High Risk Of Atherothrombotic Events Research Articles

The Diabetic Platelet

Patients with Diabetes Mellitus (DM) have accelerated atherosclerosis, which is the main essential factor contributing to the high risk of atherothrombotic events in these patients. Atherothrombotic complications are the principal cause of morbidity and mortality in patients with DM. Both atherosclerosis and the increased risk of thrombotic vascular events may result from dyslipidaemia, endothelial dysfunction, platelet hyperreactivity, an impaired fibrinolytic balance, and abnormal blood flow. Platelets of DM patients are characterised by dysregulation of several signalling pathways causing increased adhesion, activation and aggregation. Platelet function of patients with DM is complicated by several mechanisms, such as hyperglycaemia, insulin deficiency and resistance, associated metabolic conditions, and cellular abnormalities. The present manuscript purposes to provide a review on the up-to-date status of data on platelet abnormalities that characterise patients with DM.

Study of prothrombin time and activated partial thromboplastin time in type ii diabetes mellitus

Introduction:Diabetes is a major health problem and it is characterized by a high risk of atherothrombotic events. In patient with diabetes mellitus, persistent hyperglycaemia exposes red blood cells (RBCs) to elevated glucose concentration, thus resulting in glycation of haemoglobin, prothrombin, fibrinogen and other proteins involved in clotting mechanisms. Aim & Objectives: To determine hypercoagulability state of Type 2 Diabetes Mellitus patients by measuring the haemostatic profiles. Material & Method: The study was an analytical study involving diabetic patients attending S.S.G. Hospital Diabetic clinic. A total of 160 subjects aged 19-71 years participated in the study out of which 80 participants were T2DM patients and 80 were control subjects. Results & Conclusion: T2DM patients had shortened PT, APTT than the healthy non-diabetic controls. This indicates higher risk of thrombosis in T2DM patients. This study reveals that diabetic patients who had poor glycaemic control were at risk of hypercoagulability than those with good glycaemic control.

APTT (Activated Partial Thromboplastin Time) dan (Prothrombin Time) pada Penderita Diabetes Melitus Tipe 2 di RSUD dr. Doris Sylvanus Palangkaraya

Patients with type 2 diabetes mellitus (T2DM) have a high risk of atherothrombotic events. Hyperglycemia and other metabolic disorders in T2DM are associated with abnormalities of hemostasis system and thrombosis that contribute to cardiovascular disease. Routine laboratory tests to examine the hemostasis system are Activated Partial Thromboplastin Time (APTT) and Prothrombin Time (PT). This study aimed to describe the abnormalities of APTT and PT in patients with T2DM in RSUD dr. Doris Sylvanus Palangkaraya. Twenty subjects with T2DM in RSUD dr. Doris Sylvanus Palangkaraya were obtained using purposive sampling techniques and blood samples were examined with a COATX Biosystem coagulation using photocolorimetric method. This study found that was 70% APTT are shortened, 5% APTT are prolonged and 25% APTT were normal. While the PT results were 25% PT are shortened and 75% APTT were normal. Abnormalities of APTT and PT in T2DM patients in RSUD dr. Doris Sylvanus Palangkaraya showed an abnormality of the coagulation system so as to allow a tendency for bleeding and cardiovascular disease in T2DM patients. Routine coagulation test should be continued to help better diabetes mellitus management in order to prevent micro or macrovascular complications.

Does Obesity Influence the Efficacy of P2Y12 Inhibitors in Preventing Strokes? a Systematic Review and Meta-Analysis

Background Stroke is one of the leading causes of death in the United States and carries a significant risk of morbidity and mortality. P2Y12 inhibitors (Clopidogrel, Ticagrelor etc.) as monotherapy or in combination are used to decrease risk of future ischemic strokes. While standard dosing regimens are currently being used ,the effect of obesity on their efficacy remains unclear. We examined the effect of obesity on the efficacy of P2Y12 inhibitors compared to controls in preventing future incidence of ischemic stroke. Methods We conducted a systematic search on Pubmed, Embase, Cochrane Library, Cochrane Central Register of Controlled Trials and Web of Science to identify relevant randomized clinicals (RCTs) until 31st, July 2019. Our primary outcome of interest was to assess the efficacy of P2Y12 inhibitors (Clopidogrel and Ticagrelor) in preventing recurrent stroke among obese patients with recent stroke or obese individuals at high risk for atherothrombotic events. Obesity was defined as body mass index (BMI) >30kg/m2 and normal BMI was defined as 18 kg/m2 to 25kg/m2. Collected data included dosing regimens, hazard ratio (HR) and confidence interval (CI) for primary outcome in each study arm. We used DerSimonian and Laird random-effects model to estimate pooled HR along with 95% CI using Comprehensive Meta Analysis (CMA) version 3.3. We also performed a sensitivity analysis of the RCTs using Clopidogrel. Heterogeneity was assessed using I2 statistic (<25%=negligible, 25% to 50%= moderate, ≥70% =substantial). Publication bias was assessed using funnel plot and risk of bias was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool for clinical trials. Results Out of 2142 studies initially retrieved, we included three RCTS (n=49134) namely CHARISMA (clopidogrel (Clopi) plus asprin (ASA) vs ASA), PRoFESS (Clopi vs ASA plus dipyridamole (Dipy), and SOCRATES (ticagrelor (Tica) vs ASA). There was no statistical difference in the efficacy of P2Y12 inhibitors in preventing stroke when obese and normal BMI patients were compared (p-value of interaction = 0.80, HR: 0.97 [95% CI: 0.88-1.06]) (figure 1). Sensitivity analysis of patients using Clopi also revealed no statistical difference in preventing future stroke (p-value of interaction = 0.96, HR: 1.03 [95% CI: 0.91-1.16]) (figure 2) in obese vs normal BMI patients. Moreover, there was no difference in the efficacy of P2Y12 inhibitors vs control arm (HR: 0.98 [95% CI: 0.85-1.13], p-value: 0.81, I2=0%) and Clopidogrel only vs Control arm (HR: 1.03 [95% CI: 0.88-1.20], p-value: 0.75, I2=0%) in preventing stroke among obese patients. Conclusion Although Obesity is a known risk factor for cardiovascular events including stroke, and it affects the metabolism of many drugs including anticoagulants among others which was the basis of the idea to look into the published literature on the topic in an attempt to find a correlation between obesity and an increased risk of stroke in patients on P2Y12 inhibitors, there was no difference in the efficacy of standard dose P2Y12 inhibitors in obese patients as compared to normal BMI patients. Sensitivity analysis of trials using standard dose Clopidogrel also revealed no statistical difference, we believe the topic might benefit from further studies . Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.

Association of Multiple Enrichment Criteria With Ischemic and Bleeding Risks Among COMPASS-Eligible Patients

BackgroundThe COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial found clinical benefit of low-dose rivaroxaban plus aspirin, but at the expense of increased bleeding risk in patients with stable vascular disease. ObjectivesThis study evaluated the balance of ischemic and bleeding risks according to the presence of ≥1 enrichment criteria in “COMPASS-eligible” patients. MethodsKey COMPASS selection criteria were applied to identify a COMPASS-eligible population (n = 16,875) from the REACH (REduction of Atherothrombosis for Continued Health) Registry of stable atherothrombotic patients. Ischemic outcome was the composite of cardiovascular death, myocardial infarction, or stroke. Bleeding outcome was serious bleeding (hemorrhagic stroke, hospitalization for bleeding, transfusion). ResultsPatients were categorized according to the enrichment criteria: age >65 years (81.5%), diabetes (41.0%), moderate renal failure (40.2%), peripheral artery disease (33.7%), current smoker (13.8%), heart failure (13.3%), ischemic stroke (11.1%), and asymptomatic carotid stenosis (8.7%). Each criterion was associated with a consistent increase in ischemic and bleeding events, but no individual subgroup derived a more favorable trade-off. Patients with multiple criteria had a dramatic increase in ischemic risk (7.0% [95% confidence interval (CI): 5.6% to 8.7%], 12.5% [95% CI: 11.1% to 14.1%], 16.6% [95% CI: 14.7% to 18.6%], and 21.8% [95% CI: 19.9% to 23.9%] with 1, 2, 3, and ≥4 enrichment criteria, respectively), but a more modest absolute increase in bleeding risk (1.5% [95% CI: 0.9% to 2.1%], 1.8% [95% CI: 1.3% to 2.2%], 2.0% [95% CI: 1.5% to 2.6%], 3.2% [95% CI: 2.6% to 3.9%]). ConclusionsIn a population of stable vascular patients at high risk of atherothrombotic events, the subset with multiple enrichment criteria had a greater absolute increase in ischemic than in bleeding risk and may be good candidates for low-dose rivaroxaban in addition to aspirin.

Ticagrelor: A Review in Long Term Secondary Prevention of Cardiovascular Events.

Ticagrelor (Brilique®) is an orally administered P2Y12 inhibitor. A long-term (maintenance) regimen of ticagrelor 60mg twice daily is indicated in the EU for coadministration with low-dose aspirin 75-150mg/day for the secondary prevention of atherothrombotic events in high-risk patients with a history of myocardial infarction (MI) of at least 1year. Approval is based on the results of the PEGASUS-TIMI 54 trial that compared ticagrelor with placebo (in conjunction with low-dose aspirin) in stable patients who had had a spontaneous MI 1-3years prior to enrolment and were at high risk of atherothrombotic events. At 3years, the composite primary efficacy endpoint of cardiovascular (CV) death, MI or stroke occurred in significantly fewer ticagrelor 60mg twice daily than placebo recipients. Long-term ticagrelor had a manageable tolerability and safety profile. The risk of TIMI major bleeding (primary safety endpoint) was significantly increased in ticagrelor 60mg twice daily versus placebo recipients; however, the risk appeared to decline after the first year of therapy. Landmark analyses have demonstrated that patients with a history of MI remain at a persistent high risk of the composite primary endpoint up to 5years after the event. Furthermore, these analyses demonstrated that the efficacy of ticagrelor 60mg twice daily was maintained over time, with less excess in bleeding after the first year. Thus, long-term dual antiplatelet therapy with ticagrelor 60mg twice daily and low-dose aspirin is a valuable new option for the secondary prevention of atherothrombotic events in stable, high-risk patients with a history of MI of at least 1year.

Effect of Tailored Antiplatelet Therapy to Reduce Recurrent Stent Thrombosis and Cardiac Death After a First Episode of Stent Thrombosis

The recurrence rate of coronary stent thrombosis (ST) is high. Patients with ST often demonstrate high on-treatment platelet reactivity (HPR). It is suggested that patients at high risk of atherothrombotic events, that is patients with ST, could benefit from tailored antiplatelet therapy (APT). This study evaluated whether tailored APT, based on platelet function testing, reduced the rate of cardiac death and/or recurrent ST at 1 year after ST, compared with a historical cohort of patients with ST without tailored APT. Patients with definite ST visited our ST outpatient clinic for platelet function testing and tailored APT. These patients were evenly matched to a historical cohort of patients with ST treated with aspirin and clopidogrel, which was the standard of care at that time. The primary end point was a composite of cardiac death and/or recurrent definite ST after 1year. In total, 113 patients who visited the outpatient clinic were included. HPR was observed in 46%, 6.7%, and 0% of the patients on clopidogrel, prasugrel, and ticagrelor, respectively. After tailored APT, 93% of the patients with HPR demonstrated normal platelet reactivity. The primary end point was observed in 4 patients who had visited the outpatient clinic and in 23 patients of the historical cohort. The odds ratio of tailored APT on the primary end point was 0.26 (95% confidence interval 0.11 to 0.64, p= 0.003), independent from the possible confounders prior myocardial infarction and stent type. In conclusion, the outpatient ST clinic was associated with lower HPR rates in patients with ST after tailored APT. Patients who visited the ST outpatient clinic had a lower risk for cardiac death and/or recurrent ST compared with a historical cohort of patients with ST without tailored APT. Regarding the high HPR rate in patients with ST on clopidogrel, these patients might benefit in particular from the strategy of tailored APT.

JAK2V617F Promotes Atherosclerosis

Myeloproliferative disorder (MPD) patients are at high risk of atherothrombotic events including myocardial infarction and stroke. The somatic mutation (JAK2V617F) is commonly found in MPD patients and is associated with increased vascular risk. Moreover, the prevalence of JAK2V617F mutation is also significantly increased in non-MPD coronary artery disease (CAD) and peripheral artery disease (PAD) patients compared to the general population. Our goal was to investigate potential mechanisms of accelerated atherothrombosis using a JAK2V617F mouse model.Subletahlly irradiated Ldlr-/- mice were transplanted with bone marrow cells from wild type (WT) or Mx1-Cre/Jak2V617F (Jak2VF) mice and fed a high fat high cholesterol Western type diet (WTD). After 7 weeks of WTD Jak2VFmice had sustained neutrophilia, monocytosis and erythrocytosis; despite lower plasma cholesterol levels they showed ~1.6 fold larger atherosclerotic lesions in the aortic root (p=0.003) and accelerated carotid artery thrombosis (FeCl3 injury). After 12 weeks of WTD feeding, lesion area was only increased 1.3-fold compared to controls but showed features of plaque instability (increased necrotic core area). Early lesions (7 weeks) displayed significantly increased neutrophils (p=0.05, n=7) but not Mac 3+ macrophages. The increased neutrophil infiltration in Jak2VF mice correlated with atherosclerotic lesion size (p=0.001, r=0.78), suggesting a critical role of neutrophils in early atherogenesis. Advanced lesions (12 weeks) also showed significantly increased neutrophil (p=0.001) and macrophage (p=0.05) infiltration. No difference in CD3+ T cells or CD41+ platelet infiltration was observed at either time-point. In addition, five out of nine Jak2VF mice had prominent iron deposition (Prussian blue) and RBC marker Ter-119 staining in advanced atherosclerotic lesions (p<0.05). RBC marker Ter-119 co-localized with Mac-3(+) macrophages surrounding necrotic cores, indicating erythrophagocytosis and plaque instability.In summary, the Jak2V617F mutation promotes early atherosclerotic lesion development and plaque instability in advanced lesions. Neutrophil infiltration appears to be an important contributor to both early lesion development and necrotic core formation. These studies also suggest a novel role for RBC infiltration, iron deposition and erythrophagocytosis in advanced lesional necrotic core formation in JAK2V617F mice. DisclosuresLevine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Tall:Amgen: Consultancy; CSL Behring: Consultancy.

Interplay between ultrastructural findings and atherothrombotic complications in type 2 diabetes mellitus.

Accelerated atherosclerosis is the main underlying factor contributing to the high risk of atherothrombotic events in patients with diabetes mellitus and atherothrombotic complications are the main cause of mortality. Like with many bodily systems, pathology is observed when the normal processes are exaggerated or uncontrolled. This applies to the processes of coagulation and thrombosis as well. In diabetes, in fact, the balance between prothrombotic and fibrinolytic factors is impaired and thus the scale is tipped towards a prothrombotic and hypofibrinolytic milieu, which in association with the vascular changes accompanying plaque formation and ruptures, increases the prevalence of ischaemic events such as angina and myocardial infarction. Apart from traditional, modifiable risk factors for cardiovascular disease like hypertension, smoking, elevated cholesterol; rheological properties, endogenous fibrinolysis and impaired platelet activity are rapidly gaining significance in the pathogenesis of atherosclerosis especially in diabetic subjects. Blood clot formation represents the last step in the athero-thrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. It is no surprise that just like platelets and fibrin networks, erythrocytes have been shown to play a role in coagulation as well. This is in striking contrast to their traditional physiological role of oxygen transport. In fact, emerging evidence suggests that erythrocytes enhance functional coagulation properties and platelet aggregation. Among the spectrum of haematological abnormalities in diabetes, erythrocyte aggregation and decreased deformability of erythrocytes predominate. More importantly, they are implicated in the pathogenesis of microvascular complications of diabetes. The morphology of platelets, fibrin networks and erythrocytes are thus essential role players in unravelling the pathogenesis of cardiovascular complications in diabetic subjects.

Association of activated partial thromboplastin time and fibrinogen level in patients with type II diabetes mellitus

BackgroundPatients with diabetes mellitus have a high risk of atherothrombotic events. Diabetes contributes for initiation and progression of microvascular and macrovascular complications. Shortened activated partial thromboplastin time (aPTT) values may reflect hypercoaguable state, which is associated with increased thrombotic risk and adverse cardiovascular events. Increased level of fibrinogen is common in type II diabetes. The present study was conducted to study the aPTT and fibrinogen levels in diabetics in a tertiary care Teaching Hospital of Nepal.MethodsObservational study was performed at out-patients visiting Pathology Department at Tribhuvan University Teaching Hospital from August 5 to September 7, 2012. Research protocol was approved by Institutional Review Board at Tribhuvan University Institute of Medicine. Altogether 90 people who came to the hospital during study period and who met inclusion criteria were selected, out of which 72 were diabetics and 18 were normal controls. Diabetic cases were identified via verbal interview with patients themselves and review of laboratory findings and diagnosis performed by their physicians. Diabetics with a diabetic history of more than one year and stabilized with antidiabetic medicines such as insulin, metformin, glibenclamide, and gliclazide and diabetics with controlled diabetes as revealed by HbA1c in the range 6.2-7% were taken for the study purpose. Data were analyzed with chi square test and Fischer’s exact test (when each cell frequency was less than 5) using Statistical Package for Social Sciences 17.ResultsMaximum (53; 73.6%) diabetics and all non-diabetics had aPTT in the range 26–40 seconds. Maximum (51; 70.8%) patients had fibrinogen beyond 351 whereas all non-diabetics had fibrinogen in the range 151–350. Mean aPTT values of the diabetic patients and non-diabetic persons were 29.88 ± 4.89 seconds and 32.44 ± 2.25 seconds respectively. Mean fibrinogen values of the diabetic patients and non-diabetic persons were 388.57 ± 60.90 mg/dL and 320.89 ± 10.20 mg/dL respectively. Test data identified in results were statistically significant for aPTT (p value 0.000) and fibrinogen (p value 0.000) between the diabetics and non-diabetics.ConclusionsDiabetics have an increased level of fibrinogen and relatively shortened aPTT as compared to the non-diabetic patients.

Secondary prevention of atherosclerotic cardiovascular disease in older adults: a scientific statement from the American Heart Association.

Since the initial scientific statement on Secondary Prevention of Coronary Heart Disease (CHD) in the Elderly was published in 2002,1 several trends have continued that make an update highly appropriate. First, the graying of the US population and those of other industrialized countries has progressed unabated because more adults are surviving into their senior years. The number of Americans aged ≥75 years was estimated at 18.6 million in 2010, representing ≈6% of the population,2 and it is expected to double by 2050. The population aged ≥85 years is growing the most rapidly, with numbers expected to reach 19.5 million by 2040. In 2008, 67% of the 811 940 cardiovascular deaths in the United States occurred in people aged ≥75 years.3 In parallel to this increase in the older adult demographic, the number of Americans with CHD has increased to an estimated 16.3 million, more than half of whom are >65 years of age.3 Similarly, 7 million have had a stroke, the incidence of which approximately doubles with successive age decades after 45 to 54 years.3 Peripheral artery disease (PAD) affects 8 to 10 million Americans, the majority of whom are >65 years of age. Between 2015 and 2030, annual US costs related to atherosclerotic cardiovascular disease (ASCVD) are projected to increase from $84.8 billion to $202 billion.3 Moreover, given that ASCVD often undermines functional capacity and independence and increases reliance on long-term care, indirect expenses related to ASCVD are also expected to increase. Thus, the need for effective secondary prevention measures in the older adult population with known ASCVD has never been greater. Notably, the 2011 American Heart Association (AHA)/American College of Cardiology Foundation (ACCF) updated guidelines for secondary prevention of CHD broadened …

High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention

AimHigh on-clopidogrel platelet reactivity (HCPR) and high on-aspirin platelet reactivity (HAPR) are associated with atherothrombotic events following coronary stenting. There are, however, few data concerning high on-treatment platelet reactivity to...

High-sensitivity C-reactive protein and clopidogrel treatment in patients at high risk of cardiovascular events: a substudy from the CHARISMA trial

AimsThis study investigated the effect of clopidogrel treatment on inflammatory activity as evidenced by the change in high-sensitivity C-reactive protein (hsCRP) levels in a broad population of patients who are...

Prevalence of CYP2C19 polymorphisms in the Lebanese population

Clopidogrel is one of the most commonly prescribed drugs, as its combination with low-dose aspirin is the recommended oral anti-platelet therapy, to prevent ischaemic events following coronary syndromes or stent placement. Numerous recent studies have shown that polymorphisms in the gene encoding the cytochrome P450 (CYP450) 2C19 enzyme (CYP2C19) contribute to variability in response to clopidogrel; patients with certain common genetic variants of CYP2C19 (2, 3) have a reduced metabolism of clopidogrel and have a higher rate of cardiovascular events or stent thrombosis compared to patients with the CYP2C19 (1) allele. CYP2C19 2 is most common in Caucasians, Africans and Asians while CYP2C19 3 has been found mostly in Asians. Since the prevalence of these variants in the Lebanese population has not yet been reported, our aim was to determine the genotypes of CYP2C19 in our population. CYP2C19 (1/2/3) variants were assessed by Polymerase Chain Reaction-Restriction Length Polymorphism (PCR-RFLP) assays in a representative sample of 161 unrelated healthy Lebanese volunteers. The allele frequencies of CYP2C19 2 and 3 were 0.13 and 0.03. Carriers of the CYP2C19 2 or 3 represented 24.2% of the subjects. Our data show no significant difference in the frequency of CYP2C19 allelic variants when compared to Caucasian populations and demonstrate that the application of the recent FDA recommendations would also be beneficial in Lebanon, allowing physicians to identify patients at high risk for atherothrombotic events, and eventually advising them to consider other antiplatelet medications or alternative dosing strategies in poor metabolizers.

Comparison of methods to evaluate aspirin-mediated platelet inhibition after percutaneous intervention with stent implantation

Urinary 11-dehydro thromboxane B2 (d-TXB2) concentrations in the highest quartile have been associated with an increased risk of adverse outcomes in patients at high risk for atherothrombotic events. However, the determination of d-TXB2 is time consuming and not suitable for daily clinical routine. We therefore sought to determine the test correlating best with d-TXB2 to estimate aspirin-mediated platelet inhibition in 225 patients on dual antiplatelet therapy after percutaneous intervention with stent implantation. We selected light transmission aggregometry, the VerifyNow aspirin assay, the Platelet Function Analyzer-100, multiple electrode platelet aggregometry (MEA) and Impact-R for comparisons with d-TXB2. Cut-off values for high on-treatment residual arachidonic acid-inducible platelet reactivity (HRPR) were defined according to quartiles of each assay. Sensitivities and specificities of the different platelet function tests were based on d-TXB2 results. The results from all assays correlated poorly with d-TXB2. Only MEA showed a weak, but significant correlation with d-TXB2 (r = 0.14, p = 0.042). Further, the five platelet function tests showed a poor agreement with d-TXB2 regarding the determination of HRPR. Sensitivities and specificities for HRPR ranged from 17.5 to 44.6%, and from 70.8 to 77.9%, respectively. In conclusion, the evaluated assays did not mirror d-TXB2 results, suggesting that thromboxane inhibition can be circumvented in assays that determine platelet function. Therefore, large trials with clinical outcome data are needed to determine the diagnostic value of the various test systems and to define the gold standard method for assessing residual AA-inducible platelet reactivity.

Review article: Platelet abnormalities in diabetes mellitus

Patients with diabetes mellitus (DM) have accelerated atherosclerosis, which is the main underlying factor contributing to the high risk of atherothrombotic events in these patients. Atherothrombotic complications are the leading cause of morbidity and mortality in patients with DM. Among factors contributing to the prothrombotic condition which characterise patients with DM, platelet hyperreactivity plays a pivotal role. Platelets of DM patients are characterised by dysregulation of several signalling pathways leading to intensified adhesion, activation and aggregation. Multiple mechanisms are involved in platelet dysfunction of patients with DM, which can be categorised as follows: a) hyperglycaemia, b) insulin deficiency and resistance, c) associated metabolic conditions, and d) other cellular abnormalities.The present manuscript aims to provide an overview on the current status of knowledge on platelet abnormalities that characterise patients with DM.

Hyperglycemia: a prothrombotic factor?

Diabetes mellitus is characterized by a high risk of atherothrombotic events. What is more, venous thrombosis has also been found to occur more frequently in this patient group. This prothrombotic condition in diabetes is underpinned by laboratory findings of elevated coagulation factors and impaired fibrinolysis. Hyperglycemia plays an important role in the development of these hemostatic abnormalities, as is illustrated by the association with glycemic control and the improvement upon treatment of hyperglycemia. Interestingly, stress induced hyperglycemia, which is often transient, has also been associated with poor outcome in thrombotic disease. Similar laboratory findings suggest a common effect of acute vs. chronic hyperglycemia on the coagulation system. Many mechanisms have been proposed to explain this prothrombotic shift in hyperglycemia, such as a direct effect on gene transcription of coagulation factors caused by hyperglycemia-induced oxidative stress, loss of the endothelial glycocalyx layer, which harbours coagulation factors, and direct glycation of coagulation factors, altering their activity. In addition, both chronic and acute hyperglycemia are often accompanied by hyperinsulinemia, which has been shown to have prothrombotic effects as well. In conclusion, the laboratory evidence of the effects of both chronic and acute hyperglycemia suggests a prothrombotic shift. Additionally, hyperglycemia is associated with poor clinical outcome of thrombotic events. Whether intensive treatment of hyperglycemia can prevent hypercoagulability and improve clinical outcome remains to be investigated.

Combination Antiplatelet Agents for Secondary Prevention of Ischemic Stroke

Stroke is a leading cause of death and the primary cause of serious, long-term disability in the United States. Joint guidelines from the American Heart Association (AHA) and American Stroke Association (ASA), as well as recent guidelines from the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Antiplatelet Therapy, recommend aspirin, clopidogrel, or extended-release dipyridamole plus aspirin as acceptable first-line options for secondary prevention of ischemic events in patients with a history of ischemic stroke or transient ischemic attack (TIA). The ACCP strongly recommends the combination of extended-release dipyridamole plus aspirin over aspirin monotherapy (highest level of evidence) and suggests clopidogrel monotherapy over aspirin monotherapy (lower level of evidence). The AHA-ASA guidelines suggest that either extended-release dipyridamole plus aspirin or clopidogrel monotherapy should be used over aspirin monotherapy. Both guidelines recommend avoiding the combination of clopidogrel and aspirin for most patients with previous stroke or TIA. Results from recent trials evaluating combination antiplatelet therapy have been published that enhance the AHA-ASA recommendations and provide the foundation for the updated ACCP guideline. To identify pertinent combination antiplatelet trials, a MEDLINE search of the literature from 1967-2007 was performed. Two trials were identified--the European-Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA). The ESPRIT compared aspirin monotherapy with the combination of aspirin plus extended-release dipyridamole for prevention of secondary ischemic events in patients with a history of TIA or minor stroke. The CHARISMA trial compared aspirin plus clopidogrel with aspirin alone in a population at high risk for atherothrombotic events using the composite outcome of myocardial infarction, stroke, and death from cardiovascular causes. Data from ESPRIT add to evidence that the combination of aspirin plus extended-release dipyridamole is superior to aspirin alone. The findings of the CHARISMA trial reinforce recommendations from both AHA-ASA and ACCP that the combination of aspirin and clopidogrel be reserved for special populations requiring this antiplatelet combination (e.g., those who have had coronary artery stenting).

Safety of Clopidogrel and Aspirin for??Stroke Prevention

Antiplatelet therapy is universally recommended for the prevention of recurrent events in patients with noncardioembolic ischaemic stroke or transient ischaemic attack (TIA), acute and chronic coronary artery disease, or peripheral arterial disease. However, choosing which antiplatelet agents to use in these situations remains controversial. The use of aspirin, aspirin plus extended-release dipyridamole, or clopidogrel is recommended as initial therapy in patients with noncardioembolic ischaemic stroke or TIA to reduce the risk of recurrent stroke and other cardiovascular events. Based on the results of the MATCH trial, combination therapy with aspirin plus clopidogrel is not recommended for patients with ischaemic stroke or TIA due to the increased risk of haemorrhage. The results of the CHARISMA trial support this recommendation; despite previous data demonstrating a favourable benefit-risk profile of aspirin plus clopidogrel in patients with acute coronary syndrome, this combination should not be used in patients at high risk for atherothrombosis and those with previous stroke or TIA. In these patients, the CHARISMA trial demonstrated a lack of significant clinical efficacy and an increased risk of bleeding with clopidogrel plus aspirin compared with aspirin alone. Further research is needed to assess the benefit-risk ratio of clopidogrel plus aspirin in specific subpopulations of patients at high risk for atherothrombotic events, and to determine the role of clopidogrel plus aspirin in preventing cardioembolic stroke or early recurrent stroke after symptomatic large-vessel atherostenosis. Recent and ongoing studies are seeking to better define the roles of different antiplatelet regimens in preventing recurrent stroke.

Abstract 3539: Low Inflammatory Activity Evidenced By hsCRP Predicts A Benefit From Clopidogrel Treatment In Patients With High Risk For Cardiovascular Events. - A Substudy From The CHARISMA Trial

Aims We investigated the impact of clopidogrel treatment on the inflammatory activity as evidenced by a change of hsCRP levels in a broad population of high risk for atherothrombotic events. Further, the prediction of hsCRP levels for a treatment benefit of clopidogrel was explored. Methods This study included 8021 patients with overt atherosclerotic disease or multiple cardiovascular risk factors enrolled in the CHARISMA trial. Patients were randomized either to clopidogrel plus aspirin or placebo plus aspirin. HsCRP was measured at study entry and at study termination (median 28 months). The predefined primary endpoints were myocardial infarction, stroke and death from cardiovascular causes. Results There was a stepwise increase in the event rate of the combined primary endpoint with increasing quartiles of hsCRP (4.0%, 6.1%, 7.4% and 8.7% in the highest quartile). In both treatment groups the changes of hsCRP levels over time were identical. In patients with low hsCRP levels (&lt;3 mg/l) clopidogrel treatment was associated with a lower event rate as compared to placebo (4.0% vs. 6.0%, Log-rank p=0.005). In contrast no treatment effect could be observed in patients with high hsCRP levels (8.1% vs. 8.0%, ns). Conclusions Surpisingly, the reduction of cardiovascular events by antiplatelet treatment with clopidogrel occurred in patients with low levels of hs-CRP