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Rationale for the Role of Heparin and Related GAG Antithrombotics in COVID-19 Infection.
Magnani, HN
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2021;:1076029620977702
Abstract
The SARS-CoV-2 pandemic has focused attention on prevention, restriction and treatment methods that are acceptable worldwide. This means that they should be simple and inexpensive. This review examines the possible role of glycosaminoglycan (GAG) antithrombotics in the treatment of COVID-19. The pathophysiology of this disease reveals a complex interplay between the hemostatic and immune systems that can be readily disrupted by SARS-CoV-2. Some of the GAG antithrombotics also possess immune-modulatory actions and since they are relatively inexpensive they could play an important role in the management of COVID-19 and its complications.
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Molecular Basis of the Therapeutical Potential of Clove (Syzygium aromaticum L.) and Clues to Its Anti-COVID-19 Utility.
Vicidomini, C, Roviello, V, Roviello, GN
Molecules (Basel, Switzerland). 2021;(7)
Abstract
The current COronaVIrus Disease 19 (COVID-19) pandemic caused by SARS-CoV-2 infection is enormously affecting the worldwide health and economy. In the wait for an effective global immunization, the development of a specific therapeutic protocol to treat COVID-19 patients is clearly necessary as a short-term solution of the problem. Drug repurposing and herbal medicine represent two of the most explored strategies for an anti-COVID-19 drug discovery. Clove (Syzygium aromaticum L.) is a well-known culinary spice that has been used for centuries in folk medicine in many disorders. Interestingly, traditional medicines have used clove since ancient times to treat respiratory ailments, whilst clove ingredients show antiviral and anti-inflammatory properties. Other interesting features are the clove antithrombotic, immunostimulatory, and antibacterial effects. Thus, in this review, we discuss the potential role of clove in the frame of anti-COVID-19 therapy, focusing on the antiviral, anti-inflammatory, and antithrombotic effects of clove and its molecular constituents described in the scientific literature.
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Tinzaparin Sodium Pharmacokinetics in Patients with Chronic Kidney Disease: Practical Implications.
Helfer, H, Siguret, V, Mahé, I
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(3):223-228
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Abstract
Low-molecular-weight heparins (LMWHs) are the mainstay of the prophylaxis and treatment of venous thromboembolism (VTE). Due to their renal elimination, the risk of accumulation with the related bleeding risk may represent a limitation for the use of LMWHs in patients with chronic kidney disease (CKD) as the risk of major bleeding is increased in patients with creatinine clearance (CrCl) < 30 mL/min, especially in patients with cancer. LMWH structure and molecular weight (MW) are heterogeneous among available agents. The elimination of tinzaparin, which has the highest mean MW among LMWHs, is less dependent on renal function as it is also metabolized through the reticuloendothelial system. A subcutaneous therapeutic dose of tinzaparin (175 IU/kg) once daily has been shown to cause no accumulation of anti-factor Xa activity in patients with CrCl ≥ 20 mL/min. Clinical experience from randomized controlled studies has shown no significant impact of CKD on bleeding risk in cancer patients receiving treatment doses of tinzaparin. This suggests that in these patients the use of treatment doses of tinzaparin does not require anticoagulation monitoring or dose adjustment.
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Optimal Antithrombotic Regimens for Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: An Updated Network Meta-analysis.
Lopes, RD, Hong, H, Harskamp, RE, Bhatt, DL, Mehran, R, Cannon, CP, Granger, CB, Verheugt, FWA, Li, J, Ten Berg, JM, et al
JAMA cardiology. 2020;(5):582-589
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Abstract
IMPORTANCE Antithrombotic treatment in patients with atrial fibrillation (AF) and percutaneous coronary intervention (PCI) presents a balancing act with regard to bleeding and ischemic risks. OBJECTIVES To evaluate the safety and efficacy of 4 antithrombotic regimens by conducting an up-to-date network meta-analysis and to identify the optimal treatment for patients with AF undergoing PCI. DATA SOURCES Online computerized database (MEDLINE). STUDY SELECTION Five randomized studies were included (N = 11 542; WOEST, PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, ENTRUST-AF PCI). DATA EXTRACTION AND SYNTHESIS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used in this network meta-analysis, in which bayesian random-effects models were applied. The data were analyzed from September 9 to 29, 2019. MAIN OUTCOMES AND MEASURES The primary safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding and the primary efficacy outcome was trial-defined major adverse cardiovascular events (MACE). RESULTS The total number of participants included in the study was 11 532. The mean age of the participants ranged from 70 to 72 years, 69% to 83% were male, 20% to 26% were female, and the participants were predominantly white (>90%). Compared with vitamin K antagonists (VKA) plus dual antiplatelet therapy (DAPT) (reference), the odds ratios (ORs) (95% credible intervals) for TIMI major bleeding were 0.57 (0.31-1.00) for VKA plus P2Y12 inhibitor, 0.69 (0.40-1.16) for non-VKA oral anticoagulant (NOAC) plus DAPT, and 0.52 (0.35-0.79) for NOAC plus P2Y12 inhibitor. For MACE, using VKA plus DAPT as reference, the ORs (95% credible intervals) were 0.97 (0.64-1.42) for VKA plus P2Y12 inhibitor, 0.95 (0.64-1.39) for NOAC plus DAPT, and 1.03 (0.77-1.38) for NOAC plus P2Y12 inhibitor. CONCLUSIONS AND RELEVANCE The findings of this study suggest that an antithrombotic regimen of VKA plus DAPT should generally be avoided, because regimens in which aspirin is discontinued may lead to lower bleeding risk and no difference in antithrombotic effectiveness. The use of a NOAC plus a P2Y12 inhibitor without aspirin may be the most favorable treatment option and the preferred antithrombotic regimen for most patients with AF undergoing PCI.
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The changing face of venous thromboembolism management in England.
Ramagopalan, SV, Carroll, R, Ulvestad, M, Mehmud, F, Alikhan, R
Future cardiology. 2019;(3):183-185
Abstract
Aim: Venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism, poses a global disease burden. Vitamin K antagonists have traditionally been the mainstay of treatment; however, the non-vitamin K oral anticoagulants (NOACs) are emerging as an alternative. The relative use of these treatment classes in the real world is unknown. Patients & methods: We performed a retrospective study using data from the UK Clinical Practice Research Datalink to understand VTE treatment patterns. Results: NOACs have unseated vitamin K antagonist as the main form of VTE patient treatment in England. Conclusion: The data highlight how comfortable physicians have become in using NOACs to treat VTE in England and it is likely that the increasing use of NOACs will continue.
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Antithrombotic medications and their impact on fibrin clot structure and function.
Undas, A, Zabczyk, M
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2018;(4)
Abstract
Fibrin constitutes a major protein component of intravascular thrombi in all locations. Fibrin formation and its functions are essential for physiological hemostasis and the pathologic thrombosis. Formation of dense fibrin networks which are relatively resistant to lysis is observed in patients with venous or arterial thromboembolism, including myocardial infarction, ischemic stroke and venous thromboembolism. Measures of clot characteristics, in particular clot permeability and clot lysis time, may predict arterial and venous recurrent thromboembolic events. Medications, including vitamin K antagonists (VKA), direct oral anticoagulants (DOAC), and parenteral direct or indirect thrombin or activated factor X inhibitors increase clot permeability, reflecting fibrin network density, in association with enhanced efficiency of fibrinolysis. These effects are only in part related to decreased thrombin generation. There is evidence that aspirin can also favorably alter fibrin clot properties probably through acetylation of fibrinogen. No such effects were observed for P2Y12 inhibitors. Of note, plasma fibrin clot permeability has been shown to predict adverse clinical outcomes in patients receiving oral anticoagulants, which might have practical implications. The current review summarizes data on effects of antithrombotic agents on fibrin clot phenotype in cardiovascular disease.
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Intravenous tPA (Tissue-Type Plasminogen Activator) in Patients With Acute Ischemic Stroke Taking Non-Vitamin K Antagonist Oral Anticoagulants Preceding Stroke.
Jin, C, Huang, RJ, Peterson, ED, Laskowitz, DT, Hernandez, AF, Federspiel, JJ, Schwamm, LH, Bhatt, DL, Smith, EE, Fonarow, GC, et al
Stroke. 2018;(9):2237-2240
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Abstract
Background and Purpose- Although there are no trials or large cohorts to inform clinical care, current guidelines caution against giving intravenous tPA (tissue-type plasminogen activator) to patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs). We performed a literature review of intravenous tPA in patients treated with NOACs preceding stroke. Methods- A literature search of PubMed was performed encompassing January 2010 to March 2018. Patient characteristics, timing of last medication intake, laboratory testing, use of reversal, and outcomes ≤3 months after discharge were summarized. Results- We identified 55 studies with 492 NOAC patients receiving tPA (dabigatran, 181; rivaroxaban, 215; apixaban, 40; and unspecified NOAC, 56). Among patients with complete data, the median time from the last NOAC intake to symptom onset was 8 hours (interquartile range, 2.5-14.5), with 55.2% (80/145) within 12 hours. Few patients underwent sensitive laboratory tests, such as thrombin time, diluted thrombin time, or anti-Xa assays before tPA administration. The overall observed rates of symptomatic intracranial hemorrhage, mortality, and favorable outcomes (National Institutes of Health Stroke Scale score, ≤1; modified Rankin Scale score, 0-2; or neurological improvement in the National Institutes of Health Stroke Scale score, ≥8 points) were 4.3% (20/462), 11.3% (48/423), and 43.7% (164/375), respectively. Among dabigatran-treated patients, reversal with idarucizumab was associated with fewer symptomatic intracranial hemorrhage (4.5% [2/44] versus 7.4% [8/108]; unadjusted odds ratio, 0.60; 95% CI, 0.12-2.92), death (4.5% [2/44] versus 12.0% [13/108]; unadjusted odds ratio, 0.35; 95% CI, 0.08-1.61), and more favorable outcomes (79.1% [34/43] versus 39.2% [29/74]; unadjusted odds ratio, 5.86; 95% CI, 2.45-14.00), although the differences were not statistically significant for symptomatic intracranial hemorrhage and death. Conclusions- These preliminary observations suggest that tPA may be reasonably well tolerated without prohibitive risks of bleeding complications in selected patients on NOACs. Reversal of anticoagulant effects by idarucizumab for dabigatran-treated patients before tPA is an emerging strategy that was associated with more favorable outcomes.
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Antithrombotic therapy management of adult and pediatric cardiac surgery patients.
Baumann Kreuziger, L, Karkouti, K, Tweddell, J, Massicotte, MP
Journal of thrombosis and haemostasis : JTH. 2018;(11):2133-2146
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Abstract
Despite the development of catheter-based interventions for ischemic and valvular heart disease, hundreds of thousands of people undergo open heart surgery annually for coronary artery bypass graft (CABG), valve replacement or cardiac assist device implantation. Cardiac surgery patients are unique because therapeutic anticoagulation is required during cardiopulmonary bypass. Developmental hemostasis and altered drug metabolism affect management in children. This narrative review summarizes the current evidence-based and consensus guidelines regarding perioperative, intraoperative and postoperative antithrombotic therapy in patients undergoing cardiac surgery. Anticoagulation preoperatively is required in the setting of cardiac arrhythmias, prior valve replacement or history of venous thromboembolism. In patients with ischemic heart disease, aspirin is continued in the perioperative period, whereas oral P2Y12 antagonists are withheld for 5-7 days to reduce the risk of perioperative bleeding. Intraoperative management of cardiopulmonary bypass in adults and children includes anticoagulation with unfractionated heparin. Variability in dose-response to heparin and influence of other medical conditions on dosing and reversal of heparin make intraoperative anticoagulation challenging. Vitamin K antagonist therapy is the standard anticoagulant after mechanical heart valve or left ventricular assist device (LVAD) implantation. Longer duration of dual antiplatelet therapy is recommended after CABG if patients undergo surgery because of acute coronary syndrome. Antiplatelet therapy after LVAD implantation includes aspirin, dipyridamole and/or clopidogrel in children and aspirin in adults. A coordinated approach between hematology, cardiology, anesthesiology, critical care and cardiothoracic surgery can assist to balance the risk of thrombosis and bleeding in patients undergoing cardiac surgery.
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Anticancer Drug-Related Nonvalvular Atrial Fibrillation: Challenges in Management and Antithrombotic Strategies.
Tufano, A, Galderisi, M, Esposito, L, Trimarco, V, Sorriento, D, Gerusalem, G, Picardi, M, Lancellotti, P, Pane, F
Seminars in thrombosis and hemostasis. 2018;(4):388-396
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Abstract
Cancer patients may experience nonvalvular atrial fibrillation (AF) as a manifestation of cardiotoxicity. AF may be a direct effect of a neoplasm or, more often, appear as a postsurgical complication, especially after thoracic surgery. AF may also develop as a consequence of anticancer therapy (chemotherapy or radiotherapy), a condition probably underestimated. Cancer patients with AF require a multidisciplinary approach involving oncologists/hematologists, cardiologists, and coagulation experts. An echocardiogram should be performed to detect possible abnormalities of left ventricular systolic and diastolic function, as well as left atrial dilation and the existence of valvular heart disease, to determine pretest probability of sinus rhythm restoration, and identify the best treatment. The choice of antiarrhythmic treatment in cancer patients may be difficult because scanty information is available on the interactions between anticancer agents and antiarrhythmic drugs. A careful evaluation of the antithrombotic strategy with the best efficacy/safety ratio is always needed. The use of vitamin K antagonists (VKAs) may be problematic because of the unpredictable therapeutic response and high bleeding risk in patients with active cancer who are undergoing chemotherapy and who may experience thrombocytopenia and changes in renal or hepatic function. Low molecular weight heparins (in particular for short and intermediate periods) and non-VKA oral anticoagulants (NOACs) should be preferred. However, the possible pharmacological interactions of NOACs with both anticancer and antiarrhythmic drugs should be considered. Based on all these considerations, antiarrhythmic and anticoagulant therapy for AF should be tailored individually for each patient.
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Aspirin and blood pressure: Effects when used alone or in combination with antihypertensive drugs.
Costa, AC, Reina-Couto, M, Albino-Teixeira, A, Sousa, T
Revista portuguesa de cardiologia : orgao oficial da Sociedade Portuguesa de Cardiologia = Portuguese journal of cardiology : an official journal of the Portuguese Society of Cardiology. 2017;(7-8):551-567
Abstract
Arterial hypertension is a major risk factor for cardiovascular and renal events. Lowering blood pressure is thus an important strategy for reducing morbidity and mortality. Since low-dose aspirin is a cornerstone in the prevention of adverse cardiovascular outcomes, combined treatment with aspirin and antihypertensive drugs is very common. However, the impact of aspirin therapy on blood pressure control remains a subject of intense debate. Recent data suggest that the cardioprotective action of aspirin extends beyond its well-known antithrombotic effect. Aspirin has been shown to trigger the synthesis of specialized pro-resolving lipid mediators from arachidonic acid and omega-3 fatty acids. These novel anti-inflammatory and pro-resolving mediators actively stimulate the resolution of inflammation and tissue regeneration. Additionally, they may contribute to other protective effects on redox status and vascular reactivity that have also been attributed to aspirin. Of note, aspirin has been shown to improve vasodilation through cyclooxygenase-independent mechanisms. On the other hand, higher aspirin doses have been reported to exert a negative impact on blood pressure due to inhibition of cyclooxygenase-2 activity, which reduces renal blood flow, glomerular filtration rate and sodium and water excretion. This review aims to provide an overview of the effects of aspirin on blood pressure and the underlying mechanisms, focusing on the interaction between aspirin and antihypertensive drugs. Studies in both experimental and human hypertension are presented.