Current trends in the treatment of asthma: focus on the simultaneous administration of salmeterol/fluticasone

Asthma is a chronic disease of the airways that affects over 20 million people in the United States. It is a complex disease that involves airway infiltration by different types of cells and cell mediators causing chronic inflammation of the airway as well as hyper-responsiveness and edema. Management of asthma symptoms often requires combination therapy with multiple medications. Long-acting beta-2 agonists and inhaled corticosteroids have become key medications in the prevention of asthma exacerbations. The bronchodilatory effects of the beta-2 agonists coupled with the anti-inflammatory action of the corticosteroids combat the multi-factorial causes of asthma. The combination inhaler containing salmeterol and fluticasone is one such product that has been proven safe and effective for asthma therapy

The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia

Hypertriglyceridemia (triglycerides > 150 mg/dL) affects ~25 % of the United States (US) population and is associated with increased cardiovascular risk. Severe hypertriglyceridemia (≥ 500 mg/dL) is also a risk factor for pancreatitis. Three omega-3 fatty acid (OM3FA) prescription formulations are approved in the US for the treatment of adults with severe hypertriglyceridemia: (1) OM3FA ethyl esters (OM3EE), a mixture of OM3FA ethyl esters, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Lovaza®, Omtryg™, and generics); (2) icosapent ethyl (IPE), EPA ethyl esters (Vascepa®); and (3) omega-3 carboxylic acids (OM3CA), a mixture of OM3FAs in free fatty acid form, primarily EPA, DHA, and docosapentaenoic acid (Epanova®). At approved doses, all formulations substantially reduce triglyceride and very-low-density lipoprotein levels. DHA-containing formulations may also increase low-density lipoprotein cholesterol. However, this is not accompanied by increased non-high-density lipoprotein cholesterol, which is thought to provide a better indication of cardiovascular risk in this patient population. Proposed mechanisms of action of OM3FAs include inhibition of diacylglycerol acyltransferase, increased plasma lipoprotein lipase activity, decreased hepatic lipogenesis, and increased hepatic β-oxidation. OM3CA bioavailability (area under the plasma concentration-time curve from zero to the last measurable concentration) is up to 4-fold greater than that of OM3FA ethyl esters, and unlike ethyl esters, the absorption of OM3CA is not dependent on pancreatic lipase hydrolysis. All three formulations are well tolerated (the most common adverse events are gastrointestinal) and demonstrate a lack of drug-drug interactions with other lipid-lowering drugs, such as statins and fibrates. OM3FAs appear to be an effective treatment option for patients with severe hypertriglyceridemia

A systematic review of the cardiovascular risk of inhaled anticholinergics in patients with COPD

The long-term use of inhaled anticholinergic agents has recently been suggested to be associated with an excess risk of adverse cardiovascular (CV) outcomes in patients with COPD. We identified 15 published studies that reported on the association between long-term inhaled anticholinergic use and adverse CV outcomes. Only 3 of the studies were adequately designed randomized controlled trials (RCTs). The first RCT that suggested that anticholinergic agents increased the risk of adverse CV outcomes was the Lung Health Study (LHS). Smokers randomized to inhaled ipratropium had a significantly increased risk of CV death than smokers receiving placebo. The LHS results have been questioned as the statistical tests used in the study were not adjusted for multiple tests and endpoints, a convincing dose-effect relationship between ipratropium use and the adverse CV outcomes was not established, and most of the CV deaths in the ipratropium group occurred in patients who were non-compliant to ipratropium. The Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) was a RCT that compared the combination of salmeterol plus fluticasone against tiotropium in patients with COPD. All-cause mortality was significantly lower in the salmeterol plus fluticasone group (3%) compared to the tiotropium group (6%). Fatal CV events occurred in 1% of the salmeterol plus fluticasone group compared to 3% in the tiotropium group. The INSPIRE trial was not designed to be a mortality trial, lacked adequate adjudication of fatal outcomes, and lacked a full intention-to-treat analysis of the data. The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial was a RCT comparing tiotropium and placebo in patients with COPD. Follow-up in UPLIFT was planned for 1440 days (4 years) plus 30 days (1470 days) of post-treatment follow-up. At 1440 days with 95% of patient outcome accounted for, tiotropium was associated with a significant 13% reduction in all-cause mortality compared to placebo. However, at 1470 days with only 75% of patient outcome accounted for, tiotropium was associated with a non-significant 11% reduction in all-cause mortality compared to placebo. The relative risks for serious CV events, heart failure, and myocardial infarction were all significantly lower with tiotropium than placebo. It is not certain why such a wide disparity in findings exists among the published studies evaluating the CV risks of inhaled anticholinergic agents. Prospective, adequately powered RCTs are needed to provide more evidence for the CV safety of tiotropium

Comparative antiplatelet effects of chlorthalidone and hydrochlorothiazide

Chlorthalidone (CTD) may be superior to hydrochlorothiazide (HCTZ) in the reduction of adverse cardiovascular events in hypertensive patients. The mechanism of the potential benefit of CTD could be related to antiplatelet effects. The objective of this study was to determine if CTD or HCTZ have antiplatelet effects. This study was a prospective, double-blind, randomized, three-way crossover comparison evaluating the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers. The effects of these treatments on platelet activation and aggregation were assessed using a well-established method with five standard platelet agonists. Thirty-four patients completed the three-way crossover comparing pre- and post-treatment changes in platelet activation and aggregation studies. There were statistically significant antiplatelet effects with ASA but not with CTD or HCTZ. Hypokalemia occurred in 0 (0%), 10 (30%), and 6 (18%) of the ASA, CTD, and HCTZ patients, respectively. The results of our study suggest that the benefits of CTD and HCTZ in reducing adverse cardiovascular events in patients with hypertension is not a result of an antiplatelet effect. In our study, hypokalemia with CTD was more prevalent than that reported in a large outcome trial in patients with hypertension. The clinical relevance of this finding is uncertain

Economic Burden of Chronic Obstructive Pulmonary Disease: Impact of New Treatment Options

The incidence, morbidity and mortality of chronic obstructive pulmonary disease (COPD) is rising throughout the world. The total economic cost of COPD in the US in 1993 was estimated to be over $US15.5 billion, with$US6.1 billion for hospitalisation, $US4.4 billion for physician and other fees,$US2.5 billion for drugs, $US1.5 billion for nursing home care and$US1.0 billion for home care. Office visits, hospital outpatient visits and emergency department visits accounted for 17.3% of the direct costs for COPD in the US. When stratified by severity, COPD treatment costs strongly correlate with disease severity. The American Thoracic Society, the European Respiratory Society and the British Thoracic Society have developed guidelines for the pharmacological treatment of COPD. However, the guidelines establish inhaled bronchodilators (anticholinergic agents and beta2-adrenergic agonists) as the mainstay of therapy for patients with COPD. The guidelines were not based on cost analyses and thus are not a priori cost-effective guidelines. Since the publication of these guidelines, several new pharmacological products have been approved for use in patients with COPD including a combination of an anticholinergic and selective beta2-adrenergic agonist [ipratropium/salbutamol (albuterol)] and a long-acting beta2-adrenergic agonist (salmeterol). Both products are effective bronchodilators in COPD. The purpose of this report is to place these new agents in an updated pharmacological guideline scheme, utilising recently published data on clinical efficacy as well as pharmacoeconomics. The annualised healthcare costs were computed to be $US788/patient/year for the combination ipratropium/salbutamol inhaler and$US1059/patient/year for salmeterol (1999 values). Based upon an improved understanding of the complexity of COPD, the response of patients to newer bronchodilators (given individually or in combination), and recent pharmacoeconomic data for COPD treatment, a new treatment algorithm with associated costs is proposed. The use of an algorithm, based on medical and pharmacoeconomic data, will improve lung function in patients with COPD, improve patient satisfaction (e.g. quality of life, dyspnoea) and outcomes (e.g. exacerbations). It will also result in a positive effect on healthcare costs.Bronchodilators, Chronic obstructive pulmonary disease, Cost analysis, Pharmacoeconomics, Resource use

Potential Benefits of Icosapent Ethyl on the Lipid Profile: Case Studies

The cardiovascular benefits of marine-derived omega-3 fatty acids are supported by epidemiologic and clinical studies. Both healthy patients and those with confirmed coronary heart disease are advised by the American Heart Association to consume omega-3 fatty acids either through dietary fatty fish or fish oil products. We present two case reports of patients with dyslipidemia who were switched from an omega-3 dietary supplement or a prescription omega-3 drug containing eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) to a new prescription EPA-only drug, icosapent ethyl (IPE). Products containing a combination of EPA and DHA, including dietary supplements and prescription products, are more likely to increase low-density lipoprotein cholesterol (LDL-C) levels compared with pure EPA-only products. The lipid profiles of these two patients were improved with IPE treatment, illustrating the potentially favorable effects of IPE compared with other products containing both EPA and DHA