Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Clinically stable covid-19 patients presenting to acute unscheduled episodic care venues have increased risk of hospitalization: secondary analysis of a randomized control trial.

BACKGROUND: Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. METHODS: A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. RESULTS: Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p < 0.001, compared with patients enrolled at a MC setting. Upon Cox regression analysis adjustment patients enrolled at an AUEC setting remained at significant risk of the primary composite outcome, HR 3.40 (95% CI 1.46, 7.94). CONCLUSIONS: Patients with clinically stable COVID-19 presenting to an AUEC enrollment setting represent a population at increased risk of arterial and venous thrombosis complications, hospitalization for cardiopulmonary events, or death, when adjusted for other risk factors, compared with patients enrolled at a MC setting. Future outpatient therapeutic trials and clinical therapeutic delivery programs of clinically stable COVID-19 patients may focus on inclusion of higher-risk patient populations from AUEC engagement locations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498273.

Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial.

Importance: Acutely ill inpatients with COVID-19 typically receive antithrombotic therapy, although the risks and benefits of this intervention among outpatients with COVID-19 have not been established. Objective: To assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19. Design, Setting, and Participants: The ACTIV-4B Outpatient Thrombosis Prevention Trial was designed as a minimal-contact, adaptive, randomized, double-blind, placebo-controlled trial to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19. The trial was conducted at 52 US sites between September 2020 and June 2021; final follow-up was August 5, 2021. Prior to initiating treatment, participants were required to have platelet count greater than 100 000/mm3 and estimated glomerular filtration rate greater than 30 mL/min/1.73 m2. Interventions: Random allocation in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days. Main Outcomes and Measures: The primary end point was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause. The primary analyses for efficacy and bleeding events were limited to participants who took at least 1 dose of trial medication. Results: On June 18, 2021, the trial data and safety monitoring board recommended early termination because of lower than anticipated event rates; at that time, 657 symptomatic outpatients with COVID-19 had been randomized (median age, 54 years [IQR, 46-59]; 59% women). The median times from diagnosis to randomization and from randomization to initiation of study treatment were 7 days and 3 days, respectively. Twenty-two randomized participants (3.3%) were hospitalized for COVID-19 prior to initiating treatment. Among the 558 patients who initiated treatment, the adjudicated primary composite end point occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5-mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group. The risk differences compared with placebo for the primary end point were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the 2.5-mg apixaban group, and 1.4% (95% CI, -1.5% to 5.0%) in the 5-mg apixaban group. Risk differences compared with placebo for bleeding events were 2.0% (95% CI, -2.7% to 6.8%), 4.5% (95% CI, -0.7% to 10.2%), and 6.9% (95% CI, 1.4% to 12.9%) among participants who initiated therapy in the aspirin, prophylactic apixaban, and therapeutic apixaban groups, respectively, although none were major. Findings inclusive of all randomized patients were similar. Conclusions and Relevance: Among symptomatic clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of an event rate lower than anticipated. Trial Registration: ClinicalTrials.gov Identifier: NCT04498273.

Assessment of venous thromboembolism treatment in patients with cancer on low molecular weight heparin, warfarin, and the direct oral anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) are not recommended for venous thromboembolism (VTE) treatment in patients with cancer because their safety and efficacy have not been compared to low molecular weight heparin (LMWH) in large trials. Routine anti-Xa monitoring in cancer patients on LMWH is also not recommended due to limited data correlating anti-Xa levels and outcomes. OBJECTIVE: Compare the safety and efficacy of DOACs to LMWH and warfarin and assess the relationship of anti-Xa monitoring and outcomes in patients with cancer taking LMWH in an urban university setting. METHODS: This retrospective, cohort study analyzed the recurrence of VTE and number of bleeding events in patients with cancer. RESULTS: There were 131 patients included in the analysis. There was no difference seen in the rate of recurrent VTEs between the LMWH, warfarin and DOAC groups (9.3%, 5.9%, 9.1%, p = 0.89). There was also no difference in the rate of bleeding between groups (10.5%, 14.7%, 9.1%, p = 0.576). There was an increased rate of mortality seen in the LMWH group (26.7% vs. 2.9% vs. 18.2%, p = 0.006). There was no difference seen in recurrent VTE (10.3% vs. 8.5%, p = 0.53) or bleeding (10.3% vs. 10.7%, p = 0.661) between the monitored and unmonitored LMWH patients. CONCLUSION: Results of this analysis suggest DOACs may be as safe and effective as LMWH and warfarin for the treatment of VTE in patients with cancer, and there may be no clinical benefit to routine anti-Xa monitoring in patients on LMWH treatment. However, larger studies are needed to confirm these observations.

Upper-Extremity Deep-Vein Thrombosis: A Retrospective Cohort Evaluation of Thrombotic Risk Factors at a University Teaching Hospital Antithrombosis Clinic.

BACKGROUND: Upper-extremity deep-vein thrombosis (UEDVT) causes significant morbidity and mortality and is not well characterized in the existing literature, particularly in underrepresented minorities such as African Americans. OBJECTIVE: To describe the characteristics of a cohort of patients with UEDVT seen at an urban academic medical center. METHODS: This was a retrospective cohort study among patients with a confirmed UEDVT at the University of Illinois Hospital and Health Sciences System between 1996 and 2011. Patients were identified by ICD-9 code for UEDVT. Variables collected include thrombotic risk factors and outcomes, including recurrent thrombosis and bleeding. RESULTS: We identified 229 patients with UEDVT; 71% were African American, and 11% were diagnosed with sickle cell disease. The average number of UEDVT risk factors was 4.40 ± 1.5, the most common being central venous catheter (CVC) use (178, 78%). In the year following UEDVT, 13% experienced recurrent thrombosis, and 6% experienced major bleeding. Of 181 patients receiving warfarin after an UEDVT, 36% of international normalized ratio (INR) values were therapeutic. Patients with sickle cell disease had a lower proportion of INRs within the target range (25% vs 38%, P < 0.01), and were more likely to be lost to follow-up (67% vs 46%, P = 0.05) and experience a recurrent thrombotic event (29% vs 11%, P = 0.02). CONCLUSION: A CVC is the most common risk factor for UEDVT; however, patients with sickle cell disease demonstrate additional unique demographics and risk factors. Patients included in this underrepresented demographic cohort had a low quality of anticoagulation control, particularly those with sickle cell disease.

Comparison of thrombotic and clinical outcomes in SARS-CoV-2-pneumonia versus other viral pneumonia in an urban academic medical center.

BACKGROUND: Infection with viral pneumonia (PNA) is known to offset the coagulation cascade. Recent studies assessing novel SARS-CoV-2 infection observed a high frequency of systemic thrombotic events resulting in ambiguity if severity of infection or specific viral strain drive thrombosis and worsen clinical outcomes. Furthermore, limited data exists addressing SARS-CoV-2 in underrepresented patient populations. OBJECTIVES: Assess clinical outcomes events and death in patients diagnosed with SARS-CoV-2 pneumonia compared to patients with other types of viral pneumonia. METHODS: Retrospective cohort study evaluated electronic medical records in adult patients admitted to University of Illinois Hospital and Health Sciences System (UIHHSS) with primary diagnosis of SARS-CoV-2 PNA or other viral (H1N1 or H3N2) PNA between 10/01/2017 and 09/01/2020. Primary composite outcome was the following event incidence rates: death, ICU admission, infection, thrombotic complications, mechanical ventilation, renal replacement therapy, and major bleeding. RESULTS: Of 257 patient records, 199 and 58 patients had SARS-CoV-2 PNA and other viral PNA, respectively. There was no difference in primary composite outcome. Thrombotic events (n = 6, 3%) occurred solely in SARS-CoV-2 PNA patients in the ICU. A significantly higher incidence of renal replacement therapy (8.5% vs 0%, p=0.016) and mortality (15.6% vs 3.4%, p=0.048) occurred in the SARS-CoV-2 PNA group. Multivariable logistic regression analysis revealed age, presence of SARS-CoV-2, and ICU admission, aOR 1.07, 11.37, and 41.95 respectively, was significantly associated with mortality risk during hospitalization; race and ethnicity were not. CONCLUSION: Low overall incidence of thrombotic events occurred only in the SARS-CoV-2 PNA group. SARS-CoV-2 PNA may lead to higher incidence of clinical events than those observed in H3N2/H1N1 viral pneumonia, and that race/ethnicity does not drive mortality outcomes.

Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans.

OBJECTIVE: Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population. METHODS: A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5 mg/day alone and in the context of other variables known to influence dose variability. RESULTS: The GGCX rs10654848 (CAA)16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P=0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat frequency of only 0.27% (P=0.008 compared with African Americans). CONCLUSION: These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared with Caucasians.

Prescribing Pattern of Oral Anticoagulants in Patients With Obesity.

INTRODUCTION: There is limited efficacy and safety data for direct oral anticoagulants (DOACs) in patients with obesity, and it has been suggested to avoid DOACs in this patient population. OBJECTIVE: Describe the prescribing pattern of oral anticoagulants in obese patients in an urban university setting and assess efficacy, safety, and adherence. METHODS: Retrospective, cohort study in patients ≥18 years with a history of VTE and/or atrial fibrillation. Patients with a BMI >40 kg/m2 and/or weight >120 kilograms and a prescription for warfarin or a DOAC from August 25, 2014 until August 25, 2017 are included. The primary outcome is the number of warfarin or DOAC prescriptions. Secondary outcomes include thromboembolism and bleeding events. Patient adherence was evaluated using time in therapeutic range (TTR), adherence rate to clinic appointments, and medication possession ratio (MPR). RESULTS: Of the 276 patients who met eligibility criteria, 158 (57.2%) were prescribed warfarin and 118 (42.8%) were prescribed a DOAC. There was no difference in the rate of stroke or recurrent VTE between groups (3.2% vs. 3.4%, p = 0.944). There was also no difference in the rate of bleeding between groups (16.1% vs. 17.8%, p = 0.707). The TTR for the warfarin group was 44.8 ± 23%, and appointment adherence was 78.6 ± 20%. The MPR for the DOAC group was 0.93 ± 0.24. CONCLUSIONS: Despite limited data in obese patients, DOACs are prescribed in this population. Results suggest no difference in safety and efficacy compared to warfarin, but barriers to quality anticoagulation may exist in this population.

Outpatient Randomized Controlled Trials in the Covid-19 Era and Beyond.

Outpatient Trials in the Covid-19 Era and BeyondA group of investigators had a meeting at the National Heart, Lung, and Blood Institute in May 2020 to discuss ways to decrease thrombotic complications among symptomatic outpatients with Covid-19. The investigators discuss their approach to three specific challenges: conducting a trial remotely, working through regulatory hurdles, and recruiting a diverse population of participants.

Pharmacogenomics of warfarin dose requirements in Hispanics.

While Hispanics are the largest and most rapidly growing minority population in the United States, they are underrepresented in pharmacogenomic studies with warfarin. We sought to determine the combination of clinical and genetic influences of warfarin dose requirements in Hispanics. In addition, we tested the performance of published warfarin dosing algorithms derived from largely non-Hispanic cohorts in an inner-city U.S. Hispanic population. Genetic samples and clinical data were obtained from 50 Hispanics on a stable dose of warfarin. The contribution of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex-1 (VKORC1) genotypes and clinical factors to warfarin dose requirements was determined. The correlation between the predicted dose using published algorithms and therapeutic dose was also assessed. Compared to the VKORC1-1639 GG genotype, warfarin dose requirements were 30% and 62% lower with the GA and AA genotypes, respectively (p=0.001). The combination of the VKORC1-1639G>A and CYP2C9 genotypes and clinical factors explained 56% of the inter-patient variability in warfarin dose. Warfarin dose predicted using algorithms derived from mostly non-Hispanic cohorts was significantly correlated with the therapeutic dose in our Hispanic cohort (r(2)=0.43 to 0.49; p<0.001); the predicted dose was within 1.0 mg/day of the therapeutic dose for 40% to 50% of patients. Our data suggest that factors influencing warfarin dose requirements in Hispanic Caucasians are similar to those previously described in European Caucasians and that dosing algorithms derived from non-Hispanic Caucasian cohorts are applicable to Hispanics living in the U.S.

Bleeding incidence with concomitant use of antidepressants and warfarin.

INTRODUCTION: Bleeding is the major complication associated with warfarin therapy. Some antidepressants are also associated with increased bleeding risk. Warfarin and antidepressants are used frequently in combination, but it is unclear whether concomitant use increases the risk of bleeding beyond that with warfarin alone. The primary goal of this study was to determine whether the use of warfarin and an antidepressant increases the risk for bleeding outcomes compared with the use of warfarin alone. The secondary goal was to characterize the risk of bleeding in warfarin-treated patients taking one specific class of antidepressant, selective serotonin reuptake inhibitors (SSRIs). MATERIALS AND METHODS: This was a retrospective, single-center, study of warfarin-treated patients prescribed (n = 46) and not prescribed (n = 54) an antidepressant. Medical records over 6 months were reviewed for international normalized ratio values, medical history, bleeding type and incidence, and hospitalization due to bleeding. Patients were included in the antidepressant group if they were taking concomitant warfarin and antidepressant therapy consistently for a period of 6 months and in the control group if they were not taking an antidepressant with warfarin. RESULTS: The use of any antidepressant with warfarin was not associated with the incidence of any bleeding or major bleeding during the 6-month period. However, the use of an SSRI with warfarin was associated with an increase in any bleeding event (odds ratio 2.6, 95% confidence interval, 1.01-6.4 P = 0.04). The use of an SSRI remained a significant predictor of bleeding after accounting for other factors associated with bleeding risk. CONCLUSIONS: Based on these data, it is important to clarify the interaction between warfarin and SSRIs in regard to bleeding risk given the high frequency of their concomitant use.

Recruitment in a research study via chatbot versus telephone outreach: a randomized trial at a minority-serving institution.

Chatbots are software applications to simulate a conversation with a person. The effectiveness of chatbots in facilitating the recruitment of study participants in research, specifically among racial and ethnic minorities, is unknown. The objective of this study is to compare a chatbot versus telephone-based recruitment in enrolling research participants from a predominantly minority patient population at an urban institution. We randomly allocated adults to receive either chatbot or telephone-based outreach regarding a study about vaccine hesitancy. The primary outcome was the proportion of participants who provided consent to participate in the study. In 935 participants, the proportion who answered contact attempts was significantly lower in the chatbot versus telephone group (absolute difference -21.8%; 95% confidence interval [CI] -27.0%, -16.5%; P < 0.001). The consent rate was also significantly lower in the chatbot group (absolute difference -3.4%; 95% CI -5.7%, -1.1%; P = 0.004). However, among participants who answered a contact attempt, the difference in consent rates was not significant. In conclusion, the consent rate was lower with chatbot compared to telephone-based outreach. The difference in consent rates was due to a lower proportion of participants in the chatbot group who answered a contact attempt.

Development of pulmonary embolism in a nonhospitalized patient with COVID-19 who did not receive venous thromboembolism prophylaxis.

PURPOSE: Coronavirus disease 2019 (COVID-19) has been associated with thrombotic complications such as stroke and venous thromboembolism (VTE), and VTE prophylaxis for hospitalized patients with COVID-19 is recommended. However, extended postdischarge VTE prophylaxis and VTE prophylaxis for nonhospitalized patients with COVID-19 are not routinely recommended due to uncertain benefit in these populations. SUMMARY: Here we report development of a pulmonary embolism (PE) in a young patient without other VTE risk factors who was treated for COVID-19 in an emergency department (ED) and discharged home without VTE prophylaxis, which was consistent with current recommendations. The patient presented to the ED 12 days later with complaints of chest pain for 1 day and was found to have a PE within the segmental and subsegmental branches of the left lower lobe. CONCLUSION: This case suggests that nonhospitalized patients with COVID-19 may be at higher risk for VTE than patients with other medical illnesses and warrants further research into the risk of VTE in outpatients with COVID-19.

Implementation of a Direct Oral Anticoagulation Screening Service at a Large Academic Medical Center Provided by a Pharmacist-managed Antithrombosis Clinic as a Method to Expand Antithrombotic Stewardship Efforts.

BACKGROUND: How and when to monitor direct oral anticoagulants (DOACs) for safety and efficacy is a question many anticoagulation clinics are trying to answer. A pharmacist-led antithrombosis clinic (ATC) initiated a clinical service to provide oversight for all prescribed DOACs. OBJECTIVE: Describe the implementation and outcomes of a DOAC screening service. METHODS: The service was initiated utilizing a daily electronic prescribing report of DOAC prescriptions. Prescriptions were reviewed by clinical pharmacists to assess patient insurance, eligibility, and accuracy of prescribed doses. RESULTS: In the first year since service implementation in April 2016, 317 new prescriptions and 595 refill prescriptions were reviewed. A DOAC service pharmacist was able to reach 125 (39.4%) of 317 patients about their new prescription and 59 (9.9%) of 595 refill patients to provide education and follow-up on management as needed. Interventions were performed for 79 (28%) of 317 new prescriptions and 86 (14.5%) of 595 refill prescriptions. Common interventions with new prescriptions include contacting the prescriber for a medication or dose change (25.4%), assistance with medication access (21.5%), and coordinating appropriate lab and provider follow up (21.5%). Common interventions with refill prescriptions include recommending appropriate follow-up (50%) and contacting the prescriber for medication or dosage change (24.4%). CONCLUSION: Implementation of a DOAC screening service identified and resolved dosing errors, improved medication access, provided patient education, and improved follow-up.

Influence of cyclooxygenase-1 genotype on ex vivo aspirin response in patients at risk for stroke.

BACKGROUND: We sought to determine whether cyclooxygenase-1 (PTGS1) genotype is associated with the ability of aspirin to inhibit platelet aggregation in patients at risk for stroke. METHODS: Blood and urine samples were collected from 60 subjects, including 28 African Americans, who were taking aspirin for primary or secondary stroke prevention. Samples were analyzed for the PTGS1 A-707G, PTGS1 P17L, and glycoprotein IIIa (ITGB3)P1(A1/A2) genotypes, ex-vivo platelet aggregation, serum cholesterol, plasma salicylate levels, and urinary 11-dehydrothromboxane B(2) (11-dhTxB(2)) concentrations. The association between PTGS1 A-707G and P17L genotypes and aspirin response, as assessed by ex vivo studies and 11-dhTxB(2) concentrations, was evaluated by statistical testing and nonlinear mapping. RESULTS: Salicylate concentrations, ITGB3 genotype distribution and 11-dhTxB(2) concentrations were similar among PTGS1 genotype groups. More subjects with the PTGS1 17PP versus PL genotype had incomplete ex-vivo inhibition of platelet aggregation by aspirin (57 vs. 20%; p = 0.04). Fifty-nine percent of subjects homozygous for both the PTGS -707A and 17P alleles, but none with both the PTGS1 -707G and 17L alleles had incomplete inhibition with aspirin; p = 0.04. Similarly, nonlinear mapping showed a direct relationship between the PTGS1 17P allele and decreased aspirin response. When analyzed separately by ethnicity, the association with the P17L genotype and aspirin response persisted in African Americans, but not Caucasians. CONCLUSIONS: Our data suggest that the PTGS1 P17L genotype contributes to response to aspirin as assessed by ex-vivo platelet aggregation. Our data further suggest that the association between PTGS1 genotype and aspirin response might vary by ethnicity.

Effect of a warfarin adherence aid on anticoagulation control in an inner-city anticoagulation clinic population.

BACKGROUND: Poor adherence to warfarin therapy is a major contributor to subtherapeutic anticoagulation. OBJECTIVE: To determine whether use of a monthly medication organizer, filled at each clinic visit, improves anticoagulation control among warfarin-treated patients. METHODS: Patients who had a history of nonadherence to warfarin and were attending an inner-city anticoagulation clinic were enrolled in this prospective cohort study and provided with a 28-day medication organizer. Patients were instructed to bring their organizers and warfarin tablets to each anticoagulation clinic visit over the following 3 months. At each visit, the international normalized ratio (INR) was measured, warfarin adherence was assessed, and the organizer was filled with the prescribed warfarin regimen until the next scheduled visit. Data on warfarin adherence and INR values during the 3 months prior to enrollment were collected from medical records and compared with postenrollment data. RESULTS: Thirteen patients were enrolled and completed at least one postenrollment clinic visit. Adherence to warfarin therapy improved with use of the medication organizer (mean +/- SD preenrollment 55 +/- 25%, postenrollment 67 +/- 21%; p = 0.06). There was a significant decrease in the proportion of subtherapeutic INR values (60 +/- 25% to 35 +/- 29%; p = 0.04) and a significant improvement in the percent of time spent within the therapeutic INR range (32 +/- 22% to 56 +/- 28%; p = 0.03) after enrollment. CONCLUSIONS: Use of a monthly medication organizer significantly reduced the percent of subtherapeutic INR values and improved the time spent within the therapeutic anticoagulation range among previously nonadherent patients managed in an inner-city anticoagulation clinic.

Predictors of unstable anticoagulation in African Americans.

OBJECTIVE: We sought to identify contributors to unstable anticoagulation in African Americans. PATIENTS AND METHODS: Sixty African Americans on warfarin were enrolled. Cytochrome P450 2C9 and vitamin K epoxide reductase genotypes and vitamin K intake were assessed, and clinical and dietary data during the 12 months prior to enrollment were collected. Data were compared between stable and unstable patients, classified based on the proportion of international normalized ratio (INR) values outside the therapeutic range. RESULTS: The median proportion of out-of-range INRs among study participants was 44%; 28 patients had a higher proportion of INRs out-of-range and were included in the unstable group, with the remaining constituting the stable group. The median (IQR) number of clinic visits/year was higher among unstable versus stable patients [18 (15-22) vs. 16 (13-19); P = 0.03]. Higher warfarin doses, lower adherence, vomiting or diarrhea, and use of antiinfective agents were more common among unstable patients. Genotype was not associated with anticoagulation stability. After regression analysis, only poor adherence and gastrointestinal illness remained predictive of unstable anticoagulation. In a control group of Caucasians of similar age and sex distribution, poor adherence, but not gastrointestinal illness, was associated with unstable anticoagulation. CONCLUSION: We conclude that poor warfarin adherence and gastrointestinal illness are major contributors to unstable anticoagulation in African Americans. Our data suggest that, similar to Caucasians, improving warfarin adherence rates may be an important mean to improve anticoagulation control in African Americans. In addition, close monitoring during acute illness may be particularly important in this population.

New anticoagulant agents: direct thrombin inhibitors.

Decades of research have been devoted to developing effective, safe, and convenient anticoagulant agents. In recent years, much emphasis has been placed on the development of direct thrombin inhibitors (DTIs) that offer benefits over agents like heparin and warfarin including the inhibition of both circulating and clot-bound thrombin; a more predictable anticoagulant response, because they do not bind to plasma proteins and are not neutralized by platelet factor 4; lack of required cofactors, such as antithrombin or heparin cofactor II; inhibiting thrombin-induced platelet aggregation; and absence of induction of immune-mediated thrombocytopenia. Various injectable DTIs are currently available and used for many indications. In addition, research is now focusing on oral DTIs that seem promising and offer various advantages, such as oral administration, predictable pharmacokinetics and pharmacodynamics, a broad therapeutic window, no routine monitoring, no significant drug interactions, and fixed-dose administration.

Implementation of a New Clinic-Based, Pharmacist-Managed PCSK9 Inhibitor Consultation Service.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab were approved by the FDA in 2015. In anticipation of provider interest and a potential increase in referrals to the on-site specialty pharmacy, we created a pharmacist-managed consultation service. PROGRAM DESCRIPTION: The development of a clinic-based pharmacist-managed consultation service for the management of the PCSK9 inhibitor agents alirocumab and evolocumab is described. Key implementation steps included (a) creation of a pharmacy team and collaboration with cardiology; (b) completion of a needs assessment; (c) service creation; (d) collaboration with the on-site specialty pharmacy; (e) development of an electronic consult order and consult pool; (f) personnel training; and (g) service approval and marketing. The service development occurred over 9 months (July 2015-April 2016) and was implemented hospital-wide in May 2016. OBSERVATIONS: The University of Illinois Hospital and Health Sciences System PCSK9 inhibitor consultation service successfully integrated the benefits of a clinical review process, information technology capabilities of an electronic medical record system, and collaboration with the on-site specialty pharmacy to provide a comprehensive service that aimed to facilitate appropriate medication management from prescribing to patient administration and provide monitoring for this class of specialty medications. IMPLICATIONS/RECOMMENDATIONS: The PCSK9 pharmacist-managed consultation service provides a method for complex therapies to be managed comprehensively through the collaboration of ambulatory care clinics and outpatient specialty pharmacies. DISCLOSURES: No outside funding supported this study. Groo reports speaker bureau fees from Pfizer and Bristol-Myers Squibb. The other authors have nothing to disclose. All the authors contributed to study concept and design. Atande took the lead in data collection, and data interpretation was performed by Groo and Atanda. The manuscript was written by Atanda and revised by all the authors.

Prolonged anticoagulation after discontinuation of argatroban and warfarin therapy in an obese patient with heparin-induced thrombocytopenia.

A 32-year-old, morbidly obese African-American woman developed bilateral pulmonary emboli 12 days after undergoing Roux-en-Y gastric bypass surgery. Three days later, after receiving heparin and warfarin, she developed heparin-induced thrombocytopenia type II (HIT-II). An argatroban 1.5-microg/kg/minute infusion was administered for approximately 2.5 days. The patient also received four doses of warfarin, totaling 37.5 mg. The argatroban infusion was discontinued early on hospital day 6, at which time the patient's international normalized ratio (INR) was 4.36 and activated partial thromboplastin time (aPTT) 85.9 seconds. Her INR and aPTT values continued to rise after the argatroban was discontinued and peaked 3 days later at 5.28 and 123.6 seconds, respectively. At this time her platelet count had improved from 139 x 10(3)/mm(3) to 543 x 10(3)/mm(3). No additional warfarin was administered before discharge. On hospital day 11, the patient was discharged home with an INR of 4.12 and an aPTT of 67.1 seconds. Her aPTT and INR values remained elevated for 19 days after receiving her last dose of warfarin and for 20 days after argatroban discontinuation. She experienced no bleeding complications from these supratherapeutic coagulation parameters. She resumed treatment with warfarin as an outpatient and completed a 6-month course of anticoagulation without further incident. Clinicians should be aware that coagulation parameters may remain elevated longer than expected after argatroban discontinuation in certain patients taking concomitant warfarin. Patients with liver dysfunction and obesity appear most likely to be affected.