Sara Vazquez

Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment

Venous thromboembolism (VTE) is a serious medical condition associated with significant morbidity and mortality, and an incidence that is expected to double in the next forty years. The advent of direct oral anticoagulants (DOACs) has catalyzed significant changes in the therapeutic landscape of VTE treatment. As such, it is imperative that clinicians become familiar with and appropriately implement new treatment paradigms. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for VTE treatment with the DOACs. When possible, guidance statements are supported by existing published evidence and guidelines. In instances where evidence or guidelines are lacking, guidance statements represent the consensus opinion of all authors of this manuscript and are endorsed by the Board of Directors of the Anticoagulation Forum.The authors of this manuscript first developed a list of pivotal practical questions related to real-world clinical scenarios involving the use of DOACs for VTE treatment. We then performed a PubMed search for topics and key words including, but not limited to, apixaban, antidote, bridging, cancer, care transitions, dabigatran, direct oral anticoagulant, deep vein thrombosis, edoxaban, interactions, measurement, perioperative, pregnancy, pulmonary embolism, reversal, rivaroxaban, switching, \thrombophilia, venous thromboembolism, and warfarin to answer these questions. Non- English publications and publications > 10 years old were excluded. In an effort to provide practical information about the use of DOACs for VTE treatment, answers to each question are provided in the form of guidance statements, with the intent of high utility and applicability for frontline clinicians across a multitude of care settings.

Peri-procedural anticoagulation in patients undergoing ablation for atrial fibrillation.

Radiofrequency catheter ablation is being used with increasing frequency as a strategy to manage atrial fibrillation. Patients undergoing this procedure are at increased short-term risk of thromboembolism for several days and up to 4 weeks or longer after their ablation, and anticoagulation management surrounding the ablation procedure remains controversial. Although no conclusive recommendations can be made, published guidelines and data support therapeutic anticoagulation with warfarin for 3 weeks prior and intravenous heparin during the ablation. Warfarin may either be continued through the ablation or stopped 2-5 days prior. If the latter approach is chosen, a pre-ablation bridging strategy of enoxaparin 1mg/kg twice daily is reasonable in selected patients unless the patients bleeding risk dictates using a lower dose regimen (0.5mg/kg twice daily) or avoiding bridging altogether. Fewer data are available for post-ablation management strategies, and current practice patterns are based largely on single-center experiences in smaller, non-randomized studies. For lower risk patients (CHADS(2) 0-1), either warfarin or aspirin may be utilized without bridging. In higher thromboembolic risk patients (CHADS(2) >or=2), either enoxaparin (1mg/kg twice daily) or heparin may be started within the first 12-24h post-procedure. For patients with bleeding risk factors, enoxaparin may be subsequently reduced to 0.5mg/kg until the INR is therapeutic, although the efficacy of this lower dosing regimen has not been well studied. In accordance with national guidelines, warfarin should be continued post-ablation for a minimum of 2 months and then indefinitely in patients with a CHADS(2) score >or= 2.

Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation

We performed a randomised pilot trial of PerMIT, a novel decision support tool for genotype-based warfarin initiation and maintenance dosing, to assess its efficacy for improving warfarin management. We prospectively studied 26 subjects to compare PerMIT-guided management with routine anticoagulation service management. CYP2C9 and VKORC1 genotype results for 13 subjects randomly assigned to the PerMIT arm were recorded within 24 hours of enrolment. To aid in INR interpretation, PerMIT calculates estimated loading and maintenance doses based on a patients genetic and clinical characteristics and displays calculated S-warfarin plasma concentrations based on planned or administered dosages. In comparison to control subjects, patients in the PerMIT study arm demonstrated a 3.6-day decrease in the time to reach a stabilised INR within the target therapeutic range (4.7 vs. 8.3 days, p = 0.015); a 12.8% increase in time spent within the therapeutic interval over the first 25 days of therapy (64.3% vs. 55.3%, p = 0.180); and a 32.9% decrease in the frequency of warfarin dose adjustments per INR measurement (38.3% vs. 57.1%, p = 0.007). Serial measurements of plasma S-warfarin concentrations were also obtained to prospectively evaluate the accuracy of the pharmacokinetic model during induction therapy. The PerMIT S-warfarin plasma concentration model estimated 62.8% of concentrations within 0.15 mg/l. These pilot data suggest that the PerMIT method and its incorporation of genotype/phenotype information may help practitioners increase the safety, efficacy, and efficiency of warfarin therapeutic management.

Azathioprine-Induced Warfarin Resistance

OBJECTIVE To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin-azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY A 29-year-old female with Cogans syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patients warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966-December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin-azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75-200 mg daily. CONCLUSIONS This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment, and close INR monitoring in patients receiving azathioprine or its active metabolite, 6-mercaptopurine.

Advances in the diagnosis and management of postthrombotic syndrome

Postthrombotic syndrome (PTS) is a frequent long-term complication of deep vein thrombosis (DVT). Known risk factors include obesity, recurrent ipsilateral DVT, iliofemoral DVT, persistent symptoms one month after DVT diagnosis, and having subtherapeutic INRs greater than 50% of the time during the first few months on anticoagulant therapy. Other risk factors remain under investigation. The Villalta scale ranks the presence and severity of signs and symptoms of PTS. Preventive therapies include use of elastic compression stockings. Compression therapy is also used to treat PTS, in addition to wound care for associated venous ulcers, and herbal therapies for postthrombotic ulcers and edema. Though not well studied, there are surgical options for severe cases of PTS refractory to other treatments. Ongoing clinical trials should provide insight on risk factors, and interventions for PTS prevention and treatment. In particular, use of early thrombolysis for acute iliofemoral DVT to prevent PTS is currently being investigated.

Contemporary Issues in the Prevention and Management of Postthrombotic Syndrome

Objective: To provide an evidence-based review and clinical summary of postthrombotic syndrome (PTS). Data Sources: A literature review was performed via MEDLINE (1950–July 1, 2009) and International Pharmaceutical Abstracts (1970–June 2009) searches using the terms post-thrombotic syndrome, post-phlebitic syndrome, deep vein thrombosis, and compression stockings. Data Synthesis: PTS is best characterized as a chronic syndrome of clinical signs and symptoms including pain, swelling, parasthesias, and ulceration in the affected limb following deep vein thrombosis (DVT). It occurs in up to hall of patients with symptomatic DVT, usually within the first 2 years. Although the pathophysiology of PTS is not well understood, a thrombus may cause venous hypertension and valvular incompetence resulting in edema, tissue hypoxia, and in severe cases, ulceration. Risk factors for PTS include recurrent ipsilateral DVT, obesity, and poor quality of anticoagulant therapy. PTS diagnosis is based on the presence of typical signs and symptoms and may be made using one of several clinical scoring systems. Prevention of PTS should focus on DVT prevention and the use of elastic compression stockings following DVT, while fibrinolysis remains under investigation as an effective method for PTS prevention. The treatment of PTS may include either pharmacologic or mechanical modalities, although none of these regimens has been rigorously tested. Pharmacists have the opportunity to provide more comprehensive antithrombotic management by educating patients and providers on PTS, recommending appropriate preventive therapy, assisting patients in obtaining and adhering to this therapy, and assisting providers with the management of PTS. Conclusions: Providers should be proactive in preventing PTS, with pharmacists taking an active role in optimal DVT prevention, identifying patients at risk for PTS, and counseling and directing preventive therapies.

Current State of Anticoagulants to Treat Deep Venous Thrombosis

Anticoagulation remains the cornerstone of treatment in patients with deep vein thrombosis (DVT). While parenteral anticoagulants and oral vitamin K antagonists (e.g., warfarin) have been used for many decades, the recent development of novel oral anticoagulants have provided clinicians with an expanding set of therapeutic options for DVT. This review summarizes the pharmacology and clinical trial results of these new oral anticoagulants. Several practical considerations to the use of these oral anticoagulants including issues related to adherence, monitoring, and reversal are also discussed.

Current challenges in personalizing warfarin therapy

In an exciting era where novel oral anticoagulants, such as the factor Xa and direct thrombin inhibitors, are beginning to emerge as therapeutic options, the vitamin K antagonists (VKAs) such as warfarin, which have been in clinical use for over half a century, will remain an important part of the therapeutic landscape for the foreseeable future. The optimal effectiveness and safety of the VKAs is limited by significant inter- and intra- patient variability in dose response. As such, routine laboratory monitoring with subsequent dose adjustment to achieve and maintain an international normalized ratio (INR) that falls within a narrow therapeutic range is necessary; even with frequent INR monitoring, time in therapeutic range of VKAs is generally <60% in usual care settings. Yet, personalized approaches to warfarin therapy, such as the routine incorporation of pharmacogenetic data into dose selection and adjustment, the selective use of prescribed doses of vitamin K for those patients with unstable INRs, and integration of patient self-testing /self-management, has the potential to improve the safety, efficacy and ease of use of warfarin. To date, no randomized trials have proven the benefits of routine pharmacogenetic testing for warfarin initiation; however, pivotal trials are ongoing. Through further investigative work, allowing these personalized strategies to realize their full potential, warfarin may remain a preferred therapeutic oral anticoagulant for years to come.

Correction factor to improve agreement between point-of-care and laboratory International Normalized Ratio values

PURPOSE Results of a research project to quantify and improve the accuracy of point-of-care (POC) International Normalized Ratio (INR) values are reported. METHODS The accuracy of POC INR values relative to laboratory-measured INR values was retrospectively assessed in a cohort of patients with same-day INR determinations by both methods. Univariate linear regression was performed to derive a correction factor for POC INR values of >3; this correction factor was validated in a second cohort. RESULTS In the derivation cohort (259 patients and 344 paired INR results), agreement of POC values with corresponding laboratory INR values at two specified thresholds (±15% and ±25%) was 51.2% and 66.6%, respectively; for POC INR values of >3 (n = 205), agreement was lower (24.9% and 44.9%, respectively). Univariate linear regression yielded a coefficient of 0.77 (95% confidence interval, 0.76-0.79; p < 0.001). Applying a correction factor of 0.8 to POC INR values in a validation cohort (169 patients and 209 paired INR values) significantly improved the accuracy of POC INR values of >3 relative to laboratory values (from 7% to 71.1% at the lower threshold and from 23.5% to 88.8% at the higher threshold, p < 0.0001 for both comparisons). CONCLUSION Agreement between POC and laboratory INR results in one institution was poor, especially when POC INR values exceeded 3. Application of an institution-specific correction factor to POC INR values of >3 improved agreement with laboratory INR results but would not have significantly reduced differences in protocol-based warfarin dosage adjustments.

Patterns and Appropriateness of Thrombophilia Testing in an Academic Medical Center

BACKGROUND: Clinical guidelines recommend against routine use of thrombophilia testing in patients with acute thromboembolism. Thrombophilia testing rarely changes acute management of a thrombotic event. OBJECTIVE: To determine appropriateness of thrombophilia testing in a teaching hospital. DESIGN: Retrospective cohort study. SETTING: One academic medical center in Utah. PARTICIPANTS: All patients who received thrombophilia testing between July 1, 2014, and December 31, 2014. MAIN MEASUREMENTS: Proportion of thrombophilia tests occurring in situations associated with minimal clinical utility, defined as tests meeting at least 1 of the following criteria: discharged before results available; test type not recommended; testing in situations associated with decreased accuracy; duplicate testing; and testing following a provoked thrombotic event. RESULTS: Overall, 163 patients received a total of 1451 thrombophilia tests for stroke (50% of tests; 35% of patients), venous thromboembolism (21% of tests; 21% of patients), and pregnancy‐related conditions (15% of tests; 25% of patients). Of the 39 different test types performed, the most common were cardiolipin IgG and IgM antibodies (9% each), lupus anticoagulant (9%), and &bgr;2‐glycoprotein 1 IgG and IgM antibodies (8% each). In total, 911 tests (63%) were performed in situations associated with minimal clinical utility, with 126 patients (77%) receiving at least one such test. Only 2 patients (1%) had clear documentation of being offered genetic consultation. CONCLUSIONS: Thrombophilia testing in this single‐center study was often associated with minimal clinical utility. Strategies to improve testing practices (eg, hematology specialty consult prior to inpatient testing, improved order panels) might help minimize inappropriate testing and promote value‐driven care.