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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an essential role in the degradation of low-density lipoprotein C (LDL-C) receptors, and PCSK9 inhibitors have recently emerged as a potential treatment option to reduce LDL-C. Our paper reviewed the current available Phase II clinical trials of PCSK9 inhibitors for the treatment of dyslipidemia. A second objective of this review was to evaluate the potential clinical role of PCSK9 inhibitors in the management of dyslipidemia. Studies evaluating the efficacy and safety of any PCSK9 inhibitors in patients with dyslipidemia were included. The monoclonal antibodies REGN727/SAR236553 and AMG145 have the most published clinical data. Seven phase II trials were retrieved that evaluated the efficacy and safety of REGN727/SAR236553 or AMG145 in patients with either hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). These two agents significantly decreased LDL-C levels either as monotherapy or in combination with other lipid-lowering agents. REGN727/SAR236553 and AMG145 have been well tolerated. The ongoing phase III trials of these two agents are summarized. REGN727/SAR236553 and AMG145 have demonstrated the potential to further decrease LDL-C levels when added to conventional lipid-lowering therapy. Morbidity and mortality data are required to define their roles in clinical practice.

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OBJECTIVES: To evaluate the efficacy and long-term safety of transulnar approach in complex coronary interventions. BACKGROUND: The success rate of transulnar approach in complex coronary interventions and its long-term safety remains to be proven. METHODS: We conducted a retrospective chart review of patients undergoing transulnar coronary angiography and interventions at our institution from January 2004 through July 2009. Primary endpoint of the study was the success rate of the procedure. Secondary endpoints were major bleeding, local vascular and neurological complications, cerebrovascular accident (CVA)/transient ischemic attack (TIA), myocardial infarction (MI), all-cause mortality, and major adverse cardiovascular events (MACE) rate that was a composite of MI, CVA/TIA, and all-cause mortality. RESULTS: Of 81 patients undergoing transulnar approach, 41 (50.6%) patients underwent intervention on 65 lesions. Twelve percent of the interventions were performed on coronary bypass grafts and 9.2% on the left main coronary artery. Success rates for transulnar access, coronary angiography, and coronary/bypass graft interventions were 93.8%, 100%, and 92.6%, respectively. Follow-up data was available on 71 patients at short term (30 days) and 58 patients at long term (1 year). At 30-day follow-up, vascular complication rate was 2.8 %. At 1-year follow-up, there were no residual deficits from vascular or neurological complications associated with the index procedure and the overall MACE rate was 3.4%. CONCLUSION: In this first study evaluating long-term safety and feasibility of transulnar coronary angiography and complex coronary interventions, we conclude that transulnar approach appears to be safe and effective.

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BACKGROUND: There are little published data on outcomes of blood conservation (BC) patients after noncardiac surgery. The objective of this study was to compare the surgical outcomes of patients enrolled in our BC program with that of the general population of surgical patients. METHODS: BC patients at our institution undergoing various surgical procedures were identified from the 2007-2009 National Surgical Quality Improvement Program database and compared with a cohort of conventional care (CC) patients matched by age, gender, and surgical procedure. Univariate and multiple logistic regression analyses were performed to evaluate 30-d postoperative outcomes. RESULTS: One hundred twenty BC patients were compared with 238 CC patients. The two groups were similar for all preoperative variables except smoking, which was lower in the BC group. On univariate analysis, BC patients had similar mean operating time (148 versus 155 min; P = 0.5), length of stay (5.9 versus 5.5 d; P = 0.7), and rate of return to the operating room (7.5% versus 5.5%; P = 0.4) compared with CC patients. BC and CC patients had similar 30-d morbidity (18% versus 14%; P = 0.3) and mortality rates (1.6% versus 1.3%; P = 1.0), respectively. On multivariable analysis, enrollment in the BC program had no impact on postoperative 30-d morbidity (odds ratio, 1.78; 95% confidence interval, 0.71-4.47) or 30-d mortality (unadjusted odds ratio, 1.33; 95% confidence interval, 0.22-8.05). CONCLUSIONS: Short-term postoperative outcomes in BC patients are similar to the general population, and these patients should not be denied surgical treatment based on their unwillingness to receive blood products.

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BACKGROUND: Ranolazine is a novel antianginal medication approved for the treatment of chronic angina. There are only limited data concerning the efficacy of ranolazine in reducing healthcare resource utilization in patients with refractory angina pectoris. OBJECTIVE: The primary objective of this analysis was to evaluate the efficacy and safety of ranolazine in refractory angina pectoris. In addition, the impact of ranolazine on healthcare resource utilization was assessed. METHODS: Consecutive patients with refractory angina pectoris treated with ranolazine at two cardiology practices in the state of Nebraska were included in this analysis. The Canadian Cardiovascular Society (CCS) angina class and frequency and type of healthcare resource consumption were determined during the 12 months prior to and the 12 months after initiation of ranolazine. RESULTS: A total of 150 pts (64 % men) with a mean age of 66 ± 12 years were included in this analysis. All patients had previously undergone coronary revascularization. Nitrates, ß-adrenoceptor antagonists (ß-blockers), and calcium antagonists (calcium channel blockers) were being used in 83, 97, and 75 % of patients, respectively. During ranolazine treatment, a significant improvement in CCS angina class was observed, with 23 patients improving by one class and no patient experiencing a deterioration in functional class (p = 0.025). A total of 53 side effects occurred in 28 (19 %) patients receiving ranolazine. Of those patients with side effects, four required dose reduction and seven required drug discontinuation. The frequency of clinic visits and emergency room visits was lower during ranolazine treatment, but the differences in frequency were not significant. The number of patients hospitalized and the number of hospitalizations were significantly lower during ranolazine therapy than in the pre-ranolazine study period (p = 0.002). CONCLUSION: Ranolazine improved the CCS angina class and reduced hospitalizations over a 12-month follow-up period in a group of patients with difficult-to-treat refractory angina pectoris.

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The prevalence of obesity has increased dramatically in the past 20 years. As a public health concern, obesity is associated with a health care resource burden that is quickly approaching that associated with tobacco use. Although lifestyle intervention (diet and exercise) remains the mainstay of treatment of obesity, its effectiveness is limited by poor long-term adherence. Drug therapy has historically been unsuccessful in producing sustained weight loss. Many older weight loss drugs have adverse benefit-to-risk profiles. This review provides an overview of nonpharmacologic interventions for weight loss. The safety and efficacy of older weight loss drugs, as well as current data related to lorcaserin, phentermine/topiramate, and naltrexone-bupropion, are evaluated. Although associated with modest weight loss and some improvement in adverse obesity-related metabolic effects, none of these drugs has been demonstrated to reduce mortality. In addition, the long-term safety of these drugs remains largely unknown. Bariatric surgery is an option for patients with morbid obesity who have failed conventional treatment.

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OBJECTIVE: Acknowledging evidence of possible detrimental effects of tightly controlled blood glucose levels, the American Association of Clinical Endocrinologists and the American Diabetes Association published a consensus statement recommending less strict control for most diabetic patients. As a result of these recommendations, our academic center at Creighton University Medical Center revised its adult insulin infusion protocol to target blood glucose levels ranging from 120 to 180 mg/dL for regular (standard) glycemic control and 80 to 120 mg/dL for tight control; previous targets had ranged from 80 to 180 mg/dL and 70 to 110 mg/dL, respectively. The primary objective was to evaluate the time that blood glucose values were within the target range for patients receiving the new protocol, compared with patients receiving the previous protocol. METHODS: Our study was designed to evaluate the effectiveness and safety of the revised protocol. Using a retrospective chart review, we collected data for 4 months from patients on the old insulin protocol (May to August 2009) and for 4 months from patients on the new protocol (September to December 2009). Secondary endpoints included the number of hypoglycemic episodes (blood glucose below 70 mg/dL) and severe hypoglycemic episodes (blood glucose 40 mg/dL or lower) experienced by patients receiving the new insulin protocol compared with those receiving the former protocol. RESULTS: Patient characteristics were similar at baseline. Blood glucose values stayed within the target range for a significantly shorter time with the new protocol than with the former protocol (44.6% vs. 56.8%, respectively; P < 0.001), probably because of the narrower target range in the revised protocol. No statistically significant differences in hypoglycemia were observed after the protocol was changed. Hypoglycemia occurred in 31% of the former-protocol patients compared with 18% of the revised-protocol patients. Severe hypoglycemia was experienced by 2.1% of patients on the old protocol and by 3.1% of patients on the new protocol. Rates of severe hypoglycemia were low (2.6%) with the original protocol. CONCLUSION: Patients' blood glucose levels were within the target range for a shorter time with the new protocol. Fewer episodes of hypoglycemia were recorded with the new protocol, but rates of severe hypoglycemia were similar with both protocols.

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PURPOSE: This article reviews the current status of lipid-lowering drugs and their impact on cardiovascular morbidity and mortality. Because there is compelling evidence to suggest that substantial residual risk persists despite the use of current lipid-lowering treatments, novel strategies for managing dyslipidemia are discussed. SUMMARY: Statins remain the drugs of choice for the treatment of dyslipidemia in patients with coronary heart disease or substantial risk factors for coronary heart disease. The evidence supporting the use of non-statin monotherapy for reductions in cardiovascular morbidity and mortality is examined. Furthermore, the evidence supporting the use of combinations of lipid-lowering drugs, primarily a statin plus another agent, for reductions in cardiovascular morbidity and mortality is discussed. Available clinical data for novel dyslipidemia drugs that can potentially expand on the current known benefits of statin therapy are reviewed. The cholesteryl ester transfer protein inhibitors, which predominantly increase high-density lipoprotein cholesterol levels and can also substantially lower low-density lipoprotein cholesterol levels, have the most robust clinical trial data, including some phase 3 study results. The proprotein convertase subtilisin/kexin type 9 inhibitors, which predominantly impact low-density lipoprotein cholesterol, are also being tested in phase 3 studies, but their widespread application may be limited by their need to be administered by injection. Peroxisome proliferator-activated receptor (PPAR) agonists with dual agonism of PPAR-α and PPAR-γ to optimize glycemic and lipid profiles may benefit patients with both diabetes and cardiovascular disease. The other novel lipid-lowering drugs are in earlier-phase human testing. CONCLUSION: Novel agents have the potential to be valuable additions to current treatment of dyslipidemia to reduce cardiovascular morbidity and mortality. These new drugs will not only have to be able to demonstrate an improvement in patients' lipid profiles, but will also have to be able to demonstrate that they reduce cardiovascular morbidity and mortality, typically in combination with statin therapy.

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BACKGROUND: To assess the efficacy of aliskiren in patients failing to reach blood pressure (BP) goals with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). METHODS: A total of 107 patients who failed to reach BP goals on ACEI or ARB were switched to aliskiren. Changes in BP were determined during maximal ACEI, ARB, or aliskiren therapy. RESULTS: Mean reduction in sBP and dBP with ACEI was 8.5 ± 6.3 mmHg and 6.0 ± 4.7 mmHg, respectively. Mean reduction in sBP and dBP with ARB was 8.3 ± 6.7 mmHg and 5.0 ± 5.2 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 150 mg/d was 6.7 ± 5.4 mmHg and 5.4 ± 4.8 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 300 mg/d was 8.6 ± 6.3 mmHg and 6.0 ± 4.9 mmHg, respectively. BP reductions between ACEI, ARB, and aliskiren were not significantly different. CONCLUSIONS: Aliskiren is ineffective in patients failing ACEI or ARB therapy. Given the label changes restricting the use of aliskiren in combination with ACEI and ARB, excess cost compared to ACEI and ARB, and a paucity of outcome data, there is a limited role for aliskiren in practice.

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BACKGROUND: Erythropoietin stimulating agents (ESAs) are high-cost medications that have a significant impact on many pharmacy budgets. Recently, ESAs have received stronger safety warnings and reimbursement has been curtailed by third-party payers including the Centers for Medicare and Medicaid Services. For these reasons, many hospitals are developing strategies to optimize their use. A required order form with acceptable indications and dosing was implemented at an academic medical center in an attempt to improve dosing and appropriate utilization of ESAs. OBJECTIVE: To determine whether implementation of a required order form increased appropriate use and/or decreased total utilization of recombinant human erythropoietin (rHuEPO). METHODS: This was a retrospective cohort study of rHuEPO utilization for 4 months pre- and 6 months post-implementation (April 2008-January 2009). RESULTS: Implementation of a required order form for rHuEPO resulted in significantly fewer patients receiving inappropriate doses of rHuEPO (51.3% vs 19.2%, p < 0.001). The number of patients treated, adjusted to hospital census, was also reduced after implementation of the order form (0.003 vs 0.004 pts./average pt. days, p = 0.03). Annual spending for rHuEPO was reduced by 47% during 2008 despite an increased acquisition cost. CONCLUSIONS: Implementation of a required order form with evidence-based dosing recommendations can be an effective strategy to improve appropriate utilization of rHuEPO.

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OBJECTIVE: To review the literature concerning the physiology of the endocannabinoid system, current drug development of cannabinoid agonists, and current clinical research on the use of cannabinoid agonists for analgesia. DATA SOURCES: Articles were identified through a search of MEDLINE (1966-August 2005) using the key words cannabis, cannabinoid, cannabi*, cannabidiol, nabilone, THC, pain, and analgesia. No search limits were included. Additional references were located through review of the bibliographies of the articles identified. STUDY SELECTION AND DATA EXTRACTION: Studies of cannabinoid agonists for treatment of pain were selected and were not limited by pain type or etiology. Studies or reviews using animal models of pain were also included. Articles that related to the physiology and pharmacology of the endocannabinoid system were evaluated. DATA SYNTHESIS: The discovery of cannabinoid receptors and endogenous ligands for these receptors has led to increased drug development of cannabinoid agonists. New cannabimimetic agents have been associated with fewer systemic adverse effects than delta-9-tetrahydrocannabinol, including recent development of cannabis medicinal extracts for sublingual use (approved in Canada), and have had promising results for analgesia in initial human trials. Several synthetic cannabinoids have also been studied in humans, including 2 cannabinoid agonists available on the international market. CONCLUSIONS: Cannabinoids provide a potential approach to pain management with a novel therapeutic target and mechanism. Chronic pain often requires a polypharmaceutical approach to management, and cannabinoids are a potential addition to the arsenal of treatment options.

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Antiplatelet drug therapy reduces vascular events in a wide range of patients. Although antiplatelet drug resistance is becoming well documented, a universal definition has not been established. This lack and the lack of standardized measures of platelet function make estimation of the prevalence of antiplatelet drug resistance difficult. Mounting evidence suggests that antiplatelet drug resistance is associated with adverse clinical outcomes, which have been assessed in patients with coronary artery disease, myocardial infarction, cerebrovascular disease, and peripheral vascular disease. Patients with antiplatelet drug resistance have significantly more vascular events than patients without such resistance. However, there are no guidelines for the treatment of antiplatelet drug resistance. Although point-of-care platelet-function testing makes screening for resistance feasible, routine screening should not be standard practice until data regarding the management of antiplatelet drug resistance are available.

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