Roberts, Andrew W, Walid F Gellad, and Asheley Cockrell Skinner. (2016) 2016. “Lock-In Programs and the Opioid Epidemic: A Call for Evidence.”. American Journal of Public Health 106 (11): 1918-19.
Publications
2016
Baksh, Sheriza N, Walid F Gellad, and Caleb Alexander. (2016) 2016. “Maximizing the Post-Approval Safety of Flibanserin: A Role for Regulators, Clinicians, and Patients.”. Drug Safety 39 (5): 375-80. https://doi.org/10.1007/s40264-015-0389-2.
In August 2015, the US Food and Drug Administration (FDA) made the controversial decision to approve flibanserin (Addyi®) for women experiencing hypoactive sexual desire disorder. A number of factors contributed to disagreements regarding the FDA's decision, including the product's two prior failed FDA reviews, the unmet need of women with this disorder, extensive advocacy and politicization surrounding the product's relevance to women and sexual health, the potential for widespread off-label use, and the product's tenuous risk/benefit profile. Despite that, attention now shifts to maximizing the safe use of the product, including the optimal means to avoid numerous drug-drug interactions as well as the concomitant use of alcohol, both of which potentiate the risks of dizziness, hypotension, and syncope. Although the FDA has implemented a comprehensive Risk Evaluation and Mitigation Strategies program to maximize the product's safe use, patients, clinicians, and regulators must exhibit heightened vigilance early in the product's post-market life.
Marcum, Zachary A, Johanna E Bellon, Jie Li, Walid F Gellad, and Julie M Donohue. (2016) 2016. “New Chronic Disease Medication Prescribing by Nurse Practitioners, Physician Assistants, and Primary Care Physicians: A Cohort Study.”. BMC Health Services Research 16: 312. https://doi.org/10.1186/s12913-016-1569-1.
BACKGROUND: Medications to treat and prevent chronic disease have substantially reduced morbidity and mortality; however, their diffusion has been uneven. Little is known about prescribing of chronic disease medications by nurse practitioners (NPs) and physician assistants (PAs), despite their increasingly important role as primary care providers. Thus, we sought to conduct an exploratory analysis to examine prescribing of new chronic disease medications by NPs and PAs compared to primary care physicians (PCPs).
METHODS: We obtained prescribing data from IMS Health's Xponent™ on all NPs, PAs, and PCPs in Pennsylvania regularly prescribing anticoagulants, antihypertensives, oral hypoglycemics, and/or HMG-Co-A reductase inhibitors pre- and post-introduction of five new drugs in these classes that varied in novelty (i.e., dabigatran, aliskiren, sitagliptin or saxagliptin, and pitavastatin). We constructed three measures of prescriber adoption during the 15-month post-FDA approval period: 1) any prescription of the medication, 2) proportion of prescriptions in the class for the medication, and 3) time to adoption (first prescription) of the medication.
RESULTS: From 2007 to 2011, the proportion of antihypertensive prescriptions prescribed by NPs and PAs approximately doubled from 2.0 to 4.2 % and 2.2 to 4.9 %, respectively. Similar trends were found for anticoagulants, oral hypoglycemics, and HMG-Co-A reductase inhibitors. By 2011, more PCPs had prescribed each of the newly approved medications than NPs and PAs (e.g., 44.3 % vs. 18.5 % vs. 20 % for dabigatran among PCPs, NPs, and PAs). Across all medication classes, the newly approved drugs accounted for a larger share of prescriptions in the class for PCPs followed by PAs, followed by NPs (e.g., dabigatran: 4.9 % vs. 3.2 % vs. 2.8 %, respectively). Mean time-to-adoption for the newly approved medications was shorter for PCPs compared to NPs and PAs (e.g., dabigatran, 7.3 vs. 8.2 vs. 8.5 months; P all medications <0.001).
CONCLUSIONS: PCPs were more likely to prescribe each of the newly approved medications per each measure of drug adoption, regardless of drug novelty. Differences in the rate and speed of drug adoption between PCPs, NPs, and PAs may have important implications for care and overall costs at the population level as NPs and PAs continue taking on a larger role in prescribing.
2015
Liang, Rui, Guoguang Yang, Kwang E Kim, Antonio D’Amore, Aimee N Pickering, Cuiling Zhang, and Savio L-Y Woo. (2015) 2015. “Positive Effects of an Extracellular Matrix Hydrogel on Rat Anterior Cruciate Ligament Fibroblast Proliferation and Collagen MRNA Expression.”. Journal of Orthopaedic Translation 3 (3): 114-22. https://doi.org/10.1016/j.jot.2015.05.001.
BACKGROUND/OBJECTIVE: We have previously shown that an extracellular matrix (ECM) bioscaffold derived from porcine small intestine submucosa (SIS) enhanced the healing of a gap injury of the medial collateral ligament as well as the central third defect of the patellar tendon. With the addition of a hydrogel form of SIS, we found that a transected goat anterior cruciate ligament (ACL) could also be healed. The result begs the research question of whether SIS hydrogel has positive effects on ACL fibroblasts (ACLFs) and thus facilitates ACL healing.
METHODS: In the study, ECM-SIS hydrogel was fabricated from the digestion of decellularised and sterilised sheets of SIS derived from αGal-deficient (GalSafe) pigs. As a comparison, a pure collagen hydrogel was also fabricated from commercial collagen type I solution. The morphometrics of hydrogels was assessed with scanning electron microscopy. The ECM-SIS and collagen hydrogels had similar fibre diameters (0.105 ± 0.010 μm vs. 0.114 ± 0.004 μm), fibre orientation (0.51 ± 0.02 vs. 0.52 ± 0.02), and pore size (0.092 ± 0.012 μm vs. 0.087 ± 0.008 μm). The preservation of bioactive properties of SIS hydrogel was assessed by detecting bioactive molecules sensitive to processing and enzyme digestion, such as growth factors fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta 1 (TGF-β1), with enzyme-linked immunosorbent assay. ACLFs were isolated and expanded in culture from explants of rat ACLs (n = 3). The cells were then seeded on the hydrogels and cultured with 0%, 1%, and 10% foetal bovine serum (FBS) for 3 days and 7 days. Cell attachment was observed using a light microscope and scanning electron microscopy, whereas cell proliferation and matrix production (collagen types I and III) were examined with bromodeoxyuridine assays and reverse transcription-polymerase chain reaction, respectively.
RESULTS: The results showed that FGF-2 and TGF-β1 in the SIS hydrogel were preserved by 50% (65.9 ± 26.1 ng/g dry SIS) and 90% (4.4 ± 0.6 ng/g dry SIS) relative to their contents in ECM-SIS sheets, respectively. At Day 3 of culture, ACLFs on the SIS hydrogel were found to proliferate 39%, 31%, and 22% more than those on the pure collagen hydrogel at 0%, 1%, and 10% FBS, respectively (p < 0.05). Collagen type I mRNA expression was increased by 150%, 207%, and 100%, respectively, compared to collagen hydrogel (p < 0.05), whereas collagen type III mRNA expression was increased by 123% and 132% at 0% and 1% FBS, respectively (all p < 0.05) but not at 10% FBS. By Day 7, collagen type I mRNA expression was still elevated by 137% and 100% compared to collagen hydrogel at 1% and 10% FBS, respectively (p < 0.05). Yet, collagen type III mRNA levels were not significantly different between the two groups at any FBS concentrations.
CONCLUSION: Our data showed that the ECM-SIS hydrogel not only supported the growth of ACLFs, but also promoted their proliferation and matrix production relative to a pure collagen hydrogel. As such, ECM-SIS hydrogel has potential therapeutic value to facilitate ACL healing at the early stage after injury.
Scott, Frank I, Ravy K Vajravelu, Meenakshi Bewtra, Ronac Mamtani, Dale Lee, David S Goldberg, and James D Lewis. (2015) 2015. “The Benefit-to-Risk Balance of Combining Infliximab With Azathioprine Varies With Age: A Markov Model.”. Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association 13 (2): 302-309.e11. https://doi.org/10.1016/j.cgh.2014.07.058.
BACKGROUND & AIMS: Combination therapy with infliximab and azathioprine has demonstrated benefit over monotherapy for moderate-to-severe Crohn's disease. Clinical trials and models have not accounted for age-specific risks associated with these therapies, including the risk of immunosuppression-related cancer and infection. After accounting for these risks, the strategy yielding the greatest benefit may vary with age.
METHODS: We assessed age-specific risks and benefits of combination therapy compared with infliximab monotherapy by using Markov modeling. The base case was a 35-year-old male patient with a 1-year time horizon. We assumed the incidence of lymphoma to be 5.28-fold higher with combination therapy. Secondary analyses accounted for life expectancy, therapy beyond 1 year, and age-specific surgical and infection risks. Quality-adjusted life years (QALYs) were calculated for 25- to 75-year old individuals.
RESULTS: Combination therapy was found to be of greater benefit in the base case (0.7522 QALYs for combination therapy vs 0.7426 QALYs for monotherapy). Accounting for life years lost, monotherapy was the best approach if the hazard ratio for lymphoma with combination therapy was >8.1 patients who were 75 years old. Monotherapy provided greater net benefit to patients 55, 65, or 75 years old if therapy was extended for 9, 7, or 5 years, respectively. For 25-year-old men, monotherapy resulted in fewer deaths but only yielded greater QALYs if the annual incidence of hepatosplenic T-cell lymphoma exceeded 36/100,000 persons.
CONCLUSIONS: After accounting for age-specific risks of lymphoma, infection, and surgical complications, benefits of combination therapy outweighed the risks as a short-term and intermediate-term strategy for most patients with moderate-to-severe Crohn's disease who were younger than 65 years. For young male patients, combination therapy yields greater QALYs but at cost of an increased risk of death from lymphoma.
Alvarez, Carlos A, Eric M Mortensen, Una E Makris, Dan R Berlowitz, Laurel A Copeland, Chester B Good, Megan E Amuan, and Mary Jo Pugh V. (2015) 2015. “Association of Skeletal Muscle Relaxers and Antihistamines on Mortality, Hospitalizations, and Emergency Department Visits in Elderly Patients: A Nationwide Retrospective Cohort Study.”. BMC Geriatrics 15: 2. https://doi.org/10.1186/1471-2318-15-2.
BACKGROUND: High-risk medication exposure in the elderly is common and associated with increased mortality, hospitalizations, and emergency department (ED) visits. Skeletal muscle relaxants and antihistamines are high-risk medications commonly prescribed in elderly patients. The objective of this study was to determine the association between skeletal muscle relaxants or antihistamines and mortality, hospitalizations, and emergency department visits.
METHODS: This study used a new-user, retrospective cohort design using national Veteran Affairs (VA) data from 128 hospitals. Veterans ≥65 years of age on October 1, 2005 who received VA inpatient/outpatient care at least once in each of fiscal year (FY) 2005 and FY 2006 were included. Exposure to skeletal muscle relaxants and antihistamines was defined by the National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set measures for high-risk medications in the elderly. Primary outcomes identified within one year of exposure were death, ED visit, or hospitalization; ED visits or hospitalizations due to falls and fracture were also assessed. Propensity score matching (1 to 1 match) was used to balance covariates between exposed patients and non-exposed patients.
RESULTS: In this cohort of 1,807,404 patients 55,566 patients were included in the propensity-matched cohort for skeletal muscle relaxants and 60,058 patients were included in the propensity-matched cohort for anti-histamines. Mortality was lower in skeletal muscle relaxants-exposed patients (adjusted odds ratio [AOR] 0.87, 95% CI 0.81-0.94), but risk of emergency care (AOR 2.25, 95% CI 2.16-2.33) and hospitalization (AOR 1.56, 95% CI 1.48-1.65) was higher for patients prescribed skeletal muscle relaxants. Similar findings were observed for emergency and hospital care for falls or fractures. Mortality (AOR 1.93, 95% CI 1.82-2.04), ED visits (AOR 2.35, 95% CI 2.27-2.43), and hospitalizations (AOR 2.21, 95% CI 2.11-2.32) were higher in the antihistamine-exposed group, with similar findings for falls and fractures outcomes.
CONCLUSION: Skeletal muscle relaxants and antihistamines are associated with an increased risk of ED visits and hospitalizations in elderly patients. Antihistamines were also associated with an increased risk of death, further validating the classification of these drug classes as "high risk".
Gellad, Walid F, Xinhua Zhao, Carolyn T Thorpe, Maria K Mor, Chester B Good, and Michael J Fine. (2015) 2015. “Dual Use of Department of Veterans Affairs and Medicare Benefits and Use of Test Strips in Veterans With Type 2 Diabetes Mellitus.”. JAMA Internal Medicine 175 (1): 26-34. https://doi.org/10.1001/jamainternmed.2014.5405.
IMPORTANCE: Self-monitoring of blood glucose is a costly component of care for diabetes mellitus, with unclear benefits for patients not taking insulin. Veterans with dual Department of Veterans Affairs (VA) and Medicare benefits have access to test strips through both systems, raising the potential for overuse.
OBJECTIVES: To examine the patterns of test strip receipt among older veterans with diabetes and determine whether receipt of strips from dual health care systems is associated with overuse.
DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional, retrospective cohort study using national VA administrative data linked to Medicare Parts A, B, and D claims for fiscal years 2008 and 2009. A total of 363,996 community-dwelling veterans 65 years or older with diabetes who used the VA health care system and received test strips in fiscal year 2009 were included in the study.
EXPOSURES: Receipt of test strips from the VA only, Medicare only, or both the VA and Medicare; covariates included sociodemographics, comorbidity, diabetes complications, and hemoglobin A1c level.
MAIN OUTCOMES AND MEASURES: Quantity of test strips dispensed and overuse of test strips, defined as more than 1 strip per day (>365 strips per year) among those taking no diabetes medications, oral diabetes medications alone, or long-acting insulin without short-acting insulin or more than 4 strips per day (>1460 strips per year) among those taking short-acting insulin.
RESULTS: Overall, 260,688 older veterans (71.6%) with diabetes received strips from the VA only, 82,826 (22.8%) from Medicare only, and 20,482 (5.6%) from the VA and Medicare. Veterans receiving strips from both the VA and Medicare received more strips (median, 600; interquartile range [IQR], 350-1000) than the Medicare only (median, 400; IQR, 200-700) and VA only (median, 200; IQR, 100-500) groups (P < .001) and had substantially greater odds of overuse than the VA only group (55.4% vs 15.8%) (adjusted odds ratio [OR], 16.3; 95% CI, 14.6-18.1 for no medications; 55.3% vs 6.0%; OR, 19.8; 95% CI, 18.9-20.8 for oral medications; 87.4% vs 65.5%; OR, 3.69; 95% CI, 3.30-4.14 for long-acting insulin; and 32.8% vs 13.5%; OR, 3.24; 95% CI, 3.05-3.45 for short-acting insulin). Patterns were similar when using more conservative thresholds of overuse.
CONCLUSIONS AND RELEVANCE: Veterans who receive glucose test strips through both the VA and Medicare use more strips and are more likely to potentially overuse strips. These results illustrate the profound importance of understanding dual VA and Medicare coverage and are emblematic of waste and inefficiency.
Anderson, Timothy S, Chester B Good, and Walid F Gellad. (2015) 2015. “Prevalence and Compensation of Academic Leaders, Professors, and Trustees on Publicly Traded US Healthcare Company Boards of Directors: Cross Sectional Study.”. BMJ (Clinical Research Ed.) 351: h4826. https://doi.org/10.1136/bmj.h4826.
OBJECTIVE: To identify the prevalence, characteristics, and compensation of members of the boards of directors of healthcare industry companies who hold academic appointments as leaders, professors, or trustees.
DESIGN: Cross sectional study.
SETTING: US healthcare companies publicly traded on the NASDAQ or New York Stock Exchange in 2013.
PARTICIPANTS: 3434 directors of pharmaceutical, biotechnology, medical equipment and supply, and healthcare provider companies.
MAIN OUTCOME MEASURES: Prevalence, annual compensation, and beneficial stock ownership of directors with affiliations as leaders, professors, or trustees of academic medical and research institutions.
RESULTS: 446 healthcare companies met the study search criteria, of which 442 (99%) had publicly accessible disclosures on boards of directors. 180 companies (41%) had one or more academically affiliated directors. Directors were affiliated with 85 geographically diverse non-profit academic institutions, including 19 of the top 20 National Institute of Health funded medical schools and all of the 17 US News honor roll hospitals. Overall, these 279 academically affiliated directors included 73 leaders, 121 professors, and 85 trustees. Leaders included 17 chief executive officers and 11 vice presidents or executive officers of health systems and hospitals; 15 university presidents, provosts, and chancellors; and eight medical school deans or presidents. The total annual compensation to academically affiliated directors for their services to companies was $54,995,786 (£35,836,000; €49,185,900) (median individual compensation $193,000) and directors beneficially owned 59,831,477 shares of company stock (median 50,699 shares).
CONCLUSIONS: A substantial number and diversity of academic leaders, professors, and trustees hold directorships at US healthcare companies, with compensation often approaching or surpassing common academic clinical salaries. Dual obligations to for profit company shareholders and non-profit clinical and educational institutions pose considerable personal, financial, and institutional conflicts of interest beyond that of simple consulting relationships. These conflicts have not been fully addressed by professional societies or academic institutions and deserve additional review, regulation, and, in some cases, prohibition when conflicts cannot be reconciled.
Thorpe, Carolyn T, Walid F Gellad, Chester B Good, Sijian Zhang, Xinhua Zhao, Maria Mor, and Michael J Fine. (2015) 2015. “Tight Glycemic Control and Use of Hypoglycemic Medications in Older Veterans With Type 2 Diabetes and Comorbid Dementia.”. Diabetes Care 38 (4): 588-95. https://doi.org/10.2337/dc14-0599.
OBJECTIVE: Older adults with diabetes and dementia are at increased risk for hypoglycemia and other adverse events associated with tight glycemic control and are unlikely to experience long-term benefits. We examined risk factors for tight glycemic control in this population and use of medications associated with a high risk of hypoglycemia in the subset with tight control.
RESEARCH DESIGN AND METHODS: This retrospective cohort study of national Veterans Affairs (VA) administrative/clinical data and Medicare claims for fiscal years (FYs) 2008-2009 included 15,880 veterans aged ≥ 65 years with type 2 diabetes and dementia and prescribed antidiabetic medication. Multivariable regression analyses were used to identify sociodemographic and clinical predictors of hemoglobin A1c (HbA1c) control (tight, moderate, poor, or not monitored) and, in patients with tight control, subsequent use of medication associated with a high risk of hypoglycemia (sulfonylureas, insulin).
RESULTS: Fifty-two percent of patients had tight glycemic control (HbA1c <7% [53 mmol/mol]). Specific comorbidities, older age, and recent weight loss were associated with greater odds of tight versus moderate control, whereas Hispanic ethnicity and obesity were associated with lower odds of tight control. Among tightly controlled patients, 75% used sulfonylureas and/or insulin, with higher odds in patients who were male, black, or aged ≥ 75 years; had a hospital or nursing home stay in FY2008; or had congestive heart failure, renal failure, or peripheral vascular disease.
CONCLUSIONS: Many older veterans with diabetes and dementia are at high risk for hypoglycemia associated with intense diabetes treatment and may be candidates for deintensification or alteration of diabetes medications.
Aspinall, Sherrie L, Chester B Good, Xinhua Zhao, Francesca E Cunningham, Bernadette B Heron, Mark Geraci, Vida Passero, et al. (2015) 2015. “Adjuvant Chemotherapy for Stage III Colon Cancer: Relative Dose Intensity and Survival Among Veterans.”. BMC Cancer 15: 62. https://doi.org/10.1186/s12885-015-1038-y.
BACKGROUND: Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS).
METHODS: Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations.
RESULTS: 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p < 0.001) and 3-year DFS (P = 0.009) than was receipt of ≤70% RDI, with 5-year OS rates of 66.3% and 50.5%, respectively and 3-year DFS rates of 66.1% and 52.7%, respectively. In the multivariable analysis of 5-year OS, oxaliplatin + 5-FU/LV (versus 5-FU/LV) (HR = 0.55; 95% CI = 0.34-0.91), >70% RDI at the first year (HR = 0.58; 95% CI = 0.37-0.89) and married status (HR = 0.66; 95% CI = 0.45-0.97) were associated with significantly decreased risk of death, while age ≥75 (versus 55-64) (HR = 2.06; 95% CI = 1.25-3.40), Charlson Comorbidity Index (HR = 1.17; 95% CI = 1.06-1.30), T4 tumor status (versus T1/T2) (HR = 5.88; 95% CI = 2.69-12.9), N2 node status (HR = 1.68; 95% CI = 1.12-2.50) and bowel obstruction (HR = 2.32, 95% CI = 1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS.
CONCLUSION: Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA.