Clinical and Informatics Research on Large Clinical Databases

National Library Of Medicine

Investigators

Linked publications, trials & patents

Abstract

A. Possible Beneficial and Adverse Drug Effects on SARS-COV-2 Infections (COVID-19) We have identified one set of drugs used in ambulatory care that might reduce or increase incidence and/or severity of COVID-19. This combination is being tested in clinical trials, but the number of subjects has been small and observational data will likely be needed to support these studies. Some drugs that might reduce or aggravate COVID-19 include non-steroidals, anticoagulants, H2 blockers, anti-platelet agents, ACE inhibitors, and ARBs that treat rheumatologic disease (Tocilizumab, Rituximab, Sarilumab). We will study the association with the incidence and severity of COVID-19 infections. We are also studying the phenomenon described as Long COVID to assess how distinct a syndrome it is by comparing it with what might be called Long Influenza. B. Metformin and longevity In the last decade, research on aging found that metformin use was associated with a reduction in cognitive decline and longer survival among diabetics compared to those treated with other oral agents. The FDA recently approved the first human study to see if an anti-diabetic medication, metformin, can protect diabetic patients from multiple diseases from aging. We identified about 300,000 Medicare beneficiaries diagnosed with type 2 diabetes post 12/31/2006 and followed them until death, switching to capitated plans, disenrollment from Medicare, or 12/31/2016, whichever comes first. During this follow-up, we also collected socio-demographic information, as well as, the use of common maintenance drugs used among diabetics, specifically: metformin, insulin, sulfonylureas, thiazolidinedione, GLP-1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors, and other glucose lowering drugs), but also 5 antihypertensive medications (diuretics, beta-blockers, calcium-channel blockers, ACE inhibitors, and ARBs) and 1 lipid-lowering drug (statin). Controlling for other medication use and patients characteristics in time-varying manner, metformin was not strongly associated with longer survival (HR=0.95) and the association was not statistically significant. Rather, compared to the no use of each study medication, mortality risk declined with use of 3 diabetes drugs (SGLT-2 inhibitors, GLP-1 analogues, and DPP-4 Inhibitors), 3 blood pressure medications (diuretics, ARBs, and ACEI inhibitors) and statins. Statins exhibited the most consistent reduction in all-cause mortality risk but 20% of study patients never took a statin, suggesting missed prevention opportunities. C. Proton Pump Inhibitors (PPIs) and mortality PPIs have been associated with increases in the incidence of pneumonia, C Decile infection and osteoporosis/fractures, probable chronic renal failure, and cardiac events. Xie et al reported that PPIs could also increase the risk of death using Veterans Affairs (VA) data (HR of 1.15 1.25). From 2007-2016 Medicare Parts A, B and D data, we identified 1.2 million Medicare beneficiaries. We also defined a set of covariates: use of PPIs, use of H2 blockers as a control drug, admission to intensive care units or inpatient hospitals, socio-demographics, presence of 58 chronic conditions and treated them as time-dependent covariates in our main analysis of Cox proportion hazard regression. In addition to treating covariates in time-varying manner, we used the concept of lag-time to define drug exposure period in order to control for protopathic bias which occurs when the outcome of interest is associated with an exposure that actually results from early signs and symptoms of the outcome under study. With use of lag times, PPIs had no associations with death, in agreement with one RCT that showed no such association. D. Fluoroquinolones (FQ) and tendon complication FQs are among the most widely prescribed antibiotics in the outpatient setting. Several studies have reported the plausible associations between the use of FQs and tendon complications. The FDA issued black box warning labels to FQs since 2008. Several observational studies associate the use of FQ with an increased risk for tendon rupture, aortic aneurysms or dissections (AA/AD). The fact that collagen type I and III fibers provide tensile strength to both tendons and aortic walls, and that FQs can disrupt these fibers in some circumstances, magnify concerns about these reported associations. Some prior studies described the relationship between FQs and tendon rupture as a class effect and included amoxicillin as a control drug to determine whether these complications are specific to FQs. We separately included 3 FQs (ciprofloxacin, levofloxacin, moxifloxacin) and 4 non-FQ antibiotics (amoxicillin, amoxicillin-clavulanate, azithromycin or cephalexin), 5 of which were the top 5 antibiotic agents in the US. Using Fine-Gray competing risk regression analyses treating death as a competing risk, we assessed the independent risk of tendon rupture for each antibiotic use in a 1.2 million Medicare population. Precisely, we assessed the risk by temporal exposure within study antibiotics (within 30 days, 31-60 days, more than 60 days) to avoid non-differential misclassification that can occur with too simple (yes/no) drug exposure. E. Association between Female Hormone replacement therapy (HRT) and longevity, cardiovascular diseases and cancers HRT is an effective treatment for the typical menopause-related symptoms (such as hot flashes, night sweats, irregular periods etc.) and long-term health problems associated with menopause (the risk of osteoporosis, cardiovascular disease and stroke). Reports of some studies have trumpeted negative effects of HRT on outcomes such as cardiovascular diseases, cancers, and all-cause mortality. However, the evidence behind them is weak or has been reversed. In this study, we traced about 1.5 million female Medicare beneficiaries from Medicare Part D entry to the onset of each outcome, death, switching to capitated plan, disenrollment from Medicare, or end of data availability whichever comes first and then we compared each risk among women treated with HRT of various kinds with to those not treated, and we treated almost all covariates as time time-dependent in a Cox proportional hazard regression analysis. Estrogen use, but not combined estrogen+progestin use, was associated with less risk of breast and other studied cancers and a significant reduction in mortality risk. F. Characterizing the cardiac risks of commonly prescribed QT-prolonging drugs Drug-induced long QT syndrome is one of the most frequent cause of withdrawal or relabeling of marketed drugs. It is difficult to detect serious adverse events associated with QT prolongation during drug development, both in the preclinical and clinical phases of drug trials. The clinical risks of many QT-prolonging drugs are only discovered by post-marketing surveillance. This study leverages the large CMS database (over 1.2 million subjects) to provide insight into the cardiac risks of some QT-prolonging drugs with known risk of severe cardiac arrhythmia (Torsades de pointes) and showed that some medications declared to be long QT risks did exhibit risk and others did not. G. Evaluating the risk of fractures among elderly women enrolled in Medicare Osteoporosis characterized by progressive deterioration of bone structure due to decreased bone mineral density (BMD) has been found to be closely associated with fractures. There are several pharmacotherapies available for prevention and treatment of postmenopausal osteoporosis including bisphosphonate, estrogen, raloxifene, denosumab and more. However, their beneficial and/or detrimental effect on fractures is not well addressed. We are conducting a nationwide cohort study of patients with osteoporosis to compare risks of any, hip and atypical femur fractures among patients treated with any of the drugs