Transthyretin Amyloid Cardiomyopathy Risk Evaluation in a Cohort of Patients With Heart Failure.

Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, infiltrative form of heart failure (HF). Nevertheless, ATTR-CM is a largely underrecognized and misdiagnosed condition. This study's objective was to develop an efficient model to assess the chance of ATTR-CM in patients with HF. Methods This was an observational study of patients with HF who had a confirmed diagnosis of ATTR-CM and those with HF but without known ATTR-CM between January 1, 2019, and July 1, 2021. Patient characteristics were extracted from administrative and claims electronic databases and compared between the groups. A propensity score for having ATTR-CM was modeled. Samples of 50 control patients with the highest and lowest propensity scores were adjudicated to assess whether further workup to evaluate for ATTR-CM was warranted for each patient. The sensitivity and specificity of the model were calculated. Results Thirty-one patients with confirmed ATTR-CM and 7620 patients without known ATTR-CM were included in the study. Patients with ATTR-CM were more likely to be Black and to have atrial flutter/fibrillation, cardiomegaly, HF with preserved ejection fraction, pericardial effusion, carpal tunnel syndrome, joint disorders, and lumbar spinal stenosis and to use a diuretic (all p < 0.05). A propensity model with 16 inputs was developed (c-statistic = 0.875). The model's sensitivity and specificity were 71.9% and 95.2%, respectively. Conclusion The propensity model developed in this study provided an efficient means for identifying patients with HF who are more likely to have ATTR-CM and may warrant further workup.

Clinical conundrums involving statin drug-drug interactions.

Statins are the cornerstone of pharmacologic therapy for the prevention and treatment of atherosclerotic cardiovascular disease. While they are generally considered safe, statins can be affected by drug-drug interactions (DDIs) that increase their systemic exposure increasing the risk for statin-associated muscle symptoms. These interactions are primarily mediated through metabolizing enzymes such as cytochrome P450 isoenzymes and membrane-bound drug transporting proteins including P-glycoprotein and organic ion transporting polypeptide. Recognition and avoidance of clinically significant statin DDIs is important to ensure their safe use. Conversely, concern over statin DDIs that are not clinically significant may lead to inappropriate underutilization or avoidance of statins in patients who would benefit from them. While many statin DDIs are well-characterized, we present several others that are less-well-established which may warrant clinical attention.

Hyperlipidemia: effective disease management with a focus on PCSK9 inhibitors.

Hyperlipidemia is a prevalent condition in the United States and a significant contributor to atherosclerotic cardiovascular disease (ASCVD). ASCVD is a primary cause of morbidity and mortality in the United States. Low-density lipoprotein cholesterol (LDL-C) is a causal factor for the development of ASCVD. Reductions in LDL-C produce a corresponding decrease in ASCVD risk for cardiovascular events. HMG-CoA reductase inhibitors, commonly referred to as statins, remain the gold standard of hyperlipidemia treatment. However, statin monotherapy is often ineffective in reducing LDL-C to treatment guideline-recommended levels, especially in high-risk patients with established ASCVD or familial hypercholesterolemia (FH). Statin therapy causes myalgias in 5% to 10% of patients, which may lead to inadequate dose optimization, nonadherence, or inability to take a statin. Clinical guidelines recommend add-on therapy with ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors when maximally tolerated statin therapy results in suboptimal LDL-C reduction. Hyperlipidemia, especially FH, is associated with substantial clinical and financial burden and is often undertreated. Although undertreatment is partially attributable to failure to optimize statin therapy, a significant portion of patients will require a PCSK9 inhibitor for adequate LDL-C reduction. Despite this, PCSK9 inhibitor utilization rates remain low. Barriers to treatment may include clinical inertia, high out-of-pocket costs, and pharmacy benefit access issues. Managed care pharmacists can help appropriate patients overcome these barriers to PCSK9 inhibitor use and improve the attainment of LDL-C goals and outcomes, especially in high-risk patients with FH or clinical ASCVD.

Trends in high-intensity statin use and low-density lipoprotein cholesterol control among patients enrolled in a clinical pharmacy cardiac risk service.

BACKGROUND: Although high-intensity statin therapy (HIST) is recommended for most patients between 21 and 75 years of age with atherosclerotic cardiovascular disease (ASCVD), several recent analyses examining contemporary statin use trends have identified a clinical care gap in the utilization of HIST. OBJECTIVE: The objective of this study was to assess secular trends in lipid management for patients with ASCVD enrolled in a clinical pharmacy program within an integrated health care delivery system. METHODS: We performed serial cross-sectional studies over time, comprising 18,006 adults with both acute and chronic ASCVD, to assess trends in statin use and low-density lipoprotein cholesterol (LDL-C) levels from 2007 to 2016. RESULTS: Although the use of statin therapy (any intensity) remained relatively consistent throughout the 10-year study period (89% in 2007, 87% in 2016), the proportion of patients receiving HIST increased over time (44% in 2007, 67% in 2016; P < .001 for trend). Population mean LDL-C levels ranged from 73 to 83 mg/dL with a downward trend over the 10-year study period (P < .001 for trend). By 2016, the proportion of patients attaining an LDL-C <100 mg/dL and <70 mg/dL was 85% and 54%, respectively. Nonstatin lipid-lowering therapy use decreased over the study period, which was primarily driven by decreased use of ezetimibe (24% in 2007, 2% in 2016; P < .001 for trend). CONCLUSIONS: Among adults with ASCVD enrolled in a clinical pharmacy cardiac risk reduction service, guideline-directed use of HIST significantly increased over the past 10 years and coincided with decreased population LDL-C levels.

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.

Feasibility of clinical pharmacist-led CYP2C19 genotyping for patients receiving non-emergent cardiac catheterization in an integrated health system.

OBJECTIVE: To assess the feasibility of clinical pharmacist-led CYP2C19 genotype-guided P2Y12 inhibitor antiplatelet drug therapy recommendations to cardiologists in an outpatient cardiology practice. METHODS: This was a prospective, open-labeled, single-arm study conducted in an integrated healthcare delivery system between March 1, 2013 and January 23, 2014. Patients requiring non-emergent cardiac catheterization were included. A clinical pharmacist provided interpretation and recommendations from genotyping results. The feasibility of implementing CYP2C19 genotype-guided antiplatelet therapy was assessed by the: 1) percentage of patients approached who consented to CYP2C19 genotyping, 2) percentage of patients with CYP2C19 genotyping results available prior to cardiac catheterization, and 3) percentage of clinical pharmacist CYP2C19 genotype-based antiplatelet recommendations accepted by cardiologists. RESULTS: Of the 43 patients identified for potential recruitment, 22 of these were eligible for study enrollment and 6 (27%) patients consented and received CYP2C19 genotyping. All patients had genotyping results available prior to catheterization and all clinical pharmacists' antiplatelet therapy recommendations were accepted by the patients' cardiologists. Three patients had the CYP2C19 wild-type (*1/*1) genotype and the clinical pharmacist recommended clopidogrel therapy. CYP2C19 variant genotypes (i.e., *1/*2, *1/*17, and *2/*17) were found in the other three patients; alternative antiplatelet therapy was recommended for the patient with the *1/*2 genotype, while clopidogrel was recommended for those with *1/*17 and *2/*17 genotypes. CONCLUSION: A relatively small proportion of patients undergoing non-emergent cardiac catheterization consented to pharmacogenetic testing; however, their cardiologists were receptive to clinical pharmacists conducting such testing and providing corresponding pharmacotherapy recommendations. Future studies should identify patient barriers to pharmacogenetic testing.

Feasibility of clinical pharmacist-led CYP2C19 genotyping for patients receiving non-emergent cardiac catheterization in an integrated health system

Objective: To assess the feasibility of clinical pharmacist-led CYP2C19 genotype-guided P2Y12 inhibitor antiplatelet drug therapy recommendations to cardiologists in an outpatient cardiology practice. Methods: This was a prospective, open-labeled, single-arm study conducted in an integrated healthcare delivery system between March 1, 2013 and January 23, 2014. Patients requiring non-emergent cardiac catheterization were included. A clinical pharmacist provided interpretation and recommendations from genotyping results. The feasibility of implementing CYP2C19 genotype-guided antiplatelet therapy was assessed by the: 1) percentage of patients approached who consented to CYP2C19 genotyping, 2) percentage of patients with CYP2C19 genotyping results available prior to cardiac catheterization, and 3) percentage of clinical pharmacist CYP2C19 genotype-based antiplatelet recommendations accepted by cardiologists. Results: Of the 43 patients identified for potential recruitment, 22 of these were eligible for study enrollment and 6 (27%) patients consented and received CYP2C19 genotyping. All patients had genotyping results available prior to catheterization and all clinical pharmacists’ antiplatelet therapy recommendations were accepted by the patients’ cardiologists. Three patients had the CYP2C19 wild-type (*1/*1) genotype and the clinical pharmacist recommended clopidogrel therapy. CYP2C19 variant genotypes (i.e., *1/*2, *1/*17, and *2/*17) were found in the other three patients; alternative antiplatelet therapy was recommended for the patient with the *1/*2 genotype, while clopidogrel was recommended for those with *1/*17 and *2/*17 genotypes. Conclusion: A relatively small proportion of patients undergoing non-emergent cardiac catheterization consented to pharmacogenetic testing; however, their cardiologists were receptive to clinical pharmacists conducting such testing and providing corresponding pharmacotherapy recommendations. Future studies should identify patient barriers to pharmacogenetic testing (AU)

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Impact of a Clinical Pharmacy Specialist in an Emergency Department for Seniors.

STUDY OBJECTIVE: This study assesses outcomes associated with the implementation of an emergency department (ED) for seniors in which a clinical pharmacy specialist, with specialized geriatric training that included medication management training, is a key member of the ED care team. METHODS: This was a retrospective cohort analysis of patients aged 65 years or older who presented at an ED between November 1, 2012, and May 31, 2013. Three groups of seniors were assessed: treated by the clinical pharmacy specialist in the ED for seniors, treated in the ED for seniors but not by the clinical pharmacy specialist, and not treated in the ED for seniors. Outcomes included rates of an ED return visit, mortality and hospital admissions, and follow-up total health care costs. Multivariable regression modeling was used to adjust for any potential confounders in the associations between groups and outcomes. RESULTS: A total of 4,103 patients were included, with 872 (21%) treated in the ED for seniors and 342 (39%) of these treated by the clinical pharmacy specialist. Groups were well matched overall in patient characteristics. Patients who received medication review and management by the clinical pharmacy specialist did not experience a reduction in ED return visits, mortality, cost of follow-up care, or hospital admissions compared with the other groups. Of the patients treated by the clinical pharmacy specialist, 154 (45.0%) were identified as having at least 1 medication-related problem. CONCLUSION: Although at least 1 medication-related problem was identified in almost half of patients treated by the clinical pharmacy specialist in the ED for seniors, incorporation of a clinical pharmacy specialist into the ED staff did not improve clinical outcomes.

Behaviour of xyloisosaccharinic acid and xyloisosaccharino-1,4-lactone in aqueous solutions at varying pHs.

Xyloisosaccharinic acid is one of the major degradation products formed during the alkali catalysed hydrolysis of hemicelluloses. In acidic solution xyloisosaccharinic acid undergoes an acid catalysed lactonisation to generate xyloisosaccharino-1,4-lactone. We report here the solution phase properties of xyloisosaccharinic including measurement of its aqueous pK(a) (3.00 ± 0.05) using (13)C NMR methods. We also report rate constants for the acid catalysed lactonisation, k(lact(D20)), of xyloisosaccharinic acid and the results of our investigations of the kinetics of hydrolysis of xyloisosaccharino-1,4-lactone at acidic and basic pHs. The second-order rate constants for the hydrolysis reactions k(HO-) (25 M(-1)s(-1)) and k(D+) (4.13 E-4M(-1)s(-1)).

A robust method for the synthesis and isolation of ß-gluco-isosaccharinic acid ((2R,4S)-2,4,5-trihydroxy-2-(hydroxymethyl)pentanoic acid) from cellulose and measurement of its aqueous pK(a).

In alkaline pulping wood pulp is reacted with concentrated aqueous alkali at elevated temperatures. In addition to producing cellulose for the manufacture of paper, alkaline pulping also generates large amounts of isosaccharinic acids as waste products. Isosaccharinic acids are potentially useful raw materials: they are good metal chelating agents and, in their enantiomerically pure form, they are valuable carbon skeletons with predefined stereochemistry that can be easily functionalised for use in synthesis. Despite this, there is no simple procedure for isolating pure beta-(gluco)isosaccharinic acid and very limited work has been undertaken to determine the chemical and physical properties of this compound. We report here a very simple but effective method for the synthesis of a mixture containing equal portions of the two isosaccharinic acids ((2S,4S)-2,4,5-trihydroxy-2-(hydroxymethyl)pentanoic acid and (2R,4S)-2,4,5-trihydroxy-2-(hydroxymethyl)pentanoic acid) and the separation of the two as their tribenzoate esters. We also report for the first time the aqueous pK(a) of beta-(gluco)isosaccharinic acid (3.61).

Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic.

The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199-1205, 2007), Gage et al. (J Clin Ther 84:326-331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753-764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R (2) from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as >or=2x or >or=2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.