Pharmacogenetic testing in the Veterans Health Administration (VHA): policy recommendations from the VHA Clinical Pharmacogenetics Subcommittee.

PURPOSE: The Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy. METHODS: After developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation. RESULTS: Of 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing. CONCLUSION: Only half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.

Examining Interventions and Adverse Events After Nonfatal Opioid Overdoses in Veterans.

Background: Veterans are twice as likely to experience a fatal opioid overdose compared with their civilian counterparts. Recognition has increased that effective opioid overdose prevention likely requires a holistic approach that addresses the biopsychosocial factors contributing to opioid-related morbidity and mortality. Methods: This retrospective descriptive study includes veterans who were administered naloxone for treatment of opioid overdose in the emergency department at Veterans Affairs San Diego Healthcare System from July 1, 2013 through April 1, 2017. Subjects were excluded if they received palliative/hospice care or were lost to follow-up, if there was documented lack of response to naloxone administration, and if overdose occurred secondary to inpatient administration of opioids. Data were collected via chart review. Results: Thirty-five patients were included in this study. At the time of nonfatal opioid overdose, 29 (82.9%) had an active opioid prescription, and the mean morphine equivalent daily dose (MEDD) was 117 mg. Thirty-three (94.3%) had comorbid psychiatric disorders and 20 (57.1%) had substance use disorders. Within 6 months following overdose, subjects received care from mental health (45.5%), addiction treatment services (50.0%), and pain management (40.0%). Documented repeat overdose occurred in 4 patients. Conclusions: This study may aid in the identification of potential areas for improvement in the prevention of opioid overdose and opioid-related mortality among veterans. Interventions designed to improve access to, engagement, and retention in effective care are pivotal for addressing the opioid epidemic as it evolves.

Measuring patient satisfaction in the pharmacy specialty immunization clinic: a pharmacist-run Immunization Clinic at the Veterans Affairs San Diego Healthcare System.

OBJECTIVE: The aim was to measure patient satisfaction with the Pharmacy Specialty Immunization Clinic (PSIC), a pharmacist-run vaccination clinic. METHODS: Patient satisfaction was measured using a non-validated instrument containing 10 items with a five-point Likert scale (strongly agree, agree, not sure, disagree and strongly disagree). Patients who were seen at the PSIC and who received at least one vaccination were eligible to take part in the patient satisfaction survey. Priority index, a method used to identify areas where limited resources can be used to maximize patient satisfaction, was calculated for the different items of the instrument to determine areas for quality improvement. This study was conducted at the Veterans Affairs San Diego Healthcare System (VASDHS). KEY FINDINGS: A total of 188 (55.1%) out of 341 patients who received at least one vaccine in the PSIC completed the survey. Prior to any encounter with the PSIC, patients perceived that the VASDHS was doing a good job providing vaccinations (92.5% answered agree or strongly agree). This perception continued when asked about overall satisfaction after receiving vaccination through the PSIC (86.9% answered agree or strongly agree). When asked about the time the pharmacist spent with the patient, nearly all answered that the pharmacist spent as much time as necessary (97.8% answered agree or strongly agree). Patient satisfaction with pharmacist counselling was equally well received and reflected good communication between patient and pharmacist (97.8% answered agree or strongly agree). In regard to pharmacist competency, 98.9% (n = 184) of patients agreed that pharmacists in the PSIC administered vaccinations appropriately. Priority index identified access to the vaccine as an area where performance-improvement efforts should be committed to improve patient satisfaction. CONCLUSIONS: Patients perceived good overall satisfaction with the pharmacist-run immunization clinic in terms of professionalism and access to vaccination. Priority index identified access to vaccination as a focus for future quality improvement.

Reducing Benzodiazepine Prescribing in Older Veterans: A Direct-to-Consumer Educational Brochure.

This quality improvement project used an educational brochure to help older veterans reduce their benzodiazepine use.

Denosumab for treatment of breast cancer bone metastases and beyond.

INTRODUCTION: Bone metastases develop in approximately 70 - 85% of patients with metastatic breast cancer, are incurable and can result in debilitating skeletal complications. Bone-modifying agents to treat breast cancer bone metastases include bisphosphonates. Denosumab is a humanized monoclonal IgG2 antibody targeting receptor activator of NF-κB ligand (RANKL) and provides an alternative therapy for treatment of breast cancer bone metastases. AREAS COVERED: This review provides an overview on denosumab and the RANKL-RANK pathway. Denosumab pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are discussed. Based on the review of clinical studies, denosumab is efficacious in the treatment of breast cancer bone metastases. Adverse events rates of denosumab are similar to those for bisphosphonates. Preclinical studies have indicated a role of the RANKL-RANK pathway in non-bone-related mechanisms such as mammary gland development and tumorigenesis. EXPERT OPINION: Clinical use of denosumab remains limited and its place in therapy will continue to be defined. Clinical questions, such as the optimal duration of therapy, remain unanswered and need to be addressed.

Cost utility of tumour necrosis factor-α inhibitors for rheumatoid arthritis: an application of Bayesian methods for evidence synthesis in a Markov model.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects approximately 1.5 million people in the US. Tumour necrosis factor (TNF)-α inhibitors have been shown to effectively treat and maintain remission in patients with moderately to severely active RA compared with conventional agents. The high acquisition cost of TNF-α inhibitors prohibits access, which mandates economic investigations into their affordability. The lack of head-to-head comparisons between these agents makes it difficult to determine which agent is the most cost effective. OBJECTIVE: This study aimed to determine which TNF-α inhibitor was the most cost-effective agent for the treatment of moderately to severely active RA from the US healthcare payer's perspective. METHODS: A Markov model was constructed to analyse the cost utility of five TNF-α inhibitors (in combination with methotrexate [+MTX]) versus MTX monotherapy using Bayesian methods for evidence synthesis. The model had a cycle length of 3 months and an overall time horizon of 5 years. Transition probabilities and utility scores were based on published studies. Total direct costs were adjusted to year 2009 $US using the medical component of the Consumer Price Index. All costs and QALYs were discounted at a rate of 3% per year. Patient response to the different strategies was determined by the American College of Rheumatology (ACR)50 criteria. One-way and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case scenario. The base-case scenario was changed to ACR20 criteria (scenario 1) and ACR70 criteria (scenario 2) to determine the model's robustness. Cost-effectiveness acceptability curves and cost-effectiveness frontiers were used to estimate the cost-effectiveness probability of each treatment strategy. A willingness-to-pay (WTP) threshold was defined as three times the US GDP per capita ($US139,143 per additional QALY gained). Primary results were presented as incremental cost-effective ratios (ICERs). RESULTS: Etanercept+MTX was the most cost-effective treatment strategy in the base-case scenario up to a WTP threshold of $US2 185,497 per QALY gained. At a WTP threshold of greater than $US2 185,497 per QALY gained, certolizumab+MTX was the most cost-effective treatment strategy. One-way analyses showed that the base-case scenario was sensitive to the probability of achieving ACR50 criteria for MTX and each TNF-α inhibitor, and changes in the utility score for patients who achieved the ACR50 criteria. With the exception of infliximab, all of the TNF-α inhibitors were sensitive to drug cost per cycle. In the scenario analyses, certolizumab+MTX was a dominant treatment strategy using ACR20 criteria, but etanercept+MTX was a dominant treatment strategy using ACR70 criteria. CONCLUSIONS: Etanercept+MTX was a cost-effective treatment strategy in the base-case scenario; however, the model was sensitive to parameter uncertainties and ACR response criteria. Although Bayesian methods were used to determine transition probabilities, future studies will need to focus on head-to-head comparisons of multiple TNF-α inhibitors to provide valid comparisons.

Cost-utility analysis of bevacizumab versus ranibizumab in neovascular age-related macular degeneration using a Markov model.

OBJECTIVE: To evaluate the cost-effectiveness of intravitreal bevacizumab to ranibizumab in patients with neovascular age-related macular degeneration (AMD). METHODS: A cost-utility analysis using a Markov model was performed to evaluate incremental cost-effectiveness ratio [ICER, $US per quality-adjusted life year (QALY) gained] between bevacizumab and ranibizumab from a US payer perspective. Transition probabilities for ranibizumab and bevacizumab were extrapolated from published studies and local institutional data. Utility values, likewise, were obtained from another published study. Mortality rates were determined from the Centers for Disease Control 2003 Life Tables. Resource utilization and total direct costs were estimated using the Centers for Medicare and Medicaid Services and the Veterans Affairs Decision Support System. A hypothetical cohort of 1000 patients was simulated through the model for 20 years. Sensitivity analyses were performed using univariate and probabilistic sensitivity analysis (PSA) on all costs, transition probabilities and utility values. An acceptability curve was generated to illustrate the cost-effectiveness probability of bevacizumab to ranibizumab with increasing willingness-to-pay (WTP). RESULTS: The cost-effectiveness ratios (CER) for bevacizumab and ranibizumab were $1405 per QALY and $12,177 per QALY, respectively. The ICER for bevacizumab was dominant compared to ranibizumab. The base-case CER was sensitive to drug costs of the study medications with a breakeven point of $44 for ranibizumab and $2666 for bevacizumab. PSA revealed a 95% probability of bevacizumab being more cost-effective than ranibizumab at a WTP of $50,000 per QALY gained. CONCLUSION: Based on a WTP defined at $50,000 per QALY gained, bevacizumab was cost-effective versus ranibizumab 95% of the time because of lower acquisition costs and increased efficacy.

Thiopurine methyltransferase (TPMT) genotyping to predict myelosuppression risk.

Azathioprine (AZA), 6-mercaptopurine (6-MP), and thioguanine (TG) are thiopurine drugs. These agents are indicated for the treatment of various diseases including hematologic malignancies, inflammatory bowel disease (IBD), rheumatoid arthritis, and as immunosuppressants in solid organ transplants. Thiopurine drugs are metabolized, in part, by thiopurine methyltransferase (TPMT). TPMT displays genetic polymorphism resulting in null or decreased enzyme activity. At least 20 polymorphisms have been identified, of which, TPMT *2, *3A, *3B, *3C, and *4 are the most commonly studied. These polymorphisms have been associated with increased myelosuppression risk. TPMT genotyping may be useful to predict this risk.

Interleukin-28B genotype testing to determine response to the combination of pegylated-interferon and ribavirin for the treatment of hepatitis C virus.

Hepatitis C virus (HCV) is a bloodborne infection that is one of the leading causes of liver disease. If left untreated, HCV can lead to cirrhosis, hepatocellular carcinoma, and death. The current standard of care for HCV is a combination of pegylated-interferon (peg-IFN) and ribavirin (RBV) in which the goal of treatment is to decrease complications and death due to HCV. HCV displays genetic polymorphism, where patients with HCV genotype 1 may have higher viral replication rates and are less likely to respond to treatment. These patients require a longer duration of treatment and a higher RBV dose. The interleukin (IL) 28B genotype test is associated with a sustained virologic response (SVR), defined as an undetectable HCV ribonucleic acid (RNA) upon completion of treatment and 24 weeks thereafter.

A cost-benefit analysis of medical education in Jamaica: 1978-1983

Jamaica seems to be getting a poor return for its investment in medical education from manning of the public sector medical services. The Jamaican doctors have left in such numbers that nearly four times the amount of local graduates are being imported annually to man the service. The cost to the Jamaican student for a medical education is much cheaper than in the developed countries including UK's welfare state. The acquisition of this profession as with other professions in Jamaica has been taken by the recipients as insurance policy to the "good life" but the tab is being picked up by the tax-payer. Jamaica in common with other poor countries gets neaty caught - paying to educate its own nationals who give their services to rich countries who did not make the investment in them and then having to import professional skills at a high price to fill the gap (AU)