Opioid Prescribing After Implementation of Single Click Access to a State Prescription Drug Monitoring Program Database in a Health System's Electronic Health Record.

OBJECTIVES: To determine the effect of one-click integration of a state's prescription drug monitoring program (PDMP) on the number of PDMP searches and opioid prescriptions, stratified by specialty. METHODS: Our large health system worked with the state department of public health to integrate the PDMP with the electronic health record (EHR), which enabled providers to query the data with a single click inside the EHR environment. We evaluated Schedule II or III opioid prescriptions reported to the Massachusetts PDMP 6 months before (November 15, 2017-May 15, 2018) and 6 months after (May 16, 2018, to November 16, 2018) integration. Search counts, prescriptions, patients, morphine milligram equivalents, as well as prescriber specialty were compared. RESULTS: There were 3,185 unique prescribers with a record of a Schedule II and/or III opioid prescription in both study periods that met inclusion criteria. After integration, the number of PDMP searches increased from 208,684 in the pre-integration phase to 298,478 searches in the post-integration phase (+43.0%). The number of opioid prescriptions dispensed decreased by 4.8%, the number of patients receiving a prescription decreased by 5.1%, and the mean morphine milligram equivalents (MMEs) per prescriber decreased by 5.4%. There were some notable specialty-specific differences in these measures. CONCLUSIONS: Integration of the PDMP into the EHR markedly increased the number of searches but was associated with modest decreases in opioids prescribed and patients receiving a prescription. Single click EHR integration of the PDMP, if implemented broadly, may be a way for states to significantly increase PDMP utilization.

Andexanet Alfa (Andexxa) Formulary Review.

Andexanet alfa, a recombinant modified human "decoy" factor Xa (FXa) protein, is the first and only available antidote approved by the Food and Drug Administration to manage life-threatening or uncontrolled bleeding associated with the anti-Xa agents. It binds to direct and indirect anti-Xa oral anticoagulants with high specificity to reverse their inhibitory effects and restore the activity of FXa. Andexanet alfa is administered via two different dosing regimens, standard and high dose, based on the specific FXa inhibitor, dose, and time since the patient's last dose of FXa inhibitor. The approval for andexanet alfa is supported by data from two phase 3 studies (ANNEXA-A, ANNEXA-R) and preliminary data from the phase 3b/4 ANNEXA-4 trial. The first study found that andexanet alfa rapidly reduced anti-Xa activity by 92%-94% in healthy volunteers taking apixaban or rivaroxaban. The ANNEXA-4 study found that the median anti-Xa activity decreased by 89%-93% in patients with major bleeding taking apixaban or rivaroxaban. However, thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up in ANNEXA-4. Additionally, only 40% of patients had restarted anticoagulation and, in this group, the rate of thrombotic events was 12%. Four patients had a thrombotic event within 3 days after andexanet alfa treatment. The wholesale acquisition cost of the standard dose regimen is $24,750, and the high-dose regimen is $49,500. The estimated annual drug budget of treating 10-100 patients ranges from $248K to $495M. Effective October 1, 2018, Medicare will provide an add-on payment for andexanet alfa of up to $14,063 per qualifying case to Inpatient Prospective Payment System-participating acute care hospitals. In this formulary review for a health system's pharmacy and therapeutics committee, andexanet alfa clinical trials and medication package insert were summarized and, after consulting with clinical experts from our institutions, practical recommendations for use were generated to ensure appropriate and safe use of this agent.

Conversion from Filgrastim to Tbo-filgrastim: Experience of a Large Health Care System.

BACKGROUND: In 2008, tbo-filgrastim was approved as a biosimilar in Europe and then approved in the United States by the FDA in 2012 as a biologic product with 1 similar indication to filgrastim. Because tbo-filgrastim was less expensive than filgrastim, and clinical information and expert opinion supported similarity, the Pharmacy & Therapeutics Committee of a large health care system approved tbo-filgrastim as the preferred granulocyte-colony stimulating factor (G-CSF) product in March 2014. OBJECTIVES: To (a) assess the use of filgrastim and tbo-filgrastim products by comparing baseline characteristics, setting of care, indication for use, and payer type and (b) understand potential barriers of conversion to tbo-filgrastim. METHODS: A retrospective evaluation of filgrastim and tbo-filgrastim use was conducted on all patients (N = 204) who received the drugs between July 2015 and December 2015 at the 2 largest hospitals in the health system. Baseline characteristics, indication requiring use of filgrastim or tbo-filgrastim, setting of care, and payer information were collected from electronic medical records, and descriptive analyses were conducted. RESULTS: Overall, G-CSFs were administered to 204 patients for 261 episodes of care (filgrastim and tbo-filgrastim were used in 65 and 196 episodes of care, respectively). Baseline characteristics were similar between the 59 patients who received filgrastim and the 174 patients who received tbo-filgrastim. G-CSF was primarily used in the inpatient setting (163 episodes of care, 63%) with 90% of patients using tbo-filgrastim. In the outpatient setting (98 episodes of care, 38%), filgrastim and tbo-filgrastim were each used by 50% of patients. Tbo-filgrastim was the preferred G-CSF by clinical providers for all indications, except for stem cell mobilization, where filgrastim use was higher (55% vs. 45% of 71 episodes of care). In the outpatient setting, analysis by payers showed that the majority of patients on commercial plans were using filgrastim (58%), while half of Medicare patients were using filgrastim (50%, n = 12). Twelve patients were self-paid, and all were using tbo-filgrastim. Subgroup analysis by hospital showed differences in utilization patterns. CONCLUSIONS: Although tbo-filgrastim was the preferred G-CSF in our formulary, 29% of patients continued to receive filgrastim. Conversion to tbo-filgrastim has been largely successful, but extra steps may be needed to achieve full conversion to biosimilars. DISCLOSURES: No outside funding supported this study. Agboola was employed by Partners Healthcare at the time of the study. The authors have nothing to disclose. Study concept and design were contributed equally by Agboola and Reddy. Agboola collected the data, and data interpretation was performed by both authors. The manuscript was written primarily by Agboola, with assistance from Reddy. Both authors revised the manuscript.

Is There Evidence to Support Brand to Generic Interchange of the Mycophenolic Acid Products?

The uptake of generic immunosuppressants lags comparatively to other drug classes, despite that the Food and Drug Administration (FDA) uses identical bioequivalence standards for all drugs. Transplant societies acknowledge the cost savings associated with generic immunosuppressants and support their use following heart, lung, kidney, or bone marrow transplantation. Seven studies of the pharmacokinetics or clinical efficacy of generic mycophenolate mofetil compared to the innovator product are published; all studies and products were ex-United States. Three studies did not demonstrate any pharmacokinetic differences between generic and innovator products in healthy subjects, achieving FDA bioequivalence requirements. Two studies in renal allograft recipients demonstrated no difference in area under the curves between generic and innovator products, and in one, the maximum concentration (Cmax) fell outside the FDA regulatory range. Two studies revealed no difference in acute organ rejection or graft function in renal allograft recipients. Patient surveys indicate that cost is a barrier to immunosuppressant adherence. Generics present a viable method to reduce costs to payers, patients, and health care systems. Adherence to immunosuppressants is crucial to prevent graft failure. An affordable regimen potentially confers greater adherence. Concerns regarding the presumed inferiority of generic immunosuppressants should be assuaged by regulatory requirements for bioequivalency testing, transplant society position statements, and pharmacokinetic and clinical studies.

Idarucizumab (Praxbind) Formulary Review.

Idarucizumab (Praxbind), a humanized monoclonal antibody fragment was granted accelerated approval from the Food and Drug Administration in October 2015 as the first agent to reverse the effects of a novel oral anticoagulant. The drug is indicated for dabigatran reversal in patients requiring emergency surgery/urgent procedures or with life-threatening or uncontrolled bleeding. In a randomized study with healthy volunteers, compared with placebo, idarucizumab reduced the clotting times for all tests assays (assessed pre-, end of-, and 24 hours after infusion), while the results for the placebo group remained unchanged. Another randomized clinical trial assessed the safety and efficacy of idarucizumab in patients with either overt bleeding or undergoing emergency surgery where hemostasis was required. This study is ongoing, but preliminary results showed reversal efficacy demonstrated a reasonable safety profile from the time of the infusion to 90 days after. The wholesale acquisition cost of two 2.5 g vials of idarucizumab is currently $3482.50. To treat 10 or 20 patients per year with a single 5 g dose is estimated to cost $34,825 and $69,650, respectively. In the clinical trial described above, approximately 20% of patients required a second dose, which would further increase the cost of use. In this formulary review for a health system's pharmacy and therapeutics committee, idarucizumab clinical trials and medication package insert were summarized and, after consulting with clinical experts from our institutions, practical recommendations for use were generated to ensure appropriate and safe use of this agent.

The role of rivaroxaban in atrial fibrillation and acute coronary syndromes.

Rivaroxaban, a direct factor Xa inhibitor, is a novel oral anticoagulant approved for stroke prevention in patients with nonvalvular atrial fibrillation and also approved in Europe (but not in the United States) to prevent recurrent ischemic events in patients with recent acute coronary syndromes. Advantages of rivaroxaban over oral anticoagulants such as warfarin are the lack of need for ongoing monitoring, a fixed-dose regimen, and fewer drug and food interactions. Drawbacks include a lack of an antidote and the absence of a widely available method to reliably monitor the anticoagulant effect. In patients at risk of stroke due to atrial fibrillation, rivaroxaban was noninferior compared to warfarin in preventing stroke/systemic embolism in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial and was associated with a similar risk of major bleeding; the incidence of intracranial hemorrhage was 33% lower with rivaroxaban. Concerns raised about the trial were the adequacy of warfarin management and the increase in event rate at the end of the trial. The drug acquisition cost of rivaroxaban is higher than that of warfarin although decision-analytic models suggest that it is cost effective in atrial fibrillation. In patients with recent acute coronary syndrome, low-dose rivaroxaban reduced mortality and the composite end point of death from cardiovascular causes, myocardial infarction and stroke, but this was accompanied by an increased risk of intracranial hemorrhage and major bleeding in the Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction (ATLAS ACS 2-TIMI) 51 trial. Thus, rivaroxaban appears to be a valuable addition to the therapeutic armamentarium in atrial fibrillation although caution should be exercised, given the limited experience in combination with novel oral antiplatelet agents. The role of rivaroxaban as part of a modern regimen in acute coronary syndrome continues to be evaluated.

Clinical and economic evidence for intravenous acetaminophen.

Intravenous acetaminophen received United States Food and Drug Administration approval in November 2010 for the management of mild-to-moderate pain, management of moderate-to-severe pain with adjunctive opioid analgesics, and reduction of fever. Although intravenous acetaminophen generally improved pain relief and demonstrated opioid-sparing effects compared with placebo, it did not consistently reduce the frequency of opioid-related adverse events (e.g., postoperative nausea and vomiting). The safety and efficacy of intravenous acetaminophen as an antipyretic agent have been documented in adults and children; however, its cost is several-fold higher than that of the oral and rectal formulations. Although use of intravenous acetaminophen has reduced other postoperative resource utilization (e.g., hospital length of stay) in some studies outside the United States in patients undergoing abdominal surgery, a full economic evaluation in the United States has yet to be undertaken. In addition, its administration time (15-min infusion) and packaging (glass, single-use vial) have the potential to adversely affect patient flow in the postanesthesia care unit, create burden on patient care units, and lead to drug waste. Furthermore, 1 g of intravenous acetaminophen is formulated in 100 ml of solution, which may be an issue for patients with fluid restrictions. Given the clinical and economic evidence currently available, intravenous acetaminophen should not replace oral or rectal acetaminophen, but its use may be considered in a limited number of patients who cannot receive drugs orally and rectally and who cannot tolerate other parenteral nonopioid analgesic or antipyretic agents.

Dabigatran: a review of clinical and pharmacoeconomic evidence.

Dabigatran etexilate is the first commercially available oral direct thrombin inhibitor. A single trial has studied patients at risk for stroke associated with nonvalvular atrial fibrillation; in this trial, dabigatran 150 mg twice a day met the criteria for superiority over warfarin in preventing stroke and systemic embolism while reducing the rate of hemorrhagic stroke with a similar risk of major bleeding. For the treatment of venous thromboembolism, dabigatran 150 mg twice a day had comparable efficacy and safety versus warfarin. In contrast, dabigatran was less effective than enoxaparin 30 mg twice a day in venous thromboembolism prevention in orthopedic surgery. Advantages of dabigatran over warfarin include its lack of need for routine laboratory monitoring, a fixed-dose regimen, and potentially fewer clinically important drug interactions. Concerns include higher incidences of dyspepsia and gastrointestinal bleeding, twice-daily dosing, and lack of effective antidote. Additional drawbacks include higher drug cost versus warfarin, accumulation in case of renal impairment, higher discontinuation rates due to adverse events, and limited long-term safety and trial data. From a payer perspective, overall costs will be higher with dabigatran compared with warfarin, but dabigatran does meet the threshold to be considered a cost-effective therapy. In addition, the lack of need for regular laboratory monitoring is a quality of life advantage for patients on dabigatran. These observations suggest that dabigatran is a valuable addition to the therapeutic armamentarium for stroke prevention in selected patients with atrial fibrillation although caution should be exercised given the limited data on this agent and higher cost.

Comparison of healthcare resource use between patients receiving ondansetron or palonosetron as prophylaxis for chemotherapy-induced nausea and vomiting.

OBJECTIVE: To analyze the differences between ondansetron and palonosetron in healthcare resource use (i.e., inpatient/ outpatient encounters) among patients receiving intraperitoneal cisplatin. METHOD: A medical record review was performed. Intraperitoneal cisplatin administrations for gynecological cancers from January through June 2006 and from October 2007 through June 2008 were divided into two groups based on the serotonin-receptor antagonist used. The occurrence of chemotherapy-induced nausea and vomiting (CINV)-related hospital readmissions, emergency department visits, and outpatient encounters occurring within 7 days after cisplatin administration was compared. CINV-related resource use was defined as events associated with dehydration, hypovolemia, nausea/vomiting, hypokalemia, constipation, shortness of breath, or syncope/collapse. RESULTS: Ondansetron or palonosetron was used in 39 and 89 cisplatin administrations, respectively. The baseline characteristics were similar between the groups with mean age of 59 years and ovarian cancer being the most common cancer. Length of stay was approximately 2 days. Palonosetron was always administered as a single-day therapy while one- or multi-day ondansetron therapy was administered in 27% and 73% of cycles, respectively. A trend towards more CINV-related hospitalizations with ondansetron versus palonosetron was observed (5.1% vs. 0%, p = 0.09) with no significant difference in other CINV-related encounters. CONCLUSION: Palonosetron was associated with a trend to a lower risk of CINV-related hospital readmission than ondansetron in patients receiving intraperitoneal cisplatin for gynecological cancers, although not statistically significant. The duration of ondansetron therapy might be suboptimal with 27% of patients receiving only 1 day of therapy during hospital stay. These findings need to be confirmed in future studies.

Pharmacologic options to prevent postoperative ileus.

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.

Use of injectable nicardipine for neurovascular indications.

Injectable nicardipine is increasingly being used to manage neurovascular conditions. To better understand its place in therapy, we conducted an evidenced-based literature review. Two-hundred twenty-three article abstracts were identified; after independent review by two individuals and a supplemental manual search, 29 were deemed relevant and were included in this review. Nicardipine has been studied or recommended for management of hypertension in many neurovascular settings (ischemic stroke, intracerebral hemorrhage, craniotomy, and spinal surgery), for vasospasm in aneurysmal subarachnoid hemorrhage, and in acute traumatic brain injury. In the management of hypertension in acute stroke, nicardipine is one of several recommended options available; expert opinion forms the basis of these recommendations in clinical guidelines, with limited randomized controlled trial evidence to support its use. Among the various antihypertensive agents, nicardipine has the highest drug acquisition cost. In two meta-analyses, intravenous nicardipine had no impact on patient outcomes (death, disability) in patients with acute traumatic brain injury (relative risk [RR] 0.25, 95% confidence interval [CI] 0.05-1.27) or in patients with aneursymal subarachnoid hemorrhage (RR 0.97, 95% CI 0.78-1.20). Intraarterial nicardipine reduced angiographic diameter (p value not reported) and peak systolic velocities on transcranial Doppler images (p<0.001) in published case series. Given nicardipine's high cost relative to that of other agents and the limited evidence to support its use in patients with neurovascular conditions, this drug should be considered only in patients who have failed or have contraindications to alternative agents in the management of hypertension. Although intraarterial nicardipine appears to be promising in aneurysmal subarachnoid hemorrhage, well-designed studies are needed in this setting before its use can be routinely recommended.

Guidelines for pharmacoeconomic and outcomes research fellowship training programs: joint guidelines from the american college of clinical pharmacy and the international society of pharmacoeconomics and outcomes research.

Abstract Pharmacoeconomics and outcomes research (PEOR) demonstrates the added value of health services and treatments and is used by a variety of individuals in numerous settings to optimize patient care. Currently, 51 PEOR fellowship programs are publicized on Web sites from organizations such as the American College of Clinical Pharmacy (ACCP), the International Society of Pharmacoeconomics and Outcomes Research (ISPOR), and the Academy of Managed Care Pharmacy. These programs demonstrate the diversity of PEOR fellowships, as they are offered by sponsors in a variety of environments (e.g., academia, industry, consulting services, United States managed care, and government). Although the program sponsors vary, all fellowships should have the common goal of providing directed, highly individualized postgraduate training designed to prepare participants to become independent PEOR researchers. Like any health discipline, advancements in knowledge and technology along with changes in health care systems require refinement of existing training programs, including PEOR fellowships. Members of ACCP and ISPOR developed a survey instrument to assess structure, educational objectives, and outcome measures of PEOR fellowship programs. The survey objectives were to determine PEOR researchers' beliefs regarding qualifications of the training site, program, and preceptors(s) as well as fellowship applicant requirements, research commitment, didactic coursework and evaluation of fellows' research skills; and to develop PEOR fellowship guidelines based on data obtained from the survey. Pharmacoeconomics and outcomes research fellowship guidelines were originally published in 1999; this document outlines the revised PEOR fellowship guidelines based on recent literature and results of the ACCP-ISPOR survey described above. These guidelines are intended to assist PEOR researchers design, refine, and self-assess their fellowship program and to serve as a tool for prospective PEOR fellowship candidates to evaluate programs.

Cost-effectiveness of amiodarone in cardiac surgery.

Atrial fibrillation is the most common complication after open-heart surgery. The incidence rate is 25-50%. This review summarizes findings of economic studies of amiodarone prophylaxis in cardiac surgery patients. Data were pooled from more than 15 studies. Four meta-analyses combining six to 19 amiodarone trials indicated a significant decrease in the incidence of postoperative atrial fibrillation (odds ratio range: 0.50-0.54). Other studies (individual randomized controlled trials, naturalistic studies and economic models) supported this finding. A majority of studies showed that amiodarone prophylaxis was cost neutral and resulted in a decrease in the length of stay, the main cost driver in postoperative atrial fibrillation. Selective use of amiodarone in high-risk patients (over 70 years, history of atrial fibrillation and chronic obstructive pulmonary disease, and concurrent valve surgery) will potentially enhance its cost-effectiveness.

The economic impact of blue-light filtering intraocular lenses on age-related macular degeneration associated with cataract surgery: a third-party payer's perspective.

OBJECTIVES: Epidemiological data support an association between age-related macular degeneration (AMD) and cataract surgery that may be attributed to post-operative blue light exposure. By limiting the retina's blue light exposure, new blue-light filtering intraocular lenses (BLF IOLs) have the potential to reduce the development of AMD following cataract surgery. In the current economic healthcare environment, there is increased interest in the cost impact of new medical technologies. The objective of this analysis was to evaluate the cost impact of a BLF IOL versus a non-BLF IOL in cataract surgery. METHODS: An economic model was developed to emulate three age-specific cohorts and to assess the clinical and economic outcomes over 5 years. Data from the published literature was supplemented with clinical expert opinion. Key literature inputs involved the risk of AMD after cataract surgery as well as laboratory and animal data on the effectiveness of the BLF IOL in reducing the risk of AMD. Clinical experts provided information on the management of AMD. Direct medical costs including the cost of the IOL, monitoring, and AMD prophylaxis and treatment were incorporated into the model. All costs were standardized to 2004 US dollars. Age-stratified sensitivity analyses were conducted. RESULTS: In the BLF IOL group, the 5-year age-stratified incidence of AMD ranged from 0.58 to 9.23 per 100 eyes, compared with 1.69 to 24.55 per 100 eyes in the non-BLF IOL group. The incremental cost of the BLF was offset by reduced costs associated with averted AMD treatment. Estimated savings with BLF IOLs per 100 eyes were $4275, $29 997, and $111 734 in the 55 to 64 year-old, 65 to 74 year-old, and >or= 75-year-old cohorts, respectively; these findings remained robust throughout the sensitivity analyses. CONCLUSION: Limitations of this analysis include the lack of prospective clinical trial data that definitively demonstrate the efficacy of a BLF IOL in preventing AMD. Moreover, the efficacy data used to populate the model were derived from laboratory and animal studies. Thus, based on preliminary data, this study suggests that the economic benefits of implanting BLF IOLs during cataract surgery are observed in all patients over a 5-year timeframe although cost savings are greatest in patients >or= 75 years.

What are the barriers to warfarin use in atrial fibrillation?: Development of a questionnaire.

BACKGROUND: Despite evidence of their benefit and efforts to increase usage, anticoagulation for stroke prophylaxis in atrial fibrillation (AF) patients remains underutilized. Previous surveys have assessed reasons for underuse of anticoagulation but have limitations including non-structured approach for eliciting barriers and use of clinical vignettes and not patient-level data. The objectives of this study were to develop a questionnaire to assess barriers to anticoagulation use for stroke prophylaxis in AF patients at a patient- and physician-level and to conduct a preliminary field-test of the instrument. METHODS: Barriers to warfarin use were identified from a literature review, input from clinical experts, and a physician focus group. A sample of US physicians who treat AF patients completed the questionnaire. Physicians ranked their reluctance on a 1-10 scale (10 = very reluctant) in general to prescribe warfarin if a specific barrier was present in a patient and then indicated critical barriers to prescribing warfarin in a sample of their own AF patients not receiving warfarin. RESULTS: Forty-one barriers to warfarin use were identified and classified into 4 groups: patient medical characteristics (n = 17), health care system factors (n = 7), patient capability (n = 12), and patient preference (n = 5). Several new items were developed (e.g., difficulty in obtaining venous access), existing items were revised (e.g., timeframe for bleeding episodes subdivided into > or