Oral Anticoagulation in Clinical Medicine for Venous and Arterial Thrombotic Indications

This issue begins with Dr. Wittkowsky's survey of basic information concerning the pharmacology and metabolism of warfarin. The dose response to warfarin is relatively unpredictable, requiring individualization of dosing guided by therapeutic monitoring of the prothrombin time (PT). Oral anticoagulation with coumarin (OAC) has a narrow therapeutic index and is highly susceptible to other drug components, making patient education necessary.

Next, the genetic regulation of warfarin, a racemic mixture of R and S enantiomers, is examined by Drs. Daly and Aithal. The metabolism of R and S enantiomers is different. Plasma concentrates of R are two times higher than of S, but the vitamin K inhibitory activity in plasma is 60 to 70% by S and 30 to 40% by R enantiomers. Several cytochromes P450 contribute to oxidative metabolism of warfarin. The most important of these is CYP2C9, which 7-hydroxylates S-warfarin. 10-Hydroxylation by CYP3A4 followed by 8- and 6-hydroxylation by CYP1A2 are likely the most important oxidative metabolite routes of R-warfarin. CYP2C9 variant alleles result in decreased enzyme activity and have been associated with a significant decrease in warfarin dose requirement.

Dr. Beyth nicely points to important aspects of quality-of-life issues concerning oral anticoagulation.

Drs. Tripodi, Breukink-Egbers, and van den Besselaar describe PT as a global and simple test sensitive to most vitamin K-dependent factors II, VII, IX, X, C, S, and Z. PT is influenced by the type of thromboplastin and instrumentation and therefore should be transformed to the International Normalized Ratio (INR) by calculation of the reagent/instrumentation result against the International Reference Plasma held by the WHO standards, which allows the determination of the International Sensitivity Index (ISI). The ISI is accurate at INR values between 1.5 and 4 and only after stabilization but not during initiation of OAC. Knowledge of the ISI permits to convert PT results into INR = (PT_patient/ PTnormal)^ISI. ISI close to 1 seems to be preferred because of better reproducibility. INR is influenced by various factors in the patient's plasma, which cannot be standardized. INR differences between PT and point-of-care (POC) testing may be negative or positive, which cannot be avoided or eliminated, and it is not possible to know which of the two methods is better for monitoring OAC. Some clinicians are still reluctant to use INR.

Dr. Crowther describes warfarin initiation algorithms to guide initiation OAC and the use of computer systems to guide chronic OAC with the goal of maximizing the time within the therapeutic INR range because the risk of bleeding and thrombosis during OAC is increased when the INR is outside the desired range. Every effort should be made to maintain the INR result within the therapeutic range by targeting an INR level in the mid-end of the INR range, for example, 2.5 for a desired range of 2.0 to 3.0 and 3.0 for a desired range of 2.5 to 3.5. Despite adequate monitoring the time in the therapeutic INR range (TTR) is only 70 to 80% of OAC patients and the compliance of long-term OAC is poor. This complexity of OAC points to the need of cost-effective alternatives of oral anticoagulants without the need of monitoring.

This is followed by Dr. Ansell's focus on high-quality dose management of OAC, a labor-intensive therapy for which special programs and anticoagulation services have been developed, such as anticoagulant management services (AMS) or anticoagulant clinics (ACC), because the relative risk of bleeding is significantly increased at INR above 4.5 and the relative risk of thrombosis is strongly increased at INR below 2. The improved OAC for venous and arterial thrombotic indications by AMS or ACC compared with usual care will lead to significant reduction in overall health costs. POC patient self-testing and self-management (PSTM) using various instruments is now being realized and offers the potential to lower the risk/benefit ratio profile of OAC, to improve patient compliance and satisfaction, to reduce labor intensity by an AMS or ACC, and to encourage the more widespread use of long-term OAC. Patients must be educated by an AMS or ACC. The cost-effectiveness of POC/PSTM therapy needs to be studied.

Bleeding and nonbleeding complications of OAC are reported by Dr. Hylek. The rate of intracranial bleeding is 0.1 to 0.9%. The mortality rate is 34 to 68%. The risk of intracranial bleeding increases with INR above 4, but most intracranial hemorrhages were encountered in the therapeutic INR range. The rate of major extracranial bleeding is 0.4 to 2%, and its occurrence depends on INR, age, underlying occult pathologic lesions or conditions, the use of antiplatelet or anti-inflammatory drugs, etc. Coumarin skin necrosis is usually seen in conjunction with large initiating doses of coumarins and caused by transient severe protein C deficiency.

The management of life-threatening, serious, and minor bleedings in anticoagulated and overanticoagulated patients is described by Dr. Makris. The main ways to reverse anticoagulation are discontinuation OAC and the use of oral or intravenous vitamin K, fresh frozen plasma, clotting factor II, VII, IX, and X concentrates, and recombinant factor VIIa (rVIIa). For life-threatening bleeding the use of clotting factor concentrates or rVIIa is essential for immediate anticoagulation correction, whereas for less severe major bleeding intravenous or oral vitamin K is the choice. Oral vitamin K should also be used in overcoagulated patients who are not bleeding but who are at high risk of doing so.

Dr. Kearon provides detailed information on the management of anticoagulation in thrombosis patients who require invasive procedures because anticoagulation is associated with bleeding from the operative site, and interruption of anticoagulation during surgery has an increased risk of severe thrombotic complications. Some invasive procedures can be performed while patients are fully or partially anticoagulated as long as bleeding is rare and/or easily controlled. Bridging therapy refers to the use of therapeutic unfractionated heparin or low molecular weight heparin (LMWH) during surgical interventions, whereas OAC must be subtherapeutic in anticoagulated patients for either arterial or venous thromboembolism (VTE). As arterial thromboembolism often results in death or major disability, whereas recurrent VTE rarely presents in sudden death or permanent disability, the present article provides algorithms and detailed recommendations for bridging therapy for the periods just before, during, and after surgery in patients anticoagulated for arterial thromboembolism, including atrial fibrillation (AF), mechanical heart valves, etc., and in patients anticoagulated for VTE.

Next, Dr. Jacobson examines the history and requirements for the use of POC INR testing in both the professional and patient home setting as an enabling technique for PSTM of long-term OAC. Despite the FDA approval for POC INR testing, the greatest barriers for the implementation of PST and PSM in the United States are the lack of adequate insurance reimbursement, the lack of awareness among the medical community, and the lack of large clinical trials.

A review of the optimal OAC therapy in VTE is presented by Drs. Cosmi and Palareti. The optimal INR intensity for deep vein thrombosis is 2.0 to 3.0 and the target is 2.5. Home treatment of acute DVT starting with LMWH for about 5 days and OAC for 3 months is cost-effective but requires adequate patient selection. As OAC crosses the placenta barrier and appears to be teratogenic for the fetus and may induce bleeding complication in the mother, the first trimester and last week of pregnancy is an absolute contraindication for OAC. All patients with acute DVT are candidates for at least 3 months of OAC. Currently, VTE patients can be stratified using clinical and laboratory variables for risk assessment of acquired and hereditary thrombophilia into very high risk of VTE recurrence (>12%/year) for lifelong OAC, high risk (10%/year) for 6 to 12 months of OAC, moderate risk (<10%/year for 6 months of OAC, and low risk (<5%/year) for 3 months of OAC duration therapy. This risk stratification can be further improved by the use of a sensitive D-dimer and follow-up compression ultrasonography after discontinuation of OAC. Specific issues and recommendations for the treatment of a selective group of VTE patients (OAC contraindications, cancer, and children) are discussed.

Dr. Baglin describes the implementation of hereditary and acquired thrombophilic factors for the primary or secondary prevention of VTE. Heterozygosity for factor V Leiden, prothrombin 20219 mutation, and proteins C and S does not predict a greater risk of VTE recurrence after discontinuation of OAC. Homozygosity or double heterozygosity for hereditary thrombophilic factors significantly increases the risk of VTE occurrence and recurrence. The benefit/risk ratio for primary prophylaxis with OAC in asymptomatic family members with hereditary thrombophilia is unfavorable. Avoidance of and short-term anticoagulant prophylaxis during high-risk situations are likely to be safest and most effective in VTE risk reduction in thrombophilic individuals with and without a history of VTE and in asymptomatic patients with acquired thrombophilia associated with antiphospholipid syndrome or cancer.

Drs. Hackman, Anand, and Yusuf address OAC in patients with acute coronary syndromes. Recurrent myocardial infarction (MI), stroke, or death occurs in 7 to 10% of patients with acute MI during 6 weeks of follow-up and in about 20% of patients during 4 years of follow-up. Long-term OAC monotherapy after MI aiming at an INR of 2.8 to 4.2 was superior to aspirin in recent prospective management studies at the cost of some higher bleeding complications. In non-MI acute coronary syndromes the effect of OAC compared with aspirin is less pronounced or absent. Despite adequate monitoring only 70 to 80% of OAC patients are within the INR target range and the compliance of long-term OAC is poor. This complexity of OAC points to the need for cost-effective alternatives to oral anticoagulants without the need for monitoring.

Next, OAC in patients with AF is examined by Dr. Pengo. AF is prevalent in an estimated 9% of those older than 70 years and in 16% of men and 12% of women older than 75 years with a relative risk of 5.5 to develop transient ischemic attacks (TIAs) or stroke. Adjusted-dose OAC is superior to fixed-dose OAC plus aspirin or aspirin alone for the primary and secondary prevention of TIAs and stroke in nonvalvular (NV) and nonrheumatic (NR) AF with one or more high-risk factors. In the absence of thromboembolic risk factors it may be wise to treat NVAF and NRAF with antiplatelet drugs or not to treat at all if there is an associated positive bleeding tendency. Despite widely publicized guidelines, the majority of high-risk AF patients are not treated with OAC for various logistic reasons.

Finally, Drs. Visseren and Eikelboom address OAC in patients with peripheral arterial disease (PAD). Patients with PAD are at high risk for early cardiovascular complications. It is documented that patients with intermittent claudication benefit from aspirin or clopidogrel, but a comparison of OAC versus antiplatelet agents is lacking. PAD patients undergoing peripheral arterial bypass surgery benefit from aspirin therapy. OAC is more effective than aspirin in preventing infrainguinal bypass occlusion only when venous graft material is used and the bypass is considered to be at high risk of occlusion.

It is convincing that this comprehensive review on oral anticoagulation in clinical medicine helps researchers and clinicians in vascular medicine and staff members of anticoagulant management services (AMS) or anticoagulant clinics (ACC) to maintain and improve the high quality of care and cure of their patients with arterial and/or venous thromboembolic diseases. My thanks and sincere appreciation go to all of the authors for their excellent contributions. I especially thank Drs. Gualtiero Palareti, Jack Ansell, and Trevor Baglin for assembling this very important issue of Seminars in Vascular Medicine.