Anthony J. Busti

Evidence-based treatment recommendations for uremic bleeding

Uremic bleeding syndrome is a recognized consequence of renal failure and can result in clinically significant sequelae. Although the pathophysiology of the condition has yet to be fully elucidated, it is believed to be multifactorial. This article is a review of both the normal hemostatic and homeostatic mechanisms that operate within the body to prevent unnecessary bleeding, as well as an in-depth discussion of the dysfunctional components that contribute to the complications associated with uremic bleeding syndrome. As a result of the multifactorial nature of this syndrome, prevention and treatment options can include one or a combination of the following: dialysis, erythropoietin, cryoprecipitate, desmopressin, and conjugated estrogens. Here, these treatment options are compared with regard to their mechanism of action, and onset and duration of efficacy. An extensive review of the clinical trials that have evaluated each treatment is also presented. Lastly, we have created an evidence-based treatment algorithm to help guide clinicians through most clinical scenarios, and answered common questions related to the management of uremic bleeding.

Effects of perioperative antiinflammatory and immunomodulating therapy on surgical wound healing

Patients with various rheumatologic and inflammatory disease states commonly require drugs known to decrease the inflammatory or autoimmune response for adequate control of their condition. Such drugs include nonsteroidal antiinflammatory drugs (NSAIDs), cyclooxygenase (COX)‐2 inhibitors, corticosteroids, disease‐modifying antirheumatic drugs (DMARDs), and biologic response modifiers. These drugs affect inflammation and local immune responses, which are necessary for proper wound healing in the perioperative setting, thereby potentially resulting in undesirable postoperative complications. Such complications include wound dehiscence, infection, and impaired collagen synthesis. The end result is delayed healing of soft tissue and bone wounds. The current literature provides insight into the effect of some of these drugs on wound healing. For certain drugs, such as methotrexate, trials have been conducted in humans and direct us on what to do during the perioperative period. Whereas with other drugs, we must rely on either small‐animal studies or extrapolation of data from human studies that did not specifically look at wound healing. Unfortunately, no clear consensus exists on the need and optimum time for withholding therapy before surgery. Likewise, clinicians are often uncertain of the appropriate time to resume therapy after the procedure. For those drugs with limited or no data in this setting, the use of pharmacokinetic properties and biologic effects of each drug should be considered individually. In some cases, discontinuation of therapy may be required up to 4 weeks before surgery because of the long half‐lives of the drugs. In doing so, patients may experience an exacerbation or worsening of disease. Clinicians must carefully evaluate individual patient risk factors, disease severity, and the pharmacokinetics of available therapies when weighing the risks and benefits of discontinuing therapy in the perioperative setting.

Temporal Relationship between Use of NSAIDs, Including Selective COX-2 Inhibitors, and Cardiovascular Risk

AbstractBackground and Objective: The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. However, following their introduction into the market, concerns have developed regarding their safety, particularly their cardiovascular safety. The purpose of this study was to assess the cardiovascular risk (events included were myocardial infarction, stroke and myocardial infarction-related deaths) associated with long-term (>180 days of exposure) and short-term (≤180 days of exposure) use of non-selective NSAIDs, including ‘preferential COX-2 inhibitors’ (i.e. etodolac, nabumetone and salsalate), and selective COX-2 inhibitors. Methods: A retrospective analysis of the Veterans Integrated Service Network 17 Veterans Affairs (VA) database was conducted. Medicare data and Texas Department of Health mortality data were incorporated to capture events occurring outside the VA healthcare network. Patients ≥35 years of age who received celecoxib, rofecoxib, ibuprofen, etodolac and naproxen from 1 January 1999 through 31 December 2001, were included. Multivariate Cox proportional hazard models were used to analyse the relationship between cardiovascular risk and NSAID use, including selective COX-2 inhibitor use, while adjusting for various risk factors. Results: We identified 12 188 exposure periods (11 930 persons) and 146 cardiovascular events over the entire study period. Compared with long-term ibuprofen use, long-term use of celecoxib (adjusted hazard ratio [HR] 3.64; 95% CI 1.36, 9.70) and rofecoxib (adjusted HR 6.64; 95% CI 2.17, 20.28) was associated with a significant increase in cardiovascular risk. When restricted to patients ≥65 years of age, the cardiovascular risks associated with long-term celecoxib (adjusted HR 7.36; 95% CI 1.62, 33.48) and rofecoxib (adjusted HR 13.24; 95% CI 2.59, 67.68) use increased. Short-term use of celecoxib (adjusted HR 0.75; 95% CI 0.42, 1.35) and rofecoxib (adjusted HR 0.85; 95% CI 0.39, 1.86) was not associated with any significant change in cardiovascular risk when compared with short-term ibuprofen use. Neither long- nor short-term exposure to naproxen and etodolac was associated with cardionegative or cardioprotective effects when compared with ibuprofen use. Conclusions: The findings of this observational study, along with recent clinical trial results, suggest that prolonged exposure to selective COX-2 inhibitors may be associated with an increased risk of adverse cardiovascular outcomes.

Multicenter Evaluation of Vancomycin Dosing – Emphasis on Obesity

BACKGROUND There is a paucity of data available regarding the dosing of antimicrobials in obesity. However, data are available demonstrating that vancomycin should be dosed on the basis of actual body weight. METHODS This study was conducted at 2 tertiary care medical centers that did not have pharmacy-guided vancomycin dosing programs or other institutional vancomycin dosing policies or protocols. Patients who received vancomycin between July 1, 2003, and June 30, 2006, were stratified by body mass index and randomly selected from the computer-generated queries. Patients >or=18 years of age with a creatinine clearance of at least 60 mL/min who received vancomycin for at least 36 hours were included. RESULTS Data were collected on a random sampling of 421 patients, stratified by body mass index, who met the inclusion criteria. Most patients in each body mass index category received a fixed dose of vancomycin 2 g daily divided into 2 doses (underweight 82%, normal weight 90%, overweight 86%, and obese 91%). Adequate initial dosing (>or=10 mg/kg/dose) was achieved for 100% of underweight, 99% of normal weight, 93.9% of overweight, and 27.7% of obese patients (P < .0001). Ninety-seven percent of underweight, 46% of normal weight, 1% of overweight, and 0.6% of obese patients received >or=15 mg/kg/dose recommended by several Infectious Diseases Society of America guidelines. Pharmacists also failed to correct inadequate dosing because only 3.3% of patients receiving less than 10 mg/kg/dose had their regimen changed in the first 24 hours of therapy. CONCLUSION In this multicenter pilot study, obese patients routinely received inadequate empiric vancomycin using a lenient assessment of dosing. Greater efforts should be undertaken to ensure patients receive weight-based dosing because inadequate dosing can lead to subtherapeutic concentrations and potentially worse clinical outcomes.

Tegaserod-Induced Myocardial Infarction: Case Report and Hypothesis

Serotonin (5‐hydroxytryptamine [5‐HT])1 receptor agonists, such as those used for treating migraine, can cause coronary artery contraction, coronary spasm, and even myocardial infarction. Tegaserod maleate is a relatively new 5‐HT4 receptor agonist with moderate affinity for the 5‐HT1 receptor. Currently, it is approved only for treatment of irritable bowel syndrome in women who have constipation as the primary symptom. However, it is also being administered as a promotility agent in patients with gastroparesis. Since tegaserod has affinity for the 5‐HT1 receptor, it is plausible that tegaserod could cause the same types of cardiovascular adverse events seen with agents prescribed for management of migraine. We report the first case of a man who experienced a myocardial infarction after receiving only two 6‐mg doses of tegaserod; we also provide a hypothesis regarding this event. When considering prescribing a drug with 5‐HT1 receptor agonist activity, clinicians should review the patients medical history specifically for the presence of underlying cardiovascular risk factors.

Lipid-Lowering Efficacy and Safety After Switching to Atazanavir-Ritonavir-Based Highly Active Antiretroviral Therapy in Patients with Human Immunodeficiency Virus

Study Objective. To evaluate the efficacy, safety, and lipid‐lowering effects after switching from a non‐atazanavir‐containing, protease inhibitor‐based highly active antiretroviral therapy (HAART) to atazanavir‐ritonavir‐based HAART in patients infected with human immunodeficiency virus (HIV).

Safety and efficacy of simvastatin for the treatment of dyslipidemia in human immunodeficiency virus-infected patients receiving efavirenz-based highly active antiretroviral therapy.

Study Objectives. To evaluate the safety and efficacy of simvastatin for treatment of dyslipidemia in patients with the human immunodeficiency virus (HIV) who were receiving efavirenz‐based highly active antiretroviral therapy (HAART), and to evaluate the effect of simvastatin when added to efavirenz on CD4+ count, HIV viral load, and frequency of attainment of patient‐specific National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III lipid goals.

A retrospective study of the lipid-lowering efficacy and safety of ezetimibe added to hydroxy methylglutaryl coenzyme A reductase therapy in HIV-infected patients with hyperlipidemia

BACKGROUND Abnormalities in lipid metabolism are a well-described consequence of human immunodeficiency virus (HIV) infection being treated with highly active antiretroviral therapies (HAART). OBJECTIVE The purpose of this study is to evaluate the lipid-lowering efficacy and safety of ezetimibe added to existing hydroxy methylglutaryl coenzyme A reductase (statin) therapy in HIV-infected patients with hyperlipidemia. METHODS This is a retrospective study utilizing a comprehensive electronic patient registry to identify all adult HIV-infected patients seen at the Dallas Veterans Affairs (VA) Medical Center during a 4-year period from October 1, 2002 through October 1, 2006. RESULTS A total of 26 HIV-infected patients initiated on ezetimibe 10 mg were identified, with 14 adult males meeting strict criteria for inclusion. Median age was 54 years (interquartile range [IQR], 45-59) with a median duration of HIV of 13 years, CD4 count of 513 cells/mm(3) (IQR, 289-736), and 9 of 14 patients had undetectable viral loads at baseline. Initiation of ezetimibe 10 mg resulted in a significant decrease in total cholesterol (TC) from baseline (-12.9%, P = 0.001); low-density lipoprotein cholesterol (LDL-C; -25.7%, P = 0.001); and non-high-density lipoprotein cholesterol (non-HDL-C; -23.9%, P = 0.001). There was also a nonsignificant decrease in triglycerides (15.8%, P = 0.43), and an increase in number of patients achieving National Cholesterol Education Program/Adult Treatment Panel III goal for LDL-C after initiation of ezetimibe (+20.9%, P = 0.125). These improvements occurred without adverse effects or changes in virologic and immunologic control. CONCLUSION Addition of ezetimibe to existing statin therapy in HIV-infected VA patients treated with HAART significantly reduces TC, LDL-C, and non-HDL-C concentrations without apparent side effects or compromising of virologic control.

A Multimodal, Evidence-Based Approach to Achieve Lipid Targets in the Treatment of Antiretroviral-Associated Dyslipidemia: Case Report and Review of the Literature

Metabolic abnormalities associated with the treatment of human immunodeficiency virus (HIV) infection are well‐recognized problems that increase cardiovascular risk. As a result of the complexity of treating both HIV‐ and antiretroviral‐related comorbidities, strategies that improve adverse drug events while maintaining viral control are in critical need. Although guidelines have somewhat helped in the general approach and in first‐line strategies for managing dyslipidemia in patients receiving antiretrovirals, a paucity of data exist to guide clinicians in treating patients whose conditions are refractory to first‐line options or who are at substantial risk for cardiovascular events. Further complicating the choice of lipid‐lowering strategy is the lack of randomized controlled data from the HIV‐affected population and a concern about clinically significant drug‐drug interactions. We describe an HIV‐infected patient with efavirenz‐associated dyslipidemia at very high cardiovascular risk who had not achieved his primary or secondary lipid goals despite 2 years of treatment in a lipid specialty clinic. Lipid control was accomplished in 10 weeks with a targeted, stepwise approach of switching efavirenz to nevirapine, followed by rosuvastatin 20 mg/day, which was sustained for at least 10 months. Of most importance, this outcome was achieved without any clinically significant alteration in virologic or immunologic control. This case report highlights the potential for a pharmacist‐guided, multistep approach that addresses HIV‐related dyslipidemia and incorporates the pharmacokinetic literature to guide lipid‐lowering therapy and promote the attainment of goals based on current standards of care.

Prednisone for chronic obstructive pulmonary disease.

because of concern about the study design and statistical analysis. Aaron et al. state that prednisone significantly reduced the rate of relapse at 30 days (27 percent, vs. 43 percent with placebo; P=0.05) and that the relative risk of relapse after prednisone therapy was 0.63 (95 percent confidence interval, 0.40 to 1.01). We believe that these statements are misleading, given that the P value is 0.05 and that the 95 percent confidence interval for the relative risk includes 1.0 and therefore is not statistically significant. We are also concerned about the use of a t-test to analyze scores on the Chronic Respiratory Disease Index Questionnaire and transitional dyspnea index, which yield ordinal, not continuous, data. 2 Since the primary outcome was not statistically significant, we also believe that a power analysis should have been conducted and considered when the results were interpreted. 3