Workshop: Data management for a 2000-patient anticoagulation clinic

The concept of specialized anticoagulation services has attracted a great deal of enthusiasm because this type of systematic approach offers a number of benefits for patients and providers alike. The computerization of such services challenges the health care team but is ultimately a great aid to clinicians in providing quality care. The Anticoagulant Therapy Unit (ATU) at the Massachusetts General Hospital (MGH) in Boston, Massachusetts was first organized in 1969 and is among the largest in the United States. The patient population is presently more than 2400. Full computerization has been the key to the success of this unit in managing the large number of patients and the volume of anticoagulation data. We describe some aspects of how this unit operates, with emphasis on how a computerized database is essential to providing optimal monitoring and tracking for such a large patient population.     

Audit of the frequency and clinical response to excessive oral anticoagulation in an out-patient population

A retrospective review of over-anticoagulated patients with critical international normalized ratios (INRs) was undertaken in a large outpatient laboratory. In the six-month study period, 85 prothrombin times (PTs) were identified with an INR of ⩾6.0, an overall incidence of elevated PTs of 0.2% or two per 1,000 INR tests. Complete follow-up data was available on 65 patients. When compared to an age- and gender-matched control group without INR ⩾6.0, high-INR patients were significantly more likely to manifest the presence of alcoholism or liver disease, to have been anticoagulated for less than six months, to have experienced more frequent warfarin dosage changes, and to have had the addition of a medication known to interact with warfarin. In the high-INR group, a likely cause for the specific critical INR was identified in 44 patients (68%). Drug interactions followed by compliance problems were the most common factors identified. The 13 patients (20%) who received vitamin K therapy experienced no difference in the clinical outcome compared with those managed conservatively. Conservative management of critically high INR values appeared to be as efficacious as intervention with vitamin K therapy. Am. J. Hematol. 59:22–27, 1998. © 1998 Wiley-Liss, Inc.     

Reimbursement for Anticoagulation Services

Journal of Thrombosis and Thrombolysis -     

Workshop: Special problems in anticoagulation therapy: Cancer and venous thromboembolism-temporary discontinuation of warfarin for surgery and invasive procedures

Health care providers monitoring anticoagulated patients are often asked to make recommendations regarding anticoagulant management during periods when illness or treatment may complicate anticoagulant therapy. Two particularly difficult clinical problems concern the indications for and management of anticoagulant therapy in patients with cancer and the management of anticoagulated patients who must undergo some type of surgical procedure. Cancer is a significant risk factor for a variety of thromboembolic disorders, particularly venous thromboembolism. Venostasis from immobility, vessel wall damage from tumor invasion, and especially tumor-mediated activation of the coagulation system are important contributors to the prethrombotic state in cancer patients. The risk of venous thromboembolism is greatest during surgery, chemotherapy, and long-term use of central venous catheters. For selected patients, prophylaxis with subcutaneous heparin, low-intensity warfarin, or very low-intensity warfarin may substantially reduce this risk. A related concern for primary care clinicians is the increasing evidence that idiopathic venous thromboembolism may be the first manifestation of occult cancer. Whether and how these patients should be screened for malignancy is currently uncertain. Prior to surgical procedures in anticoagulated patients, clinicians must compare the risk of bleeding if anticoagulation is continued with the risk of recurrent thrombosis if anticoagulation is stopped. Bleeding risk is influenced by how a specific procedure affects the ability to assess and control bleeding and the intensity of anticoagulation at the time of the procedure. Thromboembolism risk is determined by the specific indication for the anticoagulation and the length of time during which anticoagulant therapy must be discontinued. Guidelines are suggested for perioperative anticoagulant management of patients with different thromboembolic disorders undergoing a variety of surgical procedures.     

Obtaining Reimbursement in France and Italy for New Diabetes Products

Manufacturers launching next-generation or innovative medical devices in Europe face a very heterogeneous reimbursement landscape, with each country having its own pathways, timing, requirements and success factors. We selected 2 markets for a deeper look into the reimbursement landscape: France, representing a country with central decision making with defined processes, and Italy, which delegates reimbursement decisions to the regional level, resulting in a less transparent approach to reimbursement. Based on our experience in working on various new product launches and analyzing recent reimbursement decisions, we found that payers in both countries do not reward improved next-generation products with incremental reimbursement. Looking at innovations, we observe that manufacturers face a challenging and lengthy process to obtain reimbursement. In addition, requirements and key success factors differ by country: In France, comparative clinical evidence and budget impact very much drive reimbursement decisions in terms of pricing and restrictions, whereas in Italy, regional key opinion leader (KOL) support and additional local observational data are key.     

A comparison between two activated protein C resistance methods as routine diagnostic tests for factor V Leiden mutation

The most common commercially available test measuring activated protein C (APC) resistance relies on the the anticoagulant response to added APC in an activated partial thromboplastin time (APTT) based method. Another method is a Russell Viper venom time (RVVT) based system. To improve the specificity for factor V Leiden of the APTT based method, pre-dilution of test plasma in FV-deficient plasma has recently been recommended. In this study we tested the relative suitabilities of the APTT-based system, the RVVT-based system and their corresponding assays modified by pre-dilution in FV-deficient plasma, for screening asymptomatic subjects, a group of thrombophilic patients (in particular those with low APC ratios), patients on oral anticoagulants, and patients with lupus anticoagulant (LAC). We found the RVVT-based assay to be superior to the APTT-based method in the separation of normals from those with FV Leiden mutation both in asymptomatic subjects and in the thrombophilic patient group. Both modified assays demonstrated a sensitivity and specificity of 100% for FV Leiden, as verified by genotyping in asymptomatic subjects, thrombophilic patients and patients on oral anticoagulants, with the modified RVVT-based assay giving better separation between normals and FV Leiden. Inhibition of phospholipid-dependent coagulation by LAC antibodies rendered the APTT-based system less suitable than the phospholipid-rich RVVT-based one, and as nine of the 20 LAC-positive patients were on warfarin, we showed only the modified RVVT assay to be a reliable predictor of factor V Leiden in this patient group.     

Audit of community‐based anticoagulant monitoring in patients with thromboembolic disease: is frequent testing necessary?

Oral anticoagulant monitoring is managed by general practitioners in Auckland. An audit of this service in 452 patients demonstrated that anticoagulant control was in line with recommended international guidelines, with 58.3% of international normalized ratio (INR) measurements in the therapeutic range. However, the frequency of testing was high, with the majority of patients (68%), including those on long-term treatment, having INR measurements at weekly intervals. We question the need for such frequent INR testing.     

Thromboembolic and bleeding risk of periprocedural bridging anticoagulation: A systematic review and meta-analysis

The risk and benefit of periprocedural heparin bridging is not completely clarified. We aimed to assess the safety and efficacy of bridging anticoagulation prior to invasive procedures or surgery. Heparin bridging was associated with lower risks of thromboembolism and bleeding compared to non-bridging. PubMed, Ovid and Elsevier, and Cochrane Library (2000-2016) were searched for English-language studies. Studies comparing interrupted anticoagulation with or without bridging and continuous oral anticoagulation in patients at moderate-to-high thromboembolic risk before invasive procedures were included. Primary outcomes were thromboembolic events and bleeding events. Mantel-Haenszel method and random-effects models were used to analyze the pooled risk ratio (RR) and 95% confidence interval (CI) for thromboembolic and bleeding risks. Eighteen studies (six randomized controlled trials and 12 cohort studies) were included (N = 23 364). There was no difference in thromboembolic risk between bridged and non-bridged patients (RR: 1.26, 95% CI: 0.61-2.58; RCTs: RR: 0.71, 95% CI: 0.23-2.24; cohorts: RR: 1.45, 95% CI: 0.63-3.37). However, bridging anticoagulation was associated with higher risk of overall bleeding (RR: 2.83, 95% CI: 2.00-4.01; RCTs: RR: 2.24, 95% CI: 0.99-5.09; cohorts: RR: 3.09, 95% CI: 2.07-4.62) and major bleeding (RR: 3.00, 95% CI: 1.78-5.06; RCTs: RR: 2.48, 95% CI: 1.29-4.76; cohorts: RR: 3.22, 95% CI: 1.65-6.32). Bridging anticoagulation was associated with increased bleeding risk compared to non-bridging. Thromboembolism risk was similar between two strategies. Our results do not support routine use of bridging during anticoagulation interruption.     

Managing Oral Anticoagulation Requires Expert Experience and Clinical Evidence

The management of patients on chronic oral anticoagulant therapy, namely Vitamin K antagonists such as warfarin, is often associated with difficult and challenging issues for the healthcare practitioner. Many of these issues, such as warfarin failure or resistance, the optimal warfarin initiation dose, the optimal target International Normalized Ratio in antiphospholipid syndrome, the optimal monitoring frequency and use of point-of-care monitoring, the management of oral anticoagulation during invasive procedures, and the management of over-anticoagulation, have not been evaluated in rigorously-designed clinical trials. The latest American College of Chest Physician recommendations concerning these issues are Grade 2C, the weakest recommendations available. It remains up to the experience and expertise of the individual practitioner along with whatever clinical evidence is available in a particular healthcare environment—especially one associated with an anticoagulant management service—to implement management strategies with respect to these issues in patients on oral anticoagulation.     

INR reporting in Canadian medical laboratories

A written survey of all licensed medical laboratories in Canada performing coagulation testing was performed to investigate the level of knowledge and overall usage of the INR system for reporting prothrombin time results in medical laboratories. There was an overall response rate of 857 of 1,228 laboratories surveyed. Fifty-seven percent of responding laboratories utilized some format of INR reporting. The ISi of the individual thromboplastin utilized was known by 89% of laboratories. The IS1 of the thromboplastin utilized was known to be specific for the particular reagent/Instrument combination in 44% of cases. Fifty-five percent of client physicians preferred PT results to be reported in seconds while 42% desired an INR format. The situation in Canada is similar to the United States in that further education regarding the INR system for PT reporting is required by both medical laboratories and physicians. © 1995 Wiley-Liss, Inc.     

新型抗凝药与华法林对非瓣膜性心房颤动患者抗凝效果的临床评价

[目的]研究利伐沙班、达比加群酯与华法林对非瓣膜性心房颤动抗凝效果。[方法]收集心内科接收的120例非瓣膜性心房颤动住院患者为研究对象,均服用单一抗凝药物,分为华法林组(40例)、利伐沙班组(40例)和达比加群酯组(40例),接受药物治疗6个月,比较治疗期间栓塞事件、出血事件发生率和血常规、肝肾功能及血栓弹力图指标情况。[结果]治疗6个月后,利伐沙班组和达比加群酯组栓塞事件发生率明显低于华法林组(P<0.05),而利伐沙班组与达比加群酯组比较差异无显著性(P>0.05);三组出血事件发生率、治疗前及治疗后6个月患者血常规指标(白细胞计数、血小板计数、血红蛋白)、肝肾功能指标(血清肌酐、谷丙转氨酶、血尿素氮)比较差异无显著性(P>0.05);治疗6个月后利伐沙班组与达比加群酯组血栓弹力图指标R值、K值、MA值均明显高于华法林组(P<0.05),但利伐沙班组与达比加群酯组比较差异无显著性(P>0.05)。[结论]利伐沙班、达比加群酯治疗非瓣膜性心房颤动相比华法林具有更优的抗凝效果,降低栓塞事件的发生,且对肝肾功能及血常规无明显影响,安全性高。     

Diabetes Device Reimbursement in the EU-5

The reimbursement landscape for new and innovative diabetes devices in Europe is very heterogeneous and nontransparent, with each country employing different mechanisms, pathways, and requirements. This article provides an overview of how diabetes device reimbursement works in the outpatient setting in the five major European Union markets (France, Germany, Italy, Spain, and the United Kingdom; the EU-5). It will be of particular interest to manufacturers of innovative devices. Markets are first categorized as either a centralized or a regionalized reimbursement decision-making system, and implications for device reimbursement are explored. In the second part, specific requirements and success factors for wide reimbursement in the EU-5 are analyzed in detail. Gaining early acceptance by the main influencers (key opinion leaders and payers) is the first step. Equally important is the provision of convincing evidence, be this clinical, health–economic (cost-effectiveness), or a demonstration of cost savings (budget impact). In some countries, local usage data may be a requirement as well. Lastly, as payers’ willingness to pay stems directly from their perceived value of a device, a key success factor and a necessary precondition for manufacturers is to set the right price.     

Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial

Randomized trials have indicated that well-managed anticoagulation with warfarin could prevent more than half of the strokes related to atrial fibrillation. However, many patients with atrial fibrillation who are eligible for this therapy either do not receive it or are not maintained within an optimal prothrombin time-international normalized ratio (INR) range. We sought to determine whether an anticoagulation service within a managed care organization would be a feasible alternative for providing anticoagulation care.We performed a multi-site randomized trial in six large managed care organizations in the United States. Subjects were aged 65 years or older and had nonvalvular atrial fibrillation. At each site, physician practices were divided into two geographically defined practice clusters; each site was randomly assigned to have one intervention and one control cluster. The intervention cluster received an anticoagulation service that satisfied specifications for high-quality anticoagulation care and was coordinated through the managed care organization. Control clusters continued with their usual provider-based care. We measured the proportion of time that warfarin-treated patients in each of the clusters (intervention and control) were in the target range for the INR at baseline, and again during a follow-up period.Five of the six selected sites succeeded at developing an anticoagulation service. Patients in the intervention and control clusters had similar demographic characteristics, contraindications to warfarin, and risk factors for stroke. Among patients (n = 144 in the intervention clusters; n = 118 in the control clusters) for whom data were available during the baseline and follow-up periods, the changes in percentages of time in the target range were similar for those in the intervention clusters (baseline: 47.7%; follow-up: 55.6%) and in the control clusters (baseline: 49.1%; follow-up: 52.3%; intervention effect: 5%; 95% confidence interval: -5% to 14%; P = 0.32).Although it was feasible in a managed care organization to implement anticoagulation services that were tailored to local circumstances, provision of this service did not improve anticoagulation care compared with usual care. The effect of the anticoagulation service was limited by the utilization of the service, the degree to which the referring physician supports strict adherence to recommended target ranges for the INR, and the ability of the anticoagulation service to identify and to respond to out-of-range values promptly.     

Workshop: Developing a Business Plan for an Anticoagulation Management Service

Journal of Thrombosis and Thrombolysis -     

COVID-19: Thrombosis,thromboinflammation, and anticoagulation considerations

Vascular endothelial injury is a hallmark of acute infection at both the microvascular and macrovascular levels. The hallmark of SARS-CoV-2 infection is the current COVID-19 clinical sequelae of the pathophysiologic responses of hypercoagulability and thromboinflammation associated with acute infection. The acute lung injury that initially occurs in COVID-19 results from vascular and endothelial damage from viral injury and pathophysiologic responses that produce the COVID-19–associated coagulopathy. Clinicians should continue to focus on the vascular endothelial injury that occurs and evaluate potential therapeutic interventions that may benefit those with new infections during the current pandemic as they may also be of benefit for future pathogens that generate similar thromboinflammatory responses. The current Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) studies are important projects that will further define our management strategies. At the time of writing this report, two mRNA vaccines are now being distributed and will hopefully have a major impact on slowing the global spread and subsequent thromboinflammatory injury we see clinically in critically ill patients.