prasugrel-hydrochloride and Thromboembolism

Antithrombotic agents are the cornerstones of therapy for thrombosis. The compositions of arterial and venous clots differ, rendering antiplatelet agents more effective for arterial thrombosis and anticoagulants more effective for venous disease. Despite taking acetylsalicylic acid, some patients with arterial disease experience thrombotic events. The addition of the ADP-receptor antagonist clopidogrel to therapeutic regimens containing acetylsalicylic acid improves outcomes in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. However, clopidogrel has several limitations, including variable absorption, drug-drug interactions and genetic factors that lead to reduced generation of the active metabolite, and a delayed onset and offset of action. A search for new ADP-receptor inhibitors has yielded drugs such as prasugrel, ticagrelor, and cangrelor. For patients with venous thrombosis, the coumarins have been the only available oral anticoagulants for more than 60 years. Despite their effectiveness in preventing and treating thromboembolism, coumarins have well-documented limitations, including drug-drug and drug-dietary interactions, a narrow therapeutic range, and inconvenience and cost of monitoring therapy. A search for new oral anticoagulants has yielded drugs such as dabigatran etexilate, rivaroxaban, and apixaban. In this article, we review these new antithrombotic agents and provide plausible explanations for the results of phase III randomized controlled trials of these drugs.

Topics: Adenosine; Anticoagulants; Aspirin; Clopidogrel; Coronary Thrombosis; Coumarins; Fibrinolytic Agents; Humans; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Thiophenes; Thromboembolism; Ticagrelor; Ticlopidine

Antiplatelet therapy is one of the key initial therapeutic interventions to prevent thrombotic complications associated with percutaneous coronary intervention. Aspirin and the thienopyridines, clopidogrel, and ticlopidine, are the most widely used oral antiplatelet agents in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. Recent data have demonstrated limitations with the currently approved dosing regimen of clopidogrel (loading dose, 300 mg; maintenance dose, 75 mg daily) in a significant number of patients during the first few hours-days of treatment (Gurbel et al, Circulation. 2003;107:2908-2913 and Lau et al, Circulation. 2004;109:166-171). To circumvent this problem, some centers use a higher loading dose of clopidogrel (600 mg). Prasugrel is a novel thienopyridine prodrug similar to clopidogrel and ticlopidine that is more efficiently metabolized to its active metabolite compared with the 2 older drugs, providing enhanced platelet inhibition with less intersubject variability. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) study was a phase 3, multicenter trial that studied prasugrel in comparison with Clopidogrel in patients with moderate-to-high-risk acute coronary syndromes. In this article, we discuss the findings of this major trial, review previously published literature that compares the 2 medications, and provide a clinical context for the potential role of prasugrel in practice.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Clopidogrel; Combined Modality Therapy; Coronary Angiography; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Assessment; Severity of Illness Index; Survival Analysis; Thiophenes; Thromboembolism; Ticlopidine; Treatment Outcome

Eli Lilly & Co and Daiichi Sankyo Co Ltd are developing prasugrel, a third generation thienopyridine derivative. Prasugrel is in phase III clinical trials in Western Europe and Japan, and is awaiting regulatory approval in the US for the treatment of thromboembolism in patients with ischemic strokes or acute coronary syndromes. The companies were expected to launch the drug in the US by the end of 2008.

Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Patents as Topic; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Structure-Activity Relationship; Thiophenes; Thromboembolism

High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied.. This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP.. A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094-1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010-1.466]), hemorrhagic stroke (13 events, 3.247 [1.660-6.296]), ischemic events (142 events, 1.219 [1.020-1.466]), and bleeding events (47 events, 1.629 [1.172-2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220-4.225] per 10-mm Hg increase; 3.051 [2.179-4.262]; 3.276 [1.172-9.092]; 2.865 [2.042-4.011]; 2.764 [1.524-5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP.. Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp; Unique identifier: JapicCTI-111582.

Topics: Aged; Blood Pressure; Clopidogrel; Double-Blind Method; Female; Humans; Hypertension; Ischemic Stroke; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Secondary Prevention; Thromboembolism

It has been well known that the inhibition of platelet aggregation (IPA) by anti-platelet agents was important to reduce the thrombo-embolic events in patients with ST segment elevation myocardial infarction (STEMI). However, the peri-procedural IPA by anti-platelet agents was not well known.. We compared the peri-procedural IPA between prasugrel and adjunctive cilostazol to dual anti-platelet therapy (triple anti-platelet therapy; TAP) in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). We prospectively randomized 70 consecutive clopidogrel-naive patients with STEMI planned PCI to either prasugrel [loading dose (LD) 60 mg; 37 patients] or TAP (LD aspirin 300 mg, clopidogrel 600 mg, and cilostazol 200mg; 33 patients). Primary end points of the study were the platelet reactivity unit (PRU) or % inhibition by the VerifyNow P2Y12 assay at pre-PCI and pre-discharge.. The drug loading to pre-PCI time was similar between prasugrel and TAP groups (25.4 ± 10.42 min vs. 25.5 ± 10.56 min, p=0.957). PRU at pre-PCI was significantly lower in prasugrel than in TAP (269.1 ± 71.69 vs. 306.5 ± 48.67, p=0.012). The lower PRU and greater % inhibition also observed in prasugrel than in TAP at pre-discharge (108.2 ± 60.51 vs. 238.1 ± 73.40; 63.6 ± 18.51% vs. 16.8 ± 17.91%, p<0.001 respectively). No differences in in-hospital bleeding complications between the two groups were observed.. Our study demonstrates that prasugrel could produce a significantly greater peri-procedural as well as in-hospital IPA compared with TAP in patients with STEMI undergoing primary PCI.

Topics: Aged; Cilostazol; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Perioperative Care; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Prospective Studies; Tetrazoles; Thiophenes; Thromboembolism; Treatment Outcome

Antiplatelet therapy is one of the key initial therapeutic interventions to prevent thrombotic complications associated with percutaneous coronary intervention. Aspirin and the thienopyridines, clopidogrel, and ticlopidine, are the most widely used oral antiplatelet agents in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. Recent data have demonstrated limitations with the currently approved dosing regimen of clopidogrel (loading dose, 300 mg; maintenance dose, 75 mg daily) in a significant number of patients during the first few hours-days of treatment (Gurbel et al, Circulation. 2003;107:2908-2913 and Lau et al, Circulation. 2004;109:166-171). To circumvent this problem, some centers use a higher loading dose of clopidogrel (600 mg). Prasugrel is a novel thienopyridine prodrug similar to clopidogrel and ticlopidine that is more efficiently metabolized to its active metabolite compared with the 2 older drugs, providing enhanced platelet inhibition with less intersubject variability. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) study was a phase 3, multicenter trial that studied prasugrel in comparison with Clopidogrel in patients with moderate-to-high-risk acute coronary syndromes. In this article, we discuss the findings of this major trial, review previously published literature that compares the 2 medications, and provide a clinical context for the potential role of prasugrel in practice.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Clopidogrel; Combined Modality Therapy; Coronary Angiography; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Risk Assessment; Severity of Illness Index; Survival Analysis; Thiophenes; Thromboembolism; Ticlopidine; Treatment Outcome

A patient undergoes intracranial stent insertion for stent-assisted coiling of a basilar tip aneurysm and left middle cerebral artery aneurysm. A flow diverting stent is also placed across an anterior communicating artery aneurysm. Prior to the procedure, the patient takes dual antiplatelet medications, being aspirin and clopidogrel. Because of the concern regarding in-stent thrombus and thromboembolic complications related to intracranial stenting and the high rate of clopidogrel resistance, preoperative platelet function testing (PFT) was undertaken to ensure platelet inhibition. In this case, PFT was performed on a platelet function analyser which demonstrated platelet inhibition. Ten days following the procedure, the patient represented with thromboembolic stroke. Repeat PFT performed with whole blood impedance aggregometry and despite full medication compliance demonstrated clopidogrel resistance. Clopidogrel was then ceased and prasugrel commenced. This case demonstrates the importance of appropriate platelet inhibition in patients with intracranial stents and the controversy surrounding PFT.

Topics: Aged; Aspirin; Clopidogrel; Diagnosis, Differential; Drug Resistance; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Magnetic Resonance Imaging; Male; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Preoperative Care; Stents; Stroke; Thromboembolism; Treatment Outcome; Withholding Treatment

Gastrointestinal bleeding (GIB) frequently occurs following percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) with the prescription of P2Y. To compare GIB rates associated with clopidogrel, prasugrel and ticagrelor using national medical and pharmacy claims data from privately insured and Medicare Advantage enrollees .. Propensity score and inverse probability treatment weighting were used to balance baseline characteristics among treatment groups. The 1-year GIB risk was calculated using weighted Cox proportional hazard models and expressed as hazard ratios (HR) with 95% confidence intervals (CI) and number needed to harm (NNH).. We identified 37 019 patients with ACS (non-ST elevation ACS [NSTE-ACS] and ST-elevation myocardial infarction [STEMI]) within 14 days of a PCI (mean age 63 years and 70% male). Clopidogrel prescription was most common (69%) with prasugrel (16%) and ticagrelor (14%) prescribed less frequently. When compared with clopidogrel, ticagrelor was associated with a 34% risk reduction (HR 0.66; 95% CI: 0.54-0.81) in GIB overall and with NSTE-ACS, and a 37% GIB risk reduction (HR 0.63; 95% CI: 0.42-0.93) in STEMI patients. When compared with clopidogrel, prasugrel was associated with a 21% risk reduction (HR 0.79; 95% CI: 0.64-0.97) overall, a 36% GIB risk reduction (HR 0.64; 95% CI: 0.49-0.85) in STEMI patients but no reduction of GIB risk in NSTE-ACS patients.. In the first year following PCI, ticagrelor or prasugrel are associated with fewer GIB events than clopidogrel.

Topics: Acute Coronary Syndrome; Aged; Clopidogrel; Cohort Studies; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Prasugrel Hydrochloride; Retrospective Studies; Thromboembolism; Ticagrelor; Treatment Outcome; United States

Antiplatelet premedication is widely accepted for interventional treatment of cerebral aneurysms to prevent thromboembolism. However, antiplatelet resistance sometimes limits the effectiveness of premedication.. To compare 2 groups administered low-dose prasugrel (PSG group) or clopidogrel-based tailored antiplatelet (CPG group) in terms of platelet function and procedure-related complications.. A total of 411 patients with 505 unruptured aneurysms who underwent endovascular treatment within the past 17 mo were retrospectively enrolled in this study. The PSG (225 patients with 277 aneurysms) and CPG groups (186 patients with 228 aneurysms) were administered the respective medication prior to endovascular treatment. We measure the response to the antiplatelet medication with a laboratory test. Episodes of periprocedural bleeding and thromboembolism were compared between the 2 groups.. There were significant differences between the 2 groups in terms of the mean P2Y12 reaction unit values (125.7 in the PSG group vs 251.0 in the CPG group; P < .001) and percentage inhibition (57.8% vs 18.7%, respectively; P < .001). Drug resistance was 29.6% per patient in the CPG group and 2.7% per patient in the PSG group. The PSG group reported 1 thromboembolism and bleeding each; meanwhile, the CPG group reported 7 thromboembolism and 3 bleeding. Compared to clopidogrel administration, prasugrel administration significantly decreased the risk of thromboembolism (weighted hazard ratio, 0.17; 95% confidence interval, 0.03-0.99). However, the risk of bleeding was not significant.. Prasugrel was found to be more effective in reducing periprocedural thromboembolism compared to clopidogrel.

Topics: Aged; Clopidogrel; Endovascular Procedures; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Prasugrel Hydrochloride; Premedication; Retrospective Studies; Thromboembolism

Although the new oral P2Y12 inhibitors, prasugrel/ticagrelor have shown greater efficacy than clopidogrel in patients with the acute coronary syndrome, but they have not shown better efficacy in Korean patients. So we evaluated the efficacy of the prasugrel/ticagrelor in patients with myocardial infarction (MI) and diabetes, a more high-risk patients group.From the Korea Acute Myocardial Infarction Registry-National Institute of Health, 3985 patients with MI and diabetes who underwent PCI were enrolled between November 2011 and December 2015. The patients were divided into 2 groups: clopidogrel (n = 2985) and prasugrel/ticagrelor (n = 1000).After propensity score matching, prasugrel/ticagrelor group showed a no significant difference in risk of the composite of cardiac death (CD), recurrent MI or stroke (hazard ratio [HR], 0.705; 95% confidence interval [CI], 0.474-1.048; P = .084). However, the risk of major bleeding was significantly higher in the prasugrel/ticagrelor group. (HR; 2.114, 95% CI; [1.027-4.353], P = .042). In subgroup analysis, major bleeding was significantly increased in the subgroup of creatinine clearance <60 ml/min/1.73 m, hypertension, underwent a trans-femoral approach and diagnosed as NSTEMI among the prasugrel/ticagrelor group.The use of prasugrel/ticagrelor did not improve the composite of CD, recurrent MI or stroke, however, significantly increased major bleeding events in Korean patients with MI and diabetes undergoing PCI.

Topics: Aged; Clopidogrel; Cohort Studies; Comorbidity; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Myocardial Infarction; Outcome and Process Assessment, Health Care; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Postoperative Period; Prasugrel Hydrochloride; Republic of Korea; Thromboembolism; Ticagrelor

The use of antiplatelet medications to prevent thrombosis in the treatment of cerebral aneurysms with stents has become widely emphasized.. To compare low-dose prasugrel with clopidogrel in stent-assisted coil embolization of intracranial aneurysms.. This is a retrospective review of 311 aneurysms from 297 patients who underwent stent-assisted endovascular coil embolization of unruptured intracranial aneurysm between November 2014 and March 2017. Thromboembolic and hemorrhagic adverse events were compared between 207 patients who received low-dose prasugrel (PSG group) and 90 patients who received clopidogrel (CPG group).. P2Y12 reaction unit (PRU) values were significantly lower in the PSG group (PSG group vs CPG group, 132.3 ± 76.9 vs 238.1 ± 69.1; P < .001); the percentage of inhibition was also statistically higher in the PSG group (54.0 ± 26.0% vs 20.8 ± 18.6%; P < .001). Thromboembolic events occurred less frequently in the PSG group than in the CPG group (0.9% vs 6.4%; P = .01), whereas there was no significant difference in the percentage of hemorrhagic complications (0.5% vs 2.2%; P = .22). In the multivariate analysis, clopidogrel as the antiplatelet medication was the sole significant risk factor for thromboembolism in this series of patients undergoing stent-assisted coil embolization.. Use of low-dose PSG as an antiplatelet premedication is quick, effective, and safe for stent-assisted coil embolization of unruptured intracranial aneurysms. Prasugrel premedication significantly lowered the frequency of thromboembolic events without increasing the risk of hemorrhage.

Topics: Adult; Aged; Clopidogrel; Embolization, Therapeutic; Endovascular Procedures; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Premedication; Retrospective Studies; Risk Factors; Stents; Thromboembolism

Blister like aneurysm (BLA) is extremely challenging to treat; endoluminal reconstruction has emerged as the most promising treatment method. When to treat after the ictus, the timing of administration of antiplatelet and causal relationship between platelet function testing results and thrombo-embolism is unclear. We theorized that Prasugrel with a lower incidence of resistance may be a safe suitable alternative to clopidogrel in patients treated with a flow diverter (FD).. Prospectively collected data from consecutive patients treated for a ruptured blister with an FD was reviewed. Device deployment was timed to be at 2 h following Prasugrel loading. Thrombo-embolic and hemorrhagic complications, and occlusion rates were documented.. Nine patients were included. Most were females (55%); the median age was 55 (43, 65). The median Fischer grade was 3 (2, 4). A single pipeline device was deployed in all within 24 h of admission; the median time from ictus to device deployment was 4 days (2, 30). There were no thrombo-embolic or hemorrhagic complication. Complete occlusion was noted in 89% (n = 9).. Prasugrel loading timed 2 h prior to stent delivery did not increase thrombo-embolic or hemorrhagic complications. Single stent that is well apposed against the wall appears to be an effective treatment strategy to treat BLA. Advances in knowledge: Treatment of acutely ruptured BLA with a single pipeline device deployed at 2 h after Prasugrel loading appears to be safe.

Topics: Adult; Aged; Aneurysm, Ruptured; Embolization, Therapeutic; Female; Hemorrhage; Humans; Intracranial Aneurysm; Male; Middle Aged; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Retrospective Studies; Stents; Thromboembolism; Treatment Outcome

Topics: Adenosine; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Clopidogrel; Dabigatran; Fibrinolytic Agents; Guideline Adherence; Humans; Morpholines; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Ticagrelor; Ticlopidine; Treatment Outcome