Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.

1. Permanent therapy with oral anticoagulants offers the most consistent protection in patients with mechanical heart valves. 2. Antiplatelet agents alone do not consistently protect patients with mechanical prosthetic heart valves, including patients in sinus rhythm with St. Jude Medical valves in the aortic position. 3. Levels of oral anticoagulants that prolong the INR to 2.0 to 3.0 appear satisfactory for patients with St. Jude Medical bileaflet and Medtronic-Hall tilting disk mechanical valves in the aortic position, provided they are in sinus rhythm and the left atrium is not enlarged. Presumably, this is also true for the CarboMedics bileaflet valve, based on the observation of no clinically important difference in the rate of systemic embolism with this valve and the St. Jude Medical bileaflet valve. 4. Levels of oral anticoagulants that prolong the INR to 2.5 to 3.5 are satisfactory for tilting disk valves and bileaflet prosthetic valves in the mitral position. 5. Experience in patients with caged ball valves who had prothrombin time ratios reported in terms of the INR is sparse, because few such valves have been inserted in recent years. The number of surviving patients with caged ball valves continues to decrease. It has been suggested that the most advantageous level of the INR in patients with caged ball or caged disk valves should be as high as 4.0 to 4.9. However, others have shown a high rate of major hemorrhage with an INR that is even somewhat lower, 3.0-4.5. The problem is self-limited, however, because few such valves are being inserted. 6. In patients with mechanical heart valves, aspirin, in addition to oral anticoagulants, has been shown to diminish the frequency of thromboemboli. The risk of bleeding is somewhat increased if the INR is 2.0 to 3.0 or 2.5 to 3.5. However, if the INR is 3.0 to 4.5, the risk of bleeding becomes excessive with aspirin. There are no investigations in which aspirin 80 mg/d in combination with oral anticoagulants was evaluated. 7. Data are insufficient to recommend dipyridamole over low doses of aspirin in combination with warfarin. Whether dipyridamole plus aspirin is more effective than aspirin alone when used with warfarin is undetermined. 8. Patients with bioprosthetic valves in the mitral position as well as patients with bioprosthetic valves in the aortic position may be at risk for thromboemboli during the first 3 months after operation. 9. Among patients with bioprosthetic valves in the mitral position, oral anticoagulants at an INR of 2.0 to 2.3 were as effective as an INR of 2.5 to 4.0 and were associated with fewer bleeding complications during the first 3 months after operation.10. Aspirin may reduce the long-term frequency of thromboembolism in patients with bioprosthetic valves.

A randomized, crossover comparison of warfarin products in the treatment of chronic atrial fibrillation.

OBJECTIVE: To compare the dosing requirements and international normalized ratios (INRs) associated with two bioequivalent crystalline warfarin sodium products in patients with chronic atrial fibrillation. METHODS: A multicenter, single-blind (prescriber), randomized, crossover evaluation of Apothecon warfarin and DuPont warfarin (Coumadin) was conducted in consenting adults with chronic or paroxysmal atrial fibrillation who had been receiving DuPont warfarin chronically for the prevention of thromboembolism. Patients were randomly assigned to initially either continue DuPont warfarin or receive Apothecon warfarin for four weeks, with weekly evaluation of dosage and INR changes, safety, and efficacy. Subsequently, patients crossed over and received the other product for four weeks. RESULTS: There were 113 patients randomized to receive study treatment. Neither the propensity for a dosage change or an INR change nor the magnitude of a dosage change or INR change appeared related to a particular warfarin product (NS for each variable after each study period). After four weeks of treatment, the same number of patients (n = 7) experienced a > or = 20% change in warfarin dosage from the respective baseline with each product. The number of patients with INRs outside the desired protocol range after four weeks of treatment was similar for both groups (< 1.8, n = 9 for both products, or > 3.2, n = 9 for DuPont, n = 10 for Apothecon). No major hemorrhagic or thromboemoblic events occurred. CONCLUSIONS: The results of this study show that Apothecon warfarin and DuPont warfarin provide equivalent anticoagulation in patients with chronic or paroxysmal atrial fibrillation.

Prevention of venous thromboembolism: adherence to the 1995 American College of Chest Physicians consensus guidelines for surgical patients.

BACKGROUND: The American College of Chest Physicians addressed the dilemma of identifying optimal therapy for venous thromboembolism (VTE) prophylaxis and published their Fourth Consensus Conference on Antithrombotic Therapy in 1995, with recommendations for prophylactic therapy. Despite these recommendations, appropriate VTE prophylactic therapy is underused. OBJECTIVES: To examine routine practices in the prevention of VTE in high-risk surgical patients and to determine the extent of adoption of grade A prophylactic therapies as recommended by the American College of Chest Physicians. METHODS: Retrospective medical record review in 10 teaching or community-based hospitals located in the United States. Medical charts of 1907 patients were randomly selected for review from the population of patients who underwent high-risk major abdominal surgery, total hip replacement, hip fracture repair, or total knee replacement between January 1, 1996, and February 28, 1997. RESULTS: Of 1907 patients, VTE prophylaxis was used in 89.3%; use was 93.7% in each of the 3 orthopedic surgery groups and 75.2% in the high-risk major abdominal surgery group. The percentage of patients receiving grade A therapy was highest in the hip replacement group (84.3%) vs. the other groups (knee replacement, 75.9%; hip fracture repair, 45.2%; abdominal surgery, 50.3%). CONCLUSIONS: The use of grade A prophylaxis was related to the type of surgery, with the highest use seen in total hip replacement and the lowest in hip fracture repair. One in 4 patients who underwent high-risk major abdominal surgeries failed to receive any form of VTE prophylaxis. Publication of consensus statements alone may be insufficient to ensure the incorporation of important new clinical information into routine practice.

Comparing different routes and doses of phytonadione for reversing excessive anticoagulation.

BACKGROUND: Significant controversy exists concerning how best to reverse excessive anticoagulation (due to warfarin sodium therapy) with phytonadione (vitamin K1) while avoiding overcorrection in patients who need to have anticoagulation therapy maintained. METHODS: A retrospective review of phytonadione use in reversing excessive anticoagulation was performed in 3 institutions. The effectiveness of low-dose (< or =0.5 mg) intravenous (LDIV), high-dose (1-10 mg) intravenous (HDIV), subcutaneous (1-10 mg) (SC), and oral (2.5 or 5 mg) (PO) phytonadione was evaluated within 48 hours of administration. Anticoagulation correction (international normalized ratio [INR], > or =2.0 and < or =5.0) occurred in 5 of 8 patients in the LDIV, 5 of 9 in the HDIV, 7 of 10 in the SC, and 5 of 6 in the PO groups. Correction was inadequate (INR >5.0) in 2 of 8 patients in the LDIV, 0 of 9 in the HDIV, 3 of 10 in the SC, and 1 of 6 in the PO groups. Overcorrection (INR <2.0) occurred in 1 patient in the LDIV, 4 patients in the HDIV, 0 in the SC, and 0 in the PO groups. CONCLUSIONS: Anticoagulation correction was achieved in most patients in all 4 groups. The HDIV method was most effective in lowering the INR to less than 5.0, but overcorrection occurred more frequently (4 patients in the HDIV vs 1 patient in the LDIV and 0 patients in the SC and PO groups). Failure to achieve an INR of less than 5.0 was a greater problem in the SC group (3 patients in the SC vs 2 patients in the LDIV and 1 patient in the PO groups). The LDIV and PO methods appear to be acceptable alternatives to the HDIV and SC methods currently recommended.

College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of oral anticoagulant therapy.

OBJECTIVE: To review the state of the art of laboratory monitoring of oral anticoagulant therapy, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for improvement in laboratory monitoring of oral anticoagulant therapy. DATA SOURCES: Review of the medical literature, primarily from the last 10 years, and current laboratory practices by a panel of 8 international experts in the field of oral anticoagulant monitoring. DATA EXTRACTION AND SYNTHESIS: After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and current practices relevant to each of the key points and to prepare a summary of their findings and recommendations. A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy prior to the conference. Each of the key points and associated recommendations was then presented for discussion at the Conference. Recommendations were accepted if a consensus of the 26 experts attending the Conference was reached. The results of the discussion were used to revise the manuscript into its final form. CONCLUSIONS: Consensus was reached on 12 recommendations concerning the laboratory monitoring of oral anticoagulant therapy. Detailed discussion of the rationale for each of these recommendations is found in the text of this article. Discussion of points on which consensus was not reached is also included in the text. It is hoped that widespread adoption of these recommendations will further improve the laboratory monitoring of oral anticoagulant therapy.

Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs.

BACKGROUND: The outcomes of an inception cohort of patients seen at an anticoagulation clinic (AC) were published previously. The temporary closure of this clinic allowed the evaluation of 2 more inception cohorts: usual medical care and an AC. OBJECTIVE: To compare newly anticoagulated patients who were treated with usual medical care with those treated at an AC for patient characteristics, anticoagulation control, bleeding and thromboembolic events, and differences in costs for hospitalizations and emergency department visits. RESULTS: Rates are expressed as percentage per patient-year. Patients treated at an AC who received lower-range anticoagulation had fewer international normalized ratios greater than 5.0 (7.0% vs 14.7%), spent more time in range (40.0% vs 37.0%), and spent less time at an international normalized ratio greater than 5 (3.5% vs 9.8%). Patients treated at an AC who received higher-range anticoagulation had more international normalized ratios within range (50.4% vs 35.0%), had fewer international normalized ratios less than 2.0 (13.0% vs 23.8%), and spent more time within range (64.0% vs 51.0%). The AC group had lower rates (expressed as percentage per patient-year) of significant bleeding (8.1% vs 35.0%), major to fatal bleeding (1.6% vs 3.9%), and thromboembolic events (3.3% vs 11.8%); the AC group also demonstrated a trend toward a lower mortality rate (0% vs 2.9%; P= .09). Significantly lower annual rates of warfarin sodium-related hospitalizations (5% vs 19%) and emergency department visits (6% vs 22%) reduced annual health care costs by $132086 per 100 patients. Additionally, a lower rate of warfarin-unrelated emergency department visits (46.8% vs 168.0%) produced an additional annual savings in health care costs of $29 72 per 100 patients. CONCLUSIONS: A clinical pharmacist-run AC improved anticoagulation control, reduced bleeding and thromboembolic event rates, and saved $162058 per 100 patients annually in reduced hospitalizations and emergency department visits.

Controversies in antithrombotic therapy for patients with mechanical heart valves.

Current anticoagulation guidelines for patients with mechanical heart valves are based on studies that are seriously flawed in that they used prothrombin time ratios rather than the international normalized ratio (INR) and failed to consider the level of anticoagulation actually achieved. Available data suggest that the appropriate INR range varies according to risk factors and that "tight control" of the INR is of critical importance in reducing thromboembolic and hemorrhagic events. Whether antiplatelet therapy adds benefit to an appropriately controlled level of anticoagulation is not clear. During pregnancy, warfarin is contraindicated; adjusted-dose heparin is recommended by published American and European guidelines. Even so, one small study suggests that this may be inadequate. Topical antifibrinolytic agents can negate the need to alter systemic anticoagulation during dental surgery.

A statistical and clinical evaluation of fingerstick and routine laboratory prothrombin time measurements.

STUDY OBJECTIVE: To compare prothrombin time measurements by fingerstick and routine laboratory methods. DESIGN: Prospective cohort study. SETTING: University-affiliated anticoagulation clinic. PATIENTS: Thirty-three patients receiving warfarin with stable anticoagulation for 3 months preceding the two studies. INTERVENTIONS: Groups 1 (17 patients) and 2 (16 patients) provided 150 and 125 paired samples, respectively, for fingerstick and routine laboratory analysis. The fact that no patient required a dosage change allowed for a clinical assessment. MEASUREMENTS AND MAIN RESULTS: Correlation and agreement between methods were good in group 1 but poor in group 2. Fingerstick results were less variable (smaller standard deviation and smaller coefficient of repeatability) in both groups. By analysis of discrepant pairs (25 in group 1, 63 in group 2), the routine laboratory results indicated dosage changes erroneously more often than did the fingerstick method. CONCLUSIONS: In these two trials, the fingerstick system was superior to the routine laboratory method in that it was more reliable (less variability and more repeatable) and less likely to indicate dosage changes erroneously.

A review of enzyme induction of warfarin metabolism with recommendations for patient management.

We conducted a review of literature from the MEDLINE data base (1966-January 1997), and bibliographies of published articles, reviews, and letters to classify enzyme induction of warfarin metabolism interactions by onset, extent, and offset. Ten hepatic microsomal enzyme agents were assessed. Likelihood of interaction was based on the strength of supporting literature. Enzyme induction of warfarin metabolism by rifampin and barbiturates is considered likely, although the characteristics of the interactions are different. An interaction is probable with carbamazepine, griseofulvin, aminoglutethimide, nafcillin, and dicloxacillin. A suspected interaction may occur with smoking and long-term alcohol consumption. Ingestion of a small amount of alcohol is unlikely to interact with warfarin. The effect of phenytoin on warfarin metabolism is unpredictable. Anticipation of the expected time course and extent of interaction may allow for better therapeutic decisions and decrease the chance of inappropriate anticoagulation with its potential for complications.

Diagnosis of deep vein thrombosis.

The diagnosis of deep vein thrombosis (DVT) is discussed. Accurately diagnosing DVT is critical to making appropriate treatment decisions. Careful patient assessment, combined with objective testing, improves the accuracy of the diagnosis and reduces the likelihood of inappropriate treatment. Venography remains the reference standard for the diagnosis of DVT but is expensive, invasive, and prone to inducing complications. Ultrasonography has become the most frequently used noninvasive test for symptomatic DVT because it is highly sensitive and specific in the hands of an experienced examiner. Impedance plethysmography also has been widely used, but recent studies suggest that it is less sensitive than once believed. The radiolabeled 125I-fibrinogen uptake test is no longer available because of concerns about the transmission of blood-borne pathogens. Current thermographic techniques have relatively high sensitivity but poor specificity for DVT. Magnetic resonance imaging and computed tomography are useful adjunctive tests, but their use is limited by cost and availability. D-dimer whole-blood testing may prove to be a rapid and convenient means of ruling out the diagnosis of DVT at the bedside, but further study is needed. When used alone, none of the noninvasive methods is sufficiently sensitive for the evaluation of asymptomatic patients. The diagnostic strategy used should be based on whether the patient is symptomatic or asymptomatic, whether the event is a first one or is recurrent, and a careful clinical assessment. Accurate diagnosis of deep vein thrombosis relies on both testing and patients assessment.

Thrombosis and the pharmacology of antithrombotic agents.

OBJECTIVE: To provide an overview of the current state of knowledge regarding the physiology of hemostasis, the pathophysiology of thrombosis, and the pharmacology of antithrombotic agents. DATA SOURCES: A MEDLINE search was conducted to identify pertinent literature published since 1984. Recently published textbooks devoted to the subjects of hematology, hemostasis, and thrombosis also were reviewed, particularly their bibliographies. The bibliographies of selected review articles also were reviewed. STUDY SELECTION: As the amount of literature was vast, only the most significant and noteworthy published studies were reviewed. Review articles and book chapters authored by researchers of international reputation also were reviewed. DATA EXTRACTION: Identified studies from the primary literature and selected reviews were analyzed carefully. Information regarding hemostasis, thrombosis, and antithrombotic drugs was extracted. Particular attention was given to data regarding drugs currently available or soon to be available on the US market. DATA SYNTHESIS: Knowledge regarding the regulation of blood coagulation has expanded substantially in recent years. Hemostasis involves the dynamic interplay of numerous intravascular constituents, including the vessel wall, circulating procoagulants and anticoagulants, platelets, and fibrinolytic proteins. Thrombosis is the abnormal formation of a clot within the vascular system. When sufficiently large, thrombi can prevent the flow of blood and nutrients to vital tissues. Thrombosis is associated with many common diseases and is among the leading causes of death in developed countries. Many drugs are now available to prevent the formation and propagation of thrombi. These agents work by different pharmacologic mechanisms and are useful in different clinical situations. CONCLUSIONS: Thrombosis research has increased our understanding of the pharmacology of antithrombotic drugs and promoted the discovery of new agents targeted more specifically toward the critical steps in pathologic clot formation. New agents have the potential for greater efficacy and fewer adverse effects. An increased understanding of hemostasis, thrombosis, and the pharmacology of antithrombotic drugs should enable the clinician to use these agents appropriately.