Background. New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation in non-valvular atrial fibrillation (NVAF). Methods. MEDLINE and CENTRAL,...Background. New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation in non-valvular atrial fibrillation (NVAF). Methods. MEDLINE and CENTRAL, regulatory agencies websites, clinical trials registers and conference proceedings were searched to identify randomised controlled trials of NOAC versus warfarin in NVAF. Two investigators reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes. Relative risks (RR) and 95% confidence intervals (CI) were estimated using a random effect meta-analysis. Results. Three clinical trials in 50,578 patients were included. The risk of non-hemorrhagic stroke and systemic embolic events (SEE) was similar with the NOAC and warfarin (RR = 0.93; 95% CI = 0.83-1.04), while the risk of intracranial bleeding (ICB) with the NOAC was lower than with warfarin (RR = 0.46; 95% CI = 0.33-0.65). We found differences in the effect size on all strokes and SEE depending on geographic region as well as on non-hemorrhagic stroke, SEE, bleeding and mortality depending on time in therapeutic range. Conclusion. The NOAC seem no more effective than warfarin for prevention of nonhemorrhagic stroke and SEE in the overall NVAF population, but are generally associated with a lower risk of ICB than warfarin.
Venous thrombosis is common in elective hip surgery, and prophylaxis is recommended. Clinical trials suggest that the drug dose and timing of initiating prophylaxis significantly influence antithrombotic effectiveness an...Venous thrombosis is common in elective hip surgery, and prophylaxis is recommended. Clinical trials suggest that the drug dose and timing of initiating prophylaxis significantly influence antithrombotic effectiveness and safety. We studied the time course and gradient of plasma coagulation and fibrinolysis during total hip arthroplasty (THA) in twenty patients that were randomly assigned to have the first dose of 5000 IU dalteparin subcutaneously (sc) injected 12 hours before or 6 hours after surgery. Baseline characteristics were similar in both groups. Specific biomarkers on coagulation (prothrombin fragment 1+2 (F1+2)) and fibrinolytic activity (plasmin/ α 2-antiplasmin complex (PAP) and D-dimer) were collected at six events during hospitalization and analysed. There were no significant group differences in the biomarkers at any time point. The highest concentrations were measured 6 hours after surgery and before the first postoperative injection. A marked decrease followed at the first postoperative day, and then a second increase in plasma concentrations was observed 6 days after surgery. This study showed that activation of coagulation and fibrinolysis by the operative trauma was the same when the first dose of dalteparin was injected 12 hours before or 6 hours after surgery.
Thrombotic disease is a major cause of peripartum morbidity and mortality worldwide. Development of thrombosis in pregnancy is multifactorial due to the physiologic changes of pregnancy-which induce a relative hypercoagu...Thrombotic disease is a major cause of peripartum morbidity and mortality worldwide. Development of thrombosis in pregnancy is multifactorial due to the physiologic changes of pregnancy-which induce a relative hypercoagulable state-as well as physical changes leading to increased stasis and also the effects of both the inherited and the acquired thrombophilias. In this review, we discuss the impact of each of these factors on the development of thrombosis as well as the evidence for the impact of pregnancy-associated thrombosis on pregnancy outcome. We then discuss the use of both prophylactic and therapeutic anticoagulation during pregnancy and the puerperium. We review the indications and dosing recommendations for administration of anticoagulation in a context of discussing the evidence including the lack of evidence and formal guidelines in this area. We briefly address the role of the new oral anticoagulants in pregnancy and conclude that significant further research in women with thrombophilias and pregnancy-associated thrombosis may help clarify the management of this condition in the future.
Objectives. We compared venous thromboembolism (VTE) prophylaxis practices and incidence in critically ill cirrhotic versus noncirrhotic patients and evaluated cirrhosis as a VTE risk factor. Methods. A cohort of 798 cri...Objectives. We compared venous thromboembolism (VTE) prophylaxis practices and incidence in critically ill cirrhotic versus noncirrhotic patients and evaluated cirrhosis as a VTE risk factor. Methods. A cohort of 798 critically ill patients followed for the development of clinically detected VTE were categorized according to the diagnosis of cirrhosis. VTE prophylaxis practices and incidence were compared. Results. Seventy-five (9.4%) patients had cirrhosis with significantly higher INR (2.2 ± 0.9 versus 1.3 ± 0.6, P < 0.0001), lower platelet counts (115,000 ± 90,000 versus 258,000 ± 155,000/ μ L, P < 0.0001), and higher creatinine compared to noncirrhotic patients. Among cirrhotics, 31 patients received only mechanical prophylaxis, 24 received pharmacologic prophylaxis, and 20 did not have any prophylaxis. Cirrhotic patients were less likely to receive pharmacologic prophylaxis (odds ratio, 0.08; 95% confidence interval (CI), 0.04-0.14). VTE occurred in only two (2.7%) cirrhotic patients compared to 7.6% in noncirrhotic patients (P = 0.11). The incidence rate was 2.2 events per 1000 patient-ICU days for cirrhotic patients and 3.6 events per 1000 patient-ICU days for noncirrhotics (incidence rate ratio, 0.61; 95% CI, 0.15-2.52). On multivariate Cox regression analysis, cirrhosis was not associated with VTE risk (hazard ratio, 0.40; 95% CI, 0.10-1.67). Conclusions. In critically ill cirrhotic patients, VTE incidence did not statistically differ from that in noncirrhotic patients.
Background. The knowledge is still sparse about patient related factors, influencing oral anticoagulation therapy (OAC) rates, in stroke patients with atrial fibrillation (AF). Aims. To assess the use of OAC in ischemic...Background. The knowledge is still sparse about patient related factors, influencing oral anticoagulation therapy (OAC) rates, in stroke patients with atrial fibrillation (AF). Aims. To assess the use of OAC in ischemic stroke patients diagnosed with AF and to identify patient related factors influencing the initiation of OAC. Methods. In the nationwide Danish Stroke Registry we identified 55,551 patients admitted with acute ischemic stroke from 2003 to 2011. Frequency analysis was used to assess the use of OAC in patients with AF, and logistic regression was used to determine independent predictors of OAC. Results. 17.1% (n = 9,482) of ischemic stroke patients had AF. OAC prescription rates were increasing, and in 2011 46.6% were prescribed OAC, 42.5% had a contraindication, and 3.7% were not prescribed OAC without a stated contraindication. Younger age, less severe stroke, and male gender were positive predictors of OAC, while excessive alcohol consumption, smoking, and institutionalization were negative predictors of OAC (P values < 0.05). Conclusions. Advanced age, severe stroke, female gender, institutionalization, smoking, and excessive alcohol consumption were associated with lower OAC rates. Contraindications were generally present in patients not in therapy, and the assumed underuse of OAC may be overestimated.
Background. Residual vein obstruction (RVO), the persistence of venous thrombosis with time and often after anticoagulation, may indicate a systemic prothrombotic condition. Prior studies have shown varying efficacy in u...Background. Residual vein obstruction (RVO), the persistence of venous thrombosis with time and often after anticoagulation, may indicate a systemic prothrombotic condition. Prior studies have shown varying efficacy in using RVO as a risk factor for future venous thromboembolic (VTE) recurrence. Methods. To assess whether positive RVO imaging predicts recurrent VTE events, we performed a meta-analysis on studies in which patients with documented VTEs, anticoagulated for a minimum of 4 weeks, had repeat sonography to assess RVO and were subsequently followed for recurrent events. Results. Thirteen studies met inclusion criteria: 3531 patient VTE events with 3474 evaluable results were analyzed. The presence of RVO was associated with recurrence in all VTE (OR 1.93; 95% CI: 1.29, 2.89) and secondary VTE (OR 2.78; 95% CI: 1.41, 5.5) but not for primary VTE (OR 1.35; 95% CI: 0.87, 2.08). When cancer patients were eliminated from the secondary VTE group, there was no longer a significant association of RVO with VTE recurrence (OR 1.73; 95% CI: 0.81, 3.67) while in the subset of cancer patients, presence of RVO was associated with an increase in VTE recurrence risk (OR 5.14; 95% CI: 1.59, 16.65, P < 0.006). Conclusions. We conclude that the presence of RVO is associated with recurrence in secondary VTE but not in primary VTE and that association may be driven by the subset with cancer.
Implantation of prosthetic valve requires consideration for anticoagulation. The current guideline recommends warfarin on all mechanical valves. Dabigatran is the new generation anticoagulation medication which is taken...Implantation of prosthetic valve requires consideration for anticoagulation. The current guideline recommends warfarin on all mechanical valves. Dabigatran is the new generation anticoagulation medication which is taken orally and does not require frequent monitoring. This drug is approved for treatment for atrial fibrillation and venous thromboembolism, but the latest large trial showed that this drug increases adverse events when used for mechanical valve anticoagulation. On-X valve is the new generation mechanical valve which is considered to require less anticoagulation due to its flow dynamics. The latest study showed that lower anticoagulation level lowers the incidence of bleeding, while the risk of thromboembolism and thrombosis remained the same. Anticoagulation poses dilemma in cases such as pregnancy and major bleeding event. During pregnancy, warfarin can be continued throughout pregnancy and switched to heparin derivative during 6-12 weeks and >36 weeks of gestation. Warfarin can be safely started after 1-2 weeks of discontinuation following major bleeding episode.
Posttranscriptional control of gene expression is crucial for regulating plurality of proteins and functional plasticity of the proteome under (patho)physiologic conditions. Alternative splicing as well as micro (mi)RNA-...Posttranscriptional control of gene expression is crucial for regulating plurality of proteins and functional plasticity of the proteome under (patho)physiologic conditions. Alternative splicing as well as micro (mi)RNA-mediated mechanisms play an important role for the regulation of protein expression on posttranscriptional level. Both alternative splicing and miRNAs were shown to influence cardiovascular functions, such as endothelial thrombogenicity and the vascular tone, by regulating the expression of several vascular proteins and their isoforms, such as Tissue Factor (TF) or the endothelial nitric oxide synthase (eNOS). This review will summarize and discuss the latest findings on the (patho)physiologic role of alternative splicing processes as well as of miRNAs on modulation of vascular functions, such as coagulation, thrombosis, and regulation of the vascular tone.
Venous thromboembolism (VTE) is the most common preventable cause of hospital death. Several audits in the west have demonstrated that appropriate thromboprophylaxis is not being offered to a large number of surgical pat...Venous thromboembolism (VTE) is the most common preventable cause of hospital death. Several audits in the west have demonstrated that appropriate thromboprophylaxis is not being offered to a large number of surgical patients. Similar audits are lacking in the Indian population, and a perception exists among Indian surgeons that Indian patients are not susceptible to VTE. Hence we undertook a survey to analyze the existing knowledge and practice of VTE prophylaxis amongst general surgeons in India. A questionnaire-based survey was conducted on 100 active general surgeons. We found that 97% of surgeons had encountered VTE in their practice, and 49% had encountered mortality from pulmonary embolism. 64% of surgeons do not routinely score patients preoperatively for their VTE risk, and only 33% reported the presence of an institute-based protocol for the same. There was a wide disparity in the prophylaxis methods used for each risk group, particularly in the moderate-risk group. These findings suggest the need for adoption of institute-based protocols for prophylaxis and the evolution of Indian guidelines for VTE prophylaxis.
Anticoagulation therapy is mandatory in patients with pulmonary embolism to prevent significant morbidity and mortality. The mainstay of therapy has been vitamin-K antagonist therapy bridged with parenteral anticoagulant...Anticoagulation therapy is mandatory in patients with pulmonary embolism to prevent significant morbidity and mortality. The mainstay of therapy has been vitamin-K antagonist therapy bridged with parenteral anticoagulants. The recent approval of new oral anticoagulants (NOACs: apixaban, dabigatran, and rivaroxaban) has generated significant interest in their role in managing venous thromboembolism, especially pulmonary embolism due to their improved pharmacokinetic and pharmacodynamic profiles, predictable anticoagulant response, and lack of required efficacy monitoring. This paper addresses the available literature, on-going clinical trials, highlights critical points, and discusses potential advantages and disadvantages of the new oral anticoagulants in patients with pulmonary embolism.
Venous thromboembolism (VTE) is a common complication after total hip and total knee arthroplasty. Currently used methods of VTE prophylaxis after these procedures have important limitations, including parenteral adminis...Venous thromboembolism (VTE) is a common complication after total hip and total knee arthroplasty. Currently used methods of VTE prophylaxis after these procedures have important limitations, including parenteral administration, and unpredictable plasma levels requiring frequent monitoring and dose adjustment leading to decreased patient compliance with recommended guidelines. New oral anticoagulants have been demonstrated in clinical trials to be equally efficacious to enoxaparin and allow for fixed dosing without the need for monitoring. Rivaroxaban is one of the new oral anticoagulants and is a direct factor Xa inhibitor that has demonstrated superior efficacy to that of enoxaparin. However, the data also suggest that rivaroxaban has an increased risk of bleeding compared to enoxaparin. This paper reviews the available data on the efficacy and safety of rivaroxaban for VTE prophylaxis after total hip and total knee arthroplasty.
Traditional anticoagulants, such as warfarin and enoxaparin, have several limitations, including parenteral administration, need for laboratory monitoring, and ongoing dose adjustment, which may limit optimal patient car...Traditional anticoagulants, such as warfarin and enoxaparin, have several limitations, including parenteral administration, need for laboratory monitoring, and ongoing dose adjustment, which may limit optimal patient care. Newer oral anticoagulants, such as direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban), have been developed to overcome these drawbacks, and thereby improve patient care. Several of these agents have been approved for use in the prevention and treatment of venous and/or systemic thromboembolism. The objective of this paper is to provide an overview of the available clinical trial data for these new oral anticoagulants in the prevention and treatment of venous thromboembolism and a practical update for clinicians.
Stent thrombosis (ST) is a severe and feared complication of coronary stenting. Patients who have suffered from ST are usually treated according to the "one-size-fits-all" dosing regimen of aspirin and clopidogrel. Many...Stent thrombosis (ST) is a severe and feared complication of coronary stenting. Patients who have suffered from ST are usually treated according to the "one-size-fits-all" dosing regimen of aspirin and clopidogrel. Many ST patients show high on-treatment platelet reactivity (HPR) despite this antiplatelet therapy (APT). It has been shown that HPR is a risk factor for major adverse cardiac events. Therefore, ST patients with HPR are at a high risk for recurrent atherothrombotic events. New insights into the variable response to clopidogrel and the advent of stronger P2Y12 inhibitors prasugrel and ticagrelor have changed the attention from a fixed APT treatment strategy towards "personalized APT strategies." Strategies can be based on platelet function testing, which gives insight into the overall response of a patient to APT. At our outpatient ST clinic, we practice personalized APT based on platelet function testing to guide the cardiologist to a presumed optimal antiplatelet treatment of ST patients. Beside results of platelet function testing, comedication, clinical characteristics, and genetics have to be considered to decide on personalized APT. Ongoing studies have yet to reveal the optimal personalized APT strategy for cardiologists to prevent their patients from atherothrombotic and bleeding events.
Several randomized and observational studies have reported steady increase in cumulative incidence of late and very late ST (LST/VLST) following first-generation drug-eluting stents (DES: sirolimus-(SES) and paclitaxel-(...Several randomized and observational studies have reported steady increase in cumulative incidence of late and very late ST (LST/VLST) following first-generation drug-eluting stents (DES: sirolimus-(SES) and paclitaxel-(PES)) up to 5 years. Pathologic studies have identified uncovered struts as the primary substrate responsible for LST/VLST following DES, where delayed arterial healing is associated with stent struts penetrating into the necrotic core, long/overlapping stents, and bifurcation stenting especially in flow divider region. Grade V stent fracture also induces LST/VLST and restenosis. Hypersensitivity reaction is exclusive to SES as an etiology of LST/VLST, whereas malapposition secondary to excessive fibrin deposition is associated with PES. Uncovered struts can be identified in SES and PES with duration of implant beyond 12 months, particularly in stents placed for "off-label" indications. Neoatherosclerosis is another important contributing factor for VLST in DES and bare metal stents (BMS); however, DES shows rapid and more frequent development of neoatherosclerosis than BMS. Future pathologic studies should address the long-term safety of newer generation DES including zotarolimus- and everolimus-eluting stents in terms of the improvement in reendothelialization, decreased inflammation and fibrin deposition as well as a lower incidence of stent fracture-related adverse events, and reduced neoatherosclerosis, which likely contribute to the decreased risk of LST/VLST and better patient outcomes.
Background. Patients undergoing joint replacement remain at increased risk for venous thromboembolism (VTE) compared to other types of surgery, regardless of thromboprophylactic regimen. The pathophysiologic processes re...Background. Patients undergoing joint replacement remain at increased risk for venous thromboembolism (VTE) compared to other types of surgery, regardless of thromboprophylactic regimen. The pathophysiologic processes rendering this group of patients at risk for VTE are multifactorial. Procedure-specific and patient-specific exposures play a role in the postoperative development of VTE, including the development of anti-phospholipid antibodies (aPL). Methods. We measured three aPL (anti-cardiolipin, anti-β(2) glycoprotein, and lupus anticoagulant) in 123 subjects undergoing total knee or hip arthroplasty to describe the presence of these antibodies preoperatively and to describe the rate of postoperative seroconversion among those people who were negative preoperatively. Postoperative antibodies were measured at day 7, 14, and 21. Results. The prevalence of aPL antibodies in the preoperative period was 44%, positive subjects were more likely to be smokers (P = 0.05) and were less likely to have undergone a previous arthroplasty procedure (P = 0.002). Subjects seroconverted in a 21 day postoperative period at a rate of 79%. Conclusions. These pilot data suggest that the prevalence of aPL in this population both preoperatively and postoperatively is higher than previously expected. Further studies are needed to describe aPL in a larger population and to establish their clinical significance in populations undergoing joint replacement surgeries.
Anticoagulation Clinics (ACs) are services specialized in management of patients on anticoagulant treatment. At present, ACs manage patients chiefly on antivitamin K antagonists (AVKs), but patient population has already...Anticoagulation Clinics (ACs) are services specialized in management of patients on anticoagulant treatment. At present, ACs manage patients chiefly on antivitamin K antagonists (AVKs), but patient population has already changed in the last few years, because of an increase of treatments with other anticoagulant drugs, which require different management systems. The strong increase in the number of patients at AC, mainly on long-term treatment, has determined the development of web management, through telemedicine systems, improving the quality of life and maintaining the same clinical quality levels. New oral anticoagulants (NOAs) have shown to be as effective as AVK antagonists in stroke prevention in atrial fibrillation and for treatment of venous thromboembolism in addition to VTE prophylaxis in orthopaedic surgery, when administered at a fixed dose, but patient adherence and compliance are crucial for good quality treatment. At present, lacking data from the real world, an oversimplification of treatment with NOAs could cause unjustified risks for patients and also a possible future underuse of good drugs. For these reasons the vigilance must be high and ACs can have a crucial role in defining which is the best management for NOA patients and how to do it, as it happened for AVKs.
Approximately 775,000 hip and knee arthroplasties are performed yearly in the United States, with a dramatic increase expected. Patients having hip and knee arthroplasties are at high risk of developing a venous thromboe...Approximately 775,000 hip and knee arthroplasties are performed yearly in the United States, with a dramatic increase expected. Patients having hip and knee arthroplasties are at high risk of developing a venous thromboembolism. The American College of Chest Physicians (ACCP) and the American Academy of Orthopedic Surgeons (AAOS) have updated guidelines, which outline new prophylactic strategies. Factor Xa inhibitor rivaroxaban has a new recommendation by ACCP and is gradually being adopted by the joint arthroplasty community as an effective oral agent. Other more well-known agents including warfarin, low-molecular-weight heparin, aspirin, and fondaparinux continue to be options for prophylaxis. While the goal of prophylaxis continues to be the prevention of venous thromboemboli and pulmonary emboli, it is important to consider the increased bleeding risk associated with their use. The most recent ACCP and AAOS guidelines give clinicians a greater autonomy in choosing a prophylactic agent with greater emphasis placed on dialogue between the surgeon and patient as to the choice of prophylaxis.
Venous thromboembolism (VTE) is a frequent complication of gastrointestinal cancers that increases morbidity and may impact mortality. Low-molecular-weight heparins (LMWHs) and vitamin K antagonists (VKAs) are standard a...Venous thromboembolism (VTE) is a frequent complication of gastrointestinal cancers that increases morbidity and may impact mortality. Low-molecular-weight heparins (LMWHs) and vitamin K antagonists (VKAs) are standard anticoagulation options for the ambulatory gastrointestinal cancer patient with VTE, but both of these agents are challenging to use for various reasons. Novel oral anticoagulants (NOAs) are new, orally available anticoagulants designed to be easier to administer with more reliable pharmacokinetics that eliminate the need for frequent monitoring of various laboratory parameters. This paper reviews the existing efficacy and safety data for the use of NOAs dabigatran etexilate, rivaroxaban, and apixaban and discusses the potential role of these agents in the management of gastrointestinal cancer-related VTE.
Unlike vitamin K antagonists (VKAs), the new oral anticoagulants (NOACs)-direct thrombin inhibitor, dabigatran, and direct activated factor X inhibitors, rivaroxaban, and apixaban-do not require routine INR monitoring. C...Unlike vitamin K antagonists (VKAs), the new oral anticoagulants (NOACs)-direct thrombin inhibitor, dabigatran, and direct activated factor X inhibitors, rivaroxaban, and apixaban-do not require routine INR monitoring. Compared to VKAs, they possess relatively rapid onset of action and short halflives, but vary in relative degrees of renal excretion as well as interaction with p-glycoprotein membrane transporters and liver cytochrome P450 metabolic enzymes. Recent completed phase III trials comparing NOACs with VKAs for stroke prevention in atrial fibrillation (AF)-the RE-LY, ROCKET AF, and ARISTOTLE trials-demonstrated at least noninferior efficacy, largely driven by significant reductions in haemorrhagic stroke. Major and nonmajor clinically relevant bleeding rates were acceptable compared to VKAs. Of note, the NOACs caused significantly less intracranial haemorrhagic events compared to VKAs, the mechanisms of which are not completely clear. With convenient fixed-dose administration, the NOACs facilitate anticoagulant management in AF in the community, which has hitherto been grossly underutilised. Guidelines should evolve towards simplicity in anticipation of greater use of NOACs among primary care physicians. At the same time, the need for caution with their use in patients with severely impaired renal function should be emphasised.