Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation and Cancer: A Target Trial Emulation from SEER-Medicare Database.

BACKGROUND: Direct oral anticoagulants (DOACs) are preferred over warfarin in patients with atrial fibrillation (AFib). However, their safety and effectiveness in patients with AFib and cancer are inconclusive. METHODS: We conducted a retrospective cohort study by emulating a target trial. Patients with a record of cancer (breast, prostate, or lung), newly diagnosed with AFib initiated DOACs or warfarin within 3 months after AFib diagnosis from the 2012-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare database were included. We compared the risk of ischemic stroke, major bleeding, and secondary outcomes (venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, and non-critical site bleeding) between patients who initiated DOACs and warfarin. Inverse probability treatment weights and inverse probability censoring weights were used to adjust imbalanced patient and disease characteristics and loss to follow-up between the two groups. Weighted pooled logistic regression were used to estimate treatment effect with hazard ratios (HRs) with 95% confidence interval (95% CIs). RESULTS: The incidence rates of stroke and major bleeding between DOAC and warfarin initiators were 9.97 vs. 9.91 and 7.74 vs. 9.24 cases per 1000 person-years, respectively. In adjusted intention-to-treat analysis, patients initiated DOACs had no statistically significant difference in risk of ischemic stroke (HR = 0.87, 95% CI 0.52-1.44) and major bleeding (HR = 1.14, 95% CI 0.77-1.68) compared to those initiated warfarin. In adjusted per-protocol analysis, there was no statistical difference in risk of ischemic stroke (HR = 1.81, 95% CI 0.75-4.36) and lower risk for major bleeding, but the 95% CI was wide (HR = 0.35, 95% CI 0.12-0.99) among DOAC initiators compared to warfarin initiators. The benefits in secondary outcomes were in favor of DOACs. The findings remained consistent across subgroups and sensitivity analyses. CONCLUSION: DOACs are safe and effective alternatives to warfarin in the management of patients with AFib and cancer.

Evaluation of Student Academic Performance After Curricular Content Reduction.

OBJECTIVE: To evaluate the effect of curricular content reduction in an integrated course sequence spanning 3 years of a Doctor of Pharmacy curriculum on student examination scores and course grades. METHODS: This 2-year, prepost study compared student overall average and final examination scores and overall course grades after the transition from a 5-day to a 4-day week of an integrated learning experience (ILE) course sequence. In addition, an anonymous, optional 23-item survey was distributed to first to third year pharmacy students asking about the 4-day week change, how they utilized the non-ILE day, and additional demographic and social characteristics to identify factors influencing success on examination and course performance during the 4-day week. RESULTS: There were 533 students included in the overall analysis, with no significant differences in overall course grades in the 5-day vs 4-day week. Examination scores were not significantly different after the transition, except in 2 of 12 courses where scores were higher and final examination scores were not significantly different, except for higher final examination scores in 1 course during the 5-day week. Significant positive influencers of top quartile of examination performance included prepharmacy grade point average ≥ 3.5, age 25 to 29 years, and prepharmacy coursework at the parent institution, whereas using the non-ILE day primarily to sleep negatively influenced outcomes. CONCLUSION: Curricular density is a prevalent problem and addressing it at a program level is essential. Reducing curricular content and hours at our institution did not adversely impact student examination and course performance and slight improvement was noted in some areas.

Development and Validation of Machine Learning Algorithms to Predict 1-Year Ischemic Stroke and Bleeding Events in Patients with Atrial Fibrillation and Cancer.

In this study, we leveraged machine learning (ML) approach to develop and validate new assessment tools for predicting stroke and bleeding among patients with atrial fibrillation (AFib) and cancer. We conducted a retrospective cohort study including patients who were newly diagnosed with AFib with a record of cancer from the 2012-2018 Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The ML algorithms were developed and validated separately for each outcome by fitting elastic net, random forest (RF), extreme gradient boosting (XGBoost), support vector machine (SVM), and neural network models with tenfold cross-validation (train:test = 7:3). We obtained area under the curve (AUC), sensitivity, specificity, and F2 score as performance metrics. Model calibration was assessed using Brier score. In sensitivity analysis, we resampled data using Synthetic Minority Oversampling Technique (SMOTE). Among 18,388 patients with AFib and cancer, 523 (2.84%) had ischemic stroke and 221 (1.20%) had major bleeding within one year after AFib diagnosis. In prediction of ischemic stroke, RF significantly outperformed other ML models [AUC (0.916, 95% CI 0.887-0.945), sensitivity 0.868, specificity 0.801, F2 score 0.375, Brier score = 0.035]. However, the performance of ML algorithms in prediction of major bleeding was low with highest AUC achieved by RF (0.623, 95% CI 0.554-0.692). RF models performed better than CHA2DS2-VASc and HAS-BLED scores. SMOTE did not improve the performance of the ML algorithms. Our study demonstrated a promising application of ML in stroke prediction among patients with AFib and cancer. This tool may be leveraged in assisting clinicians to identify patients at high risk of stroke and optimize treatment decisions.

Benefit and risk of oral anticoagulant initiation strategies in patients with atrial fibrillation and cancer: a target trial emulation using the SEER-Medicare database.

Oral anticoagulants (OACs) are recommended for patients with atrial fibrillation (AFib) having CHA2DS2-VASc score ≥ 2. However, the benefits of OAC initiation in patients with AFib and cancer at different levels of CHA2DS2-VASc is unknown. We included patients with new AFib diagnosis and a record of cancer (breast, prostate, or lung) from the 2012-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare database (n = 39,915). Risks of stroke and bleeding were compared between 5 treatment strategies: (1) initiated OAC when CHA2DS2-VASc ≥ 1 (n = 6008), (2) CHA2DS2-VASc ≥ 2 (n = 8694), (3) CHA2DS2-VASc ≥ 4 (n = 20,286), (4) CHA2DS2-VASc ≥ 6 (n = 30,944), and (5) never initiated OAC (reference group, n = 33,907). Confounders were adjusted using inverse probability weighting through cloning-censoring-weighting approach. Weighted pooled logistic regressions were used to estimate treatment effect [hazard ratios (HRs) and 95% confidence interval (95% CIs)]. We found that only patients who initiated OACs at CHA2DS2-VASc ≥ 6 had lower risk of stroke compared without OAC initiation (HR 0.64, 95% CI 0.54-0.75). All 4 active treatment strategies had reduced risk of bleeding compared to non-initiators, with OAC initiation at CHA2DS2-VASc ≥ 6 being the most beneficial strategy (HR = 0.49, 95% CI 0.44-0.55). In patients with lung cancer or regional/metastatic cancer, OAC initiation at any CHA2DS2-VASc level increased risk of stroke and did not reduce risk of bleeding (except for Regimen 4). In conclusion, among cancer patients with new AFib diagnosis, OAC initiation at higher risk of stroke (CHA2DS2-VASc score ≥ 6) is more beneficial in preventing ischemic stroke and bleeding. Patients with advanced cancer or low life-expectancy may initiate OACs when CHA2DS2-VASc score ≥ 6.

Screening for clinically relevant drug-drug interactions between direct oral anticoagulants and antineoplastic agents: a pharmacovigilance approach.

BACKGROUND: Use of direct oral anticoagulants (DOACs) in patients with cancer remains suboptimal due to the concern regarding potential drug-drug interactions (DDIs) with antineoplastic treatments. However, the clinical relevance of these DDIs is unknown. METHODS: We conducted a pharmacovigilance study of adverse event (AE) reports from the US Food and Drug Administration Adverse Event Reporting System from 1/1/2004 to 12/31/2021. AE reports containing DOACs and antineoplastic agents with CYP3A4/P-gp inhibitory or inducing activity suggested by published pharmacokinetic studies were included (n = 36,066). The outcomes of interest were bleeding or stroke, identified by MedDRA dictionary version 25.0. We used disproportionality analyses (DPA), logistic regression models (LR), and Multi-item Gamma-Poisson Shrinker (MGPS) (Empirical Bayes Geometric Means (EBGM) and 90% credible intervals (90% CIs)) algorithms to identify the safety signal of DDIs. RESULTS: The highest bleeding reporting rates for each drug class were the combination of DOACs with neratinib (39.08%, n = 34), tamoxifen (21.22%, n = 104), irinotecan (20.54%, n = 83), and cyclosporine (19.17%, n = 227). The highest rate of stroke was found for prednisolone (2.43%, n = 113). In the primary analysis, no signal of DDIs by the antineoplastic therapeutic class was detected by MGPS, DPA, and LR approaches. By individual antineoplastic drug, DOACs-neratinib was the only signal detected [EBGM (EB05-EB95) = 2.71 (2.03-3.54)]. CONCLUSION: No signal of DDIs between DOACs and antineoplastic agents was detected, except for DOAC-neratinib. Most DDIs between DOACs and antineoplastic agents may not be clinically relevant. The DDIs between DOACs and neratinib should be further examined in future research.

Assessment of novel oral anticoagulant use within a community teaching hospital.

Background: Novel oral anticoagulants (NOACs) are considered to be at least as effective and safe as warfarin with several advantages such as predictable pharmacokinetics, allowing for standardized dosing without monitoring, a lack of food interactions and fewer drug interactions; however, their misuse could potentially result in patient harm. Objective: To evaluate the appropriate use of the NOACs within a community teaching hospital. SETTING: A community teaching hospital in the United States. Method: A retrospective chart review of patients that were prescribed dabigatran, rivaroxaban, or apixaban at our institution from October 2012 through November 2014 was conducted. Main outcome measure: The primary objective was to determine the percentage of patients that were appropriately prescribed NOACs. Secondary objectives were to determine the number of patients who were inappropriately transitioned from warfarin or parenteral anticoagulants to a NOAC or vice versa, the number of incidents when a NOAC was held or discontinued inappropriately before a procedure and the number of bleeding or thrombotic events while taking a NOAC. Results: Of the 113 patients receiving therapy with an NOAC, appropriate prescribing was observed in 79.7%. Dabigatran, rivaroxaban, and apixaban were appropriately prescribed in 73.8%, 88.3%, and 85.8% of patients respectively. Lack of renal dose-adjustment in patients with reduced renal function was the most common reason for inappropriate use (8.8%). Ten out of 38 patients (26%) were inappropriately transitioned from/to other anticoagulants. Two out of six patients underwent a procedure without holding NOACs as recommended prior to surgery. Of all patients receiving NOACs, a total of 3 bleeding incidents were observed, one with each NOAC. Conclusion: The NOACs were appropriately prescribed for the majority of patients within our institution. Future efforts however should focus on ensuring appropriate dose adjustments for renal impairment, procedures for transitioning between NOACs and parenteral anticoagulants, and adequate withholding times for NOACs prior to surgery in order to optimize the management of NOACs usage within our institution.

Acquired Thrombophilia.

Acquired thrombophilia is associated with an increased risk of venous thromboembolism (VTE). Antiphospholipid syndrome (APS) is the most prevalent acquired thrombophilia and is associated with both venous and arterial thromboses. Human immunodeficiency virus (HIV) is another form of acquired thrombophilia. Risk factors associated with VTE in this population include those related to the disease itself, host factors, and the pharmacotherapy for HIV. A significant proportion of VTE events occur in patients with malignancies. There is an increase in mortality associated with patients having cancer who experience VTE when compared to patients having cancer without VTE. Combination oral contraceptive (COC) use infers risk of thromboembolic events. The risk is dependent upon the presence of an underlying inherited thrombophilia, the estrogen dose, and generation of progestin. Patients at highest risk of VTE include those receiving high-dose estrogen and fourth-generation, progesterone-containing contraceptives. With the exception of APS, thrombophilia status does not alter the acute treatment of an initial VTE in nonpregnant patients.

Pregnancy-Related Venous Thromboembolism.

Pregnancy is associated with an increased risk of venous thromboembolism (VTE), with a reported incidence ranging from 0.49 to 2 events per 1000 deliveries. Risk factors include advanced maternal age, obesity, smoking, and cesarian section. Women with a history of previous VTE are at a 4-fold higher risk of recurrent thromboembolic events during subsequent pregnancies. Additionally, the presence of concomitant thrombophilia, particularly factor V Leiden (homozygosity), prothrombin gene mutation (homozygosity), or antiphospholipid syndrome (APS), increases the risk of pregnancy-related VTE. Low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are the drugs of choice for anticoagulation during pregnancy. LMWH is preferred due to ease of use and lower rates of adverse events. Women with high thromboembolic risk particularly those with a family history of VTE should receive antepartum thromboprophylaxis. Women with low thromboembolic risk or previous VTE caused by a transient risk factor (ie, provoked), who have no family history of VTE, may undergo antepartum surveillance. Postpartum anticoagulation can be considered in women with both high and low thromboembolic risk.

Inherited Thrombophilia.

Thrombophilia alters normal hemostasis, shifting the balance in favor of thrombus formation. Inherited conditions include factor V Leiden (FVL), prothrombin G20210A mutation, deficiencies in natural anticoagulants (antithrombin [AT], protein C, and protein S), hyperhomocysteinemia, and elevations in clotting factors (factors VIII and XI). Although FVL and prothrombin mutation are common disorders, deficiencies in the natural anticoagulants are rare. The risk of initial thrombosis conferred by inherited thrombophilia varies with the highest risk in those homozygous for either FVL or prothrombin mutation, or with AT deficiency. In the nonpregnant patient, the presence of a thrombophilia does not affect treatment of an acute event. Although vitamin B supplementation has been shown to decrease the levels of homocysteine, the treatment has failed to show a benefit in thrombus prevention and is therefore not recommended.

Thrombophilia Screening.

Although controversial, screening for thrombophilia has become common. Testing for antiphospholipid antibodies is indicated in order to guide treatment decisions if there is clinical suspicion for antiphospholipid syndrome. The utility of identifying other thrombophilias in symptomatic venous thromboembolism (VTE) is questionable, as the risk of recurrence does not appear to be increased by an appreciable degree with the most common disorders (heterozygosity for factor V Leiden or prothrombin mutation). Although recurrence appears to be increased in those with homozygous or multiple abnormalities and potentially deficiencies in natural anticoagulants, screening to detect these conditions is difficult to justify based on their rarity. The American College of Chest Physicians' current guidelines note the increased risk of recurrence with idiopathic, proximal events regardless of thrombophilia status. They suggest duration of anticoagulation therapy be based on location and provoking factors rather than whether or not the individual has a thrombophilia. Because routine prophylaxis in asymptomatic individuals with thrombophilia is not recommended, screening of asymptomatic family members is difficult to justify. Screening prior to prescribing combination oral contraceptives is not cost effective, may result in unwanted pregnancies, and may have little effect on the overall rate of VTE.

A quality improvement course review of advanced pharmacy practice experiences.

OBJECTIVES: To determine strengths of and quality improvements needed in advanced pharmacy practice experiences (APPE) through a systematic course review process. DESIGN: Following the "developing a curriculum" (DACUM) format, course materials and assessments were reviewed by the curricular subcommittee responsible for experiential education and by key stakeholders. Course sequence overview and data were presented and discussed. A course review worksheet was completed, outlining strengths and areas for improvement. ASSESSMENT: Student feedback was positive. Strengths and areas for improvement were identified. The committee found reviewing the sequence of 8 APPE courses to be challenging. CONCLUSIONS: Course reviews are a necessary process in curricular quality improvement but can be difficult to accomplish. We found overall feedback about APPEs was positive and student performance was high. Areas identified as needing improvement will be the focus of continuous quality improvement of the APPE sequence.

Survey of patient knowledge related to acetaminophen recognition, dosing, and toxicity.

OBJECTIVE: To assess patient knowledge regarding acetaminophen dosing, toxicity, and recognition of acetaminophen-containing products. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: Alabama, January 2007 to February 2008. PATIENTS: 284 patients at four outpatient medical facilities. INTERVENTION: 12-item investigator-administered questionnaire. MAIN OUTCOME MEASURES: Degree of patient knowledge regarding acetaminophen safety, dosing recommendations, toxicity, alternative names and abbreviations, and products. RESULTS: Two-thirds of the 284 patients completing the survey reported current or recent use of pain, cold, or allergy medication. Of these, 25% reported knowing the active ingredient. Of patients, 46% and 13% knew that "acetaminophen" and "APAP," respectively, were synonymous with "Tylenol." Several patients (12%) believed that ingesting a harmful amount of acetaminophen was difficult or impossible. One-third of patients correctly identified the maximum daily dose, 10% reported a dose greater than 4 g, 25% were unsure of the dose, and 7% were unsure whether a maximum dose existed. One-half recognized liver damage as the primary toxicity. Results were similar between acetaminophen users and nonusers. CONCLUSION: Deficiencies were found in patient knowledge regarding acetaminophen recognition, dosing, and potential for toxicity. The development of effective educational initiatives is warranted to ensure patient awareness and limit the potential for acetaminophen overdose.

Survey of physician knowledge and counseling practices regarding acetaminophen.

OBJECTIVE: To assess physician knowledge regarding acetaminophen dosing, toxicity, and recognition of acetaminophen-containing products and counseling practices when prescribing acetaminophen-containing medications. METHODS: Resident and faculty physicians at 1 internal medicine and 2 family medicine residency programs in Alabama were asked to participate in a voluntary survey. Participants completed a 7-item self-administered questionnaire. Questions were designed to assess physician knowledge of acetaminophen dosing and toxicity, recognition of prescription and over-the-counter products containing acetaminophen, and education provided to patients when prescribing acetaminophen-containing products. Questions were formatted as multiple choice, yes/no, true/false, and short answer. Certain items contained an answer choice of "unsure." RESULTS: Of the 76 physicians who completed the survey, only 76% were aware of the maximum daily dose of acetaminophen. Although 93% recognized Lortab and 90% Percocet as acetaminophen-containing products, only 83% identified Lorcet and 75% Darvocet. More than 90% of physicians correctly identified nonacetaminophen prescription medications with the exception of OxyContin (84%) and Ultram (79%). Knowledge of over-the-counter products was generally less accurate. Ninety-eight percent recognized hepatotoxicity as the primary toxicity. Although 72% of physicians stated they provide specific instructions to patients when prescribing acetaminophen-containing medications, the information provided was limited. CONCLUSIONS: Many physicians are unaware of acetaminophen dosing and toxicity issues and have some difficulty identifying acetaminophen-containing products. Information provided by physicians when prescribing acetaminophen products was limited. How this may contribute to unintentional acetaminophen overdose is unclear but should raise concern. These results reinforce the importance of public awareness, patient counseling, and physician education regarding acetaminophen toxicity issues.

An anticoagulation therapy elective for third-year pharmacy students.

OBJECTIVE: To develop an anticoagulation elective course for third-year pharmacy students to enhance their knowledge and skills for providing anticoagulation services. DESIGN: Content developed for the course focused on standards of care, evaluation of primary literature, clinical application, billing and regulatory issues, written and verbal communication, and patient education. Teaching methods included lectures, discussions, demonstrations, and self-directed learning. ASSESSMENT: Assessment methods included multiple-choice examinations, evaluation of patient cases, student presentations, and a practical examination. Students demonstrated competencies in multiple areas and rated the course favorably. Students who completed the elective reported being more prepared for anticoagulation activities than those who did not. Confidence levels regarding participation in anticoagulation services postgraduation were similar. CONCLUSION: The elective provided valuable experience in anticoagulation therapy and increased students' perception of their preparedness related to dealing with anticoagulation issues while on advanced pharmacy practice experiences (APPEs). More exposure to management topics and the logistics of initiating anticoagulation services should be incorporated.

Complementary and alternative medications for women's health issues.

Women often seek alternative treatment options such as herbs, dietary supplements, and vitamins and minerals to treat women's health issues across the lifespan. Women may use complementary and alternative supplements for dysmenorrhea, premenstrual syndrome, infertility, nausea and vomiting during pregnancy, and symptoms of menopause. In general, there is a deficit of well-designed, randomized, controlled trials to evaluate the efficacy and safety of complementary and alternative medicine for these indications, which makes it difficult to provide evidence-based recommendations. This review outlines the evidence for efficacy and safety that is currently available for dietary supplement use by women to manage health conditions specific to the female patient.

Potential interaction between warfarin and high dietary protein intake.

A 55-year-old Caucasian man was receiving warfarin therapy after undergoing aortic valve replacement. His international normalized ratio (INR) was stabilized with warfarin 95 mg/week for 5 weeks. Commencement of a low-carbohydrate, high-protein diet resulted in a series of subtherapeutic INRs that led to a 16% increase in the dosage requirement to maintain therapeutic INRs. After the patient discontinued the diet, his INR increased, and several dosage reductions were required until his INR stabilized with his original dosage of 95 mg/week. Two additional case reports have described a possible interaction between warfarin and a high-protein diet. The potential for increased dietary protein intake to raise serum albumin levels and/or cytochrome P450 activity has been postulated as mechanisms for the resulting decrease in INRs. Given the available animal and human data that demonstrate alterations in drug metabolism in the presence of altered dietary protein intake, an increase in warfarin metabolism due to cytochrome P450 activation appears to be the most likely cause. In addition to the previously reported cases, this case indicates a potential interaction between warfarin and a high-protein diet. Because of the popularity of high-protein diets and because of the risks associated with inadequate or excessive warfarin anticoagulation, patients and health care providers should be aware of this interaction to ensure appropriate monitoring when warranted.