Effectiveness and safety of empagliflozin in routine care patients: Results from the EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study.

AIM: To investigate effectiveness and safety outcomes among patients with type 2 diabetes (T2D) initiating empagliflozin versus dipeptidyl peptidase-4 (DPP-4) inhibitor treatment across the broad spectrum of cardiovascular risk. METHODS: In a population-based cohort study we identified 39 072 pairs of 1:1 propensity score-matched adult patients with T2D initiating empagliflozin or DPP-4 inhibitors, using data from 2 US commercial insurance databases and Medicare between August 2014 and September 2017. The primary outcomes were a composite of myocardial infarction (MI)/stroke, and hospitalization for heart failure (HHF). Safety outcomes were bone fractures, lower-limb amputations (LLAs), diabetic ketoacidosis (DKA), and acute kidney injury (AKI). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for more than 140 baseline covariates. RESULTS: Study participants had a mean age of 60 years and only 28% had established cardiovascular disease. Compared to DPP-4 inhibitors, empagliflozin was associated with similar risk of MI/stroke (HR 0.99 [95% CI 0.81-1.21]), and lower risk of HHF (HR 0.48 [95% CI 0.35-0.67] and 0.63 [95% CI 0.54-0.74], based on a primary and any heart failure discharge diagnosis, respectively). The HR was 0.52 (95% CI 0.38-0.72) for all-cause mortality (ACM) and 0.83 (95% CI 0.70-0.98) for a composite of MI/stroke/ACM. Empagliflozin was associated with a similar risk of LLA and fractures, an increased risk of DKA (HR 1.71 [95% CI 1.08-2.71]) and a decreased risk of AKI (HR 0.60 [95% CI 0.43-0.85]). CONCLUSIONS: In clinical practice, the initiation of empagliflozin versus a DPP-4 inhibitor was associated with a lower risk of HHF, ACM and MI/stroke/ACM, a similar risk of MI/stroke, and a safety profile consistent with documented information.

Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care.

BACKGROUND: The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from August 2014 through September 2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor. METHODS: Within 2 commercial and 1 federal (Medicare) claims data sources in the United States, we identified a 1:1 propensity score-matched cohort of T2D patients ≥18 years old initiating empagliflozin or sitagliptin from August 2014 through September 2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HRs) and 95% CIs were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis. RESULTS: After propensity-score matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared with sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR, 0.50; 95% CI, 0.28-0.91), and the risk of HHF-broad by 49% (HR, 0.51;95% CI, 0.39-0.68), over a mean follow-up of 5.3 months. The results were consistent in patients with and without baseline cardiovascular disease, and for empagliflozin at both the 10- and 25-mg daily doses; analyses comparing empagliflozin versus the dipeptidyl peptidase-4 inhibitor class, and comparing sodium-glucose cotransporter-2 inhibitor versus dipeptidyl peptidase-4 inhibitor classes also produced consistent findings. CONCLUSIONS: The first interim analysis from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with T2D as treated in routine care, with and without a history of cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03363464.

A bronchial-airway gene-expression classifier to improve the diagnosis of lung cancer: Clinical outcomes and cost-effectiveness analysis.

Bronchoscopy is the safest procedure for lung cancer diagnosis when an invasive evaluation is required after imaging procedures. However, its sensitivity is relatively low, especially for small and peripheral lesions. We assessed benefits and costs of introducing a bronchial gene-expression classifier (BGC) to improve the performance of bronchoscopy and the overall diagnostic process for early detection of lung cancer. We used discrete-event simulation to compare clinical and economic outcomes of two different strategies with the standard practice in former and current smokers with indeterminate nodules: (i) location-based strategy-integrated the BGC to the bronchoscopy indication; (ii) simplified strategy-extended use of bronchoscopy plus BGC also on small and peripheral lesions. Outcomes modeled were rate of invasive procedures, quality-adjusted-life-years (QALYs), costs and incremental cost-effectiveness ratios. Compared to the standard practice, the location-based strategy (i) reduced absolute rate of invasive procedures by 3.3% without increasing costs at the current BGC market price. It resulted in savings when the BGC price was less than $3,000. The simplified strategy (ii) reduced absolute rate of invasive procedures by 10% and improved quality-adjusted life expectancy, producing an incremental cost-effectiveness ratio of $10,109 per QALY. In patients with indeterminate nodules, both BGC strategies reduced unnecessary invasive procedures at high risk of adverse events. Moreover, compared to the standard practice, the simplified use of BGC for central and peripheral lesions resulted in larger QALYs gains at acceptable cost. The location-based is cost-saving if the price of classifier declines.

Exact sequential analysis for multiple weighted binomial end points.

Sequential analysis is used in clinical trials and postmarket drug safety surveillance to prospectively monitor efficacy and safety to quickly detect benefits and problems, while taking the multiple testing of repeated analyses into account. When there are multiple outcomes, each one may be given a weight corresponding to its severity. This paper introduces an exact sequential analysis procedure for multiple weighted binomial end points; the analysis incorporates a drug's combined benefit and safety profile. It works with a variety of alpha spending functions for continuous, group, or mixed group-continuous sequential analysis. The binomial probabilities may vary over time and do not need to be known a priori. The new method was implemented in the free R Sequential package for both one- and two-tailed sequential analysis. An example is given examining myocardial infarction and major bleeding events in patients who initiated non-steroidal antiinflammatory drugs.

Competition and price among brand-name drugs in the same class: A systematic review of the evidence.

BACKGROUND: Some experts have proposed combating rising drug prices by promoting brand-brand competition, a situation that is supposed to arise when multiple US Food and Drug Administration (FDA)-approved brand-name products in the same class are indicated for the same condition. However, numerous reports exist of price increases following the introduction of brand-name competition, suggesting that it may not be effective. We performed a systematic literature review of the peer-reviewed health policy and economics literature to better understand the interplay between new drug entry and intraclass drug prices. METHODS AND FINDINGS: We searched PubMed and EconLit for original studies on brand-brand competition in the US market published in English between January 1990 and April 2019. We performed a qualitative synthesis of each study's data, recording its primary objective, methodology, and results. We found 10 empirical investigations, with 1 study each on antihypertensives, anti-infectives, central nervous system stimulants for attention deficit/hyperactivity disorder, disease-modifying therapies for multiple sclerosis, histamine-2 (H2) blockers, and tumor necrosis factor (TNF) inhibitors; 2 studies on cancer medications; and 2 studies on all marketed or new drugs. None of the studies reported that brand-brand competition lowers list prices of existing drugs within a class. The findings of 2 studies suggest that such competition may help restrain how new drug prices are set. Other studies found evidence that brand-brand competition was mediated by the relative quality of competing drugs and the extent to which they are marketed, with safer or more effective new drugs and greater marketing associated with higher intraclass list prices. Our investigation was limited by the studies' use of list rather than net prices and the age of some of the data. CONCLUSIONS: Our findings suggest that policies to promote brand-brand competition in the US pharmaceutical market, such as accelerating approval of non-first-in-class drugs, will likely not result in lower drug list prices absent additional structural reforms.

The Potential Return on Public Investment in Detecting Adverse Drug Effects.

BACKGROUND: Many countries lack fully functional pharmacovigilance programs, and public budgets allocated to pharmacovigilance in industrialized countries remain low due to resource constraints and competing priorities. OBJECTIVE: Using 3 case examples, we sought to estimate the public health and economic benefits resulting from public investment in active pharmacovigilance programs to detect adverse drug effects. RESEARCH DESIGN: We assessed 3 examples in which early signals of safety hazards were not adequately recognized, resulting in continued exposure of a large number of patients to these drugs when safer and effective alternative treatments were available. The drug examples studied were rofecoxib, cerivastatin, and troglitazone. Using an individual patient simulation model and the health care system perspective, we estimated the potential costs that could have been averted by early systematic detection of safety hazards through the implementation of active surveillance programs. RESULTS: We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773-$884 million for rofecoxib, $3-$10 million for cerivastatin, and $38-$63 million for troglitazone in the United States through the prevention of adverse events. By contrast, the yearly public investment in Food and Drug Administration initiated population-based pharmacovigilance activities in the United States is about $42.5 million at present. CONCLUSION: These examples illustrate a critical and economically justifiable role for active adverse effect surveillance in protecting the health of the public.

Increasing incidence associated with herpes zoster infection in British Columbia, Canada.

BACKGROUND: Recent studies have shown an increasing incidence of herpes zoster (HZ) infection, which may be related to the introduction of varicella vaccination programs in children. We examined the epidemiology and treatment costs of HZ and post-herpetic neuralgia (PHN) over time in British Columbia, Canada. METHODS: The cohort consisted of all cases with HZ infection from January 1, 1997 and December 31, 2012. Incident zoster was defined as a case (ICD-9 053 or ICD-10 B02) without a previous episode of HZ or PHN in the previous 12 months. We determined the incidence for HZ and PHN and the age-sex standardized rate for the overall population. We determined the association between the varicella vaccination program and increased HZ rates by evaluating the rate ratios in the publicly-funded varicella vaccine period compared to the non-publicly funded period in a regression model. We evaluated the hospitalization rates, treatment by GPs and their associated yearly costs for HZ and PHN. RESULTS: HZ incidence increased for the entire study period from 3.2 per 1000 population in 1997 to 4.5 in 2012. HZ rates were higher for females than males and all age groups had an increased incidence rate, except the 0-9 year olds, where the rate decreased. Crude and age-sex standardized incidence rates of PHN demonstrated very similar patterns to HZ incidence. Based on the regression model, rates of HZ were higher in the older individuals. No significant increase with HZ incidence was seen during the publically funded varicella vaccination program compared to the non-publicly funded period. From 1997 to 2012, the annual HZ-related costs associated with hospitalizations and GP visits were over $CDN4.9 million and $CDN537,286, respectively; treatment costs for hospitalizations have increased significantly over time. Majority of PHN-related cases are managed by GPs, with a steady increase over time in number of cases and associated annual costs. CONCLUSIONS: The incidence of zoster and PHN is increasing with time, particularly in the elderly population and the risk is greater in the over 65 year olds. Treatment costs for both HZ and PHN represent a significant burden on the Canadian healthcare system.

Cost-effectiveness of novel regimens for the treatment of hepatitis C virus.

BACKGROUND: New regimens for hepatitis C virus (HCV) have shorter treatment durations and increased rates of sustained virologic response compared with existing therapies but are extremely expensive. OBJECTIVE: To evaluate the cost-effectiveness of these treatments under different assumptions about their price and efficacy. DESIGN: Discrete-event simulation. DATA SOURCES: Published literature. TARGET POPULATION: Treatment-naive patients infected with chronic HCV genotype 1, 2, or 3. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Usual care (boceprevir-ribavirin-pegylated interferon [PEG]) was compared with sofosbuvir-ribavirin-PEG and 3 PEG-free regimens: sofosbuvir-simeprevir, sofosbuvir-daclatasvir, and sofosbuvir-ledipasvir. For genotypes 2 and 3, usual care (ribavirin-PEG) was compared with sofosbuvir-ribavirin, sofosbuvir-daclatasvir, and sofosbuvir-ledipasvir-ribavirin (genotype 3 only). OUTCOME MEASURES: Discounted costs (in 2014 U.S. dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: Assuming sofosbuvir, simeprevir, daclatasvir, and ledipasvir cost $7000, $5500, $5500, and $875 per week, respectively, sofosbuvir-ledipasvir was cost-effective for genotype 1 and cost $12 825 more per QALY than usual care. For genotype 2, sofosbuvir-ribavirin and sofosbuvir-daclatasvir cost $110 000 and $691 000 per QALY, respectively. For genotype 3, sofosbuvir-ledipasvir-ribavirin cost $73 000 per QALY, sofosbuvir-ribavirin was more costly and less effective than usual care, and sofosbuvir-daclatasvir cost more than $396 000 per QALY at assumed prices. RESULTS OF SENSITIVITY ANALYSIS: Sofosbuvir-ledipasvir was the optimal strategy in most simulations for genotype 1 and would be cost-saving if sofosbuvir cost less than $5500. For genotype 2, sofosbuvir-ribavirin-PEG would be cost-saving if sofosbuvir cost less than $2250 per week. For genotype 3, sofosbuvir-ledipasvir-ribavirin would be cost-saving if sofosbuvir cost less than $1500 per week. LIMITATION: Data are lacking on real-world effectiveness of new treatments and some prices. CONCLUSION: From a societal perspective, novel treatments for HCV are cost-effective compared with usual care for genotype 1 and probably genotype 3 but not for genotype 2. PRIMARY FUNDING SOURCE: CVS Health.

A unified framework for classification of methods for benefit-risk assessment.

BACKGROUND: Patients, physicians, and other decision makers make implicit but inevitable trade-offs among risks and benefits of treatments. Many methods have been proposed to promote transparent and rigorous benefit-risk analysis (BRA). OBJECTIVE: To propose a framework for classifying BRA methods on the basis of key factors that matter most for patients by using a common mathematical notation and compare their results using a hypothetical example. METHODS: We classified the available BRA methods into three categories: 1) unweighted metrics, which use only probabilities of benefits and risks; 2) metrics that incorporate preference weights and that account for the impact and duration of benefits and risks; and 3) metrics that incorporate weights based on decision makers' opinions. We used two hypothetical antiplatelet drugs (a and b) to compare the BRA methods within our proposed framework. RESULTS: Unweighted metrics include the number needed to treat and the number needed to harm. Metrics that incorporate preference weights include those that use maximum acceptable risk, those that use relative-value-adjusted life-years, and those that use quality-adjusted life-years. Metrics that use decision makers' weights include the multicriteria decision analysis, the benefit-less-risk analysis, Boers' 3 by 3 table, the Gail/NCI method, and the transparent uniform risk benefit overview. Most BRA methods can be derived as a special case of a generalized formula in which some are mathematically identical. Numerical comparison of methods highlights potential differences in BRA results and their interpretation. CONCLUSIONS: The proposed framework provides a unified, patient-centered approach to BRA methods classification based on the types of weights that are used across existing methods, a key differentiating feature.

Comparison of Benefit-Risk Assessment Methods for Prospective Monitoring of Newly Marketed Drugs: A Simulation Study.

OBJECTIVES: To compare benefit-risk assessment (BRA) methods for determining whether and when sufficient evidence exists to indicate that one drug is favorable over another in prospective monitoring. METHODS: We simulated prospective monitoring of a new drug (A) versus an alternative drug (B) with respect to two beneficial and three harmful outcomes. We generated data for 1000 iterations of six scenarios and applied four BRA metrics: number needed to treat and number needed to harm (NNT|NNH), incremental net benefit (INB) with maximum acceptable risk, INB with relative-value-adjusted life-years, and INB with quality-adjusted life-years. We determined the proportion of iterations in which the 99% confidence interval for each metric included and excluded the null and we calculated mean time to alerting. RESULTS: With no true difference in any outcome between drugs A and B, the proportion of iterations including the null was lowest for INB with relative-value-adjusted life-years (64%) and highest for INB with quality-adjusted life-years (76%). When drug A was more effective and the drugs were equally safe, all metrics indicated net favorability of A in more than 70% of the iterations. When drug A was safer than drug B, NNT|NNH had the highest proportion of iterations indicating net favorability of drug A (65%). Mean time to alerting was similar among methods across the six scenarios. CONCLUSIONS: BRA metrics can be useful for identifying net favorability when applied to prospective monitoring of a new drug versus an alternative drug. INB-based approaches similarly outperform unweighted NNT|NNH approaches. Time to alerting was similar across approaches.

Prospective Benefit-Risk Monitoring of New Drugs for Rapid Assessment of Net Favorability in Electronic Health Care Data.

BACKGROUND: Benefit-risk assessment (BRA) methods can combine measures of benefits and risks into a single value. OBJECTIVES: To examine BRA metrics for prospective monitoring of new drugs in electronic health care data. METHODS: Using two electronic health care databases, we emulated prospective monitoring of three drugs (rofecoxib vs. nonselective nonsteroidal anti-inflammatory drugs, prasugrel vs. clopidogrel, and denosumab vs. bisphosphonates) using a sequential propensity score-matched cohort design. We applied four BRA metrics: number needed to treat and number needed to harm; incremental net benefit (INB) with maximum acceptable risk; INB with relative-value-adjusted life-years; and INB with quality-adjusted life-years (QALYs). We determined whether and when the bootstrapped 99% confidence interval (CI) for each metric excluded zero, indicating net favorability of one drug over the other. RESULTS: For rofecoxib, all four metrics yielded a negative value, suggesting net favorability of nonselective nonsteroidal anti-inflammatory drugs over rofecoxib, and the 99% CI for all but the number needed to treat and number needed to harm excluded the null during follow-up. For prasugrel, only the 99% CI for INB-QALY excluded the null, but trends in values over time were similar across the four metrics, suggesting overall net favorability of prasugrel versus clopidogrel. The 99% CI for INB-relative-value-adjusted life-years and INB-QALY excluded the null in the denosumab example, suggesting net favorability of denosumab over bisphosphonates. CONCLUSIONS: Prospective benefit-risk monitoring can be used to determine net favorability of a new drug in electronic health care data. In three examples, existing BRA metrics produced qualitatively similar results but differed with respect to alert generation.

Parents and adolescents preferences for asthma control: a best-worst scaling choice experiment using an orthogonal main effects design.

BACKGROUND: The preferences of parents and children with asthma influence their ability to manage a child's asthma and achieve good control. Potential differences between parents and adolescents with respect to specific parameters of asthma control are not considered in clinical asthma guidelines. The objective was to measure and compare the preferences of parents and adolescents with asthma with regard to asthma control parameters using best worst scaling (BWS). METHODS: Fifty-two parents of children with asthma and 44 adolescents with asthma participated in a BWS study to quantify preferences regarding night-time symptoms, wheezing/chest tightening, changes in asthma medications, emergency visits and physical activity limitations. Conditional logit regression was used to determine each group's utility for each level of each asthma control parameter. RESULTS: Parents displayed the strongest positive preference for the absence of night-time symptoms (ß = 2.09, p < 0.00001) and the strongest negative preference for 10 emergency room visits per year (ß = -2.15, p < 0.00001). Adolescents displayed the strongest positive preference for the absence of physical activity limitations (ß = 2.17, p < 0.00001) and the strongest negative preference for ten physical activity limitations per month (ß = -1.97). Both groups were least concerned with changes to medications. CONCLUSION: Parents and adolescents placed different weights on the importance of asthma control parameters and each group displayed unique preferences. Understanding the relative importance placed on each parameter by parents and adolescents is essential for designing effective patient-focused disease management plans.

High-Dose vs. Standard-Dose Influenza Vaccine and Cardiopulmonary Hospitalization or Mortality: Emulating the INVESTED Trial Using Insurance Claims Data.

The INVESTED trial did not show benefits of high-dose (HD) vaccine vs. standard-dose (SD) for a primary composite outcome of cardiopulmonary hospitalization or all-cause mortality (hazard ratio (HR) = 1.05, 95% confidence interval (CI) = 0.96-1.15) and its components (all-cause mortality HR = 1.01, 95% CI = 0.84-1.21, cardiopulmonary hospitalization HR = 1.05, 95% CI = 0.96-1.16) during three influenza seasons (2016-2019) among participants with recent myocardial infarction or hospitalization for heart failure (HHF). We emulated INVESTED using Medicare claims data to assess whether the real-world evidence (RWE) study reached similar conclusions. We identified 1:1 propensity score (PS)-matched trial-eligible Medicare beneficiaries aged > 65 years and with prior HHF who received an HD or SD vaccine for the 2016-2019 seasons. We also re-analyzed the INVESTED trial data restricting to participants > 65 years with prior HHF to align eligibility criteria more closely with the RWE study. We compared HRs from the trial and RWE study for the main outcomes. Among 53,393 pairs of PS-matched Medicare beneficiaries, the HD vaccine group showed lower risk of the primary composite outcome (HR = 0.96, 95% CI = 0.95-0.98) and all-cause mortality (HR = 0.93, 95% CI = 0.91-0.95), and similar risk of cardiopulmonary hospitalization (HR = 0.98, 95% CI = 0.96-1.00), compared with SD. The RWE and trial results were closely concordant after the trial population was limited to participants > 65 years with prior HHF: trial-based results for the primary composite outcome (HR = 1.02, 95% CI = 0.89-1.17), all-cause mortality (HR = 0.92, 95% CI = 0.72-1.16), and cardiopulmonary hospitalization (HR = 1.02, 95% CI = 0.88-1.18). Although similar to the main trial results, the RWE was closer to the results from trial participants with aligned eligibility criteria. This study affirms the importance of considering different distributions of baseline patient characteristics when comparing trial findings to RWE.

Health Care Utilization and Costs Associated With Empagliflozin in Older Adults With Type 2 Diabetes.

OBJECTIVE: We compared health care resource utilization (HCRU) and costs for inpatient and outpatient services and dispensed medications in older adults with type 2 diabetes initiating empagliflozin versus dipeptidyl peptidase 4 inhibitors (DPP-4is). RESEARCH DESIGN AND METHODS: The study population included U.S. Medicare fee-for-service beneficiaries with diabetes (age ≥65 years) initiating empagliflozin or DPP-4is (August 2014 to September 2018). We estimated rate ratios (RRs) for HCRU outcomes using zero-inflated negative binomial regression and per-member per-year (PMPY) cost differences using generalized linear model with gamma distributions, overall and stratified by baseline cardiovascular disease (CVD), after adjusting for 143 baseline covariates using 1:1 propensity score matching. RESULTS: We identified 23,335 matched pairs (mean age 72 years, 51% with baseline CVD). HCRU rates were lower in empagliflozin versus DPP-4i initiators (number of inpatient days, RR 0.89 [95% CI 0.82, 0.97]; number of emergency department [ED] visits, 0.86 [0.82, 0.91]; number of hospitalizations, 0.86 [0.79, 0.93]; number of office visits, 0.96 [0.95, 0.98]). Inpatient cost (-$713 PMPY [95% CI -847, -579), outpatient cost (-$198 PMPY[-272, -124]), and total cost of care (-$1,109 PMPY [-1,478, -739]) were lower for empagliflozin versus DPP-4is, although diabetes medication cost was higher in empagliflozin initiators ($454 PMPY [95% CI 284, 567]). In the CVD subgroup, total cost was lower for empagliflozin initiators (-$2,005 PMPY [-2,451, -1,337]), while the difference was attenuated in the non-CVD subgroup (-$296 PMPY[-740, 148]). CONCLUSIONS: Among older adults with diabetes, empagliflozin was associated with a lower number of inpatient days, hospitalizations, ED visits, and office visits and with lower costs of care compared with DPP-4is, especially in those with history of CVD.

Barriers for integrating personalized medicine into clinical practice: a qualitative analysis.

Personalized medicine-tailoring interventions based on individual's genetic information-will likely change routine clinical practice in the future. Yet, how practitioners plan to apply genetic information to inform medical decision making remains unclear. We aimed to investigate physician's perception about the future role of personalized medicine, and to identify the factors that influence their decision in using genetic testing in their practice. We conducted three semi-structured focus groups in three health regions (Fraser, Vancouver coastal, and Interior) in British Columbia, Canada. In the focus groups, participants discussed four topics on personalized medicine: (i) physicians' general understanding, (ii) advantages and disadvantages, (iii) potential impact and role in future clinical practice, and (iv) perceived barriers to integrating personalized medicine into clinical practice. Approximately 36% (n = 9) of physicians self-reported that they were not familiar with the concept of personalized medicine. After introducing the concept, the majority of physicians (68%, n = 19 of 28) were interested in incorporating personalized medicine in their practice, provided they have access to the necessary knowledge and tools. Participants mostly believed that genetic developments will directly affect their practice in the future. The key concerns highlighted were physician's access to clinical guidelines and training opportunities for the use of genetic testing and data interpretation. Despite the challenges that personalized medicine can create, in general, physicians in the focus groups expressed strong interest in using genetic information in their practice if they have access to the necessary knowledge and tools.

Need for speed: an efficient algorithm for calculation of single-parameter expected value of partial perfect information.

BACKGROUND: The expected value of partial perfect information (EVPPI) is a theoretically justifiable and informative measure of uncertainty in decision-analytic cost-effectiveness models, but its calculation is computationally intensive because it generally requires two-level Monte Carlo simulation. We introduce an efficient, one-level simulation method for the calculation of single-parameter EVPPI. OBJECTIVE: We show that under mild regularity assumptions, the expectation-maximization-expectation sequence in EVPPI calculation can be transformed into an expectation-maximization-maximization sequence. By doing so, calculations can be performed in a single-step expectation by using data generated for probabilistic sensitivity analysis. We prove that the proposed estimator of EVPPI converges in probability to the true EVPPI. METHODS AND RESULTS: The performance of the new method was empirically demonstrated by using three exemplary decision models. Our proposed method seems to achieve remarkably higher accuracy than the two-level method with a fraction of its computation costs, though the achievement in accuracy was not uniform and varied across the parameters of the models. Software is provided to calculate single-parameter EVPPI based on the probabilistic sensitivity analysis data. CONCLUSIONS: The new method, though applicable only to single-parameter EVPPI, is fast, accurate, and easy to implement. Further research is needed to evaluate the performance of this method in more complex scenarios and to extend such a concept to similar measures of decision uncertainty.

Genomic testing to determine drug response: measuring preferences of the public and patients using Discrete Choice Experiment (DCE).

BACKGROUND: The extent to which a genomic test will be used in practice is affected by factors such as ability of the test to correctly predict response to treatment (i.e. sensitivity and specificity of the test), invasiveness of the testing procedure, test cost, and the probability and severity of side effects associated with treatment. METHODS: Using discrete choice experimentation (DCE), we elicited preferences of the public (Sample 1, N = 533 and Sample 2, N = 525) and cancer patients (Sample 3, N = 38) for different attributes of a hypothetical genomic test for guiding cancer treatment. Samples 1 and 3 considered the test/treatment in the context of an aggressive curable cancer (scenario A) while the scenario for sample 2 was based on a non-aggressive incurable cancer (scenario B). RESULTS: In aggressive curable cancer (scenario A), everything else being equal, the odds ratio (OR) of choosing a test with 95% sensitivity was 1.41 (versus a test with 50% sensitivity) and willingness to pay (WTP) was $1331, on average, for this amount of improvement in test sensitivity. In this scenario, the OR of choosing a test with 95% specificity was 1.24 times that of a test with 50% specificity (WTP = $827). In non-aggressive incurable cancer (scenario B), the OR of choosing a test with 95% sensitivity was 1.65 (WTP = $1344), and the OR of choosing a test with 95% specificity was 1.50 (WTP = $1080). Reducing severity of treatment side effects from severe to mild was associated with large ORs in both scenarios (OR = 2.10 and 2.24 in scenario A and B, respectively). In contrast, patients had a very large preference for 95% sensitivity of the test (OR = 5.23). CONCLUSION: The type and prognosis of cancer affected preferences for genomically-guided treatment. In aggressive curable cancer, individuals emphasized more on the sensitivity rather than the specificity of the test. In contrast, for a non-aggressive incurable cancer, individuals put similar emphasis on sensitivity and specificity of the test. While the public expressed strong preference toward lowering severity of side effects, improving sensitivity of the test had by far the largest influence on patients' decision to use genomic testing.

Predicting Treatment Effects of a New-to-Market Drug in Clinical Practice Based on Phase III Randomized Trial Results.

Trial results may not be generalizable to target populations treated in clinical practice with different distributions of baseline characteristics that modify the treatment effect. We used outcome models developed with trial data to predict treatment effects in Medicare populations. We used data from the Randomized Evaluation of Long-Term Anticoagulation Therapy trial (RE-LY), which investigated the effect of dabigatran vs. warfarin on stroke or systemic embolism (stroke/SE) among patients with atrial fibrillation. We developed outcome models by fitting proportional hazards models in trial data. Target populations were trial-eligible Medicare beneficiaries who initiated dabigatran or warfarin in 2010-2011 ("early") and 2010-2017 ("extended"). We predicted 2-year risk ratios (RRs) and risk differences (RDs) for stroke/SE, major bleeding, and all-cause death in the Medicare populations using the observed baseline characteristics. The trial and early target populations had similar mean (SD) CHADS2 scores (2.15 (SD 1.13) vs. 2.15 (SD 0.91)) but different mean ages (71 vs. 79 years). Compared with RE-LY, the early Medicare population had similar predicted benefit of dabigatran vs. warfarin for stroke/SE (trial RR = 0.63, 95% confidence interval (CI) = 0.50 to 0.76 and RD = -1.37%, -1.96% to -0.77%, Medicare RR = 0.73, 0.65 to 0.82 and RD = -0.92%, -1.26% to -0.59%) and risks for major bleeding and all-cause death. The time-extended target population showed similar results. Outcome model-based prediction facilitates estimating the average treatment effects of a drug in different target populations when treatment and outcome data are unreliable or unavailable. The predicted effects may inform payers' coverage decisions for patients, especially shortly after a drug's launch when observational data are scarce.

Common non-cardiovascular multimorbidity groupings and clinical outcomes in older adults with major cardiovascular disease.

BACKGROUND: Among older adults, non-cardiovascular multimorbidity often coexists with cardiovascular disease (CVD) but their clinical significance is uncertain. We identified common non-cardiovascular comorbidity patterns and their association with clinical outcomes in Medicare fee-for-service beneficiaries with acute myocardial infarction (AMI), congestive heart failure (CHF), or atrial fibrillation (AF). METHODS: Using 2015-2016 Medicare data, we took 1% random sample to create 3 cohorts of beneficiaries diagnosed with AMI (n = 24,808), CHF (n = 57,285), and AF (n = 36,277) prior to 1/1/2016. Within each cohort, we applied latent class analysis to classify beneficiaries based on 9 non-cardiovascular comorbidities (anemia, cancer, chronic kidney disease, chronic lung disease, dementia, depression, diabetes, hypothyroidism, and musculoskeletal disease). Mortality, cardiovascular and non-cardiovascular hospitalizations, and home time lost over a 1-year follow-up period were compared across non-cardiovascular multimorbidity classes. RESULTS: Similar non-cardiovascular multimorbidity classes emerged from the 3 CVD cohorts: (1) minimal, (2) depression-lung, (3) chronic kidney disease (CKD)-diabetes, and (4) multi-system class. Across CVD cohorts, multi-system class had the highest risk of mortality (hazard ratio [HR], 2.7-3.9), cardiovascular hospitalization (HR, 1.6-3.3), non-cardiovascular hospitalization (HR, 3.1-7.2), and home time lost (rate ratio, 2.7-5.4). Among those with AMI, the CKD-diabetes class was more strongly associated with all the adverse outcomes than the depression-lung class. In CHF and AF, differences in risk between the depression-lung and CKD-diabetes classes varied per outcome; and the depression-lung and multi-system classes had double the rates of non-cardiovascular hospitalizations than cardiovascular hospitalizations. CONCLUSION: Four non-cardiovascular multimorbidity patterns were found among Medicare beneficiaries with CHF, AMI, or AF. Compared to the minimal class, the multi-system, CKD-diabetes, and depression-lung classes were associated with worse outcomes. Identification of these classes offers insight into specific segments of the population that may benefit from more than the usual cardiovascular care.