Platelets in Thrombosis and Atherosclerosis: A Double-Edged Sword.

This review focuses on the dual role of platelets in atherosclerosis and thrombosis, exploring their involvement in inflammation, angiogenesis, and plaque formation, as well as their hemostatic and prothrombotic functions. Beyond their thrombotic functions, platelets engage in complex interactions with diverse cell types, influencing disease resolution and progression. The contribution of platelet degranulation helps in the formation of atheromatous plaque, whereas the reciprocal interaction with monocytes adds complexity. Alterations in platelet membrane receptors and signaling cascades contribute to advanced atherosclerosis, culminating in atherothrombotic events. Understanding these multifaceted roles of platelets will lead to the development of targeted antiplatelet strategies for effective cardiovascular disease prevention and treatment. Understanding platelet functions in atherosclerosis and atherothrombosis at different stages of disease will be critical for designing targeted treatments and medications to prevent or cure the disease Through this understanding, platelets can be targeted at specific times in the atherosclerosis process, possibly preventing the development of atherothrombosis.

Learning and memory performance following acute intranasal insulin administration in abstinent smokers.

The highest incidence of relapse to smoking occurs within the first 2 weeks of a cessation attempt. In addition to enhanced nicotine craving, this phase of smoking cessation is also marked by learning and memory dysfunction. Many smokers are not able to overcome these symptoms, and they relapse to smoking shortly after trying to quit. In two clinical studies, we evaluated intranasal insulin for efficacy in improving learning and memory function during nicotine withdrawal. Our first study was a crossover evaluation (N = 19) following 20 hr of smoking abstinence. Study 2 was a parallel design study (N = 50) following 16 hr of abstinence. Intranasal insulin (60 IU) dose was administered in both studies and cognitive function was measured using California Verbal Learning Test-II. Intranasal insulin did not improve learning over the 5 verbal learning trials. In addition, intranasal insulin did not improve either short- or long-delay recall in either study. In summary, the one-time administration of intranasal insulin does not improve verbal learning and memory in smokers. Whether longer administration schedules may be of benefit should be evaluated in future studies.

Characterization of a novel endothelial biosensor assay reveals increased cumulative serum inflammatory potential in stabilized coronary artery disease patients.

BACKGROUND: Vascular disease is promoted by systemic inflammation that can arise from sites distal to the affected vessels. We sought to characterize the net inflammatory potential of serum from patients with coronary artery disease (CAD) using cultured endothelial cells as a cumulative biosensor. METHODS AND RESULTS: Serum samples from CAD patients (N = 45) and healthy control subjects (N = 48) were incubated with primary human coronary artery endothelial cells at a 1:10 dilution for 4 h, followed by isolation of the cellular RNA. Alteration of inflammation-responsive elements (adhesion molecules and cytokines) was assessed by gene expression. Specific indicators included intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and interleukin-8 (IL-8). Additionally, the cytokine levels in serum samples from all subjects were quantified. Serum from CAD subjects induced greater endothelial ICAM-1, VCAM-1, and IL-8 expression compared to healthy control serum (p < 0.001 for each analysis). The three indicators of inflammatory potential (ICAM-1, VCAM-1, and IL-8 mRNA) trended independently of each other and also of serum inflammatory biomarkers. IL-8 expression correlated negatively with serum HDL levels but positively correlated with VLDL, plasminogen activator inhibitor-1 and C-reactive protein. Interestingly, serum levels of cytokines in CAD patients were not statistically different from healthy control subjects. A year of follow-up in a sub-group of CAD subjects revealed relatively stable measures. CONCLUSIONS: As yet unidentified circulating factors in the serum of CAD patients appear to activate endothelial cells, leading to upregulation of adhesion molecules and chemokines. This cumulative assay performed well in terms of discriminating patients with CAD compared to healthy subjects, with greater range and specificity than specific inflammatory markers.

Evinacumab-dgnb (Evkeeza-REGN1500), A Novel Lipid-Lowering Therapy for Homozygous Familial Hypercholesterolemia.

Chronically elevated low-density lipoprotein (LDL) has harmful effects on the vasculature including increased vasoconstriction and the formation of plaques which may rupture, causing coronary heart disease and stroke. In patients with familial hypercholesterolemia, adequate reduction of LDL is especially challenging. Although HMG-CoA reductase inhibitors (statins) are the mainstays for LDL lowering, other treatments such as proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, incliseran, lomitapide, and apheresis have been employed in an effort to achieve adequate LDL reduction in these patients. Despite these available therapies, many patients with familial hypercholesterolemia do not meet the LDL targets suggested in current guidelines. Evinacumab is a novel lipid-lowering therapy that exerts its LDL-lowering effect through inhibition of angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 inhibits the breakdown of triglyceride-rich lipoproteins, such as very low-density lipoprotein and chylomicrons. By inhibiting ANGPTL3, evinacumab allows these lipoproteins to be degraded, ultimately leading to reductions in LDL, high-density lipoprotein, and triglycerides. Clinical trials have demonstrated evinacumab to be safe and effective in reducing LDL. However, data are lacking regarding its potential to reduce risk of atherosclerotic cardiovascular disease. Evinacumab is generally well tolerated with the primary adverse effects comprising infusion reactions, nasopharyngitis, influenza-like illness, dizziness, rhinorrhea, and nausea. While evinacumab is an interesting therapy, until it is proven to reduce cardiovascular events, its high cost leaves its anticipated role in therapy somewhat ambiguous. In the meantime, it may be a useful therapy for those with homozygous familial hypercholesterolemia.

A Novel Subcutaneous Furosemide Formulation for Outpatient Management of Heart Failure.

In patients with fluid overload and congestion, parenteral diuretic therapy is frequently utilized. However, administration of parenteral diuretic therapy commonly requires hospital admission or outpatient clinic visits. Furoscix (scPharmaceuticals, Burlington, MA), a subcutaneous formulation of furosemide designed for home use, offers new treatment possibilities with the potential for profound cost savings for patients and health systems. Currently, subcutaneous furosemide formulations have been studied in palliative care populations and outpatient clinics, however, new literature has evaluated utility in prescribing on discharge from the emergency department. This review aims to describe the pharmacokinetic profile and utilization of subcutaneous furosemide for treatment of congestion in patients with heart failure.

Enabling Factors for the Implementation of Competency-Based Curricula in Colleges and Schools of Pharmacy.

OBJECTIVES: To review the implementation drivers of competency-based pharmacy education (CBPE) and provide recommendations for enablers. FINDINGS: Competency-based education is an emerging model in the health professions, focusing on time-variable competency development and achievement compared with a time-bound, course-based, traditional model. CBPE is an outcomes-based organized framework of competencies enabling pharmacists to meet health care and societal needs. However, challenges need to be recognized and overcome for the successful implementation of CBPE. Competency drivers include defining the competencies and roles of stakeholders, developing transparent learning trajectories and aligned assessments, and establishing lifetime development programs for stakeholders. Organization drivers include developing support systems for stakeholders; facilitating connections between all educational experiences; and having transparent assessment plans, policies, and procedures that align with core CBPE precepts, including the sustainability of time-variability. Leadership drivers include establishing growth mindset and facilitating a culture of connection between workplace and educational environments, program advocacy by institutional leaders, accepting failures as part of the process, shifting the organizational culture away from learner differentiation toward competence, and maintaining sufficient administrative capability to support CBPE. SUMMARY: The successful implementation of CBPE involves enabling the competency, organization, and leadership drivers that will lead to program success. More research is needed in the areas of creation, implementation, and assessment of CBPE to determine success in this model. We have reviewed and provided recommendations to enable the drivers of successful implementation of CBPE.

Competency-based pharmacy education definition: What components need to be defined to implement it?

OBJECTIVES: This study aimed to define the essential elements in the proposed competency-based pharmacy education (CBPE) definition, provide the key defining components of each essential element on the basis of educational theory and evidence, and define how the essential elements meet the identified needs for CBPE. METHODS: best-practice integrative review was conducted as part of the work of the American Association of Colleges of Pharmacy CBPE Task Force to define the essential elements in the CBPE definition and how these elements fit with the need for CBPE. The definition was compared with other published competency-based education definitions across K-12, higher education, medical education, and veterinary education. Task Force members then met to develop a consensus on the core components of the 5 essential elements in the definition. Next, the Task Force evaluated the fit of CBPE by matching the identified needs, discussed in detail elsewhere, across each of the stakeholder perspectives with the core components of the 5 essential elements in the derived definition of CBPE. FINDINGS: Upon review of the proposed CBPE definition, the Task Force identified 5 essential elements. These elements include the following: meeting health care and societal needs, outcomes-based curricular model, de-emphasized time, learner-centered culture, and authentic teaching and learning strategies aligned to assessments. SUMMARY: This article helps to establish a common language for CBPE by defining the essential elements of the core components of the definition, and provides a starting point for further exploration of CBPE.

The Need for Competency-Based Education.

OBJECTIVES: While pharmacy education updates learning as new information arises, changes to learning experiences can trail behind current practices and technology. There have been multiple calls for radical changes in how health professions education is delivered to ensure patients are receiving high-quality care. Competency-based education has been one way discussed in the literature for how to handle this need to develop students who have a willingness to learn and can problem-solve. The goal of this review is to examine whether competency-based education is needed to drive the profession of pharmacy forward. FINDINGS: To address, we collaboratively identified stakeholder perspectives to evaluate the need. The following stakeholders achieved consensus among the committee members: patients/society, learners, workplace/profession, and academic institutions. SUMMARY: Based on those perspectives, needs, and gaps to address those needs were identified and are presented in this review.

Use of number needed to treat in cost-effectiveness analyses.

OBJECTIVE: To review the use of number needed to treat (NNT) and/or number needed to harm (NNH) values to determine their relevance in helping clinicians evaluate cost-effectiveness analyses (CEAs). DATA SOURCES: PubMed and EconLit were searched from 1966 to September 2012. STUDY SELECTION AND DATA EXTRACTION: Reviews, editorials, non-English-language articles, and articles that did not report NNT/NNH or cost-effectiveness ratios were excluded. CEA studies reporting cost per life-year gained, per quality-adjusted life-year (QALY), or other cost per effectiveness measure were included. Full texts of all included articles were reviewed for study information, including type of journal, impact factor of the journal, focus of study, data source, publication year, how NNT/NNH values were reported, and outcome measures. DATA SYNTHESIS: A total of 188 studies were initially identified, with 69 meeting our inclusion criteria. Most were published in clinician-practice-focused journals (78.3%) while 5.8% were in policy-focused journals, and 15.9% in health-economics-focused journals. The majority (72.4%) of the articles were published in high-impact journals (impact factor >3.0). Many articles focused on either disease treatment (40.5%) or disease prevention (40.5%). Forty-eight percent reported NNT as a part of the CEA ratio per event. Most (53.6%) articles used data from literature reviews, while 24.6% used data from randomized clinical trials, and 20.3% used data from observational studies. In addition, 10% of the studies implemented modeling to perform CEA. CONCLUSIONS: CEA studies sometimes include NNT ratios. Although it has several limitations, clinicians often use NNT for decision-making, so including NNT information alongside CEA findings may help clinicians better understand and apply CEA results. Further research is needed to assess how NNT/NNH might meaningfully be incorporated into CEA publications.

Recommendations and Next Steps For Competency-Based Pharmacy Education.

In July 2021, the chairs of the American Association of Colleges of Pharmacy Council of Deans, Council of Faculties, and Council of Sections developed a task force to discuss potential ways to improve pharmacy education. The Competency-Based Education (CBE) Joint Task Force was created to explore the pros and cons of advancing a competency-based approach to pharmacy education (CBPE) and to determine ways to create more flexibility within pharmacy curricula to enable CBE. To achieve these goals, the Task Force systematically reviewed available resources and outlined the pros and cons of CBPE, best practices for implementation, strategies to minimize barriers, and recommendations on whether CBE should be implemented in pharmacy education. This commentary summarizes the Task Force's findings regarding whether CBPE is a suitable approach for pharmacy education and the next steps if implemented.

Blood pressure monitoring technique impacts hypertension treatment.

BACKGROUND: In 2005 the American Heart Association (AHA) released updated recommendations for blood pressure (BP) monitoring in order to ensure accurate BP measurements. OBJECTIVE: To determine if current methods of BP assessment in an ambulatory clinic result in significantly different BP measurements than those obtained by following the AHA recommendations and if these BP differences impact treatment decisions. RESEARCH DESIGN: Randomized prospective analysis. SETTING: University of New Mexico Hospital Adult Internal Medicine clinic. PATIENTS: Forty adults with hypertension METHODS: Patient BPs were measured using both the traditional triage method and the AHA-recommended method in cross-over fashion in random order. Two complete medical profile summaries were then constructed for each patient: one for each BP measurement obtained by each technique. These profiles were then reviewed by a panel of providers who provided hypothetical hypertension treatment recommendations. RESULTS: Individual BP results varied greatly between the two methods. SBP readings differed by ≥5 mmHg in either direction for 68% of patients while 78% of patient's DBP readings differed by ≥2 mmHg in either direction. Overall, 93% of patients had a BP difference of either ≥5 mmHg systolic or ≥2 mmHg diastolic. Five patients were determined to be at goal with the triage method, but were higher than their goal BP with the AHA method Significant differences were also seen in treatment recommendations for a given patient based on the differences seen between the two obtained BP readings. The number of patients with treatment variations between their two profiles ranged from 13% to 23% depending on the reviewing provider (p < 0.01 for all providers). CONCLUSION: Inaccurate BP assessment is common and may impact hypertension treatment decisions.

Inclisiran: Small Interfering Ribonucleic Acid Injectable for the Treatment of Hyperlipidemia.

Elevated plasma lipid levels, especially low-density lipoprotein, are correlated with atherosclerotic cardiovascular disease (ASCVD) and increased risk of ischemic heart disease and stroke. Statins are first-line agents for reducing low-density lipoprotein cholesterol (LDL-C) and the risk of major cardiovascular events, but patients with a genetic susceptibility or established ASCVD oftentimes remain subtherapeutic on statin therapy alone. Biotechnological advancements in medication therapy have led to the development of inclisiran, a recently approved twice-yearly injectable agent to help patients with heterozygous familial hypercholesterolemia and clinical ASCVD on a maximally tolerated statin to reach LDL-C targets. Inclisiran has demonstrated robust LDL-C reduction in clinical trials in combination with a favorable safety profile; however, the effect on cardiovascular clinical outcomes still remains under evaluation.

Bempedoic Acid: A New Avenue for the Treatment of Dyslipidemia.

Uncontrolled dyslipidemia, specifically elevation of low-density lipoprotein cholesterol, is a major risk factor for developing cardiovascular disease. Currently, statin therapy remains as first-line treatment for reducing both serum cholesterol levels and cardiovascular risk. However, certain patients are unable to achieve desired serum cholesterol levels despite maximally tolerated statin therapy. As a result, several nonstatin therapy avenues have been evaluated for their potential benefits in reducing cholesterol and cardiovascular risk. Bempedoic acid is one such nonstatin therapy option, which has been explored over the past few years to potentially assist patients in further reducing serum cholesterol. Bempedoic acid is a novel prodrug that inhibits cholesterol synthesis upstream of statins by inhibiting adenosine triphosphate-citrate lyase. Bempedoic acid has been studied as a single, once daily 180 mg dose. Administered as monotherapy or in combination with statin or ezetimibe, bempedoic acid significantly reduces low-density lipoprotein cholesterol. Furthermore, bempedoic acid was generally well tolerated by patients and rates of adverse events were similar to placebo with few exceptions. Despite proven reductions in cholesterol and favorable safety profile, bempedoic acid will likely remain a third- or fourth-line agent for the treatment of dyslipidemia behind other nonstatin therapies until the improvement of cardiovascular outcomes is demonstrated in future clinical trials.

Tafamidis: A Novel Treatment for Transthyretin Amyloid Cardiomyopathy.

Transthyretin (TTR) amyloid cardiomyopathy is a life-threatening condition in which amyloid fibrils accumulate in the heart, eventually leading to cardiac symptomatology and death. To date, treatment of this condition has been directed at symptom relief due to a lack of effective treatment options which target the cause of the disease. The discovery that amyloid deposition was a result of dissociation of the TTR protein structure allowed for the development of tafamidis, which acts by stabilizing the TTR tetramer. Due to the rare nature of the disease, there is limited clinical trial data with tafamidis, with the largest clinical trial enrolling only 441 patients. Nonetheless, that trial demonstrated tafamidis to reduce all-cause mortality as well as cardiovascular hospitalizations compared to placebo with a comparable adverse effect profile, although not all subgroups of patients received benefit. The United States Food and Drug Administration subsequently granted Fast Track review status to tafamidis, leading to its approval in May 2019. Important questions still remain, however, such as which patient groups will receive the most benefit with this drug, how the exceptionally high cost of the drug will be handled by third-party payers, and how the therapeutic role of tafamidis will evolve as competing or perhaps complementary medications complete their ongoing clinical trials and move into the marketplace.

Nitrosamine Impurities in Angiotensin Receptor Blockers.

Nitrosamines are known carcinogens which have been recently discovered in several angiotensin receptor blockers (ARBs). This led to the recall of valsartan in the United States in 2018, and afterward, the recall of other ARBs as well as unrelated medications (e.g., ranitidine). The presence of nitrosamine in ARBs was likely a result of changes in the manufacturing process, although nitrosamine contamination is believed to occur by different mechanisms with other medications. The United States Food and Drug Administration has since taken steps to identify products affected by nitrosamine contamination and mitigate this concern going forward. Despite the contamination of some drug products, studies estimate that the overall risk to patients is low enough to not necessitate changes in prescribing patterns at this time.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients With Coronavirus Disease 2019: Friend or Foe?

When the coronavirus disease 2019 (COVID-19) wreaked an unprecedented havoc of an escalating number of deaths and hospitalization in the United States, clinicians were faced with a myriad of unanswered questions, one of the them being the implication of the renin-angiotensin-aldosterone system in patients with COVID-19. Animal data and human studies have shown that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) increase the expression of ACE2. ACE2 is an enzyme found in the heart, kidney, gastrointestinal tract, and lung and is a coreceptor for severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV2), the virus responsible for COVID-19. Therefore, one can speculate that discontinuing ACE inhibitor or ARB therapy may lead to decreased ACE2 expression, thereby attenuating the infectivity of SARS-CoV-2, and mitigating the disease progression of COVID-19. However, several studies have also shown that ACE2 exhibits reno- and cardioprotection and preserves lung function in acute respiratory distress syndrome, which would favor ACE inhibitor or ARB therapy. This article is to examine and summarize the 2 opposing viewpoints and provide guideline recommendations to support the use or discontinuation of ACE inhibitors and ARBs in patients with COVID-19.

Chloroquine or Hydroxychloroquine for Management of Coronavirus Disease 2019: Friend or Foe?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be a threat to the health of many humans across the world as they confront coronavirus disease 2019 (COVID-19). Previous promising in vitro data that emerged after the SARS-CoV outbreak in 2003, along with the emergent need for pharmacologic management strategies in the fight against COVID-19, prompted interest in the use of chloroquine and hydroxychloroquine across the globe. Unfortunately, the in vitro activity of these drugs did not necessarily correlate with most in vivo studies, which showed no consistent efficacy. Safety is also a major concern, with these agents having a known risk of QT prolongation and proarrhythmic effects. In addition, clinical practice guidelines provide no clear consensus on the role of chloroquine or hydroxychloroquine for the management of COVID-19. The United States Food and Drug Administration has declared that the potential benefits of these agents no longer outweigh the possible risks, and unless new emerging information suggests a more favorable risk:benefit ratio, neither chloroquine nor hydroxychloroquine should be recommended for COVID-19 treatment or prevention at this time.

Andexanet Alfa for Reversing Factor Xa Inhibition.

The direct oral anticoagulants (DOACs) have gained popularity recently among both patients and providers for their comparable or better efficacy and safety profiles compared with warfarin and the lack of need for routine monitoring of anticoagulant effect. One obstacle for the more widespread use of the DOACs in clinical practice has been the lack of a reversal agent. Most DOACs act by directly binding to and inhibiting the effects of factor Xa. Andexanet alfa (Andexxa, Portola Pharmaceuticals, San Francisco, CA) is a modified form of factor Xa that acts as a decoy binding entity for DOACs, thereby allowing endogenous factor Xa to perform its normal clotting functions. Andexanet has proven efficacious in clinical trials for reversing the anticoagulant effects of apixaban, edoxaban, and rivaroxaban, although its impact on clinical outcomes has not been adequately studied. Andexanet has a boxed warning for thromboembolic risks, ischemic risks, cardiac arrest, and sudden death, with these adverse events occurring in up to 18% of patients in clinical trials. However, the occurrence of these adverse events needs to be considered in relation to the fragile nature of patients who receive this agent. Because the duration of the DOACs is much less than that of warfarin, it is unclear how many patients would actually need andexanet in clinical practice, because cessation of the DOAC may be all that is needed to effectively manage bleeding. Nonetheless, having andexanet available in cases of DOAC-associated severe or life-threatening bleeding represents a therapeutic advance and should provide an added level of comfort with the clinical use of DOACs.

Impact of Department of Veterans Affairs Cooperative Studies Program clinical trials on practice guidelines for high blood pressure management.

Knowing the extent to which a clinical trial's findings translate into clinical practice can be challenging. One practical approach to estimating a trial's influence on clinical practice can be achieved by assessing how the trial informed relevant clinical practice guidelines (CPGs). Accordingly, the objectives of this study were to provide an overview of all the clinical trials involving the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) that aimed at informing or resulted in informing the management of high blood pressure and to identify and describe the extent to which these trials informed CPGs for the management of high blood pressure. A total of 26 clinical trials involving the VA CSP were identified. Using bibliographic information, 21 CPGs for the management of hypertension representing over 40 years of treatment recommendations from eight collectives were evaluated to determine how they were informed by trials involving the VA CSP. From 1977 to 2018, 13 of the 26 trials (50.0%) were found to have informed 19 of the 21 CPGs (90.5%) a total of 54 times (mean = 2.6 trial citations per CPG, SD ±â€¯1.8). Clinical trials involving the VA CSP have informed a sizeable proportion of CPGs for the management of high blood pressure over the past 40 years. Because of this impact on the CPGs, these trials are also likely to have had at least moderate influence on clinical practice.

Are Shorter Durations of Dual Antiplatelet Therapy Acceptable Following Percutaneous Coronary Intervention?

Much debate has centered on whether or not the standard 12-month duration of dual antiplatelet therapy (DAPT) is still necessary postpercutaneous coronary intervention, given recent improvements in stent technology. The benefits of shorter (3-6 months) durations of DAPT include a potential lower risk for bleeding and less patient drug cost and pill burden. Although randomized clinical trials have shown noninferiority for shorter versus longer DAPT regimens in many regards, some endpoints (e.g., myocardial infarction) may still occur less frequently with longer DAPT regimens, particularly in higher risk populations (e.g., acute coronary syndromes). Bleeding risk is either comparable or less with shorter versus longer DAPT regimens. Given the lack of unequivocal data regarding the equality of shorter versus longer DAPT regimens in all patients, there is a growing consensus that an individualized approach is advisable for determining DAPT duration postpercutaneous coronary intervention. Clinical decision aids and updated clinical practice guidelines are available that consider risk:benefit ratios and clinical trial data to assist the clinician in developing a personalized DAPT regimen.