Annals of Pharmacotherapy

ten Berg, Maarten J; van den Bemt, Patricia MLA; Huisman, Albert; Schobben, Alfred FAM; Egberts, Toine CG; van Solinge, Wouter W

doi: 10.1345/aph.1L646pmid: 19690229

Background:Summaries of product characteristics (SPCs) and clinical guideline recommendations are available for monitoring the platelet count for heparin-induced thrombocytopenia (HIT) in patients receiving low-molecular-weight heparin (LMWH). Testing for the presence of heparin-platelet factor 4 antibodies (HPF4-Ab) and starting alternative anticoagulation is recommended when HIT is suspected.Objective:To investigate the frequency of compliance with recommendations for platelet count monitoring and management of possible HIT in hospitalized patients receiving prophylaxis and treatment dosing of LMWH for at least 5 consecutive days.Methods:A retrospective cohort study within the Utrecht Patient Oriented Database (UPOD) was conducted. For all inpatients, all episodes of exposure to dalteparin or nadroparin for at least 5 consecutive days in 2004–2005 were selected. In 4 different nonexclusive groups of patients (all pts. receiving dalteparin, all pts. receiving nadroparin, surgical pts. with a prophylactic dose of either dalteparin or nadroparin, and pts. exposed to unfractionated heparin [UFH] within 100 days before receiving either dalteparin or nadroparin), compliance with recommendations for platelet count monitoring from SPCs and a clinical guideline was studied. The frequency of compliance with these recommendations was determined. In addition, it was determined whether patient and treatment characteristics were associated with regular platelet count monitoring. Finally, the frequency of testing for HPF4-Ab and the initiation of danaparoid treatment in patients with a drop of at least 50% in platelet count were investigated.Results:A total of 6804 patients, with 7770 episodes of LMWH treatment, were included in the analysis. The frequency of compliance with platelet count monitoring recommendations was 26.3% for all patients receiving dalteparin, 35.6% for all patients receiving nadroparin, 23.0% for surgical patients receiving prophylactic dosing of either dalteparin or nadroparin, and 41.5% for patients exposed to UFH within 100 days before the start of either dalteparin or nadroparin treatment. Regular platelet count monitoring was strongly positively associated with medical patients (relative risk [RR] 2.33), surgical patients (RR 2.03), critically ill patients (RR 2.60), and those with recent exposure to UFH (RR 2.19). The frequency of testing for HPF4-Ab was 5.4% and the initiation of alternative anticoagulation with danaparoid in patients with a 50% drop in platelet count was 0%.Conclusions:The results suggest that compliance with recommendations for platelet count monitoring and management of possible HIT is low at our institution. Policies and tools to improve compliance with recommended laboratory monitoring should be developed to secure the safe use of LMWH and other medications.

Cyrus, Rachel M; Szumita, Paul M; Greenwood, Bonnie C; Pendergrass, Merri L

doi: 10.1345/aph.1M060pmid: 19654334

Background:Hyperglycemia is common in critically ill patients and is an independent risk factor for in-hospital morbidity and mortality.Objective:To assess compliance with a paper-based, multiplication-factor, intravenous insulin protocol.Methods:A retrospective chart review was conducted in a 720-bed urban, academic medical center in Boston, Massachusetts. During a 1-month period, compliance with and the consequent safety and efficacy of the Brigham and Women's Hospital paper-based, multiplication-factor, intravenous insulin protocol was evaluated.Results:The primary endpoint of protocol compliance, defined as correct adjustment to insulin infusion rate and correct timing of bedside blood glucose concentration (BBGC) checks ±10 minutes of prespecified BBGC check according to the Brigham and Women's Hospital Intravenous Insulin Protocol (BHIP), was 47.2%. Seventy-two patients met inclusion criteria. Appropriate adjustment of infusion rates occurred 68.2% (1206/1768) of the time. Compliance with the timing of BBGC checks was found to be the majority of protocol violations. BBGCs were monitored ±5 minutes of indicated time per the protocol 26.2% (463/1768) of the time. Blood glucose concentration checks within extended timing of ±10 minutes of indicated time per the protocol occurred 793 (44.8%) times. Blood glucose concentration monitoring took place greater than 20 minutes past indicated time 450 (25.5%) times. In 1768 measurements, blood glucose concentrations between 40 and 60 mg/dL occurred 23 (1.3%) times in 12 (16.7%) patients. Blood glucose concentrations 40 mg/dL or less were detected 3 (0.17%) times in 2 (2.7%) patients. None of these hypoglycemic events led to documented complications.Conclusions:Overall, a rather low level of compliance with a paper-based, multiplication-factor, intravenous insulin protocol was observed, which warrants further investigation. Compliance rates in this evaluation were found to be similar to the rates observed in previously evaluated fixed-dose intravenous insulin protocols. Protocol noncompliance may be associated with hypo- and hyperglycemia.

Burry, Lisa D; Tung, David D; Hallett, David; Bailie, Toni; Carvalhana, Virginia; Lee, David; Ramganesh, Steve; Richardson, Robert; Mehta, Sangeeta; Lapinsky, Stephen E

doi: 10.1345/aph.1M182pmid: 19690224

Stoner, Steven C; Dahmen, Megan M; Makos, Mignon; Lea, Jessica W; Carver, Lora J; Rasu, Rafia S

doi: 10.1345/aph.1M183pmid: 19690226

Background:Traditional treatment approaches for the management of restless legs syndrome (RLS) and Parkinson's disease (PD) include the use of medications that either directly or indirectly increase dopamine levels. In turn, a potential adverse event that could be expected is the development or exacerbation of psychiatric-related symptoms.Objective:To evaluate and describe the incidence of psychosis and associated behavioral features in patients taking ropinirole for RLS or PD.Methods:Patients were identified from a computerized database search of outpatients being treated with ropinirole for 1 of 2 medical conditions: PD or RLS. Data were collected in a retrospective manner from 95 patients who were tracked over the course of their therapy to determine whether psychosis or associated behavioral symptoms developed as a result and whether an intervention was needed to adjust ropinirole dosing or if additional medications had to be added to control features associated with psychosis.Results:A total of 284 patients being treated for RLS or PD were identified; of this group, 95 patients were identified as being treated for PD or RLS with ropinirole. Of the 95 patients being treated with ropinirole, 13 developed psychotic features that required therapeutic intervention with either the use of an antipsychotic or dose adjustment of ropinirole. PD patients included in this study were numerically more likely to develop psychotic features compared with RLS patients; however, the difference was not statistically significant (p = 0.122). The results do suggest that this risk is increased when ropinirole is used as part of a dual therapy approach with dopamine agonists in the treatment of either PD or RLS (p = 0.003).Discussion:Dopamine agonists have long been used as preferred treatment in the management of PD and RLS. When treating either PD or RLS in the psychiatric population, the concern arises that increased activity at dopamine receptors may induce or exacerbate psychiatric features. A potential clinical concern with the use of ropinirole is the potential for patients to develop psychiatric features, although there are few data available to demonstrate whether stimulation of targeted individual dopamine receptors is linked to the development or exacerbation of psychotic features. It is also undetermined whether concurrent antipsychotic treatment provides any protective benefit against psychosis, especially in patients already being treated for psychotic symptoms.Conclusions:Our findings suggest that ropinirole may play a role in inducing or exacerbating psychosis and its associated features, although a number of confounding variables prevent the determination of a clear association and suggest that further investigation is warranted in controlled clinical trials.

Neumiller, Joshua J; Campbell, R Keith

doi: 10.1345/aph.1M134pmid: 19638470

Objective:To review the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide, a glucagon-like peptide 1 (GLP-1) analog for the treatment of type 2 diabetes mellitus.Data Sources:A MEDLINE search (1966–May 2009) was conducted for English-language articles using the terms glucagon-like peptide 1, incretin mimetic, NN2211, and liraglutide. Abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes annual meetings in 2006, 2007, and 2008 were also searched for relevant data.Study Selection and Data Extraction:Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of liraglutide were reviewed.Data Synthesis:Liraglutide is a GLP-1 analog with pharmacokinetic properties suitable for once-daily administration. Clinical trial data from large, controlled studies demonstrate the effectiveness of liraglutide in terms of hemoglobin A1c (A1C) reduction, reductions in body weight, and the drug's low risk for hypoglycemic events when used as monotherapy. Data also support benefits of liraglutide therapy on β-cell responsiveness to glucose, with animal and in vitro data indicating potential benefits in β-cell mass and neogenesis with liraglutide treatment. Liraglutide has been studied as monotherapy and in combination with metformin, glimepiride, and rosiglitazone for the treatment of type 2 diabetes. Additionally, comparative data with insulin glargine and exenatide therapy are available from Phase 3 trials providing practitioners valuable clinical data on which to base clinical decision making. Overall, liraglutide is well tolerated with dose-dependent nausea, vomiting, and diarrhea being the most commonly reported adverse events in clinical trials.Conclusions:Once-daily administration may provide a therapeutic advantage for liraglutide over twice-daily exenatide, with similar improvements in A1C and body weight observed when liraglutide was compared with exenatide. The glucose-dependent mechanism of insulin release with GLP-1 agonist therapy holds potential clinical significance in the management of postprandial hyperglycemic excursions, with minimal risk of hypoglycemia.

Burkiewicz, Jill S; Scarpace, Sarah L; Bruce, Susan P

doi: 10.1345/aph.1M102pmid: 19622756

Objective:To review the pharmacology, pharmacokinetics, pharmacodynamics, safety, efficacy, and use of denosumab in osteoporosis, breast cancer, prostate cancer, and multiple myeloma.Data Sources:Studies and abstracts were identified through MEDLINE and International Pharmaceutical Abstracts (1966–July 2009). Key search terms include denosumab, AMG-162, and receptor activator of nuclear factor-κB ligand system. Information available in abstract form was retrieved from major oncology and bone metabolism meetings. Additional data were obtained from the manufacturer.Study Selection and Data Extraction:All available studies in humans were included except for studies in rheumatoid arthritis and giant cell tumor of the bone.Data Synthesis:In patients with osteoporosis, denosumab significantly reduces bone resorption and fractures. Studies of denosumab in the prevention and treatment of osteoporosis have demonstrated significantly increased bone mineral density and reduced bone turnover markers. Studies of denosumab versus placebo in the treatment of osteoporosis have demonstrated reductions in vertebral, hip, and nonvertebral fractures. In oncology, positive results from clinical trials in patients receiving endocrine therapy for breast and prostate cancer demonstrated decreases in bone loss and skeletal-related events. Denosumab seems to be at least as effective in reducing bone turnover markers as intravenous bisphosphonates in the oncology setting. The most common adverse effects in patients with osteoporosis were arthralgia, nasopharyngitis, back pain, and headache. The most common adverse effects in patients with cancer were infection, pain in the extremities, arthralgia, bone pain, fatigue, and pain. Serious adverse effects include infections requiring hospitalization.Conclusions:Denosumab has documented efficacy and safety in patients with osteoporosis, breast cancer, and prostate cancer. Additional clinical trial data are needed to more completely establish the effectiveness of denosumab in the treatment of osteoporosis and neoplastic disease as well as its cost-effectiveness and long-term safety.

Scanlon, James V; Exter, Benjamin P; Steinberg, Michael; Jarvis, Courtney I

doi: 10.1345/aph.1M151pmid: 19671802

Objective:To systematically review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of ustekinumab to inform pharmacists and other healthcare professionals of this new biologic therapy for psoriasis.Data Sources:A search of PubMed/MEDLINE, EMBASE, and International Pharmaceutical Abstracts was performed through July 2009, limited to publications in English, using the search terms CNTO-1275, ustekinumab, interleukin-12, interleukin-23, and/or psoriasis to identify literature sources. References from the retrieved articles were also evaluated to identify relevant literature. An abstract from a Congress of the European Academy of Dermatology and Venereology and unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov) were also reviewed. The Food and Drug Administration, European Medicines Agency, and Health Canada Web sites were used to retrieve product monographs, regulatory guidances, and advisory committee briefing packets.Study Selection and Data Extraction:All available studies relevant to the pharmacology, pharmacokinetics, and clinical safety/efficacy of ustekinumab for the treatment of psoriasis were included, with preference for human data.Data Synthesis:Ustekinumab, an anti-interleukin-12/23 monoclonal antibody, achieved the primary endpoint of 75% reduction in the Psoriasis Area and Severity Index score in a large proportion of patients in the Phase 3 PHOENIX trials. Commensurate improvements were also seen in the Physician's Global Assessment and Dermatology Life Quality Index scores. These efficacy results were reproduced in the ACCEPT trial, demonstrating superiority of ustekinumab to etanercept. The frequency of adverse events was similar between ustekinumab and placebo; common adverse events reported included nasopharyngitis, upper respiratory tract infection, headache, arthralgia, cough, and injection site reactions. Phase 3 studies indicate that the optimal dosing appears to be 45 mg for patients weighing less than 100 kg or 90 mg for patients weighing more than 100 kg, with both doses administered subcutaneously. In these studies, the second dose was given 4 weeks after the first and then every 8–12 weeks thereafter, based upon response.Conclusions:Ustekinumab, a promising new therapy, reduces the extent and severity of psoriasis and was well tolerated in clinical trials. Ongoing clinical trials will allow clinicians to further assess the efficacy/safety profile of this novel biologic.

Hegge, Karly A; Horning, Kristin K; Peitz, Gregory J; Hegge, Kassy

doi: 10.1345/aph.1M050pmid: 19654333

Objective:To summarize the role of pharmacotherapy in the management of phenylketonuria (PKU) and to review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile of sapropterin for this indication.Data Sources:A literature search was conducted using MEDLINE (1966–May 2009), International Pharmaceutical Abstracts (1970–May 2009), and Cochrane database (2008) for the following key words: sapropterin, tetrahydrobiopterin, phenylketonurias, and phenylalanine.Study Selection and Data Extraction:English-language studies involving humans examining the role of tetrahydrobiopterin (BH4) in the management of PKU were reviewed to evaluate the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile for sapropterin. All Phase 2 and 3 randomized controlled trials assessing the safety and efficacy of sapropterin were included in this literature evaluation.Data Synthesis:Sapropterin represents the only Food and Drug Administration–approved medication for BH4-responsive PKU, marking an important advance in the treatment of this condition. Among individuals with hyperphenylalaninemia and some residual phenylalanine hydroxylase function, sapropterin can enhance activity of this enzyme to decrease serum phenylalanine concentrations. Sapropterin has been compared with placebo in one Phase 2 and one Phase 3 clinical trial, demonstrating significantly better response rates. Based on available studies, this agent appears to be safe and well tolerated, with adverse event rates similar to those of placebo. However, additional studies are warranted to assess the long-term safety and efficacy of sapropterin therapy.Conclusions:Sapropterin offers a promising therapeutic option for select individuals with BH4-responsive PKU, although long-term data are limited evaluating its safety and efficacy in traditional clinical practice settings. When considering sapropterin therapy, clinicians must consider factors such as cost and patient adherence to drug therapy and/or diet.

Yeh, Yu-Chen; Klinger, Elissa V; Reddy, Prabashni

doi: 10.1345/aph.1M121pmid: 19602600

Objective:To summarize the evidence on pharmacologic options in preventing postoperative ileus (POI).Data Sources:The Cochrane Database of Reviews and OVID databases and Food and Drug Administration (FDA) Web site were searched (1950–April 2009) using the term postoperative ileus.Study Selection and Data Extraction:Meta-analyses and randomized controlled trials were included for review. The FDA Web site was searched for clinical reviews and label information for drugs indicated for the prevention of POI.Data Synthesis:Three meta-analyses, 2 on gum-chewing and 1 on alvimopan, and 18 clinical trials were identified. Only gum chewing and alvimopan were effective in preventing POI. Gum chewing reduced the time to first flatus and bowel movement (weighted mean difference 21h, p = 0.0006 and 33h; p = 0.0002, respectively). In one meta-analysis, gum chewing significantly reduced length of stay (LOS) by 2.4 days (p < 0.00001) but this was not replicated in the second meta-analysis. Alvimopan shortened the time to reach a composite endpoint of solid food intake, plus/minus flatus, and bowel movement (93 vs 105 h; p < 0.001). A higher incidence of myocardial infarction was observed in a 12-month study of alvimopan for the treatment of opioid-induced bowel dysfunction, but not in studies in patients undergoing bowel resection. Alvimopan decreased the time to written hospital discharge order (hazard ratio 1.35; p<0.01), while the significance of a reduction in LOS (0.2–1.3 days) was not reported.Conclusions:Gum chewing and alvimopan are effective in preventing POI, but given safety concerns and higher cost with alvimopan, gum chewing may be preferred.

Segarra-Newnham, Marisel; Hough, Augustus

doi: 10.1345/aph.1M153pmid: 19690227

Objective:To review studies of antibiotic prophylaxis in acute necrotizing pancreatitis published in the last decade and update recommendations.Data Sources:A search of PubMed (1998–July 2009) was conducted using the terms necrotizing pancreatitis, antibiotics, prophylaxis, and treatment. Clinical studies, meta-analyses, and review articles published in English were included. Additional references were obtained from article bibliographies. Randomized trials published before 1998 were included if indicated.Study Selection and Data Extraction:Relevant studies or meta-analyses on antibiotic prophylaxis since our previous review in 1998 were evaluated; older data were included if still relevant.Data Synthesis:Since our previous review, 4 more randomized trials, including 2 double-blind trials, have been conducted. The blinded studies found no significant difference in mortality with antibiotic prophylaxis compared with placebo, while the unblinded studies found a significant decrease in infections. Given these disparate results, available guidelines and meta-analyses provide different conclusions, usually based on exclusion or inclusion of a single trial. Based on all available data, antibiotic prophylaxis should not be used in patients with necrotizing pancreatitis. Instead, a more measured, on-demand use of antibiotics is preferred. Antibiotics should be added if signs and symptoms of infection are present (eg, fever, leukocytosis, positive results of cultures). Given improvements in intensive care and nutritional support, recent trials have found a lower incidence of infected necrotizing pancreatitis than before. Therefore, future trials are likely to need higher numbers of patients.Conclusions:Use of antibiotic prophylaxis for patients with necrotizing pancreatitis is not indicated, based on 2 blinded trials. Instead, on-demand use of antibiotics appears to be appropriate. Given progress in intensive care and the high crossover rate in studies, the need for antibiotic prophylaxis may continue to be debated for decades.