Antiplatelet Dose Research Articles

Abstract 223: Surgical Resolution of Coronary Artery Obstruction in Incomplete Kawasaki Disease

Case Report 8 months old male, who presented with 7 days fever, hematuria, conjunctival injection and limb edema; treated as a post infectious glomerulonephritis. Twenty days later, desquamation at the tip of the fingers and in palms and soles plus thrombocytosis were found. Considering Kawasaki disease (KD), an echocardiogram was performed, finding a 5mm aneurysm in right coronary artery and 4mm ectasia in the left coronary artery. The patient was on the subacute therefore IVIG was not administered; aspirin however in antiplatelet dose range was begun. He continued on surveillance by Cardiology Department without signs of cardiac malfunction. At two years follow up a new echocardiogram was performed, showing a left coronary aneurism of 6mm and a right coronary artery of 2.0mm which was difficult to identify. Left ventricular function was preserved with an ejection fraction of 72%. Four years later, posterior myocardial necrosis, without acute ischemia on electrocardiography was found. A perfusion myocardial scan showed an uptake defect in apical region, both during stress and rest phase, suggesting an old apical infarction. Cardiac catheterization reported a tortuous right coronary artery with diffuse obstruction and left coronary artery aneurysm of 6.1mm. Due to findings above, heart transplant was considered. On a second perfusion scan a large perfusion defect on the inferior and septal wall, which improved during the rest phase was seen. The finding above correlates with inferior and septal myocardial infarction and residual ischemia. The PET-CT scan showed viable tissue in the left ventricle wall. Recently, the patient underwent revascularization surgery of right coronary artery with coronary artery bypass graft. Postsurgical echocardiogram reported a left coronary giant aneurysm of 8mm, ejection fraction of 40%, and a compromised posterior and inferior left ventricular wall function. We report the first case of surgical resolution of a coronary artery obstruction due to KD in our medical center. Because of patient’s age and coronary arteries abnormalities, a surgically intervention was the best approach in order to preserve patient’s life, cardiac function, improve the prognosis and mainly to gain time for future treatment decisions.

Antiinflammatory effects of aspirin in ACS: relevant to its cardiocoronary actions?

Vascular injury in acute coronary syndromes (ACS) involves a complex cross-talk between inflammatory mediators, platelets and thrombosis, where the interaction between platelets and coagulation factors (e. g. thrombin) is a central link between thrombosis and inflammation. In ACS, aspirin at antiplatelet doses exhibits anti-inflammatory effects as seen from the decrease in inflammation markers such as CRP, M-CSF, MCP-1 and others. These actions probably occur subsequent to inhibition of platelet COX-1-dependent thromboxane formation and its action as a multipotent autocrine and paracrine agent. This likely involves inhibition of thrombin formation as well as inhibition of secondary pro-inflammatory mediators, such as sphingosine-1-phosphate. Experimental and limited clinical data additionally suggest antiinflammatory effects of aspirin independent of its antiplatelet action. For example, aspirin at antiplatelet doses might acetylate COX-2 in vascular cells, directing the activity of the enzyme into a 15-lipoxygenase which by transcellular metabolism results in the formation of 15-epi-lipoxin (´aspirin-triggered lipoxin´), an antiinflammatory mediator. Furthermore, aspirin stimulates eNOS via lysine-acetylation, eventually resulting in induction of heme oxygenase (HO-1), which improves the antioxidative potential of vascular cells. All of these effects have been seen at antiplatelet doses of 100-300 mg/day, equivalent to peak plasma levels of 10-30 µM. Many more potentially antiinflammatory mechanisms of aspirin have been described, mostly salicylate-related, at low to medium millimolar concentrations and, therefore, are of minor clinical interest. Altogether, there is a wealth of data supporting anti-inflammatory effects of aspirin in ACS, but studies generating direct evidence for antiinflammatory effects in ACS remain to be done.

Grande fréquence des prescriptions médicamenteuses à visée cardiovasculaire potentiellement inappropriées dans la population âgée

Cardiovascular disease is a leading cause of morbidity and mortality in the elderly population. We evaluated the adequacy of prescribing (miss and under used) with respect to STOPP-START criteria. A sample of 100 patients hospitalized in cardiovascular specialty divisions (medicine or surgery) or in the different sectors making up the geriatric network (day-care hospital, short or rehabilitation ward, nursing home) has been considered. Drug prescriptions at the admission time were analysed. Eight hundred and seventy-four prescriptions were analysed. In 65% of patients, from 5 to 10 medications were prescribed and in 28% over 10. Fifty-four percent of patients had, at least, one potentially inappropriate prescription (PIP) by STOPP. Among them, 48% of PIP prescriptions contained 1, 41% 2 and 11% 3 or more. The omission of one medication according to START criteria concerned 57% of the sample. Among them, 46% had one omission, 44% 2 to 3 and 10% 4 omissions or over. The cardiovascular system is the one most concerned by the PIP. Whether 28.1% of the PIP by STOPP criteria concerned cardiovascular drugs, the omission of prescription, according to START criteria, was 41.8%. There was no significant difference between the different settings studied. There was no effect of age or sex on the impact of PIP (P>0.20) or being polymédiqué (P=0.44). According to the criteria STOPP-A, the prescription of antiplatelet (indication and dose) was highlighted. Prescribing omission also concerned antiplatelet agents but also statins in patients with atherosclerosis as well as antiplatelet and anticoagulant in patients with permanent atrial fibrillation and inhibitor of angiotensin converting enzyme (ACE) after myocardial infarction or with chronic heart failure. Potentially inappropriate prescribing medications were very common in elderly patients with cardiovascular conditions. They concerned as much as underusing of important drugs with potential benefits and prescribing commission of treatment that did not fit with patients' comorbidities and/or characteristics.

Kawasaki disease with Glucose-6-Phosphate Dehydrogenase deficiency, case report

Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children younger than 5years of age. Coronary artery abnormalities are the most serious complication.Based on the literatures infusion of Intravenous Immunoglobulin of 2g/kg and a high dose of oral aspirin up to 100mg/kg/day are the standard treatment for Kawasaki disease in the acute stage, and should be followed by antiplatelet dose of aspirin for thrombocytosis. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is an inherited X-linked hereditary disorder, and aspirin can induce hemolysis in patients with G6PD deficiency. We report a case of a 5year and 8month old male with KD and G6PD deficiency.

12-hydroxyeicosatetraenoic acid is associated with variability in aspirin-induced platelet inhibition.

BackgroundAspirin is one of the most widely used non-steroidal anti-inflammatory drugs (NSAIDs). It is also a commonly used anti-platelet drug, which inhibits the formation of the platelet activator, thromboxane A2 (TxA2) via inhibition of cyclooxygenase-1 (COX-1). However, the presence of a patient subset that fails to respond to aspirin despite reduced TxA2 concentrations suggests that the effect of aspirin might be more complex than exclusive COX-1 inhibition.MethodsIn this study we evaluated the impact of in vivo oral administration of a standard anti-platelet dose (75 mg) of aspirin in healthy volunteers on the acute impact of in vitro collagen-mediated platelet aggregation and generation of platelet-derived TxA2 and the 12-lipoxygenase (LOX) metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The eicosanoids were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS).ResultsLow-dose aspirin administration not only inhibited TxA2 generation but also decreased the production of 12-HETE. Furthermore, a significant correlation was observed between the levels of 12-HETE and collagen-induced platelet aggregation. Pre-treatment of platelets with the 12-LOX inhibitor, baicalein, prior to activation attenuated platelet aggregation.ConclusionsThese findings support a role for 12-HETE as a pro-aggregatory eicosanoid in platelet function and suggest a role for 12-HETE in variable sensitivity to aspirin. The study also highlights a potentially important mechanism by which aspirin impacts upon eicosanoid generation.

Incidence and clinical features of kawasaki disease in Catalonia (Spain)

between onset of the disease and diagnostic was 7.2±5.3 days. Ethnic distribution was: Caucasian 279 patients(69.9%), North African 26 (6.5%), Amerindian 21 (5.2%), Asian 14 (3.5%) and Sub-Saharan 4 (1%). Ethnicity was not available in 55 (13.8%) patients. Distribution of classical manifestations for KD was: fever in 100% of patients, changes in extremities 40.3% (desquamation in 31% of them), exanthema 84.2%, conjunctival injection 79.7%, changes in lips and oral cavity 55.6% and lymphadenopathy 28.8%. Other clinical findings reported were: sterile pyuria in 80(20%) patients, nausea and vomiting in 96(24%), abdominal pain in 85(21.3%), gallbladder distention in 14 (3.5%), transaminase elevation in 120(30%), jaundice in 21(5.1%), irritability in 118(29.5%), aseptic meningitis in 16(4%), sensorineural hearing loss in 2 patients, uveitis in 11(2.7%) and arthritis or arthralgia in 55(13.8%). Cardiologic findings were: perivascular brightness of the coronary wall in 42(10.5%) patients, pericarditis in 9(2.3%), myocarditis in 4(1%), mitral regurgitation in 28 (7%) and CA in 53 patients(13.3%), 26(49%) of them disappearing before the 2 nd month after the onset of KD. 4 patient had giant CA. Intravenous immunoglobulin (IVIG) was administered in 389(97.5%) patients with response to the 1 st dose in 332(83.2%). Day of IVIG administration was 7.5±3.1. Other treatment plans were: 2 nd (69% response) and 3 rd IVIG doses, oral or iv corticosteroids and abciximab (administered in 3 of the patients with giant CA). 97.7% of patients received anti-platelet dose aspirin in the convalescent phase. Conclusion

Antiplatelet therapy following TAVI: time to randomise

Following the introduction of transcatheter aortic valve implantation (TAVI), it is now possible to treat elderly patients with severe aortic stenosis and a high surgical risk. This advancement in interventional cardiology has led to increased survival, health status and quality of life. However, as with many invasive interventional procedures, TAVI is associated with the risk of cerebral embolisation and consequent ischaemic cerebrovascular events with possible neurological impairment. The risk estimates of post-procedural stroke associated with TAVI vary from 1.5 to 10 % and have been reported both early and late after the procedure. In the PARTNER Cohort B study, the Canadian multicentre TAVI registry and the study by Nuis et al., about 50 % of the stroke events occurred more than 24 h post-procedure [1]. In addition to clinically overt stroke, asymptomatic silent cerebral infarcts have been frequently observed on MRI, with a prevalence ranging from 62 to 93 % [2]. Although asymptomatic, accumulating evidence implicates that these silent cerebral infarcts are related to risk of future stroke, cognitive decline, dementia, and depression. Whether stroke occurs due to incomplete endothelialisation of the valve or by new onset of silent atrial fibrillation is unknown. Early post-procedural stroke (<24 h) is more likely the result of embolisation during valve implantation. Given this high incidence of cerebral events, adequate anticoagulation is probably required both during the procedure and in the following months. However, the exact regimen of anticoagulation involves a clinical dilemma with the therapeutic potential of reducing ischaemic complications at the expense of increasing the bleeding risk. The overall incidence of bleeding following TAVI has been reported in 41 % of the patients in the meta-analysis conducted by Genereux et al., of which 16 % were life-threatening [3]. It is important to bear in mind that life-threatening bleeding is associated with a six- to nine-fold increase in 30-day mortality after procedure and acts as an independent predictor of 1-year mortality [4]. Therefore, for clinical decision-making on antithrombotic treatment, it is important to find a balance between prevention of ischaemic complications and avoidance of bleeding risk. The recently published study by Nijenhuis et al. addresses this clinical dilemma regarding decision-making on anticoagulation treatment of elderly patients treated with TAVI [5]. As pointed out by the authors, the current European and American guidelines merely provide recommendations based on retrospective registries. The European Society of Cardiology guidelines recommend a combination of low aspirin and a thienopyridine early after TAVI, followed by aspirin or a thienopyridine alone. In those cases where there is an indication for treatment with vitamin K antagonists, such as in atrial fibrillation, a combined treatment of vitamin K antagonist and aspirin or a thienopyridine is in general installed. However, the guidelines do not provide any recommendations on the duration of dual antiplatelet therapy (DAPT). As observed in the survey undertaken in the Netherlands, a wide heterogeneity in the duration of dual antiplatelet therapy (DAPT) and loading dose of clopidogrel was noted. In two-thirds of the centres (n = 9) DAPT was prescribed for 3 months. In one centre, where only transapical TAVI is performed, no concomitant clopidogrel was prescribed at all. The duration of concomitant clopidogrel was dependent on the type of prosthesis in only two centres according to the recommendations of the respective manufactures, 6 months versus 3 months for supra-annular Core Valve™ and intra-annular prostheses (e.g. SAPIEN™, JenaValve), respectively. Whether the decision on the duration of concomitant clopidogrel and its loading dose indeed should be dependent on the valve type (SAPIEN™ or Medtronic Core Valve™) or procedural approach (transfemoral or apical) has not been described in the literature. Moreover, clinical decision-making becomes more complex in circumstances where there is a high bleeding risk, PCI (<1 year) prior to TAVI, triple therapy pre-TAVI and new-onset atrial fibrillation. This is nicely illustrated in the survey of the participating centres showing different approaches to these scenarios. In conclusion, the appropriate regimen of antiplatelet and anticoagulant therapy following TAVI is undefined and warrants the conduction of randomised controlled trials for clinical decision-making in this steadily growing patient population.

Microfluidic thrombosis under multiple shear rates and antiplatelet therapy doses.

The mainstay of treatment for thrombosis, the formation of occlusive platelet aggregates that often lead to heart attack and stroke, is antiplatelet therapy. Antiplatelet therapy dosing and resistance are poorly understood, leading to potential incorrect and ineffective dosing. Shear rate is also suspected to play a major role in thrombosis, but instrumentation to measure its influence has been limited by flow conditions, agonist use, and non-systematic and/or non-quantitative studies.In this work we measured occlusion times and thrombus detachment for a range of initial shear rates (500, 1500, 4000, and 10000 s−1) and therapy concentrations (0–2.4 µM for eptifibatide, 0–2 mM for acetyl-salicylic acid (ASA), 3.5–40 Units/L for heparin) using a microfluidic device. We also measured complete blood counts (CBC) and platelet activity using whole blood impedance aggregometry. Effects of shear rate and dose were analyzed using general linear models, logistic regressions, and Cox proportional hazards models.Shear rates have significant effects on thrombosis/dose-response curves for all tested therapies. ASA has little effect on high shear occlusion times, even at very high doses (up to 20 times the recommended dose). Under ASA therapy, thrombi formed at high shear rates were 4 times more prone to detachment compared to those formed under control conditions. Eptifibatide reduced occlusion when controlling for shear rate and its efficacy increased with dose concentration. In contrast, the hazard of occlusion from ASA was several orders of magnitude higher than that of eptifibatide. Our results show similar dose efficacy to our low shear measurements using whole blood aggregometry. This quantitative and statistically validated study of the effects of a wide range of shear rate and antiplatelet therapy doses on occlusive thrombosis contributes to more accurate understanding of thrombosis and to models for optimizing patient treatment.

Comparison of Effectiveness of Different Antiplatelet Doses of Aspirin in Patients with Acute Coronary Syndrome

Comparison of Effectiveness of Different Antiplatelet Doses of Aspirin in Patients with Acute Coronary Syndrome

Acetylsalicylsäure und Prävention kolorektaler Karzinome

Observational and some randomized clinical trials suggest that aspirin protects from occurrence and progression of colorectal neoplasias (adenomas, carcinomas). However, there are still open questions, regarding the benefit/risk ratio (bleedings) as well as dosage and duration of treatment during the probably long-term medication, before stringent recommendations regarding clinical use of aspirin can be made. Specifically, there is currently no generally accepted mode of action or molecular target of aspirin, though a relationship to tumor-associated enhanced PGE2 levels in the affected mucosa is likely. Regular daily intake of aspirin in antiplatelet doses of 100mg appears to be sufficient in responding persons. If this is confirmed in prospective randomized trials that are currently underway, this might add to the prophylactic use of aspirin and would suggest a pharmacological relationship to inhibition of COX-1 mediated prostaglandin/thromboxane biosynthesis as a common primary target for both cardiocoronary and antineoplastic prophylaxis. Prophylactic aspirin use might then add to an undoubtedly important healthy lifestyle including appropriate diet.

207 PLATELET COX-1 SUPPORTS THE PRODUCTION OF BOTH PROSTANOIDS AND HETES

<h3>Backround</h3> Prostaglandins (PGs) and hydroxyeicosatetraeinoic acids (HETEs) are synthesized from arachidonic acid (AA), which is released from the membrane phospholipids of cells through the activity of cytosolic phospholipase A_2α (cPLA_2α). It is known that in platelets AA is metabolised through the enzymes cyclooxygenase-1 (COX-1) and 12-lipoxygenase (12-LOX) leading to the production of a range of eicosanoids. Here we have determined the enzyme sources of the major prostanoid and HETE products released by platelets following activation by selective platelet agonists. To better model platelet activation we used either platelet rich plasma or whole blood within a platelet aggregometer, warmed and stirred at 1200rpm, and assessed whether HETEs originate from platelets or other blood cells. Furthermore, to investigate how the production of these eicosanoids is affected by anti-platelet therapy we examined the effects of the cyclooxygenase inhibitor, aspirin (100 µM), with or without the addition of the P2Y₁₂ receptor blocker, prasugrel (3 µM). <h3>Methods</h3> Blood from healthy volunteers was collected into hirudin and incubated (30 min, 37°C) either intact or following preparation into platelet rich plasma (PRP) in the presence of collagen (30 µg/ml), TRAP-6 (30 µM) or vehicle, in a platelet aggregometer with stirring (1200rpm). Plasma was then separated from the samples and the levels of prostanoids and HETEs were determined by LC/MS/MS analysis. In some experiments, blood and PRP were pre-treated with aspirin (100 µM), prasugrel (3 µM) or aspirin+prasugrel. <h3>Results</h3> LC/MS/MS analysis of collagen- and TRAP-stimulated PRP and blood showed large increases in the levels of thromboxane (TX) A₂, prostaglandin (PG) E₂, and PGD₂, as well as 8-, 11-, 15-and 12-HETE compared to unstimulated samples. Interestingly, as well as inhibiting the production of TXA₂, PGE₂ and PGD₂, aspirin also strongly inhibited the productions of 11-HETE and 15-HETE by both PRP and blood. The production of 12-HETE was reduced by aspirin and prasugrel used in combination. <h3>Conclusions</h3> LC/MS/MS analysis demonstrated that platelets are the main source of both prostanoids (TXA₂, PGE₂ and PGD₂) and HETEs (8-, 11-, 15- and 12) in blood exposed to platelet activators. Interestingly, in addition to abolishing the production of prostanoids, aspirin also blocked the production of 11-HETE and 15-HETE in both PRP and blood, indicating these HETEs are also formed through the activity of platelet COX-1. Aspirin in combination with prasugrel reduced, but did not abolish, the production of 12-HETE, consistent with this drug inhibiting the processes of platelet activation but not directly inhibiting platelet 12-LOX. It is possible these data may well help provide explanations for the beneficial effects of anti-platelet doses of aspirin in a range of cardiovascular diseases and cancers.

Aspirin and exodontia: A comparative study of bleeding complications with aspirin therapy

AimsThe fear of excessive bleeding prompts the physicians and treating surgeons to stop the aspirin therapy prior to invasive surgical procedure. Although this decreases the risk of bleeding complications, but predispose the patient to risk of thromboembolic events. With this background in mind, this study was done to evaluate the effect of aspirin on incidence of bleeding complications. MethodsPatient on anti-platelet dose of aspirin requiring extraction of single tooth was enrolled in the study. These patients were divided into two groups with 30 patients in each group. Group 1: patients were on aspirin therapy (75–325 mg/day) who continued it during simple dental extraction and Group 2: patients stopped aspirin 7–10 days prior to procedure. Single tooth was extracted by simple intra-alveolar technique. ResultThere was no post-operative bleeding complication in any group. ConclusionBased on the result of the study. It can be concluded that there is no need to stop the antiplatelet dose of aspirin prior to simple tooth extraction.

The discovery and development of prasugrel

Introduction: Prasugrel (CS-747, LY640315) is a third-generation thienopyridine, which gained approval by the FDA in 2009 for its use in patients with acute coronary syndrome undergoing percutaneous coronary intervention.Areas covered: This article focuses on the preclinical profile of prasugrel. Using published preclinical and clinical studies, the authors summarize the pharmacokinetics, pharmacodynamics, and pharmacogenomics of prasugrel and their distinguishing features in efficacy and safety.Expert opinion: Prasugrel has a more rapid, more potent antiplatelet effect with less interindividual response variability when compared to clopidogrel. Those therapeutic advantages are attributed to features of its chemical structure that favor the metabolic conversion of prasugrel to its active metabolite. However, the increased risk of bleeding has been associated with a greater antiplatelet effect and dosing profile; this is especially the case in those patients who are at a higher risk of bleeding complications. It is therefore important for an optimal dosing strategy of prasugrel to be identified to provide a formulation that has the best balance for efficacy and safety.

High on treatment platelet reactivity against aspirin by non-steroidal anti-inflammatory drugs – pharmacological mechanisms and clinical relevance

Inhibition of platelet function by aspirin results from irreversible inhibition of platelet cyclooxygenase (COX)-1. While sufficient inhibition is obtained at antiplatelet doses (75-325 mg/day) in most (≥95%) treated patients, the antiplatelet effect of aspirin and subsequent cardiovascular risk reduction is much less in clinical settings and disease-dependent. Several reasons for this "high on treatment platelet reactivity" are known. This paper reviews the evidence for an interaction between aspirin and other COX inhibitors, namely non-steroidal anti-inflammatory drugs (NSAIDs). Numerous experimental studies demonstrated a pharmacodynamic interaction between aspirin and NSAIDs. This likely occurs within the hydrophobic substrate channel of platelet COX-1 and might be explained by molecular competition between inhibitor drugs and substrate (arachidonic acid) at overlapping binding sites. This interaction is found with some compounds, notably ibuprofen and dipyrone (metamizole), but not with others, such as diclofenac and acetaminophen (paracetamol). Hence, this interaction is not a class effect of NSAIDs and/or non-steroidal analgesics but rather due to specific structural requirements which still remain to be defined. In vivo studies on healthy subjects and patients tend to confirm this type of interaction as well as large differences between NSAIDs and non-steroidal analgesics, respectively. These interactions may be clinically relevant and may increase the cardiovascular risk in long-term treatment for primary and secondary cardiovascular prevention in patients with chronic inflammation, such as rheumatoid arthritis. These patients have an elevated risk for myocardial infarctions and may require chronic antiplatelet treatment by aspirin in addition to treatment of inflammatory pain.

Toward a guided approach to platelet activation in diabetes

Diabetes is associated with substantially poorer cardiovascular outcomes. Furthermore, people with diabetes are at greatly increased risk of not responding to standard antiplatelet therapy for acute coronary syndromes, leading to higher mortality and stent thrombosis [1]. Poor glucose control likely contributes to these cardiovascular events through changes in platelet membrane fluidity and signalling, increased production of platelets leading to a greater fraction of younger and more reactive platelets not yet exposed to antiplatelet therapy, and increased triggering of platelet activation arising from an underlying thromboinflammatory milieu [2]. While patients with higher thrombotic risk may be prospectively identified through laboratory identification of elevated blood glucose or HbA1c [3], the approach to treatment for diabetic platelet hyper-responsiveness remains unclear. Options such as increasing frequency of antiplatelet therapy, additional and more aggressive antiplatelet therapy or more intensive glucose control have been suggested (Fig. 1). However, the data to support these are limited and, particularly where more aggressive antiplatelet therapy is proposed, must be measured against the potential for increased bleeding risk in patients with hyperglycemia. In patients with type-2 diabetes, Capodanno et al. [4] demonstrated enhanced inhibition of platelet function when patients took 81 mg of aspirin twice per day compared with 81 mg daily. Spectre et al. [5] showed greater inhibition of platelet function with 75 mg twice per day when compared to 75 mg daily in patients with type-2 diabetes and vascular complications. In a recent study Rocca et al. [6] showed that increasing frequency of dose better attenuated platelet activation over 24 h in both diabetic and non-diabetic patients. Therefore increasing the frequency of antiplatelet therapy dosing represents an appealing strategy in patients with diabetes and poor glycemic control. However, the clinical effectiveness of this approach on cardiovascular outcome, as well as the net benefit against increased bleeding risk remains to be investigated. Similarly, the addition of more aggressive antiplatelet therapy, such as newer ADP receptor antagonists with greater potency and bioavailability, or emerging thrombin receptor antagonists have been suggested [2]. The use of these must be weighed against the potentially increased risk of bleeding. While altering antiplatelet therapy strategies in patients with diabetes and poor glycemic control is an appealing avenue for further clinical investigation, a potential alternative or complimentary approach might be to achieve improved glycemic control in order to attenuate platelet activation. Several studies have assessed the ability of infused insulin in patients with diabetes to attenuate platelet function and improve cardiovascular outcome in acute coronary syndromes [7]. While evidence of improvement in cardiovascular outcome is variable, intensive treatment with insulin in patients with diabetes may attenuate platelet activation relative to conventional approaches to glycemic control [8]. In this issue of the Journal of Thrombosis and Thrombolysis, Vivas et al. [9] explore whether tight glycemic control with insulin infusion attenuates platelet reactivity in patients with an acute coronary syndrome and hyperglycemia at admission. In a post hoc analysis of the prospective, randomized, open-label CHIPs study, 67 patients with poor glycemic control (as measured by HbA1c [ 6.5 %) were M. D. Linden (&) Centre for Microscopy, Characterisation and Analysis, M510, University of Western Australia, 35 Stirling Highway, Nedlands, WA 6009, Australia e-mail: matthew.linden@uwa.edu.au

ARCTIC: Randomized Trial of Bedside Platelet Function Monitoring

Responses to oral antiplatelet therapy between patients are variable; thus, bedside assessment has been regarded as an opportunity for individualizing therapy for patients following coronary stent implantation to ensure the optimal platelet inhibition is obtained. The Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation and Interruption Versus Continuation of Double Antiplatelet Therapy [ARCTIC; NCT00827411; Collet JP et al. N Engl J Med 2012] trial evaluated platelet function testing with antiplatelet dose adjustment in suboptimal responders compared with standard of care.

Functional Testing Methods for the Antiplatelet Effects of Aspirin

At antiplatelet doses of 75-325 mg/day, aspirin irreversibly inhibits the platelet cyclooxygenase (COX)-1-dependent thromboxane A(2) (TXA(2)) formation. This is the pharmacological mode of action of aspirin, and it can be predicted that if aspirin does not inhibit COX-1 sufficiently, patients will not benefit from its antiplatelet effects. A pharmacodynamic failure of aspirin occurs in 1-2% of patients. The vast majority of atherothrombotic events in patients treated with aspirin result from mechanisms that are dependent on residual (non-COX-1-dependent) platelet reactivity. Global tests of platelet activation in vitro may identify patients with high residual platelet reactivity but are not sufficiently specific to test the pharmacological effect of aspirin. A further problem is the absence of standardized normal ranges for many assays and the fact that different equipment measures different signals, which are also influenced by the agonist and the anticoagulant used. Similar considerations apply for the determination of platelet-derived biomarkers such as circulating P-selectin, soluble CD40 ligand and others. The direct measurement of inhibition of thromboxane-forming capacity is the most specific pharmacological assay for aspirin. However, there is no linear correlation between inhibition of TXA(2) formation and inhibition of platelet function. Measurement of urinary levels of the TXB(2) metabolite, 11-dehydro-thromboxane B(2), represents an index of TXA(2) biosynthesis in vivo, but is also sensitive to other cellular sources of TXA(2). One general problem of all assays is the relationship with clinical outcome, which is still unclear. Monitoring aspirin treatment by testing platelet function or measuring biomarkers in clinical practice should not be recommended until a clear relationship for the predictive value of these assays for clinical outcome has been established.

Poor Responsiveness to Antiplatelet Drugs in Acute Coronary Syndromes: Clinical Relevance and Management

Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.

ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

This expert consensus document was developed by the American College of Cardiology Foundation (ACCF), the American College of Gastroenterology (ACG), and the American Heart Association (AHA). Expert consensus documents inform practitioners, payers, and other interested parties of the opinion of ACCF and document cosponsors concerning evolving areas of clinical practice or medical technologies. Expert consensus documents cover topics for which the evidence base, experience with technology, or clinical practice is not considered sufficiently well developed to be evaluated by the formal ACCF/AHA Practice Guidelines process. Often, the topic is the subject of considerable ongoing investigation. Thus, the reader should view the expert consensus document as the best attempt of the ACCF and document cosponsors to inform clinical practice in areas where rigorous evidence may not yet be available. To avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the writing committee, all members of the writing committee, as well as peer reviewers of the document, are asked to disclose all current healthcare-related relationships and those existing 12 months before initiation of the writing effort. The ACCF Task Force on Clinical Expert Consensus Documents (CECD) reviews these disclosures to determine which companies make products (on market or in development) that pertain to the document under development. Based on this information, a writing committee is formed to include a majority of members with no relevant relationships with industry (RWI), led by a chair with no relevant RWI. Authors with relevant RWI are not permitted to draft or vote on text or recommendations pertaining to their RWI. RWI are reviewed on all conference calls and updated as changes occur. Author and peer reviewer RWI pertinent to this document are disclosed in Appendixes 1 and 2, respectively. Additionally, to ensure complete transparency, …

Role of TGF-β1 and MAP Kinases in the Antiproliferative Effect of Aspirin in Human Vascular Smooth Muscle Cells

BackgroundWe aimed to test the antiproliferative effect of acetylsalicylic acid (ASA) on vascular smooth muscle cells (VSMC) from bypass surgery patients and the role of transforming growth factor beta 1 (TGF-β1).Methodology/Principal FindingsVSMC were isolated from remaining internal mammary artery from patients who underwent bypass surgery. Cell proliferation and DNA fragmentation were assessed by ELISA. Protein expression was assessed by Western blot. ASA inhibited BrdU incorporation at 2 mM. Anti-TGF-β1 was able to reverse this effect. ASA (2 mM) induced TGF-β1 secretion; however it was unable to induce Smad activation. ASA increased p38MAPK phosphorylation in a TGF-β1-independent manner. Anti-CD105 (endoglin) was unable to reverse the antiproliferative effect of ASA. Pre-surgical serum levels of TGF-β1 in patients who took at antiplatelet doses ASA were assessed by ELISA and remained unchanged.Conclusions/Significance In vitro antiproliferative effects of aspirin (at antiinflammatory concentration) on human VSMC obtained from bypass patients are mediated by TGF-β1 and p38MAPK. Pre-surgical serum levels of TGF- β1 from bypass patients who took aspirin at antiplatelet doses did not change.