Complication Prevention and Cost Savings in Total Joint Arthroplasty. The Effect of Orthopedic Procedure Migration within Hospital Referral Regions in the United States.

BACKGROUND: The shift to value based total joint arthroplasty (TJA) reimbursement strategies has led to an increased focus on quality and the avoidance of poor outcomes. As a result, there has been greater encouragement for patients to undergo joint replacements in high volume centers of excellence. In this study, we examined the potential complications avoided if TJA procedure volume was shifted from poor quality (high incidence) facilities to high quality (low incidence) facilities within Hospital Referral Regions (HRRs). METHODS: Using Medicare 100% claims data linked to the Dartmouth Atlas of Health Care, we examined the clinical and cost benefits of shifting TJA procedures from low performing hospital to high performing hospitals within HRRs. RESULTS: Across all HRRs, we identified 1,878 cases of deep infection and 3,393 annual readmissions in the Medicare population that could have potentially been avoided, resulting in a mean cost savings of $41 million and $62 million, respectively, solely due to shifting procedure location from lower third performing hospitals to the upper third performing hospitals. CONCLUSIONS: Our study demonstrates that the incidence of deep infection and all-cause readmission varies widely among and within HRRs. Further, the potential reallocation of joint procedures from low quality facilities to high quality Centers of Excellence within an HRR could result in over $103 million in annual savings related to mitigated deep infections and readmissions.

Use of Add-on Treatment to Metformin Monotherapy for Patients with Type 2 Diabetes and Suboptimal Glycemic Control: A U.S. Database Study.

BACKGROUND: The American Diabetes Association (ADA) recommends metformin to treat individuals diagnosed with type 2 diabetes and recommends that hemoglobin A1c (HbA1c) be maintained below or around 7%. If the HbA1c target is not achieved or maintained by metformin monotherapy at maximal tolerated dose over 3 to 6 months, treatment modification with addition of a second oral antihyperglycemic agent or by initiating insulin is recommended. Despite the importance of attaining and maintaining HbA1c goals, actual treatment behavior may not follow ADA guidelines to add a second oral agent or to initiate insulin as expected even considering that individual patient's needs are taken into account when treatment decisions are made. OBJECTIVE: To evaluate treatment addition for metformin monotherapy users with suboptimal glycemic control and associated factors. METHODS: A retrospective health care claims study identified 7,109 subjects aged 18 to 89 years, treated for type 2 diabetes with an HbA1c > 7% following at least 60 days of continuous metformin monotherapy. Subjects were required to have 12 months continuous enrollment with the health plan before and after the index lab date. Pharmacological treatment additions after the HbA1c lab result and time to treatment addition were evaluated. A logistic regression model was used to evaluate the patient characteristics and comorbidities associated with the treatment addition. RESULTS: Thirty-eight percent of study subjects had evidence of addition of a second antidiabetic medication to primary metformin monotherapy, 57.5% remained on metformin monotherapy, and 4.5% discontinued metformin altogether. A logistic regression model found age inversely related to treatment addition: age 45-64 versus 18-44 (OR = 0.77, 95% CI = 0.59-0.99) and age 65-89 versus 18-44 (OR = 0.57, 95% CI = 0.43-0.74). HbA1c was positively related to treatment addition: > 8%-9% versus > 7%-8% (OR = 2.31, 95% CI = 2.00-2.67); > 9%-10% versus > 7%-8% (OR = 2.88, 95% CI = 2.32-3.58); and > 10% versus > 7%-8% (OR = 3.54, 95% CI = 2.92-4.28). Evidence of ophthalmic disorder was not related to treatment addition (P = 0.056), but evidence of hypertension (OR = 1.56, 95% CI = 1.28-1.89); hyperlipidemia (OR = 1.28, 95% CI = 1.05-1.55); other cardiovascular diseases (OR = 1.30, 95% CI = 1.16-1.45); obesity (OR = 1.21, 95% CI = 1.08-1.36); and renal disease (OR = 1.35, 95% CI = 1.21-1.51) were associated. CONCLUSIONS: The majority of the metformin monotherapy users with suboptimal glycemic control did not initiate add-on therapy as recommended by guidelines, and prolonged time on metformin monotherapy demonstrated clinical inertia in real-world clinical practice. Several factors were associated with this delay including older age, lower index HbA1c, and lack of evidence of certain comorbidities.

Treatment of obesity: Pharmacotherapy trends in the United States from 1999 to 2010.

OBJECTIVE: To describe the antiobesity drug-prescribing patterns of US physicians over the past decade. METHODS: Data for adult patients were obtained from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Obesity was identified using ICD-9 codes, BMI values, and a chronic-obesity-condition variable. For patients with obesity, a logistic-regression model was estimated to determine the odds of receiving pharmacotherapy. RESULTS: Of the 987 million visits by patients with obesity from 2005 to 2010, 2.0% mentioned an antiobesity drug. Additionally, there were 6.5 million visits by patients without obesity but with an antiobesity drug mention. Visits made by females (OR = 2.89; 95% CI: 2.08-4.03), by white patients (OR = 1.55; 95% CI: 1.08-2.24), by younger adults (OR = 1.71; 95% CI: 1.34-2.20), and in the South (OR = 3.39; 95% CI: 1.49-7.72) were more likely to involve an antiobesity drug prescription. CONCLUSIONS: Only 1 in 50 patients with obesity received a prescription for an antiobesity medication. Moreover, in contrast to what the 1998 Guidelines suggested, physicians tended to prescribe antiobesity medications to self-paying, young, white females, many of whom lived in the South, and not all of whom had obesity.

Firm- and drug-specific patterns of generic drug payments by US medicaid programs: 1991-2008.

BACKGROUND: The entry of generic drugs into markets previously monopolized by patented, branded drugs often represents large potential savings for healthcare payers in the USA. OBJECTIVES: Our objectives were to describe and explain the trends in drug reimbursement by public Medicaid programmes post-generic entry for as many drug markets and for as long a time period as possible. METHODS: The data were the Medicaid State Drug Utilization Data maintained by the Centers for Medicare and Medicaid Services. Quarterly utilization and expenditure data from 1991 to 2008 were extracted for 83 drugs, produced by 229 firms, that experienced initial generic entry between 1992 and 2004. A relative 'price' for a specific drug, firm and quarter was constructed as Medicaid reimbursement per unit (e.g. tablet, capsule or vial) divided by average reimbursement per unit for the branded drug the year before entry. Fixed-effects models controlling for time-, firm- and drug-specific differences were estimated to explain reimbursement. RESULTS: Twelve quarters after generic entry, 18 % of drugs had average per-unit reimbursement less than 50 % of the original branded-drug reimbursement. For each additional firm manufacturing the drug, reimbursement per unit, relative to the pre-generic-entry branded-drug reimbursement, was estimated to fall by 17 (p < 0.01) and 3 (p < 0.01) percentage points for generic and branded-drug companies, respectively. Each additional quarter post-generic entry brought a 2 (p < 0.01) percentage point drop in relative reimbursement. CONCLUSIONS: State Medicaid programmes generally have been able to obtain relief from high drug prices following patent expirations for many branded-drug medications by adjusting reimbursement following the expanded competition in the pharmaceutical market.

Safety of long-acting beta agonists and inhaled corticosteroids in children and adolescents with asthma.

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy for adult, as well as pediatric, patients with asthma. However, the use of LABAs has raised safety concerns, especially the potential for severe asthma exacerbations (SAEs) resulting in hospitalizations or even death. Meanwhile, the use of inhaled corticosteroids (ICSs), a cornerstone in the treatment of mild-to-severe persistent asthma, has been associated with growth suppression in children. The purpose of this review was to identify and discuss the major published safety studies surrounding LABA, ICS, and combined LABA/ICS usage in children. By way of a critical search for influential published clinical trials, meta-analyses, and observational studies, six studies relevant to the safety of LABA monotherapy, seven studies relevant to ICS monotherapy, and four studies on the subject of LABA/ICS combination usage were identified and reviewed. Based on the reviewed literature, the controversy surrounding these anti-asthma medications was clearly exposed. On the one hand, there is some evidence that LABA monotherapy may be associated with SAEs and asthma-related death, while ICS monotherapy may be associated with a higher risk of growth suppression. On the other hand, the concurrent use of a LABA with an ICS has been associated with positive outcomes including symptom reduction and reduced rate and severity of exacerbations. Further clinical research is warranted and has been called for by the US Food and Drug Administration.

Long-term Medicaid excess payments from alleged price manipulation of generic lorazepam.

BACKGROUND: Cost savings from the use of generic drugs versus brand-name drugs are well known. Both private and public prescription drug plans encourage the use of generic drugs through a variety of mechanisms. The magnitude of cost savings for a given generic drug is dependent on the degree to which the generic market is competitive. Should the competitive structure become compromised, higher prices and reduced cost savings may result. An alleged conspiracy between Mylan Laboratories and its active-ingredient suppliers in 1997 was associated with an increase in seller concentration in the generic lorazepam market. The Federal Trade Commission (FTC) alleged that Mylan raised costs to consumers by $120 million because of price increases for generic lorazepam from March through December 1998 and for generic clorazepate from January through December 1998. In November 2002, a settlement with Mylan was approved by the FTC, and a federal district court required Mylan to pay $147 million, including $28.2 million to state agencies including Medicaid. OBJECTIVES: To (a) describe the seller concentration in the national Medicaid generic lorazepam market over a 19-year period from January 1991 through December 2009, (b) estimate the excess payments for generic lorazepam by Medicaid between 1998 and 2009, and (c) investigate potentially increased utilization and prices of 2 substitute pharmaceuticals: branded lorazepam (Ativan) and generic alprazolam (another widely used intermediate-acting benzodiazepine). METHODS: Using Medicaid State Drug Utilization Data from the Centers for Medicare Medicaid Services, we calculated the 4-firm concentration ratio (CR4) and the Herfindahl-Hirschman Index (HHI) for the Medicaid generic lorazepam market, along with pre-rebate reimbursement for pharmacy claims, number of claims (utilization), and average pre-rebate reimbursement per claim (average "price") for generic lorazepam, from 1991 through 2009. Medicaid's excess payments were estimated under 2 different assumptions regarding what the average generic lorazepam price would have been in the absence of the alleged conspiracy. To find counterfactual prices, the average per-claim reimbursement for lorazepam for the 4 quarters prior to the alleged conspiracy, $6.80, was inflated using (a) the quarterly change in the average per-claim reimbursement for generic alprazolam and (b) the Consumer Price Index (CPI) for all urban consumers, all goods. Potential impact of the alleged conspiracy on the branded lorazepam and generic alprazolam markets was investigated. RESULTS: The average pre-rebate reimbursements per claim for generic lorazepam were $10.25, $23.12, and $8.48 in 1991, 1998, and 2009, respectively. For the same 3 years, CR4 = 52.80, 76.02, and 86.74, while HHI = 905.71, 2,166.25, and 2,233.36. Medicaid's excess payments from 1998-2009 were estimated at approximately $625-$657 million. The data also suggest the possibility of small impacts on the utilization of branded lorazepam and the price of generic alprazolam. CONCLUSIONS: Prior to the alleged conspiracy in 1997, average pre-rebate reimbursement per claim for generic lorazepam was declining, while seller concentration was rising. After a jump in average payment per claim in the years immediately following the alleged conspiracy, prices have gradually returned to their pre-1998 levels. However, the generic lorazepam market was more concentrated in 2009 than prior to the alleged conspiracy.

Utilization, spending, and price trends for benzodiazepines in the US Medicaid program: 1991-2009.

BACKGROUND: Although it is well-known that drug costs in the US have risen precipitously over the last 25 years, what is much less appreciated is how this rise in cost has occurred across so many seemingly distinct drug markets. OBJECTIVE: To describe trends in the utilization, spending, and average per-prescription cost of benzodiazepines individually, in subgroups, and overall, in the Medicaid program. Medicaid has been the primary public payer for benzodiazepines over the past 2 decades. METHODS: A retrospective, descriptive analysis was performed for the years 1991-2009 using the publicly available national Summary Files from the Medicaid State Drug Utilization Data maintained by the Centers for Medicare & Medicaid Services. Quarterly prescription counts and reimbursement amounts were calculated for all benzodiazepines reimbursed by Medicaid. Average per-prescription spending as a proxy for drug price was found by dividing reimbursement by the number of prescriptions. RESULTS: Prescriptions for benzodiazepines among Medicaid beneficiaries increased from 8.0 million in 1991 to 17.1 million in 2009. Expenditures rose from $131.6 million to $171.1 million over the same time period. The average per-prescription price was a little over $10 in 2009. Whereas utilization of intermediate- and long-acting agents increased over time, prescriptions for short-acting drugs fell from 1.1 million to 0.3 million (1991-2009). The percentage rise in Medicaid spending on benzodiazepines since 1991 (30.0%) was less than the general rate of inflation (57.5%), as measured by the percentage change in the consumer price index over the same time period. CONCLUSIONS: Relative to the rise in the number of Medicaid beneficiaries (more than doubled over the study period), there is no evidence of an extraordinary rise in the utilization of benzodiazepines. Moreover, both nominal and real average prices of benzodiazepines have fallen, primarily because of generic entry over the last 2 decades.

Evidence-based prediction of statin use with lipid-panel data from the National Health and Nutrition Examination Survey.

OBJECTIVES: This study compared actual use of individual statin drugs to expected use based on their efficacy and safety profiles. METHODS: Five panels covering the years 1999 to 2008 from the National Health and Nutrition Examination Survey provided interview, demographic, and laboratory data for 8769 (365,503,838 weighted) people aged 20 years or older who were not taking a statin medication. An individual's risk for coronary heart disease and low-density lipoprotein (LDL) cholesterol goal were determined, following the Adult Treatment Panel III Cholesterol Guidelines. The percentage LDL cholesterol lowering required to reach his/her LDL cholesterol level goal was calculated. Depending on the amount of LDL cholesterol lowering needed and on if the individual had a liver condition (i.e., enhanced risk of rhabdomyolysis) statins were hypothetically prescribed. Predicted use was compared to actual use by U.S. Medicaid beneficiaries in the third quarter of 2009, obtained from the Medicaid State Drug Utilization Data maintained by the Centers for Medicare and Medicaid Services. RESULTS: Results showed that 72.34% of the population was in the lowest coronary heart disease risk group and that 86.30% required no statin therapy. Among the people who did require LDL cholesterol lowering, a significant majority (37.3 million or 10.22% of the population) needed 30% lowering or less. Only 314,784 (0.09%) required LDL cholesterol lowering of greater than 60%. Utilization shares based on safety and efficacy were estimated at 19.26% (rosuvastatin), 18.67% (atorvastatin), 16.48% (simvastatin), 16.30% (lovastatin), 14.93% (pravastatin), and 14.36% (fluvastatin). CONCLUSIONS: Actual statin use differed substantially from predicted use. It may be appropriate to develop and maintain policies that encourage use of less costly products that have essentially equivalent safety profiles and efficacy.

Risk of serious asthma exacerbations associated with long-acting beta agonists among patients with asthma: a retrospective cohort study.

BACKGROUND: After the Serevent Nationwide Surveillance clinical trial, controversy has surrounded the safety of long-acting beta agonists (LABAs). OBJECTIVE: Examine the association between LABAs and severe asthma exacerbations (SAEs). METHODS: From a multistate Medicaid database, for the years 2002-2007, a total of 940,449 patients (age <40) with asthma were selected and divided into a cohort with newly-diagnosed asthma and one with pre-existing asthma. SAEs included asthma-related emergency department (ED) visits, hospitalizations, and intubations. Patients' asthma severity was determined based on medication regimen as suggested by the 2002 National Asthma Guidelines. Specific use of inhaled corticosteroids (ICSs), LABAs, ICS/LABA combination drugs, short-acting beta agonists (SABAs), and other drugs was tracked. Cox proportional hazard regressions were estimated to assess the risk of SAEs associated with patient severity, drug use, and covariates. RESULTS: Compared to patients taking a SABA only, estimated SAE hazard ratios for newly diagnosed and pre-existing-asthma patients were as follows: 0.63 (95% CI 0.58-0.69) and 0.74 (0.70-0.79) for patients on a LABA without ICS, and 0.79 (0.77-0.81) and 0.90 (0.87-0.92) for those on a LABA/ICS single inhaler. Although hazard ratios were estimated to be similar for ED visits, LABA use was found to be positively associated with hospitalizations and intubations. Other key risk factors (P < .0001) included being African American, an alcohol/substance use disorder, pregnancy, and obesity. CONCLUSION: Relative to SABA-only therapy, LABA use is associated with a lower risk of ED visit. Certain patients with asthma, such as pregnant women and African Americans, are particularly vulnerable to SAE risk of all types.

ACE Inhibitor and ARB utilization and expenditures in the Medicaid fee-for-service program from 1991 to 2008.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are widely prescribed for the treatment of hypertension and heart failure, as well as for kidney disease prevention in patients with diabetes mellitus and the management of patients after myocardial infarction. OBJECTIVE: To (a) describe ACE inhibitor and ARB utilization and spending in the Medicaid fee-for-service program from 1991 through 2008, and (b) estimate the potential cost savings for the collective Medicaid programs from a higher ratio of generic ACE inhibitor utilization. METHODS: A retrospective, descriptive analysis was performed using the National Summary Files from the Medicaid State Drug Utilization Data, which are composed of pharmacy claims that are subject to federally mandated rebates from pharmaceutical manufacturers. For the years 1991-2008, quarterly claim counts and expenditures were calculated by summing data for individual ACE inhibitors and ARBs. Quarterly per-claim expenditure as a proxy for drug price was computed for all brand and generic drugs. Market shares were calculated based on the number of pharmacy claims and Medicaid expenditures. RESULTS: In the Medicaid fee-for-service program, ACE inhibitors accounted for 100% of the claims in the combined market for ACE inhibitors and ARBs in 1991, 80.6% in 2000, and 64.7% in 2008. The Medicaid expenditure per ACE inhibitor claim dropped from $37.24 in 1991 to $24.03 in 2008 when generics accounted for 92.5% of ACE inhibitor claims; after adjusting for inflation for the period from 1991 to 2008, the real price drop was 59.2%. Brand ACE inhibitors accounted for only 7.5% of the claims in 2008 for all ACE inhibitors but 32.1% of spending; excluding the effects of manufacturer rebates, Medicaid spending would have been reduced by $28.7 million (9%) in 2008 if all ACE inhibitor claims were generic. The average price per ACE inhibitor claim in 2008 was $24.03 ($17.64 per generic claim vs. $103.45 per brand claim) versus $81.98 per ARB claim. If the ACE inhibitor ratio had been 75% in 2008 rather than 64.7%, the Medicaid program would have saved approximately 13% or about $41.8 million, again excluding the effects of manufacturer rebates. If the ACE inhibitor ratio had been 90% in 2008, the cost savings for the combined Medicaid fee-forservice programs would have been about 33% or about $102.3 million. The total cost savings opportunity with 100% generic ACE inhibitor utilization in 2008 and an ACE inhibitor ratio of 75% was $75.1 million (24%) or $142.3M (46%) with a 90% ACE inhibitor ratio. CONCLUSION: Factors that affect Medicaid spending by contributing to increased utilization of ACE inhibitors and ARBs, such as the rising prevalence of hypertension, heart disease, and diabetes, can be offset by reduction in the average price attained through a higher proportion of ACE inhibitors and a higher percentage of generic versus brand ACE inhibitors.

A review of quantitative risk-benefit methodologies for assessing drug safety and efficacy-report of the ISPOR risk-benefit management working group.

OBJECTIVE: Although regulatory authorities evaluate the risks and benefits of any new drug therapy during the new drug-approval process, quantitative risk-benefit assessment (RBA) is not typically performed, nor is it presented in a consistent and integrated framework when it is used. Our purpose is to identify and describe published quantitative RBA methods for pharmaceuticals. METHODS: Using MEDLINE and other Internet-based search engines, a systematic literature review was performed to identify quantitative methodologies for RBA. These distinct RBA approaches were summarized to highlight the implications of their differences for the pharmaceutical industry and regulatory agencies. RESULTS: Theoretical models, parameters, and key features were reviewed and compared for the 12 quantitative RBA methods identified in the literature, including the Quantitative Framework for Risk and Benefit Assessment, benefit-less-risk analysis, the quality-adjusted time without symptoms and toxicity, number needed to treat (NNT), and number needed to harm and their relative-value-adjusted versions, minimum clinical efficacy, incremental net health benefit, the risk-benefit plane (RBP), the probabilistic simulation method, multicriteria decision analysis (MCDA), the risk-benefit contour (RBC), and the stated preference method (SPM). Whereas some approaches (e.g., NNT) rely on subjective weighting schemes or nonstatistical assessments, other methods (e.g., RBP, MCDA, RBC, and SPM) assess joint distributions of benefit and risk. CONCLUSIONS: Several quantitative RBA methods are available that could be used to help lessen concern over subjective drug assessments and to help guide authorities toward more objective and transparent decision-making. When evaluating a new drug therapy, we recommend the use of multiple RBA approaches across different therapeutic indications and treatment populations in order to bound the risk-benefit profile.

Evaluating safety of long-acting beta agonists (LABAs) in patients with asthma.

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy with evidence that their use led to improved lung function and quality of life. However, the use of LABAs has raised safety concerns, such as their potential to provoke severe asthma exacerbations (SAEs) and death. This systematic review of major findings discusses the safety controversy surrounding LABA therapy and provides background for the U.S. Food and Drug Administration's warnings concerning LABA use. Findings from large clinical trials and several meta-analyses are described and compared in terms of their implications for the safety of LABAs. Monotherapy LABA therapy in the treatment of asthma remains controversial and is not recommended by the most recent asthma management guidelines. Despite the existence of numerous published studies, we conclude that more well-designed research on this topic --- to determine whether LABAs are associated with SAEs, such as asthma-related hospitalizations, intubations, and emergency room visits, or death --- is required. Particularly needed is research that makes use of large, secondary longitudinal databases.