The Impact of SGLT2 Inhibitors on Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: To evaluate the role of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF). DATA SOURCES: A literature search of PubMed, the Cochrane Library, and Google Scholar databases (January 2015 to June 20, 2023) was performed with keywords: sodium-glucose co-transporter 2 inhibitors OR SGLT2 inhibitors OR bexagliflozin OR canagliflozin OR dapagliflozin OR empagliflozin OR ertugliflozin OR sotagliflozin AND heart failure OR heart failure with preserved ejection fraction, and terms related to CV outcomes including cardiovascular death, hospitalization, hospitalization for heart failure, mortality, death, and major adverse cardiovascular event (MACE). STUDY SELECTION AND DATA EXTRACTION: The reference list from retrieved articles as well as relevant review articles was considered. Pivotal randomized controlled trials and meta-analyses with a primary or secondary end point of CV death or heart failure hospitalization were included. Studies conducted solely in a diabetic patient population were excluded. DATA SYNTHESIS: Dapagliflozin and empagliflozin, in a broad population of heart failure patients including, HFrEF, HFmrEF, HFpEF, and without diabetes, have shown consistent improvement in the combined outcome of CV death and hospitalization for heart failure (HR 0.80, 95% CI 0.73-0.87) and in the reduction of heart failure hospitalizations (HR 0.74, 95% CI 0.67-0.83). In patients with HFpEF, cardiovascular mortality was not demonstrated (HR 0.88, 95% CI 0.77-1.00). Rates of adverse events were low. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Patients with HFpEF and NYHA class II-III with frequent symptoms or hospitalizations for heart failure derive the most benefit from SGLT2 inhibitors with an overall goal of a reduction in heart failure hospitalizations. CONCLUSIONS: The treatment of HFpEF has made progress, but there is still work to be done. Now, SGLT2 inhibitor therapy can be used to further help with symptom control and reduce overall hospitalizations for heart failure.

SGLT2 Inhibitors to Slow Chronic Kidney Disease Progression: A Review.

PURPOSE: One in seven Americans is at risk for chronic kidney disease (CKD). For decades, the only treatment proven to slow progression of CKD was the use of renin-angiotensin-aldosterone system inhibitors. Based on promising secondary kidney outcomes in the cardiovascular outcome trials with sodium-glucose co-transporter-2 inhibitors, kidney outcome trials in patients with CKD were published for canagliflozin, dapagliflozin, and empagliflozin. METHODS: A literature search was conducted of PubMed using the MeSH terms "Sodium-Glucose Transporter 2 Inhibitors" and "Renal Insufficiency, Chronic" and looking for clinical trials, meta-analyses, or randomized controlled trials in humans between 2015 and 2023. FINDINGS: Primary and secondary outcomes from CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease), and EMPA-KIDNEY (Empagliflozin in Patients with Chronic Kidney Disease) are described along with complete descriptions of the patient populations studied. IMPLICATIONS: This review describes the role of sodium-glucose co-transporter-2 inhibitors in slowing the progression of CKD, describes guideline changes that have occurred because of these data, and provides information on how these agents may be used clinically.

Direct Oral Anticoagulants for the Treatment of Venous Thromboembolism in Obesity.

Background: Direct oral anticoagulants (DOACs) are known to have similar efficacy with a decreased risk of bleeding when compared to warfarin for the treatment of venous thromboembolism (VTE). In patients with obesity, there are limited data regarding the safety and efficacy of DOACs. Despite concerns for both under- and over-dosing patients with extremes of body weight, there are no dose adjustment recommendations in the package inserts for any of the DOACs. Objective: To evaluate the safety and efficacy of DOACs versus warfarin for the treatment of VTE in patients with obesity. Methods: This single-center, retrospective cohort study included obese patients initiated on DOAC or warfarin therapy for VTE from January 2015 to January 2022. Patients with cancer, hypercoagulable disorders, end-stage kidney disease, or pregnancy were excluded. The primary endpoint was VTE recurrence. Secondary endpoints included major and minor bleeding. Results: A total of 120 patients met criteria for inclusion. Ninety-two received DOAC therapy and 28 received warfarin. The primary endpoint occurred in 4 patients in the DOAC group and 3 patients in the warfarin group (P = 0.35). Major bleeding occurred in 2 patients. Minor bleeding events occurred in 10 (8.33%) patients. Of those, 6 (6.5%) events occurred in patients receiving a DOAC and 4 (14.3%) events occurred in patients receiving warfarin (P = 0.28). Limitations of this study include the retrospective single-center study design. Conclusions: There was a comparable risk of bleeding and recurrent VTE between DOACs and warfarin in patients initiated on therapy for VTE.

If you don't test, they will not treat: Impact of stopping preoperative screening for asymptomatic bacteriuria.

Objective: Screening for asymptomatic bacteriuria (ASB) is not recommended outside of patients undergoing invasive urological procedures and during pregnancy. Despite national guidelines recommending against screening for ASB, this practice is prevalent. We present outcomes from a quality-improvement intervention targeting patients undergoing cardiac artery bypass grafting surgery (CABG) at Massachusetts General Hospital, a tertiary-care hospital in Boston, Massachusetts, where preoperative testing checklists were modified to remove routine urinalysis and urine culture. This was a before-and-after intervention study. Methods: Prior to the intervention, screening for ASB was included in the preoperative check list for all patients undergoing CABG. We assessed the proportion of patients undergoing screening for ASB in the 6 months prior to and after the intervention. We estimated cost savings from averted laboratory analyses, and we evaluated changes in antibiotic prescriptions. We additionally examined the incidence of postoperative surgical-site infections (SSIs), central-line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs) and Clostridioides difficile infections (CDIs). Results: Comparing the pre- and postintervention periods, urinalyses decreased by 76.5% and urine cultures decreased by 87.0%, with an estimated cost savings of $8,090.38. There were 50% fewer antibiotic prescriptions for bacteriuria after the intervention. Conclusions: Removal of urinalysis and urine culture from preoperative checklists for cardiac surgery led to a statistically significant decrease in testing without an increase in SSIs, CLABSIs, CAUTIs, or CDI. Challenges identified included persistence of checklists in templated order sets in the electronic health record.

Dual Antiplatelet Therapy After an Acute Nonminor Stroke.

Background: In select patients with minor ischemic stroke, dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel is recommended if initiated early and continued for 21 to 90 days. Dual antiplatelet therapy use, in a broader population, has shown to increase the risk of bleeding without an increased antithrombotic benefit. An ongoing area of uncertainty is whether DAPT would benefit the nonminor stroke population when continued for 21 to 90 days.?s. Objective: To describe the effects of DAPT after a nonminor stroke. Methods: This single-center, retrospective cohort study included patients initiated on antiplatelet therapy started within 1 week of symptom onset for a nonminor ischemic stroke from January 2013 to January 2020. Patients with any bleeding disorder or National Institutes of Health Stroke Scale score <4 were excluded. The primary endpoint was major bleeding at 3 months. Secondary endpoints included recurrent stroke and minor bleeding. Results: A total of 158 patients met criteria for inclusion. Ninety (57%) received DAPT, and 68 (43%) received single antiplatelet therapy (SAPT). The primary endpoint occurred in 3 patients in the DAPT group and 1 patient in the SAPT group (P = 0.463). Minor bleeding occurred in 1 patient receiving DAPT and 2 patients receiving SAPT (P = 0.402). There were 10 patients in the DAPT group and 5 patients in the SAPT group who experienced recurrent stroke or transient ischemic attack (P = 0.429). Limitations of this study include the retrospective single-center study design. Conclusion: There was a comparable risk of bleeding and recurrent stroke between DAPT and SAPT in patients admitted with an acute nonminor stroke.

Safety of Nonvitamin K Antagonists Compared with Warfarin in Patients with Atrial Fibrillation and End-Stage Kidney Disease.

OBJECTIVES: This study evaluated the occurrence of major bleeding following the initiation of oral anticoagulation therapy in patients with end-stage kidney disease (ESKD) in a community teaching hospital. METHODS: This was a single-center retrospective study that enrolled patients admitted to the study hospital with ESKD and who received oral anticoagulation (warfarin or nonvitamin K oral antagonists [NOACs]). The primary endpoint was the occurrence of major bleeding at any time while taking oral anticoagulation. Key secondary endpoints included occurrence of minor bleeding, thrombotic events, and hospitalizations because of bleeding or thrombosis. RESULTS: There were 36 patients who received warfarin and 32 patients who received a NOAC. A major bleeding event occurred in 15 of 36 patients (42%) in the warfarin group and in 5 of 32 patients (16%) in the NOAC group (P = 0.032). Hospitalizations as a result of either a bleeding event or a thrombosis occurred in 19 of 36 patients (53%) in the warfarin group and in 8 of 32 patients (25%) in the NOAC group (P = 0.026). The majority of patients in the NOAC group (69%) received a reduced dose for the indication. CONCLUSIONS: Warfarin increased the risk of major bleeding in patients with ESKD compared with NOACs and did not reduce the risk of thrombotic events.

A Review of Direct Oral Anticoagulants in Patients With Stage 5 or End-Stage Kidney Disease.

OBJECTIVE: To evaluate the role of oral anticoagulation in patients with stage 5 chronic kidney disease (CKD-5) or end-stage kidney disease (ESKD). DATA SOURCES: A literature search of PubMed (January 2000 to July 1, 2021), the Cochrane Library, and Google Scholar databases (through April 1, 2021) was performed with keywords DOAC (direct-acting oral anticoagulant) OR NOAC or dabigatran OR rivaroxaban OR apixaban OR edoxaban AND end-stage kidney disease combined with atrial fibrillation (AF) or venous thromboembolism (VTE) OR pulmonary embolism OR deep-vein thrombosis. STUDY SELECTION AND DATA EXTRACTION: Case-control, cohort, and randomized controlled trials comparing DOACs to an active control for AF or VTE in patients with CKD-5 or ESKD and reporting outcomes of stroke, recurrent thromboembolism, or major bleeding were included. DATA SYNTHESIS: Nine studies were included. Efficacy data supporting routine use of warfarin or DOACs in CKD-5 or ESKD are limited. Rivaroxaban and apixaban may provide enhanced safety compared to warfarin in patients with AF. Data for VTE are limited to 1 retrospective study. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Because of the paucity of rigorous, prospective studies in CKD-5 or ESKD, OACs should not be broadly used in this population. It is clear that data regarding efficacy of DOACs cannot be reliably and safely extrapolated from the non-ESKD population. Therefore, use of OACs in this population should be individualized. CONCLUSIONS: If OACs for stroke prevention with AF are deemed necessary, apixaban or rivaroxaban can be considered. DOACs cannot currently be recommended over warfarin in patients with CKD-5 or ESKD and VTE.

Impact of SGLT2 inhibitors on cardiovascular outcomes in patients with heart failure with reduced ejection fraction.

Heart failure (HF) impacts more than 6 million Americans with an annual mortality rate approaching 22%. Along with optimizing guideline-directed management and therapy (GDMT), the development of treatment options to improve mortality and morbidity in patients with HF with reduced ejection fraction (HFrEF) is paramount. Cardiovascular outcome trials in patients with type 2 diabetes have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors improve both cardiovascular (CV) and renal outcomes and have consistently reduced hospitalizations for HF in patients with and without a previous history of HF. A precise mechanism by which SGLT2 inhibitors provide benefits for patients with HFrEF has not been identified, and it is probable that multiple pathways may best explain the outcomes seen in recent clinical trials. The mounting evidence that SGLT2 inhibitors reduce HF-related hospitalizations in patients with type 2 diabetes led to the publication of two pivotal trials, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial and the Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced) trial. Data from these publications demonstrate significant benefit of dapagliflozin and empagliflozin on a variety of CV and HF quality of life end points in patients with HFrEF independent of the presence of type 2 diabetes. Now, widespread application of the clinical findings from the DAPA-HF and EMPEROR-Reduced trials must follow with SGLT2 inhibitors incorporated into GDMT for HFrEF regardless of the presence or absence of diabetes. In this review, we examine key literature surrounding the CV outcome data for SGLT2 inhibitors with a specific focus on patients with HFrEF.

Efficacy and Safety of Nonvitamin K Oral Anticoagulants following Cardiac Valve Replacement.

OBJECTIVE: To compare the efficacy and safety of nonvitamin K oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) following bioprosthetic cardiac valve replacement. METHODS: This was a retrospective analysis conducted at a community teaching hospital in the southeastern United States between August 2015 and August 2018. Patients 18 years of age and older who underwent cardiac valve replacement and were prescribed oral anticoagulation were screened for inclusion. Patients were excluded if they had a mechanical valve replacement, experienced a venous thromboembolism, cerebrovascular accident, or acute coronary syndrome within 1 month before valve replacement, changed oral anticoagulation during the study period, were lost to follow-up, or declined to participate in the follow-up survey. The primary outcome was a composite of thromboembolic events within 90 days following bioprosthetic cardiac valve replacement. The safety outcome was major bleeding within 180 days of bioprosthetic cardiac valve replacement. RESULTS: The primary outcome of a composite of thromboembolic events within 90 days following bioprosthetic cardiac valve replacement occurred in 1 patient (4.3%) in the VKA group and 4 patients (7.4%) in the NOAC group. Major bleeding occurred in 2 patients (8.7%) in the VKA group and 0 patients in the NOAC group. CONCLUSION: Our study is the first to report the efficacy and safety of NOACs compared with VKA therapy following bioprosthetic cardiac valve replacement irrespective of an atrial fibrillation diagnosis. Notably, two of the thromboembolic events in the NOAC group occurred while therapy was held or inappropriately dosed; when these events are removed, the rate of thromboembolism is 3.8%. This rate is consistent with the VKA group. Our study adds to a small pool of literature regarding the use of NOACs following bioprosthetic cardiac valve replacement and suggests that NOACs may have similar efficacy and improved safety as compared with VKA therapy. Large randomized controlled trials are warranted to confirm our observations.

Timing of Anticoagulation in Atrial Fibrillation Status Post Cardioembolic Stroke.

BACKGROUND: Anticoagulation is the mainstay of secondary stroke prevention in patients with atrial fibrillation; however, few studies have assessed the optimal timing for initiation of anticoagulation post cardioembolic stroke. In the 2 weeks following an acute cardioembolic stroke, the risk of recurrent stroke is as high as 8%, but this risk must be balanced against the risk of hemorrhagic transformation with early initiation of anticoagulation. PURPOSE: This study described the time to initiation of anticoagulation and evaluated the in-hospital incidence of hemorrhagic and ischemic complications in 106 patients with atrial fibrillation post an acute cardioembolic stroke. METHODS: A single-center retrospective cohort study was conducted to describe the time to initiation of therapeutic anticoagulation in patients with atrial fibrillation admitted to the hospital for an acute cardioembolic stroke. The primary outcome was the time to initiation of anticoagulation from the time of stroke onset. Secondary outcomes included the incidence of in-hospital hemorrhagic and ischemic complications. RESULTS: The median time to initiation of anticoagulation was 59.5 hours after stroke onset for those who did not receive thrombolytic therapy and 82.6 hours for those who did received thrombolytic therapy. Out of 100 patients initiated on anticoagulation, no ischemic complications were observed. Four patients experienced a hemorrhagic conversion following initiation of anticoagulation. In 3 of these patients, anticoagulation was initiated within 48 hours of stroke onset. CONCLUSION: A small percentage of patients experienced an in-house hemorrhagic conversion when anticoagulation was initiated between 48 hours and 7 days.

Frequency of ß-Blocker Use Following Exacerbations of COPD in Patients with Compelling Indication for Use.

OBJECTIVE: To assess the current use of ß-blockers in patients with compelling indications for use, following the acute exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: We performed a multicenter retrospective observational study using data from all of the patients admitted to five institutions for an acute exacerbation of COPD. Patients were included if they were admitted for an acute exacerbation of COPD and had a compelling indication for the use of a ß-blocker, defined as previous myocardial infarction or heart failure with left ventricular ejection fraction ≤40%. RESULTS: There were 396 patients meeting the criteria for inclusion in the study. The population was predominantly white men with myocardial infarction as the most prevalent compelling indication. On admission, 267 (67.4%) patients were receiving ß-blockers, which increased to 278 (70.2%) at discharge. There were 118 (29.8%) patients discharged without ß-blockers. Of the predictors tested, none were significantly predictive of a patient not receiving ß-blockers upon discharge; however, home and in-hospital ß-blockers reduced the likelihood of being discharged without a ß-blocker. Of the 129 patients not receiving ß-blockers prehospitalization, 23 (17.8%) were discharged with a new prescription for a ß-blocker. CONCLUSIONS: Nearly one-third of patients with compelling indications for ß-blockers were not prescribed the therapy at discharge.

Current Understanding of Epidemiology, Pathophysiology, and Management of Atypical Femur Fractures.

PURPOSE OF REVIEW: To summarize reports published since the 2013 American Society of Bone and Mineral Research Task Force Report on atypical femoral fractures (AFF). RECENT FINDINGS: The absolute incidence of AFFs remains low. AFFs are primarily associated with prolonged bisphosphonate (BP) exposure, but have also been reported in unexposed patients and those receiving denosumab for osteoporosis and metastatic bone disease. Asians may be more susceptible to AFFs. Lateral femoral bowing and varus hip geometry, which increase loading forces on the lateral femoral cortex, may increase AFF risk. Altered bone material properties associated with BP therapy may predispose to AFFs by permitting initiation and increasing propagation of micro-cracks. Relevant genetic mutations have been reported in patients with AFFs. Single X-ray absorptiometry femur scans permit early detection of incomplete and/or asymptomatic AFFs. Orthopedists recommend intramedullary rods for complete AFFs and for incomplete, radiologically advanced AFFs associated with pain and/or marrow edema on MRI. Teriparatide may advance AFF healing but few data support its efficacy. Greater understanding of biological and genetic predisposition to AFF may allow characterization of individual risk prior to initiating osteoporosis therapy and help allay fear in those at low risk for this complication, which remains rare in comparison to the osteoporotic fractures prevented by antiresorptive therapy.

Robust Trabecular Microstructure in Type 2 Diabetes Revealed by Individual Trabecula Segmentation Analysis of HR-pQCT Images.

Type 2 diabetes (T2D) patients have an increased fracture risk, which may be partly explained by compromised bone microarchitecture within the cortical bone compartment. Data on trabecular bone parameters in T2D are contradictory. By high-resolution peripheral quantitative computed tomography (HR-pQCT), trabecular microarchitecture is preserved, yet larger trabecular holes are detected in T2D by MRI and DXA-based trabecular bone scores are abnormal. To determine if there are differences in trabecular microstructure, connectivity, and alignment in postmenopausal women with T2D as compared with controls, we performed an individual trabecula segmentation (ITS) analysis on HR-pQCT scans of the distal radius and tibia in 92 women with (n = 42) and without (n = 50) T2D. Unadjusted analyses showed that T2D subjects had greater total trabecular bone volume, trabecular plate volume fraction, plate number density, plate junction density, and axial alignment at the radius and tibia, and increased plate tissue fraction, but decreased rod tissue fraction and rod length at the radius (p < 0.05 for all). After adjustments for clinical covariates, plate number density and plate junction density remained higher at the radius and tibia, whereas total trabecular bone volume was increased and trabecular rod length was decreased at the radius. These differences remained significant after adjustment for hip BMD and trabecular volumetric bone density. Notably, the increased plate-like ITS qualities were seen in those with T2D duration of <10 years, whereas ITS parameters in subjects with T2D duration ≥10 years did not differ from those of control subjects. In conclusion, postmenopausal women with early T2D had a greater plate-like and less rod-like trabecular network. This early advantage in trabecular plate quality does not explain the well-established increased fracture risk in these patients and does not persist in the later stage of T2D. © 2018 American Society for Bone and Mineral Research.

Evaluation of weight-based vancomycin dosing for hospitalized hemodialysis patients.

BACKGROUND: Current vancomycin dosing guidelines recommend targeting trough concentrations of 15-20 mg/L in complicated infections to avoid treatment failure and resistance. How to accomplish this in the intermittent hemodialysis (IHD) population has not been adequately described. A weight-based vancomycin dosing protocol for IHD patients was developed to provide standardization of vancomycin dosing for this patient population. Prior to implementation of this protocol, clinical pharmacists used their individual judgment for dosing and monitoring. OBJECTIVE: Compare achievement of goal (15-20 mg/L) pre-IHD vancomycin levels between a group of patients dosed prior to implementation of this weight-based vancomycin dosing protocol and a group dosed after implementation. METHODS: This retrospective study evaluated hospitalized IHD patients who received vancomycin and had an appropriate pre-IHD vancomycin level. Any patients with acute kidney injury or who required continuous renal replacement therapy or peritoneal dialysis were excluded. RESULTS: A total of 145 vancomycin courses (94 pre-protocol and 51 post-protocol) were included in this study. The post-protocol group had an increased percentage of patients who achieved a pre-IHD vancomycin level of 15-20 mg/L. We also found improvement in pre-IHD vancomycin levels attained in patients weighing less than 75 kg and the need for additional study in patients weighing more than 105 kg. CONCLUSION: Simplifying and standardizing vancomycin dosing for hospitalized IHD patients based on weight resulted in 37% of patients achieving goal pre-IHD vancomycin level of 15-20 mg/L with zero patients having a pre-IHD vancomycin level <10 mg/L.

Daily life evidence of environment-incongruent emotion in schizophrenia.

Researchers have recently hypothesized that negative emotion in positive situations may be one mechanism for understanding emotion dysfunction in schizophrenia. Using ecological momentary assessment, we examined the relationship between emotion experience and environmental context in the daily lives of participants with and without schizophrenia. Participants with (n=47) and without schizophrenia (n=41) were provided a cellular telephone and called four times a day for one week. During each call participants rated their emotion experiences, described their current activities, and rated enjoyment from those activities. In line with previous research, participants with schizophrenia reported higher negative emotion overall relative to participants without schizophrenia, but equivalent levels of positive emotion and activity enjoyment. In line with the environment-incongruent negative emotion hypothesis, participants with schizophrenia evidenced a weaker relationship between reported enjoyment of current activities and current negative emotion compared to participants without schizophrenia. In addition, lower neurocognition predicted this weak relationship between negative emotion and context in the schizophrenia group. These findings provide ecologically valid support for environment-incongruent negative emotion in schizophrenia, and suggest that people with schizophrenia with more impaired neurocognition may have more difficulties regulating negative emotion.

Using self-determination theory to understand motivation deficits in schizophrenia: the 'why' of motivated behavior.

Self-determination theory (SDT) provides a model for understanding motivation deficits in schizophrenia, and recent research has focused on problems with intrinsic motivation. However, SDT emphasizes that motivated behavior results from three different factors: intrinsic motivators (facilitated by needs for autonomy, competency, and relatedness), extrinsic motivators (towards reward or away from punishment), or when intrinsic and extrinsic motivators are absent or thwarted a disconnect-disengagement occurs resulting in behavior driven by boredom or 'passing time'. Using a novel approach to Ecological Momentary Assessment, we assessed the degree to which people with schizophrenia were motivated by these factors relative to healthy control participants. Forty-seven people with and 41 people without schizophrenia were provided with cell phones and were called four times a day for one week. On each call participants were asked about their goals, and about the most important reason motivating each goal. All responses were coded by independent raters (blind to group and hypotheses) on all SDT motivating factors, and ratings were correlated to patient functioning and symptoms. We found that, relative to healthy participants, people with schizophrenia reported goals that were: (1) less motivated by filling autonomy and competency needs, but equivalently motivated by relatedness; (2) less extrinsically rewarding, but equivalently motivated by punishment; (3) more disconnected-disengaged. Higher disconnected-disengaged goals were significantly associated with higher negative symptoms and lower functioning. These findings indicate several important leverage points for behavioral treatments and suggest the need for vigorous psychosocial intervention focusing on autonomy, competence, and reward early in the course of illness.

Nebivolol for the treatment of heart failure.

PURPOSE. The pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of nebivolol are reviewed. SUMMARY. Nebivolol, a third-generation, highly ß(1)-specific ß-blocker, is labeled for the treatment of hypertension in the United States. In addition to its ß-blocking effects, nebivolol has been shown to increase endothelin-dependent nitric oxide, giving it a unique peripheral vasodilatory action. Nebivolol is extensively metabolized by cytochrome P-450 isoenzyme 2D6. In patients with heart failure, certain ß-blockers antagonize excessive adrenergic stimulation and can slow the progression of the disease. Clinical trials have compared nebivolol at target dosages of 5 and 10 mg once daily with placebo and, in small trials, with carvedilol in the treatment of adults with chronic heart failure. Nebivolol appears to have beneficial effects in patients with heart failure, including improvements in left ventricular ejection fraction, left ventricular volumes, and exercise capacity. In addition, the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure showed a reduction in morbidity and mortality after treatment with nebivolol when compared with placebo, though this effect appeared to be less than that of other ß-blockers currently recommended for the treatment of heart failure. Nebivolol was well tolerated in all clinical trials, with the most frequently reported adverse events including bradycardia, hypotension, and dizziness. To date, no large clinical trials have compared nebivolol with currently recommended ß-blockers in patients with heart failure. CONCLUSION. Nebivolol has beneficial effects in heart failure but cannot be considered equivalent to other currently accepted therapies.

Role of tissue plasminogen activator in acute ischemic stroke.

OBJECTIVE: To evaluate the literature regarding the use of intravenous tissue plasminogen activator (tPA) in the treatment of acute ischemic stroke, focusing on the appropriate usage criteria and administration time window. DATA SOURCES: A PubMed and MEDLINE search was performed (1990-November 2010) using the key words alteplase, tissue plasminogen activator, thrombolytic, ischemic stroke, and cerebrovascular accident. STUDY SELECTION AND DATA EXTRACTION: Clinical trials published in English were evaluated and relevant primary literature evaluating the use of tPA in acute ischemic stroke was included. DATA SYNTHESIS: The NINDS (National Institute of Neurological Disorders and Stroke) trial revealed clinical efficacy of tPA in the treatment of acute ischemic stroke when administered within 3 hours of stroke symptom onset and served as the foundation for the American Heart Association/American Stroke Association (AHA/ASA) acute ischemic stroke guideline recommendations. The ECASS (European Cooperative Acute Stroke Study) I, ECASS II, and ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke), part A and B, trials each assessed the efficacy of tPA when administered beyond 3 hours of ischemic stroke onset, but the results of each trial did not support its use beyond 3 hours. The ECASS III trial showed clinical efficacy of tPA when administered up to 4.5 hours. The SITS-MOST (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) and SITS-ISTR (Safe Implementation of Thrombolysis in Stroke International Stroke Thrombolysis Register) registries evaluated the safety and efficacy of tPA at both 3 and 4.5 hours and showed promising results. In 2009, the AHA/ASA stroke guidelines were updated to support the use of tPA in select patients up to 4.5 hours after symptom onset. CONCLUSIONS: tPA is effective when administered up to 4.5 hours after ischemic stroke symptom onset in select patients. However, timely administration remains paramount to achievement of optimal therapeutic outcomes.

Survey of physician knowledge and counseling practices regarding acetaminophen.

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