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.
Abstract Objectives Recent research suggests that rheumatoid arthritis increases the risk of venous thromboembolism. This study compared the risk of venous thromboembolism in patients with newly ...diagnosed rheumatoid arthritis initiating a biologic disease-modifying antirheumatic drug (DMARD) with those initiating methotrexate or a nonbiologic DMARD. Methods We conducted a population-based cohort study using US insurance claims data (2001-2012). Three mutually exclusive, hierarchical DMARD groups were used: (1) a biologic DMARD with and without nonbiologic DMARDs; (2) methotrexate without a biologic DMARD; or (3) nonbiologic DMARDs without a biologic DMARD or methotrexate. We calculated the incidence rates of venous thromboembolism. Cox proportional hazard models stratified by propensity score (PS) deciles after asymmetric PS trimming were used for 3 pairwise comparisons, controlling for potential confounders at baseline. Results We identified 29,481 patients with rheumatoid arthritis with 39,647 treatment episodes. From the pairwise comparison after asymmetric PS trimming, the incidence rate of hospitalization for venous thromboembolism per 1000 person-years was 5.5 in biologic DMARD initiators versus 4.4 in nonbiologic DMARD initiators and 4.8 in biologic DMARD initiators versus 3.5 in methotrexate initiators. The PS decile-stratified hazard ratio of venous thromboembolism associated with biologic DMARDs was 1.83 (95% confidence interval CI, 0.91-3.66) versus nonbiologic DMARDs and 1.39 (95% CI, 0.73-2.63) versus methotrexate. The hazard ratio of venous thromboembolism in biologic DMARD initiators was the highest in the first 180 days versus nonbiologic DMARD initiators (2.48; 95% CI, 1.14-5.39) or methotrexate initiators (1.80; 95% CI, 0.90-3.62). Conclusions The absolute risk for venous thromboembolism was low in patients with newly diagnosed rheumatoid arthritis. Initiation of a biologic DMARD seems to be associated with an increased short-term risk of hospitalization for venous thromboembolism compared with initiation of a nonbiologic DMARD or methotrexate.
Background Identification of patients at high risk of death is critical for appropriate management of patients and health care resources. The impact of repeated heart failure (HF) hospitalization on ...mortality has not been studied for a large community population with HF. We aimed to characterize survival of patients in relation to the number of HF hospitalizations. Method Using the health care utilization databases, we identified a cohort of patients with a first hospitalization for HF among all residents of British Columbia between 2000 and 2004. Survival time was measured after patients' first and each subsequent HF hospitalization. Kaplan-Meier cumulative mortality curves were constructed after each subsequent HF hospitalization. Hazard ratios for the number of HF hospitalizations were estimated using a multivariate Cox regression adjusting for major comorbidities. Results Of 14 374 patients hospitalized for HF, 7401 died during the 24 766 person-years of follow-up. Mortality significantly increased after each HF hospitalization. After adjusting for age, sex, and major comorbidities, the number of HF hospitalizations was a strong predictor of all-cause death. Median survival after the first, second, third, and fourth hospitalization was 2.4, 1.4, 1.0, and 0.6 years. Advanced age, renal disease, and history of cardiac arrest attenuated the impact of the number of HF hospitalizations. Conclusions The number of HF hospitalizations is a strong predictor of mortality in community HF patients. This simple predictor of mortality in HF patients should help triage management and resources for HF and trigger patient planning for prognosis.
Abstract Background Dabigatran, rivaroxaban, and apixaban have been approved for use in patients with atrial fibrillation based upon randomized trials demonstrating their comparable or superior ...efficacy and safety relative to warfarin. Little is known about their adoption into clinical practice, whether utilization is consistent with the controlled trials on which their approval was based, and how their use has affected health spending for patients and insurers. Methods We used medical and prescription claims data from a large insurer to identify patients with nonvalvular atrial fibrillation who were prescribed an oral anticoagulant in 2010-2013. We plotted trends in medication initiation over time, assessed corresponding insurer and patient out-of-pocket spending, and evaluated the cumulative number and cost of anticoagulants. We identified predictors of novel anticoagulant initiation using multivariable logistic models. Finally, we estimated the difference in total drug expenditures over 6 months for patients initiating warfarin versus a novel anticoagulant. Results There were 6893 patients with atrial fibrillation that initiated an oral anticoagulant during the study period. By the end of the study period, novel anticoagulants accounted for 62% of new prescriptions and 98% of anticoagulant-related drug costs. Female sex, lower household income, and higher CHADS2 , CHA2 DS2 -VASC, and HAS-BLED scores were significantly associated with lower odds of receiving a novel anticoagulant ( P <.001 for each). Average combined patient and insurer anticoagulant spending in the first 6 months after initiation was more than $900 greater for patients initiating a novel anticoagulant. Conclusions This study demonstrates rapid adoption of novel anticoagulants into clinical practice, particularly among patients with lower CHADS2 and HAS-BLED scores, and high health care cost consequences. These findings provide important directions for future comparative and cost-effectiveness research.
Abstract Objective Six oral medication classes have been approved by the Food and Drug Administration for the treatment of type 2 diabetes. Although all of these agents effectively lower blood ...glucose, the evidence supporting their impact on other clinical events is variable. There also are substantial cost differences between agents. We aimed to evaluate temporal trends in the use of specific drugs for the initial management of type 2 diabetes and to estimate the economic consequences of non-recommended care. Methods We studied a cohort of 254,973 patients, aged 18 to 100 years, who were newly initiated on oral hypoglycemic monotherapy between January 1, 2006, and December 31, 2008, by using prescription claims data from a large pharmacy benefit manager. Linear regression models were used to assess whether medication initiation patterns changed over time. Multivariate logistic regression models were constructed to identify independent predictors of receiving initial therapy with metformin. We then measured the economic consequences of prescribing patterns by drug class for both patients and the insurer. Results Over the course of the study period, the proportion of patients initially treated with metformin increased from 51% to 65%, whereas those receiving sulfonylureas decreased from 26% to 18% ( P <.001 for both). There was a significant decline in the use of thiazolidinediones (20.1%-8.3%, P <.001) and an increase in prescriptions for dipeptidyl peptidase-4 inhibitors (0.4%-7.3%, P <.001). Younger patients, women, and patients receiving drug benefits through Medicare were least likely to initiate treatment with metformin. Combined patient and insurer spending for patients who were initiated on alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, or dipeptidyl peptidase-4 inhibitors was $677 over a 6-month period compared with $116 and $118 for patients initiated on metformin or a sulfonylurea, respectively, a cost difference of approximately $1120 annually per patient. Conclusion Approximately 35% of patients initiating an oral hypoglycemic drug did not receive recommended initial therapy with metformin. These practice patterns also have substantial implications for health care spending.
Abstract Background Patient nonadherence to prescribed medication is common and limits the effectiveness of treatment for many conditions. Most adherence studies evaluate behavior only among patients ...who have filled a first prescription. The advent of electronic prescribing (e-prescribing) systems provides the opportunity to track initial prescriptions and identify nonadherence that may have previously been undetected. Methods We analyzed e-prescribing data and filled claims for all patients with CVS Caremark (Woonsocket, RI) drug coverage who received e-prescriptions from the iScribe e-prescribing system in calendar 2008. We matched e-prescriptions with filled claims by using data on the drug name, date of e-prescription, and date of filled claims, allowing up to 180 days for patients to fill e-prescriptions. We evaluated the rate of primary nonadherence to newly prescribed medications across multiple characteristics of patients, prescribers, and prescriptions and developed multivariable models to identify predictors of nonadherence. Results We identified 423,616 e-prescriptions for new medications, with 3634 prescribers and 280,081 patients. The primary nonadherence rate was 24.0%. Several factors were associated with nonadherence to e-prescriptions, including nonformulary status of medications (odds ratio OR 1.31 compared with preferred medications; 95% confidence interval CI, 1.26-1.36; P <. 001) and residence in a low-income ZIP code (OR 1.23 compared with high-income ZIP code; 95% CI, 1.17-1.30; P <. 001) Nonadherence occurred less often when e-prescriptions were transmitted directly to the pharmacy rather than printed to give to patients (OR 0.54; 95% CI, 0.52-0.57; P <. 001). Conclusion 24% of e-prescriptions for new medications were not filled. Our results suggest that interventions to address economic barriers and increase electronic integration in the healthcare system may be promising approaches to improve medication adherence.
Abstract Clopidogrel is a pro-drug that requires activation by the cytochrome P450 (CYP) enzyme system. Patients receiving clopidogrel are often treated with selective serotonin reuptake inhibitors ...(SSRIs) for co-existing depression. SSRIs that inhibit the CYP2C19 enzyme have the potential to reduce the effectiveness of clopidogrel. Using 5 US databases (1998-2013), we conducted a cohort study of adults who initiated clopidogrel while being treated with either an SSRI that inhibits CYP2C19 (fluoxetine and fluvoxamine) or a non-inhibiting SSRI. Patients were matched by propensity score and followed for as long as they were exposed to both clopidogrel and the index SSRI group (primary analysis) or for 180 days following clopidogrel initiation (sensitivity analysis). Outcomes included a composite ischemic event (myocardial infarction, ischemic stroke, or a revascularization procedure) and a composite major bleeding event (gastrointestinal bleed or hemorrhagic stroke). The final PS-matched cohort comprised 9,281 clopidogrel initiators on CYP2C19-inhibiting SSRIs and 44,278 clopidogrel initiators on a non-inhibiting SSRIs. As compared to those treated with a non-inhibiting SSRI, patients on a CYP2C19-inhibiting SSRI had an increased risk of ischemic events (hazard ratio (HR), 1.12; 95% confidence interval (CI), 1.01 to 1.24), which was more pronounced in patients 65 years of age and older (HR, 1.22; 95% CI, 1.00 to 1.48). The HR for major bleeding was 0.76 (95% CI, 0.50 to 1.17). In conclusion, the findings from this large, population-based study suggest that being treated with a CYP2C19-inhibiting SSRI when initiating clopidogrel may be associated with slight decrease in effectiveness of clopidogrel.
Objectives The aim of this study was to evaluate the impact of reductions in statin and clopidogrel copayments on cardiovascular resource utilization, major coronary events, and insurer spending. ...Background Copayments are widely used to contain health spending but cause patients to reduce their use of essential cardiovascular medications. Reducing copayments for post–myocardial infarction secondary prevention has beneficial effects, but the impact of this strategy for lower risk patients and other drugs remains unclear. Methods An evaluation was conducted of health care spending and resource use by a large self-insured employer that reduced statin copayments for patients with diabetes or vascular disease and reduced clopidogrel copayments for all patients prescribed this drug. Eligible individuals in the intervention company (n = 3,513) were compared with a control group from other companies without such a policy (n = 49,803). Analyses were performed using segmented regression models with generalized estimating equations. Results Lowering copayments was associated with significant reductions in rates of physician visits (relative change: statin users 0.80; 95% confidence interval CI: 0.57 to 0.98; clopidogrel users: 0.87; 95% CI: 0.59 to 0.96) and hospitalizations and emergency department admissions (relative change: statin users 0.90; 95% CI: 0.80 to 0.92; clopidogrel users: 0.89; 95% CI: 0.74 to 0.90) although not major coronary events. Patient out-of-pocket spending for drugs and other medical services decreased (relative change: statin users 0.79; 95% CI: 0.75 to 0.83; clopidogrel users 0.74; 95% CI: 0.66 to 0.82). Providing more generous coverage did not increase overall spending (relative change: statin users 1.03; 95% CI: 0.97 to 1.09; clopidogrel users 0.94; 95% CI: 0.87 to 1.03). Conclusions Lowering copayments for statins and clopidogrel was associated with reductions in health care resource use and patient out-of-pocket spending. The policy appeared cost neutral with respect to overall health spending.
Background Clinical trials have shown that tumor necrosis factor-α antagonists (TNFAs) confer little benefit, and some may cause potential harm in advanced heart failure (HF). Although TNFAs had ...significant benefits in treating rheumatoid arthritis (RA), little is known whether the drugs pose an increased risk of HF in older patients with RA. Methods A cohort study was conducted using data from Medicare and drug benefit programs in 2 states (1994-2004). We identified patients with RA aged ≥65 who received TNFA or methotrexate (MTX). The cohort was divided into patients with and without previous HF. We considered demographic variables, cardiovascular risk factors, RA severity-related measures, and other comorbidities. The primary end point was hospitalization with HF. We used stratified Cox proportional hazards regression to estimate the adjusted effect of TNFAs on HF hospitalization. Results The cohort consisted of 1,002 TNFA users and 5,593 MTX users. There were 59 HF admissions during 1,680 person-years of TNFA use and 227 HF admissions during 10,623 person-years of MTX use. Comparing TNFA with MTX users, the adjusted hazard ratio for HF hospitalization was 1.70 (95% confidence interval 1.07-2.69). We found similar results in patients with and without previous HF. Among patients with previous HF, the adjusted hazard ratio for death was 4.19 (95% confidence interval 1.48-11.89). Conclusions TNFAs may increase the risk of both first hospitalization and exacerbation of HF in elderly patients with RA. The potential for residual confounding in our study cannot be ruled out; larger and more detailed studies are needed to confirm the findings.
Objective The incidence of hospital-acquired Clostridium difficile infection (CDI) has increased rapidly over the past decade; patients undergoing major surgery, including coronary artery bypass ...grafting (CABG), are at particular risk. Intravenous vancomycin exposure has been identified as an independent risk factor for CDI, but this is controversial. It is not known whether vancomycin administered for surgical site infection prophylaxis increases the risk of CDI. Methods Using data from the Premier Perspective Comparative Database, we assembled a cohort of 69,807 patients undergoing CABG surgery between 2004 and 2010 who received either a cephalosporin alone (65.1%) or a cephalosporin plus vancomycin (34.9%) on the day of surgery. Patients were observed for CDI until discharge from the index hospitalization. In these groups, we evaluated the comparative rate of postoperative CDI with Cox models; confounding was addressed using propensity scores. Results In all, 77 (0.32%) of the 24,393 patients receiving a cephalosporin plus vancomycin and 179 (0.39%) of the 45,414 patients receiving a cephalosporin alone had postoperative CDI (unadjusted hazard ratio HR, 0.73; 95% confidence interval CI, 0.56-0.95). After adjusting for confounding variables with either propensity score matching or stratification, there was no meaningful association between adjuvant vancomycin exposure and postoperative CDI (HR, 0.85; 95% CI, 0.61-1.19; and HR, 0.85; 95% CI, 0.63-1.15, respectively). Results of multiple sensitivity analyses were similar to the main findings. Conclusions After adjustment for patient and surgical characteristics, a short course of prophylactic vancomycin was not associated with an increased risk of CDI among patients undergoing CABG surgery.
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