Effect of type 2 diabetes on the inducible degrader of LDL receptor.

The inducible degrader of LDL receptor (IDOL) acts as a post-transcriptional degrader of the LDL receptor (LDLR). IDOL is functionally active in the liver and in peripheral tissues. We have evaluated IDOL expression in circulating monocytes in subjects with and without type 2 diabetes and determined whether changes in IDOL expression could affect macrophage function like cytokine production in vitro. One hundred forty individuals with type 2 diabetes and 110 healthy control subjects were recruited. Cellular expression of IDOL and LDLR in peripheral blood CD14+ monocytes was measured by flow cytometry. The expression of intracellular IDOL was lower in individuals with diabetes than control (21.3 ± 4.6 mean fluorescence intensity × 1,000 vs. 23.8 ± 6.2, P < 0.01), and this was accompanied by an increase in cell surface LDLR (5.2 ± 3.0 mean fluorescence intensity × 1,000 vs. 4.3 ± 1.5, P < 0.01), LDL binding, and intracellular lipid (P < 0.01). IDOL expression correlated with HbA1c (r = -0.38, P < 0.01) and serum fibroblast growth factor-21 (FGF21) (r = -0.34, P < 0.01). Multivariable regression analysis, including age, sex, BMI, smoking, HbA1c, and log(FGF21), showed that HbA1c and FGF21 were significant independent determinants of IDOL expression. IDOL knockdown human monocyte-derived macrophages produced higher concentrations of interleukin 1 beta, interleukin 6, and TNFα than control macrophages upon stimulation with lipopolysaccharide (all P < 0.01). In conclusion, the expression of IDOL in CD14+ monocytes was decreased in type 2 diabetes and was associated with glycemia and serum FGF21 concentration.

Effect of physical exercise on fear of falling in patients with stroke: A systematic review and meta-analysis.

OBJECTIVE: To consolidate the evidence on the effect of physical exercise on fear of falling in individuals with stroke. DATA SOURCES: PubMed, CINAHL, Cochrane Database and MEDLINE. METHODS: An extensive database search was conducted to identify the randomised controlled trials that examined the effect of physical exercise on fear of falling post-stroke. Grading of Recommendation, Assessment, Development and Evaluation (GRADE) was used to assess the quality of evidence for each meta-analysis. RESULTS: Fourteen trials totalling 1211 participants were included in this review. Thirteen of these (1180 participants) were included in the meta-analyses. In the primary analysis, very low-quality evidence suggested that exercise reduced fear of falling post-stroke (standardized mean difference (SMD) 0.48; 95% confidence interval (CI) 0.23 to 0.72). The effect was diminished at three- to six-month follow-up after exercise training ended (SMD -0.09; 95% CI -0.27 to 0.10; high-quality evidence). In the sensitivity analyses, the treatment effect was more pronounced in individuals with a lower baseline Berg balance score (BBS ≤45; SMD 0.53; 95%CI 0.17 to 0.88) and for those trials with exercise frequency of ≥3 sessions per week (SMD 0.70; 95%CI 0.39 to 1.01). Compared with circuit-based training consisting of a combination of walking, balance and strengthening exercises (SMD 0.27; 95% CI -0.09 to 0.63), walking programmes seemed to generate a larger effect on fear of falling (SMD 1.06; 95%CI 0.43 to 1.70). CONCLUSION: Physical exercise was beneficial for reducing fear of falling in individuals with stroke, particularly those with poorer balance ability.

Therapy Update for Insomnia in the Elderly.

OBJECTIVE: To offer an update on insomnia in older adults and treatment options. DATA SOURCES: A search of PubMed using the terms "insomnia" and "older adults" was performed. Current guidelines, review articles, and drug database and manufacturer package inserts were utilized to provide relevant information. STUDY SELECTION: All English-language articles from 2012 to February 2017 and their bibliographies were reviewed for relevance. Current guidelines from the American College of Physicians, the American Academy of Sleep Medicine, and the American Geriatrics Society's Beers criteria were reviewed. DATA SYNTHESIS: Insomnia is a frequent complaint in the elderly. Treatment guidelines for this specific population are lacking. Anticholinergics, doxepin > 6 mg, benzodiazepines (BZDs), and non BZD receptor agonists (BzDRAs) are potentially inappropriate drugs for older adults. For adults with chronic insomnia, sleep hygiene practices and cognitive behavioral therapy should be considered as the initial treatments. If drug therapy is required or desired, the guidelines recommend short-term uses of BZDs (triazolam or temazepam), BzDRAs, low-dose doxepin (≤ 6 mg), ramelteon, or suvorexant. Risks and benefits of pharmacotherapy should be discussed with patients and caregivers prior to treatment initiation. Frequent and regular monitoring for adverse events is warranted to prevent detrimental outcomes. CONCLUSION: Nonpharmacologic interventions are the first-line therapy for adults with chronic insomnia. Short-term drug therapy may be considered as an alternative or add-on treatment. Hypnotic use is associated with harm and requires close monitoring, especially in older adults.

Discontinuation of memantine standard release and its impact on patient therapy.

The recently announced discontinuation of Namenda (memantine HCl) and consequent shortage of Namenda XR (memantine HCl extended-release) is a matter that affects physicians, patients with Alzheimer's disease, caregivers, and consultant pharmacists. The manufacturer's announcement to discontinue standard-release product came eight months after the extended-release formulation became available in June 2013. The manufacturer planned to discontinue the standard-release tablets to focus on XR capsules by August 2014, giving patients and their caregivers-who prefer immediate-release formulations-no other options except the oral solution formulation. This article updates pharmacists with the current development on the various pharmacy and therapeutic issues on memantine products. Consultant pharmacists play an important role in educating prescribers and caregivers of the recent changes on this matter. They shall help to ensure proper dosage switching among various formulations. Consultant pharmacists can also help caregivers to identify the most cost-effective options when generic memantine becomes available in the future.

Serum Tsukushi Level Is Associated With the Severity of Liver Fibrosis Independent of Type 2 Diabetes.

BACKGROUND AND AIMS: Tsukushi (TSK) is a recently identified hepatokine, and we aimed to investigate the association between systemic TSK and the severity of nonalcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes mellitus (DM). METHODS: Three hundred ninety-three DM and 289 without DM individuals were recruited for transient elastography assessment to determine liver steatosis and fibrosis. Serum TSK was measured by ELISA. The presence of NAFLD was defined as controlled attenuation parameter ≥ 248 dB/m. RESULTS: NAFLD was present in 276 (70.2%) and 129 (44.6%) subjects with and without DM respectively, and they had higher serum TSK levels than those without NAFLD [DM group: 91.0 ng/mL (61.7-133.8) vs 82.5 (60.9-118.5), P < .01 respectively; without DM group: 97.1 ng/mL (69.3-148.6) vs 80.8 (53.4-111.6) respectively, P < .01]. Univariate analysis showed that serum TSK significantly correlated with the degree of steatosis and fibrosis both in subjects with and without DM. On multivariable regression analysis, only liver stiffness and estimated glomerular filtration rate were significant determinants of TSK level, and the relationship was independent of diabetes and serum adiponectin. Out of 405 subjects with NAFLD, 49 had either advanced fibrosis or cirrhosis. The area under receiver operating characteristic curve of serum TSK to indicate advanced fibrosis or cirrhosis was 0.70 (95% CI .62-.77), which was significantly better than that of fibrosis-4 index, 0.64 (95% CI .55-.72), P < .05. CONCLUSION: Serum TSK levels were increased in subjects with NAFLD and reflected the severity of liver fibrosis.

Linezolid-associated thrombocytopenia.

A 76-year-old man with end-stage renal disease and multiple comorbidities developed progressive thrombocytopenia while receiving linezolid therapy. His platelet count dropped by more than 50% from the baseline after one week of treatment. He subsequently experienced active gastrointestinal bleeding requiring blood transfusion. Drug-induced thrombocytopenia was suspected, and linezolid was discontinued after 10 days of therapy. However, his platelet count continued to decline and reached a nadir of 31 × 103/mm3 on day 13 of his hospital stay. This hematologic adverse effect resolved within nine days after linezolid cessation (day 19). Multiple risk factors for developing linezolid-associated thrombocytopenia were identified in this patient. The accumulation of linezolid and its metabolites because of reduced renal clearance may be contributory to this adverse drug reaction. Clinicians should be vigilant in monitoring platelet counts in elderly patients who are receiving linezolid, especially in those who are at risk for bleeds or who have end-stage renal disease.

Effect of type 2 diabetes on A disintegrin and metalloprotease 10.

BACKGROUND: As a type 1 transmembrane protein, a disintegrin and metalloprotease 10 (ADAM10) is responsible for the cleavage of a variety of cell surface molecules and has been implicated in the pathogenesis of Alzheimer disease, atherosclerosis, and inflammatory and neoplastic disorders. It has been suggested that systemic ADAM10 concentration may potentially be used as a prognostic biomarker. Since high glucose can upregulate ADAM10 expression in vitro, we investigated whether serum levels of ADAM10 and its substrate, the lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), can be influenced by type 2 diabetes. METHODS: A total of 1091 individuals with type 2 diabetes and 358 age-matched healthy control subjects were recruited. Serum concentrations of ADAM10 and the soluble form of LOX-1 (sLOX-1) released by cleavage of LOX-1 by ADAM were measured by enzyme-linked immunosorbent assay kits (ELISA). RESULTS: Serum ADAM10 was increased in subjects with diabetes compared with control (40.5 ng/mL [22.3-65.7] vs 10.3 ng/mL [7.0-17.9], respectively; P < .01); the highest levels were seen in insulin-treated subjects. On multiple linear regression analysis, glycosylated hemoglobin, age, body mass index, and insulin use were independent determinants of ADAM10 level. The increase in serum ADAM10 levels in diabetes was accompanied by changes in serum sLOX-1. Subjects with diabetes had higher serum sLOX-1 than the control (110 pg/mL [89-153] vs 104 pg/mL [85-138], respectively; P < .01), and there was a significant correlation between serum ADAM10 and sLOX-1 (r = 0.26, P < .01). CONCLUSIONS: Serum concentration of ADAM10 is increased in type 2 diabetes and is associated with glycemia and insulin therapy, which may potentially affect the specificity of systemic ADAM10 level as a biomarker.

Semaglutide: A Novel Oral Glucagon-Like Peptide Receptor Agonist for the Treatment of Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) is a complex and chronic condition that requires continuous medical care. Uncontrolled hyperglycemia can lead to serious microvascular and macrovascular complications, such as coronary artery disease, peripheral arterial disease, and stroke. Type 2 DM occurs when the pancreas is unable to produce adequate insulin to regulate glucose levels and when there is a decrease in sensitivity to insulin in the body. Insufficient glucagon-like peptide (GLP-1), a normal body hormone, plays an important role in the pathophysiology of DM. The introduction of the GLP-1 receptor agonists expanded therapeutic options in achieving glycemic control in adult patients. In 2005, the US Food and Drug Administration approved exenatide as the first injectable formulation, which led to the advancement of other injectable formulations within the class of GLP-1 receptor agonists. In 2019, semaglutide was approved as the first oral GLP-1 receptor agonist addressing the unmet needs in patients who benefit from therapy with this therapeutic class yet are unwilling to use an injectable drug. This article will provide an overview of the GLP-1 receptor agonists, including the pharmacology of semaglutide, its clinical evidence and role in therapy in type 2 DM.

Vaccines for older adults.

OBJECTIVE: To update senior care pharmacists with current recommendations on influenza, pneumococcal, zoster, and tetanus vaccines for older adults 65 years of age or older. DATA SOURCES: A search of immunization guidelines on influenza, pneumococcal, zoster, and tetanus infection was performed at various Web sites, including Immunization Action Coalition (www.immunize.org) and the Centers for Disease Control and Prevention (www.cdc.gov). MEDLINE (January 1966 to September 2008) and Pub-Med (January 1955-September 2008) databases and manual bibliographic searches were used to identify additional information. Search terms included influenza, herpes zoster, shingles, pneumococcal pneumonia, pneumovax, tetanus, and vaccine, used alone or in combination. STUDY SELECTION AND DATA EXTRACTION: Relevant English language articles identified from the data sources were evaluated. DATA SYNTHESIS: Trivalent influenza vaccine is recommended to high-risk groups and persons who are likely to transmit the infection, including selected health care staff and caretakers, adults 50 years of age or older, and those with comorbidities that increase the risk of influenza complications. Pneumococcal vaccine is recommended for all persons 65 years of age or older and those with certain medical conditions. One-time revaccination can be offered to the elderly who initially received the vaccine before they turned age 65 and at least five years passed since the initial vaccination. Zoster vaccine should be offered to all persons 60 years of age or older unless contraindications or precautions exist. Tetanus booster every 10 years should be considered in adults who have completed the primary series. Influenza and pneumococcal vaccines, as well as tetanus booster for post-exposure management, are covered under Medicare Part B. Zoster vaccine is covered under Medicare Part D. CONCLUSION: The Advisory Committee on Immunization Practices offers detailed recommendations for the prevention of influenza, invasive pneumococcal disease, zoster, and tetanus infection for target groups.

Patterns of Antihypertensive Drug Utilization among US Adults with Diabetes and Comorbid Hypertension: The National Health and Nutrition Examination Survey 1999-2014.

BACKGROUND: Diabetes and hypertension are the 2 leading risk factors for suboptimal cardiovascular and renal outcomes. These 2 conditions often coexist and can benefit from antihypertensive therapy, which may lead to blood pressure control and reduced risk for nephropathy (as evidenced by albuminuria). OBJECTIVE: To quantify the trends of antihypertensive drug use and to assess the impact of antihypertensive treatment on the prevalence of blood pressure control and albuminuria, among US adults with coexisting diabetes and hypertension. METHODS: In this serial cross-sectional study, we analyzed data from the 1999-2014 National Health and Nutrition Examination Survey (N = 3586). We determine the prevalence of antihypertensive use, drug classes used, and their association with blood pressure control and albuminuria. RESULTS: During the study period, the study population experienced substantial increase in antihypertensive treatment (from 84.6% in 1999-2002 to 90.1% in 2011-2014, Ptrend < .01) and blood pressure control (from 37.1% to 46.9%, Ptrend < .01) and decrease in albuminuria (from 39.1% to 31.3%, Ptrend = .02). These trends were particularly pronounced in the subgroups using angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers. In multivariate analysis, Blacks, Hispanics, and males were found more likely to have albuminuria than their respective counterparts. Achieving blood pressure control (odds ratio = 0.40, 95% confidence interval [CI]: 0.32-0.49) was associated with lower rates of albuminuria. CONCLUSION AND RELEVANCE: Despite continued improvement in antihypertensive therapy, the burden of uncontrolled blood pressure and albuminuria remains substantial among US adults with diabetes and hypertension. Tailoring pharmacotherapy based on patient characteristics and comorbidities is needed to further improve these outcomes.

Emerging therapies for the treatment of Helicobacter pylori infections.

OBJECTIVE: To describe emerging therapies, such as levofloxacin, moxifloxacin, rifabutin, rifaximin, tinidazole, doxycycline, minocycline, lactoferrin, and plaunotol for the eradication of Helicobacter pylori infection. DATA SOURCES: Relevant information was identified through a search of MEDLINE (1966-July 2008), PubMed (1955-July 2008), American Search Premier (1975-July 2008), International Pharmaceutical Abstracts (1960-2008), Science Citation Index Expanded (1996-2008), Cochrane Databases (publications archived until July 2008), and various tertiary sources using the terms Helicobacter pylori, fluoroquinolones, levofloxacin, moxifloxacin, rifabutin, rifaximin, lactoferrin, plaunotol, tinidazole, doxycycline, minocycline, faropenem, new treatments, refractory, and salvage alone or in combination. STUDY SELECTION AND DATA EXTRACTION: Relevant information was identified and selected based on clinical relevance and value of information. In vitro and in vivo data were included if available. DATA SYNTHESIS: Data exist supporting the use of levofloxacin or rifabutin as salvage therapies for H. pylori infection. Levofloxacin triple therapy has been recommended in the current treatment guideline, but more data are needed, especially from studies conducted in the US. A rifabutin-based regimen is better tolerated than conventional quadruple therapy, but its use is limited due to cost, hematologic adverse effects, drug interactions, and predicted development of resistance. Tinidazole appears to be an option, particularly as sequential therapy when combined with other agents; however, its use is limited by the high prevalence of nitroimidazole-resistant H. pylori strains in the US. Moxifloxacin data are limited. Data supporting the use of rifaximin, doxycycline, and minocycline are lacking or do not show benefit of these drugs over standard treatments. CONCLUSIONS: H. pylori infection remains one of the most significant infections worldwide, and treatment failure rate with the current standard therapy continues to rise. Other treatment options should be explored to meet the emerging challenge.

Interferon-beta1b for the treatment of multiple sclerosis.

BACKGROUND: Multiple sclerosis is a debilitating autoimmune disorder that causes disability in young adults. OBJECTIVE: To review the efficacy and safety of IFN-beta1b in the management of relapsing-remitting and secondary progressive multiple scleroses and clinical isolated syndrome. METHODS: A MEDLINE (1966-May 2007) search of clinical trials using the terms 'multiple sclerosis' and 'interferon' was performed. Manual bibliographic search was conducted. English-language articles were evaluated. RESULTS: IFN-beta1b is more efficacious than placebo and at least as efficacious as IFN-beta1a or glatiramer for the management of relapsing-remitting multiple sclerosis. IFN-beta1b also delayed the time to diagnosis of definite multiple sclerosis and reduced brain lesion burden in patients with clinical isolated syndrome. More long-term, large scale clinical data are warranted to ascertain its relative efficacy compared to other treatments. CONCLUSION: IFN-beta1b is an effective treatment for multiple sclerosis. Common side effects are lymphopenia, injection site reactions, asthenia, flu-like symptoms and headache.

Strontium ranelate for the management of osteoporosis.

OBJECTIVE: To evaluate the role of strontium ranelate in the management of osteoporosis. DATA SOURCES: A MEDLINE (January 1966 to May 2007) search using the terms osteoporosis, strontium ranelate, bonemineral density, and fractures. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. DATA SYNTHESIS: Strontium ranelate stimulates bone formation and inhibits bone resorption. Its safety and efficacy for osteoporosis were evaluated in four prospective, randomized, double-blind, placebo-controlled trials. The PREVOS (Prevention of Early Postmenopausal Bone Loss by Strontium Ranelate) trial suggested that 1 g daily is the optimal dose for preventing postmenopausal bone loss and was associated with a 1.41% increase in lumbar bone-mineral density (BMD). However, the STRATOS (Strontium Administration for Treatment of Osteoporosis) study found that a 1 g daily regimen was associated with a higher incidence of new vertebral deformities, and a 2 g daily regimen reduced lumbar BMD by 3% in postmenopausal, osteoporotic women. The SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis) studies suggested that a 2 g daily regimen reduced vertebral fractures by 39% to 41%, nonvertebral fractures by 16%, in postmenopausal, osteoporotic women. Most common adverse events reported were nausea and diarrhea. CONCLUSION: Four clinical trials demonstrated the efficacy and safety of strontium ranelate for the management of postmenopausal osteoporosis; however, the Food and Drug Administration has not approved it for this indication.

Betrixaban: A Novel Factor Xa Inhibitor for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients.

Venous thromboembolism (VTE) is a common and preventable cause of morbidity and mortality in hospitalized patients. Low-molecular-weight heparin, low-dose unfractionated heparin, fondaparinux, and warfarin have been the mainstay options for the prevention and treatment of VTE before the emergence of nonvitamin K antagonist oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban. Despite the advantages of NOACs in improving patient adherence, none of them are approved for the prevention of VTE in acutely ill medical patients at high risk of thromboembolism. Betrixaban is a new NOAC and a factor Xa inhibitor that was approved for extended-duration thromboprophylaxis in these high-risk patients. The approval was based on the results of the APEX (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban) study. In this Phase III randomized controlled trial, once-daily oral betrixaban (35 to 42 days extended duration) was associated with a reduction of composite VTE with no difference in major bleeding when compared to once-daily subcutaneous enoxaparin (6 to 14 days standard duration). Betrixaban differs from other NOACs by having a longer half-life, minimal CYP450 interactions, and minimal renal clearance. This article provides an overview of betrixaban's pharmacological profile, clinical trial results, and potential roles in therapy.

Role of Ramelteon in Reduction of As-Needed Antipsychotics in Elderly Patients with Delirium in a General Hospital Setting.

BACKGROUND AND OBJECTIVE: Abnormalities in melatonin levels have been linked to delirium. This dysregulation may be offset with the use of ramelteon, a melatonin receptor agonist. The purpose of this study was to evaluate the role of ramelteon in decreasing the need for as-needed (PRN) use of antipsychotics in elderly patients with delirium. METHODS: This was a single-center, retrospective study involving 488 patients who were placed on constant observation and received care by psychiatric service from May 2015 through October 2015. Of these patients, 125 patients were age 65 years or above, had a diagnosis of delirium, and had no standing orders for antipsychotics. These 125 patients were divided into the non-ramelteon group (who received no ramelteon and PRN antipsychotics) and the ramelteon group (who received ramelteon plus PRN antipsychotics). The use of PRN antipsychotics for agitation in each group was recorded. RESULTS: The ramelteon group had a lower incidence of PRN antipsychotic use compared to those not given ramelteon (60 vs. 80%, p value = 0.001). After adjustment for race, age, length of stay, and gender, patients in the non-ramelteon group were more likely to have been given antipsychotics compared to those in the ramelteon group (odds ratio = 4.3, p value = 0.002). CONCLUSION: Ramelteon use in elderly patients with delirium may be associated with statistically significant reduction of PRN antipsychotic use for agitation.

Cefepime neurotoxicity: case report, pharmacokinetic considerations, and literature review.

A 67-year-old woman with diabetes mellitus, chronic renal insufficiency, and recurrent urinary tract infections experienced encephalopathy and myoclonus while receiving cefepime. The adverse drug event was accompanied by elevated cefepime levels and abnormal electroencephalograms. This syndrome resolved after discontinuation of cefepime. Neurotoxicity is a known but possibly underreported adverse event associated with cefepime in patients with renal impairment who receive relatively excessive doses. Most cases reverse on drug cessation. In patients with renal disease, the maintenance dosage should be reduced and the patient monitored for neurotoxicity. Cefepime toxicity should be suspected whenever a patient receiving the drug experiences a change in mental status or myoclonus.

Omega-3-carboxylic acid (Epanova) for hypertriglyceridemia.

Hypertriglyceridemia is a prevalent yet under-addressed condition, often seen in association with uncontrolled diabetes mellitus, obesity, and physical inactivity. The control of triglyceride (TG) levels is essential to prevent the development of coronary artery disease and pancreatitis associated with hypertriglyceridemia. Omega-3-carboxylic acid (Epanova) is the third prescription omega-3 fatty acid product approved in the United States as an adjunct to diet for treating severe hypertriglyceridemia (≥ 500 mg/dL). At the approved dosage, it reduced baseline serum TG levels by 25-30% in a placebo-controlled study. It reduced serum TG levels by an additional 8-15% in patients who were already taking statin therapy. It appeared to have a better bioavailability profile compared with an equivalent dose of omega-3-acid ethyl ester (Lovaza) in both low-fat and high-fat diets. However, evidence behind the effects of omega-3-carboxylic acid on cardiovascular morbidity and mortality, and pancreatitis risk, is lacking. Overall, it is well tolerated, but may induce common gastrointestinal side effects, such as abdominal pain, nausea, and diarrhea. At this time, omega-3-carboxylic acid is an alternative adjunct therapy (in addition to diet) for hypertriglyceridemia. Its potential clinical benefits over other omega-3 formulations have yet to be evaluated.

Vorapaxar: A Protease-Activated Receptor Antagonist for the Prevention of Thrombotic Events.

Antiplatelet therapy reduces the risks for cardiovascular morbidity and mortality in patients with atherosclerotic disease, and it is also beneficial in managing peripheral arterial disease (PAD). These agents work through various therapeutic pathways to achieve antithrombotic effects. Although single- or two-drug regimens have been deployed to prevent vascular events, approximately 10% of the patients with acute coronary syndrome remain at risk for recurrent thrombotic events and may need a more aggressive preventative strategy. Vorapaxar offers a unique mechanism for platelet inhibition via the antagonism of protease-activated receptor-1. It is approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or PAD. This new drug approval was mainly based on the results from subgroup analyses from a large landmark trial (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50), which found that vorapaxar reduces the rate of the combined end point of cardiovascular death, MI, stroke, and urgent coronary revascularization when used in addition to aspirin and/or clopidogrel in patients without a history of stroke. In this study, vorapaxar was discontinued in patients with a history of stroke due to excessive risk for intracranial hemorrhage after 2 years of therapy. As an adjunctive therapy to standard regimens, vorapaxar provides a greater net clinical benefit in MI patients who are at a lower risk for bleeding. In patients with PAD, it reduces the rates of recurrent acute limb ischemia with rehospitalization or peripheral revascularization. The most concerning adverse effect is bleeding. Vorapaxar should not be used in patients with a history of stroke, transient ischemic attack, intracranial hemorrhage, or active pathological bleeding. The risks and benefits of adding vorapaxar to intensify antiplatelet regimens should be assessed in individual patients to aim for additional therapeutic outcomes with minimal bleeding risks.

Changes in heart rate associated with nebulized racemic albuterol and levalbuterol in intensive care patients.

The effects of equipotent doses of racemic albuterol and levalbuterol on heart rate (HR) in intensive care patients with and without baseline tachycardia were studied. Patients were included if they were hemodynamically stable and required bronchodilator therapy every four hours; patients were excluded if they were maintained on a beta-blocker. Four hours after the most recent bronchodilator treatment, each patient was randomized to receive at least two consecutive doses of albuterol 2.5 mg or levalbuterol 1.25 mg four hours apart via nebulization. HR was recorded at the end of the second dose and 5, 10, 15, 30, 60, 90, 120, 180, and 240 minutes after treatment. Twenty intensive care patients, including 10 with baseline tachycardia and 10 without baseline tachycardia, were enrolled. In patients with baseline tachycardia, the mean largest HR increase was 1.4 beats/min (1.3%) with albuterol and 2.0 beats/min (2.1%) with levalbuterol (both increases were not significant). In patients without baseline tachycardia, the mean largest HR increase was 4.4 beats/min (6.7%) with albuterol (p = 0.04) and 3.6 beats/min (5.0%) with levalbuterol (p = 0.03). Short-term use of nebulized albuterol and levalbuterol was associated with similar changes in HR in intensive care patients with or without baseline tachycardia.