Sangramiento posextracción dentaria y medidas para su control en pacientes tratados con antiagregantes plaquetarios / Bleeding after tooth extraction and measures for its control in patients treated with antiplatelet agents

Introducción: El desarrollo de las ciencias médicas trae consigo un incremento en la expectativa de vida, junto a la detección temprana de un gran número de enfermedades crónicas como las cerebrovasculares y cardiovasculares, que son tratadas rutinariamente con medicamentos antiagregantes plaquetarios. El conocimiento del manejo de estos pacientes ante los procedimientos quirúrgicos estomatológicos constituye un reto en la práctica diaria profesional. Objetivo: Determinar el nivel de sangramiento posextracción dentaria en pacientes con enfermedad cardiovascular y cerebrovascular, según el tipo de antiagregantes plaquetarios y grupo dentario, así como la frecuencia de utilización de las medidas para su control. Métodos: Se efectuó un estudio observacional, descriptivo, longitudinal y prospectivo con un universo de 136 pacientes de más de 20 años, remitidos por su cardiólogo y que necesitaban realizarse extracciones dentarias sin modificar su tratamiento con antiagregantes plaquetarios. Las variables estudiadas fueron la enfermedad sistémica, el tipo de antiagregante plaquetario, el nivel de sangramiento, grupo dentario intervenido y método hemostático utilizado. Resultados: La mitad de los pacientes estudiados no presentó sangramiento posextracción dentaria. En los pacientes tratados con aspirina o clopidogrel predominaron los sujetos sin sangramiento para un 84,3 por ciento y 62,5 por ciento, respectivamente. En los de doble antiagregación prevaleció el sangramiento moderado con un 46,3 por ciento. Los grupos dentarios incisivo, canino y premolar no presentaron episodios de sangramiento para un 64,1 por ciento, 51,6 por ciento y 53,3por ciento, respectivamente. El método hemostático más utilizado fue la compresión de las corticales y termoterapia fría (47,8 por ciento). Conclusiones: La mitad de los pacientes con enfermedades cardiovasculares y cerebrovasculares no presentaron sangramiento posextracción dentaria(AU)

Introduction: The development of medical sciences brings with it an increase in life expectancy, together with the early detection of a large number of chronic diseases such as cerebrovascular and cardiovascular diseases, which are routinely treated with antiplatelet aggregation drugs. Knowledge on the treatment of these patients before stomatological surgical procedures constitutes a challenge in daily professional practice. Objective: To determine the level of bleeding after tooth extraction in patients with cardiovascular and cerebrovascular disease, according to the type of antiplatelet agents and dental group, as well as the frequency of use of measures for their control. Methods: An observational, descriptive, longitudinal and prospective study was carried out with a universe of 136 patients over 20 years of age, referred by their cardiologist, who needed dental extractions without modifying their treatment with antiplatelet agents. The variables studied were systemic disease, type of antiplatelet agent, level of bleeding, dental group treated and hemostatic method used. Results: Half of the patients studied did not present bleeding after tooth extraction. In patients treated with aspirin or clopidogrel, 84.3 percent and 62.5por ciento, respectively, had no bleeding. In those with double antiplatelet therapy, modera te bleeding prevailed with 46.3 The incisor, canine and premolar tooth groups did not present bleeding episodes (64.1 percent, 51.6and 53.3 percent respectively). The most commonly used hemostatic method was cortical compression and cold thermotherapy (47.8%). Conclusions: Half of the patients with cardiovascular and cerebrovascular diseases did not present bleeding after tooth extraction(AU)

Safety and Efficacy Evaluation of Antithrombotic Therapy with Rivaroxaban and Clopidogrel After PCI in Chinese Patients.

OBJECTIVE: To investigate the efficacy and safety of the antithrombotic therapy using the oral anticoagulant rivaroxaban and clopidogrel in Chinese patients with acute coronary syndrome complicated with atrial fibrillation after percutaneous coronary intervention. METHODS: A total of 100 patients were selected. Patients were randomly divided into two groups: the treatment group (rivaroxaban group) received a therapy of rivaroxaban and clopidogrel. The control group (warfarin group) receivied a combined treatment of warfarin, clopidogrel, and aspirin. The primary outcome endpoint was evaluated based on the adverse cardiac and cerebrovascular events within 12 months. RESULTS: A total of 8 (8.00%) main adverse cardiac and cerebrovascular events occurred during the 12 months of follow-up, including 5 (9.80%) in the warfarin group and 3 (6.10%) in the rivaroxaban group. The risk of having main adverse cardiac and cerebrovascular events in the two groups was comparable (P = 0.479). A total of 9 patients (9.00%) were found to have bleeding events, among which 8 patients (15.7%) were in the warfarin group, whereas only 1 patient (2.00%) was in the rivaroxaban group. Therefore, the risk of bleeding in the warfarin group was significantly higher than that in the rivaroxaban group (P = 0.047). CONCLUSIONS: In Chinese patients with acute coronary syndrome complicated with atrial fibrillation, the efficacy of the dual therapy of oral anticoagulant rivaroxaban plus clopidogrel after percutaneous coronary intervention was similar to that of the traditional triple therapy combined with warfarin, aspirin and clopidogrel, but it has a better safety property, which has potential to widely apply to antithrombotic therapy after PCI.

Effect of Rivaroxaban and Clopidogrel Combination Therapy on In-Stent Responses After Everolimus-Eluting Stent Implantation in a Porcine Coronary Model.

AIM: According to recent clinical trials, a combination of direct oral anticoagulants with antiplatelet drugs is often recommended for atrial fibrillation patients who receive drug-eluting stents (DESs). Although the optimal combination comprises direct factor Xa inhibitors and a P2Y12 receptor antagonist (or aspirin), their influence on vascular responses to DESs remains unclear. METHODS: Pigs were given either aspirin and clopidogrel (dual antiplatelet therapy [DAPT] group), aspirin and rivaroxaban (AR group), or clopidogrel and rivaroxaban (CR group), followed by everolimus-eluting stent (Promus Element) implantation into the coronary artery. Stented coronary arteries were evaluated via intravascular optical coherence tomography (OCT) and histological analysis at 1 and 3 months. RESULTS: OCT revealed lower neointimal thickness in the DAPT group and comparable thickness among all groups at 1 and 3 months, respectively. Histological analyses revealed comparable neointimal area among all groups and the smallest neointimal area in the CR group at 1 and 3 months, respectively. In the DAPT and AR groups, the neointima continued to grow from 1 to 3 months. A shortened time course for neointima growth was observed in the CR group, with rapid growth within a month (maintained for 3 months). A higher incidence of in-stent thrombi was observed in the AR group at 1 month; no thrombi were found in either group at 3 months. More smooth muscle cells with contractile features were found in the CR group at both 1 and 3 months. CONCLUSIONS: Our results proved the noninferiority of the combination of rivaroxaban with an antiplatelet drug, particularly the dual therapy using rivaroxaban and clopidogrel, compared to DAPT after DES implantation.

Assessment of Platelet Reactivity and Inflammatory Markers in Coronary Artery Bypass Graft Patients Treated with Acetylsalicylic Acid with Flavonoid Supplementation.

The recommended pharmacological therapy for patients with coronary artery disease (CAD) treated by coronary artery bypass grafting (CABG) is acetylsalicylic acid (ASA). To improve the antiplatelet effect, supplementation with flavonoids is also recommended. The aim of this study was to estimate anti-aggregation properties of diosmin, in combination with ASA, pre- and postoperatively and assess the relationship of this therapy with inflammatory processes in CAD patients undergoing CABG. The study patients (n = 26) took diosmin (1000 mg/day); the control patients (n = 27) took a placebo. The therapeutic period for taking diosmin was from at least 30 days before to 30 days after CABG. All patients also took 75 mg/day ASA. Platelet aggregation and IL-6, CRP, and fibrinogen concentrations were determined before and 30 days after surgery. Results showed that diosmin did not enhance the anti-aggregation effect of ASA at any assessment time. However, there was a stronger anti-aggregation effect 30 days after surgery that was diosmin independent and was associated with acute-phase markers in the postoperative period. Increased levels of inflammatory markers in the late phase of the postoperative period may provide an unfavorable prognostic factor in long-term follow-up, which should prompt the use of stronger antiplatelet therapy in patients after CABG.

Dose-dependent effects of anthocyanin supplementation on platelet function in subjects with dyslipidemia: A randomized clinical trial.

BACKGROUND: Dyslipidemia induces platelet hyperactivation and hyper-aggregation, which are linked to thrombosis. Anthocyanins could inhibit platelet function in vitro and in mice fed high-fat diets with their effects on platelet function in subjects with dyslipidemia remained unknown. This study aimed to investigate the effects of different doses of anthocyanins on platelet function in individuals with dyslipidemia. METHODS: A double-blind, randomized, controlled trial was conducted. Ninety-three individuals who were initially diagnosed with dyslipidemia were randomly assigned to placebo or 40, 80, 160 or 320 mg/day anthocyanin groups. The supplementations were anthocyanin capsules (Medox, Norway). Platelet aggregation by light aggregometry of platelet-rich plasma, P-selectin, activated GPⅡbⅢa, reactive oxygen species (ROS), and mitochondrial membrane potential were tested at baseline, 6 weeks and 12 weeks. FINDINGS: Compared to placebo group, anthocyanins at 80 mg/day for 12 weeks reduced collagen-induced platelet aggregation (-3.39±2.36%) and activated GPⅡbⅢa (-8.25±2.45%) (P < 0.05). Moreover, compared to placebo group, anthocyanins at 320 mg/day inhibited collagen-induced platelet aggregation (-7.05±2.38%), ADP-induced platelet aggregation (-7.14±2.00%), platelet ROS levels (-14.55±1.86%), and mitochondrial membrane potential (7.40±1.56%) (P < 0.05). There were dose-response relationships between anthocyanins and the attenuation of platelet aggregation, mitochondrial membrane potential and ROS levels (P for trend <0.05). Furthermore, significantly positive correlations were observed between changes in collagen-induced (r = 0.473) or ADP-induced (r = 0.551) platelet aggregation and ROS levels in subjects with dyslipidemia after the 12-week intervention (P < 0.05). INTERPRETATION: Anthocyanin supplementation dose-dependently attenuates platelet function, and 12-week supplementation with 80 mg/day or more of anthocyanins can reduce platelet function in individuals with dyslipidemia. FUNDING: None.

The Synergistic Effect of Ginkgo biloba Extract 50 and Aspirin Against Platelet Aggregation.

PURPOSE: We aimed to investigate potential synergistic antiplatelet effects of Ginkgo biloba extract (GBE50) in combination with aspirin using in vitro models. METHODS: Arachidonic acid (AA), platelet activating factor (PAF), adenosine 5'-diphosphate (ADP) and collagen were used as inducers. The antiplatelet effects of GBE50, aspirin and 1:1 combination of GBE50 and aspirin were detected by microplate method using rabbit platelets. Synergy finder 2.0 was used to analyze the synergistic antiplatelet effect. The compounds in GBE50 were identified by UPLC-Q/TOF-MS analysis and the candidate compounds were screened by TCMSP database. The targets of candidate compounds and aspirin were obtained in TCMSP, CCGs, Swiss target prediction database and drugbank. Targets involving platelet aggregation were obtained from GenCLiP database. Compound-target network was constructed and GO and KEGG enrichment analyses were performed to identify the critical biological processes and signaling pathways. The levels of thromboxane B2 (TXB2), cyclic adenosine monophosphate (cAMP) and PAF receptor (PAFR) were detected by ELISA to determine the effects of GBE50, aspirin and their combination on these pathways. RESULTS: GBE50 combined with aspirin inhibited platelet aggregation more effectively. The combination displayed synergistic antiplatelet effects in AA-induced platelet aggregation, and additive antiplatelet effects occurred in PAF, ADP and collagen induced platelet aggregation. Seven compounds were identified as candidate compounds in GBE50. Enrichment analyses revealed that GBE50 could interfere with platelet aggregation via cAMP pathway, AA metabolism and calcium signaling pathway, and aspirin could regulate platelet aggregation through AA metabolism and platelet activation. ELISA experiments showed that GBE50 combined with aspirin could increase cAMP levels in resting platelets, and decreased the levels of TXB2 and PAFR. CONCLUSION: Our study indicated that GBE50 combined with aspirin could enhance the antiplatelet effects. They exerted both synergistic and additive effects in restraining platelet aggregation. The study highlighted the potential application of GBE50 as a supplementary therapy to treat thrombosis-related diseases.

Antithrombotic effects of Huanglian Jiedu decoction in a rat model of ischaemia-reperfusion-induced cerebral stroke.

CONTEXT: Huanglian Jiedu Decoction (HLJJD) has a variety of pharmacological activities, such as anti-inflammatory and neuroprotection against ischaemic brain injury. OBJECTIVES: This ex vivo study explores its antithrombosis activity and inhibition of platelet aggregation. MATERIAL AND METHODS: To study the antithrombosis activity of HLJJD ex vivo, saline, or HLJDD (100, 200, and 500 mg/kg) was treated prophylactically by gavage for 3 days in Wistar rats (n = 4). Based on the rat model of transient middle cerebral artery infarction (MCAO) or normal rats (n = 4), the antithrombotic activity in the normal group and HLJDD subgroups on prothrombin time, thrombus weight, platelet aggregation, and others was evaluated, followed by the antiplatelet aggregation of its main components (n = 4). RESULTS: The weight of the thrombus increased significantly at 24 h after MCAO onset. HLJJD did not influence the change of PT, but significantly inhibited thrombosis by 12.5, 20.0, and 20.5% in reducing the dry weight of thrombus, and blocked collagen-induced platelet aggregation by 25.5, 39.0, and 42.7% and adhesion of blood platelet by 17.3, 26.2, and 27.3%. The IC50 value of HLJJD on collagen-induced platelet aggregation was 670 mg/kg. Geniposide only facilitated antiplatelet aggregation induced by collagen, but not AA or ADP. Both baicalin and berberine showed markedly antiplatelet aggregation induced by all activators. The antithrombotic activity of baicalin was relatively higher than that of berberine (35.0-47.8% vs. 20.6-33.5%). CONCLUSION: Our results indicated that HLJDD regulated blood circulation by inhibiting platelet aggregation and thrombosis, which might also extensively contribute to the clinical prevention and treatment of cerebrovascular diseases.

Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis.

BACKGROUND: In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. METHODS: In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. RESULTS: Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. CONCLUSIONS: The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.

Acute bilateral cerebral infarction in the presence of neuromyelitis optica spectrum disorder: A case report.

RATIONALE: Neuromyelitis optica spectrum disorders (NMOSDs) are inflammatory demyelinating disorders of the central nervous system; they are characterized by severe optic neuritis and transverse myelitis. Intravenous methylprednisolone pulse (IVMP) therapy is an effective treatment that is administered to patients in the acute phase of NMOSD; this therapy has achieved remarkable results in clinical practice. However, there are no reports on NMOSD patients who have experienced an acute bilateral cerebral infarction while undergoing IVMP treatment. PATIENT CONCERNS: We report on a 62-yr-old woman who was undergoing IVMP therapy for the primary diagnosis of NMOSD. Unexpectedly, the patient's existing limb weakness worsened, and she developed motor aphasia on the second day of IVMP treatment. Additionally, brain magnetic resonance imaging revealed acute bilateral cerebral infarction. DIAGNOSIS: The patient's clinical manifestations, medical imaging results, and laboratory test results were taken into consideration; the final diagnosis was acute bilateral cerebral infarction in the presence of NMOSD. INTERVENTIONS: Subsequent to the onset of acute cerebral infarction, the patient was immediately treated with oral aspirin, atorvastatin, and intravenous butylphthalide. The hormone dose was adjusted to an oral 60-mg/d dose for maintenance; this was followed by immunoadsorption plasmapheresis for 3 days, and double-filtration plasmapheresis for 2 days. OUTCOMES: Following treatment onset, the patient's ocular symptoms significantly improved, and her limb muscle strength gradually recovered. Two months after discharge, the patient's husband reported that she was able to walk with the help of others and take care of herself, and that there was no recurrence. LESSONS: Medical professionals must be aware of the possibility of NMOSD patients with cerebrovascular risk factors suffering an acute cerebral infarction while undergoing high-dose IVMP therapy, as this therapy can exacerbate existing problems.

Cervical Artery Dissection Caused by Electrical Cupping Therapy with High-Negative Pressure - Case Report.

BACKGROUND: Cervical artery dissection is an important cause of stroke in the young. The etiology is still discussed controversial. The most obvious reason for a dissection of extracranial arteries is due to a trauma, eg. after car accidents or other high speed traumas such as high-velocity road traffic accidents. Besides these clear cases, chiropractic neck maneuvers represent potential reasons for vessel injuries. CASE PRESENTATION: We here report a rare case of secondary cervical artery dissection after so-called cupping therapy and a preventive treatment with a direct oral anticoagulant. CONCLUSIONS: Therapists using this technique should be aware of the potentially devastating side effects. The diagnosis of ICA dissection should be considered with any new onset of unknown neck pain or headache, specifically in combination with neurological deficits.

Reduced Rivaroxaban Dose Versus Dual Antiplatelet Therapy After Left Atrial Appendage Closure: ADRIFT a Randomized Pilot Study.

BACKGROUND: Percutaneous left atrial appendage closure (LAAC) exposes to the risk of device thrombosis in patients with atrial fibrillation who frequently have a contraindication to full anticoagulation. Thereby, dual antiplatelet therapy (DAPT) is usually preferred. No randomized study has evaluated nonvitamin K antagonist oral anticoagulant after LAAC, and we decided to evaluate the efficacy and safety of reduced doses of rivaroxaban after LAAC. METHODS: ADRIFT (Assessment of Dual Antiplatelet Therapy Versus Rivaroxaban in Atrial Fibrillation Patients Treated With Left Atrial Appendage Closure) is a multicenter, phase IIb study, which randomized 105 patients after successful LAAC to either rivaroxaban 10 mg (R10, n=37), rivaroxaban 15 mg (R15, n=35), or DAPT with aspirin 75 mg and clopidogrel 75 mg (n=33). The primary end point was thrombin generation (prothrombin fragments 1+2) measured 2 to 4 hours after drug intake, 10 days after treatment initiation. Thrombin-antithrombin complex, D-dimers, rivaroxaban concentrations were also measured at 10 days and 3 months. Clinical end points were evaluated at 3-month follow-up. RESULTS: The primary end point was reduced with R10 (179 pmol/L [interquartile range (IQR), 129-273], P<0.0001) and R15 (163 pmol/L [IQR, 112-231], P<0.0001) as compared with DAPT (322 pmol/L [IQR, 218-528]). We observed no significant reduction of the primary end point between R10 and R15 while rivaroxaban concentrations increased significantly from 184 ng/mL (IQR, 127-290) with R10 to 274 ng/mL (IQR, 192-377) with R15, P<0.0001. Thrombin-antithrombin complex and D-dimers were numerically lower with both rivaroxaban doses than with DAPT. These findings were all confirmed at 3 months. The clinical end points were not different between groups. A device thrombosis was noted in 2 patients assigned to DAPT. CONCLUSIONS: Thrombin generation measured after LAAC was lower in patients treated by reduced rivaroxaban doses than DAPT, supporting an alternative to the antithrombotic regimens currently used after LAAC and deserves further evaluation in larger studies. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03273322.

New Horizons in Pharmacologic Therapy for Secondary Stroke Prevention.

Importance: Even with currently available therapies and lifestyle modifications following an ischemic stroke, there remains a substantial residual lifetime risk of stroke recurrence and cardiovascular morbidity. This review summarizes emerging novel therapeutic approaches that have demonstrated signals of efficacy for prevention of noncardioembolic stroke from phase II and phase III randomized clinical trials (RCTs) and provides an overview of drug regimens that have had promising results in primary stroke prevention and could be considered for further evaluation. Observations: After a minor acute ischemic stroke or transient ischemic attack, patients bear a high cardiovascular risk that is insufficiently addressed by long-term antiplatelet treatment. The potent combination of low-dose rivaroxaban with aspirin as an antithrombotic option for the secondary prevention in patients with clinical atherosclerosis and a history of previous stroke warrants further study. Two international RCTs are currently evaluating the utility of oral factor XI inhibitors combined with antiplatelets for secondary, noncardioembolic ischemic stroke prevention. Aggressive lipid management with statins has been shown to ameliorate ischemic stroke recurrence and total cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors are drug regimens that researchers have suggested confer additional protection against stroke recurrence, while antisense oligonucleotide therapies targeting lipoprotein(a) have been reported to hold great promise as a future therapeutic strategy to decrease the residual cardiovascular risk mediated through lipoprotein(a). Glucagon-like peptide-1 receptor agonists are newer antidiabetic medications, recently highlighted because of their consistently greater benefit on stroke reduction compared with other cardiovascular outcomes. Conclusions and Relevance: There are currently several exciting emerging opportunities in secondary stroke prevention, with RCTs investigating novel antithrombotic, hypolipidemic, anti-inflammatory, and antidiabetic agents with novel mechanisms that are likely to reduce the future burden of recurrent stroke.

Synergistic platelet inhibition between Omega-3 and acetylsalicylic acid dose titration; an observational study.

BACKGROUND: Omega-3 and acetylsalicylic acid (ASA) are two widely used "over-the-counter" drugs. Previous research has shown multiple electrode aggregometry (MEA) can detect ASA and varying Omega-3 platelet inhibiting effects. Synergistic platelet inhibiting effects of ASA and Omega-3 have been found using other methods than MEA. The aim of this study was to investigate the antiplatelet effects of Omega-3, and ASA synergism with MEA. METHODS: Ten healthy male volunteers ingested Omega-3 (1260 mg/day) for 5 days. MEA was used to analyse platelet function before and after Omega-3 intake. Aggregation was initiated using three different agonists and measured as area under the curve (AUC): adenosine diphosphate (ADP), thrombin receptor activating peptide (TRAP) and arachidonic acid (ASPI). Two concentrations of ASA were dose titrated ex vivo to 2 out of 3 ASPI test cells in order to measure synergism between Omega-3 and ASA. RESULTS: Following 5 days Omega-3 intake, ADP, TRAP and ASPI AUC did not change significantly. In vitro ASA before Omega-3 intake, reduced ASPI AUC < 30 U, indicating a strong platelet inhibiting effect. Below this AUC level, the 5 days Omega-3 intake increased ASPI-AUC with the ex vivo added low dose ASA (P = 0.02) and high dose ASA (P = 0.04). CONCLUSIONS: No synergism between ASA and Omega-3 was found using the MEA ASPI test. The surprising increase in ASPI-AUC following Omega-3 intake and ex vivo ASA suggest that there are methodological issuses with the MEA ASPI test. TRIAL REGISTRATION: Trial registration ISRCTN78027929 . Registered 19 May 2015.

Intracranial and systemic atherosclerosis in the NAVIGATE ESUS trial: Recurrent stroke risk and response to antithrombotic therapy.

BACKGROUND: Non-stenotic intracranial and systemic atherosclerosis are associated with ischemic stroke. We report frequency and response to anticoagulant vs. antiplatelet prophylaxis of patients with embolic stroke of undetermined source (ESUS) who have non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis. METHODS: Exploratory analysis of the international NAVIGATE ESUS randomized trial comparing rivaroxaban 15mg daily with aspirin 100mg daily in 7213 patients with recent ESUS. Among participants with results of intracranial arterial imaging with either computed tomographic angiography (CTA) or magnetic resonance angiography (MRA), the frequency and predictors of non-stenotic intracranial and systemic atherosclerosis and responses to antithrombotic therapy were assessed. RESULTS: Among 4723 participants with available intracranial CTA or MRA results (65% of the trial cohort), the prevalence of intracranial atherosclerosis was 16% (n=739). Patient features independently associated with intracranial atherosclerosis included East Asian region (odds ratio 2.7, 95%CI 2.2,3.3) and cervical carotid plaque (odds ratio 2.3, 95%CI 1.9,2.7), among others. The rate of recurrent ischemic stroke averaged 4.8%/year among those with intracranial atherosclerosis vs. 5.0.%/year for those without (HR 0.95, 95%CI 0.65, 1.4). Among those with intracranial atherosclerosis, the recurrent ischemic stroke rate was higher if assigned to rivaroxaban (5.8%/year) vs. aspirin (3.7%/year), but the difference was not statistically significant (HR 1.6, 95%CI 0.78, 3.3). There was trend for the effect of antithrombotic treatments to be different according to the presence or absence of intracranial atherosclerosis (pinteraction=0.09). Among participants with evidence of systemic atherosclerosis by either history or imaging (n=3820), recurrent ischemic stroke rates were similar among those assigned to rivaroxaban (5.5%/year) vs. aspirin (4.9%/year)(HR 1.1, 95%CI 0.84, 1.5). CONCLUSIONS: East Asia region was the strongest factor associated with intracranial atherosclerosis. There were no statistically significant differences between rivaroxaban and aspirin prophylaxis for recurrent ischemic stroke in patients with non-stenotic intracranial atherosclerosis and/or systemic atherosclerosis.

Early Anticoagulation or Antiplatelet Therapy Is Critical in Craniocervical Artery Dissection: Results from the COMPASS Registry.

INTRODUCTION: Craniocervical artery dissection (CeAD) is a leading cause of stroke in the young patient population. Recent studies reported a low rate of major adverse cardiac events (MACEs) in patients with CeAD, with no significant difference between patients randomized to anticoagulation or antiplatelet therapy. OBJECTIVE: To compare the effectiveness of anticoagulation and antiplatelet therapy in patients with CeAD. METHODS: All CeAD patients from 2015 to 2017 were consecutively identified by an electronic medical record-based application and enrolled in this prospective longitudinal registry. CeAD was confirmed by imaging and graded using the Denver scale for blunt cerebrovascular injury. Patients were followed for 12 months for MACE defined as stroke, transient ischemic attack (TIA), or death. RESULTS: The cohort included 111 CeAD patients (age 53 ± 15.9 years, 56% Caucasian, 50% female). CeAD was detected by magnetic resonance (5%), computed tomography (88%), or catheter angiography (7%). CeAD was noted in the carotid (59%), vertebral (39%), and basilar (2%) arteries, 82% of which were extracranial dissections. CeAD was classified as grade I, II, III, and IV in 16, 33, 19, and 32%, respectively. A total of 40% of dissections were due to known trauma. A predisposing factor was noted in the majority (78%) of patients, including violent sneezing (21%), carrying a heavy load (19%), sports/recreational activity (11%), chiropractic manipulation (9%), abrupt/prolonged rotation of head (9%), and prolonged phone use (9%). At presentation, 41% had a stroke, 5% had TIA, 39% had headache, and 36% were asymptomatic. Favorable outcome defined as a modified Rankin Scale score of 0-2 was noted in 68% at 3 months and 71% at 12 months. The rate of MACEs at 3 and 12 months was 11 and 14%, respectively, with more events observed in patients who were not receiving anticoagulation/antiplatelet therapy due to contraindications (p = 0.008). CONCLUSIONS: We report diagnostic characteristics, as well as short- and long-term outcomes of CeAD. A high MACE rate was observed within the first 2 weeks of CeAD diagnosis, notably in patients not initiated on anticoagulation or antiplatelet therapy.

[Mortality benefit with different antithrombotic therapies in patients with stable vascular disease: from pathophysiology to the clinical impact in the real world. The COMPASS study]. / Beneficio di mortalità delle terapie antitrombotiche in pazienti con malattia vascolare stabile: dalla fisiopatologia all'impatto clinico e al suo ruolo nel mondo reale. Focus sullo studio COMPASS.

The evaluation and application of antithrombotic strategies able to reduce total and cardiovascular mortality in patients with documented vascular disease have an important clinical and epidemiological role and may also impact on health costs. In the COMPASS trial, the association of rivaroxaban at the dose of 2.5 mg twice daily with aspirin in a population with stable vascular disease has significantly reduced the incidence of cardiovascular events compared to the standard regimen of aspirin alone; this reduction translated into greater cardiovascular and total survival. Such mortality benefit was not observed in previous randomized trials that in this setting of patients had previously evaluated antiplatelet strategies alternative to aspirin (with clopidogrel) or had compared a dual antiplatelet therapy with aspirin plus clopidogrel, vorapaxar, or ticagrelor vs a single antiplatelet treatment with aspirin. The results of the COMPASS trial strengthen the role of antithrombotic strategies that, beside the platelet phase, also involve the coagulative phase with the aim at preventing the recurrence of cardiovascular, atherothrombotic events at the site of polyvascular beds, with a degree of benefit proportional to the baseline risk of the patient.

Dual Pathway Inhibition for Vascular Protection in Patients with Atherosclerotic Disease: Rationale and Review of the Evidence.

Despite advances in secondary prevention strategies in patients with cardiovascular disease, the residual risk of recurrent atherothrombotic events remains high. Dual-antiplatelet therapy is the standard of care for secondary prevention in patients with acute coronary syndrome (ACS), whereas single antiplatelet therapy, generally with aspirin, is the standard of care for secondary prevention in stable patients with coronary artery disease (CAD), peripheral artery disease (PAD), or cerebrovascular disease. However, atherosclerotic plaque disruption not only triggers platelet activation but also results in thrombin generation because of tissue factor exposure. Therefore, blocking both pathways by combining antiplatelet therapy with an anticoagulant, or dual pathway inhibition (DPI), has the potential to be more effective than inhibiting either pathway alone. The benefit of DPI has been demonstrated in the ATLAS ACS 2-TIMI 51, COMPASS, and VOYAGER PAD trials, where the combination of rivaroxaban vascular dose (2.5 mg twice daily) plus aspirin significantly reduced the risk of atherothrombotic events compared with aspirin across a broad range of patients, including those with recent ACS, those with chronic CAD and/or PAD, and patients with PAD who have undergone peripheral revascularization. This article provides the rationale for this regimen in more detail, including why the DPI regimen with the rivaroxaban vascular dose was developed for vascular protection in a broad spectrum of patients with atherosclerotic disease.

Improved Oral Pharmacokinetics of Pentoxifylline with Palm Oil and Capmul® MCM Containing Self-Nano-Emulsifying Drug Delivery System.

Pentoxifylline (PTX), an anti-hemorrhage drug used in the treatment of intermittent claudication, is extensively metabolized by the liver resulting in a reduction of the therapeutic levels within a short duration of time. Self-nano-emulsifying drug delivery system (SNEDDS) is well reported to enhance the bio-absorption of drugs by forming nano-sized globules upon contact with the biological fluids after oral administration. The present study aimed to formulate, characterize, and improve the oral bioavailability of PTX using SNEDDS. The formulated SNEDDS consisted of palm oil, Capmul® MCM, and Tween® 80 as oil, surfactant, and co-surfactant, respectively. The mixture design module under the umbrella of the design of experiments was used for the optimization of SNEDDS. The dynamic light-scattering technique was used to confirm the formation of nanoemulsion based on the globule size, in addition to the turbidity measurements. In vivo bioavailability studies were carried out on male Wistar rats. The pharmacokinetic parameters upon oral administration were calculated using the GastroPlus software. The optimized SNEDDS had a mean globule size of 165 nm with minimal turbidity in an aqueous medium. Bioavailability of PTX increased 1.5-folds (AUC = 1013.30 ng h/mL) as SNEDDS than the pure drug with an AUC of 673.10 ng h/mL. In conclusion, SNEDDS was seen to enhance the bioavailability of PTX and can be explored to effectively control the incidents of intermittent claudication.

Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial.

BACKGROUND: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events. METHODS: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding. RESULTS: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P=0.002; and hazard ratio, 0.77, P=0.005, respectively, Pinteraction=0.77) and all-cause mortality (hazard ratio, 0.81, P=0.05; and hazard ratio, 0.84, P=0.09, respectively; Pinteraction=0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative Pinteraction<0.0001; 1.9% versus 0.6% for all-cause mortality, Pinteraction=0.02; 2.7% versus 1.7% for major vascular events, Pinteraction<0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative Pinteraction=0.001). CONCLUSIONS: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Effect of tea polyphenols on the oral and intravenous pharmacokinetics of ticagrelor in rats and its in vitro metabolism.

Green tea is widely consumed as a beverage and/or dietary supplement worldwide, resulting in the difficulty to avoid the comedication with ticagrelor for acute coronary syndrome (ACS) patients receiving antiplatelet therapy. This study was designed to investigate the effect of the most abundant content in green tea, tea polyphenols on the oral and intravenous pharmacokinetics of ticagrelor in rats and its in vitro metabolism. Rats were orally treated with either saline or tea polyphenol extracts (TPEs) dissolved in saline once daily for 6 consecutive days. On day 6, after the last dose of saline or TPE, ticagrelor was given to the rats orally or intravenously. Plasma samples were collected for pharmacokinetic analysis. Human liver and intestinal microsomes were then used to investigate the inhibition by TPE, as well as its major constituents on the metabolism of ticagrelor to its two metabolites, AR-C124910XX and AR-C133913XX. Apparent kinetic constants and inhibition potency (IC50 ) for each metabolic pathway of each compound were estimated. Oral study indicated that exposure of ticagrelor and AR-C124910XX was significantly decreased after TPE administration, while no significant differences were observed in pharmacokinetic parameters after intravenous administration of ticagrelor. TPE effectively inhibited the metabolism of ticagrelor in vitro, with epigallocatechin-3-gallate as the major constituent responsible for the observed inhibitory effects in human liver microsomes and intestinal microsomes (IC50 = 4.23 ± 0.18 µM). Caution should be taken for ACS patients receiving ticagrelor therapy with daily drinking of green tea. PRACTICAL APPLICATION: Potential interactions between tea polyphenols and ticagrelor were revealed for the first time. Results can provide suggestions for clinicians to optimize the dosing of ticagrelor while they are in the face of ACS patients receiving ticagrelor therapy, who also take green tea or its related products in their daily life.