Extended International Normalized Ratio testing intervals for warfarin-treated patients.

Essentials Warfarin typically requires International Normalized Ratio (INR) testing at least every 4 weeks. We implemented extended INR testing for stable warfarin patients in six anticoagulation clinics. Use of extended INR testing increased from 41.8% to 69.3% over the 3 year study. Use of extended INR testing appeared safe and effective. SUMMARY: Background A previous single-center randomized trial suggested that patients with stable International Normalized Ratio (INR) values could safely receive INR testing as infrequently as every 12 weeks. Objective To test the success of implementation of an extended INR testing interval for stable warfarin patients in a practice-based, multicenter collaborative of anticoagulation clinics. Methods At six anticoagulation clinics, patients were identified as being eligible for extended INR testing on the basis of prior INR value stability and minimal warfarin dose changes between 2014 and 2016. We assessed the frequency with which anticoagulation clinic providers recommended an extended INR testing interval (> 5 weeks) to eligible patients. We also explored safety outcomes for eligible patients, including next INR values, bleeding events, and emergency department visits. Results At least one eligible period for extended INR testing was identified in 890 of 3362 (26.5%) warfarin-treated patients. Overall, the use of extended INR testing in eligible patients increased from 41.8% in the first quarter of 2014 to 69.3% in the fourth quarter of 2016. The number of subsequent out-of-range next INR values were similar between eligible patients who did and did not have an extended INR testing interval (27.3% versus 28.4%, respectively). The numbers of major bleeding events were not different between the two groups, but rates of clinically relevant non-major bleeding (0.02 per 100 patient-years versus 0.09 per 100 patient-years) and emergency department visits (0.07 per 100 patient-years versus 0.19 per 100 patient-years) were lower for eligible patients with extended INR testing intervals than for those with non-extended INR testing intervals. Conclusions Extended INR testing for stable warfarin patients can be successfully and safely implemented in diverse, practice-based anticoagulation clinic settings.

The Michigan Risk Score to predict peripherally inserted central catheter-associated thrombosis.

Essentials How best to quantify thrombosis risk with peripherally inserted central catheters (PICC) is unknown. Data from a registry were used to develop the Michigan Risk Score (MRS) for PICC thrombosis. Five risk factors were associated with PICC thrombosis and used to develop a risk score. MRS was predictive of the risk of PICC thrombosis and can be useful in clinical practice. SUMMARY: Background Peripherally inserted central catheters (PICCs) are associated with upper extremity deep vein thrombosis (DVT). We developed a score to predict risk of PICC-related thrombosis. Methods Using data from the Michigan Hospital Medicine Safety Consortium, image-confirmed upper-extremity DVT cases were identified. A logistic, mixed-effects model with hospital-specific random intercepts was used to identify factors associated with PICC-DVT. Points were assigned to each predictor, stratifying patients into four classes of risk. Internal validation was performed by bootstrapping with assessment of calibration and discrimination of the model. Results Of 23 010 patients who received PICCs, 475 (2.1%) developed symptomatic PICC-DVT. Risk factors associated with PICC-DVT included: history of DVT; multi-lumen PICC; active cancer; presence of another CVC when the PICC was placed; and white blood cell count greater than 12 000. Four risk classes were created based on thrombosis risk. Thrombosis rates were 0.9% for class I, 1.6% for class II, 2.7% for class III and 4.7% for class IV, with marginal predicted probabilities of 0.9% (0.7, 1.2), 1.5% (1.2, 1.9), 2.6% (2.2, 3.0) and 4.5% (3.7, 5.4) for classes I, II, III, and IV, respectively. The risk classification rule was strongly associated with PICC-DVT, with odds ratios of 1.68 (95% CI, 1.19, 2.37), 2.90 (95% CI, 2.09, 4.01) and 5.20 (95% CI, 3.65, 7.42) for risk classes II, III and IV vs. risk class I, respectively. Conclusion The Michigan PICC-DVT Risk Score offers a novel way to estimate risk of DVT associated with PICCs and can help inform appropriateness of PICC insertion.

D-dimer levels and recurrence in patients with unprovoked VTE and a negative qualitative D-dimer test after treatment.

BACKGROUND: The rate of recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who had a negative qualitative D-dimer test one month after stopping anticoagulant therapy was higher than expected in the D-dimer Optimal Duration Study (DODS). OBJECTIVES: To determine whether quantitative D-dimer levels using a low threshold, age- and sex-specific thresholds, or repeated measurements, would improve identification of patients at low risk of recurrent VTE. MATERIALS AND METHODS: D-dimer levels were quantified in banked samples from 307 patients in DODS who had a negative qualitative D-dimer test while on, and 1month after stopping, anticoagulant therapy and the rates of recurrent VTE were determined in patients with D-dimer levels below various predefined thresholds. RESULTS: The rate (per patient year) of recurrent VTE was: 5.9% with D-dimer levels<250µg/l at one month; 5.2% with D-dimer levels between 250 and 499µg/l at one month; 5.0% with D-dimer levels less than predefined age- and sex-specific thresholds at one month; and 6.3% when D-dimer levels were <500µg/l at both one and 7months after stopping anticoagulant therapy. These rates are similar to the overall event rate of 6.3% in patients who stopped treatment. CONCLUSIONS: Among unprovoked VTE patients who had a negative qualitative D-dimer test during and after anticoagulant therapy, low D-dimer thresholds, age and sex-adjusted thresholds or repeated measurements, did not identify subgroups with a very low rate of recurrence.

Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial.

Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

Risk factors associated with myocardial infarction in venous thromboembolism patients.

BACKGROUND: Although risk factors for MI have been described in the general population, there is a lack of data on the assessment of risk factors associated with MI in venous thromboembolism (VTE) patients. OBJECTIVE: The purpose of this study was to identify risk factors associated with MI in VTE patients. PATIENTS AND METHODS: Health insurance claims between January 2004 and September 2008 from the Ingenix IMPACT database were analyzed. Patients aged ≥18 years were identified as of the date of their first VTE diagnosis with ≥1 year of continuous insurance coverage before the index VTE. The risk of MI for VTE patients with 1, 2, and ≥3 major risk factors as identified by published guidelines was calculated. Multivariate Cox proportional hazard models were conducted to identify the most predictive risk factors associated with MI. RESULTS: A total of 177,885 VTE patients were identified; 4412 (2.5%) developed an MI during a mean follow-up period of 1.3 years. Previous MI, age (≥65 years), and coronary artery disease were the most predictive risk factors of MI with adjusted hazard ratios (HRs; 95% CI) of 5.47 (5.01-5.97), 1.78 (1.66-1.91), and 1.60 (1.48-1.74), respectively. Adjusted HRs (95% CI) for VTE patients with 1, 2, and ≥3 major risk factors relative to no major risk factor were 2.34 (1.94-2.81), 3.21 (2.67-3.85), and 6.93 (5.85-8.22), respectively. LIMITATIONS: These included possible inaccuracies or omissions in diagnoses, classification bias such as the identification of false-positive MI events, and the likely undercoding of some risk factors such as social issues. CONCLUSIONS: Traditional major cardiovascular risk factors are also predictive of MI in VTE patients. Having multiple major risk factors significantly increases the probability of developing MI events in VTE patients.

Risk of stroke after surgery in patients with and without chronic atrial fibrillation.

SUMMARY BACKGROUND: The extent to which chronic atrial fibrillation affects the risk of postoperative stroke is largely unknown. OBJECTIVES: We sought to determine the 30-day rate of stroke among patients with and without chronic AF who underwent 10 different types of surgery. PATIENTS/METHODS: The crude incidence of stroke was retrospectively determined using a population-based linked administrative database of hospitalized patients who underwent specified operations between 1 January 1996 and 30 November 2005. The risk of stroke in patients with AF was adjusted for age, race, sex, presence of diabetes, heart failure, hypertension and prior stroke. RESULTS: The overall 30-day rate of stroke in 69 202 patients with chronic AF was 1.8% (95% CI, 1.7-1.9%) vs. 0.6% (CI, 0.58-0.62%) in 2 470 649 patients without AF. The risk-adjusted odds of a postoperative stroke in patients with chronic AF were 2.1 (CI, 2.0-2.3). The highest incremental difference in the crude rate of stroke was observed in patients undergoing neurologic or vascular surgery, with a difference of approximately 2%. CONCLUSION: Patients with chronic AF had twice the risk of postoperative stroke. Randomized trials are needed to determine if aggressive perioperative anticoagulation can reduce the incidence of postoperative stroke in patients with AF.

Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study.

BACKGROUND: The efficacy and safety of vitamin K antagonists for the prevention of thromboembolism are dependent on the time for which the International Normalized Ratio (INR) is in the therapeutic range. The objective of our study was to determine the effect of introducing a simple two-step dosing algorithm, as compared with dosing by anticoagulation clinic staffs on the basis of their experience, on time in therapeutic range (TTR) of warfarin therapy. METHODS: We compared TTRs of all clinic patients before and after the introduction of a simple two-step dosing algorithm at a single anticoagulation clinic in Canada, between 1 August 2006 and 24 December 2008. TTR was calculated using the linear interpolation method of Rosendaal. RESULTS: We included 873 patients in the 'before' phase and 1088 patients in the 'after' phase. Introduction of the dosing algorithm significantly increased TTR of patients with a therapeutic INR range of 2-3 from 67.2% to 73.2% (P < 0.001), and that of patients with a therapeutic INR range of 2.5-3.5 from 49.8% to 63.8% (P < 0.001). CONCLUSIONS: The introduction of a simple two-step warfarin-dosing algorithm in place of dosing by experienced anticoagulation clinic staff significantly improved mean TTR for patients in a tertiary-care anticoagulation clinic. This inexpensive and widely applicable algorithm has the potential to improve warfarin control.

Anticoagulation clinics and patient self-testing for patients on chronic warfarin therapy: A cost-effectiveness analysis.

This study was intended to evaluate the cost-effectiveness of anticoagulation clinic care and self-testing for the management of patients on chronic warfarin therapy. Using a 5-year Markov model, we evaluated the health and economic outcomes associated with each of three different anticoagulation management approaches: (1) usual care, (2) anticoagulation clinic testing with a capillary monitor, and (3) patient self-testing with a capillary monitor. Data available in the published literature and data from a large health system were used to develop model assumptions. Model results indicate that over a 5-year period, compared with usual care, anticoagulation clinic testing results in a total of 1.7 fewer thromboembolic events and 2.0 less hemorrhagic events per 100 patients. Another 4.0 thromboembolic events and 0.8 hemorrhagic events are avoided with patient self-testing compared with anticoagulation clinic testing. In addition to the health advantages of these strategies, both also have cost advantages. When the costs incurred by provider organizations and patients are considered, patient self-testing is the most cost-effective alternative, resulting in an overall cost saving.

The cost-effectiveness of different management strategies for patients on chronic warfarin therapy.

OBJECTIVE: To examine the cost-effectiveness of moving from usual care to more organized management strategies for patients on chronic warfarin therapy. DESIGN: Using information available in the scientific literature, supplemented with data from a large health system and, when necessary, expert opinion, we constructed a 5-year Markov model to evaluate the health and economic outcomes associated with each of three different anticoagulation management approaches: usual care, anticoagulation clinic testing with a capillary monitor, and patient self-testing with a capillary monitor. PATIENTS: Three hypothetical cohorts of patients beginning long-term warfarin therapy were used to generate model results. MAIN RESULTS: Model results indicated that moving from usual care to anticoagulation clinic testing would result in a total of 1.7 thromboembolic events and 2.0 hemorrhagic events avoided per 100 patients over 5 years. Another 4.0 thromboembolic events and 0.8 hemorrhagic events would be avoided by moving to patient self-testing. When direct medical care costs and those incurred by patients and their caregivers in receiving care were considered, patient self-testing was the most cost-effective alternative, resulting in an overall cost saving. CONCLUSIONS: Results illustrate the potential health and economic benefits of organized care management approaches and capillary monitors in the management of patients receiving warfarin therapy.

The venous side: current directions in anticoagulant therapy.

The past 10 years have seen dramatic changes in how we treat deep vein thrombosis (DVT). A decade ago, we would treat patients for 5 days with intravenous heparin and then start warfarin sodium therapy and continue administering both anticoagulants for another 5 to 7 days. In the early 1990s, we started warfarin therapy at the same time heparin was begun and decreased the hospital stay from 10 to 14 days to 5 to 7 days. With the development of low-molecular-weight heparin and the approval for use as outpatient treatment, patients are now spending 1 to 2 days in the hospital, and many times, they are not admitted. A case scenario (in italics) is integrated into this review to illustrate the cost-effective application of an evidence-based approach.

Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism.

BACKGROUND: Surgery is the usual therapy for patients with primary hyperparathyroidism. We investigated the ability of a calcimimetic drug that inhibits parathyroid hormone secretion in vitro to decrease serum parathyroid hormone and calcium concentrations in patients with this disorder. METHODS: We performed a randomized, placebo-controlled study of single oral doses of 4 to 160 mg of the calcium-receptor agonist drug R-568 in 20 postmenopausal women with mild primary hyperparathyroidism. At base line, the mean (+/-SE) serum calcium concentration was 10.7+/-0.2 mg per deciliter (2.67+/-0.05 mmol per liter). Serum parathyroid hormone and calcium were measured repeatedly after each dose, and safety was assessed. RESULTS: Administration of R-568 resulted in a dose-dependent inhibition of parathyroid hormone secretion. The mean serum parathyroid hormone concentration, which was 77+/-11 pg per milliliter (18.8+/-2.7 pmol per liter; normal range, 16 to 65 pg per milliliter [3.9 to 15.9 pmol per liter) at base line, fell by 26+/-8 percent after 20 mg of R-568 (P=0.03), by 42+/-7 percent after 80 mg (P = 0.01), and by 51+/-5 percent after 160 mg (P=0.005). Serum ionized calcium concentrations fell only after the 160-mg dose, with the decrease closely following the decrease in the serum parathyroid hormone concentration. CONCLUSIONS: The calcimimetic drug R-568 reduces serum parathyroid hormone and ionized calcium concentrations in postmenopausal women with primary hyperparathyroidism.

Accuracy of laboratory and portable monitor international normalized ratio determinations. Comparison with a criterion standard.

BACKGROUND: Portable instruments that measure the prothrombin time and automatically calculate the international normalized ratio (INR) with the use of a drop of whole blood have simplified the treatment of patients who are receiving warfarin therapy. The accuracy of these portable monitors has never been determined by comparing INR results with a criterion (gold) standard INR determination. METHODS: Duplicate whole-blood INR determinations were made with two commercially available portable INR monitors. Duplicate frozen-plasma samples were measured with four different thromboplastin reagents, each with a different international sensitivity index. The criterion standard INR was determined by using an international reference thromboplastin and the manual tilt-tube technique. Agreement was evaluated by determining how accurately laboratory and monitor INR determinations matched criterion standard values in designating a sample to be within or outside of currently recommended INR target ranges. RESULTS: Two of the laboratory methods, which used relatively sensitive thromboplastins, showed close agreement with the criterion standard, whereas two laboratory methods that used less sensitive thromboplastin reagents showed poor agreement. Both of the portable monitors fell between these extremes. The two best laboratory methods ere significantly better (P < .003) than both monitors, which in turn were better (P < .003) than the remaining two laboratories. CONCLUSIONS: There is large interlaboratory variation in the accuracy of INR determinations. Laboratory methods that used insensitive (high international sensitivity index) thromboplastins performed poorly. Accuracy of monitor measurements appears satisfactory.

The transition to medication system performance indicators.

Economic and competitive pressures in the health care market are causing hospitals and other health care providers to seek more effective ways to improve the quality of care and to decrease costs. Integrating total quality management and continuous quality improvement techniques into traditional drug use evaluation methodology allows for the development of critical performance indicators. These indicators integrate the selection, use, delivery methods, and outcomes of drug therapy with other operational therapeutic modalities. The article describes the development of medication system performance indicators using heparin dosing as a model.