Approaches to Precision-based Anticoagulation management in the critically Ill.

Anticoagulant therapy is commonly associated with a high incidence of avoidable adverse events, especially in the acute care setting. This has led to several initiatives by key national health care stakeholders, including specific attention to The Joint Commission's National Patient Safety Goals, to improve anticoagulation management. The subject of special populations has long been identified as challenging by clinicians with the use of anticoagulants. This is driven in part by numerous variables that can contribute to hard outcomes such as bleeding, thrombosis, length of stay, hospital re-admission, morbidity, and mortality. Despite the notable effort to improve the use of anticoagulants with numerous clinical trials, guidelines, guidance statements, and other sources of published evidence, notable difficulties continue to challenge practitioners in managing this class of medications. This is especially the case with very diverse critically ill populations where countless variables exist, many of which were never explored in trials or have historically been frequently excluded. Trials evaluating anticoagulation therapy often can only account for small portions of variables that may affect thrombosis and hemostasis, and study methods often do not reflect the constantly changing dynamic conditions seen in unique critically ill patients. Clinicians providing care to the numerous critically ill populations are faced with conditions that lead to relatively small therapeutic windows, which makes designing safe optimal anticoagulation management plans difficult when dealing with complex patients and mechanical support devices. The approach to crafting a successful management plan for anticoagulant therapy must incorporate the numerous variables that are continuously assessed and revised during the patient's time in the intensive care unit. We explore considerations and approaches when developing, assessing, and implementing an individualized or precision-based management plan that involves the use of anticoagulants in the critically ill. The skills and thought process provided will assist clinicians in managing this unique, variable, and challenging population.

Evaluation of safety and efficacy outcomes of direct oral anticoagulants versus warfarin in normal and extreme body weights for the treatment of atrial fibrillation or venous thromboembolism.

Despite evolving evidence, the use of direct oral anticoagulants (DOACs) in patients with extremes of body weight remains controversial. This study aimed to measure the impact of DOACs compared to warfarin on safety and efficacy outcomes in extreme body weight patients. This multi-center, health system, retrospective study examined the outcomes of patients with all body weights and extreme body weights prescribed a DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) or warfarin for atrial fibrillation or venous thromboembolism over a 9-year period. The primary outcome was a composite of thromboembolism, symptomatic recurrent VTE, or severe bleeding; analyzed by pre-determined BMI cutoffs. A total of 19,697 patients were included in the study: 11,604 in the DOAC group and in the 8093 in the warfarin group. 295 patients were underweight and 9108 patients were pre-obese to obese class 3. After adjusting for potential confounders, warfarin patients had higher odds of experiencing the composite outcome compared to DOAC patients (OR 1.337, 95% CI 1.212-1.475). Additionally, obese patients were 24.6% more likely to experience the outcome compared to normal BMI patients. Adjusted modeling showed that warfarin patients experienced higher bleed rates compared to DOAC patients (OR 1.432, 95% CI 1.266-1.620). Obese patients were less likely to be diagnosed with a bleed (OR 0.749, 95% CI 0.658-0.854), and underweight patients were more likely to be diagnosed with a bleed (OR 1.522, 95% CI 1.095-2.115) compared to normal BMI patients. In conclusion, DOACs for atrial fibrillation or VTE in patients with extreme body weights appear safe and effective when compared to warfarin.

Evaluation of the Clinical Impact of Thromboprophylaxis in Patients With COVID-19 Following Hospital Discharge.

BACKGROUND: Data are limited regarding the incidence of thromboembolism post-hospital discharge among COVID-19 patients. Guidelines addressing the role of extended thromboprophylaxis for COVID-19 patients are limited and conflicting. OBJECTIVE: The purpose of this study was to evaluate the incidence of post-discharge thromboembolic and bleeding events and the role of thromboprophylaxis among COVID-19 patients. METHODS: A retrospective analysis was conducted of hospitalized patients with symptomatic COVID-19 infection who were discharged from a University of Colorado Health (UCHealth) hospital between March 1, 2020, and October 31, 2020. The primary outcome was objectively confirmed thromboembolism within 35 days post-discharge. The main secondary outcome was the incidence of bleeding events within 35 days post-discharge. Outcomes were compared between those who received extended prophylaxis and those who did not. RESULTS: A total of 1171 patients met the study criteria. A total of 13 (1.1%) of patients had a documented thromboembolic event and 10 (0.9%) patients had a documented bleeding event within 35 days post-discharge. None of the 132 patients who received extended prophylaxis had a thromboembolic event compared to 13 of 1039 who did not receive extended prophylaxis (0 and 1.3%, respectively; P = .383). The incidence of bleeding was higher among patients who received extended prophylaxis compared to those who did not (3.0% vs 0.6%, P = .019). CONCLUSIONS AND RELEVANCE: These results suggest that post-discharge extended prophylaxis may be beneficial for select COVID-19 patients, while carefully weighing the risk of bleeding. Application of our findings may assist institutions in development of thromboprophylaxis protocols for discharged COVID-19 patients.

Evaluation of a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol in hospitalized patients with COVID-19.

Patients with COVID-19 are at higher risk of thrombosis due to the inflammatory nature of their disease. A higher-intensity approach to pharmacologic thromboprophylaxis may be warranted. The objective of this retrospective cohort study was to determine if a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol incorporating severity of illness, weight, and biomarkers decreased incidence of thrombosis in hospitalized patients with COVID-19. Included patients were hospitalized with COVID-19 and received thromboprophylaxis within 48 h of admission. Exclusion criteria included receipt of therapeutic anticoagulation prior to or within 24 h of admission, history of heparin-induced thrombocytopenia, extracorporeal membrane oxygenation, pregnancy, or incarceration. Per-protocol patients received thromboprophylaxis according to institutional protocol involving escalated doses of anticoagulants based upon severity of illness, total body weight, and biomarker thresholds. The primary outcome was thrombosis. Secondary outcomes included major bleeding, mortality, and identification of risk factors for thrombosis. Of 1189 patients screened, 803 were included in the final analysis. The median age was 54 (42-65) and 446 (55.5%) were male. Patients in the per-protocol group experienced significantly fewer thrombotic events (4.4% vs. 10.7%, p = 0.002), less major bleeding (3.1% vs. 9.6%, p < 0.001), and lower mortality (6.3% vs. 11.8%, p = 0.02) when compared to patients treated off-protocol. Significant predictors of thrombosis included mechanical ventilation and male sex. Post-hoc regression analysis identified mechanical ventilation, major bleeding, and D-dimer ≥ 1500 ng/mL FEU as significant predictors of mortality. A targeted pharmacologic thromboprophylaxis protocol incorporating severity of illness, body weight, and biomarkers appears effective and safe for preventing thrombosis in patients with COVID-19.

Optimizing anticoagulation for patients receiving Impella support.

Anticoagulation of patients treated with the Impella percutaneous mechanical circulatory support (MCS) devices is complex and lacks consistency across centers, potentially increasing the risk of complications. In order to optimize safety and efficacy, an expert committee synthesized all available evidence evaluating anticoagulation for patients receiving Impella support in order to provide consensus recommendations for the management of anticoagulation with these devices. The evidence synthesis led to the creation of 42 recommendations to improve anticoagulation management related to the use of the Impella devices. Recommendations address purge solution management, intravenous anticoagulation, monitoring, evaluation and management of heparin-induced thrombocytopenia (HIT), and management during combination MCS support. The use of a heparinized, dextrose-containing purge solution is critical for optimal device function, and a bicarbonate-based purge solution may be an alternative in certain situations. Likewise, intravenous (ie, systemic) anticoagulation with heparin is often necessary, although evidence supporting the optimal assay and target range for monitoring the level of anticoagulation is generally lacking. Patients treated with an Impella MCS device may develop HIT, which is more difficult to evaluate and treat in this setting. Lastly, the use of Impella with extracorporeal membrane oxygenation or for biventricular support creates additional anticoagulation challenges.

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding.

The aim of this retrospective study was to compare andexanet alfa and 4-factor prothrombin complex (4F-PCC) for reversal of factor Xa (FXa)-inhibitor bleeding. Patients that received andexanet alfa for reversal were included. An equivalent number of patients administered 4F-PCC for FXa-inhibitor bleeding were randomly selected as historical controls. The primary outcome was effective hemostasis achievement within 12 h, defined using ANNEXA-4 criteria. Thromboembolic events and mortality within 30 days were also evaluated. A total of 32 patients were included. Baseline characteristics were not statistically different between andexanet alfa (n = 16) and 4F-PCC (n = 16). Intracranial bleeding was the primary reversal indication in 43.8% versus 62.5% of patients, respectively. Effective hemostasis was reached in 75.0% of andexanet alfa patients compared to 62.5% of 4F-PCC patients (P = .70). Thromboembolic events occurred in 4 (25.0%) patients and 3 (18.8%) patients, respectively (P = .99). Mortality incidence was 12.5% and 31.3%, respectively (P = .39). Andexanet alfa and 4F-PCC attained hemostasis in a majority of patients. A high, but a similar rate of thromboembolic events was seen with both treatments. Prospective studies are needed to elucidate comparative risks and benefits of the 2 agents.

Multi-centered evaluation of a novel fixed-dose four-factor prothrombin complex concentrate protocol for warfarin reversal.

INTRODUCTION: Previous studies have shown fixed-dose 4PCC to be as effective as standard-dose 4PCC for warfarin reversal. However, certain patient populations such as those with high total body weight (TBW) or elevated baseline INR may be at increased risk for treatment failure. The purpose of this study was to validate the efficacy of a novel fixed-dose 4PCC protocol for warfarin reversal. METHODS: This was a multi-centered observational comparison of patients who received 4PCC for warfarin reversal. Fixed-dose patients received 1500 units of 4PCC with the dose increased to 2000 units in patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or for intracranial hemorrhage (ICH). Standard-dosing followed manufacturer recommendations. The primary outcome was achievement of a post-4PCC INR of ≤1.4. Secondary outcomes included target INR achievement among patients with a baseline INR ≥ 7.5, a TBW ≥ 100 kg, or neurologic bleeding indications; hospital length of stay; cost of therapy; and thromboembolic complications. RESULTS: A total of 116 patients were included in the standard-dose group and 75 in the fixed-dose group. There was no difference in the primary outcome (65% vs 57%, p = 0.32). There was no difference in secondary outcomes aside from cost of therapy in which fixed-dose 4PCC was less expensive than standard-dose 4PCC. CONCLUSION: A fixed-dose 4PCC regimen for warfarin reversal of 1500 units, with an increased dose of 2000 units for select patients, is as effective as standard-dose 4PCC for INR reversal.

Coagulopathy, Venous Thromboembolism, and Anticoagulation in Patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic, and patients with the infection are referred to as having COVID-19. Although COVID-19 is commonly considered a respiratory disease, there is clearly a thrombotic potential that was not expected. The pathophysiology of the disease and subsequent coagulopathy produce an inflammatory, hypercoagulable, and hypofibrinolytic state. Several observational studies have demonstrated surprisingly high rates of venous thromboembolism (VTE) in both general ward and intensive care patients with COVID-19. Many of these observational studies demonstrate high rates of VTE despite patients being on standard, or even higher intensity, pharmacologic VTE prophylaxis. Fibrinolytic therapy has also been used in patients with acute respiratory distress syndrome. Unfortunately, high quality randomized controlled trials are lacking. A literature search was performed to provide the most up-to-date information on the pathophysiology, coagulopathy, risk of VTE, and prevention and treatment of VTE in patients with COVID-19. These topics are reviewed in detail, along with practical issues of anticoagulant selection and duration. Although many international organizations have produced guidelines or consensus statements, they do not all cover the same issues regarding anticoagulant therapy for patients with COVID-19, and they do not all agree. These statements and the most recent literature are combined into a list of clinical considerations that clinicians can use for the prevention and treatment of VTE in patients with COVID-19.

Dual Antiplatelet Therapy for Long-term Secondary Prevention of Atherosclerotic Cardiovascular Events.

PURPOSE: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is currently recommended to prevent further ischemic events after percutaneous coronary intervention and acute coronary syndrome (ACS). Guidelines currently recommend a minimum of 6 months after elective drug-eluting stent placement and at least 12 months of DAPT after ACS; however, the benefits of prolonged treatment are unclear. The purpose of this review was to conduct a detailed examination of the data refuting or supporting the use of DAPT beyond 1 year in patients with ACS and in patients receiving percutaneous coronary intervention with stenting. METHODS: A search of PubMed was performed to identify articles published in the last 20 years that addressed the role of DAPT beyond 12 months' duration. FINDINGS: A number of studies have shown ischemic benefits associated with prolonging DAPT beyond 12 months, but this finding is dependent on the patient population studied and the quality of the study design. Many studies also show that longer duration therapy has been associated with increased bleeding risk. In patients with previous myocardial infarction completing at least 1 year of DAPT, continuing DAPT with a reduced dose of ticagrelor 60 mg BID is a regimen to be considered for these patients; in general ACS patients, a reduced dose of 60 mg BID of ticagrelor after the first year of DAPT should be considered; and in the post-percutaneous coronary intervention patients, DAPT beyond 1 year should be considered after careful evaluation of the patient's thrombotic and bleeding risks. IMPLICATIONS: The duration of DAPT, and the choice of P2Y12 inhibitor, should be tailored to the individual patient. To optimize patient outcomes, the benefits and risks associated with prolonging DAPT need to be evaluated, considering comorbidities and the presence of bleeding and ischemic risk factors. Despite some limitations, risk scores, such as the DAPT score, are available to help guide decisions for the best approach for each patient.

Evaluation of intravenous direct thrombin inhibitor monitoring tests: Correlation with plasma concentrations and clinical outcomes in hospitalized patients.

The parenterally administered direct thrombin inhibitors (DTIs) argatroban and bivalirudin are effective anticoagulants for acute heparin-induced thrombocytopenia (HIT) treatment. The activated partial thromboplastin time (aPTT) has classically been used as the monitoring test to assess degree of anticoagulation, however concerns exist with using aPTT to monitor DTI therapy. In this observational study plasma samples from DTI treated patients were analyzed by aPTT, dilute thrombin time (dTT) and ecarin chromogenic assay (ECA) to delineate results into concordant and discordant groups. Discordant samples were further analyzed via liquid chromatography with tandem mass spectrometry (LC MS/MS). In total 101 patients with 198 samples were evaluated. Discordance between tests were frequent (59% of DTI treated patients). Bivalirudin aPTT vs dTT discordance was observed in 45% (57/126) of samples. Amongst bivalirudin samples with test discordance dTT results were more likely to be concordant with LC MS/MS than the aPTT (77% vs 9%, p < 0.0001). Argatroban aPTT vs dTT discordance was observed in 43% (31/72) and aPTT vs ECA discordance was observed in 40% (29/72) of samples. Amongst argatroban samples with test discordance both the dTT and ECA tests were more likely to have concordant results with LC MS/MS than the aPTT (88% vs 9%, p < 0.0001 for both dTT and ECA tests). There were no differences between discordant and concordant patient groups in a composite outcome of bleeding/thrombosis rate (23% vs 27%, p = 0.689). Further investigation is warranted to elucidate the effect of suitable monitoring assays on patient outcomes in the setting of DTI therapy.

Antidotes for reversal of direct oral anticoagulants.

The main advantage of the direct oral anticoagulants over vitamin K antagonists is reduced rates of major bleeding, especially intracranial hemorrhage. While use of different clotting factor supplements have been used in patients with direct oral anticoagulant induced major bleeding or when there is need for urgent surgery, the lack of preclinical and clinical data are concerning. Idarucizumab is a specific antibody developed with a 350-fold greater affinity for dabigatran than its pharmacologic target thrombin. Andexanet is a modified factor Xa molecule that binds the direct and indirect Xa inhibitors without being enzymatically active. Ciraparantag, has potential to reverse the anticoagulant activity of multiple agents. The pharmacology, preclinical, and clinical data that have developed these specific antidotes are reviewed in this manuscript.

Contemporary Management of Direct Oral Anticoagulants During Cardioversion and Ablation for Nonvalvular Atrial Fibrillation.

As overall prevalence of atrial fibrillation (AF) continues to rise, the number of patients who undergo ablation, or electrical/chemical cardioversion, to restore normal sinus rhythm continues to increase as well. As direct oral anticoagulants (DOACs) have continued to be incorporated into clinical practice for long-term anticoagulation for AF, experience with how best to manage use of DOACs during electrophysiologic procedures is evolving. This review is intended to provide health care providers with a summary of current evidence regarding the use of DOACs during cardioversion and catheter ablation and provide key considerations for their use during such electrophysiologic procedures. PubMed and MEDLINE were searched from inception through June 2018 for studies in humans comparing DOACs alone or against vitamin K antagonists (VKAs) in adult patients (> 18 yrs) who underwent cardioversion or AF catheter ablation using the following key words: "rivaroxaban," "dabigatran," "apixaban," "edoxaban," "non-vitamin K antagonists," "direct or new oral anticoagulants," "warfarin," "vitamin K antagonists," "cardioversion," "ablation of atrial fibrillation," "uninterrupted," and "catheter ablation." Four retrospective studies and three prospective trials comparing DOACs with VKA in patients undergoing cardioversion and three prospective studies in patients undergoing catheter ablation for AF were identified. Observational data and meta-analyses were also critically reviewed. Prospective trials to date suggest similar efficacy and safety with using DOACs in the setting of cardioversion and AF ablation compared to traditional therapy with VKA, with or without bridging. Injectable anticoagulant overlap can be avoided in patients receiving DOACs in the setting of cardioversion for AF. Minimal interruption in anticoagulation may be only necessary for AF ablation in those with highest bleeding risk, such as in renal dysfunction and where drug-drug interactions may increase risk for anticoagulant accumulation. Periprocedural advantages of DOACs include convenience, rapid and predictable onset of effect, improved patient satisfaction, and potential for reduced costs.

Periprocedural Management of Direct Oral Anticoagulants Surrounding Cardioversion and Invasive Electrophysiological Procedures.

As direct oral anticoagulants (DOACs) have demonstrated favorable efficacy and safety outcomes compared with vitamin K antagonists for the treatment and prevention of venous thromboembolism and the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, their role in the management of anticoagulation during electrophysiological procedures continues to evolve. At present, guidelines are limited regarding specific recommendations for the use of DOACs in these clinical settings. Here, we review available data regarding the risks and benefits associated with various periprocedural anticoagulation management approaches when patients receiving DOACs undergo electrophysiologic procedures including cardioversion, ablation, and device implantation. This discussion is intended to provide clinicians with an overview of available evidence and best practices to minimize the risk of both thromboembolic and bleeding events in the periprocedural setting.

Management of Venous Thromboembolism: Recent Advances in Oral Anticoagulation Therapy.

OBJECTIVE: To review clinical data on direct oral anticoagulants (DOACs) used in the acute treatment of venous thromboembolism (VTE) as well as practical considerations when using these products. DATA SOURCES: Searches of PubMed and Google Scholar for VTE, deep vein thrombosis, pulmonary embolism, and relevant drug international nonproprietary names were conducted. Additional online searches were conducted for prescribing information. STUDY SELECTION AND DATA EXTRACTION: Relevant articles on dabigatran, rivaroxaban, apixaban, and edoxaban for the management of VTE compared with oral vitamin K antagonists (VKAs; published between 1966 and December 2015) were reviewed and summarized, together with information on dosing, pharmacokinetics/pharmacodynamics, and drug-drug interactions. DATA SYNTHESIS: The DOACs have the potential to circumvent many of the disadvantages of VKAs. At a minimum, they greatly increase the available therapeutic options, thus providing a greater opportunity for clinicians to select a management option that best fits the needs of individual patients. Despite the significant advance that DOACs represent, they are not without risk and require careful consideration of a number of clinical issues to optimize safety and efficacy. CONCLUSIONS: The emergence of DOACs for the management of thromboembolic disorders represents a paradigm shift from oral VKAs. The DOACs provide similar efficacy and improved safety in selected patients as compared with VKAs. Clinicians treating VTE need to be familiar with the intricacies involved in using these agents, including the appropriate dose selection for the relevant indication, avoidance of drug-drug and drug-disease interactions, and consideration of dose adjustments in specific clinical situations, such as organ dysfunction.

The Impact of a Standalone, Patient-centered Communication Course Series on Student Achievement, Preparedness, and Attitudes.

Objective. To evaluate the impact of a standalone, patient-centered communication (PCC) course series on student achievement of and perceived preparedness for PCC skills and to assess student attitudes regarding learning methods used. Design. During curriculum renewal, a standalone PCC course series that integrated horizontally and vertically within the curriculum was developed. Student achievement of outcomes was evaluated by aggregate performance on simulated evaluations. Students who completed the PCC series were surveyed to assess preparedness and attitudes. Students in the prior curriculum were also surveyed. Assessment. The majority of students who completed the PCC series met or exceeded expectations for the simulated evaluations. Preparedness responses were more positive from students who completed the PCC series than from those who completed the prior curriculum. Student attitudes about the learning methods use in the courses also were more positive. Conclusion. The standalone PCC course series effectively achieved PCC outcomes and improved student preparedness for communication-based activities.

When patients on target-specific oral anticoagulants need surgery.

The target-specific oral anticoagulants (TSOACs), eg, dabigatran, rivaroxaban, and apixaban, are changing the way we manage thromboembolic disease. At the same time, many clinicians wonder how best to manage TSOAC therapy when patients need surgery. An in-depth understanding of these drugs is essential to minimize the risk of bleeding and thrombosis perioperatively.

Antithrombotic therapy in patients with thrombocytopenic cancer: outcomes associated with reduced-dose, low-molecular-weight heparin during hospitalization.

BACKGROUND: Guidelines are discordant concerning management of patients having thrombocytopenia with cancer-associated thrombosis (CAT). METHODS: Hospitalized adults with CAT and platelets ≤50 × 10(9) cells/L were managed with dalteparin 100 units/kg subcutaneously once daily. Comparator patients with CAT and platelets >50 × 10(9) cells/L were managed with dalteparin 200 units/kg/d. RESULTS: Outcomes of 35 patients with thrombocytopenia (mean platelet count 26 ± 8.3 × 10(9) cells/L) and 58 comparator patients (mean platelet count 155 ± 75 × 10(9) cells/L) were evaluated. In all, 2 (5.7%) patients in the thrombocytopenia group and 1 patient (1.9%) in the comparator group experienced new-onset venous thromboembolism (odds ratio 3.31, 95% confidence interval [CI] 0.29-37.90, P = .556). The incidence of bleeding in patients with thrombocytopenia (8.6%) was similar to that in comparator patients (9.4%; risk ratio 0.94, 95% CI 0.37-2.39, P = .607). CONCLUSION: In hospitalized patients having thrombocytopenia with CAT, reduced-dose low-molecular-weight heparin was generally efficacious.

Educational outcomes necessary to enter pharmacy residency training.

It is the position of the American College of Clinical Pharmacy (ACCP) that formal postgraduate residency training, or equivalent experience, is required to enter direct patient care practice. Therefore, it is important to align professional degree educational outcomes with the knowledge, skills, and attitudes needed to enter residency training. This position statement addresses the outcomes necessary in the professional degree program curriculum to ensure the ability of pharmacy graduates to transition effectively into postgraduate year one residency training. Five key outcome areas are identified: communication, direct patient care, professionalism, research, and practice management. The position statement examines how performance in each of the five outcome areas should be addressed by professional degree programs. The ACCP believes that for the student to achieve the clinical proficiency necessary to enter residency training, the professional degree program should emphasize, assess, and provide adequate opportunities for students to practice: communication with patients, caregivers, and members of the health care team in direct patient care environments; provision of direct patient care in a wide variety of practice settings, especially those involving patient-centered, team-based care; professionalism under the supervision and guidance of faculty and preceptors who model and teach the traits of a health care professional; application of principles of research that engender an appreciation for the role of research and scholarship in one's professional development; and application of practice management, including documentation of direct patient care activities that affect drug-related outcomes.