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.

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.

The influence of rifampin on quinidine and digoxin.

Serum drug concentration data from the first of the two patients described herein suggest that rifampin may directly increase the metabolism of quinidine and thereby negate the influence of quinidine on the serum digoxin concentration (SDC). Data on the second patient suggest that rifampin may directly increase the metabolism of digoxin producing lower SDC values. In both cases, the discontinuation of rifampin therapy appears to have allowed reversion toward prerifampin metabolism of both quinidine and digoxin.

Reliance on prothrombin time ratios causes significant errors in anticoagulation therapy.

BACKGROUND: The intensity of warfarin anticoagulation in the United States may be inappropriate if the international normalized ratio (INR) is not used, or if the international sensitivity index (ISI) of the thromboplastin is outside the range of 2.2 to 2.6. METHODS: Fifty-three hospital laboratories provided data on the sensitivity of their thromboplastin and whether they reported INR values. Additional data on thromboplastin sensitivity were obtained from 140 laboratories involved in the Stroke Prevention in Atrial Fibrillation study. The three major manufacturers of thromboplastin confirmed the range of thromboplastin sensitivity reported by the laboratories. RESULTS: Of 53 laboratories surveyed, 16 (30%) could not provide ISI data and only 11 (21%) reported INR results. Unlabeled thromboplastin was being used by 20% to 24% of laboratories, and only 8% to 20% were using thromboplastins with an ISI of 2.2 to 2.6. At the time the three manufacturers were contacted, they reported marketing thromboplastins with ISI values from 1.2 to 2.8, but none of the thromboplastins at that time had ISI values between 2.2 and 2.6. CONCLUSION: Warfarin therapy in the United States is managed inappropriately because most laboratories do not report INRs and the variability in thromboplastin sensitivity produces misleading prothrombin time ratio results. Additionally, recent research may require reexamination if INR or ISI data were not provided.

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.

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 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.

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.

Promising uses of calcium-channel blocking agents.

It is not surprising that calcium-channel blocking agents, which have numerous effects on various physiologic systems, have been employed for several "unapproved" uses. This manuscript reviews reports that have appeared within the last two years describing unapproved cardiovascular and noncardiovascular uses of the three available calcium-channel blocking agents. The cardiovascular uses discussed include hypertensive emergencies, pulmonary hypertension, congestive heart failure, aortic insufficiency, Raynaud's phenomenon, migraine headaches, antiplatelet effects and cardiac surgery. Areas of noncardiovascular use include muscular dystrophy, achalasia, esophageal spasm, dysmenorrhea, preterm labor, asthma, hyperuricemia, mania and depression and endocrinologic and oncologic conditions. While some of the data appear promising, other reports are conflicting and contradictory. Furthermore, because much of the information comes from poorly controlled trials or anecdotal reports, even the more promising uses must be studied further and compared with conventional therapy.

A comparative trial of digoxin and digitoxin in the treatment of congestive heart failure.

A randomized, crossover, single-blind study compared the efficacy and dosing accuracy of digoxin and digitoxin in 15 ambulatory patients wth congestive heart failure. Loading doses and maintenance doses were calculated according to published equations that adjust for sex, height, and lean body weight (for digitoxin), plus estimated creatinine clearance (for digoxin). At each 2-week visit, serum drug concentrations were measured and compliance with the prescribed regimen was assessed by tablet count. At the end of each study period, a congestive heart failure (CHF) score was determined in a blinded fashion by the same physician. Patient compliance was unusually high (greater than or equal to 80%) at every visit. Therapeutic concentrations were achieved with digoxin and digitoxin in 5 and 14 patients, respectively (p less than 0.05). During digitoxin therapy, CHF scores were lower than pretreatment values (p less than 0.05). The difference between CHF scores during the digoxin and digitoxin periods did not achieve significance (0.05 less than p less than 0.06). Therapeutic serum concentrations can be achieved more easily and frequently with digitoxin than digoxin without compromising the patient's CHF status.

The safety and effectiveness of long-term warfarin therapy in an anticoagulation clinic.

Whenever long-term anticoagulation is prescribed, the risks of such therapy must be evaluated accurately. Whether these risks are influenced by the duration of therapy, the indication for therapy, patient demographics and social habits, or the use of an anticoagulation clinic is controversial. This study examined the occurrence rates of major hemorrhage, minor hemorrhage, and thromboembolic events among an inception cohort of 82 patients receiving long term-warfarin therapy in an anticoagulation clinic. During 199.34 patient-years of observation, there were 4 major hemorrhages (0.0201/patient-year), 31 minor hemorrhages (0.1555/patient-year), and 7 thromboembolic events (0.0351/patient-year). Although each type of event tended to occur during the first 6 months of therapy, this trend was not statistically significant. Failure to demonstrate statistically significant influence of any of the evaluated variables may have been due to the unusually low rate of complications, a finding that may reflect the safety of anticoagulant therapy when managed by a specialized clinic.

Evaluation of factors associated with stability of anticoagulation therapy.

Eighty-two patients receiving long-term warfarin therapy provided 199.34 patient-years of data that were evaluated to determine if certain variables could identify those who might be monitored safely at less frequent intervals. Most patient demographics, social habits, medical histories, indications for anticoagulation, and concurrent therapy were not useful in discriminating between patients with stable (n = 67) and unstable (n = 15) anticoagulation. A few trends were noted, but they failed to achieve statistical significance. Patients who never achieved stability (the unstable group) tended to be younger than those who did (p 0.13). Among the stable patients, those with a diagnosis of deep vein thrombosis or pulmonary embolus, or with elevated alanine aminotransferase values, were significantly more likely to require a dosage change. The probability of requiring a dosage change at monthly visits did not correlate with the time required to become stable, but it did correlate inversely with the duration of stable anticoagulation. This probability declined from almost 16% when monitoring frequency was first extended to monthly intervals to less than 8% at 2 months of stable anticoagulation, and tended to decline further with longer periods of stable therapy. Of the 67 patients who became stable, 23 did not require a dosage change during an average of 526 days of follow-up. Among the 44 stable patients who required a dosage change, the mean time to the change was 250 days after becoming stable. Few complications occurred, almost all of them early in therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Potential warfarin-ciprofloxacin interaction in patients receiving long-term anticoagulation.

This study prospectively evaluated the potential interaction between the oral anticoagulant warfarin and the quinolone antimicrobial agent ciprofloxacin. After a 10-day placebo lead-in phase, 16 patients stabilized with long-term warfarin therapy were randomized to receive ciprofloxacin 500 mg or a matching placebo twice/day for 10 days. International normalized ratios (INRs) measured by both standard laboratory analysis and by Coumatrak (finger-stick) methods were evaluated at 3- to 5-day intervals. No patient experienced a significant increase in INR. No patient experienced a bleeding event. These data support the fact that a warfarin-ciprofloxacin interaction does not routinely occur at this dosage and duration of ciprofloxacin therapy.

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.

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.