The Role of Pharmaceutical Innovation in Clinical Practice Guidelines for Chronic Diseases.

Background: Over the last 25 years, clinical practice guidelines have emerged as a means to standardize and improve care. As pharmaceutical innovations develop, guidelines are updated to incorporate new interventions. However, the extent to which pharmacotherapies are represented as treatment options in guideline recommendations has not been well elucidated. This study aimed to quantify the role pharmacotherapy has played in clinical practice guidelines across a range of chronic diseases over the past 20 years. Methods: Clinical practice guidelines published from 2000 to 2021 were identified for five chronic diseases: ischemic heart disease (IHD), non-small cell lung cancer (NSCLC), chronic obstructive pulmonary disease (COPD), Alzheimer's disease (AD), and type 2 diabetes (T2D). Guidelines were reviewed and data on treatment recommendations were collected, including the type of intervention, line of therapy, and, for pharmacotherapies, year of regulatory approval and year of inclusion in guidelines. Results: In total, 92 clinical practice guidelines were reviewed. Among the 184 discrete recommended interventions across the five disease areas, 146 (79.3%) were pharmacotherapies, 21 (11.4%) were behavioral modifications, 6 (3.3%) were surgical interventions, and 11 (6%) were other interventions. Across guidelines, when a line of therapy was specified, behavioral modifications and pharmacotherapies were most frequently recommended as first-line interventions, whereas surgical interventions were more often recommended for subsequent lines of treatment. The time from regulatory approval of novel pharmacotherapies to inclusion in guideline recommendations varied considerably by disease area and geography. Conclusions: Across the reviewed disease areas, behavioral interventions and pharmacotherapies are shown to be critical components of clinical practice. Over the last 20 years, novel pharmaceutical innovations have been incorporated into clinical practice guideline recommendations; however, with varying speeds of adoption. Given the increasing pace of pharmacologic innovation, timely updates of clinical practice guidelines are critical to evolving the standard of care and practicing evidence-based medicine.

The effect of medication nonadherence on progression-free survival among patients with renal cell carcinoma.

OBJECTIVE: To examine how observed medication nonadherence to 2 second-line, oral anticancer medications (axitinib and everolimus) affects progression-free survival (PFS) among patients with renal cell carcinoma. METHODS: We used an adherence-exposure-outcome model to simulate the impact of adherence on PFS. Using a pharmacokinetic/pharmacodynamic (PK/PD) population model, we simulated drug exposure measured by area under the plasma concentration-time curve (AUC) and minimum blood or trough concentration (Cmin) under 2 scenarios: 1) optimal adherence and 2) real-world adherence. Real-world adherence was measured using the medication possession ratios as calculated from health insurance claims data. A population PK/PD model was simulated on individuals drawn from the Medical Expenditure Panel Survey (MEPS), a large survey broadly representative of the US population. Finally, we used previously published PK/PD models to estimate the effect of drug exposure (i.e., Cmin and AUC) on PFS outcomes under optimal and real-world adherence scenarios. RESULTS: Average adherence measured using medication possession ratios was 76%. After applying our simulation model to 2164 individuals in MEPS, drug exposure was significantly higher among adherent patients compared with nonadherent patients for axitinib (AUC: 249.5 vs. 159.8 ng×h/mL, P<0.001) and everolimus (AUC: 185.4 vs. 118.0 µg×h/L, P<0.001). Patient nonadherence in the real world decreased the expected PFS from an optimally adherent population by 29% for axitinib (8.4 months with optimal adherence vs. 6.0 months using real-world adherence, P<0.001) and by 5% (5.5 vs. 5.2 months, P<0.001) for everolimus. CONCLUSION: Nonadherence by renal cell carcinoma patients to second-line oral therapies significantly decreased the expected PFS.

Engagement in health and wellness: An online incentive-based program.

Increasingly, corporate health promotion programs are implementing wellness programs integrating principles of behavioral economics. Employees of a large firm were provided a customized online incentive program to design their own commitments to meet health goals. This study examines patterns of program participation and engagement in health promotion activities. Subjects were US-based employees of a large, nondurable goods manufacturing firm who were enrolled in corporate health benefits in 2010 and 2011. We assessed measures of engagement with the workplace health promotion program (e.g., incentive points earned, weight loss). To further examine behaviors indicating engagement in health promotion activities, we constructed an aggregate, employee-level engagement index. Regression models were employed to assess the association between employee characteristics and the engagement index, and the engagement index and spending. 4220 employees utilized the online program and made 25,716 commitments. Male employees age 18-34 had the highest level of engagement, and male employees age 55-64 had the lowest level of engagement overall. Prior year health status and prior year spending did not show a significant association with the level of engagement with the program (p > 0.05). Flexible, incentive-based behavioral health and lifestyle programs may reach the broader workforce including those with chronic conditions and higher levels of health spending.

Projecting long-term graft and patient survival after transplantation.

OBJECTIVE: In spite of increases in short-term kidney transplant survival rates and reductions in acute rejection rates, increasing long-term graft survival rates remains a major challenge. The objective here was to project long-term graft- and survival-related outcomes occurring among renal transplant recipients based on short-term outcomes including acute rejection and estimated glomerular filtration rates observed in randomized trials. METHODS: We developed a two-phase decision model including a trial phase and a Markov state transition phase to project long-term outcomes over the lifetimes of hypothetical renal graft recipients who survived the trial period with a functioning graft. Health states included functioning graft stratified by level of renal function, failed graft, functioning regraft, and death. Transitions between health states were predicted using statistical models that accounted for renal function, acute rejection, and new-onset diabetes after transplant and for donor and recipient predictors of long-term graft and patient survival. Models were estimated using data from 38,015 renal transplant recipients from the United States Renal Data System. The model was populated with data from a 3-year, randomized phase III trial comparing belatacept to cyclosporine. RESULTS: The decision model was well calibrated with data from the United States Renal Data System. Long-term extrapolation of Belatacept Evaluation of Nephroprotection and Efficacy as Firstline Immunosuppression Trial was projected to yield a 1.9-year increase in time alive with a functioning graft and a 1.2 life-year increase over a 20-year time horizon. CONCLUSIONS: This is the first long-term follow-up model of renal transplant patients to be based on renal function, acute rejection, and new-onset diabetes. It is a useful tool for undertaking comparative effectiveness and cost-effectiveness studies of immunosuppressive medications.

How cancer patients value hope and the implications for cost-effectiveness assessments of high-cost cancer therapies.

Assessments of the medical and economic value of therapies in diseases such as cancer traditionally focus on average or median gains in patients' survival. This focus ignores the value that patients may place on a therapy with a wider "spread" of outcomes that offer the potential of a longer period of survival. We call such treatments "hopeful gambles" and contrast them with "safe bets" that offer similar average survival but less chance of a large gain. Real-world therapy options do not have these stylized forms, but they can differ in the spread of survival gains that patients face. We found that 77 percent of surveyed cancer patients with melanoma, breast cancer, or other kinds of solid tumors preferred hopeful gambles to safe bets. This suggests that current technology assessments, which often determine access to such cancer therapies, may be missing an important source of value to patients and should either incorporate hope into the value of therapies or set a higher threshold for an acceptable cost-effectiveness ratio in the end-of-life context.

Patients value metastatic cancer therapy more highly than is typically shown through traditional estimates.

There is a growing emphasis on promoting medical treatments that provide the most benefits relative to their costs. However, objective criteria for determining the value patients receive from treatment are lacking. This study used data on the treatment choices of terminally ill patients to estimate the value they associate with care. We found that patients place high valuations on metastatic cancer therapy--on average, twenty-three times higher than its cost--and that other traditional methods used to estimate the value of these treatments for patients significantly undervalues how patients view them. Our methods provide another framework for an evidence-based approach to assessing the value of treatments for terminal illness.

Quantifying the impact of nonadherence patterns on exposure to oral immunosuppressants.

BACKGROUND AND OBJECTIVES: Nonadherence to oral immunosuppressive drugs in renal transplant patients remains a major challenge. The objective of this study was to develop an adherence-exposure model that 1) quantifies the impact of nonadherence patterns on cyclosporine levels and 2) identifies nonadherence patterns that are associated with unfavorable transplantation outcomes. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This model quantified variability in drug exposure, expressed as the coefficient of variation (CV%), for time-averaged and trough cyclosporine levels (C(avg) and C(min), respectively), and percentage of days spent below the therapeutic C(min) target. Simulated patterns of nonadherence closely matched those observed in clinical practice for four nonadherence clusters and an "Others" category. RESULTS: Patients in simulated nonadherence clusters 1-3 spent a mean (standard deviation) 5.8% (4.9), 9.0% (5.0), and 6.5% (3.4) of days below the C(min) target, compared with 76.8% (6.5) for cluster 4 and 38.3% (6.4) for the "Others" category. Mean (standard deviation) CV% values for C(min) were 24.1 (7.9), 35.4 (11.7), and 34.1 (10.6) for clusters 1-3, compared with 136.4 (23.6) for cluster 4 and 64.8 (10.3) for the "Others" category. Findings for C(avg) were similar. CONCLUSION: Based on nonadherence patterns and known relationships between CV% for C(min) and C(avg), and transplantation outcomes, patients in cluster 4 and the "Others" category are expected to be at high risk of allograft rejection. The proposed drug adherence-exposure model is useful to identify high-risk patients who can be targeted for interventions aimed at enhancing drug adherence to optimize clinical long-term outcomes.

Who is caring for kidney transplant patients? Variation by region, transplant center, and patient characteristics.

BACKGROUND/AIMS: Despite implications for long-term care, little is known about outpatient care for kidney transplant patients. METHODS: In this retrospective observational cohort study, outpatient claims were examined for 42,078 Medicare kidney transplant patients using United States Renal Data System data to ascertain location and timing of outpatient visits and type of physician seen. Logistic regression with generalized estimating equations was used to determine the odds and clinical correlates of visits in 4 post-transplant time periods. RESULTS: In months 1-3, 88% of patients visited their transplant centers, but this declined to 69% in months 25-36. In the adjusted analysis, Native Americans (odds ratio 0.56, 95% confidence interval 0.48-0.65) and Hispanics (OR 0.86, 95% CI 0.80-0.92) were less likely than whites to visit their transplant centers. Centers performing 18-34 (OR 1.44, 95% CI 1.30-1.59) and 35-61 transplants per year (OR 1.30, 95% CI 1.18-1.43) were more likely to see patients than centers performing <18 or >61. Almost 80% of patients saw nephrologists in months 1-3 after transplant. African-Americans (OR 0.85, 95% CI 0.80-0.90), Asians (OR 0.87, 95% CI 0.77-0.97), and Native Americans (OR 0.63, 95% CI 0.53-0.75) were less likely than whites to see nephrologists, as were Hispanics (OR 0.78, 95% CI 0.72-0.84) compared with non-Hispanics. CONCLUSION: Frequency of visits to transplant centers varied by center and region; most visits were to nephrologists. Patients from minority groups were less likely to visit transplant centers and nephrologists, with possibly significant public health implications.

Drug titration patterns and HbA 1c levels in type 2 diabetes.

OBJECTIVE: To evaluate oral antidiabetes drug (OAD) use, haemoglobin A(1c) (HbA(1c)) testing and glycaemic control in type 2 diabetes patients. STUDY DESIGN: Retrospective analysis based on claims data from the Integrated Healthcare Information Services (IHCIS) National Managed Care Benchmark Database. METHODS: OAD use and HbA(1c) testing were analysed for patients with >or= 2 claims indicating diagnosis of type 2 diabetes and >or= 1 90-day OAD treatment period between 1 January, 2000 and 30 June, 2006. Likelihood of HbA(1c) testing was examined using multivariable logistic regression analyses, adjusting for OAD regimen and patients' sociodemographical characteristics. RESULTS: Patients were classified based on initial OAD regimen: metformin (MET) (n = 22,203; 41.3%), sulphonylurea (SFU) (n = 18,439; 34.3%), thiazolidinedione (TZD) (n = 7663; 14.3%), SFU + MET (n = 5467; 10.2%) and TZD + MET (n = 2355; 4.2%). A total of 51.5% of patients had HbA(1c) testing during 90 days preceding OAD initiation through regimen completion. Approximately, 65% of MET and 58% of SFU patients had no titration of initial regimen. Patients demonstrating inadequate glucose control decreased from 68.5% at baseline to 46.9% within 90 days of regimen initiation. Multivariable logistic regression indicated several negative predictors of HbA(1c) testing, including SFU use, age 65+ years, moderate insurance copayment and preindex inpatient utilisation. Multivariable logistic regression of variables associated with reduced likelihood of up-titration included TZD, SFU + MET, or TZD + MET treatment, age 18-34 years, Medicare insurance and any preindex healthcare utilisation. CONCLUSIONS: Patients are not being transitioned to additional OADs in a stepwise fashion and/or are receiving inadequate titration on current OAD regimens. The low rate of HbA(1c) testing and rates of control are contributing factors.

Depressive disorder in renal transplantation: an analysis of Medicare claims.

BACKGROUND: Little is known about depression after kidney transplantation. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: US Renal Data System data; first kidney-only recipients who underwent transplantation in 1995 to 2003 with Medicare as primary payer (n = 47,899). PREDICTOR: Demographic and clinical characteristics of recipients (age, sex, race, ethnicity, primary cause of kidney disease, pretransplantation time on dialysis therapy, body mass index, initial immunosuppressive medications, and use of induction antibodies) and donors (age, sex, race, and living or deceased), transplantation year, and number of HLA mismatches. OUTCOMES & MEASUREMENTS: Depression incidence identified in Medicare claims and associations with clinical outcomes during the first 3 years posttransplantation. RESULTS: Depression was identified in 3,360 transplant recipients in the 3 years posttransplantation. Cumulative incidences were 5.05%, 7.29%, and 9.10% at 1, 2, and 3 years posttransplantation. In Cox proportional hazards analysis, white race, female sex, diabetes as primary cause of kidney disease, more than 3 years on dialysis therapy before transplantation, marked obesity (body mass index >or= 35 kg/m(2)), rapamycin use, antilymphocyte globulin or antithymocyte globulin for antibody induction therapy, donor age of 65 years or older, more recent transplantation, and presence of 6 HLA mismatches were associated with more depression, as identified in claims. Controlling for other known risk factors, time-dependent Cox proportional hazards analysis showed that depression was associated with increased graft failure (hazard ratio, 2.10; 95% confidence interval, 1.94 to 2.27; P < 0.001), return to dialysis therapy (hazard ratio, 1.97; 95% confidence interval, 1.76 to 2.19; P < 0.001), and death with a functioning graft (hazard ratio, 2.24; 95% confidence interval, 2.00 to 2.50; P < 0.001). LIMITATIONS: Depression identified through Medicare claims, limiting case ascertainment; limited number of recipient- or donor-related factors explored for potential associations; and limited depression treatment and pretransplantation depression information. CONCLUSIONS: Depression is associated with several identifiable factors and a 2-fold greater risk of graft failure and death with a functioning graft.

The effects of rheumatoid arthritis on labor force participation, work performance, and healthcare costs in two workplace samples.

OBJECTIVE: To assess the workplace costs of rheumatoid arthritis (RA) from the employer perspective. METHOD: Samples included 4485 manufacturing firm (MF) employees (109 with RA) and 915 commercially insured (CO) subscribers (333 with RA). Respondents completed the Health and Work Performance Questionnaire (HPQ) and the Health Assessment Questionnaire (HAQ). The effects of RA were estimated using regression analysis. RESULTS: RA was associated with increased probability of no longer working (CO), increased effort to maintain work performance (CO), increased sickness absence (MF), and increased non-RA pharmacy costs (CO). RA was not associated with hours worked or hourly wage. Indirect costs of RA did not exceed direct medical costs. CONCLUSIONS: Indirect costs of RA to employers are significant and warrant further research to increase our understanding of the contribution of different RA treatment interventions to optimizing workforce productivity.

Acute myocardial infarction and kidney transplantation.

Although the risk for acute myocardial infarction (AMI) is lower after transplantation than on the waiting list, this risk may vary by patient population and may be different early versus late after transplantation. Risk factors for AMI were examined among 53,297 Medicare beneficiaries who were placed on the deceased-donor waiting list in 1995 to 2002. Early (3 mo) effects of receiving a deceased- or living-donor kidney transplant were examined using time-dependent covariates in Cox nonproportional hazards analysis. Overall, transplantation was associated with a 17% lower adjusted risk for AMI (0.83; 95% confidence interval [CI] 0.77 to 0.90) versus the waiting list. However, the relative risk (versus the waiting list) for AMI was greater for deceased- compared to living-donor transplants, with both being much greater early (deceased-donor 3.57 [95% CI 3.21 to 3.96] compared to living-donor 2.81 [95% CI 2.31 to 3.42]) than late (deceased-donor 0.45 [95% CI 0.41 to 0.50] compared to living-donor 0.39 [95% CI 0.33 to 0.47]) posttransplantation. Individuals who were >or=65 yr of age had a much higher risk (versus 18- to 34-yr-olds) for AMI early posttransplantation (8.01; 95% CI 5.12 to 12.53) compared with the waiting list (3.68; 95% CI 3.98 to 4.54) or late posttransplantation (4.37; 95% CI 3.07 to 6.20). Black patients had less reduction in AMI risk (versus white patients) late posttransplantation (0.78; 95% CI 0.64 to 0.95) compared with early posttransplantation (0.60; 95% CI 0.48 to 0.74) or on the waiting list (0.62; 95% CI 0.56 to 0.68). The AMI risk that was associated with chronic kidney disease from diabetes (versus glomerulonephritis) was relatively greater on the waiting list (1.64; 95% CI 1.45 to 1.85) compared with early (1.34; 95% CI 1.08 to 1.68) and late (1.39; 95% CI 1.12 to 1.72) posttransplantation. Thus the risk reduction for AMI with transplantation versus the waiting list varies by patient population and time after transplantation.

A randomized study to decrease the use of potentially inappropriate medications among community-dwelling older adults in a southeastern managed care organization.

BACKGROUND: Despite progress in describing the problem of potentially inappropriate medication (PIM) use, there have been few prospective studies demonstrating that interventions with specific medication criteria can make a difference in decreasing the use of problematic drugs in older adults. OBJECTIVE: To design an intervention study to change physician behavior regarding PIM prescribing to older patients. STUDY DESIGN AND METHODS: A prospective randomized block design was used during an 18-month period from January 2001 to June 2002. The study population was primary care physicians (n = 355) in the Medicare + Choice product line of a southeastern managed care organization and their patients 65 years and older. There were 170 physicians in the treatment group and 185 in the control group. Physicians were assigned to the treatment or usual-care, groups using a randomization table, and each group included physicians who had and had not prescribed a PIM. RESULTS: Approximately 71% (84/118) of the physicians in the intervention group who prescribed a PIM completed and faxed back at least 1 potentially inappropriate medication form to the managed care organization. On 15.4% (260/1692) of the medication forms, physicians made some change regarding PIM use. CONCLUSIONS: Although many studies have addressed medication use among older adults, intervention studies aimed at influencing physician prescribing in this population are limited. This study describes a low-cost, replicable method to contact and educate physicians on drug therapy issues in older adults.

Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts.

BACKGROUND: Medication toxic effects and drug-related problems can have profound medical and safety consequences for older adults and economically affect the health care system. The purpose of this initiative was to revise and update the Beers criteria for potentially inappropriate medication use in adults 65 years and older in the United States. METHODS: This study used a modified Delphi method, a set of procedures and methods for formulating a group judgment for a subject matter in which precise information is lacking. The criteria reviewed covered 2 types of statements: (1) medications or medication classes that should generally be avoided in persons 65 years or older because they are either ineffective or they pose unnecessarily high risk for older persons and a safer alternative is available and (2) medications that should not be used in older persons known to have specific medical conditions. RESULTS: This study identified 48 individual medications or classes of medications to avoid in older adults and their potential concerns and 20 diseases/conditions and medications to be avoided in older adults with these conditions. Of these potentially inappropriate drugs, 66 were considered by the panel to have adverse outcomes of high severity. CONCLUSIONS: This study is an important update of previously established criteria that have been widely used and cited. The application of the Beers criteria and other tools for identifying potentially inappropriate medication use will continue to enable providers to plan interventions for decreasing both drug-related costs and overall costs and thus minimize drug-related problems.

Comparison of 2 systems for clinical practice profiling in diabetic care: medical records versus claims and administrative data.

OBJECTIVES: To (1) describe the rate of glycosylated hemoglobin (HbA1c) testing and control in a primary care clinic at an academic medical center; (2) compare academic medical center and health maintenance organization (HMO) data for a subgroup of the same patients; and (3) discuss the challenges to accurate clinical practice profiling. STUDY DESIGN: Retrospective analysis of medical records and claims and administrative data. PATIENTS AND METHODS: We reviewed the medical records of 300 patients with diabetes mellitus from the Primary Care practice at an academic medical center (AMC). The HMO and AMC were in the southeastern United States. The study adhered to the National Committee for Quality Assurance's Health Plan Employer Data and Information Set 3.0 (1998) guidelines for collection of the numerator and denominator data. RESULTS: Overall, 275 (91.7%) of 300 patients underwent a documented HbA1c test (range, 77.8%-98.0% across the 5 Primary Care Associates clinic physicians). Of these 275 patients, 206 (74.9%; range, 52.4%-84.7%) were under "good control" (defined by the National Committee for Quality Assurance as an HbA1c level of < or = 9.5%). The mean (SD) HbA1c level was 8.45% (1.98%). Data from the HMO documented a rate of HbA1c testing of 36.3% (45/124) compared with 92.7% (115/124) based on case note review at the academic medical center. CONCLUSIONS: Current administrative and claims-based information systems have inherent weaknesses if used for performance measurement. Reliance solely on medical record review is time and cost prohibitive. To ensure complete reporting of mandated "quality measures" will necessitate the tracking of data across different healthcare systems.