Anticoagulation Stewardship to Bridge the Implementation Gap in Perioperative Anticoagulation Management.

Lack of alignment of care protocols among providers in health care is a driver of increased costs and suboptimal patient outcomes. Perioperative anticoagulation management is a good example of a complex area where protocol creation is a clinical challenge that demands input from multiple experts. Questions regarding the need for anticoagulation interruptions are frequent. Yet, due to layers of complexity involving analysis of anticoagulation indication, surgical risk, and anesthesia-associated bleeding risk as well as institutional practices, there is heterogeneity in how these interruptions are approached. The recent perioperative anticoagulation guidelines from the American College of Chest Physicians summarize extensive evidence for the management of anticoagulant and antiplatelet medications in patients who undergo elective interventions. However, implementation of these guidelines by individual clinicians is highly varied and often does not follow the best available clinical evidence. Against this background, anticoagulation stewardship units, which exist to improve safety and quality monitoring for the anticoagulated patient, are of growing interest. These units provide a bridge for the implementation of value-based, high-quality guidelines for patients who need perioperative anticoagulation interruption. We use a case to pragmatically illustrate the problem and tactics for change management and implementation science that may facilitate the adoption of perioperative anticoagulation guidelines.

Building Your Peripheral Artery Disease Toolkit: Medical Management of Peripheral Artery Disease in 2022.

Peripheral artery disease (PAD) is associated with substantial morbidity, including a high risk of cardiovascular and limb events and death. A growing body of evidence has demonstrated the benefits of antithrombotic therapy, lipid lowering, blood pressure control, diabetes management, smoking cessation, and exercise programs on improving symptoms and reducing these complications. Guidelines make specific recommendations on how to use these strategies to prevent adverse cardiovascular and limb outcomes in patients with PAD. Unfortunately, antithrombotic therapies, statins, optimal antihypertensives, smoking cessation counselling and therapies, and exercise programs have all been consistently shown to be underutilised in PAD patients both in Canada and globally. A variety of barriers to optimal utilisation of evidence-based medical therapies have been described at the patient, health care provider, and system levels. These include lack of knowledge among patients and health care providers, and lack of access to secondary prevention programs. We review the evidence for preventive therapies in PAD, evidence for underutilisation of these therapies, and barriers to their use. Core elements of PAD secondary prevention clinics are proposed, and a summary of optimal medical therapies and relevant tools is provided. This review may help clinicians who treat patients with PAD to develop a toolkit to overcome these barriers in order to improve utilisation of medical therapies, with the ultimate goal of improving outcomes for PAD patients.

Can a Single Measurement of Apixaban Levels Identify Patients at Risk of Overexposure? A Prospective Cohort Study.

Background Patients with atrial fibrillation (AF) are frequently treated with apixaban 2.5-mg twice daily (BID) off-label, presumably to reduce the bleeding risk. However, this approach has the potential to increase the risk of ischemic stroke. If a single measurement could reliably identify patients with high drug levels, the increased stroke risk may be mitigated by confining off-label dose reduction to such patients. Objectives This study aimed to determine whether a single high apixaban level is predictive of a similarly high level when the test is repeated in 2 months. Methods In this prospective cohort study of clinic patients receiving apixaban 5-mg BID for AF or venous thromboembolism, peak and trough apixaban levels were measured using the STA-Liquid anti-Xa assay at baseline and 2 months. We calculated the proportions of patients with levels that remained in the upper quintile. Results Of 100 enrolled patients, 82 came for a second visit, 55 of whom were treated with apixaban 5-mg BID. Seven (63.6%, 95% confidence interval [CI]: 35.4-84.8%) and nine (81.8%, 95% CI: 52.3-94.9%) of 11 patients with a baseline trough and peak level in the upper quintile, respectively, had a subsequent level that remained within this range. Only one (9.1%, 95% CI: 1.6-37.7%) patient had a subsequent level that fell just lower than the median. Conclusion The trough and peak levels of apixaban in patients who have a high level on a single occasion, usually remain high when the assay is repeated in 2 months. Accordingly, the finding of a high apixaban level in patients deemed to be at high risk of bleeding, allows physicians contemplating off-label use of the 2.5-mg BID dose to limit its use to selected patients who are less likely to be exposed to an increased risk of thrombosis.

Plasma Rivaroxaban Level to Identify Patients at Risk of Drug Overexposure: Is a Single Measurement of Drug Level Reliable?

Introduction Dose adjustment based on laboratory monitoring is not routinely recommended for patients treated with rivaroxaban but because an association has been reported between high drug level and bleeding, it would be of interest to know if measuring drug level once could identify patients at risk of bleeding who might benefit from a dose reduction. Objective This study was aimed to investigate the reliability of a single measurement of rivaroxaban level to identify clinic patients with persistently high levels, defined as levels that remained in the upper quintile of drug-level distribution. Methods In this prospective cohort study of 100 patients with atrial fibrillation or venous thromboembolism, peak and trough rivaroxaban levels were measured using the STA-Liquid Anti-Xa assay at baseline and after 2 months. Values of 395.8 and 60.2 ng/mL corresponded to the 80th percentile for peak and trough levels, respectively, and levels above these cut-offs were categorized as high for our analyses. Results Among patients with a peak or trough level in the upper quintile at baseline, only 26.7% (95% confidence interval [CI]: 10.9-52.0%), and 13.3% (95% CI: 2.4-37.9%), respectively, remained above these thresholds. Conclusion Our findings do not support the use of a single rivaroxaban level measurement to identify patients who would benefit from a dose reduction because such an approach is unable to reliably identify patients with high levels.

Mortality benefit in the COMPASS trial: is it related to superior statistical power or better efficacy and safety?

Until recently, attempts to improve the benefit of aspirin by adding another antithrombotic agent have not resulted in a mortality reduction in patients with chronic symptomatic atherosclerosis. In this population, COMPASS is the only one among six trials to show a significant mortality reduction, thereby providing evidence of a clear net clinical benefit with the combination of low-dose rivaroxaban plus aspirin. In this systematic review, we sought to determine whether the mortality benefit of the combination arm in COMPASS is best explained by greater statistical power or by a more favorable efficacy-safety profile than the other regimens evaluated in patients with chronic symptomatic atherosclerosis.

Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?-A Systematic Review.

BACKGROUND: Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients. OBJECTIVES: To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis. RESULTS AND DISCUSSION: We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs. CONCLUSION: The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

Rivaroxaban and Aspirin in Peripheral Vascular Disease: a Review of Implementation Strategies and Management of Common Clinical Scenarios.

PURPOSE OF REVIEW: Peripheral artery disease (PAD) affects an estimated 200 million people worldwide and is associated with significant cardiovascular morbidity and mortality. Cardiovascular risk is further increased among individuals with polyvascular disease, where either cerebrovascular or coronary artery disease is present in addition to PAD. In this review, we present common clinical scenarios encountered when managing patients with PAD and provide an evidence-based approach to prescribing optimal antithrombotics in this population. RECENT FINDINGS: The COMPASS trial recently demonstrated that rivaroxaban 2.5 mg BID + ASA daily significantly reduces major adverse cardiac and limb events in patients with PAD. Despite these advances, morbidity following MALE events remains high. With widespread approval by federal health regulators, the COMPASS regimen should be strongly considered in PAD patients who do not have a high bleeding risk. Implementing the COMPASS regimen in patients with PAD, along with other vascular risk reduction strategies, will have a substantial impact on reducing atherothromboembolic risk in patients with established vascular disease.

NOACs only for those who cannot tolerate a VKA: where is the evidence?

The 2016 European Society of Cardiology Guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) in preference to vitamin K antagonists (VKA) for stroke prevention in atrial fibrillation. A recent report from the Belgian Healthcare Knowledge Centre (KCE) raised concerns about the results of the phase 3 randomised trials that led to the approval of the NOACs for this indication and concluded that NOACs should only be used for patients who fail or cannot undergo treatment with a vitamin K antagonist because they cannot achieve stable INR values. Evidence from community-based studies suggests that NOACs are often not optimally used; however, our critical review of the randomised trial data provides no support for the concerns raised by the Belgian KCE about the trials. Furthermore, the results of observational studies involving more than 700,000 participants replicate those of the randomised trials, indicating that the benefits of NOACs seen in the trials can be readily translated to patient care. Due to their superior convenience and safety, NOACs also have the potential to reduce undertreatment of atrial fibrillation patients.

Low-dose rivaroxaban plus aspirin for the prevention of cardiovascular events: an evaluation of COMPASS.

The cardiovascular outcomes for people using anticoagulation strategies (NCT01776424) trial randomized 27,395 patients with stable coronary artery disease or peripheral artery disease (PAD) to receive rivaroxaban 5 mg twice-daily alone, the combination of rivaroxaban 2.5 mg twice-daily and aspirin 100 mg daily, or aspirin 100 mg daily alone. The combination arm resulted in a 24% reduction in the primary end point of cardiovascular death, stroke or myocardial infarction, and an 18% reduction in mortality. Rivaroxaban alone did not produce any additional benefit compared with aspirin. The combination therapy also reduced major adverse limb events, including amputation, in patients with PAD. Based on these results, the addition of rivaroxaban to aspirin is expected to substantially reduce morbidity and mortality in patients with stable coronary or PAD.

In Vitro Reversal of the Anti-Aggregant Effect of Ticagrelor Using Untreated Platelets.

BACKGROUND: Ticagrelor is an anti-platelet agent that is indicated for prevention of thrombosis after acute coronary syndrome or intra-coronary artery stent implantation, but it increases the risk of bleeding. Platelet transfusion has the potential to treat or prevent bleeding in patients taking ticagrelor, but the optimal quantity of platelets and timing of administration have not been fully defined. METHODS AND RESULTS: Ten healthy subjects took ticagrelor in combination with acetylsalicylic acid for 5 days, and had blood collected prior to treatment and at 2, 10, 24, 48, 72 and 96 hours after the last doses. The potential of platelet transfusion to prevent or reverse bleeding was evaluated by mixing subject and donor platelet-rich plasma in vitro in nine different proportions, and measuring adenosine diphosphate-mediated aggregation by light transmission aggregometry. Spontaneous offset of the anti-aggregant effect of ticagrelor occurred gradually and was complete at 72 hours after the last dose. The addition of donor platelets enhanced the recovery. The addition of the equivalent of six apheresis platelet units produced a 50% relative reversal at 10 hours, and > 90% reversal at 24 hours. CONCLUSION: Donor platelets enhance reversal of the anti-aggregant effect of ticagrelor in vitro. Donor platelets given in clinically relevant amounts partially reversed ticagrelor at 10 hours after the last dose, and almost fully reversed ticagrelor at 24 hours. The results inform on the potential to reverse ticagrelor in patients who develop bleeding or require emergency surgery.

Impact of cost on use of non-vitamin K antagonists in atrial fibrillation patients in Ontario, Canada.

Canadian guidelines recommend non vitamin K antagonists (NOACs) in preference to vitamin K antagonists (VKAs) for stroke prevention in patients with atrial fibrillation (AF), but NOACs are more expensive than VKAs. Canada has a universal healthcare system that covers the cost of NOACs for select patient groups. Ability to pay for NOACs may influence their use. We reviewed medical charts of Hamilton General Hospital outpatients under the age of 65 with a new diagnosis of AF who were referred for initiation of OAC therapy. We contacted these patients by phone and asked them to complete a questionnaire regarding their OAC choice, economic factors that may have influenced this choice (income, insurance) and the financial burden of OAC therapy. We included 110 patients, mean age 56 years, and 26.4% females. NOAC users had a higher median neighborhood income than VKA users (p = 0.0144, n = 110). 73 patients responded to the questionnaire. NOAC users reported higher annual household income (p = 0.0038, n = 73). Patients with private insurance were more likely to use NOACs than those without insurance (p = 0.0496, n = 73). The cost of NOACs and ability to pay is a determinant of their use Ontario patients under the age of 65. This two tiered provision of care appears to contradict the values of Canada's universal healthcare system.

The Massive Online Needs Assessment (MONA) to inform the development of an emergency haematology educational blog series.

BACKGROUND: Online educational resources are criticized as being teacher-centred, failing to address learner's needs. Needs assessments are an important precursor to inform curriculum development, but these are often overlooked or skipped by developers of online educational resources due to cumbersome measurement tools. Novel methods are required to identify perceived and unperceived learning needs to allow targeted development of learner-centred curricula. OBJECTIVES: To evaluate the feasibility of performing a novel technique dubbed the Massive Online Needs Assessment (MONA) for the purpose of emergency haematology online educational curricular planning, within an online learning community (affiliated with the Free Open Access Medical education movement). METHODS: An online survey was launched on CanadiEM.org using an embedded Google Forms survey. Participants were recruited using the study website and a social media campaign (utilizing Twitter, Facebook, Blogs, and a poster) targeting a specific online community. Web analytics were used to monitor participation rates in addition to survey responses. RESULTS: The survey was open from 20 September to 10 December 2016 and received 198 complete responses representing 6 medical specialties from 21 countries. Most survey respondents identified themselves as staff physicians (n = 109) and medical trainees (n = 75). We identified 17 high-priority perceived needs, 17 prompted needs, and 10 topics with unperceived needs through our MONA process. CONCLUSIONS: A MONA is a feasible, novel method for collecting data on perceived, prompted, and unperceived learning needs to inform an online emergency haematology educational blog. This methodology could be useful to the developers of other online education resources.

Clinical implications of reversal agents for direct oral anticoagulants.

Direct oral anticoagulants (DOACs) are effective in preventing and treating venous thromboembolism, and preventing stroke in atrial fibrillation. Until recently, there has been no specific reversal agent for DOACs. Now, a specific antidote for the direct thrombin inhibitor, dabigatran has been approved for use, and antidotes for factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) are being developed. We review the evidence for currently used and emerging reversal strategies, and discuss possible clinical implications, including increased prescription of DOACs, use of DOACs in clinical situations previously felt to pose too great a risk of bleeding, and use of reversal agents beyond currently approved indications.

Apixaban-Calibrated Anti-FXa Activity in Relation to Outcome Events and Clinical Characteristics in Patients with Atrial Fibrillation: Results from the AVERROES Trial.

Background In patients with nonvalvular atrial fibrillation (AF), apixaban is given in doses of 5 or 2.5 mg twice daily, according to clinical characteristics. The usual on-treatment range of apixaban drug levels, as determined by apixaban-calibrated anti-factor Xa (anti-Xa) activity, has previously been measured in small cohorts; however, the association between anti-Xa activity and clinical outcomes and the predictors of variability in anti-Xa activity have not been well studied in the AF population. Methods and Results Anti-Xa activity was measured before taking the morning dose, 3 months after enrollment in the AVERROES study using a calibrated anti-Xa assay (Rotachrom). Patients with two of the following criteria-age >80; weight <60 kg; or creatinine >133 µg/L-received 2.5 mg twice daily ( n = 145), while all others received 5 mg twice daily ( n = 2,247). A total of 2,392 patients were included, with median follow-up of 1.1 years. Median apixaban anti-Xa activity was 122 ng/mL (interquartile range [IQR]: 63-198 ng/mL) for the entire group; 99 ng/mL (IQR: 60-146 ng/mL) for the 2.5-mg group; and 125 ng/mL (IQR: 64-202 ng/mL) for the 5-mg group ( p = 0.003). A relationship was evident between bleeding and anti-Xa activity ( p = 0.01), which was driven by minor bleeding. No relationship was evident between major bleeding or stroke/systemic embolism and anti-Xa activity. In those receiving the 5-mg dose, estimated glomerular filtration rate, sex, and age had the strongest association with anti-Xa activity. Conclusion There is considerable variability in anti-Xa activity among AF patients receiving apixaban. Rates of major bleeding and stroke/systemic embolism were low irrespective of anti-Xa activity. Clinical Trial Registration ClinicalTrials.gov NCT00496769; https://clinicaltrials.gov/ct2/show/NCT00496769 .

Quantification of Cell-Free DNA in Red Blood Cell Units in Different Whole Blood Processing Methods.

Background. Whole blood donations in Canada are processed by either the red cell filtration (RCF) or whole blood filtration (WBF) methods, where leukoreduction is potentially delayed in WBF. Fresh WBF red blood cells (RBCs) have been associated with increased in-hospital mortality after transfusion. Cell-free DNA (cfDNA) is released by neutrophils prior to leukoreduction, degraded during RBC storage, and is associated with adverse patient outcomes. We explored cfDNA levels in RBCs prepared by RCF and WBF and different storage durations. Methods. Equal numbers of fresh (stored ≤14 days) and older RBCs were sampled. cfDNA was quantified by spectrophotometry and PicoGreen. Separate regression models determined the association with processing method and storage duration and their interaction on cfDNA. Results. cfDNA in 120 RBC units (73 RCF, 47 WBF) were measured. Using PicoGreen, WBF units overall had higher cfDNA than RCF units (p = 0.0010); fresh WBF units had higher cfDNA than fresh RCF units (p = 0.0093). Using spectrophotometry, fresh RBC units overall had higher cfDNA than older units (p = 0.0031); fresh WBF RBCs had higher cfDNA than older RCF RBCs (p = 0.024). Conclusion. Higher cfDNA in fresh WBF was observed compared to older RCF blood. Further study is required for association with patient outcomes.

Comparison of the Proinflammatory and Procoagulant Properties of Nuclear, Mitochondrial, and Bacterial DNA.

PURPOSE: Cell-free DNA (CFDNA) is elevated in sepsis and correlates with mortality. This DNA may come from nuclear, mitochondrial, or bacterial sources. Cell-free DNA from all three sources may play a pathogenic role in sepsis via activation of coagulation through the contact pathway, whereas CpG motifs on bacterial and mitochondrial DNA may additionally stimulate inflammatory responses via Toll-like receptor 9. This study elucidates the relative effects of nuclear, mitochondrial, and bacterial DNA on inflammatory and procoagulant pathways with relevance to sepsis. METHODS: DNA was extracted from plasma of septic patients and control subjects, and nuclear and mitochondrial CFDNA concentrations were measured by quantitative polymerase chain reaction. Viability of primary cultured human neutrophils was measured by flow cytometry for phosphatidyl serine exposure and cell permeability to propidium iodide. Continuous thrombin generation was measured with a fluorogenic substrate (Technothrombin, Vienna, Austria). Interleukin 6 secretion was measured by enzyme-linked immunosorbent assay. Platelet activation was measured by flow cytometry for P-selectin and activated αIIbß3. RESULTS: Mitochondrial DNA and nuclear DNA were elevated in plasma from septic patients compared with control subjects. Both mitochondrial and bacterial DNA prolonged neutrophil viability. Bacterial DNA increased neutrophil interleukin 6 secretion, but mitochondrial and nuclear DNA did not. Nuclear, mitochondrial, and bacterial DNA increased thrombin generation in platelet-poor plasma to a similar degree in a FXI- and FXII-dependent manner, indicating dependence on the intrinsic pathway of coagulation. Independently of coagulation, DNA from all three sources was capable of causing activation of platelet integrin αIIbß3. CONCLUSIONS: Cell-free DNA from nuclear, mitochondrial, and bacterial sources have varying proinflammatory effects, although all three have similar procoagulant and platelet-stimulating potential. The pathophysiological effects of CFDNA in sepsis may vary with the source of DNA.

Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura.

BACKGROUND: Rituximab, an anti-CD20 chimeric monoclonal antibody, has been used successfully to treat patients with relapsed or refractory thrombotic thrombocytopenic purpura (TTP); however, the optimal dose and frequency and the role of rituximab maintenance remain uncertain. STUDY DESIGN AND METHODS: We describe a 45-year-old woman with chronic relapsing immune thrombocytopenia who responded to rituximab retreatment administered in four doses over the course of 12 months. Previously, she had received four doses of rituximab and sustained a remission for 19 months. During her latest TTP relapse, multiple treatments were administered including rituximab retreatment. After the first dose (375 mg/m2), she developed serum sickness requiring further doses to be deferred. Three subsequent doses were administered at 4-month intervals over the course of 12 months. ADAMTS13 activity was measured by von Willebrand factor (VWF) digestion. ADAMTS13 inhibition was measured by a modification of the VWF digestion assay and anti-ADAMTS13 antibodies were measured by enzyme-linked immunoassay (enzyme-linked immunosorbent assay, American Diagnostica). RESULTS: Clinical and laboratory remission were achieved after one dose of rituximab, with normalization of ADAMTS13 activity and disappearance of ADAMTS13 inhibitor. Three subsequent doses of rituximab were given without incident and the patient remained in remission after 3.5 years of follow-up (2.5 years since her last dose of rituximab). CONCLUSION: Maintenance dosing of rituximab should be considered in some patients with relapsing TTP.