Annals of Pharmacotherapy

Background: HIV-infected patients receiving antiretroviral therapy (ART) are at risk for contraindicated drug-drug interactions (XDDIs). Objective: This study compared the frequency of XDDIs between different types of ART regimens. Methods: A retrospective cohort study was performed among adult HIV-infected patients receiving care at either the Upstate New York Veterans’ Healthcare Administration or the University of New Mexico Truman Health Services between 2000 and 2013. The cohort consisted of patients receiving traditional ART regimens composed of 2 nucleoside reverse transcriptase inhibitors plus either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase strand transfer inhibitor (INSTI). The primary outcome was the presence of XDDIs. Lexi-Interact was used to define XDDIs. Results: Of the 1329 patients who met inclusion criteria, 45.7%, 34.2%, and 20.1% were receiving an NNRTI-, PI-, or INSTI- based ART regimen, respectively. Among the 128 (9.6%) patients with an XDDI, more than half (53.9%) had an interaction involving ART. The presence of XDDIs was highest for PI-based regimens (16.3%) compared with INSTI- (7.9%) and NNRTI-based (5.4%) regimens; P < 0.001. The variables independently associated with XDDIs were ART regimen type (prevalence ratio [PR] = 1.91; 95% CI = 1.51-2.40, P < 0.001), use of ≥6 non-HIV medications (PR = 5.84; 95% CI = 3.92-8.71, P < 0.001), and age ≥40 years (PR = 1.62; 95% CI = 0.92-2.86, P = 0.10). Conclusion: The probability of XDDIs varies as a function of ART regimen type, advanced age, and use of multiple non-HIV medications.

Background: Improved anticoagulation control with warfarin reduces adverse events and represents a target for quality improvement. No previous study has described an effort to improve anticoagulation control across a health system. Objective: To describe the results of an effort to improve anticoagulation control in the New England region of the Veterans Health Administration (VA). Methods: Our intervention encompassed 8 VA sites managing warfarin for more than 5000 patients in New England (Veterans Integrated Service Network 1 [VISN 1]). We provided sites with a system to measure processes of care, along with targeted audit and feedback. We focused on processes of care associated with site-level anticoagulation control, including prompt follow-up after out-of-range international normalized ratio (INR) values, minimizing loss to follow-up, and use of guideline-concordant INR target ranges. We used a difference-in-differences (DID) model to examine changes in anticoagulation control, measured as percentage time in therapeutic range (TTR), as well as process measures and compared VISN 1 sites with 116 VA sites located outside VISN 1. Results: VISN 1 sites improved on TTR, our main indicator of quality, from 66.4% to 69.2%, whereas sites outside VISN 1 improved from 65.9% to 66.4% (DID 2.3%, P < 0.001). Improvement in TTR correlated strongly with the extent of improvement on process-of-care measures, which varied widely across VISN 1 sites. Conclusions: A regional quality improvement initiative, using performance measurement with audit and feedback, improved TTR by 2.3% more than control sites, which is a clinically important difference. Improving relevant processes of care can improve outcomes for patients receiving warfarin.

Background: HIV-infected patients are at an increased risk of developing venous thromboembolism (VTE), and minimal data are available to describe the need for extended treatment. Objective: To evaluate the frequency of and determine predictive risk factors for extended anticoagulation of VTE in HIV-infected patients in rural, western Kenya. Methods: A retrospective chart review was conducted at the Anticoagulation Monitoring Service affiliated with Moi Teaching and Referral Hospital and the Academic Model Providing Access to Healthcare. Data were collected on patients who were HIV-infected and receiving anticoagulation for lower-limb deep vein thrombosis. The need for extended anticoagulation, defined as receiving ≥7 months of warfarin therapy, was established based on patient symptoms or Doppler ultrasound–confirmed diagnosis. Evaluation of the secondary outcomes utilized a univariate analysis to identify risk factors associated with extended anticoagulation. Results: A total of 71 patients were included in the analysis; 27 patients (38%) required extended anticoagulation. The univariate analysis showed a statistically significant association between the need for extended anticoagulation and achieving a therapeutic international normalized ratio within 21 days in both the unadjusted and adjusted analysis. Patients with a history of opportunistic infections required an extended duration of anticoagulation in the adjusted analysis: odds ratio = 3.42; 95% CI = 1.04-11.32; P = 0.04. Conclusions: This study shows that there may be a need for increased duration of anticoagulation in HIV-infected patients, with a need to address the issue of long-term management. Guideline recommendations are needed to address the complexity of treatment issues in this population.

Background: The introduction of anti–tumor necrosis factor α (anti-TNFα) drugs has improved the clinical outcomes in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, these drugs may cause adverse effects that motivate a change in or discontinuation of the treatment. Objective: To evaluate the causes of discontinuation or changes in the dosage regimen in a cohort of patients with RA and AS treated with infliximab, adalimumab, etanercept, and golimumab under clinical practice conditions. Methods: This was a retrospective observational study that included patients with RA or AS treated with anti-TNFα drugs between 2008 and 2013. Changes in the dosage regimen, reasons for treatment discontinuation, and adverse effects were recorded and analyzed. Time to discontinuation was estimated using Kaplan-Meier survival analysis. Results: A total of 123 patients with RA and 93 patients with AS were treated with anti-TNFα therapy. During the study, 55.3% of RA patients and 41.7% of AS patients had stopped the treatment. The most frequent changes were modifications in the dosing, and the most frequent adverse effects were reactions after the infusion or injection (53.8% and 66.7% in RA and AS, respectively). Drug survival of etanercept in RA (67.9%) is greater than for adalimumab and infliximab, whereas drug survival of infliximab in AS (70.0%) is greater than for etanercept and adalimumab at 5 years, although there were no significant differences (P = 0.098 in RA and 0.194 in AS). Conclusions: The main cause of discontinuation of anti-TNFα is therapeutic failure in both diseases. Etanercept and infliximab have the best survival rates in RA and AS, respectively.

Background: Despite evidence on poor adherence to guideline-directed statin therapy (GDST) following an acute coronary syndrome (ACS), little information has been published on pharmacist-led statin pilot programs for secondary prevention. Objective: We sought to evaluate the impact of a pharmacist intervention (PI) on GDST during an ACS hospitalization. Methods: A historical control (HC) group consisting of 125 ACS hospitalizations was retrospectively identified, with prospective data of 113 patients captured over 6 months in the PI group. The primary outcome of GDST was defined according to 2013 clinical guidelines and evaluated in all 238 qualifying patients. Secondary outcomes included number of interventions and use of logistic regression to investigate the relationship of ACS subtype with statin dose. Results: On admission, GDST was ordered in 62.5% of the HC and 75.9% of the PI group. At discharge, the PI group had a higher rate of GDST relative to HC among all patients (86.7 % vs 77.4%, P = 0.06), and after exclusion of contraindications (84.8% vs 74.5%; P = 0.1), 10 patients required PI, accounting for an increase in GDST of 5.3%. Statin dose selection did not differ by ACS subtype (odds ratio = 0.79; 95% CI = 0.0.29-2.17; P = 0.18). Conclusion: PI did not significantly increase GDST. Increased compliance rates measured were primarily driven by higher baseline adherence and guideline incorporation over time.

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of the glucagon-like peptide-1 receptor agonist (GLP-1RA), lixisenatide, in the treatment of type 2 diabetes mellitus. Data Sources: A PubMed (1966-2016) search was conducted using the following keywords: lixisenatide, AVE0010, glucagon-like peptide-1 agonist, and type 2 diabetes. References were reviewed to identify additional sources. Study Selection and Data Extraction: Articles written in English were included if they evaluated the pharmacology, pharmacokinetics, efficacy, or safety of lixisenatide in human subjects. Data Synthesis: Lixisenatide lowers blood glucose through a glucose-dependent increase in insulin release from pancreatic β-cells and a decreased release of glucagon from pancreatic α-cells. Additionally, lixisenatide delays gastric emptying and increases satiety. Lixisenatide has been studied head to head against exenatide and insulin glulisine. It has also been studied as monotherapy and in combination with metformin, sulfonylureas, pioglitazone, and insulin glargine. In the GetGoal clinical trial series, lixisenatide resulted in a hemoglobin A_1C reduction of 0.6% to 1% and a reduction in body weight of 0.2 to 2.96 kg. The adverse effect profile of lixisenatide was consistent with that of other GLP-1RAs, with nausea, vomiting, and diarrhea most commonly reported. Conclusion: Lixisenatide provides an additional GLP-1RA option, which may have more postprandial blood glucose-lowering effects than the other agents in the class because of its shorter half-life and effects on delaying gastric emptying.

Objective: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. Data Sources: A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta. Study Selection/Data Extraction: Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified. Data Synthesis: Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration–approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations. Conclusion: Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.

Objective: To review the efficacy and safety of pharmacological and nonpharmacological strategies used to treat primary orthostatic hypotension (OH). Data Sources: A literature review using PubMed and MEDLINE databases searching hypotension, non-pharmacological therapy, midodrine, droxidopa, pyridostigmine, fludrocortisone, atomoxetine, pseudoephedrine, and octreotide was performed. Study Selection and Data Extraction: Randomized or observational studies, cohorts, case series, or case reports written in English between January 1970 and November 2016 that assessed primary OH treatment in adult patients were evaluated. Data Synthesis: Based on the chosen criteria, it was found that OH patients make up approximately 15% of all syncope patients, predominantly as a result of cardiovascular or neurological insults, or offending medication. Nonpharmacological strategies are the primary treatment, such as discontinuing offending medications, switching medication administration to bedtime, avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration, adding salt to diet, and so on. If these fail, pharmacotherapy can help ameliorate symptoms, including midodrine, droxidopa, fludrocortisone, pyridostigmine, atomoxetine, sympathomimetic agents, and octreotide. Conclusions: Midodrine and droxidopa possess the most evidence with respect to increasing blood pressure and alleviating symptoms. Pyridostigmine and fludrocortisone can be used in patients who fail to respond to these agents. Emerging evidence with low-dose atomoxetine is promising, especially in those with central autonomic failure, and may prove to be a viable alternative treatment option. Data surrounding other therapies such as sympathomimetic agents or octreotide are minimal. Medication management of primary OH should be guided by patient-specific factors, such as tolerability, adverse effects, and drug-drug and drug-disease interactions.

Proficiency in research design and statistical analysis is crucial to the success of a clinical pharmacist. However, new pharmacy graduates and residents may not have received adequate training and education in these areas. During the authors’ tenure as clinical pharmacists, several statistical “myths” were consistently maintained by residents and new clinical practitioners. The purpose of this narrative review is to discuss and dispel several of these statistical fallacies. The myths discussed involve 3 common areas of consideration when evaluating any clinical study: assessing the risk of bias from confounding (propensity score analysis and multivariable modeling), interpretation of the main study findings (P values and hypothesis testing), and secondary evaluations (subgroup analyses). Literature examples are used to illustrate each of the topics. The authors hope that the discussion will augment each pharmacist’s knowledge of medical literature interpretation leading to improvements in patient care, education of future residents, and personal research endeavors.