Anti‐platelet therapy: cyclo‐oxygenase inhibition and the use of aspirin with particular regard to dual anti‐platelet therapy

Warner, Timothy D.; Nylander, Sven; Whatling, Carl

doi:10.1111/j.1365-2125.2011.03943.x

Cited by 200 publications

(166 citation statements)

References 139 publications

(187 reference statements)

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“…13 Furthermore, it has been suggested that P2Y 12 inhibition alone may partially inhibit platelet thromboxane A 2 synthesis, 14,15 and in the presence of strong P2Y 12 inhibition, the additional effects of higher aspirin doses may result in a reduction of prostacyclin release, potentially shifting the influence of aspirin to a prothrombotic effect. 16 Consistent with the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7) trial, 17 no association of aspirin maintenance dose with ischemic event rates in the clopidogrel group was observed. Further investigations in vitro and in animals and humans, and preferably prospective randomized, controlled trials, are needed to understand the role of these complex pathobiological interactions.…”

Section: Discussionmentioning

confidence: 70%

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

et al. 2011

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on behalf of the PLATO Investigators Background-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (Pϭ0.045), with less effect of ticagrelor in North America than in the rest of the world. Methods and Results-Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose Ն300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort. Conclusions-The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872. (Circulation. 2011;124:544-554.)

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Section: Discussionmentioning

confidence: 70%

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

et al. 2011

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“…a well-characterized sequence of events, including the important release of secondary mediators of aggregation, notably ADP and thromboxane A 2 (1)(2)(3). These mediators are the targets of antithrombotic drugs taken by many millions of patients as prophylactic protection against heart attacks and strokes.…”

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confidence: 99%

Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide

Kirkby

Lundberg

Chan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Circulating platelets are constantly exposed to nitric oxide (NO) released from the vascular endothelium. This NO acts to reduce platelet reactivity, and in so doing blunts platelet aggregation and thrombus formation. For successful hemostasis, platelet activation and aggregation must occur at sites of vascular injury despite the constant presence of NO. As platelets aggregate, they release secondary mediators that drive further aggregation. Particularly significant among these secondary mediators is ADP, which, acting through platelet P2Y 12 receptors, strongly amplifies aggregation. Platelet P2Y 12 receptors are the targets of very widely used antithrombotic drugs such as clopidogrel, prasugrel, and ticagrelor. Here we show that blockade of platelet P2Y 12 receptors dramatically enhances the antiplatelet potency of NO, causing a 1,000-to 100,000-fold increase in inhibitory activity against platelet aggregation and release reactions in response to activation of receptors for either thrombin or collagen. This powerful synergism is explained by blockade of a P2Y 12 receptor-dependent, NO/cGMPinsensitive phosphatidylinositol 3-kinase pathway of platelet activation. These studies demonstrate that activation of the platelet ADP receptor, P2Y 12 , severely blunts the inhibitory effects of NO. The powerful antithrombotic effects of P2Y 12 receptor blockers may, in part, be mediated by profound potentiation of the effects of endogenous NO.anti-platelet therapy | atherothrombosis | prostacyclin A ctivation of platelets in a damaged blood vessel leads to a well-characterized sequence of events, including the important release of secondary mediators of aggregation, notably ADP and thromboxane A 2 (1-3). These mediators are the targets of antithrombotic drugs taken by many millions of patients as prophylactic protection against heart attacks and strokes. In particular, inhibition of thromboxane A 2 production by aspirin explains the antithrombotic utility of this drug, whereas blockade of the ADP receptor, P2Y 12 , by drugs such as clopidogrel, prasugrel, and ticagrelor provides a second, and possibly even stronger, antithrombotic protection (4). Within the circulation, platelets are constantly exposed to antithrombotic mediators, notably prostaglandin I 2 (PGI 2 ), which is derived from the vascular endothelium, and nitric oxide (NO), which can be produced by the vascular endothelium (5) and platelets themselves (6, 7). This leads to the understanding that there is an important interplay between endothelial-derived antiaggregatory mediators and platelet-derived proaggregatory mediators. For example, it has been demonstrated that activation of platelet P2Y 12 receptors by ADP causes inhibition of platelet adenylyl cyclase, which reduces the ability of PGI 2 acting through prostaglandin IP receptors to elevate cAMP, and thus reduces platelet aggregation. Hence, blockade of platelet P2Y 12 receptors increases the sensitivity of platelets to the antiaggregatory and antisecretory effects of PGI 2 (8, 9). This interaction is re...

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“…A plausible mechanism was proposed for the interaction between higher aspirin dose and ticagrelor that is linked to the level of P2Y 12 inhibition and the potential prothrombotic effects of high-dose aspirin through the suppression of prostacyclin. 24,25,31,32 However, even though the study design is different, the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibition with prasugrelThrombolysis In Myocardial Infarction (TRITON-TIMI) 38 study that compared the effects of prasugrel with clopidogrel showed that prasugrel reduced the risk of the composite of cardiovascular mortality, myocardial infarction, and stroke in patients with ACS scheduled for percutaneous coronary intervention, 33 irrespective of the aspirin dose. 34 Moreover, such an adverse interaction has not been reported to occur between aspirin and clopidogrel in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.…”

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Chronic Treatment With Ticagrelor Limits Myocardial Infarct Size

Nanhwan

Ling

Kodakandla

et al. 2014

ATVB

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Objective-In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y 12 -receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS). Approach and Results-Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A 2A /A 1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low-dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation. Conclusions-Ticagrelor Nanhwan et al Ticagrelor Limits Infarct Size 2079and that higher doses of aspirin may attenuate COX2 activity 1 and thereby part of the beneficial effects mediated by ticagrelor.In this study, we evaluated whether pretreatment with ticagrelor or clopidogrel limits myocardial IS, using an experimental model of transient mechanical coronary artery occlusion that is independent of intraluminal thrombus formation. Next, we studied the signaling pathways mediating this protective effect with special emphasis on the role of adenosine-receptor activation and COX2 activity. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results Ticagrelor Limits Myocardial ISA total of 8 rats died during surgery (2 in the control, 1 in the ticagrelor 75 mg/kg/d, 1 in the ticagrelor 150 mg/kg/d, 2 in the clopidogrel 30 mg/kg/d, and 2 in the clopidogrel 90 mg/kg/d group). Body weight, left ventricular (LV) weight, and the size of the area at risk (AR) were comparable among groups (Table 1). IS, expressed as percentage of the LV (Table 1) or percentage of the AR ( Figure 1A), was significantly and dose-dependently reduced in the ticagrelor-treated animals, whereas clopidogrel at 30 and 90 mg/kg/d had no effect. Hemodynamic data are presented in Figure IA and IB in the online-only Data Supplement.Plasma levels of ticagrelor 16 ho...

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Anti‐platelet therapy: cyclo‐oxygenase inhibition and the use of aspirin with particular regard to dual anti‐platelet therapy

Cited by 200 publications

References 139 publications

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide

Chronic Treatment With Ticagrelor Limits Myocardial Infarct Size

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Anti‐platelet therapy: cyclo‐oxygenase inhibition and the use of aspirin with particular regard to dual anti‐platelet therapy

Cited by 200 publications

References 139 publications

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Blockade of the purinergic P2Y 12 receptor greatly increases the platelet inhibitory actions of nitric oxide

Chronic Treatment With Ticagrelor Limits Myocardial Infarct Size

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Blockade of the purinergic P2Y ₁₂ receptor greatly increases the platelet inhibitory actions of nitric oxide