Efficacy and Safety of De-Escalation of Anti-Platelet Therapy after Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome: A Meta-Analysis of Randomized Clinical Trials

Purpose: This meta-analysis was conducted to study the efficacy and safety of switching from potent P2Y12 inhibitors to clopidogrel, because there is no definite conclusion on the strategy.Method: We conducted a systematic review and meta-analysis of patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention, and compared the efficacy and safety of de-escalation or not of anti-platelet therapy. The relevant randomized controlled trials were included by searching several databases. Net adverse clinical events were identified as the composite endpoint, which was defined as a composite of cardiovascular death, myocardial infarction, revascularization, stroke and bleeding at 12 months after ACS. The efficacy endpoints were cardiovascular death, myocardial infarction, revascularization, stroke, all-cause death and stent thrombosis. Bleeding was designed as the safety endpoint. The relative risk (RR) and 95% confidence intervals (CI) of endpoint events were calculated by the fixed effects model. Result: Six randomized controlled trials with 7627 patients met inclusion criteria. There were significant differences in the risk of net adverse clinical events (RR 0.67, CI 0.58–0.78, P < 0.00001), and bleeding endpoint (0.61, 0.52–0.71, P < 0.00001) between the two groups. However, there were no significant differences in the risk of all efficacy endpoints.Conclusions: The strategy of de-escalation from prasugrel/ticagrelor to clopidogrel can reduce the incidence of net adverse clinical events and bleeding events in patients with ACS undergoing percutaneous coronary intervention (Registered by PROSPERO at July 04 2021, ID 265782).

Platelet Toll-like Receptors in Healthy and Acute Myocardial Infarction Subjects

<p>Platelet activation is pathological in acute myocardial infarction (AMI). Despite treatment with dual anti-platelet therapy (DAPT), platelet activation can continue to occur post-AMI and has been linked to an increased risk of recurrent cardiovascular events. Toll-like receptors (TLRs) are important innate immune receptors, and platelets are known to express a subset of TLRs. The functional significance of these platelet-TLR pathways in AMI has not been fully examined but may contribute to persistent post-AMI platelet activation. Platelet-TLR expression, TLR-mediated platelet activation and the platelet effect on leukocyte responses to TLR stimulation were examined in this thesis. Platelet-TLR expression and TLR-mediated platelet activation was examined for a subset of these receptors (TLR1, 2, 4, 6 and 9) in healthy subjects and in AMI subjects on DAPT. We observed an increase in platelet expression of TLR1, 4 and 9 in AMI platelets compared to healthy subjects. Further investigation into platelet-TLR9 expression showed an increase in expression upon platelet activation in healthy, but not AMI, subjects. We observed direct, dose-dependent platelet activation in response to Pam3CSK4 (TLR2/1 agonist) and ODN2009 (TLR9 agonist) in healthy subjects and in AMI on DAPT. For both cohorts, platelets were also directly activated by a high dose of LPS (TLR4 agonist) but were not directly activated by FSL-1 (TLR6 agonist). These results demonstrate that some (TLR1, 2, 4 and 9), but not other (TLR6), platelet-TLR pathways can cause platelet activation in AMI despite treatment with potent anti-platelet therapy. For the results described above, we were unable to assess TLR-mediated platelet activation in the absence of anti-platelet therapy in AMI subjects as these drugs are administered before or immediately upon presentation to hospital. It was therefore not possible to exclude the possibility that DAPT was providing a degree of inhibition of platelet activation in AMI patients. To address this, we determined the extent to which aspirin monotherapy or DAPT could inhibit platelet activation in response to TLR2/1, TLR4 and TLR9 stimulation in a cross-over study in healthy subjects. We demonstrated that DAPT only modestly inhibited, and aspirin monotherapy did not inhibit, platelet activation in response to all TLR agonists tested and platelets still became potently activated despite treatment with anti-platelet agents. These platelet-TLRs represent intact on-treatment platelet activation pathways. Lastly, we determined the extent to which platelets modulate leukocyte responses to TLR2/1, TLR2/6 and TLR4 stimulation. Platelets were able to reduce neutrophil responses to TLR stimulation, and modulated PBMC cytokine and chemokine production in a complex manner following stimulation with LPS and FSL-1. The presence of platelets did not change cytokine/chemokine production in response to Pam3CSK4, demonstrating a TLR agonist-specific manner of platelet modulation. We further investigated the effect of platelets on neutrophil responses to TLR stimulation. With platelets, neutrophil activation was attenuated, and phagocytic activity was increased in unstimulated cultures and in response to various doses of Pam3CSK4 and FSL-1. Neutrophil elastase secretion was attenuated in unstimulated cultures and in response to low-dose stimulation with all three TLR agonists. We show that platelets can both augment and attenuate various markers of neutrophil function. Together, this work indicates that platelets express functional TLR pathways that can differentially regulate a number of thrombotic and inflammatory responses in healthy subjects and in subjects with AMI.</p>

Platelet Toll-like Receptors in Healthy and Acute Myocardial Infarction Subjects

<p>Platelet activation is pathological in acute myocardial infarction (AMI). Despite treatment with dual anti-platelet therapy (DAPT), platelet activation can continue to occur post-AMI and has been linked to an increased risk of recurrent cardiovascular events. Toll-like receptors (TLRs) are important innate immune receptors, and platelets are known to express a subset of TLRs. The functional significance of these platelet-TLR pathways in AMI has not been fully examined but may contribute to persistent post-AMI platelet activation. Platelet-TLR expression, TLR-mediated platelet activation and the platelet effect on leukocyte responses to TLR stimulation were examined in this thesis. Platelet-TLR expression and TLR-mediated platelet activation was examined for a subset of these receptors (TLR1, 2, 4, 6 and 9) in healthy subjects and in AMI subjects on DAPT. We observed an increase in platelet expression of TLR1, 4 and 9 in AMI platelets compared to healthy subjects. Further investigation into platelet-TLR9 expression showed an increase in expression upon platelet activation in healthy, but not AMI, subjects. We observed direct, dose-dependent platelet activation in response to Pam3CSK4 (TLR2/1 agonist) and ODN2009 (TLR9 agonist) in healthy subjects and in AMI on DAPT. For both cohorts, platelets were also directly activated by a high dose of LPS (TLR4 agonist) but were not directly activated by FSL-1 (TLR6 agonist). These results demonstrate that some (TLR1, 2, 4 and 9), but not other (TLR6), platelet-TLR pathways can cause platelet activation in AMI despite treatment with potent anti-platelet therapy. For the results described above, we were unable to assess TLR-mediated platelet activation in the absence of anti-platelet therapy in AMI subjects as these drugs are administered before or immediately upon presentation to hospital. It was therefore not possible to exclude the possibility that DAPT was providing a degree of inhibition of platelet activation in AMI patients. To address this, we determined the extent to which aspirin monotherapy or DAPT could inhibit platelet activation in response to TLR2/1, TLR4 and TLR9 stimulation in a cross-over study in healthy subjects. We demonstrated that DAPT only modestly inhibited, and aspirin monotherapy did not inhibit, platelet activation in response to all TLR agonists tested and platelets still became potently activated despite treatment with anti-platelet agents. These platelet-TLRs represent intact on-treatment platelet activation pathways. Lastly, we determined the extent to which platelets modulate leukocyte responses to TLR2/1, TLR2/6 and TLR4 stimulation. Platelets were able to reduce neutrophil responses to TLR stimulation, and modulated PBMC cytokine and chemokine production in a complex manner following stimulation with LPS and FSL-1. The presence of platelets did not change cytokine/chemokine production in response to Pam3CSK4, demonstrating a TLR agonist-specific manner of platelet modulation. We further investigated the effect of platelets on neutrophil responses to TLR stimulation. With platelets, neutrophil activation was attenuated, and phagocytic activity was increased in unstimulated cultures and in response to various doses of Pam3CSK4 and FSL-1. Neutrophil elastase secretion was attenuated in unstimulated cultures and in response to low-dose stimulation with all three TLR agonists. We show that platelets can both augment and attenuate various markers of neutrophil function. Together, this work indicates that platelets express functional TLR pathways that can differentially regulate a number of thrombotic and inflammatory responses in healthy subjects and in subjects with AMI.</p>

Abstract 17085: An Anomalous Outcome Of Renal Transplant

Case Presentation: A 65 year old man with diabetic renal disease developed acute dyspnea at rest on the first post-operative day after an uncomplicated deceased donor renal transplant. He was hypertensive, tachycardic, and hypoxemic. His electrocardiogram showed anterior ST elevations with reciprocal inferior ST depressions and his chest x-ray revealed pulmonary edema. He was given anti-platelet therapy, nitroglycerin, beta blocker and taken emergently for angiography. He had a thrombotic occlusion of a co-dominant anomalous left circumflex artery arising from the ostium of a moderate caliber right coronary artery. He underwent successful percutaneous coronary intervention. His post-revascularization echocardiogram showed a hypokinetic to akinetic inferior wall with preserved global left ventricular systolic function. Coronary CT for further assessment of the course of the anomalous artery was not pursued given minimal benefit and the risk of worsening graft function. He was discharged on dual anti-platelet therapy, beta blocker and a statin. Discussion: There is no consensus about risk stratification before renal transplant. Our patient’s pre-operative exercise treadmill test (ETT) showed reduced functional capacity at 5.6 metabolic equivalents, failure to reach target heart rate, with 1.0 mm down sloping ST depression in infero-lateral leads with no ischemic symptoms. While our patient had an equivocal ETT, his lack of angina argued against further work-up. Post-operatively, a pro-inflammatory state, increased shear stress, acquired thrombophilia and immunosuppressive medications can all contribute to plaque rupture with thrombus formation. Atherosclerosis due to diabetes and renal disease coupled with mechanical factors such as passive compression at the intraarterial course, acute angle take-off or valve-like closure of the slit orifice may have subjected our patient with an anomalous left circumflex artery to an acute ST-elevation MI.

Platelet Abnormalities in Chronic Kidney Disease and Their Implications for Antiplatelet Therapy

Patients with chronic kidney disease (CKD) display a highly increased risk of cardiovascular and thromboembolic complications, with around half of patients with advanced CKD ultimately dying of cardiovascular disease. Paradoxically, these patients also have a higher risk of hemorrhages, greatly complicating patient therapy. Platelets are central to hemostasis, and altered platelet function resulting in either platelet hyper- or hypo-reactivity may contribute to thrombotic or hemorrhagic complications. Different molecular changes have been identified that may underlie altered platelet activity and hemostasis in CKD. Here, we summarize the current knowledge on CKD-induced aberrations in hemostasis with a special focus on platelet abnormalities. We also discuss how prominent alterations in vascular integrity, coagulation as well as red blood cell count in CKD may contribute to altered hemostasis in these high-risk patients. Furthermore, with CKD patients commonly receiving anti-platelet therapy to prevent secondary atherothrombotic complications, we discuss anti-platelet treatment strategies and their risk vs. benefit in terms of thrombosis prevention, bleeding and clinical outcome depending on CKD-stage. This reveals a careful consideration of benefits vs. risks of antiplatelet therapy in CKD patients, balancing thrombotic vs. bleeding risk. Nonetheless, despite antiplatelet therapy, CKD patients remain at increased cardiovascular risk. Thus, deep insights into altered platelet activity in CKD as well as underlying mechanisms are important for the optimization and development of current and novel anti-platelet treatment strategies, specifically tailored to these high-risk patients. Ultimately, this review underlines the importance of a closer investigation of altered platelet function, hemostasis, and anti-platelet therapy in CKD patients.