have been reported mainly for clopidogrel and there has not yet been any study specifically conducted to provide the expected on treatment reference ranges following administration of prasugrel and ticagrelor. This was a prospective single center investigation conducted in 120 patients with ACS who were treated with prasugrel or ticagrelor as per standard of care. Patients who underwent percutaneous coronary interventions (PCI) were treated with a loading dose of prasugrel (60 mg) or ticagrelor (180 mg), and patients who were on maintenance therapy were taking prasugrel (10 mg qd or 5 mg qd) or ticagrelor (90 mg bid). Platelet function testing was performed using the VerifyNow™ PRUTest™. The overall range of PRUTest values was lower than that observed in studies of patients treated with clopidogrel. The use of a maintenance dose regimen had a wider range of PRUTest values compared to the use of a loading dose for both prasugrel (1–179 vs. 2–128) and ticagrelor (1–196 vs. 1–177). The average PRUTest values in patients on prasugrel and ticagrelor maintenance dosing were 20% and 9% higher those observed in patients treated with a loading dose. PRUTest results following loading dose administration were very similar between drugs, but were 20% higher with prasugrel compared with ticagrelor during maintenance dosing. This study establishes expected PRUTest ranges for patients taking loading and maintenance doses of prasugrel and ticagrelor.Clinical Trial Registrationhttp://www.clinicaltrials.gov Unique Identifier: NCT04492423, registered July 2020 retrospectively registered.

ADP-induced platelet aggregation in patients with acute coronary syndrome treated with prasugrel or ticagrelor. Results of the ISAR REACT 5 platelet aggregation substudy

Abstract Introduction The recently published randomized multicenter open label ISAR REACT 5 trial showed that prasugrel was superior to ticagrelor with respect to the composite primary end point of death, myocardial infarction, or stroke at one year after randomization in patients with acute coronary syndrome with planned invasive evaluation. The reasons for this finding are speculative. Purpose The aim of this prespecified platelet aggregation substudy was to assess platelet aggregation induced by adenosine-diphosphate (ADP) in patients who received prasugrel or ticagrelor treatment and underwent PCI. Methods We assessed all patients who underwent PCI and who had valid ADP-induced platelet aggregation values at hospital admission and at 2–24 hours after administration of prasugrel or ticagrelor loading dose followed by maintenance dose. ADP-induced platelet aggregation values were measured using the Mulitplate Analyzer®. Patients were recruited in the German Heart Center, Munich, Germany or in Klinikum rechts der Isar, Munich, Germany, Technical University of Munich. Results A total of 608 patients were analyzed. Patients in the prasugrel group were slightly but significantly older than patients in the ticagrelor group (66,5 years versus 64,6 years, P=0,048). The remaining baseline characteristics did not significantly differ between the two treatment groups. ADP-induced platelet aggregation (median [IQR]) at baseline did not differ between prasgurel- and ticagrelor treated patients (809 [556; 1057] AU x min versus 797 [534–1095] AU x min. At 2–24 hours after study drug administration ADP-induced platelet aggregation was significantly lower in patients who had received prasugrel in comparison to ticagrelor (105 [57–176] AU x min versus 138 [77–207] AU x min (Figure 1). Conclusion ADP-induced platelet aggregation was significantly lower in patients who received prasugrel in comparison to patients who received ticagrelor, which could have influenced patients' outcome in the ISAR-REACT 5 trial. Figure 1 Funding Acknowledgement Type of funding source: None

Ischemic and Bleeding Events Among Patients With Acute Coronary Syndrome Associated With Low-Dose Prasugrel vs Standard-Dose Clopidogrel Treatment

Prasugrel was approved at a lower dose in 2014 in Japan than in the West because East Asian patients are considered more susceptible to bleeding than Western patients. However, real-world outcomes with low-dose prasugrel treatment remain unclear. To investigate the association of low-dose prasugrel vs standard-dose clopidogrel administration with short-term outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). This study used data from the Japan Cardiovascular Database-Keio Interhospital Cardiovascular Studies registry, a large, ongoing, multicenter, retrospective cohort of consecutive patients who underwent PCI. The present cohort study evaluated 2770 patients with acute coronary syndrome who underwent PCI and received either low-dose prasugrel (loading dose, 20 mg; maintenance dose, 3.75 mg) or clopidogrel (loading dose, 300 mg; maintenance dose, 75 mg) in combination with aspirin between 2014 and 2018. Propensity score-matching analysis was conducted to balance the baseline characteristics of patients receiving low-dose prasugrel and those receiving clopidogrel. Data analysis was conducted in June 2019. Prescription of either low-dose prasugrel or standard-dose clopidogrel prior to PCI. Primary ischemic events (in-hospital death, recurrent myocardial infarction, and ischemic stroke) and primary bleeding events, defined as bleeding complications within 72 hours after PCI consistent with the National Cardiovascular Data Registry CathPCI Registry definition. Of 2559 patients included in the study, the mean (SD) age was 67.8 (12.7) years, and 78.2% were male. In total, 1297 patients (50.7%) received low-dose prasugrel, and 1262 patients (49.3%) received clopidogrel. After propensity score matching, primary ischemic events among patients receiving low-dose prasugrel and those receiving clopidogrel were comparable (odds ratio [OR], 1.42; 95% CI, 0.90-2.23), but primary bleeding events were significantly higher among patients receiving prasugrel (OR, 2.91; 95% CI, 1.63-5.18). This increase in bleeding events was associated with the presence of a profile of high-bleeding risk (≥75 years of age, body weight <60 kg, or history of stroke or transient ischemic attack) (OR, 4.08; 95% CI, 1.86-8.97), being female (OR, 3.84; 95% CI, 1.05-14.0), or the presence of ST-segment elevation myocardial infarction (OR, 2.07; 95% CI, 1.05-4.09) or chronic kidney disease (OR, 4.78; 95% CI, 1.95-11.7). Since its approval, low-dose prasugrel has been used by nearly 80% of patients who undergo PCI. Despite the modified dose, bleeding events were higher among patients receiving low-dose prasugrel than among patients receiving clopidogrel, with no difference in ischemic events between the 2 groups. These results suggest the importance of a risk assessment of bleeding prior to selecting a P2Y12 inhibitor, even for the use of a lower approved dose, when treating patients of East Asian descent.

COMPARison of pre-hospital CRUSHed vs. uncrushed Prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary interventions: Rationale and design of the COMPARE CRUSH trial

Dual antiplatelet therapy constitutes the cornerstone of medical treatment in patients with ST elevation myocardial infarction (STEMI). However, oral antiplatelet agents, such as prasugrel or ticagrelor, are characterized by slow gastrointestinal drug absorption in the acute phase of STEMI, leading to decreased bioavailability and therefore delayed onset of platelet inhibition. Evidence suggests that administration of crushed tablets of the P2Y12 inhibitor prasugrel improves drug absorption and achieves earlier antiplatelet effects in STEMI patients undergoing primary percutaneous coronary intervention (PCI). However, the clinical implications of these pharmacokinetic and pharmacodynamic findings are unknown. The present study is designed to test the hypothesis that patients presenting with STEMI planned for primary PCI will have improved markers of optimal reperfusion and clinical outcomes by prehospital administration of crushed tablets of prasugrel loading dose. COMPARE CRUSH (NCT03296540) is a randomized trial in a regionally organized ambulance care setting evaluating the efficacy and safety of pre-hospital loading dose with prasugrel crushed tablets versus integral tablets in approximately 674 patients presenting with STEMI planned for primary PCI. The independent primary endpoints are percentage of patients reaching thrombolysis in myocardial infarction (TIMI) flow grade 3 in the infarct-related artery at initial angiography, or achieving ≥70% ST-segment elevation resolution at 1 hour post-PCI. Secondary clinical endpoints are death, myocardial infarction, revascularization, and stent thrombosis followed up to 1 year. Moreover, the primary safety endpoint is bleeding events assessed at 48 hours. The COMPARE CRUSH trial will assess whether prehospital administration of loading dose prasugrel in form of crushed tablets - which is expected to provide faster platelet inhibition compared to standard treatment with integral tablets - results in improved reperfusion and clinical outcomes. RCT# NCT03296540.

Comparison between prasugrel and clopidogrel used as antiplatelet medication for endovascular treatment of unruptured intracranial aneurysms. A meta-analysis

Background Clopidogrel is routinely used to decrease ischemic complications during neurointerventional procedures. However, the efficacy may be limited by the antiplatelet resistance. Purpose To analyze the efficacy of prasugrel (PS) compared to clopidogrel (CP) in the cerebrovascular field. Data sources A systematic search of two large databases was performed for studies published from 2000 to 2018. Study selection According to PRISMA guidelines, we included studies reporting treatment-related outcomes of patients undergoing neurointerventional procedures under PS, and studies comparing PS and CP. Data analysis Random-effects meta-analysis was used to pool the following: overall rate of complications, ischemic and hemorrhagic events, influence of the dose of PS. Data synthesis Including 7 studies, 682 and 672 unruptured intracranial aneurysms were treated under PS (cases) and CP (controls), respectively. Low-dose (20 mg/5 mg) (loading and maintenance doses) of PS compared with the standard dose of CP (300 mg/75 mg) showed a significant reduction of the complication rate (OR = 0.36, 95% CI = 0.17–74, P = 0.006, I2 = 0%). Overall, ischemic complication rate was significantly higher among the CP group (40/672 = 6%, 95% CI = 3%–13%, I2 = 83% vs 16/682 = 2%, 95% CI = 1%–5%, I2 = 73%, P = 0.03). Low and high loading doses of PS were associated with 0.6% (5/535, 95% CI = 0.1%–1.6%, I2 = 0%) and 9.3% (13/147, 95% CI = 0.2%–18%, I2 = 60%) of intra-periprocedural hemorrhages, respectively (P = 0.001), whereas low and high maintenance doses of PS were associated with 0% (0/433) and 0.9% (2/249, 95% CI = 0.3%–2%, I2 = 0%) of delayed hemorrhagic events, respectively (P = 0.001). Limitations Retrospective series and heterogeneous endovascular treatments. Conclusions In our study, low-dose of prasugrel, compared with clopidogrel premedication, is associated with an effective reduction of the ischemic events with an acceptable rate of hemorrhagic complications.

Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over PrasugreL: a MUlticenter Randomized Open-label Trial in PatientS with ST-elevation Myocardial InFarction Referred for PrimAry PercutaneouS InTERvention (FABOLUS FASTER) Trial: Design and Rationale : The FABOLUS FASTER Trial.

Antithrombotic therapy is a critical component of the management of ST-elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PCI). Rapid and profound inhibition of platelet reactivity has been shown to mitigate the ischemic risks and improve myocardial salvage. High residual platelet reactivity (HRPR) has been reported up to 4 or 6h after loading dose of prasugrel or ticagrelor; therefore, multiple alternative strategies, including crushed or chewed oral tables or intravenous agents, have been investigated to provide a more rapid and sustained inhibition of platelet function and bridge the initial treatment gap. The FABOLUS FASTER is the first investigator-initiated, multicentre, open-label, prospective, randomized study to directly compare the pharmacodynamics effects of cangrelor, tirofiban, chewed or integer prasugrel. This study will add new insights in the management of antiplatelet therapy in patients with STEMI undergoing primary PCI and might be hypothesis-generating for future clinical trials in this field. The trial is registered on clinicaltrials.gov NCT02978040, and EudraCT 2017-001065-24.