An Evaluation of the Early Pharmacodynamic Response After Simultaneous Initiation of Warfarin and Amiodarone

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97172/1/0091270009351885.pd

Optimizing preoperative antibiotics in patients with β-lactam allergies: A role for pharmacy

PURPOSE: Patients with a reported β-lactam allergy (BLA) are often given alternative perioperative antibiotic prophylaxis, increasing risk of surgical site infections (SSIs), acute kidney injury (AKI), and Clostridioides difficile infection (CDI). The purpose of this study was to implement and evaluate a pharmacist-led BLA clarification interview service in the preoperative setting. METHODS: A pharmacist performed BLA clarification telephone interviews before elective procedures from November 2018 to March 2019. On the basis of allergy history and a decision algorithm, first-line preoperative antibiotics, alternative antibiotics, or allergy testing referral was recommended. The pharmacist intervention (PI) group was compared to a standard of care (SOC) group who underwent surgery from November 2017 to March 2018. RESULTS: Eighty-seven patients were included, with 50 (57%) and 37 (43%) in the SOC and PI groups, respectively. The most common surgeries included orthopedic surgery in 41 patients (47%) and neurosurgery in 17 patients (20%). In the PI group, all BLA labels were updated after interview. Twenty-three patients were referred for allergy testing, 12 of the 23 (52%) completed BLA testing, and penicillin allergies were removed for 9 of the 12 patients. Overall, 28 of the 37 (76%) pharmacy antibiotic recommendations were accepted. Cefazolin use significantly increased from 28% to 65% after the intervention (P = 0.001). SSI occurred in 5 (10%) patients in the SOC group and no patients in the PI group (P = 0.051). All of these SSIs were associated with alternative antibiotics. Incidence of AKI and CDI was similar between the groups. No allergic reactions occurred in either group. CONCLUSION: Implementation of a pharmacy-driven BLA reconciliation significantly increased β-lactam preoperative use without negative safety outcomes

Cumulative mutagenesis of the basic residues in the 201-218 region of insulin-like growth factor (IGF)-binding protein-5 results in progressive loss of both IGF-I binding and inhibition of IGF-I biological action

We have reported previously that mutation of two conserved nonbasic amino acids (G203 and Q209) within the highly basic 201–218 region in the C-terminal domain of IGF-binding protein-5 (IGFBP-5) decreases binding to IGFs. This study reveals that cumulative mutagenesis of the 10 basic residues in this region, to create the C-Term series of mutants, ultimately results in a 15-fold decrease in the affinity for IGF-I and a major loss in heparin binding. We examined the ability of mutants to inhibit IGF-mediated survival of MCF-7 cells and were able to demonstrate that this depended not only upon the affinity for IGF-I, but also the kinetics of this interaction, because IGFBP-5 mutants with similar affinity constants (KD) values, but with different association (Ka) and dissociation (Kd) rate values, had markedly different inhibitory properties. In contrast, the affinity for IGF-I provided no predictive value in terms of the ability of these mutants to enhance IGF action when bound to the substratum. Instead, these C-Term mutants appeared to enhance the actions of IGF-I by a combination of increased dissociation of IGF-IGFBP complexes from the substratum, together with dissociation of IGF-I from IGFBP-5 bound to the substratum. These effects of the IGFBPs were dependent upon binding to IGF-I, because a non-IGF binding mutant (N-Term) was unable to inhibit or enhance the actions of IGF-I. These results emphasize the importance of the kinetics of association/dissociation in determining the enhancing or inhibiting effects of IGFBP-5 and demonstrate the ability to generate an IGFBP-5 mutant with exclusively IGF-enhancing activity

EVALUATION OF GUIDELINE DIRECTED MEDICAL THERAPY IN A PHARMACIST-LED HEART FAILURE CLINIC

Background: Guideline directed medical therapy (GDMT) for the treatment of heart failure with reduced ejection fraction (HFrEF) improves morbidity and mortality. According to the CHAMP-HF registry, only 15% of patients with HFrEF achieve target dosing. Published literature reports increased achievement of GDMT by 25-40% through a multidisciplinary approach. However, the pharmacists’ role on the impact of GDMT is not well described. The purpose of this study is to evaluate the impact that the CVD Ambulatory Care Pharmacy Clinic has on achievement of GDMT for patients with HFrEF. Methods: This is the interim analysis of an IRB approved retrospective cohort study. This study compares achievement of GDMT in HFrEF patients managed by the pharmacy clinic versus the control group. GDMT is defined as achievement of target dosing or maximum tolerated doses. Control group represents those not seen by CVD Pharmacy clinic. Inclusion criteria includes adult patients with EF ≤ 45%, hospitalization in the previous 12 months, followed by a cardiologist within the health system, and not on maximum tolerated doses of GDMT. The primary outcome is the number of patients on GDMT 12 months after the initial visit. Secondary outcomes include days from initial visit until GDMT, number of patients on moderate dosing of GDMT and change in EF after GDMT. Patients were enrolled from October 1, 2019 through September 30, 2020. Results: Achievement of GDMT at 12 months was 67.2% (39/58) in the intervention group compared to 16.2% (7/43) in the control (P \u3c0.001). Days to GDMT was a median of 95.5 [57-175.5] days and 143 [64-214] days for the intervention and control group respectively (P = 0.493). In the intervention group, 50% (29/58) of patients achieved moderate dosing at 12 months compared to 11.6% (5/43) in the control group (P\u3c0.001). Patients in the intervention group who had an echo after achieving GDMT had a median increase in EF of 12% [5-20] after GDMT achievement. For all patients who achieved GDMT, 32.6% (15/46) achieved target dosing of medications. Conclusion: The CVD Ambulatory Care Pharmacy Clinic was associated with higher rates of GDMT achievement compared to the control and a shorter time to GDMT achievement

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions

Antithrombotic alternatives for stroke prevention in atrial fibrillation: critical differences and remaining questions

Three therapeutic alternatives for prevention of stroke in patients with atrial fibrillation are available in dabigatran (an oral direct thrombin inhibitor), rivaroxaban, and apixaban (both oral blood coagulation factor Xa inhibitors). Compared with warfarin, these new agents have a more predictable pharmacodynamic response and fewer major clinically relevant drug–drug interactions. These agents also have few, if any, food–drug interactions, and infrequent or no need for routine laboratory monitoring. These agents also bring new disadvantages, particularly lack of clearly defined reversal strategies, inability to effectively monitor patient response, and higher cost. Selection of the most appropriate oral antithrombotic agent for a given patient is dependent on clinician knowledge of the similarities and critical differences between the available antithrombotic medications

Overview of betrixaban and its role in clinical practice

PURPOSE: The role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely medically ill patients and its efficacy and safety profiles are reviewed. SUMMARY: Acutely medically ill patients have a high risk of developing VTE during hospitalization, and this risk continues into the postdischarge phase. Extended-duration betrixaban therapy has been evaluated in a large clinical trial (the APEX trial) and in a meta-analysis of pooled data on acutely medically ill patients. These studies have shown positive outcomes when betrixaban was compared with conventional-duration subcutaneous enoxaparin therapy for prevention of VTE in acutely medically ill patients. In parallel with these results, oral betrixaban therapy was found to be associated with a rate of major bleeding comparable to that associated with subcutaneous enoxaparin therapy; however, betrixaban use was associated with a higher cumulative rate of major and clinically relevant nonmajor bleeding. In the APEX trial, the primary endpoint was not met in 1 of the prespecified cohorts, but betrixaban appeared to confer benefit in another cohort and in the overall study population. Certain populations of patients, including the elderly, are at high risk for bleeding (mainly attributable to altered pharmacokinetics and polypharmacy); such patients are not appropriate candidates for extended-duration betrixaban therapy. Betrixaban can be a potential option for VTE prevention in medical patients; however, drug interaction potential and third-party coverage should be evaluated prior to prescribing. CONCLUSION: Betrixaban is an oral option for VTE prevention in medical patients

Cardiovascular Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics for the Clinical Practitioner

Current clinical cardiovascular practice requires a clinician to have a strong foundation in multiple aspects of pharmacology. Modern cardiovascular regimens are complex, and optimal management, application of evolving guidelines, and adoption of new therapies build off a more basic understanding of pharmacokinetics and pharmacodynamics. In addition, it is likely time to add a third pillar into this discussion, the expanding field of pharmacogenomics referring to the genetic influences on drug response. This field has increasing applications in medicine and clearly holds significant promise for cardiovascular disease management. Awareness of pharmacogenomic advances and the fundamentals of pharmacokinetics and pharmacodynamics can help the clinician more easily deliver great care. Here we attempt to briefly summarize and simplify key concepts of pharmacokinetics, pharmacodynamics, and pharmacogenomics relevant to the cardiovascular disease practitioner

Pharmacoeconomic analysis for diagnosis and treatment of suspected heparin-induced thrombocytopenia

Learning Objectives: Heparin-induced thrombocytopenia (HIT) is an immune-mediated condition that is associated with a 30-75% increased risk of thrombosis. The variation in interpretation of laboratory data and clinical diagnosis of HIT has led to different management approaches for HIT, which contributes to significant healthcare cost. The aim of this project was to evaluate the economic impact from treatment of patients with suspected HIT in order to identify cost reduction opportunities. Methods: Single-center, retrospective analysis of patients evaluated for HIT at Henry Ford Hospital between December 2013 and August 2016. Data was collected for adult patients with a platelet-factor 4 enzyme linked immunosorbent assay (PF4-ELISA) result during the study period. Cost (composite of hospital, drug, and laboratory costs) was evaluated for patients with a low optical density (OD \u3c 1.0) compared to those with a high result (OD ≥ 1.0). Predictive value of the Warkentin 4T score and the PF4-ELISA was determined when confirmatory serotonin-release assay (SRA) result was available. Results: A total of 119 patients were included in the analysis. Only 92 patients had a confirmatory SRA. Baseline characteristic were similar between the groups. The total cost of HIT therapy was near double in the high OD group ($33,023 vs.$18.342, p \u3c 0.00001). Patients in the high OD group were also more likely to have an intermediate risk 4T score compared to higher frequency of low risk in the low OD group (4 vs. 2, p = 0.009). Sensitivity and specificity of the 4T score and PF4-ELISA were similar to previous literature. A cost-minimization analysis identified $30,000 per patient of cost savings with standardization of the approach to patients with suspected HIT. Conclusions: There are significantly higher hospital expenditures for patients with a higher OD, which is largely driven by cost of hospital stay; however, not all patients with an OD ≥ 1.0 were diagnosed with HIT and confusion with interpretation of lab assays persists. Our study gives merit to the establishment of a more streamlined and systematic process for diagnosis and treatment of HIT to reduce hospital expenditures