Appropriate anti-thrombotic/anti-thrombin therapy for thrombotic lesions.
ABSTRACT: Managing coronary thrombus is a challenging task and requires adequate knowledge of the various antithrombotic agents available. In this article, we will briefly analyze the risk-benefit profile of antithrombotic agents, with critical analysis of the scientific evidence available to support their use. Since thrombus consists of platelets and coagulation cofactors, an effective antithrombotic strategy involves using one anticoagulant with two or more antiplatelet agents. Unfractionated heparin traditionally has been the most commonly used anticoagulant but is fast being replaced by relatively newer agents like LMWH, direct thrombin inhibitors, and Factor Xa inhibitors. In recent years, the antiplatelet landscape has changed significantly with the availability of more potent and rapidly acting agents, like prasugrel and ticagrelor. These agents have demonstrated a sizeable reduction in ischemic outcomes in patients with ACS, who are treated invasively or otherwise, with some concern for an increased bleeding risk. Glycoprotein IIb/IIIa inhibitors have an established role in high risk NSTE ACS patients pretreated with dual antiplatelets, but its role in STEMI patients, treated with invasive approach and dual antiplatelets, has not been supported consistently across the studies. Additionally, in recent years, its place as a directly injected therapy into coronaries has been looked into with mixed results. In conclusion, a well-tailored antithrombotic strategy requires taking into account each patient's individual risk factors and clinical presentation, with an effort to strike balance between not only preventing ischemic outcomes but also reducing bleeding complications.
Project description:In recent years, much progress has been made in the field of antithrombotic drugs in acute coronary syndrome (ACS) treatment, as reflected by the introduction of the more potent P2Y12-inhibitors prasugrel and ticagrelor, and novel forms of concomitant anticoagulation, such as fondaparinux and bivalirudin. However, despite substantial improvements in contemporary ACS treatment, there remains residual ischemic risk in this group and hence the need for even more effective antithrombotic drugs, while balancing antithrombotic efficacy against bleeding risk. This review discusses recently introduced and currently developed antiplatelet and anticoagulant drugs in ACS treatment.
Project description:Despite dual antiplatelet therapy (DAPT) including potent P2Y12 inhibitors, recurrent ischaemic events occur in a significant number of patients after acute coronary syndrome (ACS), warranting new antithrombotic strategies. Combinations of non-vitamin K antagonist oral anticoagulant (NOAC) with antiplatelet therapy have been tested in several large phases II and III randomised trials. Overall, current evidence suggests that the use of NOACs on top of DAPT after ACS reduces the rate of recurrent ischaemic events, albeit at the price of increased risk for major bleeding. In the particular field of patients with ACS and atrial fibrillation, NOACs may be associated with reduced bleeding complications compared with vitamin K antagonist. Further randomised trials evaluating low-dose NOAC combined with single antiplatelet therapy are warranted.
Project description:The risks of stroke or systemic embolism and major bleeding are considered similar between paroxysmal and sustained atrial fibrillation (AF), and warfarin has demonstrated superior efficacy to aspirin, irrespective of the AF type. However, with the advent of novel oral anticoagulants (NOACs) and antiplatelet agents, the optimal antithrombotic prophylaxis for paroxysmal AF remains unclear.We searched Medline, Embase, CENTRAL, and China Biology Medicine up to October week 1, 2015. Randomized controlled trials of AF patients assigned to NOACs, warfarin, or antiplatelets, with reports of outcomes stratified by the AF type, were included. A fixed-effects model was used if no statistically significant heterogeneity was indicated; otherwise, a random-effects model was used.Six studies of 69,990 nonvalvular AF patients with ≥1 risk factor for stroke were included. Postantithrombotic treatment, paroxysmal AF patients showed lower risks of stroke (risk ratio [RR], 0.72; 95% confidence interval [CI], 0.59-0.87), stroke or systemic embolism (RR, 0.74; 95% CI, 0.63-0.86), and all-cause mortality (RR, 0.75; 95% CI, 0.67-0.83), while the major bleeding risk was comparable (RR, 0.96; 95% CI, 0.85-1.08). We were unable to detect the superiority of anticoagulation over antiplatelets for paroxysmal AF (RR, 0.72; 95% CI, 0.43-1.23), while it was more effective than antiplatelets for sustained AF (RR, 0.42; 95% CI, 0.33-0.54). NOACs showed superior efficacy over warfarin and trended to show reduced major bleeding irrespective of the AF type.The AF type is a predictor for thromboembolism, and might be helpful in stroke risk stratification model in combination with other risk factors. With the appearance of novel anticoagulant and antiplatelet agents, the best antithrombotic choice for paroxysmal AF needs further exploration.
Project description:Patients with acute coronary syndrome (ACS) represent a major clinical burden, because they tend to experience recurrent ischemic events. Acute management of patients with ACS includes combination antithrombotic therapy composed of a parenteral anticoagulant and dual-antiplatelet therapy. Dual-antiplatelet therapy is also recommended for long-term secondary prevention of ACS. Despite advances in the antithrombotic therapies available, clinical trials suggest that patients with ACS still faceã10% risk of another event within 12-15 months of the index event. Certain patient populations, such as elderly patients and those with renal impairment or heart failure, are at higher risk of recurrent ACS events, because these patients have more vascular ischemic and bleeding risk factors than most other patients. Evidence from the GRACE and CRUSADE registries suggests underuse of the guideline-recommended evidence-based therapies for the management of ACS in such patients. This review summarizes the current standard of care for patients with ACS, focusing on long-term secondary antithrombotic strategies. Registry data are used to identify high-risk patient populations; the recent antiplatelet and anticoagulant Phase III trial data are summarized to highlight any patient populations who receive greater or lesser benefit from specific long-term antithrombotic strategies. Guideline recommendations are discussed and suggestions are provided to help improve implementation of long-term secondary prevention strategies and patient prognosis after an ACS event.
Project description:BACKGROUND & AIMS:The safety of different antithrombotic strategies for patients with 1 or more indication for antithrombotic drugs has not been determined. We investigated the risk and time frame for gastrointestinal bleeding (GIB) in patients prescribed different antithrombotic regimens. We proposed that risk would increase over time and with combination regimens, especially among elderly patients. METHODS:We performed a retrospective analysis of nationwide claims data from privately insured and Medicare Advantage enrollees who received anticoagulant and/or antiplatelet agents from October 1, 2010, through May 31, 2017. Patients were stratified by their prescriptions (anticoagulant alone, antiplatelet alone, or a combination) and by their primary diagnosis (atrial fibrillation, ischemic heart disease, or venous thromboembolism). The 1-year GIB risk was estimated using parametric time-to-event survival models and expressed as annualized risk and number needed to harm (NNH). RESULTS:Our final analysis included 311,211 patients (mean ages, 67 years for monotherapy and 69.8 years for combination antithrombotic therapy). There was no significant difference in the proportion of patients with bleeding after anticoagulant or antiplatelet monotherapy (?3.5%/year). Combination antithrombotic therapy increased GIB risk compared with anticoagulant (NNH, 29) or antiplatelet (NNH, 31) monotherapy, regardless of the patients' diagnosis or time point analyzed. Advancing age was associated with increasing 1-year probability of GIB. Patients prescribed combination therapy were at the greatest risk for GIB, especially after the age of 75 years (GIB occurred in 10%-17.5% of patients/y). CONCLUSIONS:In an analysis of nationwide insurance and Medicare claims data, we found GIB to occur in a higher proportion of patients prescribed combinations of anticoagulant and antiplatelet agents compared with monotherapy. Among all drug exposure categories and cardiovascular conditions, the risk of GIB increased with age, especially among patients older than 75 years.
Project description:Despite advances in antithrombotic therapy, the risk of recurrent coronary/cerebrovascular ischemia or venous thromboembolism remains high. Dual pathway antithrombotic blockade, using both antiplatelet and anticoagulant therapy, offers the promise of improved thrombotic protection; however, widespread adoption remains tempered by substantial risk of major bleeding. Here, we report a dual pathway therapeutic capable of site-specific targeting to activated platelets and therapeutic enrichment at the site of thrombus growth to allow reduced dosing without compromised antithrombotic efficacy. We engineered a recombinant fusion protein, SCE5-TAP, which consists of a single-chain antibody (SCE5) that targets and blocks the activated GPIIb/IIIa complex, and tick anticoagulant peptide (TAP), a potent direct inhibitor of activated factor X (FXa). SCE5-TAP demonstrated selective platelet targeting and inhibition of thrombosis in murine models of both carotid artery and inferior vena cava thrombosis, without a significant impact on hemostasis. Selective targeting to activated platelets provides an attractive strategy to achieve high antithrombotic efficacy with reduced risk of bleeding complications.
Project description:Patients with atrial fibrillation affected by an acute coronary syndrome have indications for oral anticoagulation and dual antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate receptor inhibitor after coronary artery stenting. The concurrent use of all 3 agents, termed triple oral antithrombotic therapy, significantly increases the risk of bleeding. To date, there is a lack of evidence on the proper combination and duration of anticoagulant and antiplatelet agents in patients with indications for both therapies. As such, care has been guided by expert opinion, and there is wide variation in clinician practice. In this review, the latest evidence on the risks and benefits of triple oral antithrombotic therapy in patients with atrial fibrillation after coronary artery stenting is summarized. We discuss the clinical risk scores useful in guiding the prediction of stroke, bleeding, and stent thrombosis. Additionally, we highlight where additional evidence is needed to determine the proper balance of anticoagulant and antiplatelet agents in this patient population.
Project description:Dabigatran and rivaroxaban are novel oral anticoagulants that specifically inhibit thrombin and factor Xa, respectively. The aim of this study is to elucidate antithrombotic properties of these anticoagulant agents under arterial and venous shear conditions. Whole blood samples treated with dabigatran or rivaroxaban at 250, 500, and 1000 nM, with/without aspirin and AR-C66096, a P2Y12 antagonist, were perfused over a microchip coated with collagen and tissue thromboplastin at shear rates of 240 and 600 s(-1). Fibrin-rich platelet thrombus formation was quantified by monitoring flow pressure changes. Dabigatran at higher concentrations (500 and 1000 nM) potently inhibited thrombus formation at both shear rates, whereas 1000 nM of rivaroxaban delayed, but did not completely inhibit, thrombus formation. Dual antiplatelet agents weakly suppressed thrombus formation at both shear rates, but intensified the anticoagulant effects of dabigatran and rivaroxaban. The anticoagulant effects of dabigatran and rivaroxaban were also evaluated under static conditions using thrombin generation (TG) assay. In platelet-poor plasma, dabigatran at 250 and 500 nM efficiently prolonged the lag time (LT) and moderately reduce peak height (PH) of TG, whereas rivaroxaban at 250 nM efficiently prolonged LT and reduced PH of TG. In platelet-rich plasma, however, both anticoagulants efficiently delayed LT and reduced PH of TG. Our results suggest that dabigatran and rivaroxaban may exert distinct antithrombotic effects under flow conditions, particularly in combination with dual antiplatelet therapy.
Project description:Despite the evidence that some commonly used Chinese medications (CMs) have antiplatelet/anticoagulant effects, many patients still used antiplatelets combined with CMs. We conducted a nested case-crossover study to examine the associations between the concomitant use of antiplatelets and CMs and major bleeding using population-based health database in Taiwan. Among the cohort of 79,463 outpatients prescribed antiplatelets (e.g., aspirin and clopidogrel) continuously, 1,209 patients hospitalized with new occurring bleeding in 2012 and 2013 were included. Those recruited patients served as their own controls to compare different times of exposure to prespecified CMs (e.g., Asian ginseng and dong quai) and antiplatelet agents. The periods of case, control 1, and control 2 were defined as 1-4 weeks, 6-9 weeks, and 13-16 weeks before hospitalization, respectively. Conditional logistic regression analyses found that concurrent use of antiplatelet drugs with any of the prespecified CMs in the case period might not significantly increase the risks of bleeding over that in the control periods (OR = 1.00, 95% CI 0.51 to 1.95 and OR = 1.13, 95% CI 0.65 to 1.97). The study showed no strong relationships between hospitalization for major bleeding events and concurrent use of antiplatelet drugs with the prespecified CMs.
Project description:Perioperative management of antithrombotic therapy is a situation that occurs frequently and requires consideration of the patient, the procedure, and an expanding array of anticoagulant and antiplatelet agents. Preoperative assessment must address each patient's risk for thromboembolic events balanced against the risk for perioperative bleeding. Procedures can be separated into those with a low bleeding risk, which generally do not require complete reversal of the antithrombotic therapy, and those associated with an intermediate or high bleeding risk. For patients who are receiving warfarin who need interruption of the anticoagulant, consideration must be given to whether simply withholding the anticoagulant is the optimal approach or whether a perioperative "bridge" with an alternative agent, typically a low-molecular-weight heparin, should be used. The new oral anticoagulants dabigatran and rivaroxaban have shorter effective half-lives, but they introduce other concerns for perioperative management, including prolonged drug effect in patients with renal insufficiency, limited experience with clinical laboratory testing to confirm lack of residual anticoagulant effect, and lack of a reversal agent. Antiplatelet agents must also be considered in the perioperative setting, with particular consideration given to the potential risk for thrombotic complications in patients with coronary artery stents who have antiplatelet therapy withheld.