Publications

2016
Choudhry NK, Denberg TD, Qaseem A, Clinical Guidelines Committee of the American College of P. Improving Adherence to Therapy and Clinical Outcomes While Containing Costs: Opportunities From the Greater Use of Generic Medications: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Annals of Internal Medicine 2016;164:41-9.Abstract

DESCRIPTION: The discrepancy between health care spending and achieved outcomes in the United States has fueled efforts to identify and address situations where unnecessarily expensive therapies are used when less costly, equally effective options are available. The underuse of generic medications is an important example. METHODS: A literature review was conducted to answer 5 questions about generic medications: 1) How commonly are brand-name medications used when a generic version is available? 2) How does the use of generic medications influence adherence? 3) What is the evidence that brand-name and generic medications have similar clinical effects? 4) What are the barriers to increasing the use of generic medications? 5) What strategies can be used to promote cost savings through greater generic medication use? This article was reviewed and approved by the American College of Physicians Clinical Guidelines Committee. BEST PRACTICE ADVICE: Clinicians should prescribe generic medications, if possible, rather than more expensive brand-name medications.

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Lauffenburger JC, Choudhry NK. Text Messaging and Patient Engagement in an Increasingly Mobile World. Circulation 2016;133(6):555-556.Abstract

The potential of short message system (SMS) text messaging and other mobile-phone based methods (collectively often called "mHealth") to engage patients in their own health care has been met with great enthusiasm because of the relatively low cost, transportability, and widespread use of these technologies - more than six billion people worldwide have access to mobile phones.1 By providing reminders and enhancing communication and interaction with healthcare professionals, there is compelling evidence for patients with HIV/AIDS that mHealth can improve adherence to medications and suppress viral loads.2-4.

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Lee JL, Choudhry NK, Wu AW, Matlin OS, Brennan TA, Shrank WH. Patient Use of Email, Facebook, and Physician Websites to Communicate with Physicians: A National Online Survey of Retail Pharmacy Users. Journal of General Internal Medicine 2016;31:45-51.Abstract

BACKGROUND: Patient-physician communication often occurs outside the clinic setting; many institutions discourage electronic communication outside of established electronic health record systems. Little empirical data are available on patient interest in electronic communication and Web-based health tools that are technically feasible but not widely available. RESEARCH OBJECTIVE: To explore patient behavior and interest in using the Internet to contact physicians. DESIGN: National cross-sectional online survey. PARTICIPANTS: A sample of 4,510 CVS customers with at least one chronic condition in the household was used to target patients with chronic conditions and their caregivers. Subjects were identified from a national panel of over 100,000 retail pharmacy customers. Of those sampled, 2,252 responded (50.0 % response rate). MAIN MEASURES: Survey measures included demographic and health information, patient use of email and Facebook to contact physicians, and patient interest in and use of Web-based tools for health. KEY RESULTS: A total of 37 % of patients reported contacting their physicians via email within the last six months, and 18 % via Facebook. Older age was negatively associated with contacting physicians using email (OR 0.57 [95 % CI 0.41-0.78]) or Facebook (OR 0.28 [0.17-0.45]). Non-white race (OR 1.61 [1.18-2.18] and OR 1.82 [1.24-2.67]) and caregiver status (OR 1.58 [1.27-1.96] and OR 1.71 [1.31- 2.23]) were positively associated with using email and Facebook, respectively. Patients were interested in using Web-based tools to fill prescriptions, track their own health, and access health information (37-57 %), but few were currently doing so (4-8 %). CONCLUSIONS: In this population of retail pharmacy users, there is strong interest among patients in the use of email and Facebook to communicate with their physicians. The findings highlight the gap between patient interest for online communication and what physicians may currently provide. Improving and accelerating the adoption of secure Web messaging systems is a possible solution that addresses both institutional concerns and patient demand.

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Franklin JM, Shrank WH, Lii J, Krumme AK, Matlin OS, Brennan TA, Choudhry NK. Observing versus Predicting: Initial Patterns of Filling Predict Long-Term Adherence More Accurately Than High-Dimensional Modeling Techniques. Health Services Research 2016;51:220-39.Abstract

OBJECTIVE: Despite the proliferation of databases with increasingly rich patient data, prediction of medication adherence remains poor. We proposed and evaluated approaches for improved adherence prediction. DATA SOURCES: We identified Medicare beneficiaries who received prescription drug coverage through CVS Caremark and initiated a statin. STUDY DESIGN: A total of 643 variables were identified at baseline from prior claims and linked Census data. In addition, we identified three postbaseline predictors, indicators of adherence to statins during each of the first 3 months of follow-up. We estimated 10 models predicting subsequent adherence, using logistic regression and boosted logistic regression, a nonparametric data-mining technique. Models were also estimated within strata defined by the index days supply. RESULTS: In 77,703 statin initiators, prediction using baseline variables only was poor with maximum cross-validated C-statistics of 0.606 and 0.577 among patients with index supply

30 days, respectively. Using only indicators of initial statin adherence improved prediction accuracy substantially among patients with shorter initial dispensings (C = 0.827/0.518), and, when combined with investigator-specified variables, prediction accuracy was further improved (C = 0.842/0.596). CONCLUSIONS: Observed adherence immediately after initiation predicted future adherence for patients whose initial dispensings were relatively short.

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Lieberman DA, Polinski JM, Choudhry NK, Avorn J, Fischer MA. Medicaid prescription limits: policy trends and comparative impact on utilization. BMC Health Services Research 2016;16:15.Abstract

BACKGROUND: Medicaid programs face growing pressure to control spending. Despite evidence of clinical harms, states continue to impose policies limiting the number of reimbursable prescriptions (caps). We examined the recent use of prescription caps by Medicaid programs and the impact of policy implementation on prescription utilization. METHODS: We identified Medicaid cap policies from 2001-2010. We classified caps as applying to all prescriptions (overall caps) or only branded prescriptions (brand caps). Using state-level, aggregate prescription data, we developed interrupted time-series analyses to evaluate the impact of implementing overall caps and brand caps in a subset of states with data available before and after cap initiation. For overall caps, we examined the use of essential medications, which were classified as preventive or as providing symptomatic benefit. For brand caps, we examined the use of all branded drugs as well as branded and generic medications among classes with available generic replacements. RESULTS: The number of states with caps increased from 12 in 2001 to 20 in 2010. Overall cap implementation (n = 3) led to a 0.52 % (p < 0.001) annual decrease in the proportion of essential prescriptions but no change in cost. For preventive essential medications, overall caps led to a 1.12 % (p = 0.001) annual decrease in prescriptions (246,000 prescriptions annually) and a 1.20 % (p < 0.001) decrease in spending (-$12.2 million annually), but no decrease in symptomatic essential medication use. Brand cap implementation (n = 6) led to an immediate 2.29 % (p = 0.16) decrease in branded prescriptions and 1.26 % (p = 0.025) decrease in spending. For medication classes with generic replacements, the decrease in branded prescriptions (0.74 %, p = 0.003) approximately equaled the increase in generics (0.79 %, p = 0.009), with estimated savings of $17.4 million. CONCLUSIONS: An increasing number of states are using prescription caps, with mixed results. Overall caps decreased the use of preventive but not symptomatic essential medications, suggesting that patients assign higher priority to agents providing symptomatic benefit when faced with reimbursement limits. Among medications with generic replacements, brand caps shifted usage from branded drugs to generics, with considerable savings. Future research should analyze the patient-level impact of these policies to measure clinical outcomes associated with these changes.

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2015
Gagne JJ, Kesselheim AS, Choudhry NK, Polinski JM, Hutchins D, Matlin OS, Brennan TA, Avorn J, Shrank WH. Comparative effectiveness of generic versus brand-name antiepileptic medications. Epilepsy and Behavior 2015;52:14-18.Abstract

OBJECTIVE: The objective of this study was to compare treatment persistence and rates of seizure-related events in patients who initiate antiepileptic drug (AED) therapy with a generic versus a brand-name product. METHODS: We used linked electronic medical and pharmacy claims data to identify Medicare beneficiaries who initiated one of five AEDs (clonazepam, gabapentin, oxcarbazepine, phenytoin, zonisamide). We matched initiators of generic versus brand-name versions of these drugs using a propensity score that accounted for demographic, clinical, and health service utilization variables. We used a Cox proportional hazards model to compare rates of seizure-related emergency room (ER) visit or hospitalization (primary outcome) and ER visit for bone fracture or head injury (secondary outcome) between the matched generic and brand-name initiators. We also compared treatment persistence, measured as time to first 14-day treatment gap, between generic and brand-name initiators. RESULTS: We identified 19,760 AED initiators who met study eligibility criteria; 18,306 (93%) initiated a generic AED. In the matched cohort, we observed 47 seizure-related hospitalizations and ER visits among brand-name initiators and 31 events among generic initiators, corresponding to a hazard ratio of 0.53 (95% confidence interval, 0.30 to 0.96). Similar results were observed for the secondary clinical endpoint and across sensitivity analyses. Mean time to first treatment gap was 124.2days (standard deviation [sd], 125.8) for brand-name initiators and 137.9 (sd, 148.6) for generic initiators. SIGNIFICANCE: Patients who initiated generic AEDs had fewer adverse seizure-related clinical outcomes and longer continuous treatment periods before experiencing a gap than those who initiated brand-name versions.

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Bowry AD, Lewey J, Dugani SB, Choudhry NK. The Burden of Cardiovascular Disease in Low- and Middle-Income Countries: Epidemiology and Management. Canadian Journal of Cardiology 2015;31:1151-9.Abstract

Cardiovascular disease (CVD) is the second leading cause of mortality worldwide, accounting for 17 million deaths in 2013. More than 80% of these cases were in low- and middle-income countries (LMICs). Although the risk factors for the development of CVD are similar throughout the world, the evolving change in lifestyle and health behaviours in LMICs-including tobacco use, decreased physical activity, and obesity-are contributing to the escalating presence of CVD and mortality. Although CVD mortality is falling in high-income settings because of more effective preventive and management programs, access to evidence-based interventions for combating CVD in resource-limited settings is variable. The existing pressures on both human and financial resources impact the efforts of controlling CVD. The implementation of emerging innovative interventions to improve medication adherence, introducing m-health programs, and decentralizing the management of chronic diseases are promising methods to reduce the burden of chronic disease management on such fragile health care systems.

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Lewey J, Shrank WH, Avorn J, Liu J, Choudhry NK. Medication Adherence and Healthcare Disparities: Impact of Statin Co-Payment Reduction. American Journal of Managed Care 2015;21:696 - 704.Abstract

Objectives: Minority patients have lower rates of cardiovascularmedication adherence, which may be amenable to co-payment reductions.Our objective was to evaluate the effect of race on adherencechanges following a statin co-payment reduction intervention.Study Design: Retrospective analysis.Methods: The intervention was implemented by a large selfinsuredemployer. Eligible individuals in the intervention cohort(n = 1961) were compared with a control group of employees ofother companies without such a policy (n = 37,320). As a proxy forrace, we categorized patients into tertiles based on the proportionof black residents living in their zip code of residence. Analyseswere performed using difference-in-differences design with generalizedestimating equations.Results: Prior to the new co-payment policy, adherence rateswere higher for individuals living in areas with fewer black residents.In multivariable models adjusting for demographic factors,clinical covariates and baseline trends, the co-payment reductionincreased adherence by 2.0% (P = .14), 2.1% (P = .15) and 6% (P<.0001) for intervention patients living in areas with the bottom,middle and top tertiles of the proportion of black residents. Theseresults persisted after adjusting for income.Conclusions: Co-payment reduction for statins preferentiallyimproved adherence among patients living in communities witha higher proportion of black residents. Further research is neededon the impact of value-based insurance design programs onreducing racial disparities in cardiovascular care.

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Franklin JM, Krumme AA, Tong AY, Shrank WH, Matlin OS, Brennan TA, Choudhry NK. Association between trajectories of statin adherence and subsequent cardiovascular events. Pharmacoepidemiology and Drug Safety 2015;24:1105-13.Abstract

PURPOSE: Trajectory models have been shown to (1) identify groups of patients with similar patterns of medication filling behavior and (2) summarize the trajectory, the average adherence in each group over time. However, the association between adherence trajectories and clinical outcomes remains unclear. This study investigated the association between 12-month statin trajectories and subsequent cardiovascular events. METHODS: We identified patients with insurance coverage from a large national insurer who initiated a statin during January 1, 2007 to December 31, 2010. We assessed medication adherence during the 360 days following initiation and grouped patients based on the proportion of days covered (PDC) and trajectory models. We then measured cardiovascular events during the year after adherence assessment. Cox proportional hazards models were used to evaluate the association between adherence measures and cardiovascular outcomes; strength of association was quantified by the hazard ratio, the increase in model C-statistic, and the net reclassification index (NRI). RESULTS: Among 519 842 statin initiators, 8777 (1.7%) had a cardiovascular event during follow-up. More consistent medication use was associated with a lower likelihood of clinical events, whether adherence was measured through trajectory groups or PDC. When evaluating the prediction of future cardiovascular events by including a measure of adherence in the model, the best model reclassification was observed when adherence was measured using three or four trajectory groups (NRI = 0.189; 95% confidence interval: [0.171, 0.210]). CONCLUSIONS: Statin adherence trajectory predicted future cardiovascular events better than measures categorizing PDC. Thus, adherence trajectories may be useful for targeting adherence interventions. Copyright (c) 2015 John Wiley & Sons, Ltd.

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Matlin OS, Kymes SM, Averbukh A, Choudhry NK, Brennan TA, Bunton A, Ducharme TA, Simmons PD, Shrank WH. Community pharmacy automatic refill program improves adherence to maintenance therapy and reduces wasted medication. American Journal of Managed Care 2015;21:785-91.Abstract

OBJECTIVES: Automatic prescription refill programs are a popular means of improving medication adherence. A concern is the potential for prescription drug wastage and unnecessary healthcare spending. We evaluated the impact of an automatic refill program on patterns of medication use. STUDY DESIGN: Retrospective propensity score matched cohort study with multivariable generalized linear modeling. METHODS: The setting of the study was a pharmacy benefit manager administering benefits for patients of retail pharmacies. Participants included patients on medication for chronic conditions; those receiving a 30-day supply (n = 153,964) and a 90-day supply (n = 100,394) were analyzed separately. The intervention was the automatic prescription refill program. Measures included medication possession ratio (MPR) and average days excess at the time of refill. The results are reported across 11 therapeutic classes. RESULTS: Overall, patients receiving 30-day supplies of medication in the automatic refill program had an MPR that was 3 points higher than those not in the refill program; among those receiving 90-day fills and in the refill program, the MPR was 1.4 points higher (P < .001 for both 30- and 90-day fills). The MPR was higher for members in the refill program across all therapeutic classes. Limiting our analysis to members receiving more than 365 days of medication, we found that patients who received 30-day fills and enrolled in the automatic refill program had 2.5 fewer days' oversupply than those in the control group, whereas automatic refill patients receiving 90-day supplies had 2.18 fewer days' oversupply than the controls (P < .001 for both 30- and 90-day fills). CONCLUSIONS: For this pharmacy provider, automatic refill programs result in improved adherence without adding to medication oversupply.

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Ito K, Avorn J, Shrank WH, Toscano M, Spettel C, Brennan T, Choudhry NK. Long-term cost-effectiveness of providing full coverage for preventive medications after myocardial infarction. Circulation Cardiovascular Quality and Outcomes 2015;8:252-9.Abstract

BACKGROUND: Adherence to drugs that are prescribed after myocardial infarction remains suboptimal. Although eliminating patient cost sharing for secondary prevention increases adherence and reduces rates of major cardiovascular events, the long-term clinical and economic implications of this approach have not been adequately evaluated. METHODS AND RESULTS: We developed a Markov model simulating a hypothetical cohort of commercially insured patients who were discharged from the hospital after myocardial infarction. Patients received beta-blockers, renin-angiotensin system antagonists, and statins without cost sharing (full coverage) or at the current level of insurance coverage (usual coverage). Model inputs were extracted from the Post Myocardial Infarction Free Rx Event and Economic Evaluation trial and other published literature. The main outcome was an incremental cost-effectiveness ratio as measured by cost per quality-adjusted life year gained. Patients receiving usual coverage lived an average of 9.46 quality-adjusted life years after their event and incurred costs of $171,412. Patients receiving full coverage lived an average of 9.60 quality-adjusted life years and incurred costs of $167,401. Compared with usual coverage, full coverage would result in greater quality-adjusted survival (0.14 quality-adjusted life years) and less resource use ($4011) per patient. Our results were sensitive to alterations in the risk reduction for post-myocardial infarction events from full coverage. CONCLUSIONS: Providing full prescription drug coverage for evidence-based pharmacotherapy to commercially insured post-myocardial infarction patients has the potential to improve health outcomes and save money from the societal perspective over the long-term. CLINICAL TRIAL REGISTRATION INFORMATION: https://www.clinicaltrials.gov. Unique identifier: NCT00566774.

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Najafzadeh M, Andersson K, Shrank WH, Krumme AA, Matlin OS, Brennan T, Avorn J, Choudhry NK. Cost-effectiveness of novel regimens for the treatment of hepatitis C virus. Annals of Internal Medicine 2015;162:407-19.Abstract

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.

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Najafzadeh M, Schneeweiss S, Choudhry N, Bykov K, Kahler KH, Martin DP, Gagne JJ. A unified framework for classification of methods for benefit-risk assessment. Value in Health 2015;18:250-9.Abstract

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.

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Wang B, Choudhry NK, Gagne JJ, Landon J, Kesselheim AS. Availability and utilization of cardiovascular fixed-dose combination drugs in the United States. American Heart Journal 2015;169:379-386 e1.Abstract

BACKGROUND: Solid clinical evidence supports the effectiveness and safety of multiple drugs in treating diabetes, dyslipidemia, and hypertension, and numerous fixed-dose combination products (FDCs) containing such drugs have been developed for patients with more severe forms of these diseases. We sought to evaluate the extent to which utilization of treatment combinations for these conditions corresponded to the availability of FDCs. METHODS: Using claims data from a large national commercial insurer, we identified 2 cohorts of patients: those who filled multiple single-agent drugs to treat diabetes, dyslipidemia, and hypertension in 2012, and those who used FDCs containing these products during the same period. We determined the fill rate of single-agent pairs and FDCs, availability of FDCs for the most frequently filled single-agent and drug class pairs, and the number of conditions treated by frequently filled single-agent pairs and FDCs. RESULTS: During our study period, 848,082 patients filled prescriptions for 3,248 unique single-agent pairs (mean 4.7 per patient, standard deviation [SD] 5.0); and 568,923 patients received prescriptions for 43 unique FDCs (mean 1.1 per patient, SD 0.3). Three (15%) of the 20 most frequently filled single-agent pairs were available as FDCs, whereas 9 (45%) of the 20 most frequently filled drug class pairs were available as FDCs. Nearly all of the frequently filled FDCs had lower fill rates than the most frequently filled single-agent pairs. CONCLUSIONS: Utilization of drug combinations to treat cardiovascular conditions does not correspond well with availability of FDCs containing these agents. A concerted set of strategies should be implemented to streamline the development of useful combination products, including expedited approval pathways and increased investment in formulation studies.

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Sarpatwari A, Choudhry NK, Avorn J, Kesselheim AS. Paying physicians to prescribe generic drugs and follow-on biologics in the United States. PLoS Medicine 2015;12:e1001802.Abstract

Aaron Kesselheim and colleagues examine potential strategies to promote greater prescribing of generic drugs and follow-on biologics.

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Kim SC, Schneeweiss S, Choudhry N, Liu J, Glynn RJ, Solomon DH. Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study. American Journal of Medicine 2015;128:653 e7-653 e16.Abstract

BACKGROUND: Hyperuricemia and gout are associated with an increased risk of cardiovascular disease (CVD). It is unknown whether treating hyperuricemia with xanthine oxidase inhibitors (XOIs), including allopurinol and febuxostat, modifies cardiovascular risks. METHODS: We used US insurance claims data to conduct a cohort study among gout patients, comparing XOI initiators with non-users with hyperuricemia defined as serum uric acid level >/=6.8 mg/dL. We calculated incidence rates of a composite nonfatal cardiovascular outcome that included myocardial infarction, coronary revascularization, stroke, and heart failure. Propensity score (PS)-matched Cox proportional hazards regression compared the risk of composite cardiovascular endpoint in XOI initiators vs those with untreated hyperuricemia, controlling for baseline confounders. In a subgroup of patients with uric acid levels available, PS-matched Cox regression further adjusted for baseline uric acid levels. RESULTS: There were 24,108 PS-matched pairs with a mean age of 51 years and 88% male. The incidence rate per 1000 person-years for composite CVD was 24.1 (95% confidence interval [CI] 22.6-26.0) in XOI initiators and 21.4 (95% CI, 19.8-23.2) in the untreated hyperuricemia group. The PS-matched hazard ratio for composite CVD was 1.16 (95% CI, 0.99-1.34) in XOI initiators vs those with untreated hyperuricemia. In subgroup analyses, the PS-matched hazard ratio for composite CVD adjusted for serum uric acid levels was 1.10 (95% CI, 0.74-1.64) among XOI initiators. CONCLUSIONS: Among patients with gout, initiation of XOI was not associated with an increased or decreased cardiovascular risk compared with those with untreated hyperuricemia. Subgroup analyses adjusting for baseline uric acid levels also showed no association between XOI and cardiovascular risk.

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Kulik A, Bykov K, Choudhry NK, Bateman BT. Non-steroidal anti-inflammatory drug administration after coronary artery bypass surgery: utilization persists despite the boxed warning. Pharmacoepidemiology and Drug Safety 2015;24:647-53.Abstract

PURPOSE: In 2005, the US Food and Drug Administration (FDA) issued a boxed warning against the administration of non-steroidal anti-inflammatory drugs (NSAIDs) after coronary artery bypass graft (CABG) surgery because of cardiovascular safety concerns. We assessed utilization rates before and after the advisory and evaluated predictors of NSAID administration following CABG. METHODS: We assembled a cohort of 277,576 patients who underwent CABG from 2004 to 2010. Temporal trends in NSAID exposure were evaluated, and predictors of postoperative NSAID use were identified using generalized estimating equations. RESULTS: Over the study period, 92,938 CABG patients (33.5%) received NSAIDs following surgery. The frequency of NSAID administration declined steadily over time, from a peak of 38.9% in 2004 to a low of 29.0% in 2010 (p < 0.0007). Ketorolac was the most frequent NSAID prescribed, commonly on the first postoperative day. Surgery performed after the boxed warning was independently associated with a 20% lower odds of NSAID administration [odds ratio (OR): 0.80; p = 0.0003]. Other factors that predicted a lower odds of NSAID use following surgery included a history of renal disease (OR: 0.33; p < 0.0001) and liver disease (OR: 0.66; p < 0.0001), and the need for concurrent valve surgery (OR: 0.78; p < 0.0001). A mammary graft at the time of surgery increased the odds of NSAID administration (OR: 1.23; p < 0.0001). CONCLUSIONS: The frequency of NSAID administration after CABG has declined since the FDA advisory, yet many patients continue to receive them in recent years. Our data highlight the need for future research initiatives to further define the risks associated with NSAID use in this population.

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Gagne JJ, Polinski JM, Rassen JA, Fischer MA, Seeger JD, Franklin JM, Liu J, Schneeweiss S, Choudhry NK. Selective Serotonin Reuptake Inhibitor Use and Perioperative Bleeding and Mortality in Patients Undergoing Coronary Artery Bypass Grafting: A Cohort Study. Drug Safety 2015;Abstract

INTRODUCTION: Several small studies have reported inconsistent findings about the safety of selective serotonin reuptake inhibitors (SSRIs) among patients undergoing coronary artery bypass grafting (CABG). We sought to investigate post-CABG bleeding and mortality outcomes related to antidepressant exposure. METHODS: We identified patients who underwent CABG between 2004 and 2008 in the Premier Perspective Comparative Database. We determined whether they received SSRIs, other antidepressants, or no antidepressants on any pre-CABG hospital day and used Cox proportional hazards models to compare bleeding and mortality rates among the exposure groups while adjusting for potential confounders based on administrative data, pre-CABG charge codes, and discharge diagnosis codes. RESULTS: We identified 132,686 eligible patients: 7112 exposed to SSRIs, 1905 exposed to other antidepressants, and 123,668 unexposed. As compared with no exposure, neither SSRIs (hazard ratio [HR] 0.98; 95 % confidence interval [CI] 0.90-1.07) nor other antidepressants (HR 1.11; 95 % CI 0.96-1.28) increased major bleeds, and neither SSRIs (HR 0.93; 95 % CI 0.80-1.07) nor other antidepressants (HR 0.84; 95 % CI 0.62-1.14) increased mortality. Both SSRIs (HR 1.14; 95 % CI 1.10-1.18) and other antidepressants (HR 1.11; 95 % CI 1.03-1.19) were associated with a slight increase in receipt of one or more packed red blood cell (pRBC) units, but neither were associated with substantial increases in receipt of three or more pRBC units (HR 1.06; 95 % CI 0.96-1.17 for SSRIs; HR 1.09; 95 % CI 0.91-1.31 for other antidepressants). CONCLUSION: In this large cohort study, neither SSRIs nor other antidepressants were associated with elevated rates of major bleed, or in-hospital mortality.

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Polinski JM, Kesselheim AS, Seeger JD, Connolly JG, Choudhry NK, Shrank WH. A cross-national comparison of 17 countries' insulin glargine drug labels. Pharmacoepidemiology and Drug Safety 2015;24:159-65.Abstract

PURPOSE: Type 2 diabetes mellitus has reached epidemic proportions worldwide. Many patients with type 2 diabetes mellitus will require insulin, and the evidence-based use of insulin is described in the prescription drug label. Product labels in different countries may provide inconsistent information. We evaluated the variability in drug label content for one brand of basal insulin across diverse settings. METHODS: We examined the drug label content pertinent to effective and safe use of insulin glargine across 17 countries: Abu Dhabi (United Arab Emirates), Argentina, Brazil, Canada, China, Germany, Israel, Italy, Japan, Mexico, Russia, Saudi Arabia, South Korea, Spain, Turkey, UK, and the USA. We compared label characteristics in settings where drug labels were governed by a local regulatory authority versus countries where labels were administered by a regional body or adopted from another locale. RESULTS: All 17 labels cautioned that providers should consider age, illness, diet, and exercise when prescribing. Only two (12%) described care of the fasting patient. Caution was urged for patients with renal or hepatic impairment in 16 (94%) labels. Four (24%) did not describe responses to missed doses, and five (29%) failed to recommend patient counseling about the risk of hypoglycemia. Labels emerging from regional or adopted regulatory bodies reported fewer patients in efficacy studies than did labels from settings with their own drug regulatory agencies (365 +/- 0 patients vs. 3560 +/- 2938, p = 0.04). CONCLUSIONS: There is substantial variation in the content of drug labels for glargine, which may lead to international inconsistency in quality of care for diabetic patients.

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Kesselheim AS, Huybrechts KF, Choudhry NK, Fulchino LA, Isaman DL, Kowal MK, Brennan TA. Prescription drug insurance coverage and patient health outcomes: a systematic review. American Journal of Public Health 2015;105:e17-30.Abstract

Previous reviews have shown that changes in prescription drug insurance benefits can affect medication use and adherence. We conducted a systematic review of the literature to identify studies addressing the association between prescription drug coverage and health outcomes. Studies were included if they collected empirical data on expansions or restrictions of prescription drug coverage and if they reported clinical outcomes. We found 23 studies demonstrating that broader prescription drug insurance reduces use of other health care services and has a positive impact on patient outcomes. Coverage gaps or caps on drug insurance generally led to worse outcomes. States should consider implementing the Affordable Care Act expansions in drug coverage to improve the health of low-income patients receiving state-based health insurance.

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