Ann K. Wittkowsky

Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND The objective of this article is to summarize the published literature concerning the pharmacokinetics and pharmacodynamics of oral anticoagulant drugs that are currently available for clinical use and other aspects related to their management. METHODS We carried out a standard review of published articles focusing on the laboratory and clinical characteristics of the vitamin K antagonists; the direct thrombin inhibitor, dabigatran etexilate; and the direct factor Xa inhibitor, rivaroxaban RESULTS The antithrombotic effect of each oral anticoagulant drug, the interactions, and the monitoring of anticoagulation intensity are described in detail and discussed without providing specific recommendations. Moreover, we describe and discuss the clinical applications and optimal dosages of oral anticoagulant therapies, practical issues related to their initiation and monitoring, adverse events such as bleeding and other potential side effects, and available strategies for reversal. CONCLUSIONS There is a large amount of evidence on laboratory and clinical characteristics of vitamin K antagonists. A growing body of evidence is becoming available on the first new oral anticoagulant drugs available for clinical use, dabigatran and rivaroxaban.

An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients

The objective of this study was to assess the relative influence of VKORC1 and CYP2C9 genetic variants on several clinical outcomes related to warfarin treatment. We conducted a retrospective cohort analysis of 172 anticoagulation clinic patients followed from warfarin initiation. We assessed the following clinical outcomes: time to stable dose; time in, above, and below therapeutic range; the probability of overanticoagulation (international normalized ratio [INR] >5); frequency of anticoagulation clinic visits; and the contribution of genetics to maintenance dose. Patients with CYP2C9 variants, compared to those without, achieved stable dose 48% later (p < 0.01), spent a higher proportion of time above range in the first month of therapy (14% vs. 25%, p = 0.07), and had a higher odds ratio (OR) of an INR >5 (OR: 4.15, p = 0.03). In contrast, the only statistically significant effect with VKORC1 was a higher odds of an INR >5 (OR: 4.47, p = 0.03) for patients homozygous for the VKORC1 low-dose haplotype (AA) compared to heterozygotes. We did not detect an influence of CYP2C9 nor VKORC1 on the frequency of clinic visits. CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of the variation in warfarin maintenance dose. In conclusion, genetic variation in VKORC1 appears to have a different influence than CYP2C9 on anticoagulation-related outcomes such as bleeding events and time in therapeutic range. This difference may be due, in part, to pharmacokinetics factors (e.g. drug half-life), which are influenced primarily by CYP2C9; these findings should be confirmed in additional studies.

Delivery of Optimized Anticoagulant Therapy: Consensus Statement from the Anticoagulation Forum

Objective: To provide recommendations, policies, and procedures pertaining to the provision of optimized anticoagulation therapy designed to achieve desired clinical endpoints while minimizing the risk of anticoagulant-related adverse outcomes (principally bleeding and thrombosis). Study Selection and Data Extraction: Due to this documents scope, the medical literature was searched using a variety of strategies. When possible, recommendations are supported by available evidence; however, because this paper deals with processes and systems of care, high-quality evidence (eg, controlled trials) is unavailable. In these cases, recommendations represent the consensus opinion of all authors who constitute the Board of Directors of The Anticoagulation Forum, an organization dedicated to optimizing anticoagulation care. The Board is composed of physicians, pharmacists, and nurses with demonstrated expertise and significant collective experience in the management of patients receiving anticoagulation therapy. Data Synthesis: Recommendations for delivering optimized anticoagulation therapy were developed collaboratively by the authors and are summarized in 9 key areas: (I) Qualifications of Personnel, (II) Supervision, (III) Care Management and Coordination, (IV) Documentation. (V) Patient Education, (VI) Patient Selection and Assessment, (VII) Laboratory Monitoring, (VIII) Initiation and Stabilization of Warfarin Therapy, and (IX) Maintenance of Therapy. Recommendations are intended to inform the development of care systems containing elements with demonstrated benefit in improvement of anticoagulation therapy outcomes. Recommendations for delivering optimized anticoagulation therapy are intended to apply to all clinicians involved in the care of outpatients receiving anticoagulation therapy, regardless of the structure and setting in which that care is delivered. Conclusions: Anticoagulation therapy, although potentially life-saving, has inherent risks. Whether a patient is managed in a solo practice or a specialized anticoagulation management service, a systematic approach to the key elements outlined herein will reduce the likelihood of adverse events. The need for continued research to validate optimal practices for managing anticoagulation therapy is acknowledged.

Frequency and causes of overanticoagulation and underanticoagulation in patients treated with warfarin.

Study Objective. To determine the frequency and the specific causes of over‐and underanticoagulation in patients who receive warfarin therapy and are managed in an anticoagulation clinic.

Frequency of Concurrent Use of Warfarin with Potentially Interacting Drugs

Study Objective. To determine the rates of concomitant use of drugs known to interact with warfarin by increasing the prothrombin time expressed as the international normalized ratio (INR), decreasing the INR, or increasing bleeding risk without apparent changes in INR in a cohort of patients receiving long‐term warfarin therapy.

Drug Interactions Update: Drugs, Herbs, and Oral Anticoagulation

Management of warfarin drug interactions is often complicated by lack of information regarding interactions with new drugs and with herbal medicinals. The pharmaceutical industry has increased both the number and quality of drug interaction studies prior to marketing new agents. Interactions may still occur in patients, however, despite negative pre-marketing studies in healthy volunteers. The clinical significance and intensity of warfarin interactions with prescription drugs (e.g., celecoxib, proton pump inhibitors, and selective serotonin reuptake inhibitors) can often be predicted on the basis of known metabolic characteristics of the drugs and warfarin enantiomers. Drug interactions with herbal medicinals are much more difficult to characterize and predict because of the lack of federal regulations regarding safety, efficacy, and manufacturing standards. Published case reports of interactions between warfarin and even the most widely used herbal medicinals are limited. Practitioners are encouraged to report such interactions through the FDA MedWatch program.

New oral anticoagulants: a practical guide for clinicians.

The search for an oral anticoagulant with acceptable efficacy and safety in the treatment and prevention of venous and arterial thromboembolism, but with practical advantages over warfarin, has been a focus of drug development for many years. Three oral agents, dabigatran, rivaroxaban, and apixaban, are nearing approval in the US. Their use in practice will be guided by the clinical trials available, as well as their pharmacokinetic and pharmacodynamic properties. Practitioners need to be fully aware of these characteristics in order to use these agents appropriately in clinical practice. This review compares the results of the phase 3 trials investigating these agents in the prevention of venous thromboembolism in patients undergoing orthopedic surgery, examines the reporting of bleeding complications in the trials, and highlights various practical considerations regarding their use in clinical practice.

Direct Thrombin Inhibitors for Anticoagulation

OBJECTIVE: To review the progress in developing direct thrombin inhibitors (DTIs) for anticoagulation within the context of existing anticoagulation therapies. DATA SOURCES: Searches of MEDLINE (1993–June 2003) were conducted. STUDY SELECTION AND DATA EXTRACTION: We examined English-language articles, human studies, and relevant animal studies, and obtained additional citations from the references of these articles. DATA SYNTHESIS: Because of its pivotal role in hemostasis, thrombin is a key therapeutic target in the treatment and prevention of thromboembolic disorders. Conventional anticoagulant therapies, such as warfarin, unfractionated heparin, and low-molecular-weight heparin, exert their pharmacologic action by indirect thrombin inhibition. Although these agents are effective, each has limitations, prompting a search for more effective, specific, better-tolerated, and convenient anticoagulants. The efficacy and safety of factor Xa inhibitors are being investigated. Furthermore, the development of DTIs such as recombinant hirudin (lepirudin), bivalirudin, and argatroban continues. Challenges in the development of DTIs include establishing a binding affinity for thrombin that is not associated with excessive bleeding, attaining high thrombin specificity, achieving inhibition of both unbound and clot-bound thrombin, and producing an effective, fixed-dose oral anticoagulant to improve the practicality of anticoagulation therapy. Ximelagatran, an oral DTI designed to meet these standards, is currently in Phase III clinical trials. CONCLUSIONS: Significant progress has been made in developing DTIs. The recent emergence of orally administered DTIs may simplify the prevention and treatment of thrombosis.

Anticoagulation Monitoring Part 2: Unfractionated Heparin and Low-Molecular-Weight Heparin

OBJECTIVE To review the availability, mechanisms, limitations, and clinical application of point-of-care (POC) devices used in monitoring anticoagulation with unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs). DATA SOURCES Articles were identified through a MEDLINE search (1966–August 2004), device manufacturer Web sites, additional references listed in articles and Web sites, and abstracts from scientific meetings. STUDY SELECTION AND DATA EXTRACTION English-language literature from clinical trials was reviewed to evaluate the accuracy, reliability, and clinical application of POC monitoring devices. DATA SYNTHESIS The activated partial thromboplastin time (aPTT) and activated clotting time (ACT) are common tests for monitoring anticoagulation with UFH. Multiple devices are available for POC aPTT, ACT, and heparin concentration testing. The aPTT therapeutic range for UFH will vary depending upon the reagent and instrument employed. Although recommended by the American College of Chest Physicians Seventh Conference on Antithrombotic and Thrombolytic Therapy, establishing a heparin concentration–derived therapeutic range for UFH is rarely performed. Additional research evaluating anti-factor Xa monitoring of LMWHs using POC testing is necessary. CONCLUSIONS Multiple POC devices are available to monitor anticoagulation with UFH. For each test, there is some variability in results between devices and between reagents used in the same device. Despite these limitations, POC anticoagulation monitoring of UFH using aPTT and, more often, ACT is common in clinical practice, particularly when evaluating anticoagulation associated with interventional cardiology procedures and cardiopulmonary bypass surgery.

Argatroban for Prevention and Treatment of Thromboembolism in Heparin-Induced Thrombocytopenia

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, adverse events, and cost of argatroban in the prevention and treatment of thromboembolism in patients with heparin-induced thrombocytopenia (HIT). DATA SOURCES: A MEDLINE search (1980 to August 2000) of English-language literature was conducted using the search term argatroban to identify pertinent case reports, clinical trials, abstracts, and review articles. Additional reports were identified from the reference lists compiled in the literature reviewed, as well as from the manufacturer. DATA SYNTHESIS: Argatroban is a synthetic direct thrombin inhibitor indicated for parenteral use in the prevention and treatment of thromboembolism in patients with HIT. Its elimination half-life is approximately 40–50 minutes, and it is primarily eliminated by hepatic metabolism and biliary secretion. Compared with historical controls, argatroban-treated patients with HIT or HIT with thrombosis (HITTS) experienced lower rates of the composite end point of death, amputation, and new thrombosis. Dosing is initiated at 2 μg/kg/min and adjusted to maintain the activated partial thromboplastin time at 1.5–3 × the patients baseline. In Japan, argatroban is approved for use in acute ischemic stroke and chronic peripheral occlusive disease. It has also been used as an alternative to unfractionated heparin (UFH) in patients with a history of HIT or HITTS undergoing percutaneous coronary intervention and other procedures. Additionally, argatroban has been compared with UFH in patients with acute myocardial infarction who were receiving thrombolytic therapy. Hemorrhage is the primary adverse event associated with argatroban. Argatroban increases the prothrombin time, making assessment of the intensity of warfarin therapy during concurrent administration more complex. CONCLUSIONS: The use of argatroban in patients with HIT and HITTS is associated with improvement in clinical outcomes compared with historical controls. Argatroban offers several practical advantages over other available agents with respect to dosing, monitoring, reversibility of effect with discontinuation of the drug, and cost.