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Background and purpose In this post-hoc analysis using acute dual study dataset, the impacts of cerebral microbleeds (MBs) after mild stroke on clinical outcome were investigated. Methods The number of MBs on admission was categorized as 1) no MBs, 2) MBs 1–4, 3) MBs 5–9, and 4) MBs ≥ 10. The efficacy outcome was defined as neurological deterioration and stroke recurrence within 14 days. Safety outcomes included ICH and/or SAH as well as extracranial hemorrhages. Results Of the 1102 patients, 780 (71%) had no MBs on admission, while 230 (21%) had MBs 1–4, 48 (4%) had MBs 5–9, and 44 (4%) had MBs ≥ 10. The number of MBs was not associated with the neurological deterioration and/or stroke recurrence (p = 0.934), ICH and/or SAH (p = 0.743), and extracranial hemorrhage (p = 0.205). Favorable outcome was seem in 84% in the No MBs group, 83% in the MBs 1–4, 94% in the MBs 5–9, and 85% in the MBs ≥ 10 (p = 0.304). Combined cilostazol and aspirin therapy did not alter any rates of efficacy and safety outcomes among the no MBs, MBs 1–4, MBs 5–9, and MBs ≥ 10 groups compared to aspirin alone (all p > 0.05). By multivariate regression analysis, a history of ICH and diastolic blood pressure were the independent parameters to all of the MBs criteria (presence, MBs ≥ 5, and MBs ≥ 10). Conclusions MBs did not alter the clinical outcome at 3 months of onset. Elevated diastolic blood pressure and a history of ICH were the essential parameters related to the MBs.

The authors hypothesized that the cytokine storm described in COVID-19 patients may lead to consistent cell-based tissue factor (TF)-mediated activation of coagulation, procoagulant microvesicles (MVs) release, and massive platelet activation. COVID-19 patients have higher levels of TF+ platelets, TF+ granulocytes, and TF+ MVs than healthy subjects and coronary artery disease patients. Plasma MV-associated thrombin generation is present in prophylactic anticoagulated patients. A sustained platelet activation in terms of P-selectin expression and platelet–leukocyte aggregate formation, and altered nitric oxide/prostacyclin synthesis are also observed. COVID-19 plasma, added to the blood of healthy subjects, induces platelet activation similar to that observed in vivo. This effect was blunted by pre-incubation with tocilizumab, aspirin, or a P2Y12 inhibitor.

Background After myocardial infarction, guidelines recommend pharmaceutical treatment with a combination of five different types of drugs for prevention in patients. However, studies from different countries have shown that this goal is not achieved in many patients. The aim of this study was to assess both healthcare and prescribed pharmaceutical treatment in the fourth quarter after index myocardial infarction. Methods We conducted a claims data analysis with the data of patients who had had a myocardial infarction in the years 2013 or 2014, using information from the largest German health insurance fund (‘AOK’). We analysed contact with physicians, hospital care and actual prescriptions for medication recommended in international guidelines, referring to beta-blockers, ACE inhibitors or angiotensin II receptor blockers, P2Y12-antiplatelet agents, acetylsalicylic acid and statins, one year after myocardial infarction. Analysis was stratified by age and sex, compared between patient groups and over time. Results We identified 2352 patients who had survived myocardial infarction. Some 96.9% of these participants had at least one contact with their general practitioner (GP) one year after myocardial infarction, 22.8% contacted a cardiologist and 19.7% were hospitalised. Prescription rates range from 37.8% for acetylsalicylic acid to 70.4% for ACE inhibitors. However, only 24.1% received statins, beta-blockers, ACE inhibitors and an antiplatelet drug simultaneously. Prescription of recommended drugs after myocardial infarction decreased steadily over time. Discussion Long-term medical prevention after myocardial infarction is improvable. GPs should take care of the pharmaceutical prevention after myocardial infarction as they are the physicians seen most intensively in this period.

Background: Ultrasound-guided axillary venous puncture (UGAVP) for cardiac devices implantation has been developed because of its rapidity, safety and potential long-term lead protection. Early work excluded defibrillators (ICD), cardiac resynchronization therapy (CRT) and upgrade procedures. Compared to the cephalic approach, in previous studies, there was a greater use of pressure dressings with this technique, suggesting a higher risk of bleeding. Aims: To assess UGAVP in patients under antithrombotic therapy (ATT) undergoing cardiac devices implantation including CRT/ICD. Methods: Prospectively, consecutive patients eligible for a pacemaker or ICD implantation were included. All procedures were performed by a single operator, experienced with UGAVP for femoral access, and fluoroscopy-guided axillary vein access. Guidewires insertion time (from lidocaïne administration), and complications were systematically studied. Results: From 457 cardiac device implantations, 200 patients (77.8 ± 10 y, male 58%) 360 leads were implanted by UGAVP including 36 ICD, 54 CRT and 14 upgrade procedures. A majority (90%) was under ATT: Vitamin K Antagonist or Heparin (n = 58, 29%), direct oral anticoagulant (n = 46, 23%), dual antithrombotic therapy (n = 18, 9%) and single antiplatelet drug (n = 82, 41%). UGAVP was successful in 95.78%. Mean insertion time for 1.8 guidewires per patient was 4.68 ± 3.6 min. No complication (no hematoma) was observed during the follow-up (mean of 45 ± 10 months). Guidewires insertion time reached its plateau after 15 patients. Conclusion: UGAVP is fast, feasible and safe for patients under ATT undergoing device implantation including CRT/ICD and upgrade procedures, with a short learning curve. Keywords: Cardiac devices implantation, Vascular complications, Ultrasound guidance, Antithrombotic therapy

Clopidogrel is an antiplatelet drug whose performance at a low dose (25 mg) have not been evaluated in Chinese patients, who may be subject to different effects from Caucasians. We carried out this evaluation and compared a generic (Taijia) and a reference drug (Plavix®). We evaluated Taijia and Plavix® in 128 subjects, with 64 in a fasted state and 64 receiving a high-fat diet, and computed Cmax, AUC0-∞, and AUC0-t. Reference-scaled average bioequivalence (RSABE) methods and average bioequivalence (ABE) methods were used, and adverse events were assessed. Average maximum plasma concentrations (Cmax) of clopidogrel were significantly greater after 25 mg dose under fed conditions compared to fasted. Reference-scaled Cmax, AUC0-t, and AUC0-∞ were higher than the 0.294 cutoff during fasted, meeting RSABE criteria. Under fed conditions, SWR for AUC0-t and AUC0-∞ were lower than 0.294, permitting use of ABE. The 90% confidence intervals for AUC0-t and AUC0-∞ indicated bioequivalence. Pharmacokinetic parameters differed between fasted and fed states. The generic product was bioequivalent to the reference drug, and was safe and well tolerated. This suggests that they can be used interchangeably in a clinical setting.

Neurologists are worried about bleeding and complications from lumbar punctures in patients who use antiplatelet agents, such as aspirin and clopidogrel. We evaluated the bleeding risks of performing lumbar punctures in patients who are using or have recently used antiplatelet agents by retrospective review of lumbar punctures performed at the Johns Hopkins Hospital between 2004 and 2018 in patients who were actively using or recently used aspirin or clopidogrel, or both. Patients were stratified into time groups based on when the lumbar puncture was done relative to the time the antiplatelet drug was discontinued:1 week, 1-4 weeks,4 weeks. We recorded red blood cell counts for the earliest and latest spinal fluid collections to determine the risk of traumatic bleeding; we also noted any complications. Antiplatelet medication use within 1 week of lumbar puncture was associated with a 3% incidence of bloody tap and 4% incidence of traumatic tap that cleared. In the group of patients who waited for a lumbar puncture at least 4 weeks after discontinuation of antiplatelet drug, there was a 5% incidence of bloody or traumatic tap. There was no difference in rates of bleeding between aspirin versus aspirin plus clopidogrel. The rate of hematoma complications was highest in the group of patients on aspirin at the time of the procedure (0.7%). Aspirin or clopidogrel, or both, did not meaningfully increase hemorrhagic complications in patients undergoing lumbar punctures, regardless of when the antiplatelet drug was discontinued relative to the time of the procedure.

Background As adult congenital heart disease (ACHD) patients are aging, a high prevalence of cardiovascular risk factors is encountered similar to the general population. Currently, data regarding the primary and secondary prevention of acquired cardiovascular disease in ACHD is lacking. Methods The German National Register of Congenital Heart Defects was systematically screened for ACHD patients with established cardiovascular risk factors or documented acquired cardiovascular conditions. Data were analyzed with regard to the according medical treatment. Results Overall, 539 patients were included (mean age 38.4 ± 17.7 years, 49.2% female). Diabetes was present in 57 pts. (10.6%), arterial hypertension in 113 pts. (21.0%), hyperlipidaemia in 81 pts. (15.0%) and obesity in 271 pts. (50.2%). 31 pts. (5.8%) were smokers. Coronary artery disease was established in 16 pts. (3.0%), peripheral vascular disease in 9 pts. (1.7%), and cerebrovascular accidents in 141 pts. (26.2%). Out of the patients with coronary artery disease only 81.3% received antithrombotic treatment. Only 18.8% were prescribed a statin. Of the pts. with peripheral arterial disease, 44.4% received an antiplatelet drug, and only 22.2% were on a statin. Patients with arterial hypertension received antihypertensive drugs in 66.4%. Conclusions Primary and secondary prevention of acquired cardiovascular disease in ACHD is underutilized. This highlights the importance of educating primary physicians as well as ACHD physicians about the need of primary and secondary prevention for acquired cardiovascular disease.

Nowadays, the most common revascularization procedure to combat coronary artery disease is through Percutaneous Coronary Intervention (PCI) with the use of arterial stents. Two of the most recurrent drawbacks of stenting are restenosis and late stent thrombosis. To render the stent effective, a long-term antiplatelet drug delivery system have to be incorporated into a biodegradable polymer to target directly the malevolent site. A novel drug delivery nanosystem of Poly(D, L-lactic acid) (PLA) nanoparticles (NPs) loaded with Dipyridamole (DPM) was fabricated via electrospraying that forms monodispersed, biodegradable drug loaded NPs, as coating for cardiovascular stents. This study presents a feasible degradable NP delivery system that encapsulates, protects and controls the release of DPM, intended to reduce the possibility of thrombosis inside the stent.

P2Y12 receptor antagonists are a class of drugs that act on platelet P2Y12 receptors and inhibit adenosine diphosphate-induced platelet aggregation. As a thienopyridine antiplatelet agent which is approved by the US Food and Drug Administration for the treatment of cardiovascular diseases, currently, clopidogrel was once considered to be the most safe and effective antiplatelet drug in the P2Y12 receptor antagonists, however, it has become increasingly clear that clopidogrel does not satisfactorily inhibit the platelets of approximately one-third of patients. This is in part due to clopidogrel is a prodrug and reliance on multiple cytochrome P450 enzymes for conversion into its active metabolite. Prasugrel and ticagrelor reduces the risk of adverse cardiovascular events compared to clopidogrel in acute coronary syndromes patients, however, the cardiovascular benefit of both drugs is counter-balanced by increased rates of spontaneous bleeding. Unlike clopidogrel, which is a prodrug, cangrelor is an active drug not requiring metabolic conversion, despite fewer bleeding events during cardiac surgery, cangrelor carries the risk of potential autoimmune reactions manifesting as breathlessness. DV-127 was synthesized by using three generations of thienopyridine P2Y12 receptor antagonists as research models, using high resolution mass spectrometry, selective deuteration, and 2,7-position replacement groups technologies in order to maximize cardiovascular benefit while minimizing adverse effects on hemostasis. Our results show that although the dose of DV-127 is greatly reduced, it can achieve similar anticoagulant and antiplatelet effects as clopidogrel, and DV-127 can more strongly inhibit the release of α-granules even though the inhibitory effect of dense granules is similar to clopidogrel.

Objectives The purpose of this qualitative study was to explore perceptions of nuisance bleeding and medication-related beliefs among adults taking dual antiplatelet drug therapy. Methods We conducted qualitative telephone interviews with 34 community-dwelling adults with cardiovascular disease. Results Using qualitative content analysis, we identified 4 dominant themes: nuisance bruising, nuisance bleeding, importance of medication adherence, and duration of therapy. Participants' bruising was frequently more severe than expected given the force of the bump that caused it. Concerns focused on whether increased bleeding tendencies would lead to hemorrhage in the event of a major traumatic injury, confusion about the duration of therapy, and the rationale for when and why therapy should be discontinued. Conclusion Excessive bruising and medication-related concerns about hemorrhage and duration of treatment were salient issues for participants. Effective clinician-patient communication should be used to assist individuals in managing concerns to help assure positive health outcomes with antiplatelet drugs.

Objectives The goal of this study was to evaluate the efficacy and safety of uninterrupted direct oral anticoagulant (DOAC) use and uninterrupted warfarin administration in elderly patients undergoing catheter ablation for atrial fibrillation (AF). Background There is limited knowledge regarding the uninterrupted use of oral anticoagulant agents in elderly patients undergoing catheter ablation for AF. Methods This retrospective study included 2,164 patients (n = 325 ≥75 years of age and n = 1,839 Results Major bleeding events (3.1% vs. 1.3%; p = 0.023) and minor bleeding events (9.2% vs. 5.0%; p = 0.002), except for thromboembolic events (0% vs. 0.8%; p = 0.248), were significantly higher in the elderly group than in the younger group. No significant differences in thromboembolic and bleeding events were found between the DOAC and warfarin groups of both the elderly and younger groups. Adverse complications did not differ between the groups after adjustment using propensity score matching analysis. Multivariate analysis revealed that lower body weight (odds ratio: 0.96; p = 0.010) and antiplatelet drug use (odds ratio: 2.21; p = 0.039) were independent predictors of adverse events in the elderly group. Conclusions The periprocedural bleeding risk during the use of uninterrupted oral anticoagulants was higher in the elderly group than in the younger group. This area needs more attention for these patients in whom caution is required.

Introduction Chronic subdural hematoma (cSDH) is a common pathology encountered in neurosurgical practice, especially in elderly patients, who frequently require antithrombotic agents. The aim of this study was to investigate the influence of antithrombotic agents on recurrence rates and clinical outcomes in patients operated for cSDH. Methods A cohort of patients operated for cSDH at one center during a 5 years period was analyzed retrospectively. Presenting symptoms, coagulation testing, history of antithrombotic agents and comorbidities were obtained from the patient charts. The standard neurosurgical procedure was a single burr hole under local anesthesia with insertion of a subdural drainage. Questionnaires and telephone interviews were used to assess the clinical outcome using the modified Rankin Scale (mRS). Good outcome was defined as mRS 0 to 3 and poor outcome as mRS 4 to 6. Results 201 patients with cSDH underwent initial surgical treatment and were enrolled in the study. The median follow-up was 81 weeks. 41 patients (20.4%) were on antiplatelet drug and 43 (21.4%) were on phenprocoumon. A recurrent hematoma required surgery in 37 patients (18.4%). A poor outcome was seen in 36 patients (17.9%). Each of older age and administration of phenprocoumon at admission was an independent risk factor predictive of poor outcome, ( p = 0.001 and p = 0.031, respectively)) Administration of antithrombotic agents had no impact on hematoma recurrence. Conclusion Administration of phenprocoumon and older age might increase the risk of poor outcome in patients with cSDH. Neither the administration of phenprocoumon nor antiplatelet drug influenced the recurrence rate of subdural hematoma in our patient cohort.

Objective Facing mild traumatic brain injury, clinicians must decide whether to perform a computed tomography (CT) scan to detect a potential intracranial hemorrhage. Many useful guidelines have been developed for the general population, but there is no general consensus about the best practice to adopt when dealing with patients on antiplatelet or anticoagulation drugs. The relatively recent introduction of new anticoagulants and second-generation antiplatelet drugs poses new challenges in this field. There are no data in the literature about the relative risk of intracranial bleeding in such categories. Methods We enrolled 2773 consecutive patients presenting at our emergency department with mild traumatic brain injury as chief complaint and evaluated the results of their head CT scans, stratifying their anticoagulation and/or antiplatelet drug regime. Results Of these patients, 1608 matched the criteria for head CT scan and had a Glasgow Coma Scale (GCS) score of 15; 517 were on antiplatelet drugs, whereas 213 were on anticoagulants. The risk of developing intracranial bleeding was significantly higher for patients on antiplatelet drugs, whereas the risk of anticoagulated patients overlapped with that of the general population. The trend for second-generation drugs was of higher risk of bleeding only for antiplatelets. Conclusions Patients with a GCS score of 15 on long-term anticoagulation therapy seem to be at no higher risk for intracranial hemorrhage than are nonanticoagulated patients. On the contrary, patients with a GCS score of 15 on antiplatelet therapy seem to be more prone to developing intracranial bleeding than are the general population, with a trend to be more at risk when it comes to second-generation drugs.

Thrombolytic treatment is the primary method for thrombotic diseases. However, uncontrollable bleeding and secondary vascular embolism are prone. Based on the thrombus microenvironment, this project constructed an "on-off " drug depot that can accurately identify thrombus and respond to changes of shear force to solve above problems. The fucoidan (Fuc)-based core-shell NPs were prepared by β-CD host-guest inclusion interaction. The thrombolytic drug urokinase (UK) and antiplatelet drug tirofiban (TI) were loaded into outer shell and inner core, respectively. In vitro and in vivo results proved that UK@Fuc-TI/PPCD was closed under low blood shear force to reduce bleeding risk. Once arriving at thrombus site, UK@Fuc-TI/PPCD can realize precise “homing” by recognizing P-selectin overexpressed by thrombus. Then sharply increased shear force at targeted thrombus broke the core-shell structure to release UK rapidly, realizing site-specific thrombolysis. Subsequently, TI loaded in PPCD core was slowly released at thrombolysis site, preventing re-embolization of blood vessels. Thrombolysis results demonstrated the in vitro thrombolysis rate of UK@Fuc-TI/PPCD pre-treated with 1000 dyne/cm2 shear force was 91.59%. And in vivo, the percentage of residual thrombus in UK@Fuc-TI/PPCD treatment group was only 9.37% with relatively low bleeding risk, suggested this shear fore-responsive detachable system with thrombus targeting ability and sequential drug release profile can realize the efficient recanalization of embolized vessels.

Background Ticagrelor is an orally active antiplatelet drug belonging to 1,2,3-triazolo[4,5-d]pyrimidines, which acts by reversibly inhibiting the platelet P2Y12 receptor for ADP. Although ticagrelor does not need to be metabolized to be active in vivo, it is extensively metabolized to form a main metabolite known as AR-C124910, equally potent to inhibit P2Y12 receptors. Importantly, we recently discovered that ticagrelor and AR-C124910 exert bactericidal and anti-biofilm activity against gram-positive bacteria. Aim The present work aimed at establishing structure-activity relationships of a series of 1,2,3-triazolo[4,5-d]pyrimidines in order to identify structural determinants of antiplatelet and antibacterial activity. Methods Ticagrelor, five main metabolites and eighteen 1,2,3-triazolo[4,5-d]pyrimidines lacking different chemical groups or bearing atom substitutions were synthetized. The antiplatelet activity of the test molecules was analysed by light transmission aggregometry upon platelet stimulation with ADP in citrated platelet-rich-plasma. The antibacterial activity against Staphylococcus aureus strains was determined by the broth microdilution method. Results Only ticagrelor and AR-C124910 showed antibacterial activity. We found out that molecules lacking either the difluorphenylcyclopropyl group or the hydroxyethoxy cyclopentane-1,2-diol were all inactive against bacteria. Interestingly, such restriction did not apply to the antiplatelet activity. Indeed, seven of these molecules, devoid of antibacterial activity, still inhibited the ADP-induced platelet aggregation. Conclusions We identified molecules that preserved potent antiplatelet activity while being inactive against S. aureus. These molecules might help demonstrating ticagrelor antibacterial activity in vivo, independently of or in addition to its antiplatelet activity.

The antiplatelet drug clopidogrel is widely used for prophylaxis of arterial thromboses in cats in a standard dosage of 18.75mg per cat once daily. The aim of the study was to verify if a reduced daily dose of 10mg clopidogrel per cat has a similar antiplatelet effect as the standard dosage. Platelet function was measured with the platelet function analyser PFA-100® and a novel impedance aggregometer. Suitability of the platelet function analyser was tested in citrated blood samples of 59 healthy cats and reference ranges were established. In addition, agonist concentrations for impedance aggregometry were optimised. In the main experiment two groups of 6 healthy cats received clopidogrel either in a dosage of 10 or 18.75mg per cat over a period of seven days. Analyses were performed on days 1, 2, 3, 5, and 7. In comparison to baseline both clopidogrel dosages showed an inhibitory effect on results of the platelet function analyser and velocity of ADP-induced platelet aggregation. Values at all times were different from baseline, with the exception of day 1 in cats receiving 10mg clopidogrel where the closure time of the platelet function analysis and part of ADP-induced aggregation did not show a significant difference. Significant differences were not found between the two doses. In conclusion, our study indicates that 10mg clopidogrel per day may be as effective as 18.75mg although the latter may be advantageous as an initial loading dosage to achieve effective levels more rapidly.

Platelets are the smallest blood cells, and their activation (platelet cohesion or aggregation) at sites of vascular injury is essential for thrombus formation. Since the use of antiplatelet therapy is an unsolved problem, there are now focused and innovative efforts to develop novel antiplatelet compounds. In this context, we assessed the antiplatelet effect of an acylhydroquinone series, synthesized by Fries rearrangement under microwave irradiation, evaluating the effect of diverse acyl chain lengths, their chlorinated derivatives, and their dimethylated derivatives both in the aromatic ring and also the effect of the introduction of a bromine atom at the terminus of the acyl chain. Findings from a primary screening of cytotoxic activity on platelets by lactate dehydrogenase assay identified 19 non-toxic compounds from the 27 acylhydroquinones evaluated. A large number of them showed IC50 values less than 10 µM acting against specific pathways of platelet aggregation. The highest activity was obtained with compound 38, it exhibited sub-micromolar IC50 of 0.98 ± 0.40, 1.10 ± 0.26, 3.98 ± 0.46, 6.79 ± 3.02 and 42.01 ± 3.48 µM against convulxin-, collagen-, TRAP-6-, PMA- and arachidonic acid-induced platelet aggregation, respectively. It also inhibited P-selectin and granulophysin expression. We demonstrated that the antiplatelet mechanism of compound 38 was through a decrease in a central target in human platelet activation as in mitochondrial function, and this could modulate a lower response of platelets to activating agonists. The results of this study show that the chemical space around ortho-carbonyl hydroquinone moiety is a rich source of biologically active compounds, signaling that the acylhydroquinone scaffold has a promising role in antiplatelet drug research.

Adherence to drugs and healthy lifestyles is low after acute coronary syndrome. We assessed whether trained community health workers could improve adherence to drugs, lifestyle changes, and clinical risk markers in patients with acute coronary syndrome in India.In this study done at 14 hospitals in India we randomly assigned (1:1) patients with acute coronary syndrome 1 or 2 days before discharge from hospital to a community health worker-based intervention group or a standard care group. Patients were randomly assigned with a telephone randomisation service. In the intervention group, during four in-hospital and two home visits, community health workers used unstructured discussions, visual methods, and patient diaries to educate patients on healthy lifestyle and drugs, and measures to enhance adherence. The primary outcome was adherence to proven secondary prevention drugs (antiplatelet drugs, β blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins) estimated using a Composite Medication Adherence Scale at 1 year. The secondary outcomes were difference in lifestyle factors (diet, exercise, and tobacco and alcohol use), and clinical risk markers (blood pressure, bodyweight, BMI, heart rate, and lipids). All analyses were by intention to treat. This trial is registered with the Clinical Trial Registry of India, number REF/2013/03/004737, and ClinicalTrials.gov, number NCT01207700.Between Aug 23, 2011, and June 25, 2012, 806 participants were randomly assigned (405 to a community health worker-based intervention group and 401 to a standard care group). At 1 year, 40 patients had died and 15 had discontinued or been lost to follow-up, so 750 (93%) were included in the analyses (375 in each group). Secondary prevention drugs prescribed at discharge were 98% (786/803) for any antiplatelet drug, 79% (638/803) for dual antiplatelet drugs, 69% (555/803) for β blockers, 69% (552/803) for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and 95% (762/803) for statins. At one year, overall adherence (≥80%) to prescribed evidence-based drugs was higher in the intervention group than in the control group (97% vs 92%, odds ratio [OR] 2·62, 95% CI 1·32-5·19; p=0·006). For individual drugs, we recorded significant differences for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (97% [233/240] in the intervention group vs 93% [223/240] in the control group; p=0·036) and statins (97% [346/356] vs 93% [321/345]; p=0·011). The intervention group had significantly greater adherence to smoking cessation (85% [110/129] vs 52% [71/138], OR 5·46, 95% CI 3·03-9·86; p0·0001), regular physical activity (89% [333/375] vs 60% [226/375], OR 5·23, 95% CI 3·57-7·66; p0·0001), and healthy diet (score 5·0 vs 3·0, OR 2·47, 95% CI 1·88-3·25; p0·0001). More patients in the intervention group had stopped alcohol use at 1 year (87% [64/74] vs 46% [46/67], OR 2·92, 95% CI 1·26-6·79; p =0·010). At 1 year, the mean systolic blood pressure (124·4 mm Hg [SD 13·5] vs 128·0 mm Hg [15·9]; p=0·002), weight (65·0 kg [11·0] vs 66·5 kg [11·5]; p0·0001), cholesterol (157·0 [40·2] vs 166·9 [48·4]; p=0·184), LDL (81·0 [20·6] vs 87·3 [29·9]; p=0·191), HDL (42·0 [11·4] vs 38·2 [6·5]; p=0·042), and BMI (24·4 kg/m(2) [SD 3·7] vs 25·0 kg/m(2) [3·8]; p0·0001) were lower in the intervention group than in the control group. However, we noted no significant difference in diastolic blood pressure and heart rate.A community health worker-based personalised intervention strategy in patients with acute coronary syndrome improved adherence to evidence-based drugs and healthy lifestyles, and resulted in an improvement in clinical risk markers. Integration of trained community health workers can improve secondary prevention in coronary artery disease.US National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Department of Health and Human Services, and the UnitedHealth group, USA.

Rofecoxib (ROF), a potent selective COX-II inhibitor NSAID, has been withdrawn from the market due to its high risk on patients with cardiovascular disorders (CVD). In the current study, an attempted to re-introduce ROF into the market via co-formulation with the antiplatelet drug, Aspirin, to neutralize ROF effect on the platelet function has been investigated. Solubility and dissolution profiles of ROF were studied and improved through formulation into solid dispersions with Soluplus® before being mixed with a low dose of Aspirin. The novel drug combination was incorporated into oral tablets with various compositions to optimize the tablets physico-chemical performance. In addition, a new validated HPLC method was developed for simultaneous assessment of both drugs in the tablets. The optimized tablets demonstrated satisfactory physico-chemical performance. The developed HPLC method was accurate, precise, robust and sensitive with limits of detection (LODs) of 2.96 and 0.25 μg/mL and limits of quantitation (LOQs) of 8.77 and 0.77 μg/mL for Aspirin and ROF, respectively. The novel co-therapy showed normal platelet function in rabbits in opposite to ROF monothrapy. The data presented in this study can be promising to re-utilize ROF as an effective and selective NSAID, to satisfy the market's demand, while ensuring its safety in CVD patients.

We thank Dr. Pauley and colleagues for their insightful comments on our consensus statement [(1)][1]. The potential for inadequate antiplatelet drug response in the distinct cohort of patients requiring oral anticoagulation (OAC) who commonly drop aspirin and receive single antiplatelet treatment (

Background Antiplatelet therapy is a potential risk factor for intracerebral hemorrhage, and cerebral microbleeds reflect small perivascular hemorrhages without clinical symptoms. The question regarding whether antiplatelet therapy increases the risk of cerebral microbleeds has not yet reached a consensus. Methods We conducted a search in English database and extracted data from studies assessing the relationship between antiplatelet therapy and cerebral microbleeds. Then, we adopted the Review Manager 5.2 package to calculate pooled odds ratios (ORs) with the method of the inverse variance. Results We pooled data from 11 studies involving 10429 participants. The results revealed that there was a significant association between antiplatelet therapy and cerebral microbleeds in hemorrhagic stroke patients (OR, 1.96; 95% confidence interval [CI], 1.22-3.16) and ischemic stroke patients (OR, 1.65; 95% CI, 1.06-2.59), but not stroke-free population (OR, 1.30; 95% CI, .96-1.74). When stratified by population ethnicity, the association between antiplatelet therapy and cerebral microbleeds was significant in hemorrhagic stroke (OR, 2.26; 95% CI, 1.25-4.08) and ischemic stroke (OR, 2.18; 95% CI, 1.02-4.67) patients from Asian countries, but not significant in hemorrhagic stroke (OR, 1.95; 95% CI, .33-11.37) and ischemic stroke (OR, 1.16; 95% CI, .87-1.54) patients from European countries. Conclusions Antiplatelet therapy may increase the risk of cerebral microbleeds in stroke population. In addition, the relationship between antiplatelet therapy and cerebral microbleeds may be influenced by ethnic factors. More and larger prospective studies are urgently required to verify our results, because the studies to date are retrospective and the available data are limited.

Clopidogrel is an antiplatelet drug that requires biotransformation steps to its active metabolite via cytochromes P450 (CYP), particularly CYP2C19 and CYP3A5 as well as paraoxonase-1 (PON1). The impact of CYP3A5 and PON1 genetic polymorphisms on the response of this drug is unclear. This study aimed to elucidate the degree of genetic polymorphisms of key drug metabolizing enzymes on the antiplatelet effect of clopidogrel. Thirty-five healthy subjects were treated with 75 mg/day clopidogrel for 7 days and serial blood samples were collected for measurement of antiplatelet effect using whole blood impedance aggregometry and VerifyNow ® P2Y12 methods. The areas under the antiplatelet effect–time curves, maximal and minimal antiplatelet effects of clopidogrel obtained from both methods were significantly different among subjects with different CYP2C19 genotypes. In contrast, these pharmacodymamic parameters measured by both methods of subjects with different PON1 or CYP3A5 genotypes were not significantly different. Among the heterozygous CYP2C19 * 2 subjects, all pharmacodynamic parameters measured by whole blood impedance aggregometry were significantly different between subjects with different CYP3A5 * 3 genotypes. Our data suggest s that CYP2C19 genetic polymorphism play a major role in the clopidogrel response, however, the impact of CYP3A5 genetic polymorphism, may be pronounced in the subjects who carried the loss-functional allele of CYP2C19 .

Antiplatelet drugs are prescribed to patients with cardiovascular disease in order to reduce their risk of clinically important atherothrombotic events. However, a proportion of patients fail to appropriately respond to these drugs in a heterogeneous phenomenon known as 'antiplatelet drug resistance'. Individuals who are identified as being resistant have a higher cardiovascular risk, but currently there is no clinically validated approach to identify and treat these individuals. Large randomised control trials have attempted to personalise antiplatelet therapy based on platelet function testing, but these have failed to demonstrate improved clinical outcomes. An alternative approach to this non-specific assessment of platelet function is to consider whether antiplatelet therapy may be personalised based on the identification of molecular mechanisms that are known to confer resistance. Here we present molecular insights into the mechanisms for aspirin and clopidogrel resistance, with a discussion of their clinical implications.

Introduction The antiplatelet drug aspirin is considered as a cornerstone in medical treatment of patients with CV or cerebrovascular diseases. Despite its use, a significant number of patients had recurrent adverse ischemic events. Inter-individual variability of platelet aggregation in response to aspirin may be an explanation for some of these events. Multiple trials have linked aspirin resistance to these adverse events. Objectives The aim of this study was to estimate the prevalence of aspirin resistance among patients with coronary artery disease (CAD) in Egypt and evaluate its impact on clinical outcome. Methods A total of 50 patients with documented history of CAD were included; they were on aspirin 150 mg/day for more than seven days and no other antiplatelet drugs. They were evaluated for aspirin resistance using light transmission aggregometry. Aspirin resistance was defined as a mean aggregation of >20% with 0.5 mg/ml arachidonic acid. They were followed up after six months for cardiac death, unstable angina (UA), myocardial infarction (MI), and stroke. Results Prevalence of aspirin resistance was 48% in our study group. Aspirin resistance was significantly higher in patients with family history of CAD ( p = 0.044), smoking ( p = 0.011), history of MI ( p = 0.024), history of percutaneous coronary intervention (PCI) ( p = 0.001), and concomitant NSAIDs intake ( p = 0.047). Moreover, aspirin resistance was more common among patients with multi-vessel CAD ( p = 0.024). Aspirin-resistant patients had a significantly higher rate of UA ( p = 0.001) and all major adverse cardiac events (MACE) ( p

Background and purpose Many patients with atrial fibrillation (AF) and coronary artery stent deployment are given both antiplatelet drug and warfarin. Little information is available as to the relationship between the antithrombotic therapies in the late phase after stenting and the clinical outcomes of these patients. We examined the clinical outcomes of AF patients 12 months after coronary artery stenting. Methods We retrospectively examined 146 patients and classified them into three groups according to the antithrombotic therapies [dual antiplatelet therapy (DAPT), single antiplatelet therapy (SAPT) plus warfarin, and DAPT plus warfarin] 12 months after stenting. We defined the primary endpoint as Thrombolysis in Myocardial Infarction major bleeding and the secondary endpoint as a composite of adverse events (CAE: all-cause death, nonfatal myocardial infarction, intracranial bleeding, and cerebral infarction). Results During a median follow-up of 37 months, major bleeding and CAE were observed in 14 (9.6%) and 46 (31.5%) patients, respectively. DAPT plus warfarin was an independent risk factor for major bleeding in a multivariate Cox hazard regression model after adjustment for age, gender, and the type of AF (hazard ratio: 4.20; 95% confidence interval: 1.13–17.27; p = 0.033). No significant clinical variables were found for CAE. Conclusions Prolonged use of DAPT with warfarin significantly increases the risk of major bleeding in AF patients after coronary artery stenting. Individualized antithrombotic treatment is required in these patients to prevent major bleeding.

Background The effect of a combined antithrombotic drug regimen on lower GI bleeding (LGIB) remains unknown. Objective To investigate the risk of LGIB associated with nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, thienopyridine (ticlopidine or clopidogrel), or other antiplatelets used. Design Prospective study. Setting Emergency hospital, gastroenterology department. Patients A cohort of 319 patients emergently hospitalized for acute, continuous, or frequent LGIB and 3358 patients with no bleeding on colonoscopy. Main Outcome Measurements Odds ratios (ORs) for the risk of LGIB associated with drug exposure adjusting for age, sex, smoking, alcohol, medications, comorbidities, and GI symptom scores. Results After considering antithrombotic drugs by dividing them into single- and combined-use, single use of nonselective NSAID or cyclooxygenase-2 inhibitor was independently associated with LGIB. The combined use of NSAIDs with low-dose aspirin (OR 4.3) or with other antiplatelets (OR 4.9) was more associated with LGIB than the use of NSAIDs alone (OR 2.3). Use of low-dose aspirin, thienopyridine, or other antiplatelets alone was not significantly associated with LGIB, but combined use of low-dose aspirin with thienopyridine (OR 2.2) or with other antiplatelets (OR 3.6) was associated with LGIB. Combined use of different NSAIDs carried a higher risk than single use (combined use, OR 4.9; single use, OR 2.3). Limitations Single-center study. Conclusion The use of nonselective or selective NSAIDs alone was associated with LGIB. Although antiplatelet use alone was not significantly associated with LGIB, combined use of NSAIDs with antiplatelets or of low-dose aspirin with thienopyridine or with nonthienopyridine antiplatelets was independently associated with LGIB.

Decisions on antiplatelet therapy may appear increasingly complex, and vary according to the clinical situation. Concerning P2Y12 antagonists, drug choice, administration route, timing of administration, and duration of therapy need to be factored into the decision making. There are less evidence

In 2003, Gurbel et al. [(1)][1] observed that the response of platelets to the P2Y12 inhibitor clopidogrel was nonuniform and suggested that patients who have persistently high ex vivo platelet reactivity while receiving clopidogrel might be prone to stent thrombosis and myocardial infarction.

Million Hearts is a national initiative to prevent 1 million heart attacks and strokes over 5 years. The degree to which outpatient providers are controlling risk factors has not been fully described.We examined adherence to the Million Hearts clinical quality measures using The Guideline Advantage, a nationwide quality improvement program for outpatient care. Specifically, we determined the proportion of patients with (1) ischemic vascular disease who were prescribed an antiplatelet drug; (2) hypertension whose blood pressure was controlled; (3) diabetes mellitus whose most recent low-density lipoprotein cholesterol level was100 mg/dL; and 4) a tobacco use screening and who received a smoking cessation intervention as needed.From January 1, 2010, to March 31, 2012, there were 147,038 patients enrolled from 25 US practices. At the practice level, antiplatelet prescription ranged from 50.0% to 82.3% (median 71.9%, interquartile range [IQR] 66.7-82.1), hypertension control ranged from 48.6% to 75.3% (median 66.6%, IQR 60.1-70.9), hyperlipidemia control among patients with diabetes mellitus ranged from 53.3% to 100.0% (median 75.8%, IQR 65.8-83.0), and tobacco use screening and intervention ranged from 31.0% to 98.8% (median 79.8%, IQR 72.0-83.2). Black and people of color races were associated with a lower likelihood of blood pressure control and cholesterol control. Female gender was associated with a lower likelihood of antiplatelet prescription and cholesterol control.Compliance with quality measures for the Million Hearts initiative varies widely and is notable for racial and gender disparities. Our findings identify multiple opportunities to improve the quality of cardiovascular prevention.

Background Gastrointestinal angiodysplasias are an important cause of difficult to manage bleeding, especially in older patients. Aim To retrospectively evaluate the long-term efficacy of long acting release-octreotide in controlling angiodysplasia bleeding. Methods 98 patients with a history of bleeding due to gastrointestinal angiodysplasias lasting over 2 years were retrospectively selected among those treated from January 2000 to December 2008. All patients had received octreotide 0.1 mg tid for 28 days and, then from day 14, long acting release-octreotide 20 mg monthly, for 6 months. Results The mean follow-up was 78 months. In all patients mean haemoglobin levels significantly increased and the number of bleeding episodes, hospitalizations, patients requiring blood transfusions and units of transfused red cells significantly decreased, compared to the two-year observation period before starting therapy. According to outcome patients were classified as: 40 full responders (40.8%), 32 relapsers (32.6%) and 26 poor responders (26.5%). At multivariate analysis age >65 years, male sex, chronic antiplatelet therapy, chronic obstructive pulmonary disease and chronic renal failure were the only covariates independently associated with poor response to therapy. Conclusion Our study suggests that long acting release-octreotide could be used as rescue therapy to control bleeding due to gastrointestinal angiodysplasias in patients not suitable for endoscopic or surgical treatments.

Key pathophysiological steps in preeclampsia include 1) placental oxidative stress, 2) elevated sFlt1 and 3) endothelial dysfunction. While the antiplatelet drug aspirin has shown potential to prevent preeclampsia, its effectiveness remains limited. New generation antiplatelet drugs (Clopidogrel, Prasugrel and Ticagrelor) have distinct properties beyond antiplatelet actions (inflammation and endothelial dysfunction), thus may be more effective to prevent preeclampsia. We examined whether new generation antiplatelet drugs are better than aspirin at countering various pathophysiological steps in models of preeclampsia. Methods Primary human cytotrophoblast, placental explants and endothelial cells (HUVEC and uterine microvascular (UtMVs)) were treated with increasing doses of Clopidogrel, Prasugrel, Ticagrelor or Aspirin (0–100 μM). Endothelial dysfunction was induced and antiplatelet agents were added. Functional assays measured the adherence of primary human monocytes to stimulated endothelial cells. Media and cell lysates were collected to assess 1) ROS production, 2) antioxidant response element signaling pathways, 3) production of vasoactive mediators, 4) production of sFlt1, PlGF and pro-inflammatory mediators and 4) markers of endothelial dysfunction. Results New generation antiplatelet agents induced nuclear Nrf2 translocation (antioxidant transcription factor), increased antioxidant gene expression (HO-1, NQO1 and GCLC). Consistently reactive oxygen species (ROS) production was reduced with new generation antiplatelet treatment. Furthermore the new generation antiplatelets potently reduced sFlt1 secretion from preeclamptic placental explants, and importantly they also increased PlGF mRNA expression. Antiplatelet agents rescued endothelial dysfunction, mitigating monocyte-endothelial adhesion, and reduced VCAM1 and ET-1 expression (both mRNA and protein) and enhanced eNOS activity. Aspirin however had no beneficial effects in our in vitro/ex vivo models of preeclampsia. Conclusions In contrast to aspirin, new generation antiplatelets potently upregulate antioxidant defences, reduce ROS formation, decrease sFlt1 secretion, enhance activity of vasoactive mediators and counter endothelial dysfunction in human models of preeclampsia. Given they are classified as category B/C drugs, they represent exciting candidate therapies to prevent preeclampsia.

Antiplatelet drugs serve as a first-line antithrombotic therapy for the management of acute ischemic events and the prevention of secondary complications in vascular diseases. Numerous antiplatelet therapies have been developed; however, currently available agents are still associated with inadequate efficacy, risk of bleeding, and variability in individual response. Understanding the mechanisms of platelet involvement in thrombosis and the clinical development process of antiplatelet agents is critical for the discovery of novel agents. The functions of platelets in thrombosis are regulated by two major mechanisms: the interaction between surface receptors and their ligands, and the downstream intracellular signaling pathways. Recently, most of the progress made in antiplatelet drug development has been achieved with P2Y receptor antagonists. Additionally, the usage of GP IIb/IIIa receptor antagonists has decreased, because it is associated with a higher risk of bleeding and thrombocytopenia. Agents targeting other platelet surface receptors such as PARs, TP receptor, EP3 receptor, GPIb-IX-V receptor, P-selectin, as well as intracellular signaling factors, such as PI3Kβ, have been evaluated in an attempt to develop the next generation of antiplatelet drugs, reduce or eliminate interpatient variability of drug efficacy and significantly lower the risk of drug-induced bleeding. The aim of this review is to describe the pathways of platelet activation in thrombosis, and summarize the development process of antiplatelet agents, as well as the preclinical and clinical evaluations performed on these agents.

Goal: There are an increasing idea that the inflammation contributes to vascular diseases in various organs. The pathogenesis of both cerebral small vessel disease such as cerebral microbleeds and carotid plaque may be associated with chronic inflammation. This study was aimed to evaluate the correlation between microbleeds and carotid plaque characteristics. Materials and Methods: This study enrolled 85 patients who underwent surgical/endovascular treatments for carotid artery stenosis between January 2009 and July 2016. Their clinical data were precisely analyzed. T2*-weighted magnetic resonance (MR) imaging was performed to detect the cerebral microbleeds. The carotid plaque with high signal intensity on T1-weighted MR imaging was categorized into vulnerable plaque. Findings: The microbleeds was detected in 17 of 85 (20%). The prevalence of vulnerable carotid plaque and previous symptomatic lacunar infarction was significantly greater in the patients with microbleeds than in those without (P = .001 and P = .03, respectively). Multiple logistic regression analysis showed that the vulnerable plaque was significantly associated with the presence of microbleeds when adjusted for age, alcohol intake, antiplatelet drug use, the presence of previous symptomatic lacunar infarction, and coronary artery disease (P = .009, OR = 5.38, 95% CI = 1.51-21.0). Conclusions: These findings suggest the correlation between microbleeds and vulnerable plaque in patients with severe (>70%) carotid artery stenosis. Systemic, chronic inflammation may play a key role in both small and large arteries’ disease of the brain. The knowledge may be valuable to fully understand the entity of cerebrovascular diseases as one of systemic, chronic inflammation.

About 40% of patients (pts) with ST-segment elevation myocardial infarction successfully reperfused have some degree of microcirculation flow (MF) compromised; this leads to worse left ventricular remodeling and higher mortality. Clopidogrel is the only antiplatelet drug with proved benefit on MF.

Purpose Aspirin is an antiplatelet drug which is commonly used in secondary prevention in ischemic heart disease and cerebrovascular events, and in newly diagnosed myocardial infarction. The aim of the present study was to examine effect of aspirin on the level of selected sphingolipid intermediates in plasma, erythrocytes and platelets. Material and Method Forty two healthy volunteers participated in the study. They were divided into two groups. In one group aspirin was given orally, daily, for one week in a dose of 75mg (n=25). The subjects from the second group received one 300mg dose of the drug (n=17). In both groups the blood was taken 4h after the last dose of aspirin. The following sphingolipid intermediates were quantified using high-pressure liquid chromatography: sphinganine, sphingosine, sphingosine-1-phosphate (S1P), sphinganine-1-phosphate (SA1P) and ceramide. Results It was found that lower dose of aspirin increased the level of S1P and ceramide in erythrocytes (by 23 and 37%, respectively) having no effect on plasma and platelet sphingolipid levels. Higher dose of the drug reduced S1P and SA1P concentration in the plasma (by 16 and 10%, respectively). Conclusion We conclude that aspirin interferes with sphingolipid metabolism in blood and that this effect depends on a dose of the drug. Since S1P is a potent cardioprotectant, the reduction in its plasma concentration after the loading dose of aspirin could be undesired side effect of the drug.

HMG Co-A (3-hydroxy-3 methylglutaryl coenzyme A) reductase inhibitors, or statins, are the most successful class of medications in cardiovascular history. By blocking cholesterol synthesis, and upregulating low-density lipoprotein (LDL) receptors, these drugs decrease LDL-cholesterol (LDL-C) by up to 50%, significantly reducing cardiovascular events. More than 25 randomized placebo controlled studies have demonstrated their efficacy, establishing statins as the drug of choice for cardiovascular risk reduction in a primary and secondary prevention setting. All major national guidelines recommend statins as first-line therapy in subjects at appropriate risk for pharmaceutical intervention. Despite these impressive results, significant residual risk remains for subjects at highest risk. In individuals who have established vascular disease, or present with an acute coronary syndrome (ACS), fully 75% of the events are not prevented by current therapy with statins. Of course, this is statin therapy in addition to interventions including coronary revascularization, cardiac rehabilitation, antiplatelet drug(s), b-blockers, and inhibition of the renin-angiotensin-aldosterone axis. This residual risk has been the focus of a great deal of epidemiological and interventional research over the past decade. Statins predominantly lower LDL-C with minimal effects on other lipid targets such as triglycerides, high-density lipoprotein (HDL) cholesterol (HDL-C), or lipoprotein (a). All of these lipid moieties have been associated with adverse cardiovascular events in cohort studies. As such, it was natural to test the hypothesis that drugs that target these molecules would improve cardiovascular events. In addition, there was evidence from a number of sources that suggested that lowering LDL-C as aggressively as possible would be another strategy to reduce risk. The “lower is better” sentiment was very prevalent among researchers in this field.

SummaryBackground 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a tumor vascular disrupting agent under clinical trials as an adjacent antitumor agent. DMXAA is structurally similar to flavone-8-acetic acid (FAA), an old tumor vascular disrupting agent with antiplatelet and antithrombotic effects. In contrast to FAA, which causes bleeding in tumor patients, no bleeding has been reported in patients receiving DMXAA. Whether DMXAA also affects platelet function is not clear. Objectives To determine the effects of DMXAA on platelet function and explore the underlying mechanisms. Methods and Results DMXAA concentration-dependently inhibited human platelet aggregation and ATP release induced by U46619, arachidonic acid, ADP, collagen, or ristocetin. Furthermore, DMXAA inhibited phosphorylation of Erk1/2 and Akt downstream of thromboxane A2 signaling inhibition. DMXAA also inhibited human platelet phosphodiesterase. The antiplatelet effects were further confirmed using mice administered DMXAA intravenously. DMXAA dramatically inhibited thrombus formation in FeCl3-injured mouse mesenteric arterial thrombus model and laser-injured mouse cremaster arteriole thrombus model. Notably, at a dose exhibiting antithrombotic effects similar to those of clopidogrel in mice, DMXAA did not significantly increase bleeding. Conclusions For the first time, we found that tumor vascular disrupting agent DMXAA has potent antiplatelet and antithrombotic effects without any bleeding diathesis. As DMXAA inhibits platelet activity with safe profile, DMXAA could be used as an efficacious and safe antiplatelet drug.

BackgroundPeriprocedural management of antiplatelet or anticoagulant therapy at the time of device implantation remains controversial.MethodsWe reviewed all cases for whom a pacemaker was implanted in our institution between January 2008 and June 2009. In addition, beginning in June 2009, we prospectively collected data from all patients admitted to our institution, for whom a pacemaker was placed. Clinical characteristics and anticoagulant/antiplatelet drug use were evaluated.ResultsA total of 574 patients underwent a permanent pacemaker implantation. Of these, 20 patients (3.6%, 9 women) experienced a hematoma on pacemaker pocket site. Patients were aged between 35 and 79 years (mean 60.6±12 years). The frequency of hematoma formation was significantly higher (p0.05). Eleven pocket revisions for hematoma evacuation were needed in 9 patients (1.6%), six of whom were on warfarin therapy (p>0.05). Co-morbidities were similar in patients with and without hematoma (p>0.05).ConclusionThe frequency of hematoma is within acceptable ranges after pacemaker placement. The use of warfarin seriously increases the risk of hematoma. Bridging to LMWH safely prevents thromboembolism.

Objective A review of the perioperative management of patients with hip fractures and concomitant therapy with antiplatelet agents, and to analyse the differences in mortality and perioperative bleeding in early surgery ( 5 days). Platelet aggregation was measured on admission and immediately before surgery in all patients included in the study Patients and methods A total of 175 patients over 65 years old, with low energy hip fracture were randomised into 3 groups: Patients on antiplatelet therapy undergoing early surgery, patients on antiplatelet therapy undergoing delayed surgery, and patients not on antiplatelet therapy undergoing early surgery. The same clinical and laboratory data were collected prospectively up to 12 months for all the patients. The platelet aggregation was determined by a semi-quantitative computerised system based on impedance aggregometry in whole blood. Results Bleeding, transfusion requirements and analytical results showed no significant differences between groups. More than half (59.8%) of the patients not taking antiplatelet therapy had normal platelet aggregation on admission, while 13.5% of those taking antiplatelet agents did not have that. Multivariate analysis showed increased mortality at 12 months for the variables, low Barthel index before hip fracture (OR: 0.9–0.9) and number of transfusions (OR: 1.1–1.5). The average length of stay was 4.1 days greater in the delayed surgery group. Conclusion Early surgery for patients receiving antiplatelet therapy has similar clinical outcomes to the delayed, but improves hospital efficiency by reducing the average length of stay. The antiplatelet drug reported by the patient showed low concordance with the determination of the platelet aggregation.

This review is a critical evaluation of publications in the past decade on the usefulness of platelet function tests (PFTs) in clinical cardiology, in aiding diagnosis, predicting risk, and monitoring therapy. The ideal PFT should: 1) detect baseline platelet hyperreactivity; 2) allow individualization of antiplatelet medication; 3) predict thrombotic risk; and 4) predict bleeding risk. The practicalities of clinical cardiology demand rapid, accurate, and reliable tests that are simple to operate at the bedside and available 24 h a day, 7 days a week. Point-of-care PFTs most widely evaluated clinically include PFA-100 and VerifyNow. None of these tests can reliably detect platelet hyperreactivity and thus identify a prothrombotic state. Identification of antiplatelet nonresponsiveness or hyporesponsiveness is highly test specific, and does not allow individualization of therapy. The power of PFTs in predicting thrombotic events for a given individual is variable and often modest, and alteration of antithrombotic treatment on the basis of the results of PFTs has not been shown to alter clinical outcome. PFTs in current mainstream use cannot reliably assess bleeding risk. These tests have been in use for over a decade, but the hopes raised by PFTs in clinical practice remain unfulfilled. Although physiologically relevant measurement of platelet function now is more important than ever, a critical reappraisal of available techniques in light of clinical requirements is needed. The use of native blood, global stimulus instead of individual agonists, contribution of thrombin generation by activated platelets to the test results, and establishment of a PFT therapeutic range for each antiplatelet drug should be considered and is discussed.

Patients who undergo placement of a drug-eluting coronary artery stent are prescribed dual antiplatelet therapy for one year. Early cessation of this therapy is a risk factor for a major adverse cardiac event, especially in high-risk patients. The perioperative physician team must evaluate the risk of surgical bleeding relative to the thrombotic risk during the perioperative period in patients taking dual antiplatelet therapy who must undergo intracranial neurosurgery. A 67 year old woman presented with right-sided hearing loss. Neurologic examination was significant for early papilledema and decreased hearing in the right ear. Magnetic resonance imaging showed a > 5 cm contrast-enhancing mass within her right-middle fossa with surrounding vasogenic edema and midline shift. Additional medical history was significant for diabetes, hypertension, and placement of a drug-eluting stent for coronary artery disease three months before her initial presentation. Medications included aspirin and clopidogrel. She underwent embolization of the middle meningeal arterial supply to the meningioma, then was admitted to the hospital for perioperative management of her antiplatelet therapy and telemetry monitoring. Her clopidogrel was stopped and aspirin continued perioperatively. An intravenous infusion of the antiplatelet drug, eptifibatide, replaced clopidogrel and was continued until 8 hours prior to surgical incision. During resection of the meningioma, no unusual surgical bleeding was noted. The patient was discharged on postoperative day 3 with satisfactory recovery.

Objectives The goal of this study was to assess the risk associated with double antiplatelet therapy (DAT) discontinuation, and specifically, temporary discontinuation, during the first year after drug-eluting stent (DES) implantation. Background Doubts remain about the risk of temporary DAT discontinuation within 1 year after DES implantation. Methods A total of 1,622 consecutive patients undergoing DES implantation at 29 hospitals were followed up at 3, 6, 9, and 12 months to record the 1-year antiplatelet therapy discontinuation (ATD) rate, the number of days without DAT, and the rate of 1-year major cardiac events. Cox regression was used to analyze the association between ATD considered as a time-dependent covariate and 1-year cardiac events. Results One hundred seventy-two (10.6%) patients interrupted at least 1 antiplatelet drug during the first year after DES implantation, although only 1 during the first month. Most (n = 111, 64.5%) interrupted DAT temporarily (median: 7 days; range: 5 to 8.5): 79 clopidogrel (31 temporarily), 38 aspirin (27 temporarily), and 55 both drugs (53 temporarily). Discontinuation was followed by acute coronary syndrome in 7 (4.1%; 95% confidence interval [CI]: 1.7 to 8.2), a similar rate of major cardiac events to that in patients without ATD (n = 80; 5.5%; 95% CI: 4.4 to 6.8; p = 0.23). ATD was not independently associated with 1-year major cardiac events (hazard ratio: 1.32 [95% CI: 0.56 to 3.12]). Conclusions ATD within the first year and beyond the first month after DES is not exceptional, is usually temporary, and does not appear to have a large impact on risk.

Indications for percutaneous coronary intervention with stent placement are increasing; some candidates already require oral anticoagulation. Safety of triple antithrombotic therapy — aspirin (ASA), clopidogrel and oral anticoagulation (OAC) — remains largely unknown. In order to study hemorrhagic complications in those patients, we identified thirty-three patients from our anticoagulation clinic registry who were prescribed triple antithrombotic therapy. All hemorrhagic events were collected and classified as non-severe (NSH) or severe (SH). The same population provided a control to determine increased risk from addition of a second antiplatelet drug. Overall, patients were followed for 53 patient-months while on triple therapy (TT) and 869 patient-months on double therapy. Patients in TT group had more hemorrhages (90.6% patient-years vs 8.29% patient-years, p p

There is a wide consensus that intensified antiplatelet therapy contributes to the reduction of major atherothrombotic complications in cardiovascular (CV) disease. In the setting of PCI (percutaneous coronary intervention) and acute coronary syndromes, dual antiplatelet therapy at optimal dosing and timing has significantly lowered the risk of thrombotic complications. There is a growing body of evidence that there is variability in response to antiplatelet treatments and this represents a potentially important clinical problem. Understanding the mechanisms underlying this phenomenon is important in improving patient care, but due to the diversity of factors involved, a clear predictive model for responsiveness to antiplatelet therapy is still missing. Attempts have been made to characterize the efficacy of antiplatelet therapy using platelet function testing but based on current information, its routine use is not recommended particularly as costs and cost effectiveness have not been established and agreement between laboratory methods is lacking. Hence, it is necessary to identify risk factors for decreased efficacy of standard antiplatelet drug treatment. It may be useful to adjust antiplatelet therapy based on individual risk assessment, especially as new platelet inhibitors are being introduced or are in development including prasugrel as well as the non-thienopyridines, ticagrelor, elinogrel, the ATP analog cangrelor, and thrombin receptor antagonists. This article focuses on antiplatelet therapy in patients at high risk for cardiovascular events and discusses the options for individual risk assessment and strategies to personalize therapy in the light of the large number of recent developments.

Surface-induced thrombosis is a major complication associated with blood-contacting biomaterials. Cross-linked albumin films possessing native albumin characteristics such as resistance to cell adhesion and drug binding ability are available for improving the blood compatibility of biomaterial surfaces. In the present study, we aimed to evaluate the blood compatibility of cross-linked albumin films. Platelet adhesion analysis showed that albumin film coated substrates exhibited very low platelet adhesion, and platelet adhesion was further suppressed by loading the antiplatelet drug, cilostazol, into the film. Monitoring the coagulation process of whole blood using a coaxial-cylinder rotational viscometer showed that the initial time of coagulation in albumin film coated cylinders was delayed compared with that in uncoated cylinders, suggesting that activation of the intrinsic coagulation cascade was reduced on the albumin film coated surface. Thus, surface coating with cross-linked albumin films is a promising approach to conferring biomaterials with antithrombogenic surfaces due to the resistance to platelet adhesion and the antiplatelet drug-releasing capability afforded by the films.

Antiplatelet therapy is the mainstay of treatment for patients with cardiovascular disease. However, some patients experience adverse cardiac events despite treatment with single- or dual-antiplatelet (aspirin and clopidogrel) therapy. Some of those events could be caused by low responsiveness to aspirin or clopidogrel. The frequency of this phenomenon has been reported to range from 1% to 45% for the 2 drugs. This wide range arises from the lack of a "gold-standard" definition to assess antiplatelet drug response and differences in assays, agonist concentrations, and cut-off points. Regardless of the variability in the incidence of aspirin or clopidogrel low responsiveness, several studies have indicated a clear relation between clopidogrel or aspirin low responsiveness and cardiovascular events. The evidence for an association between adverse clinical events and the results of ex vivo platelet function tests is stronger for clopidogrel than for aspirin. Currently, there is no established therapeutic approach for managing low response to aspirin or clopidogrel that has been shown in large trials to have clinical benefit. This review focuses on laboratory testing of antiplatelet response to aspirin and clopidogrel, the prevalence of low response, potential mechanisms, clinical significance, and prognostic value of this phenomenon and alternative approaches to optimize treatment in patients with low response to the drugs.

A simple, validated method to measure platelet function is unavailable for bedside use. Measurement of platelet retention rate using a column of collagen-coated beads and whole blood is a new, simple assay that reflects platelet aggregation. This study was aimed to examine the utility of this assay to assess efficacy of antiplatelet drug therapy.Citrated whole blood (1.5 ml) in a syringe was passed through a polyvinyl tube packed with collagen-coated beads for 40 seconds using a syringe pump. Platelet retention rate in the column was calculated from platelet counts in blood before and after passage. An increase in the retention rate reflects an increase in platelet activity. This new platelet retention assay and the traditional optical aggregometry assay were performed in 331 patients with stable coronary artery disease (CAD).The retention rate was significantly reduced in patients taking dual antiplatelet therapy (aspirin plus clopidogrel or ticlopidine) compared with aspirin alone. There was a significant linear correlation between the platelet retention rate and platelet aggregability measured by the traditional method (r=0.44, p0.001). In multivariate Cox proportional hazards analysis, higher platelet retention rate was an independent predictor of future cardiovascular events in patients on dual antiplatelet therapy (hazard ratio 3.9, 95% CI 1.6 to 9.5, p=0.003).Measurement of the platelet retention rate in a column of collagen-coated beads may be useful for monitoring the efficacy of antiplatelet drug therapy in patients with CAD.

Aspirin is the first-line oral antiplatelet drug to prevent thromboembolic arterial occlusions. Aspirin irreversibly inhibits cyclooxygenase (COX) 1 involved in the platelet production of thromboxane (TX) A(2), an inducer of vasoconstriction and a platelet activating agent. Recurrent vascular events despite aspirin intake, combined with laboratory evidence of poor antiplatelet effect, suggested what has been called "aspirin resistance". For clarity's sake a real aspirin resistance would be the absence of COX1 inhibition due to intrinsic platelet factors (which has never been reported). What has been described is (expected) variability. COX1 inhibition can be insufficient to modify TX-dependent platelet behaviour. Other agonists, the production of which does not involve COX1, can stimulate TX-receptors. The antiplatelet effect of aspirin can be insufficient for pharmacokinetic or pharmacodynamic reasons, the latter being further classified as TX-dependent or not. If platelets are so reactive that responses are more TX-independent than normally, then neither aspirin nor any drugs acting on this pathway can do the job. These mechanisms should be better understood and diagnosed, and this is the prerequisite for the development of newer antiplatelet agents.