Prasugrel Loading Research Articles

Safety of dual antiplatelet therapy using aspirin and low-dose Prasugrel with platelet reactivity testing in flow diverter treatment of intracranial aneurysms.

Dual antiplatelet therapy (DAPT) is standard care for intracranial stenting to prevent thrombotic complications. Clopidogrel resistance has resulted in patients receiving newer P2Y12 inhibitors like Prasugrel, which may reduce thrombotic complications but could increase haemorrhagic complications. This study, utilising platelet reactivity testing, compared thrombotic and haemorrhagic complications associated with Clopidogrel or 20 mg Prasugrel loading in patients treated with flow diverters (FD) for intracranial aneurysms. We retrospectively analysed prospectively collected data from 225 consecutive FD procedures. All patients received aspirin. 147 cases received Clopidogrel and 82 received Prasugrel. All patients had VerifyNow testing before the procedure. P2Y12 non-responders were significantly more likely to have thrombotic complications than responders and hyper-responders (7% vs. 2%, p = 0.01). Low-dose Prasugrel resulted in a significantly lower rate of non-responders when compared with Clopidogrel (7% vs. 25%, p < 0.01). We found no statistically significant difference in rates of haemorrhage between the Clopidogrel and Prasugrel groups (2.4% vs. 3.9%, p = 0.47). There were 12 complications (≤7 days) in the Clopidogrel group versus 6 in the Prasugrel group (9% vs. 7.8%, respectively, p = 0.91) and a non-significant reduction in thrombotic complications in the Prasugrel group (5.2% vs. 3.9%, p = 0.88). No significant difference was shown in long-term complications between the groups (p = 0.33). These results support the use of platelet reactivity testing and the safety of low-dose Prasugrel for FD treatment of intracranial aneurysms.

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.

Thrombus architecture is influenced by the antiplatelet loading treatment in patients with acute myocardial infarction

BackgroundIntracoronary thrombus formation is a main cause of acute myocardial infarction triggered by platelet activation. However, there are no data on the impact of different treatment strategies with antiplatelet agents before percutaneous coronary intervention (PCI) on histological characteristics of thrombus formation. ObjectiveIn this study, we investigate the impact of preinterventional administration of the P2Y12-inhibitors clopidogrel and prasugrel on thrombus composition, highlighting significant changes associated with the antiplatelet pre-treatment. MethodsWe prospectively enrolled 104 consecutive patients with ST-segment elevation myocardial infarction (STEMI) undergoing immediate PCI and thrombus aspiration by immunohistochemical staining along with RNA-sequencing employing Nanostring analysis. Fifty-two patients were treated with either prasugrel loading (60 mg) or clopidogrel loading (600 mg) prior to PCI, respectively. ResultsIn Patients with STEMI, intracoronary thrombus architecture was significantly altered between patients pre-treated with prasugrel when compared to clopidogrel. Fibrin content of thrombi was significantly decreased (41.8 % versus 66.7 %, p = 0.009) after pre-treatment with prasugrel compared to clopidogrel. Furthermore, levels of MPO positive cells in intracoronary thrombi were significantly decreased in patients with prasugrel pre-treatment (90.5 versus 201.1, p = 0.014) indicating an association of antiplatelet pre-treatment and the inflammatory responses during thrombus formation. Most strikingly, we observed significant differences among both pre-treatment groups regarding altered RNA expression and signaling pathways of thrombo-inflammatory processes within the thrombotic material, which were independently associated with antiplatelet strategies. ConclusionsOur study elucidates the impact of antiplatelet pre-treatment on thrombus remodeling and architecture, thereby lowering the risk of recurrent adverse cardiovascular events in prasugrel-treated patients.

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.

Hyperacute postprocedural high platelet reactivity: a novel predictor for in-hospital adverse events in acute coronary syndrome with prasugrel loading

Abstract Introduction Postprocedural High platelet reactivity (HPR) seems to associate long term adverse cardiovascular events, mainly intrastent thrombosis. However, the relationship between hyper-acute postprocedural HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) is still unclear. Moreover, factors contributing HPR in ACS with prasugrel loading are also unknown. Purpose This study aimed to assess the impact of hyper-acute postprocedural HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, as well as to define appropriate cut-off values and identify contributing factors of HPR. Methods We performed a single-centre, retrospective observational study that enrolled 207 patients who underwent emergent PCI for ACS with prasugrel loading. The P2Y12reaction unit (PRU) value was measured immediately after PCI with the VerifyNow System. The primary endpoint was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results Mean patient age (standard deviation) was 70.5 (±13.0) years, 78.7% were male, and average time from prasugrel intake to PRU calculation was 98.3 (±49.1) min. During a mean hospital stay of 15.9 (±9.3) days, there were 34 in-hospital MACE (16.4%) and 10 deaths (4.8%). Thrombosis events, didn't stand out and mechanical complications, such as cardiac rupture and cardiac tamponade occupies most of cardiovascular death which occurred before 10 days on admission. PRU was significantly higher in MACE group than Non-MACE group (279±65 vs 227±72, p&amp;lt;0.001 respectively). The ROC curve analysis of PRU for discriminating significant in-hospital MACE showed the cut off value of 293 (sensitivity:52.9%, specificity:83.2% [AUC=0.709, p&amp;lt;0.0001]). 47patients (29.4%) were thus categorized as HPR (PRU&amp;gt;293) immediately after emergent PCI. Kaplan-Meyer curve showed MACE events occurred in HPR group than non-HPR group (38.2% vs 10.0%, p&amp;lt;0.001). Multiple cox analysis demonstrated that HPR was independent predictors of MACE in patients with ACS underwent PCI (OR 5.416, 95% CI 2.157–13.598, p&amp;lt;0.0001). Multiple logistic regression model showed female sex, low haemoglobin value, and large mean platelet volume were independent predictors of HPR. Conclusion PRU was significantly higher in MACE group, and appropriate cut-off value of HPR in this study was 293. HPR was independent predictor of MACE during hospitalization, however thrombosis event was not significant. Evidence of clinical impact with postprocedural HPR within 120 minutes after prasugrel loading is scarce. This study shows post-procedural HPR, even without sufficient time after prasugrel intake, can be a useful predictive marker of adverse events during hospitalization. Funding Acknowledgement Type of funding sources: None. PRU between Non-MACE and MACE groupKaplan-Meyer curve

Impact of high platelet reactivity on left ventricular remodeling in patients with acute coronary syndrome

Abstract Background/Introduction Previous studies demonstrated that high platelet reactivity (HPR) predicts future cardiovascular death and coronary events in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). However, few studies have focused on the impact of HPR on left ventricular remodeling (LVR) and each echocardiographic parameter. Purpose The purpose of this study was to investigate the impact of HPR in ACS patients on LVR and changes in echocardiographic volume indexes and LV ejection fraction. Methods This is a retrospective cohort study of prospectively collected data in a single center that enrolled patients who underwent emergency PCI for ACS including STEMI and NSTEMI with prasugrel loading. The primary outcome of the study was LVR associated with HPR. Secondary endpoints were changes in indexed LVESV, LVEDV, LVEF, E/e' and LAVI between baseline and follow-up. The P2Y12 reaction unit (PRU) value in response to prasugrel was assessed by the VerifyNow P2Y12 assay. Blood samples were collected once per procedure immediately after PCI. LVR index was calculated as the relative change in LVEDV observed at follow-up compared with baseline. LVR was defined as a relative increase in LVEDV ≥20%, measured at follow-up visit compared with the baseline value before discharge. Results A total of 196 ACS patients who underwent emergency PCI between January 2016 and July 2020 were enrolled in the study. The mean age of the study population was 69.9 years, and 76.0% were male. On echocardiography at follow up visit of mean duration of 7.0±4.0 months, LVR was found in 38 patients (19.4%). The optimal cutoff for PRU associated with increased LVR assessed by receiver-operating characteristic curve analysis was 245.5 (AUC: 0.656; 95% CI: 0.564 to 0.749; p=0.003). On the basis of this cutoff, HPR was found in 82 patients (42.1%) and the prevalence of LVR was significantly higher in the HPR group compared to the non-HPR group (30.5% vs. 11.4%; p=0.001). Multiple Cox regression analysis showed that HPR was an independent predictor of LVR (OR 4.22, 95% CI 1.83–9.71, p=0.001). In addition, Δ% EDV and Δ% ESV increased in the HPR group, and decreased in the non-HPR group with significant differences (5.8±32.6% vs. −8.0±26.2% in Δ% EDV; p=0.002, 2.0±37.5% vs. −13.3±33.0% in Δ% ESV; p=0.004, respectively). Δ%EF, Δ%E/e', Δ%LAVI were numerically improved in the non-HPR group compared with the HPR group, but this difference did not reach statistical significance. Conclusion In patients with ACS, HPR defined as PRU ≥246 immediately after emergency PCI was an independent predictor of LVR in the chronic phase. Funding Acknowledgement Type of funding sources: None. Predictors of the presence of LVRChanges (Δ%) of LVEDV and LVESV

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.

Post-procedural high platelet reactivity with prasugrel loading predicts in-hospital adverse events in ACS patients

Abstract Background/Introduction High platelet reactivity (HPR) is associated with adverse cardiovascular events, primarily intrastent thrombosis, after a percutaneous coronary intervention (PCI). However, the relationship between hyperacute postprocedural HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) remains unclear. Moreover, factors contributing to HPR in ACS with prasugrel loading are also unknown. Purpose To assess the effects of post-procedural HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, and to define the appropriate cut-off values and identify factors contributing to HPR. Methods A single-center, retrospective observational study that enrolled 154 patients who underwent emergent PCI for ACS with prasugrel loading was performed. The P2Y12 reaction unit (PRU) value was measured immediately after PCI using the VerifyNowR system. The primary end-point was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results The mean patient age (standard deviation) was 70.7 (±12.5) years, 76.6% were men, and the average time from the prasugrel intake to PRU calculation was 103.2 (±48.5) min. During the mean hospital stay of 15.6 (±8.5) days, 24 in-hospital MACE (15.5%) and 8 deaths (5.2%) occurred. Thrombosis events, including myocardial infarction recurrence, did not occur (only one case of spontaneous coronary artery dissection was considered as myocardial infarction recurrence). PRU was significantly higher in the MACE group than that in Non-MACE group (287±55 and 232±64, respectively, p&amp;lt;0.001). The ROC curve analysis of PRU for discriminating the significant in-hospital MACE showed the cut-off value of 293 (sensitivity: 62.5%, specificity: 83.1% [AUC=0.756, p&amp;lt;0.0001]). A total of 37 patients (24%) were thus categorized as HPR (PRU&amp;gt;293) immediately after the emergent PCI. Kaplan-Meier curve showing MACE events occurred in the HPR group than that in the non-HPR group (40.5% vs 7.6%, p&amp;lt;0.001). Multiple cox analysis demonstrated that HPR was independent predictors of MACE in patients with ACS who underwent PCI (OR 11.01, 95% CI 2.39–20.2, p&amp;lt;0.0001). Multiple logistic regression model showed old age, female sex, low systolic blood pressure, short prasugrel intake to measure time, and large acute gain were independent predictors of HPR. Conclusion PRU was significantly higher in the MACE group, with an appropriate cut-off value of HPR of 293 in this study. HPR was an independent predictor of MACE during hospitalization; however, thrombosis events were not significant. HPR predictors were old age, female sex, low systolic blood pressure, short prasugrel intake to measure time, and large acute gain. This study shows the post-procedural HPR with prasugrel loading in patients with ACS can be a useful predictive marker of adverse events during hospitalization. Funding Acknowledgement Type of funding source: None

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.

Prasugrel for Japanese Patients With Ischemic Heart Disease in Long-Term Clinical Practice (PRASFIT-Practice II) - 1-Year Follow-up Results of a Postmarketing Observational Study.

Although the effectiveness and safety of prasugrel for the prevention of cardiovascular events in patients with ischemic heart disease (IHD) undergoing percutaneous coronary intervention (PCI) have been demonstrated, long-term real-world data of Japanese unique doses are insufficient. Therefore, we report the results of an analysis of 1-year follow-up data from a postmarketing observational study (PRASFIT-Practice II).Methods and Results:The safety and effectiveness analysis sets included 4,155 IHD patients receiving prasugrel (loading dose/maintenance dose, 20/3.75 mg) as dual antiplatelet therapy (DAPT) with aspirin. At 360 days (after treatment start), 62.2% continued DAPT. Cumulative incidences of major adverse cardiovascular events and stent thrombosis were 1.6% and 0.2%, respectively. Cumulative incidences of Thrombolysis In Myocardial Infarction (TIMI) major bleeding and TIMI major or minor bleeding were 1.0% and 2.0%, respectively. Risk factors for TIMI major or minor bleeding in the first 30 days of treatment were age ≥80 years, anemia, female sex, and liver disease, and from day 31 to the end of month 12, hypertension and peptic ulcer. The 1-year follow-up results showed long-term effectiveness and safety of prasugrel at dosages approved in Japan for the treatment of IHD patients undergoing PCI.

P4634Acute-phase high platelet reactivity with prasugrel loading is correlated with clinical outcomes during hospitalization in acute coronary syndrome

Abstract Background/Introduction Although high platelet reactivity (HPR) seems to be associated with adverse cardiovascular events after percutaneous coronary intervention (PCI), the relationship between post-procedure HPR with prasugrel loading and clinical outcomes in acute coronary syndrome (ACS) is still unclear. Moreover, factors contributing to HPR in ACS with prasugrel loading are also unknown. Purpose This study aimed to assess the impact of post-procedure HPR with prasugrel loading on clinical outcomes in ACS during hospitalization, as well as to define appropriate cut-off values and identify factors contributing to HPR. Methods We performed a single-centre, retrospective observational study that enrolled 132 patients who underwent emergent PCI for ACS with prasugrel loading. The P2Y12 reaction unit (PRU) value was measured immediately after PCI with the VerifyNowR System. The primary endpoint was major adverse cardiac events (MACE, defined as the composite of death, myocardial infarction, stroke, heart failure, ventricular arrhythmia needing defibrillation). Results Mean patient age (standard deviation) was 70.7 (±12.5) years, 76% were male, and average time from prasugrel intake to PRU calculation was 101 (±48.8) min. During a mean hospital stay of 15.4 (±8.0) days, there were 22 (16%) MACE events and 6 (4%) deaths. The post-procedure PRU value was 241±66. HPR was significantly higher in MACE group than non-MACE group [287 (±55) vs 232 (±64), p&lt;0.001]. The ROC curve analysis of PRU for discriminating significant in-hospital MACE showed a cut off value of 293 (sensitivity: 64%, specificity: 84% [AUC=0.764, p&lt;0.0001]). Thus, 33 patients (25%) were found to have HPR (PRU&gt;293) immediately after emergent PCI. Kaplan-Meier curve analysis showed MACE events occurred more frequently in the HPR group than in the non-HPR group (42% vs 8%, log rank p&lt;0.001). Multiple Cox regression analysis showed that peak creatine phosphokinase &gt;3,000 U/L and HPR were independent predictors of MACE in patients with ACS who underwent PCI (OR 4.96, 95% CI 1.86–13.26, p=0.001, and OR 7.52, 95% CI 2.73–20.7, p&lt;0.0001, respectively). HPR was significantly correlated with age, female sex, and reference lumen short diameter (pre-dilation) used in PCI. Conclusion HPR was significantly associated with adverse event during hospitalization in ACS patients. Female patients with large culprit lesion diameter were more likely to have HPR. Appropriate cut-off value of HPR in this study was 293. HPR in early-phase of ACS with prasugrel loading is a useful predictor of adverse events during hospitalization.

Aggregometry Response to Half-dose Prasugrel inFlow-diverting Stent Implantation.

The aim of this study was to determine whether half-dose loading (30 mg) of prasugrel is sufficient to achieve adequate platelet inhibition, and whether such aloading dose of prasugrel together with aspirin followed by a10 mg/day prasugrel maintenance, could serve as afirst-line antiplatelet strategy for patients undergoing flow-diverting stent (FDS) implantation. Data from agroup of consecutive patients treated for intracranial aneurysm with FDS were retrospectively collected. Platelet P2Y12 receptor responsiveness was assessed by arapid platelet function test just prior to the procedure. All ischemic and hemorrhagic complications as well as morbidity and mortality rates were documented. Atotal of 138 patients with 153 aneurysms (32were symptomatic and 121 were incidental) underwent FDS treatment in atotal of 147 loading sessions. Adequate platelet inhibition was obtained in 136/138 (98.5%) patients and 145/147 (98.6%) loading sessions. Overall, there was one case of (hemorrhagic) mortality (0.7%), one of (ischemic) morbidity (0.7%), one of symptomatic (hemorrhagic) clinical complications without permanent deficits (0.7%), and six transient ischemic attacks (4.1%). The 6‑month control angiography, available for all patients, revealed a95.4% aneurysm occlusion rate. Half-dose (30 mg) prasugrel loading results in effective platelet P2Y12 receptor inhibition in more than 98% of patients. Dual antiaggregant loading with half dose prasugrel followed by prasugrel maintenance as afirst-line therapy appears to be feasible in patients treated with FDS implantation for intracranial aneurysm.

Prasugrel versus clopidogrel for residual thrombus burden in patients with ST-segment elevation myocardial infarction

Prasugrel was shown to inhibit platelet activity more rapidly and consistently than clopidogrel. We compared the effects of prasugrel and clopidogrel on residual thrombus burden assessed by optical coherence tomography after stent implantation in patients with ST-segment elevation myocardial infarction (STEMI). A total of 76 patients with STEMI undergoing percutaneous coronary intervention (PCI) within 12 h after the onset were retrospectively enrolled. Of them, 34 patients were treated with prasugrel (loading dose, 20 mg) and the remaining 42 with clopidogrel (loading dose, 300 mg). Stent volume and in-stent thrombus volume were assessed by post-PCI optical coherence tomography. Baseline clinical characteristics, angiographic findings, and PCI procedure did not differ between the two groups. There was no difference in in-stent volume between patients with prasugrel and clopidogrel [169 (134-214) versus 166 (128-210) mm, P=0.83]. Patients with prasugrel had a significantly reduced in-stent thrombus volume compared with those with clopidogrel [0.59 (0.16-1.09) vs. 1.08 (0.32-2.30) mm, P=0.03]. The mean area and maximum area of in-stent thrombus were also significantly smaller in prasugrel than in clopidogrel group [0.03 (0.01-0.05) vs. 0.05 (0.01-0.10) mm, P=0.04, and 0.45 (0.27-0.75) vs. 0.77 (0.34-1.23) mm, P=0.03, respectively]. Prasugrel more effectively reduced residual thrombus burden after stent implantation in patients with STEMI, indicating a faster and more potent platelet inhibitory effect of prasugrel compared with clopidogrel.