Neoadjuvant Phase II Trial of Chemoradiotherapy in Patients With Resectable and Borderline Resectable Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma is a largely incurable cancer. Surgical resection remains the only potential option for cure. Even in surgically resectable patients, only about 10% to 20% are long-term survivors. Emerging data suggest a role for neoadjuvant therapy to target occult micrometastatic disease. AIM: To report our institutional experience with a novel neoadjuvant chemoradiation (CRT) regimen in resectable and borderline resectable pancreatic cancer. MATERIALS AND METHODS: Patients were treated with 2 cycles of induction chemotherapy with FOLFOX and then received CRT with gemcitabine and intensity-modulated radiotherapy (IMRT). RESULTS: From April 2014 to June 2017, 24 patients were enrolled. Eighteen patients were borderline resectable and 6 patients were resectable. All patients received induction chemotherapy with FOLFOX. Thirteen patients underwent pancreatectomy after CRT with a resection rate of 62%. R0 resection achieved in 11 patients (84.6%) and 2 patients had R1 resection (15.4%). For patients who underwent resection, the median progression-free survival (PFS) was 31 months, 1-year PFS rate was 69.2% (95% confidence interval [CI], 0.48-0.99), and 2-year PFS rate was 51.9% (95% CI, 0.3-0.89). Median overall survival (OS) was 34.8 months (95% CI, 1.045 to infinity), 1-year OS rate was 91.7% (95% CI, 0.77-1.0), and 2-year OS rate was 75% (95% CI, 0.54-1.0). Median CA 19-9 at screening for patients who underwent surgery was 659 (range, 18 to 2154), which decreased to 146.9 (range, 18 to 462) after CRT before resection. CONCLUSION: Neoadjuvant therapy for borderline resectable and resectable pancreatic ductal adenocarcinoma with CRT facilitated R0 resection in 84% patients who underwent surgery.

Dual antiplatelet therapy in patients with diabetes and acute coronary syndromes managed without revascularization.

OBJECTIVE: Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) derived enhanced benefit with dual antiplatelet therapy (DAPT) with prasugrel vs. clopidogrel. The risk profile and treatment response to DAPT for medically managed ACS patients with DM remains uncertain. METHODS: The TRILOGY ACS trial compared aspirin + prasugrel vs. aspirin + clopidogrel for up to 30months in non-ST-segment elevation (NSTE) ACS patients managed medically without revascularization. We compared treatment-related outcomes among 3539 patients with DM vs. 5767 patients without DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. RESULTS: Patients with vs. without DM were younger, more commonly female, heavier, and more often had revascularization prior to the index ACS event. The frequency of the primary endpoint through 30months was higher among patients with vs. without DM (24.8% vs. 16.3%), with a higher risk for those patients with DM treated with insulin vs. those treated without insulin (35.3% vs. 19.9%). There was no significant difference in the frequency of the primary endpoint by treatment with prasugrel vs. clopiodgrel in those with or without DM (Pint=0.82) and with or without insulin treatment among those with DM (Pint=0.304). CONCLUSIONS: Among NSTE ACS patients managed medically without revascularization, patients with DM had a higher risk of ischemic events that was amplified among those treated with insulin. There was no differential treatment effect with a more potent DAPT regimen of aspirin + prasugrel vs. aspirin + clopidogrel.

Temporal Biomarker Profiling Reveals Longitudinal Changes in Risk of Death or Myocardial Infarction in Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: There are conflicting data on whether changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) concentrations between time points (delta NT-proBNP and hs-CRP) are associated with a change in prognosis. METHODS: We measured NT-proBNP and hs-CRP at 3 time points in 1665 patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Cox proportional hazards was applied to the delta between temporal measurements to determine the continuous association with cardiovascular events. Effect estimates for delta NT-proBNP and hs-CRP are presented per 40% increase as the basic unit of temporal change. RESULTS: Median NT-proBNP was 370.0 (25th, 75th percentiles, 130.0, 996.0), 340.0 (135.0, 875.0), and 267.0 (111.0, 684.0) ng/L; and median hs-CRP was 4.6 (1.7, 13.1), 1.9 (0.8, 4.5), and 1.8 (0.8, 4.4) mg/L at baseline, 30 days, and 6 months, respectively. The deltas between baseline and 6 months were the most prognostically informative. Every +40% increase of delta NT-proBNP (baseline to 6 months) was associated with a 14% greater risk of cardiovascular death (adjusted hazard ratio (HR) 1.14, 95% CI, 1.03-1.27) and with a 14% greater risk of all-cause death (adjusted HR 1.14, 95% CI, 1.04-1.26), while every +40% increase of delta hs-CRP (baseline to 6 months) was associated with a 9% greater risk of the composite end point (adjusted HR 1.09, 95% CI, 1.02-1.17) and a 10% greater risk of myocardial infarction (adjusted HR 1.10, 95%, CI 1.00-1.20). CONCLUSIONS: Temporal changes in NT-proBNP and hs-CRP are quantitatively associated with future cardiovascular events, supporting their role in dynamic risk stratification of NSTEACS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00699998.

Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes.

OBJECTIVES: Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patient's bleeding risk during DAPT treatment in the post-ACS setting. METHODS: To develop a longitudinal bleeding risk prediction model, we analy sed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revasculari sation and treated with DAPT for a median of 14.8 months. RESULTS: We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomi sation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomi sation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneau's C-indices: 0.78 (SE = 0.024) for the GUSTO model and 0.67 (SE = 0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68). CONCLUSIONS: Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform risk -benefit considerations regarding the duration of DAPT following ACS. TRIAL REGISTRATION: ClinicalTrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT00699998.

The Rationale for and Clinical Pharmacology of Prasugrel 5 mg.

Prasugrel is a third-generation thienopyridine platelet P2Y12 adenosine diphosphate (ADP) receptor antagonist administered with aspirin for the treatment of patients with acute coronary syndrome (ACS) with planned percutaneous coronary intervention. Prasugrel is administered periprocedurally at an oral loading dose of 60 mg followed by daily maintenance doses (MDs) of 10 mg for most patients and 5 mg for patients weighing <60 kg or aged ≥75 years. Data from a prasugrel phase III study, TRITON-TIMI 38, suggested that a lower MD might be more suitable for patients weighing <60 kg or aged ≥75 years; subsequent pharmacokinetic and pharmacodynamic studies have indicated that prasugrel 5 mg reduced platelet reactivity in these populations to an extent similar to that of prasugrel 10 mg in heavier or younger patients. Clinical experience with prasugrel 5 mg is limited, and additional studies are needed to verify the clinical efficacy and safety of this dose in these challenging populations.

Dual Antiplatelet Therapy and Outcomes in Patients With Atrial Fibrillation and Acute Coronary Syndromes Managed Medically Without Revascularization: Insights From the TRILOGY ACS Trial.

Associations between atrial fibrillation (AF), outcomes, and response to antiplatelet therapies in patients with acute coronary syndrome (ACS) managed medically without revascularization remain uncertain. We examined these associations for medically managed ACS patients randomized to dual antiplatelet therapy (DAPT) using patient data from the TRILOGY ACS trial. DAPT included aspirin plus clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d for those <60 kg or age ≥75 years). Patients receiving oral anticoagulants were excluded. Cox proportional hazards regression modeling was used to characterize associations between patients with AF (AF+) vs those without (AF-) and risk of ischemic and bleeding events, and to explore effects of randomized treatment on outcomes. Among 9101 patients with baseline AF status, 710 (7.8%) had AF. AF+ patients were older and had more comorbidities. Unadjusted associations of the composite of cardiovascular death/myocardial infarction/stroke were significantly higher among AF patients at 30 months (31.1% vs 18.4%; HR: 1.61, 95% CI: 1.35-1.92, P < 0.001), but differences did not persist after adjustment (HR: 1.16, 95% CI: 0.97-1.39, P = 0.11). When individual components of the composite endpoint were evaluated, 30-month risk of events in AF+ patients was significantly higher. Thirty-month risk of all-cause death was significantly higher in AF+ patients: 18.1% vs 11.1% (HR: 1.62, 95% CI: 1.30-2.02, P < 0.001). There was no significant interaction with randomized treatment and AF for the primary endpoint. Among medically managed high-risk ACS patients receiving DAPT, AF was associated with higher unadjusted risks of ischemic and bleeding outcomes that were similar by treatment group.

Prasugrel 5 mg inhibits platelet P-selectin and GPIIb-IIIa expression in very elderly and non elderly: results from the GENERATIONS trial, a pharmacodynamic study in stable CAD patients.

UNLABELLED: Platelet P-selectin and activated glycoprotein IIb-IIIa (GPIIb-IIIa) are markers of platelet activation and mediates platelet aggregation. Prasugrel (Pras) 5 mg may be used in very elderly (VE) acute coronary syndrome (ACS) patients undergoing PCI, but its effect on platelet P-selectin and activated GPIIb-IIIa in those patients is not known. Stable ACS patients, VE (78 ± 5 years, n = 23) and non-elderly (NE) (55 ± 5 years, n = 22) were randomized to Pras (5 or 10 mg) or clopidogrel (Clop) 75 mg during three 12-day periods. Platelet activation markers were measured by flow cytometry on unstimulated or stimulated (adenosine diphosphate (ADP) 20 µM) platelets, before and after each dosing period. RESULTS: At baseline there was no difference in platelet activation markers, either unstimulated or ADP-stimulated, between NE and VE. Pras 5 mg reduced both ADP-stimulated platelet P-selectin and activated GPIIb-IIIa in VE (p < 0.01 for both analyses) and NE (p < 0.001 and p < 0.05, respectively). Clop 75 mg had a similar effect as Pras 5 mg but did not significantly reduce activated GPIIb-IIIa in VE. Prasugrel 10 mg resulted in decreased platelet activation in both age groups compared to Clop 75 mg (p < 0.01). CONCLUSIONS: In VE and NE-patients, Pras 5 mg inhibited platelet P-selectin expression similar to Clop 75 mg and Pras 10 mg. Prasugrel 10 mg inhibited platelet P-selectin expression better than Clop 75 mg. Prasugrel 10 mg and 5 mg, but not Clop 75 mg, significantly inhibited activated GPIIb-IIIa in VE. This platelet reactivity data support the use of Pras 5 mg for VE patients.

Association Between Very Low Levels of High-Density Lipoprotein Cholesterol and Long-term Outcomes of Patients With Acute Coronary Syndrome Treated Without Revascularization: Insights From the TRILOGY ACS Trial.

BACKGROUND: Low levels of high-density lipoprotein cholesterol (HDL-C; <40 mg/dL) are associated with increased risk of cardiovascular events, but it is unclear whether lower thresholds (<30 mg/dL) are associated with increased hazard. HYPOTHESIS: Very low levels of HDL-C may provide prognostic information in acute coronary syndrome (ACS) patients treated medically without revascularization. METHODS: We examined data from 9064/9326 ACS patients enrolled in the TRILOGY ACS trial. Participants were randomized to clopidogrel or prasugrel plus aspirin. Study treatments continued for 6 to 30 months. Relationships between baseline HDL-C and the composite of cardiovascular death, myocardial infarction (MI), or stroke, and individual endpoints of death (cardiovascular and all-cause), MI, and stroke, adjusted for baseline characteristics through 30 months, were analyzed. The HDL-C was evaluated as a dichotomous variable-very low (<30 mg/dL) vs higher (≥30 mg/dL)-and continuously. RESULTS: Median baseline HDL-C was 42 mg/dL (interquartile range, 34-49 mg/dL) with little variation over time. Frequency of the composite endpoint was similar for very low vs higher baseline HDL-C, with no risk difference between groups (hazard ratio [HR]: 1.13, 95% confidence interval [CI]: 0.95-1.34). Similar findings were seen for MI and stroke. However, risks for cardiovascular (HR: 1.42, 95% CI: 1.13-1.78) and all-cause death (HR: 1.36, 95% CI: 1.11-1.67) were higher in patients with very low baseline HDL-C. CONCLUSIONS: Medically managed ACS patients with very low baseline HDL-C levels have higher risk of long-term cardiovascular and all-cause death but similar risks for nonfatal ischemic outcomes vs patients with higher baseline HDL-C.

Effect of prior clopidogrel use on outcomes in medically managed acute coronary syndrome patients.

OBJECTIVE: We investigated whether prior clopidogrel influenced long-term ischaemic and bleeding risks and modified the randomised treatment effect of clopidogrel versus prasugrel among medically managed patients with acute coronary syndromes (ACS) treated with dual antiplatelet therapy. METHODS: Medically managed patients with ACS in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial were randomised to clopidogrel versus prasugrel (plus aspirin), stratified by prior clopidogrel use. From the analysis population (n=8927), we compared two groups: 'clopidogrel in-hospital (n=6513)' (clopidogrel started ≤72 h of presentation for index ACS event) and 'prior-clopidogrel (n=2414)' (on clopidogrel ≥5 days before index hospitalisation). Treatment-related differences in ischaemic (all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stroke and the composite of CV death/MI/stroke) and bleeding outcomes (severe/life-threatening or moderate bleeding events based on Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria) through 30 months were analysed between patients in the two groups. RESULTS: Compared with 'clopidogrel in-hospital,' 'prior clopidogrel' patients were younger (median 64 years vs 66 years, p<0.001), more likely to have prior CV events/revascularisation, and had a higher frequency of CV death, MI or stroke through 30 months (20.8% vs 18.2%, p=0.002), with no difference in bleeding events (2.3% vs 3.4%, p=0.50). Randomised treatment effect (prasugrel vs clopidogrel) was similar for ischaemic and bleeding outcomes in both groups (all pinteraction>0.05). CONCLUSIONS: Patients receiving clopidogrel before admission for ACS and subsequently treated only medically are at higher risk for CV events versus those not previously receiving clopidogrel. More potent antiplatelet inhibition with prasugrel versus clopidogrel did not significantly reduce this risk. TRIAL REGISTRATION NUMBER: NCT00699998.

Spontaneous MI After Non-ST-Segment Elevation Acute Coronary Syndrome Managed Without Revascularization: The TRILOGY ACS Trial.

BACKGROUND: Patients with acute coronary syndrome (ACS), especially those receiving medical management without revascularization, are at high risk for spontaneous myocardial infarction (MI), but its frequency and predictors are unknown. OBJECTIVES: This study sought to characterize spontaneous MI events in a randomized population during 30 months of follow-up and develop a prediction model for spontaneous MI to assign risk of spontaneous MI events in ACS populations. METHODS: We analyzed data from the randomized TRILOGY ACS (TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medically manage Acute Coronary Syndromes) trial of aspirin plus prasugrel or clopidogrel following ACS. The trial included 9,326 patients with non-ST-segment elevation myocardial infarction (NSTEMI)/unstable angina (UA) who were managed medically without planned revascularization. Our study population included 9,294 patients. A multivariable Cox proportional hazards model was developed to determine predictors of time to first spontaneous MI event through 30 months. After model validation, we developed a calculator for model implementation. RESULTS: Among 9,294 patients, 695 spontaneous MI events occurred over a median of 17 months, representing 94% of adjudicated MI events (n = 737). The Kaplan-Meier event rate of spontaneous MI through 30 months was 10.7%. The strongest predictors of spontaneous MI were older age, NSTEMI versus UA as index event, diabetes mellitus, no pre-randomization angiography, and higher baseline creatinine values. The model exhibited good predictive capabilities (c-index = 0.732) and had good calibration, especially for patients with low-to-moderate risk of spontaneous MI. CONCLUSIONS: Spontaneous MI following a medically managed UA/NSTEMI event is common. Baseline characteristics can be used to predict subsequent risk of spontaneous MI in this population. These findings provide insight into the long-term natural history of medically managed UA/NSTEMI patients and could be used to optimize risk stratification and treatment of these patients. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects [TRILOGY ACS]; NCT00699998).

Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel.

BACKGROUND: Certain alleles of the CYP2C19 gene are associated with higher platelet reactivity and increased ischemic events among patients treated with clopidogrel. However, the relationship of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known. OBJECTIVES: This study sought to assess the effect of CYP2C19 genotype on ischemic outcomes in patients with ACS initially managed medically without revascularization who were randomized to either clopidogrel or prasugrel. METHODS: We classified patients as extensive metabolizers (EM) or reduced metabolizers (RM) based on CYP2C19 genotype and evaluated ischemic outcomes and platelet reactivity. Among 9,326 patients enrolled from 2008 to 2011, 5,736 participated in the genetics cohort; of these, 2,236 had platelet function testing data. RESULTS: There was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR]: 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR: 0.82) or clopidogrel (HR: 0.91; p for interaction = 0.495). After adjusting for clinical and treatment variables, EM patients had a lower risk of MI versus RM patients (HR: 0.80), but risks of other outcomes were similar. RM patients had significantly higher mean P2Y12 reaction units versus EM patients when treated with clopidogrel (39.93), but not with prasugrel (3.87). CONCLUSIONS: CYP2C19 metabolizer status is not associated with the composite outcome of cardiovascular death, MI, or stroke in medically managed ACS patients treated with clopidogrel or prasugrel. Our findings do not support routine CYP2C19 genetic testing in this population. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects [TRILOGY ACS]; NCT00699998).

Time-Varying Effects of Prasugrel Versus Clopidogrel on the Long-Term Risks of Stroke After Acute Coronary Syndromes: Results From the TRILOGY ACS Trial.

BACKGROUND AND PURPOSE: The role of more intense, sustained platelet inhibition in preventing stroke after acute coronary syndrome (ACS) is unclear. We observed a signal for reduced stroke risk in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial after 12 months of treatment with prasugrel versus clopidogrel in medically managed patients with ACS. METHODS: We examined 7243 patients with ACS, aged <75 years and without prior stroke, analyzing differences in baseline characteristics between patients with and without a stroke event through 30 months with a Cox proportional hazards model. We also assessed the effect of prasugrel versus clopidogrel (plus aspirin) on risk of all stroke events and ischemic stroke over time with an extended Cox proportional hazards model. RESULTS: Stroke events were infrequent through 30 months (ischemic stroke=62; hemorrhagic stroke=15). Patients with stroke were older, had more comorbidities, and had a higher Global Registry of Acute Coronary Events (GRACE) risk score. There was a trend for a lower unadjusted frequency of all stroke events through 30 months for prasugrel versus clopidogrel: 31 (1.5%) versus 46 (2.2%); P=0.08. There was a significant treatment-by-time interaction for those with ischemic stroke (P=0.03), consistent with the 12-month landmarked Kaplan-Meier log-rank test showing a reduced hazard of ischemic stroke after 12 months with prasugrel (P=0.04). No significant interactions between treatment effect of prasugrel versus clopidogrel and time were observed for all stroke events. CONCLUSIONS: We observed a potential late treatment effect for prasugrel versus clopidogrel for a reduced risk of ischemic stroke in medically managed patients with ACS aged <75 years. These hypothesis-generating findings suggest that longer duration and more potent platelet inhibition with prasugrel may be associated with lower risk of ischemic stroke after 12 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00699998.

Design of the DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) trial: A global Phase 3 double-blind, randomized, placebo-controlled, multicenter study of the efficacy and safety of prasugrel in pediatric patients with sickle cell anemia utilizing a dose titration strategy.

BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder characterized by painful vaso-occlusive crises (VOC) with limited treatment options, particularly for children. Emerging knowledge of the pathophysiology of SCD suggests antiplatelet therapies may hold promise for treatment of VOC. Multiple small studies have evaluated antiplatelet agents on the frequency of VOC with varying results, but there has not been an adequately powered study to definitively determine the effect of antiplatelet agents on VOC. Prasugrel, a third-generation thienopyridine that irreversibly inhibits platelet activation and aggregation, is approved in adults with acute coronary syndrome managed with percutaneous coronary intervention. PROCEDURE: Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) is a double-blind, randomized study with planned enrollment of >220 children from 14 countries across the Americas, Europe, Asia, and Africa, designed to test the hypothesis that prasugrel reduces the rate of VOC in children with sickle cell anemia (SCA) (homozygous hemoglobin S [HbSS] and hemoglobin Sß(0) thalassemia [HbSß(0)]). Secondary study endpoints include reductions in rate and intensity of vaso-occlusive pain as recorded in daily electronic diaries. Safety assessments include incidence of hemorrhagic events requiring medical intervention and treatment-emergent adverse events. DOVE incorporates a dose-titration strategy to reduce potential bleeding risks inherent with antiplatelet therapy while maintaining blinded treatment assignment. CONCLUSIONS: DOVE presents a unique opportunity to determine whether antiplatelet therapy reduces frequency of patient-reported VOC and daily vaso-occlusive pain in a global study of children with SCA.

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome.

AIMS: Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS. METHODS AND RESULTS: The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79). CONCLUSIONS: Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00699998.

Frailty is associated with worse outcomes in non-ST-segment elevation acute coronary syndromes: Insights from the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial.

AIMS: Little is known regarding consequences of frailty in patients with acute coronary syndrome (ACS). We assessed the associations of frailty and outcomes in ACS patients who were participating in a clinical trial. METHODS AND RESULTS: The TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial randomized 9326 patients planned for medical management to prasugrel or clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), or stroke over a period of 30 months. A frailty score based upon the Fried score was self-reported at baseline in patients aged ⩾65 years. Five frailty questions were recorded for 4996/5102 (97.9%) patients: 72.3% were classified as not-frail (0 items), 23.0% as pre-frail (1-2 items), and 4.7% as frail (⩾3 items). Increasing frailty score was associated with older age, diabetes, and higher Global Registry of Acute Coronary Events (GRACE) scores. Frailty was associated with a higher unadjusted incidence of the primary endpoint (pre-frail vs not-frail: 29.2% vs 23.1%; hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.19-1.61; p<0.001; frail vs not-frail: 39.7% vs 23.1%; HR: 1.76; 95% CI: 1.36-2.28; p<0.001), and all-cause mortality (pre-frail vs not-frail: 21.7% vs 15.0%; HR: 1.45; 95% CI: 1.22-1.73; p<0.001; frail vs not-frail: 30.2% vs 15.0%; HR: 1.98; 95% CI: 1.47-2.68; p<0.001). After adjustment for baseline characteristics and GRACE covariates, frailty remained independently associated with the primary endpoint: pre-frail vs not-frail, HR: 1.33; 95% CI: 1.15-1.54; p<0.001; frail vs not-frail, HR: 1.52; 95% CI: 1.18-1.98; p=0.002. There was no association of frailty with bleeding. CONCLUSION: Frailty is associated with the composite of cardiovascular death, MI, or stroke. Frailty assessment contributes to risk prediction and adds to the GRACE score.

Concomitant proton-pump inhibitor use, platelet activity, and clinical outcomes in patients with acute coronary syndromes treated with prasugrel versus clopidogrel and managed without revascularization: insights from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial.

UNLABELLED: Concomitant use of proton-pump inhibitors (PPIs) has been implicated in diminished antiplatelet response to clopidogrel and an increased risk of ischemic events, but primarily among patients undergoing percutaneous coronary intervention. We sought to examine the potential influence of interactions between PPIs and clopidogrel versus prasugrel on platelet reactivity and clinical outcomes after acute coronary syndromes (ACS) in patients managed medically without revascularization. METHODS: This analysis from the TRILOGY ACS trial focused upon the 7,243 ACS patients aged <75 years who were managed without revascularization, randomized to clopidogrel or prasugrel, and followed for a median of 17 months. Proton-pump inhibitor type and use were assessed at each study visit, and 2,049 of the patients in this cohort underwent serial platelet reactivity assessments. RESULTS: Proton-pump inhibitor use (23%) was similar between the clopidogrel and prasugrel groups at baseline and throughout the study. Median on-treatment platelet reactivity values were consistently lower with prasugrel versus clopidogrel irrespective of PPI use. For the primary end point (composite of cardiovascular death, myocardial infarction [MI], or stroke), PPI use modified the unadjusted treatment effect of prasugrel versus clopidogrel (interaction P = .02). After adjusting for differences in baseline characteristics, this treatment effect modification was attenuated for the composite end point (interaction P = .06) but was significant for the MI component end point (interaction P = .01). Similarly, among patients on a PPI, the frequency of MI was significantly lower with prasugrel versus clopidogrel (hazard ratio = 0.61; 95% CI 0.42-0.88). These findings were similar by PPI type (omeprazole and pantoprazole). CONCLUSIONS: Among ACS patients managed without revascularization, use of PPIs did not result in a differential antiplatelet response between prasugrel versus clopidogrel but was associated with a lower incidence of MI with prasugrel. These hypothesis-generating findings suggest that factors besides platelet reactivity may underlie the differential risk of MI observed by treatment assignment with PPI use.

The effect of prasugrel on ADP-stimulated markers of platelet activation in patients with sickle cell disease.

Platelets of patients with sickle cell disease (SCD) show evidence of mild activation in the non-crisis steady state and greater activation during vaso-occlusive crises (VOC). Prasugrel, a potent inhibitor of ADP-mediated platelet activation and aggregation, may be useful in attenuating VOC. We compared platelet responses to ADP stimulation in patients with SCD and healthy subjects before and after treatment with prasugrel. In a phase 1 study, platelet biomarker levels were assessed in 12 adult patients with SCD and 13 healthy subjects before and after 12 ± 2 days of 5.0 or 7.5 mg/day prasugrel. The following were determined in whole blood samples stimulated with 20 µM ADP: (i) percentages of monocytes and neutrophils with adherent platelets (cell-platelet aggregates); (ii) the relative number (mass) of platelets associated with each monocyte and neutrophil as reported by CD61 mean fluorescence intensity (MFI) of the monocyte-platelet and neutrophil-platelet aggregates; (iii) the percentages of platelets positive for surface expression of CD40 ligand (CD40L), P-selectin (CD62p) and activated glycoprotein IIb-IIIa (GPIIb-IIIa); and (iv) the percentages of platelets and monocyte-platelet aggregates positive for surface tissue factor (TF) expression. At baseline, there were no significant differences between cohorts in the percentages of platelets expressing activation biomarkers. Following 12 days of prasugrel administration, the percentages of platelets expressing activation biomarkers following ADP stimulation were reduced in both cohorts, and there were no significant differences between groups. Both patients with SCD and healthy subjects had significant reductions in the monocyte-platelet and neutrophil-platelet aggregate MFI and the percentage of platelets expressing P-selectin and activated GPIIb-IIIa (all p < 0.05). Healthy subjects also had significant reductions in monocyte-platelet aggregate percentages (p = 0.004), neutrophil-platelet aggregate percentages (p = 0.011) and the percentage of CD40L-positive platelets (p = 0.044) that were not observed in patients with SCD. Prasugrel administration to SCD patients attenuates ex vivo ADP-stimulated platelet activation as measured by the percentage of platelets positive for P-selectin and GPIIb-IIIa, thus reducing the proportion of platelets that may participate in aggregates. Furthermore, prasugrel decreases ex vivo ADP-stimulated platelet aggregation with monocytes and neutrophils as measured by the monocyte-platelet and neutrophil-platelet aggregate MFI. This implies that in the presence of prasugrel, fewer platelets adhere to monocytes and neutrophils, which may result in reducing cell-platelet aggregate size. Therefore, reduced platelet reactivity and decreased size of leukocyte-platelet aggregates suggest additional mechanisms by which prasugrel may provide benefit to patients with SCD and support further investigation of possible therapeutic benefits of prasugrel in this population.

Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after TAXUS Liberté paclitaxel-eluting coronary stent placement.

BACKGROUND: The TAXUS Liberté Post Approval Study (TL-PAS) contributed patients treated with TAXUS Liberté paclitaxel-eluting stent and prasugrel to the Dual Antiplatelet Therapy Study (DAPT) that compared 12 and 30 months thienopyridine plus aspirin therapy after drug-eluting stents. METHODS AND RESULTS: Outcomes for 2191 TL-PAS patients enrolled into DAPT were assessed. The DAPT coprimary composite end point (death, myocardial infarction [MI], or stroke) was lower with 30 compared with 12 months prasugrel treatment (3.7% versus 8.8%; hazard ratio [HR], 0.407; P<0.001). Rates of death and stroke were similar between groups, but MI was significantly reduced with prolonged prasugrel treatment (1.9% versus 7.1%; HR, 0.255; P<0.001). The DAPT coprimary end point, stent thrombosis, was also lower with longer therapy (0.2% versus 2.9%; HR, 0.063; P<0.001). MI related to stent thrombosis (0% versus 2.6%; P<0.001) and occurring spontaneously (1.9% versus 4.5%; HR, 0.407; P=0.007) were both reduced with prolonged prasugrel. MI rates increased within 90 days of prasugrel cessation after both 12 and 30 months treatment. Composite Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) moderate or severe bleeds were modestly increased (2.4% versus 1.7%; HR, 1.438; P=0.234) but severe bleeds were not more frequent (0.3% versus 0.5%; HR, 0.549; P=0.471) in the prolonged treatment group. CONCLUSIONS: Prasugrel and aspirin continued for 30 months reduced ischemic events for the TAXUS Liberté paclitaxel-eluting stent patient subset from DAPT through reductions in MI and stent thrombosis. Withdrawal of prasugrel was followed by an increase in MI after both 12 and 30 months therapy. The optimal duration of dual antiplatelet therapy with prasugrel after TAXUS Liberté paclitaxel-eluting stent remains unknown, but appears to be >30 months. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00997503.

Prasugrel in children with sickle cell disease: pharmacokinetic and pharmacodynamic data from an open-label, adaptive-design, dose-ranging study.

INTRODUCTION: This phase 2 study was designed to characterize the relationship among prasugrel dose, prasugrel's active metabolite (Pras-AM), and platelet inhibition while evaluating safety in children with sickle cell disease. It was open-label, multicenter, adaptive design, dose ranging, and conducted in 2 parts. Part A: Patients received escalating single doses leading to corresponding increases in Pras-AM exposure and VerifyNow®P2Y12 (VN) platelet inhibition and decreases in VNP2Y12 reaction units and vasodilator-stimulated phosphoprotein platelet reactivity index. Part B: Patients were assigned daily doses (0.06, 0.08, and 0.12 mg/kg) based on VN pharmacodynamic measurements at the start of 2 dosing periods, each 14±4 days. Platelet inhibition was significantly higher at 0.12 mg/kg (56.3%±7.4%; least squares mean±SE) compared with 0.06 mg/kg (33.8%±7.4%) or 0.08 mg/kg (37.9%±5.6%). Patients receiving 0.12 mg/kg achieved ≥30% platelet inhibition; only 1 patient receiving 0.06 mg/kg exceeded 60% platelet inhibition. High interpatient variability in response to prasugrel and the small range of exposures precluded rigorous characterization of the relationship among dose, Pras-AM, and platelet inhibition. SAFETY: No hemorrhagic events occurred in Part A; 3 occurred in Part B, all mild and self-limited. CONCLUSIONS: Most children with sickle cell disease may achieve clinically relevant platelet inhibition with titration of daily-dose prasugrel.