Clinical implications of aspirin resistance

Zimmermann, Norbert; Hohlfeld, Thomas

doi:10.1160/th08-01-0056

Cited by 76 publications

(66 citation statements)

References 62 publications

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“…Poor response to aspirin and clopidogrel therapy, as evaluated by LTA, has been associated with an increased risk of thrombotic events. 7,32 Jakubowski et al…”

Section: Discussionmentioning

confidence: 99%

Effect of antiplatelet therapy on thromboembolism after flow diversion with the Pipeline Embolization Device

Heller¹,

Dandamudi²,

Lanfranchi

et al. 2013

JNS

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F low-diverting stents are rapidly altering the basic principles for the embolization of intracranial aneurysms. 15,16 Through diversion of hemodynamic force from the aneurysm and restoration of anatomical arterial flow through the parent artery, flow-diverting stents such as the Pipeline Embolization Device (PED; Chestnut Medical) promote targeted aneurysm occlusion and involution.Initial reports of PED use demonstrated high rates of aneurysm occlusion, with complication rates comparable to those of other intracranial stents used for the treatment of aneurysms. 18,21 Although the authors of previous studies in the literature have evaluated the rate of clinically evident complications following PED deployment, to our knowledge there have been no study authors who have described the total incidence of acute ischemic infarcts following PED deployment in all patients. Using routine Object. Flow-diverting stents offer a novel treatment approach to intracranial aneurysms. Data regarding the incidence of acute procedure-related thromboembolic complications following deployment of the Pipeline Embolization Device (PED) remain scant. The authors sought to determine the rate of embolic events in a bid to identify potential risk factors and assess the role of platelet inhibition.Methods. Data in all patients receiving a PED for treatment of an intracranial aneurysm were prospectively maintained in a database. Diffusion-weighted 3-T MRI was performed within 24 hours of PED deployment. The incident rate of procedural embolism was established, and univariate analysis was then performed to determine any associations of embolic events with measured variables. The degree of platelet inhibition in response to aspirin and clopidogrel was evaluated by challenging the platelet samples with arachidonic acid and adenosine diphosphate, respectively, and then performing formal light transmission platelet aggregometry.Results. Twenty-three patients with 26 aneurysms were eligible for inclusion in the study. Thirty-one PEDs were deployed in 25 procedures. All ischemic lesions detected on diffusion-weighted 3-T MRI were identified as embolic based on their location and distribution, with none appearing to be due to perforator artery occlusion. Procedural embolic events were found in the target parent vessel territory in 13 (52%) of 25 procedures, with no patients harboring lesions contralateral to the deployed PED. The number of embolic events per procedure ranged from 3 to 16, with a mean of 5.4. There was no significant difference between cases with and without procedural embolism in platelet inhibition by aspirin (mean 15% vs 12% residual activation; p = 0.28), platelet inhibition by clopidogrel (mean 41% vs 41% residual activation; p = 0.98), or intraprocedural heparin-induced anticoagulation (mean activated clotting time 235 seconds vs 237 seconds; p = 0.81). By multivariate analysis, the authors identified larger aneurysm size (p = 0.03) as the single variable significantly associated with procedural embolism. There was no significa...

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“…Poor response to aspirin and clopidogrel therapy, as evaluated by LTA, has been associated with an increased risk of thrombotic events. 7,32 Jakubowski et al…”

Section: Discussionmentioning

confidence: 99%

Effect of antiplatelet therapy on thromboembolism after flow diversion with the Pipeline Embolization Device

Heller¹,

Dandamudi²,

Lanfranchi

et al. 2013

JNS

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“…The definition of aspirin 15 and clopidogrel 16 resistance is controversial. Lab response to antiplatelet agents appears to be normally distributed, and it therefore depends on where the cutoff of sufficient platelet inhibition lies.…”

Section: Resistance To Antiplatelet Drugsmentioning

confidence: 99%

Role of Ticagrelor in Clopidogrel Nonresponders: Resistance Is Futile?

2010

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D ual antiplatelet therapy with aspirin and a thienopyridine drug that blocks the platelet adenosine diphosphate receptor P2Y12 is the cornerstone of management in patients presenting with acute coronary syndrome (ACS). Clopidogrel is the most widely used thienopyridine, with evidence of benefit in non-ST-elevation myocardial infarction (MI), 1 percutaneous coronary intervention (PCI), 2 and ST-elevation MI treated with thrombolysis or primary PCI. 3,4 Article see p 1188However, clopidogrel has several suboptimal characteristics. First, despite administration of a 600 mg loading dose, clopidogrel requires at least 2 hours to achieve effective platelet inhibition, which is clearly disadvantageous during urgent PCI. Second, the irreversible P2Y12 receptor inhibition may be associated with an increased risk of hemorrhagic complications, particularly in patients requiring urgent coronary artery bypass grafting or other surgery. Furthermore, clopidogrel is a prodrug that requires 2-stage hepatic activation by cytochrome P450 (CYP) enzymes. This is susceptible to genetic polymorphisms, resulting in a variable response and an attenuated antiplatelet effect. Indeed, reduced function alleles (especially CYP2C19*2), which are present in Ϸ30% of the population, lead to diminished production of the active metabolite. 5 This phenomenon, often called clopidogrel resistance, is associated with increased risk of atherothrombotic complications, including stent thrombosis. 5,6 Clopidogrel's limitations have stimulated the search for alternative antiplatelet agents.The development of prasugrel was a major step forward. Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel and a more rapid onset of action. Like clopidogrel, prasugrel also requires biotransformation to active metabolites via CYP enzymes. In contrast, CYP polymorphisms do not affect active metabolite levels, platelet inhibition, or clinical cardiovascular event rates in patients treated with prasugrel. 7 In the study by Mega et al, 7 the common CYP functional variants associated with clopidogrel resistance were assessed in healthy volunteers and a cohort of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) patients allocated to prasugrel. CYP polymorphisms did not attenuate the pharmacological response to prasugrel and were not associated with adverse cardiovascular outcomes. These important observations may contribute to the differences in clinical response to these drugs.The TRITON-TIMI 38 trial 8 demonstrated a relative risk reduction of 19% in the primary efficacy endpoint (death from cardiovascular causes, nonfatal MI, and nonfatal stroke) with prasugrel compared with clopidogrel in ACS patients scheduled for PCI. This benefit was amplified in high-risk groups, such as patients with diabetes mellitus or STelevation MI, and it was apparent as early as day 3. Additionally, the frequency of both e...

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“…acetylsalicylic acid, clopidogrel, eptifibatide, triflusal and tirofiban) (Fig. 1); however, some have several collateral effects and resistance in long term therapy, such as the known clinical aspirin resistance 6) . In fact, numerous studies have documented inter-individual variability in platelet responsiveness to aspirin and clopidogrel, some of the most used oral antiplatelet drugs 7) .…”

Section: Introductionmentioning

confidence: 99%

Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

Geraldo

Bello

Dias

et al. 2010

JAT

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Aim: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N '-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). Methods: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPAR-TAN' 08 program, in silico ADMET screening and the Lipinski "rule of five" using Osiris Property Explorer and molinspiration on-line programs. Results: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c -IC50 61 M and 68 M respectively) almost 5-fold more potent than aspirin (IC50 300 M). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. Conclusion: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases. J Atheroscler Thromb, 2010; 17:730-739.

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Clinical implications of aspirin resistance

Cited by 76 publications

References 62 publications

Effect of antiplatelet therapy on thromboembolism after flow diversion with the Pipeline Embolization Device

Effect of antiplatelet therapy on thromboembolism after flow diversion with the Pipeline Embolization Device

Role of Ticagrelor in Clopidogrel Nonresponders: Resistance Is Futile?

Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

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