Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

Mediation analysis of urinary metals and stroke risk by inflammatory markers.

BACKGROUND: The association between metals and stroke has been reported, but the mediating role of inflammation between metals and stroke remains unclear. METHODS: We included 9326 adults from the National Health and Nutrition Examination Survey in this study. Through least absolute selection and shrinkage operator (LASSO) regression, weighted quantile sum (WQS) regression, logistic regression, linear regression, restricted cubic spline analysis, and mediation analysis, we explored the association between metals and stroke, as well as the association between metals and inflammatory indicators, and further evaluated the mediating effect of inflammatory indicators on the association between selected metals and stroke risk. RESULTS: The results of the present study suggested positive associations between mixed metals, cadmium and uranium and stroke risk. There is a positive correlation and dose‒response relationship between cadmium and C-reactive protein (CRP). Moreover, CRP mediates 10.1% of the association between cadmium and stroke. CONCLUSIONS: At the epidemiological level, CRP mediates the association between cadmium and stroke risk, suggesting that inflammation may be a potential mechanism for metal-induced stroke.

High- vs. low-dose diclofenac and cardiovascular risks: a target trial emulation.

AIMS: To examine the dose dependency of diclofenac's cardiovascular risks. METHODS AND RESULTS: Using Danish health registries and the target trial emulation design, we conducted a series of 300 nationwide cohort studies during 1996-2020, each mimicking the strict design criteria of a clinical trial. Adults eligible for inclusion had no recent non-steroidal anti-inflammatory drug prescriptions, contraindications (gastrointestinal diseases, thrombocytopenia, or heart failure), or conditions with low adherence (dementia or psychiatric disease). Diclofenac initiators were compared to healthcare-seeking non-initiators and head-to-head using an approximated high dose of ≥150 mg/day vs. low dose of <150 mg/day. Cox regression was used to compute the incidence rate ratio (IRR) of major adverse cardiovascular events (MACE) within 30 days following initiation. We adjusted for age, sex, calendar period, comorbidity, comedication, and socioeconomic position. Compared with non-initiators (n = 3 789 617), diclofenac initiators (n = 1 894 834) had an approximately 50% increased rate of MACE (IRR 1.53, 95% confidence interval [CI]: 1.43-1.63), reflecting IRRs of 1.54 (95% CI: 1.40-1.69) for myocardial infarction, 1.29 (1.14-1.45) for ischaemic stroke, and 1.92 (1.71-2.16) for cardiac death. The risk increase was observed for most conditions with chronic pain, in particular headache (IRR 5.10, 95% CI: 1.46-17.85). The risk increase was similar for initiators of high- (IRR 1.55, 95% CI: 1.40-1.71) and low-dose diclofenac (IRR 1.52, 1.41-1.63), which was confirmed in a head-to-head analysis (IRR 1.01, 95% CI: 0.90-1.12). CONCLUSIONS: Initiators of high- and low-dose diclofenac had comparably increased cardiovascular risks. This finding provides evidence against the assumption that low-dose diclofenac is risk-neutral.

Severe Bleeding Risk of Direct Oral Anticoagulants Versus Vitamin K Antagonists for Stroke Prevention and Treatment in Patients with Atrial Fibrillation: A Systematic Review and Network Meta-Analysis.

PURPOSE: We aimed to determine the safety of direct oral anticoagulants (DOACs) for stroke prevention and treatment in patients with atrial fibrillation (AF). METHODS: A systematic search of four databases (PubMed, EMBASE, Web of Science, and Cochrane Library) was performed to identify randomized controlled trials (RCTs) reporting severe bleeding events in patients taking DOACs or vitamin K antagonists (VKAs). In this frequency-based network meta-analysis, odds ratios and 95% confidence intervals were used for reporting. Based on the surface under the cumulative ranking curves (SUCRA), the relative ranking probability of each group was generated. RESULTS: Twenty-three RCTs met the inclusion criteria, and a total of 87,616 patients were enrolled. The bleeding safety of DOACs for stroke prevention and treatment in patients with AF was ranked from highest to lowest as follows: fatal bleeding: edoxaban (SUCRA,80.2), rivaroxaban (SUCRA,68.3), apixaban (SUCRA,48.5), dabigatran (SUCRA,40.0), VKAs (SUCRA,12.9); major bleeding: dabigatran (SUCRA,74.0), apixaban (SUCRA,71.5), edoxaban (SUCRA,66.5), rivaroxaban (SUCRA,22.7), VKAs (SUCRA,15.4); gastrointestinal bleeding: apixaban (SUCRA,55.9), VKAs (SUCRA,53.7), edoxaban (SUCRA,50.5), rivaroxaban (SUCRA,50.4), dabigatran (SUCRA,39.5); intracranial hemorrhage: dabigatran (SUCRA,84.6), edoxaban (SUCRA,74.1), apixaban (SUCRA,65.8), rivaroxaban (SUCRA,24.4), VKAs (SUCRA,1.1). CONCLUSION: Based on current evidence, for stroke prevention and treatment in patients with AF, the most safe DOAC is edoxaban in terms of fatal bleeding; dabigatran in terms of major bleeding and intracranial hemorrhage and apixaban in terms of gastrointestinal bleeding. However, given the nature of indirect comparisons, more high-quality evidence from head-to-head comparisons is still needed to confirm them.

Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation.

BACKGROUND: The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated. METHODS: From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months. RESULTS: Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54). CONCLUSIONS: Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

Safety and Effectiveness of Direct Oral Anticoagulants Versus Warfarin for Treating Left Ventricular Thrombus.

BACKGROUND: Patients with left ventricular thrombus are at high risk for ischemic stroke and systemic embolization. The mainstay of treatment is anticoagulation, but it remains unclear if direct-acting oral anticoagulants (DOACs) are a safe and effective treatment strategy compared to warfarin. We conducted a population-based retrospective cohort study to evaluate the effectiveness and safety of DOACs compared to warfarin in an integrated health system in the United States. METHODS: Consecutive patients with left ventricular thrombus on transthoracic echocardiogram from May 2010 to April 2020 were identified. Comparative effectiveness and safety of DOACs and warfarin were evaluated using multivariable Cox proportional hazard models and inverse probability of treatment weighting. RESULTS: Among 433 patients with left ventricular thrombus, 134 (30.9%) were treated with DOACs and 299 (69.1%) were treated with warfarin. Patients were followed for a median of 3.4 years. For the primary effectiveness outcome of ischemic stroke, systemic embolism, and transient ischemic attack, no significant difference was observed between use of DOACs compared to warfarin (adjusted hazard ratio [HR] of 0.75, 95% confidence interval [CI] 0.48-1.18, p = 0.21). For the primary safety outcome of intracranial hemorrhage, gastrointestinal bleeding, and other bleed requiring hospitalization, DOAC usage was associated with a lower risk of bleeding (HR 0.58, 95% CI 0.39-0.87, p = 0.0008). CONCLUSIONS: In this diverse population-based cohort of patients, DOAC treatment for left ventricular thrombus appears to be as safe and effective as warfarin treatment. These findings support the use of DOACs for patients with left ventricular thrombus.

Influence of rivaroxaban compared to vitamin K antagonist treatment upon development of cardiovascular calcification in patients with atrial fibrillation and/or pulmonary embolism.

BACKGROUND: Vitamin K antagonists (VKA) such as warfarin or phenprocoumon have been the mainstay of therapy for long-term oral anticoagulant therapy (OAT) in patients with atrial fibrillation or with pulmonary embolism. Due to interferences with matrix Gla-protein, an important vitamin K-dependent local calcification inhibitor in cardiovascular structures, VKA antagonists stimulate cardiovascular calcification (CVC). In contrast, rivaroxaban, a nonvitamin K-dependent oral anticoagulant (NOAC), should be neutral in terms of CVC. We seek to investigate these potential differences in CVC development between VKA versus NOACs in a randomized controlled trial (RCT). METHODS: The influence of rivaroxaban compared to vitamin K antagonist treatment upon development of cardiovascular calcification in patients with atrial fibrillation and/or pulmonary embolism trial (NCT02066662) is a multicenter, prospective RCT with a two-arm, open-label study design. The primary endpoint is the progression of coronary and aortic valve calcification (quantified as calcification volume score) as assessed by cardiac computed tomography (CT) at 24 months in patients either treated by rivaroxaban or VKA. A total of 192 patients were randomized in a 1:1 fashion. The main inclusion criteria were the presence of atrial fibrillation and/or pulmonary embolism with the indication for OAT and pre-existent coronary calcification. The development of CVC will be assessed by follow-up CT at 12 and 24 months. RESULTS: In total 192 patients (median age 70, 72% male) were enrolled over a period of 5 years and followed up for 2 years.

The Therapeutic Effect and Mechanism of Qishen Yiqi Dripping Pills on Cardiovascular and Cerebrovascular Diseases and Diabetic Complications.

The alterations in vascular homeostasis are deeply involved in the development of numerous diseases, such as coronary heart disease, stroke, and diabetic complications. Changes in blood flow and endothelial permeability caused by vascular dysfunction are the common mechanisms for these three types of diseases. The disorders of glucose and lipid metabolism can bring changes in the energy production patterns in endothelium and surrounding cells which may consequently cause energy metabolic disorders, oxidative stress, and inflammatory responses. Traditional Chinese medicine (TCM) follows the principle of the "treatment by the syndrome differentiation." TCM considers coronary heart disease, stroke, and diabetes complications all as the type of Qi-deficiency and blood stasis syndrome, which mainly occurs in the vascular system. Therefore, the common pathogenesis of these three types of diseases suggests that the treatment strategy by TCM should be in a close manner and referred to as "treating different diseases by the same treatment." Qishen Yiqi dripping pill is a modern Chinese herbal medicine that has been widely used for the treatment of patients with coronary heart disease characterized as Qi-deficiency and blood stasis in China. Recently, many clinical reports have demonstrated the potential therapeutic effects of Qishen Yiqi dripping pills on ischemic stroke and diabetic nephropathy. Based on these reports, we will summarize the clinical applications of Qishen Yiqi dripping pills on coronary heart disease, ischemic stroke, and diabetic nephropathy, including the involved mechanisms discussed in various research works.

Bridging Therapy With Heparin Before Starting Rivaroxaban in Ischemic Stroke or Transient Ischemic Attack With Non-Valvular Atrial Fibrillation.

BACKGROUND: The present observational study aimed to clarify the association between bridging therapy with heparin before starting rivaroxaban and clinical outcomes after ischemic stroke or transient ischemic attack (TIA) in patients with non-valvular atrial fibrillation (NVAF).Methods and Results: Patients with NVAF who experienced acute ischemic stroke or TIA of the middle cerebral artery territory and started rivaroxaban within 30 days after onset were enrolled and were followed up for 90 days. Outcome measures were ischemic events, major bleeding, their composite, and death or disability 90 days after onset. Ischemic events were defined as ischemic stroke, TIA, and systemic embolism. Of 1,308 analyzed patients, 638 received bridging therapy with unfractionated or low-molecular-weight heparin with a median of 10,000 IU/day. Associations between bridging therapy and ischemic events or major bleeding were not statistically significant individually, but the association between bridging therapy and their composite was statistically significant (multivariable-adjusted hazard ratio, 1.80; 95% confidence interval, 1.01-3.29). The association between bridging therapy and death or disability 90 days after onset was not statistically significant. CONCLUSIONS: The composite of ischemic events and major bleeding was more frequent in patients with NVAF who received bridging therapy with low-dose heparin than in those who started treatment directly with rivaroxaban after ischemic stroke or TIA.

Proton Pump Inhibitors, Associated Complications, and Alternative Therapies: A Shifting Risk Benefit Ratio.

OBJECTIVE: Our goal was to compile the most recent and accurate data on the side effects of proton pump inhibitors (PPI). We also compared the efficacy of PPI to the efficacy of different surgical options for acid reflux control. BACKGROUND: Proton pump inhibitors are the primary therapy for chronic control of gastroesophageal reflux disease (GERD), but newer studies demonstrate deleterious side effects. Collating this information and contrasting it with surgical therapy for GERD provides evidence for possible practice changes in treatment. METHODS: A literature search utilizing PubMed was performed evaluating for PPI and anti-reflux surgery (ARS), focusing on articles that reflected information regarding the usage and efficacy of symptom control of both PPI and ARS. Search terms included "ARS, fundoplication, MSA, acute interstitial nephritis, acute kidney injury, chronic kidney disease, meta-analysis, PPI, H2 blocker, cardiovascular risk, and gut dysbiosis." We evaluated 271 articles by title, abstract, and data for relevance and included 70. RESULTS: Long-term control of GERD with PPI may have a greater than expected side effect profile than initially thought. Surgical options may provide greater symptom control than PPI without the side effects of long-term medical therapy. CONCLUSIONS: Anti-reflux control can be safely achieved with either PPI or surgical options; however, the long-term side effects noted in the review such as increased risk of cardiovascular events, renal disease, and gut dysbiosis may suggest surgical anti-reflux control as a better long-term option.

Calcium supplementation and cardiovascular disease in postmenopausal women: a study in South Brazil / Suplementação de cálcio e doença cardiovascular em mulheres na pós-menopausa: um estudo no Sul do Brasil

Objective: To evaluate the link between calcium supplementa- tion and cardiovascular disease in postmenopausal women (aged 55 years or older). Methods: A standardized questionnaire was employed to collect data about calcium supplements, eart di- sease, and demographic of women attended at Primary Care in the South Region of Brazil. Generalized linear regression models were performed to evaluate the association and adjust for poten- tial confounders. Results: Overall, 1,057 women completed the questionnaire. Information about calcium supplementation was present in 1,035 questionnaires. The mean ± standard deviation of the age of participants was 67.2±7.6 years. The frequency of calcium supplementation was 18.6%. There was no association between heart failure, stroke, and ischemic heart disease and cal- cium supplementation (prevalence ratio; 95% confidence interval of 0.3; -0.9-0.4, -0.2; -0.8-0.4 and -0.5; -1.0-0.02, respectively. Con- clusions: Our study did not find an association of higher risk of cardiovascular disease in women using calcium supplementation at Primary Care in South Brazil.

Objetivo: Avaliar a ligação entre a suplementação de cálcio e doença cardiovascular em mulheres na pós-menopausa (com 55 anos ou mais). Métodos: Um questionário padronizado foi em- pregado para coletar dados sobre suplementos de cálcio, doenças cardíacas e demográficos de mulheres que frequentavam a Aten- ção Primária na Região Sul do Brasil. Modelos de regressão linear generalizada foram realizados para avaliar a associação e ajustar os potenciais fatores de confusão. Resultados: No total, 1.057 mulheres responderam ao questionário. As informações sobre su- plementação de cálcio estavam presentes em 1.035 questionários. A média ± desvio-padrão da idade dos participantes foi de 67,2 ± 7,6 anos. A frequência de suplementação de cálcio foi de 18,6%. Não houve associação entre insuficiência cardíaca, acidente vas- cular cerebral e doença cardíaca isquêmica e suplementação de cálcio (razão de prevalência; intervalo de confiança de 95% de -0,3; -0,9-0,4, -0,2; -0,8-0,4 e -0,5; -1,0-0,02, respectivamente). Con- clusão: Nosso estudo não encontrou associação de maior risco de doença cardiovascular em mulheres em uso de suplementação de cálcio na Atenção Primária no Sul do Brasil.

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

Preventive Effects of Neuroprotective Agents in a Neonatal Rat of Photothrombotic Stroke Model.

Neonatal ischemic stroke has a higher incidence than childhood stroke. Seizures are the first sign for the need for clinical assessment in neonates, but many questions remain regarding treatments and follow-up modalities. In the absence of a known pathophysiological mechanism, only supportive care is currently provided. Stroke-induced microglia activation and neuroinflammation are believed to play a central role in the pathological progression of neonatal ischemic stroke. We induced a photothrombotic infarction with Rose Bengal in neonatal rats to investigate the effects of pre- and post-treatment with Aspirin (ASA), Clopidogrel (Clop), and Coenzyme Q10 (CoQ10), which are known for their neuroprotective effects in adult stroke. Pre-stroke medication ameliorates cerebral ischemic injury and reduces infarct volume by reducing microglia activation, cellular reactive oxygen species (ROS) production, and cytokine release. Post-stroke administration of ASA, Clop, and CoQ10 increased motor function and reduced the volume of infarction, and the statistical evidence was stronger than that seen in the pre-stroke treatment. In this study, we demonstrated that ASA, Clop, and CoQ10 treatment before and after the stroke reduced the scope of stroke lesions and increased behavioral activity. It suggests that ASA, Clop, and CoQ10 medication could significantly have neuroprotective effects in the neonates who have suffered strokes.

Cryptogenic Intracranial Hemorrhagic Strokes Associated with Hypervitaminosis E and Acutely Elevated α-Tocopherol Levels.

OBJECTIVES: Up to 41% of intracerebral hemorrhages (ICH) are considered cryptogenic despite a thorough investigation to determine etiology. Certain over-the-counter supplements may increase proclivity to bleeding, and we hypothesize that specifically vitamin E may have an association with ICH and acutely elevated serum levels of α-tocopherol. Our aim is to report 3 cases of recently admitted patients with hypervitaminosis E and otherwise cryptogenic ICH. METHODS: At our institution between January and December 2018, 179 patients were admitted with ICH with 73 imputed to be "cryptogenic" (without clear etiology as per Structural vascular lesions, Medication, Amyloid angiopathy, Systemic disease, Hypertension, or Undetermined and Hypertension, Amyloid angiopathy, Tumor, Oral anticoagulants, vascular Malformation, Infrequent causes, and Cryptogenic criteria). Of these, we found 3 (4.1%) clearly admitted to consistent use of vitamin E supplementation for which α-tocopherol levels were checked. We describe the clinical presentation and course of these patients and their etiologic and diagnostic evaluations including neuroimaging and α-tocopherol laboratory data. RESULTS: All patients in this series were consistently consuming higher than recommended doses of vitamin E and developed acute ICH. The first 2 patients both had subcortical (thalamic) intraparenchymal hemorrhages while the third had an intraventricular hemorrhage. Serum α-tocopherol levels in patient A, B, and C were elevated at 30.8, 46.7, and 23.3 mg/L, respectively (normal range 5.7-19.9 mg/L) with a mean of 33.6 mg/L. No clear alternate etiologies to their ICH could be conclusively determined despite thorough workups. CONCLUSIONS: In patients with cryptogenic ICH, clinicians should consider hypervitaminosis E and check serum α-tocopherol level during admission. Reviewing the patient's pharmacologic history, including over-the-counter supplements such as vitamin E, may help identify its association, and its avoidance in the future may mitigate risk. With its known vitamin K antagonism, hypo-prothrombinemic effect, cytochrome p-450 interaction, and antiplatelet activity, vitamin E may not be as benign as presumed. Its consumption in nonrecommended doses may increase ICH risk, which may be underestimated and under-reported.

Coronary Risks Associated with Diclofenac and Other NSAIDs: An Update.

The risk of coronary events with non-steroidal anti-inflammatory drugs has been the subject of much debate since the original trial of rofecoxib raised the issue. Since then, over almost 20 years, such risks have been shown in clinical trials of long-term high-dose users, and in observational studies comparing users with non-users. The roles of cyclooxygenase (COX)-2/COX-1 selectivity and COX-2 inhibitory potency have been proposed to explain this increased risk of myocardial infarction (MI). Among NSAIDs, diclofenac appeared to be associated with a relatively higher risk of MI, similar to that of rofecoxib, compatible with the drug's high COX-2 inhibitory potency. Recent studies have resulted in further information being available. A study in the Danish healthcare system using active comparators found a slightly increased risk of MI in healthy persons. However, risk decreased with increasing baseline cardiovascular risk, to the point that in patients at high cardiovascular risk, there was no additional risk associated with diclofenac compared with paracetamol or other NSAIDs. The other major study, from the SOS project, studied several million persons in four countries in Europe, comparing the use of many NSAIDs with non-use. That study found a slightly increased risk with diclofenac compared with non-use, but this was not different from other NSAIDs. Comparing risks with selectivity or potency found no effect of either. These studies refute the main hypotheses to explain the coronary risk of NSAIDs. Finding risk in healthy low-risk patients only questions the reality of a link between the use of the drugs and the occurrence of MI in these conditions. Biases or confounding may be the major reason for small increases in cardiovascular risks in healthy users of NSAIDs in real life.

Use of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus: Systematic Review of Current Literature.

BACKGROUND: Left ventricular thrombus (LVT) is an important complication in the setting of systolic dysfunction, particularly after acute myocardial infarction. Current guidelines recommend the vitamin-K antagonist, warfarin, for the treatment of LVT. AREA OF UNCERTAINTY AND STUDY QUESTION: The direct oral anticoagulants (DOACs) are being increasingly used for the management of this entity, despite lack of randomized trials in support of it or knowledge about their efficacy. We aimed to assess the frequency of use and the efficacy of DOACs in the treatment of LVT. DATA SOURCES: We searched published articles in Google Scholar, PubMed, MEDLINE, and Embase from the introduction of DOACs in any therapy until April 2018. Reports describing patients diagnosed with LVT and who were treated with a DOAC were examined. Patient characteristics, comorbidities, pharmacologic treatments, and outcomes were collected. The primary end points of this study were thrombus resolution and time to resolution. Other end points were bleeding and thromboembolic events. RESULTS: Thirty articles describing 41 patients were analyzed. The most common risk factors for LVT formation were male gender, ischemic heart disease, and low ejection fraction. Most patients were treated with rivaroxaban (51.2%), followed by apixaban (26.8%) and dabigatran (22%). Patients were treated with DOAC alone (46.3%), DOAC and aspirin (12.2%), DOAC and clopidogrel (2.4%), and triple therapy (39%). Thrombus resolution success rate was 81%, 100%, and 88.9% for rivaroxaban, apixaban, and dabigatran, respectively. The median time of thrombus resolution was 40 days, 36 days, and 24 days for rivaroxaban, apixaban, and dabigatran, respectively. One nonfatal bleeding event and one stroke event were reported while on a DOAC. CONCLUSIONS: The use of DOACs is a reasonable alternative to vitamin-K antagonists in the management of LVT.

Gender, hyperandrogenism and vitamin D deficiency related functional and morphological alterations of rat cerebral arteries.

Hyperandrogenism is a risk factor of cerebrovascular diseases as androgens can alter markedly the regulation of cerebrovascular tone. We examined the combined impact of androgen excess and vitamin D deficiency (VDD), a common co-morbidity in hyperandrogenic disorders, on remodeling and testosterone-induced vascular responses of anterior cerebral arteries (ACA) in order to evaluate the interplay between androgens and VDD in the cerebral vasculature. Male and female Wistar rats were either fed with vitamin D deficient or vitamin D supplemented diet. Half of the female animals from both groups received transdermal testosterone treatment. After 8 weeks, vessel lumen, wall thickness and testosterone-induced vascular tone of isolated ACA were determined using pressure microangiometry and histological examination. Androgen receptor protein expression in the wall of cerebral arteries was examined using immunohistochemistry. In female rats only combined VDD and testosterone treatment decreased the lumen and increased the wall thickness of ACA. In males, however VDD by itself was able to decrease the lumen and increase the wall thickness. Vascular reactivity showed similar alterations: in females, testosterone constricted the ACA only after combined VDD and hyperandrogenism, whereas in males VDD resulted in increased testosterone-induced contractions in spite of decreased androgen receptor expression. In conclusion, a marked interplay between hyperandrogenism and VDD results in inward remodeling and enhanced testosterone-induced constrictions of cerebral arteries, which might compromise the cerebral circulation and thus, increase the risk of stroke in the long term. In addition, the early cerebrovascular manifestation of VDD appears to require androgen excess and thus, depends on gender.

Facing real-life with direct oral anticoagulants in patients with nonvalvular atrial fibrillation: outcomes from the first observational and prospective study in a Spanish population.

AIM: To analyze the effectiveness and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients attended in clinical practice. METHODS: Observational and prospective study of AF patients that started treatment with DOACs. RESULTS: 1443 patients (age 77.2 ± 9.7 years, CHA2DS2-VASc = 4.1 ± 1.5) were included. 46.0% were taking rivaroxaban, 24.4% dabigatran, 22.5% apixaban and 7.1% edoxaban. Patients taking dabigatran were younger, had lower CHA2DS2-VASc and lesser renal insufficiency. Patients taking apixaban had higher CHA2DS2-VASc and more renal insufficiency. Rates of stroke/major bleeding/intracranial bleeding were 0.7/1.3/0.2 events/100 patient-years, respectively. CONCLUSION: This was the first prospective study that analyzed the use of all DOACs in AF patients in Spain, showing a good profile in terms of safety and effectiveness in accordance with pivotal studies.

Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation.

BACKGROUND: The comparative effectiveness and safety of individual direct oral anticoagulants (DOACs) in clinical practice is largely unknown. The study objectives were to compare effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation (NVAF). METHODS: Based on nationwide registers we established a population-based historical cohort study of 12,638 new users of standard dose DOACs (apixaban 5 mg twice daily, dabigatran 150 mg twice daily and rivaroxaban 20 mg once daily) with NVAF in Denmark, July 2013 to March 2016. Patients were matched on propensity scores in a 1:1 ratio comparing apixaban vs. dabigatran (for a total of 6470 patients), apixaban vs. rivaroxaban (7352 patients), and rivaroxaban vs. dabigatran (5440 patients). Hazard ratios (HRs) for stroke or systemic embolism (effectiveness outcome) and major bleeding (safety outcome) were estimated. RESULTS: In propensity-matched comparisons of the risk of stroke or systemic embolism, the HRs were 1.27 (95% confidence interval [CI], 0.82-1.96) for apixaban vs. dabigatran, 1.25 (95% CI, 0.87-1.79) for apixaban vs. rivaroxaban, and 1.17 (95% CI, 0.69-1.96) for rivaroxaban vs. dabigatran. For the risk of major bleeding, the HRs were 0.94 (95% CI, 0.62-1.41) for apixaban vs. dabigatran, 0.88 (95% CI, 0.64-1.22) for apixaban vs. rivaroxaban, and 1.35 (95% CI, 0.91-2.00) for rivaroxaban vs. dabigatran. CONCLUSIONS: Among patients with NVAF in routine clinical practice, there were no statistically significant differences in risk of stroke or systemic embolism or major bleeding in propensity-matched comparisons between apixaban, dabigatran, and rivaroxaban used in standard doses. While analyses indicate that more than moderate differences can be excluded, smaller differences cannot be ruled out.

Cannabis can augment thrombolytic properties of rtPA: Intracranial hemorrhage in a heavy cannabis user.

Cannabis is one of the most commonly used illicit drugs in the United States and is considered to have several adverse health effects. There is evidence suggesting that its recreational use is associated with both increased cardio- and cerebrovascular events. Recently, multiple cases of ischemic and hemorrhagic strokes associated with cannabis use were reported in the literature (Goyal et al., 2017). It has been suggested that cannabis can affect cerebral auto-regulation and vascular tone leading to vasoconstriction and acute ischemic stroke. However, hemorrhagic strokes, which are often seen with sympathomimetic illicit drugs (e.g. cocaine and amphetamines), have rarely been reported due to cannabis. Many cellular mechanisms within non-ischemic tissue post stroke may be augmented by heavy cannabis use. Here, we describe a rapid development of hemorrhage following thrombolytic therapy in a patient with heavy cannabis use with an ischemic stroke.