Temporal trends in first-line outpatient anticoagulation treatment for cancer-associated venous thromboembolism.

BACKGROUND: First-line treatment and secondary prevention of venous thromboembolism (VTE) in patients with cancer consisted, historically, of unfractionated heparin or low-molecular weight heparin (LMWH). With recent clinical trials of direct oral anticoagulants (DOAC) showing similar efficacy as LMWH, little is known about anticoagulant prescribing patterns in patients with cancer and a VTE. This study characterized the temporal trends in first-line outpatient anticoagulation therapy for cancer-associated VTE. MATERIALS AND METHODS: This retrospective cohort study of patients who were hospitalized for a cancer-associated venous thromboembolism (VTE) between 01/01/2000 and 10/31/2017 identified patients from the cancer registries at two regions of an integrated healthcare delivery system. The primary outcome was the trend in age- and sex-adjusted rates of first-line anticoagulant therapy during the 30 days post-hospital discharge. Therapies were categorized as 1) injectable LMWH monotherapy, 2) warfarin ± injectable, 3) injectable fondaparinux monotherapy, or 4) DOAC ± injectable. RESULTS: Overall, 9816 patients were included with a mean age of 66 ± 13 years and 54% were female. From 2000 to 2003, warfarin ± injectable was used in ≈90% of cases. After 2003, there was a steady decline in warfarin use (25% in 2017) corresponding with increased LMWH use: 11% in 2003 to 55% in 2017. The DOAC ± injectable use has rapidly increased from <1% in 2014 to 20% in 2017. CONCLUSIONS: From 2000 to 2017, first-line anticoagulant therapy for cancer-associated VTE has experienced a substantial increase in LMWH and DOAC use with a resultant decline in warfarin use.

Vitamin K versus warfarin interruption alone in patients without bleeding and an international normalized ratio > 10.

BACKGROUND: Reversal of an international normalized ratio (INR) > 10 with vitamin K is recommended in patients experiencing bleeding; however, information on outcomes with reversal using vitamin K in non-bleeding patients is lacking. OBJECTIVE: To compare clinical and safety outcomes between non-bleeding patients receiving warfarin with an INR > 10 who did and did not receive a prescription for vitamin K. PATIENTS/METHODS: This was a retrospective cohort study conducted in an integrated health-care delivery system. Adult patients receiving warfarin therapy who experienced an INR > 10 without bleeding between 01/01/2006 and 06/30/2018 were included. Patients were assessed for an outpatient dispensing or in-office administration of vitamin K on the day of or the day after an INR > 10 and then clinically relevant bleeding, thromboembolism, all-cause mortality, and time to INR < 4 within the next 30 days. RESULTS: A total of 809 patients was included with 332 and 477 who were and were not dispensed vitamin K, respectively. Overall, mean patient age was 71.7 years, 60.1% were female and the mean INR was 10.4 at presentation. There were no differences between groups in 30-day rates of bleeding or thromboembolism (both P > .05). Patients dispensed vitamin K had a higher likelihood of mortality (15.1% versus 10.1%, P = .032, adjusted odds ratio = 1.63, 95% confidence interval 1.03 to 2.57). Overall, time to an INR < 4 was similar between groups. CONCLUSION: Vitamin K administration was not associated with improved clinical outcomes in asymptomatic patients with an INR > 10.

Survey of current treatment practices for venous thromboembolism in patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) and venous thromboembolism (VTE) pose therapeutic challenges including potential drug interactions between CF-related therapies and anticoagulants. Despite these challenges, there are no recommendations for VTE management specific to patients with CF. Our objective was to describe VTE treatment practices among Cystic Fibrosis Foundation (CFF)-accredited care centers and affiliate programs in the United States. METHODS: An online survey was distributed to CF center directors. The survey included questions regarding centers' demographics and posed a series of hypothetical clinical scenarios to gather centers' VTE treatment practices including choice of anticoagulant, dosing practices, duration decisions, and monitoring efforts. Descriptive statistics were utilized to summarize the survey results. RESULTS: The survey response rate was 56.3%. Most centers reported treating zero to five VTE episodes per year. The following anticoagulants were used most often for VTE treatment: low-molecular-weight heparin (LMWH) (73.2%), apixaban (36.6%), warfarin (35.2%), rivaroxaban (33.8%), and unfractionated heparin (18.3%). On a scale of 0 to 100, the median confidence level in managing anticoagulant therapy was 50. Many centers expressed a desire for a CF-specific VTE treatment guideline. The most commonly cited challenging clinical situations were managing anticoagulant therapy complications (26.5%) and drug-drug interactions (21.3%). For common VTE scenarios, pediatric patients were most often treated with LMWH and warfarin, whereas adult patients were more often treated with apixaban or rivaroxaban. CONCLUSIONS: Survey results indicated CF care centers find managing VTE in patients with CF challenging and indicated that a CF-specific VTE treatment guideline would be helpful.

Treatment and Outcomes of Acute Pulmonary Embolism and Deep Venous Thrombosis: The CVRN VTE Study.

BACKGROUND: Few studies describe both inpatient and outpatient treatment and outcomes of patients with acute venous thromboembolism in the United States. METHODS: A multi-institutional cohort of patients diagnosed with confirmed pulmonary embolism or deep venous thrombosis during the years 2004 through 2010 was established from 4 large, US-based integrated health care delivery systems. Computerized databases were accessed and medical records reviewed to collect information on patient demographics, clinical risk factors, initial antithrombotic treatment, and vital status. Multivariable Cox regression models were used to estimate the risk of death at 90 days. RESULTS: The cohort comprised 5497 adults with acute venous thromboembolism. Pulmonary embolism was predominantly managed in the hospital setting (95.0%), while 54.5% of patients with lower extremity thrombosis were treated as outpatients. Anticoagulant treatment differed according to thromboembolism type: 2688 patients (92.8%) with pulmonary embolism and 1625 patients (86.9%) with lower extremity thrombosis were discharged on anticoagulants, compared with 286 patients (80.1%) with upper extremity thrombosis and 69 (54.8%) patients with other thrombosis. While 4.5% of patients died during the index episode, 15.4% died within 90 days. Pulmonary embolism was associated with a higher 90-day death risk than lower extremity thrombosis (adjusted hazard ratio 1.23; 95% confidence interval, 1.04-1.47), as was not being discharged on anticoagulants (adjusted hazard ratio 5.56; 95% confidence interval, 4.76-6.67). CONCLUSIONS: In this multicenter, community-based study of patients with acute venous thromboembolism, anticoagulant treatment and outcomes varied by thromboembolism type. Although case fatality during the acute episode was relatively low, 15.4% of people with thromboembolism died within 90 days of the index diagnosis.

Direct comparative effectiveness and safety between non-vitamin K antagonist oral anticoagulants for stroke prevention in nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies.

The non-vitamin K antagonist oral anticoagulants (NOACs) have been increasingly prescribed in clinical practice for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Direct comparisons between NOACs in trials are lacking, leaving an important clinical decision-making gap. We aimed to perform a systematic review and meta-analysis to summarize the evidence of observational studies for direct comparative effectiveness and safety amongst NOACs in patients with AF. Conference proceedings and electronic databases including MEDLINE, CINAHL, EMBASE and PUBMED were systematically searched. We included observational studies directly comparing individual NOACs in patients with nonvalvular AF who were aged ≥ 18 years for stroke prevention. Primary outcome included effectiveness outcome (stroke or systemic embolism) and safety outcome (major bleeding). Data were extracted in duplicated by two reviewers independently. A random-effects meta-analysis was conducted to synthesize the data from included observational studies. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the overall quality of evidence for each outcome. Fifteen studies were included for qualitative synthesis, twelve studies for meta-analyses. It was found that rivaroxaban and dabigatran were similar with regard to risk of stroke or systemic embolism (Hazard ratio [HR] = 1.00, 95% CI 0.91-1.10; evidence quality: low), but rivaroxaban was associated with higher risk of major bleeding (HR = 1.39, 95% CI 1.28-1.50; evidence quality: moderate). Compared with apixaban, a significantly higher risk of major bleeding was observed with rivaroxaban (HR = 1.71, 95% CI 1.51-1.94; evidence quality: low). Apixaban was associated with lower risk of major bleeding, in comparison with dabigatran (HR = 0.80, 95% CI 0.68-0.95; evidence quality: low). No differences in risk of stroke or systemic embolism was observed between rivaroxaban versus apixaban, and apixaban versus dabigatran. In this study, apixaban was found to have the most favorable safety profile amongst the three NOACs. No significant difference was observed in risk of stroke or systemic embolism between the NOACs. Such findings may provide some decision-making support for physicians regarding their choices amongst NOACs in patients with AF.Registration PROSPERO (identifier: CRD42016052908).

Effect of increased time in the therapeutic range on atrial fibrillation outcomes within a centralized anticoagulation service.

BACKGROUND: Clinical pharmacy anticoagulation services have improved the quality of anticoagulant therapy and are associated with lower rates of bleeding and thromboembolism compared to usual care. Several studies have found that higher time-in-therapeutic range (TTR) during warfarin therapy is associated with better warfarin outcomes. However, whether increasing TTR over time within an established anticoagulation service is associated with further reduction in bleeding and thromboembolic outcomes is unknown. METHODS: This was a retrospective cohort study of patients with atrial fibrillation conducted at an integrated healthcare delivery system with a centralized, pharmacist-managed anticoagulation service. Clinical outcomes (clinically-relevant bleeding, ischemic stroke or systemic embolism, and all-cause mortality) and TTR were compared between two distinct time periods: 1/1/2006 through 12/31/2007 (control group) and 1/1/2012 through 12/31/2013 (observation group) with regression modeling to adjustment for potential confounders. RESULTS: There were 3641 and 4764 patients in the control and observation groups, respectively. The mean age was 74.3 years and 54.4% of the cohort was female. Mean TTR was higher in the observation group (70.5% vs. 63.4%, p < 0.001). The composite outcome of clinically-relevant bleeding, thromboembolism and all-cause mortality occurred in 4.6% and 3.6% of the control and observation groups, respectively (adjusted odds ratio = 0.69; 95% confidence interval 0.54-0.87). Individual rates of stroke/systemic embolism and all-cause mortality were each lower in the observation group (both p < 0.05) while clinically-relevant bleeding was not significantly different (p = 0.256). CONCLUSION: Increased TTR within a clinical pharmacy anticoagulation management service was associated with a lower risk of the composite outcomes of bleeding, thromboembolism and death in a large atrial fibrillation population receiving warfarin.

Assessment of the coding accuracy of warfarin-related bleeding events.

INTRODUCTION: Using International Classification of Diseases, 9th edition (ICD-9) diagnosis codes to identify potential warfarin-related bleeding events from administrative datasets is highly efficient but may be prone to identifying non-events. The objective of this study was to evaluate the ability of bleeding-related ICD-9 codes to identify true bleeding events in patients who were receiving warfarin therapy at the time of hospitalization. METHODS: This was a cross-sectional study conducted in an integrated healthcare delivery system. Anticoagulated patients aged ≥18years and hospitalized between January 1, 2014 and March 31, 2014 were identified using administrative data queries. All hospitalizations were manually chart reviewed by a trained abstractor blinded to hospitalization diagnoses to assess for true bleeding events. Identification of the presence or lack of bleeding-related ICD-9 diagnosis code(s) for each hospitalization was then performed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each ICD-9 code present. RESULTS: There were 486 hospitalizations in 468 anticoagulated patients with 57 true bleeding events identified. Patients had a mean age of 73.4years and 50% were female. For codes in the principal position, sensitivity, specificity, PPV, and NPV were 7.0%, 99.8%, 80.0%, and 89.0%, respectively. For codes in any position, sensitivity, specificity, PPV, and NPV were 94.7%, 90.9%, 58.1%, and 99.2%, respectively. For major bleeding, sensitivity, specificity, PPV, and NPV were 100%, 83.1%, 14.0%, and 100%, respectively. CONCLUSIONS: While the absence of a bleeding ICD-9 code reliably ruled-out hospitalization for warfarin-related bleeding, bleeding ICD-9 codes in the principal position were rarely used and undesirable false positive rates were identified when ICD-9 codes when recorded in any position and for major bleeding. Manual chart review is recommended to validate bleeding events from administrative data.

Bridge Therapy Outcomes in Patients With Mechanical Heart Valves.

BACKGROUND: Bridge therapy is associated with an increased risk of major bleeding in patients with atrial fibrillation and venous thromboembolism (TE) without a corresponding reduction in TE. The benefits of bridge therapy in patients with mechanical heart valve (MHV) prostheses interrupting warfarin for invasive procedures are not well described. METHODS AND RESULTS: A retrospective cohort study was conducted at an integrated health-care delivery system. Anticoagulated patients with MHV interrupting warfarin for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified. Patients were categorized according to exposure to bridge therapy during the periprocedural period and TE risk (low, medium, and high). Outcomes validated via manual chart review included clinically relevant bleeding, TE, and all-cause mortality in the 30 days following the procedure. There were 547 procedures in 355 patients meeting inclusion criteria. Mean cohort age was 65.2 years, and 38% were female. Bridge therapy was utilized in 466 (85.2%) procedures (95.2%, 77.3%, and 65.8% of high, medium, and low TE risk category procedures, respectively). The 30-day rate of clinically relevant bleeding was numerically higher in bridged (5.8%; 95% confidence interval [CI], 3.9%-8.3%) versus not bridged procedures (1.2%; 95% CI, <0.1%-6.7%; P = .102). No TEs or deaths were identified. CONCLUSION: The use of bridge therapy is common among patients with MHV and may be associated with increased bleeding risk. Further research is needed to determine whether bridge therapy reduces TE in patients with MHV interrupting warfarin for invasive procedures.

Effect of Vitamin K Intake on the Stability of Treatment with Vitamin K Antagonists: A Systematic Review of the Literature.

Vitamin K antagonists (VKA) are highly effective for the primary and secondary prevention of arterial and venous thromboembolic events. However, patients treated with VKA have on average only 60% of their international normalized ratio (INR) values within the therapeutic range and INR instability is associated with an increased risk of thrombosis and bleeding events. Recent evidence suggests that poor dietary vitamin K intake may affect anticoagulation control, but the role of vitamin K in INR stability remains to be established. We performed a systematic review of the literature to assess the role of vitamin K dietary intake on the stability of VKA and the potential effect of daily vitamin K supplementation on VKA therapy. After a search in Medline and EMBASE databases, 15 studies for a total of 1,838 patients were included in our systematic review. Observational studies suggest an increased risk of unstable anticoagulation control in patients with lower daily vitamin K intake. On the other hand, the role of daily vitamin K supplementation or a diet with controlled vitamin K content in patients on VKA treatment remains to be established. Use of daily vitamin K supplementation may be associated with a clinically relevant increase in the time in therapeutic range in patients with unstable anticoagulation control. Conversely, this effect appears small and not clinically relevant when vitamin K was administered to an unselected population receiving VKA. Other large prospective studies are necessary to confirm our preliminary findings.

Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for intracranial hemorrhage.

BACKGROUND: Whether and when to resume oral anticoagulant therapy for patients who survive warfarin-related intracranial hemorrhage (ICH) remains a dilemma lacking consensus recommendations and high-quality evidence to guide clinical decision making. OBJECTIVE: To determine the incidences of recurrent ICH, thrombosis, and death in relation to resumption or non-resumption of warfarin therapy during the 365 days after incident ICH. METHODS: We conducted a retrospective cohort study of adult patients in an integrated healthcare delivery system who were receiving warfarin therapy at the time of incident (index) ICH between 1/1/2000 and 12/31/2007 and survived to hospital discharge. The primary outcomes were recurrent ICH, thrombosis (stroke, systemic embolism, and venous thromboembolism), and all-cause mortality during the 365 days following index ICH. Patients were assigned to one of two groups defined by warfarin therapy resumption after the index ICH. RESULTS: There were 160 patients discharged from the hospital following warfarin-related index ICH; of these 54 (33.8%) resumed warfarin therapy and 106 (66.2%) did not. Recurrent ICH occurred in a numerically greater, but statistically non-significant, proportion of patients who did not resume warfarin therapy (7.6% vs. 3.7%, p=0.497). Similarly, patients who did not resume warfarin had a three-fold higher (12.3% vs. 3.7%, p=0.092) and approximately two-fold higher (31.1% vs. 18.5%, p=0.089) rates of thrombosis and all-cause mortality, respectively, during follow up. CONCLUSION: Resumption of warfarin therapy following warfarin-associated ICH appeared not to be associated with increased risk of recurrent ICH but trended toward reduced thrombosis and all-cause mortality.

Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures.

IMPORTANCE: The risk of bleeding and recurrent venous thromboembolism (VTE) among patients receiving long-term warfarin sodium therapy for secondary VTE prevention who require temporary interruption of anticoagulant therapy for surgery or invasive diagnostic procedures has not been adequately described. OBJECTIVE: To describe the rates of clinically relevant bleeding and recurrent VTE among patients in whom warfarin therapy is interrupted for invasive procedures and compare these rates among patients who did and did not receive bridge therapy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at Kaiser Permanente Colorado, an integrated health care delivery system. Patients in whom warfarin therapy was interrupted for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified via queries of administrative data sets. A total of 1812 procedures in 1178 patients met inclusion criteria. Data on outcomes and exposures were collected between June 1, 2005, and April 30, 2012. EXPOSURES: Use of bridge therapy vs no bridge therapy during warfarin interruption. MAIN OUTCOMES AND MEASURES: Thirty-day clinically relevant bleeding, recurrent VTE, and all-cause mortality. Outcomes were verified via manual review of medical records. RESULTS: Among the 1178 patients, the mean (SD) age was 66.1 (12.7) years, 830 procedures (45.8%) were in men, and the most common indication for warfarin therapy was deep vein thrombosis (56.3%). Most patients were considered to be at low risk for VTE recurrence at the time of warfarin interruption (1431 procedures [79.0%]) according to the consensus guidelines of the American College of Chest Physicians. Clinically relevant bleeding within 30 days after the procedure in the bridge therapy and non-bridge therapy groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95% CI, 3.9-75.1). There was no significant difference in the rate of recurrent VTE between the bridge and non-bridge therapy groups (0 vs 3; P = .56). No deaths occurred in either group. CONCLUSIONS AND RELEVANCE: Bridge therapy was associated with an increased risk of bleeding during warfarin therapy interruption for invasive procedures in patients receiving treatment for a history of VTE and is likely unnecessary for most of these patients. Further research is needed to identify patient- and procedure-related characteristics associated with a high risk of perioperative VTE recurrence during warfarin therapy interruption.

Warfarin interactions with antibiotics in the ambulatory care setting.

IMPORTANCE: The effect of antibiotic coadministration on the international normalized ratio (INR) in a relatively stable, real-world warfarin population has not been adequately described. Case reports and studies of healthy volunteers do not account for the potential contribution of acute illness to INR variability. OBJECTIVE: To compare the risk of excessive anticoagulation among patients with stable warfarin therapy purchasing an antibiotic (antibiotic group) with the risk in patients purchasing a warfarin refill (stable controls) and patients with upper respiratory tract infection but not receiving an antibiotic (sick controls). DESIGN, SETTING, AND PARTICIPANTS: A retrospective, longitudinal cohort study evaluated patients receiving warfarin between January 1, 2005, and March 31, 2011, at Kaiser Permanente Colorado, an integrated health care delivery system. Continuous data were expressed as mean (SD) or median (interquartile range). Multivariable logistic regression analysis was used to identify factors independently associated with a follow-up INR of 5.0 or more. A total of 5857 (48.8%), 5579 (46.5%), and 570 (4.7%) patients were included in the antibiotic, stable control, and sick control groups, respectively. Mean age was 68.3 years, and atrial fibrillation was the most common (44.4%) indication for anticoagulation. EXPOSURES: Warfarin therapy with a medical visit for upper respiratory tract infection or coadministration of antibiotics. MAIN OUTCOMES AND MEASURES: Primary outcomes were the proportion of patients experiencing a follow-up INR of 5.0 or more and change between the last INR measured before the index date and the follow-up INR. RESULTS: The proportion of patients experiencing an INR of 5.0 or more was 3.2%, 2.6%, and 1.2% for the antibiotic, sick, and stable groups, respectively (P < .001, antibiotic vs stable control group; P < .017, sick vs stable control group; P = .44, antibiotic vs sick control group). Cancer diagnosis, elevated baseline INR, and female sex predicted a follow-up INR of 5.0 or more. Among antibiotics, those interfering with warfarin metabolism posed the greatest risk for an INR of 5.0 or more. CONCLUSIONS AND RELEVANCE: Acute upper respiratory tract infection increases the risk of excessive anticoagulation independent of antibiotic use. Antibiotics also increase the risk; however, most patients with previously stable warfarin therapy will not experience clinically relevant increases in INR following antibiotic exposure or acute upper respiratory tract infection.

Anticoagulation control with daily low-dose vitamin k to reduce clinically adverse outcomes and international normalized ratio variability: a systematic review and meta-analysis.

STUDY OBJECTIVES: Difficulties managing warfarin therapy have led to speculation that daily supplementation with a low dose of vitamin K might improve anticoagulation control and clinical outcomes. Thus we sought to review the available medical literature systematically examining the effectiveness of low-dose vitamin K supplementation for the reduction of clinically relevant adverse events due to vitamin K antagonist (VKA) use and for stabilization of the international normalized ratio (INR). DESIGN: We searched the Medline and Embase databases, the Cochrane Library, International Pharmaceutical Abstracts, and the U.S. National Institutes of Health clinical trials registry for randomized controlled trials of vitamin K supplementation versus placebo in patients receiving a VKA. We evaluated the outcomes of hemorrhage, thromboembolic events, and percentage of time in therapeutic range (TTR) of INRs by using the Grading of Recommendations Assessment, Development and Evaluation system for rating quality of evidence in the abstracted studies. SETTING: All randomized controlled trials studies published between 1970 and August 2012 which fitted our search strategy. PATIENTS: Patients over the age of 18 years on VKA therapy. RESULTS: Of the 624 studies we identified and screened, three studies (626 patients) were included in the meta-analysis. Most of the patients had a satisfactory TTR at baseline. We found low-quality evidence--downgraded for imprecision and risk of bias (i.e., limitation in study design and/or execution)--of no effect of vitamin K use (100 to 200 µg) on hemorrhagic events (relative risk [RR] 3.2, 95% confidence interval [CI] 0.2-64.2) and thromboembolic events (RR 2.2, 95% CI 0.1-47.5) and a significant but clinically unimportant effect on TTR with an absolute increase of 3.5% (95% CI 1.1-6.0). CONCLUSION: This meta-analysis, despite the few studies and overall low quality, suggests no beneficial role of low-dose (100 to 200 µg) vitamin K supplementation on the reduction of clinically relevant adverse events in patients taking VKAs, despite a small improvement of the TTR. Data were insufficient, however, from patients with unstable INRs.

Assessment of warfarin dosing requirements after bariatric surgery in patients requiring long-term warfarin therapy.

STUDY OBJECTIVE: To quantify the change in weekly warfarin dose after bariatric surgery in patients requiring long-term warfarin therapy. DESIGN: Retrospective matched-cohort study. SETTING: Anticoagulation management service in an integrated health care delivery system. PATIENTS: Patients receiving long-term warfarin anticoagulation who underwent bariatric surgery between January 1, 1996, and December 31, 2010 (27 patients), were matched by date of surgery (± 2 years), age (± 5 years), and target international normalized ratio (INR) range to patients receiving long-term anticoagulation therapy who underwent other abdominal surgical procedures: cholecystectomy or endoscopic retrograde cholangiopancreatography (59 patients [control group]). MEASUREMENT AND MAIN RESULTS: The main end point was change in postoperative warfarin dose from baseline (preoperative dose), measured at weekly postoperative intervals from weeks 1 to 8 and again at months 3 and 6. After surgery, patients in the bariatric surgery group had statistically significant decreases in weekly warfarin doses compared with preoperative dose at all postoperative time points (week 1 dose vs preoperative dose, p<0.01; doses at all other time points vs preoperative dose, p<0.001), except at 6 months (p>0.05). No statistically significant decreases in warfarin dose were detected at any postoperative time points in the control group. Twenty patients (74.1%) in the bariatric surgery group experienced a 20% or more decrease in weekly warfarin dose compared with 19 patients (32.2%) in the control group (p=0.004). No significant differences in warfarin-related adverse events were noted between groups. CONCLUSION: Weekly warfarin doses decreased in the immediate postoperative period in anticoagulated patients after bariatric surgery but returned to their preoperative doses after approximately 6 months. A similar pattern was not observed in patients in the control group who underwent other types of abdominal surgery. Compared with preoperative anticoagulation control, this resulted in reduced anticoagulation control despite close INR monitoring. If a causal relationship between bariatric surgery and warfarin sensitivity is established in future research, developing and validating a postbariatric surgery warfarin-dosing algorithm would be valuable.

Evolution, current structure, and role of a primary care clinical pharmacy service in an integrated managed care organization.

The impact of the declining number of primary care physicians is exacerbated by a growing elderly population in need of chronic disease management. Primary care clinical pharmacy specialists, with their unique knowledge and skill set, are well suited to address this gap. At Kaiser Permanente of Colorado (KPCO), primary care clinical pharmacy specialists have a long history of integration with medical practices and are located in close proximity to physicians, nurses, and other members of the health care team. Since 1992, Primary Care Clinical Pharmacy Services (PCCPS) has expanded from 4 to 30 full-time equivalents (FTEs) to provide services in all KPCO medical office buildings. With this growth in size, PCCPS has evolved to play a vital role in working with primary care medical teams to ensure that drug therapy is effective, safe, and affordable. In addition, PCCPS specialists provide ambulatory teaching sites for pharmacy students and pharmacy residents. There is approximately 1 specialist FTE for every 13,000 adult KPCO members and every 9 clinical FTEs of internal medicine and family medicine physicians. All clinical pharmacy specialists in the pharmacy department are required to have a PharmD degree, to complete postgraduate year 2 residencies, and, as a condition of employment, to become board certified in an applicable specialty. The evolution, current structure, and role of PCCPS at KPCO, including factors facilitating successful integration within the medical team, are highlighted. Patient and nonpatient care responsibilities are described.

Approaches to optimal dosing of vitamin K antagonists.

Although vitamin K antagonists (VKAs) such as warfarin have been used clinically for decades, evidence supporting how best to manage their use in clinical practice is lacking, but continues to emerge. This article summarizes available information regarding the clinical management of VKAs with focus on dosing strategies. For patients with previously stable international normalized ratio (INR) control, the single mildly out-of-range INR does not warrant a change in VKA dose. For out-of-range INRs, prompt repeat testing is associated with better INR control. After the first or second in-range INR value a maximum recall interval of 28 days is optimal, but after the third or greater consecutive in-range INR, longer recall intervals (up to 12 weeks for very stable patients) can be used. The use of validated VKA dosing nomograms is suggested as a means of reducing unwanted variability in VKA dosing decisions. Ensuring timely INR monitoring, and adjusting VKA doses when necessary, is important when interacting medications are prescribed during VKA therapy. Daily low-dose vitamin K supplementation is unlikely to improve INR control in patients with stable INR control but may be of benefit in VKA patients with unexplainable variability in the INR response. Dosing decisions during VKA therapy should follow a systematic and coordinated process as used in dedicated anticoagulation management services. Patient self-management of VKA therapy offers advantages for motivated patients who can demonstrate competency in self-management including fingerstick INR testing. Most patients with excessive anticoagulation who are not bleeding can be managed without administering vitamin K. There is an ongoing need for research evaluating VKA dosing practices that can consistently improve the outcomes of VKA therapy.

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

BACKGROUND: High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS: Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS: We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Unfractionated heparin dose requirements targeting intermediate intensity antifactor Xa concentration during pregnancy.

STUDY OBJECTIVE: To describe unfractionated heparin (UFH) dosing requirements and monitoring parameters to achieve target antifactor Xa concentrations in pregnant women receiving intermediate-dose UFH therapy. DESIGN: Retrospective cohort analysis. SETTING: Centralized anticoagulation service in an integrated health care delivery system. PATIENTS: Twenty-five pregnant women (who had 27 pregnancies) who received intermediate-dose UFH between January 1, 1998, and March 31, 2005. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data were retrieved by using an integrated electronic medical, pharmacy, and laboratory records system. The primary outcome was the required UFH dose at the time of first target antifactor Xa level achieved. Antifactor Xa levels were measured at the mid-dosing interval for UFH. An antifactor Xa assay concentration of 0.1-0.3 unit/ml was used as the target range for intermediate-dose UFH for antithrombotic management of pregnant women as described in the American College of Chest Physicians clinical practice guidelines. The mean UFH dose required to achieve this target antifactor Xa range was 236.9 units/kg/day. The UFH doses required to achieve target antifactor Xa levels correlated significantly with patient weight (r = 0.682, p<0.001). The final UFH dose/kg required at the end of pregnancy was similar to that at the first target level (p>0.05) when adjusted for weight. However, the total daily amount of UFH did increase by the end of pregnancy (21,889 vs 19,320 units, p=0.02). There was an average of 7.9 antifactor Xa determinations and 3.1 dosage modifications during the mean of 19 weeks of antenatal UFH therapy. Most (62%) antifactor Xa levels were within the target range. No thromboembolic events, heparin-induced thrombocytopenia, or osteopenic fracture occurred. There was one hemorrhagic complication that resolved with temporary withdrawal of UFH. CONCLUSIONS: Pregnant women required a mean UFH dose of 236.9 units/kg/day to achieve the targeted antifactor Xa level of 0.1-0.3 unit/ml. The required UFH doses correlated with patient weight, and most antifactor Xa levels were within the desired target range. These findings may assist clinicians in more precisely initiating and monitoring intermediate-dose UFH in pregnant patients.

Thromboembolic consequences of subtherapeutic anticoagulation in patients stabilized on warfarin therapy: the low INR study.

STUDY OBJECTIVE: To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin. DESIGN: Retrospective, matched cohort analysis. SETTING: Centralized anticoagulation service in an integrated health care delivery system. PATIENTS: A total of 2597 adult patients receiving warfarin from January 1998-December 2005; 1080 patients were in the low INR cohort and were matched to 1517 patients in the therapeutic INR cohort based on index INR date, indication for warfarin, and age. MEASUREMENTS AND MAIN RESULTS: Stable, therapeutic anticoagulation was defined as two INR values, measured at least 2 weeks apart, within or above the therapeutic range. The low INR cohort included patients with a third INR value of 0.5 or more units below their therapeutic range. The therapeutic INR cohort included patients with a third therapeutic INR value and no INR value 0.2 or more units below their target INR range in the ensuing 90 days. The primary outcome was anticoagulation-related thromboembolism during the 90 days after the index INR. Secondary outcomes were times to the first occurrence of anticoagulation-related complications (bleeding, thromboembolism, or death) in the 90 days after the index INR. Four thromboembolic events (0.4%) occurred in the low INR cohort and one event (0.1%) in the therapeutic INR cohort (p=0.214). The differences in the proportions of thromboembolism, bleeding, or death were not significant between the cohorts (p>0.05). No significant differences were noted in the hazard of thromboembolism, bleeding, or death between the cohorts (p>0.05). CONCLUSION: Patients with stable INRs while receiving warfarin who experience a significant subtherapeutic INR value have a low risk of thromboembolism in the ensuing 90 days. The risk was similar to that observed in a matched control population in whom therapeutic anticoagulation was maintained. These findings do not support the practice of anticoagulant bridge therapy for patients stabilized on warfarin therapy to reduce their risk for thromboembolism during isolated periods of subtherapeutic anticoagulation.

Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program.

BACKGROUND: Substitution of generic warfarin initially was discouraged because of concerns regarding therapeutic failure or toxicity. Although subsequent research with AB-rated (i.e., bioequivalent) warfarin did not confirm initial concerns, the issue is not settled for all clinicians. OBJECTIVES: We sought to provide additional information regarding the clinical and economic impact of warfarin conversion by analyzing a real-life sample of patients receiving long-term anticoagulation therapy who were switched from brand name to generic warfarin. METHODS: Patients who had been taking warfarin for at least 180 days and had received uninterrupted oral anticoagulation 90 days before and 90 days after switching to generic warfarin were included. The switch date was based on the first time generic warfarin was dispensed from our pharmacies. The primary end point was the calculated amount of time each patient's international normalized ratio (INR) values were within the patient-specific target INR range in the 90 days before and after the switch. Data regarding adverse events and medical resource utilization were also collected. Pharmacoeconomic analyses were performed. RESULTS: The analysis included 2299 patients. The overall difference in calculated time INR values were below (22.6% before vs 26.1% after switch, p<0.0001) and within (65.9% before vs 63.3% after switch, p=0.0002) the therapeutic INR range was statistically but not clinically significant. Only 28.0% of patients experienced a change in therapeutic INR control of 10% or less, 33.1% experienced INR control that improved by greater than 10%, and 38.9% experienced INR control that worsened by more than 10%. The difference in total treatment costs associated with brand name and generic warfarin was 3128 dollars/100 patient-years in favor of the generic product. Sensitivity analyses revealed that cost savings associated with warfarin conversion in this health care system were highly dependent on the difference between warfarin costs and cost of treating anticoagulation-related adverse events. CONCLUSIONS: Most of these patients were successfully switched from brand name to generic warfarin. However, supplemental INR monitoring is warranted when one warfarin product is substituted for another to allow timely detection of those patients who experience significant changes in anticoagulation response.