Use of Low-Density Lipoprotein-Lowering Therapies Before and After PCSK9 Inhibitor Initiation.

Background Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are used to reduce low-density lipoprotein (LDL) cholesterol. PCSK9i use after initiation, as well as persistence with or alterations to other LDL-lowering therapy after PCSK9i initiation, is not well understood. Methods and Results We conducted a retrospective study of alirocumab or evolocumab (PCSK9i) new users from July 2015 to December 2017 in the MarketScan Early View database of US commercial insurance beneficiaries. We determined the prevalence of PCSK9i interruption (≥30-day gap in supply) and LDL-lowering therapy use in the year after PCSK9i initiation. The average age of 6151 patients initiating PCSK9i therapy was 63 years, 44.4% were women, and 76.8% had atherosclerotic cardiovascular disease. Overall, 52.2% (95% CI, 50.8%-53.7%) of patients had an interruption in PCSK9i therapy in the first year after treatment initiation and 62.5% remained on PCSK9i therapy at 1-year postinitiation. Also, 27.7% of patients were taking a statin at the time of PCSK9i initiation, with only 22.4% on statin therapy at 1 year after PCSK9i initiation. Ezetimibe use decreased from 20.9% at the time of PCSK9i initiation to 12.0% a year later. By 1 year after PCSK9i initiation, 44.0% of patients had experienced an interruption in all LDL-lowering therapies, and 26.6% were no longer on any LDL-lowering therapies. Conclusions After PCSK9i initiation, statins were often discontinued, whereas more than half of patients experienced an interruption in PCSK9i therapy. These results suggest that many new PCSK9i users may remain at high risk for cardiovascular events because of interruptions in LDL-lowering therapy.

Excess Risk for Atherosclerotic Cardiovascular Outcomes Among US Adults With HIV in the Current Era.

Background In the 2000s, adults with HIV had a higher risk for atherosclerotic cardiovascular disease (ASCVD) compared with those without HIV. There is uncertainty if this excess risk still exists in the United States given changes in antiretroviral therapies and increased statin use. Methods and Results We compared the risk for ASCVD events between US adults aged ≥19 years with and without HIV who had commercial or supplemental Medicare health insurance between January 1, 2011, and December 31, 2016. Beneficiaries with HIV (n=82 426) were frequency matched 1:4 on age, sex, and calendar year to those without HIV (n=329 704). Beneficiaries with and without HIV were followed up through December 31, 2016, for ASCVD events, including myocardial infarction, stroke, and lower extremity artery disease hospitalizations. Most beneficiaries were aged <55 years (79%) and men (84%). Over a median follow-up of 1.6 years (maximum, 6 years), there were 3287 ASCVD events, 2190 myocardial infarctions, 891 strokes, and 322 lower extremity artery disease events. The rate per 1000 person-years among beneficiaries with and without HIV was 5.53 and 3.49 for ASCVD, respectively, 3.58 and 2.34 for myocardial infarction, respectively, 1.49 and 0.94 for stroke, respectively, and 0.65 and 0.31 for lower extremity artery disease hospitalizations, respectively. The multivariable-adjusted hazard ratio (95% CI) for ASCVD, myocardial infarction, stroke, and lower extremity artery disease hospitalizations comparing beneficiaries with versus without HIV was 1.29 (1.18-1.40), 1.26 (1.13-1.39), 1.30 (1.11-1.52), and 1.46 (1.11-1.92), respectively. Conclusions Adults with HIV in the United States continue to have a higher ASCVD risk compared with their counterparts without HIV.

Association of Region and Hospital and Patient Characteristics With Use of High-Intensity Statins After Myocardial Infarction Among Medicare Beneficiaries.

Importance: High-intensity statin use after myocardial infarction (MI) varies by patient characteristics, but little is known about differences in use by hospital or region. Objective: To explore the relative strength of associations of region and hospital and patient characteristics with high-intensity statin use after MI. Design, Setting, and Participants: This retrospective cohort analysis used Medicare administrative claims and enrollment data to evaluate fee-for-service Medicare beneficiaries 66 years or older who were hospitalized for MI from January 1, 2011, through June 30, 2015, with a statin prescription claim within 30 days of discharge. Data were analyzed from January 4, 2017, through May 12, 2019. Exposures: Beneficiary characteristics were abstracted from Medicare data. Hospital characteristics were obtained from the 2014 American Hospital Association Survey and Hospital Compare quality metrics. Nine regions were defined according to the US Census. Main Outcomes and Measures: Intensity of the first statin claim after discharge characterized as high (atorvastatin calcium, 40-80 mg, or rosuvastatin calcium, 20-40 mg/d) vs low to moderate (all other statin types and doses). Trends in high-intensity statins were examined from 2011 through 2015. Associations of region and beneficiary and hospital characteristics with high-intensity statin use from January 1, 2014, to June 15, 2015, were examined using Poisson distribution mixed models. Results: Among the 139 643 fee-for-service beneficiaries included (69 968 men [50.1%] and 69 675 women [49.9%]; mean [SD] age, 76.7 [7.5] years), high-intensity statin use overall increased from 23.4% in 2011 to 55.6% in 2015, but treatment gaps persisted across regions. In models considering region and beneficiary and hospital characteristics, region was the strongest correlate of high-intensity statin use, with 66% higher use in New England than in the West South Central region (risk ratio [RR], 1.66; 95% CI, 1.47-1.87). Hospital size of at least 500 beds (RR, 1.15; 95% CI, 1.07-1.23), medical school affiliation (RR, 1.11; 95% CI, 1.05-1.17), male sex (RR, 1.10; 95% CI, 1.07-1.13), and patient receipt of a stent (RR, 1.35; 95% CI, 1.31-1.39) were associated with greater high-intensity statin use. For-profit hospital ownership, patient age older than 75 years, prior coronary disease, and other comorbidities were associated with lower use. Conclusions and Relevance: This study's findings suggest that geographic region is the strongest correlate of high-intensity statin use after MI, leading to large treatment disparities.

Medical Expenditures Among Medicare Beneficiaries with Statin-Associated Adverse Effects Following Myocardial Infarction.

PURPOSE: Compare medical expenditures among adults with statin-associated adverse effects (SAAE) and high statin adherence (HSA) following myocardial infarction (MI). METHODS: We analyzed expenditures in 2016 US dollars among Medicare beneficiaries with SAAE (n = 1741) and HSA (n = 55,567) who were ≥ 66 years of age and initiated moderate/high-intensity statins following an MI in 2007-2013. SAAE were identified through a claims-based algorithm, which included down-titrating statins and initiating ezetimibe, switching to ezetimibe monotherapy, having a rhabdomyolysis or antihyperlipidemic adverse event followed by statin down-titration or discontinuation, or switching between ≥ 3 statin types within 365 days following MI. HSA was defined by having a statin available to take for ≥ 80% of the days in the 365 days following MI. RESULTS: Expenditures among beneficiaries with SAAE and HSA were $40,776 (95% CI $38,329-$43,223) and $26,728 ($26,482-$26,974), respectively, in the 365 days following MI, and $34,238 ($31,396-$37,080) and $29,053 ($28,605-$29,500), respectively, for every year after the first 365 days. Multivariable-adjusted ratios comparing expenditures among beneficiaries with SAAE versus HSA in the first 365 days and after the first 365 days following MI were 1.51 (95% CI 1.43-1.59) and 1.23 (1.12-1.34), respectively. Inpatient and outpatient expenditures were higher among beneficiaries with SAAE versus HSA during and after the first 365 days following MI. Compared to beneficiaries with HSA, medication expenditures among those with SAAE were similar in the 365 days following MI, but higher afterwards. Other medical expenditures were higher among beneficiaries with SAAE versus HSA. CONCLUSION: SAAE are associated with increased expenditures following MI compared with HSA.

Titration to High-Intensity Statin Therapy Following Acute Myocardial Infarction in Patients With and Without Diabetes Mellitus.

BACKGROUND: Patients with diabetes mellitus (DM) have a high risk for cardiovascular disease (CVD) events after an acute myocardial infarction (AMI). High-intensity statins reduce CVD risk following AMI among patients with and without DM. METHODS: We determined the proportion of Medicare beneficiaries 66 to 75 years of age taking a low/moderate-intensity statin with (n = 6718) and without (n = 6414) DM who titrated to a high-intensity statin dosage (i.e., atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) following an AMI hospitalization in 2014-2015. All patients had a pharmacy claim for a statin fill within 365 days prior to, and within 30 days after their AMI hospitalization. We excluded beneficiaries without Medicare fee-for-service coverage including pharmacy benefits during the study period and those with a pharmacy claim for a high-intensity statin prior to their AMI. RESULTS: The first statin fill following hospital discharge was for a high-intensity dosage among 37.7% and 44.4% of patients with and without DM, respectively. After multivariable adjustment, the risk ratio (RR) for titrating to a high-intensity statin comparing patients with versus without DM was 1.01 (95% CI 0.96, 1.06). Among patients whose first statin fill post-AMI was for a low/moderate-intensity dosage, 7.5% of those with DM titrated to a high-intensity statin within 182 days, compared with 9.2% of those without DM (multivariable-adjusted RR 0.90 [95% CI 0.75, 1.08]). CONCLUSIONS: Most patients taking a low/moderate-intensity statin were not titrated to a high-intensity dosage following AMI irrespective of their diabetes status, potentially leaving substantial residual risk for recurrent CVD events.

Healthcare Utilization and Statin Re-Initiation Among Medicare Beneficiaries With a History of Myocardial Infarction.

BACKGROUND: Contact with the healthcare system represents an opportunity for individuals who discontinue statins to re-initiate treatment. To help identify opportunities for healthcare providers to emphasize the risk-lowering benefits accrued through restarting statins, we determined the types of healthcare utilization associated with statin re-initiation among patients with history of a myocardial infarction. METHODS AND RESULTS: Medicare beneficiaries with a statin pharmacy fill claim within 30 days of hospital discharge for a myocardial infarction in 2007 to 2012 (n=158 795) were followed for 182 days postdischarge to identify treatment discontinuation, defined as 60 continuous days without statins (n=24 461). Re-initiation was defined as a statin fill within 365 days of the discontinuation date (n=13 136). Using a case-crossover study design and each beneficiary as their own control, healthcare utilization during 0 to 14 days before statin re-initiation (case period) was compared with healthcare utilization 30 to 44 days before statin re-initiation (control period). The mean age of beneficiaries was 75.4 years; 52.8% were women and 81.9% were white. For routine healthcare utilization, the odds ratio (95% confidence interval) for statin re-initiation associated with lipid panel testing was 2.65 (1.93-3.65), outpatient primary care was 1.31 (1.23-1.40), and outpatient cardiologist care was 1.38 (1.28-1.50). For acute healthcare utilization, the odds ratio (95% confidence interval) for statin re-initiation associated with emergency department visits was 1.77 (1.31-2.40), coronary heart disease (CHD) hospitalizations was 3.16 (2.41-4.14) and non-coronary heart disease hospitalizations was 1.73 (1.49-2.01). CONCLUSIONS: The weaker association of routine versus acute healthcare utilization with statin re-initiation suggests missed opportunities to reinforce the importance of statin therapy for secondary prevention.

Development of algorithms for identifying fatal cardiovascular disease in Medicare claims.

BACKGROUND: Cause of death is often not available in administrative claims data. OBJECTIVE: To develop claims-based algorithms to identify deaths due to fatal cardiovascular disease (CVD; ie, fatal coronary heart disease [CHD] or stroke), CHD, and stroke. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) study data were linked with Medicare claims to develop the algorithms. Events adjudicated by REGARDS study investigators were used as the gold standard. Stepwise selection was used to choose predictors from Medicare data for inclusion in the algorithms. C-index, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were used to assess algorithm performance. Net reclassification index (NRI) was used to compare the algorithms with an approach of classifying all deaths within 28 days following hospitalization for myocardial infarction and stroke to be fatal CVD. RESULTS: Data from 2,685 REGARDS participants with linkage to Medicare, who died between 2003 and 2013, were analyzed. The C-index for discriminating fatal CVD from other causes of death was 0.87. Using a cut-point that provided the closest observed-to-predicted number of fatal CVD events, the sensitivity was 0.64, specificity 0.90, PPV 0.65, and NPV 0.90. The algorithms resulted in positive NRIs compared with using deaths within 28 days following hospitalization for myocardial infarction and stroke. Claims-based algorithms for discriminating fatal CHD and fatal stroke performed similarly to fatal CVD. CONCLUSION: The claims-based algorithms developed to discriminate fatal CVD events from other causes of death performed better than the method of using hospital discharge diagnosis codes.

Association of Prior Authorization and Out-of-pocket Costs With Patient Access to PCSK9 Inhibitor Therapy.

Importance: Although PCSK9 inhibitors (PCSK9i) were approved in 2015, their high cost has led to strict prior authorization practices and high copays, and use of PSCK9i in clinical practice has been low. Objective: To evaluate patient access to PCSK9i among those prescribed therapy. Design, Setting, and Participants: Using pharmacy transaction data, we evaluated 45 029 patients who were newly prescribed PCSK9i in the United States between August 1, 2015, and July 31, 2016. Main Outcomes and Measures: The proportion of PCSK9i prescriptions approved and abandoned (approved but unfilled); multivariable analyses examined factors associated with approval/abandonment including payor, prescriber specialty, pharmacy benefit manager, out-of-pocket cost (copay), clinical diagnoses, lipid-lowering medication use, and low-density lipoprotein cholesterol levels. Results: Of patients given an incident PCSK9i prescription, 51.2% were women, 56.6% were 65 years or older, and 52.5% had governmental insurance. Of the patients given a prescription, 20.8% received approval on the first day, and 47.2% ever received approval. Of those approved, 65.3% filled the prescription, resulting in 30.9% of those prescribed PCSK9i ever receiving therapy. After adjustment, patients who were older, male, and had atherosclerotic cardiovascular disease were more likely to be approved, but approval rates did not vary by patient low-density lipoprotein cholesterol level nor statin use. Other factors associated with drug approval included having government vs commercial insurance (odds ratio [OR], 3.3; 95% CI, 2.8-3.8), and those filled at a specialty vs retail pharmacy (OR, 1.96; 95% CI, 1.66-2.33). Approval rates varied nearly 3-fold among the top 10 largest pharmacy benefit managers. Prescription abandonment by patients was most associated with copay costs (C statistic, 0.86); with abandonment rates ranging from 7.5% for those with $0 copay to more than 75% for copays greater than $350. Conclusions and Relevance: In the first year of availability, only half of patients prescribed a PCSK9i received approval, and one-third of approved prescriptions were never filled owing to copay.

Statin Discontinuation, Reinitiation, and Persistence Patterns Among Medicare Beneficiaries After Myocardial Infarction: A Cohort Study.

BACKGROUND: Although the benefits of statins accrue over time, treatment discontinuation is common. Examining the patterns of statin discontinuation, reinitiation, and persistence after reinitiation among Medicare beneficiaries after hospital discharge for a myocardial infarction may help increase statin use in high-risk patients. METHODS AND RESULTS: Medicare beneficiaries with a statin fill claim within 30 days after hospital discharge for myocardial infarction in 2007 to 2012 (n=158 795) were followed for 182 days post-discharge to identify discontinuation, defined as 60 continuous days without statins available. Reinitiation, defined by a statin fill, was identified in the 365 days post-discontinuation. High persistence was defined as proportion of days covered ≥80% with ≥1 day of statin supply 182 days after reinitiation. Follow-up ended on December 31, 2014. In the 182 days after myocardial infarction hospital discharge, 15.4% of beneficiaries discontinued statins. Of this group, 53.7% reinitiated statins. On reinitiation, 27.1% changed statin type, 6.9% up-titrated intensity, 14.4% down-titrated intensity, and 66.0% had the same statin and intensity. In the 182 days after reinitiation, 45.8% had high persistence. Moderate- and high- versus low-intensity statins were associated with a lower risk for statin discontinuation (moderate intensity: relative risk [RR], 0.93; 95% confidence interval [CI], 0.89-0.96; high-intensity: RR, 0.95; 95% CI, 0.91-0.99). High persistence was less common after reinitiating high- versus low-intensity statins (RR, 0.80; 95% CI, 0.75-0.86), but no association was present for those reinitiating a moderate- versus low-intensity statin (RR, 0.95; 95% CI, 0.90-1.01). Down-titrating versus reinitiating the same statin intensity (RR, 1.10; 95% CI, 1.05-1.16) and reinitiating a different versus the same statin (RR, 1.10; 95% CI, 1.06-1.14) were associated with high persistence after treatment reinitiation. CONCLUSIONS: Although many people who discontinue a statin reinitiate treatment, statin persistence after reinitiation was low. Reinitiating therapy with moderate-intensity statins, down-titration, and using a different statin may promote persistence.

Adherence to High-Intensity Statins Following a Myocardial Infarction Hospitalization Among Medicare Beneficiaries.

Importance: High-intensity statins are recommended following myocardial infarction. However, patients may not continue taking this medication with high adherence. Objective: To estimate the proportion of patients filling high-intensity statin prescriptions following myocardial infarction who continue taking this medication with high adherence and to analyze factors associated with continuing a high-intensity statin with high adherence after myocardial infarction. Design, Setting, and Participants: Retrospective cohort study of Medicare patients following hospitalization for myocardial infarction. Medicare beneficiaries aged 66 to 75 years (n = 29 932) and older than 75 years (n = 27 956) hospitalized for myocardial infarction between 2007 and 2012 who filled a high-intensity statin prescription (atorvastatin, 40-80 mg, and rosuvastatin, 20-40 mg) within 30 days of discharge. Beneficiaries had Medicare fee-for-service coverage including pharmacy benefits. Exposures: Sociodemographic, dual Medicare/Medicaid coverage, comorbidities, not filling high-intensity statin prescriptions before their myocardial infarction (ie, new users), and cardiac rehabilitation and outpatient cardiologist visits after discharge. Main Outcomes and Measures: High adherence to high-intensity statins at 6 months and 2 years after discharge was defined by a proportion of days covered of at least 80%, down-titration was defined by switching to a low/moderate-intensity statin with a proportion of days covered of at least 80%, and low adherence was defined by a proportion of days covered less than 80% for any statin intensity without discontinuation. Discontinuation was defined by not having a statin available to take in the last 60 days of each follow-up period. Results: Approximately half of the beneficiaries were women and fourth-fifths were white. At 6 months and 2 years after discharge among beneficiaries 66 to 75 years of age, 17 633 (58.9%) and 10 308 (41.6%) were taking high-intensity statins with high adherence, 2605 (8.7%) and 3315 (13.4%) down-titrated, 5182 (17.3%) and 4727 (19.1%) had low adherence, and 3705 (12.4%) and 4648 (18.8%) discontinued their statin, respectively. The proportion taking high-intensity statins with high adherence increased between 2007 and 2012. African American patients, Hispanic patients, and new high-intensity statin users were less likely to take high-intensity statins with high adherence, and those with dual Medicare/Medicaid coverage and more cardiologist visits after discharge and who participated in cardiac rehabilitation were more likely to take high-intensity statins with high adherence. Results were similar among beneficiaries older than 75 years of age. Conclusions and Relevance: Many patients filling high-intensity statins following a myocardial infarction do not continue taking this medication with high adherence for 2 years postdischarge. Interventions are needed to increase high-intensity statin use and adherence after myocardial infarction.

Algorithms to Identify Statin Intolerance in Medicare Administrative Claim Data.

PURPOSE: To compare characteristics of patients with possible statin intolerance identified using different claims-based algorithms versus patients with high adherence to statins. METHODS: We analyzed 134,863 Medicare beneficiaries initiating statins between 2007 and 2011. Statin intolerance and discontinuation, and high adherence to statins, defined by proportion of days covered ≥80 %, were assessed during the 365 days following statin initiation. Definition 1 of statin intolerance included statin down-titration or discontinuation with ezetimibe initiation, having a claim for a rhabdomyolysis or antihyperlipidemic event followed by statin down-titration or discontinuation, or switching between ≥3 types of statins. Definition 2 included beneficiaries who met Definition 1 and those who down-titrated statin intensity. We also analyzed beneficiaries who met Definition 2 of statin intolerance or discontinued statins. RESULTS: The prevalence of statin intolerance was 1.0 % (n = 1320) and 5.2 % (n = 6985) using Definitions 1 and 2, respectively. Overall, 45,266 (33.6 %) beneficiaries had statin intolerance by Definition 2 or discontinued statins and 55,990 (41.5 %) beneficiaries had high adherence to statins. Compared with beneficiaries with high adherence to statins, those with statin intolerance and who had statin intolerance or discontinued statins were more likely to be female versus male, and black, Hispanic or Asian versus white. The multivariable adjusted odds ratio for statin intolerance by Definitions 1 and 2 comparing patients initiating high versus low/moderate intensity statins were 2.82 (95%CI: 2.42-3.29), and 8.58 (8.07-9.12), respectively, and for statin intolerance or statin discontinuation was 2.35 (2.25-2.45). CONCLUSIONS: Definitions of statin intolerance presented herein can be applied to analyses using administrative claims data.

Effects of Epoetin Alfa Titration Practices, Implemented After Changes to Product Labeling, on Hemoglobin Levels, Transfusion Use, and Hospitalization Rates.

BACKGROUND: Little is known about epoetin alfa (EPO) dosing at dialysis centers after implementation of the US Medicare prospective payment system and revision of the EPO label in 2011. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Approximately 412,000 adult hemodialysis patients with Medicare Parts A and B as primary payer in 2009 to 2012 to describe EPO dosing and hemoglobin patterns; of these, about 70,000 patients clustered in about 1,300 dialysis facilities to evaluate facility-level EPO titration practices and patient-level outcomes in 2012. PREDICTOR: Facility EPO titration practices when hemoglobin levels were <10 and >11g/dL (grouped treatment variable) determined from monthly EPO dosing and hemoglobin level patterns. OUTCOMES: Patient mean hemoglobin levels, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates using a facility-based analysis. MEASUREMENTS: Monthly EPO dose and hemoglobin level, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates. RESULTS: Monthly EPO doses declined across all hemoglobin levels, with the greatest decline in patients with hemoglobin levels < 10g/dL (July-October 2011). In 2012, nine distinct facility titration practices were identified. Across groups, mean hemoglobin levels differed slightly (10.5-10.8g/dL) but within-patient hemoglobin standard deviations were similar (∼0.68g/dL). Patients at facilities implementing greater dose reductions and smaller dose escalations had lower hemoglobin levels and higher transfusion rates. In contrast, patients at facilities that implemented greater dose escalations (and large or small dose reductions) had higher hemoglobin levels and lower transfusion rates. There were no clinically meaningful differences in all-cause or cause-specific hospitalization events across groups. LIMITATIONS: Possibly incomplete claims data; excluded small facilities and those without consistent titration patterns; hemoglobin levels reported monthly; inferred facility practice from observed dosing. CONCLUSIONS: Following prospective payment system implementation and labeling revisions, EPO doses declined significantly. Under the new label, facility EPO titration practices were associated with mean hemoglobin levels (but not standard deviations) and transfusion use, but not hospitalization rates.

Epoetin Alfa and Outcomes in Dialysis amid Regulatory and Payment Reform.

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia in patients with CKD, including those receiving dialysis, although clinical trials have identified risks associated with ESA use. We evaluated the effects of changes in dialysis payment policies and product labeling instituted in 2011 on mortality and major cardiovascular events across the United States dialysis population in an open cohort study of patients on dialysis from January 1, 2005, through December 31, 2012, with Medicare as primary payer. We compared observed rates of death and major cardiovascular events in 2011 and 2012 with expected rates calculated on the basis of rates in 2005-2010, accounting for differences in patient characteristics and influenza virulence. An abrupt decline in erythropoietin dosing and hemoglobin concentration began in late 2010. Observed rates of all-cause mortality, cardiovascular mortality, and myocardial infarction in 2011 and 2012 were consistent with expected rates. During 2012, observed rates of stroke, venous thromboembolic disease (VTE), and heart failure were lower than expected (absolute deviation from trend per 100 patient-years [95% confidence interval]: -0.24 [-0.08 to -0.37] for stroke, -2.43 [-1.35 to -3.70] for VTE, and -0.77 [-0.28 to -1.27] for heart failure), although non-ESA-related changes in practice and Medicare payment penalties for rehospitalization may have confounded the results. This initial evidence suggests that action taken to mitigate risks associated with ESA use and changes in payment policy did not result in a relative increase in death or major cardiovascular events and may reflect improvements in stroke, VTE, and heart failure.

Controlling confounding of treatment effects in administrative data in the presence of time-varying baseline confounders.

PURPOSE: Confounding, a concern in nonexperimental research using administrative claims, is nearly ubiquitous in claims-based pharmacoepidemiology studies. A fixed-length look-back window for assessing comorbidity from claims is common, but it may be advantageous to use all historical claims. We assessed how the strength of association between a baseline-identified condition and subsequent mortality varied by when the condition was measured and investigated methods to control for confounding. METHODS: For Medicare beneficiaries undergoing maintenance hemodialysis on 1 January 2008 (n = 222 343), we searched all Medicare claims, 1 January 2001 to 31 December 2007, for four conditions representing chronic and acute diseases, and classified claims by number of months preceding the index date. We used proportional hazard models to estimate the association between time of condition and subsequent mortality. We simulated a confounded comorbidity-exposure relationship and investigated an alternative method of adjustment when the association between the condition and mortality varied by proximity to follow-up start. RESULTS: The magnitude of the mortality hazard ratio estimates for each condition investigated decreased toward unity as time increased between index date and most recent manifestation of the condition. Simulation showed more biased estimates of exposure-outcome associations if proximity to follow-up start was not considered. CONCLUSIONS: Using all-available claims information during a baseline period, we found that for all conditions investigated, the association between a comorbid condition and subsequent mortality varied considerably depending on when the condition was measured. Improved confounding control may be achieved by considering the timing of claims relative to follow-up start.

Comparative changes in treatment practices and clinical outcomes following implementation of a prospective payment system: the STEPPS study.

BACKGROUND: The aim of the US dialysis Prospective Payment System bundle, launched in January 2011, was reduction and more accurate prediction of costs of services, whilst maintaining or improving patient care. Dialysis facilities could either adopt the bundle completely (100%) in the first year of launch, or phase-in (25%) over four years. Differences in practice patterns and patient outcomes were hypothesized to occur in facilities that phased-in 25% compared to those that did not. METHODS: Data are from STEPPS, a study of 51 small dialysis organization facilities designed to describe trends in dialytic treatment before and after bundle implementation. Baseline was defined as October-December 2010; follow-up as January-December 2011. Facility- and patient-level data were collected at enrollment and regularly thereafter. Cox proportional hazards and linear multi-level models were used to estimate the effect of opting-in 25% (vs. 100%) on practice patterns and clinical outcomes. RESULTS: 12 facilities (patient n = 346) opted-in 25% and 37 facilities (patient n = 1296) opted-in 100% to the dialysis bundle. At baseline, patients at 25% facilities were primarily covered by Medicare, were more likely to be black, and were receiving higher monthly epoetin alfa (EPO) doses. Throughout 2011, patients in 100% facilities received lower monthly EPO doses, and had lower mean hemoglobin concentrations; hospitalization and mortality rates were numerically lower in 25% facilities but not statistically different. CONCLUSIONS: The economic pressure for dialysis providers to work within an expanded composite rate bundle whilst maintaining patient care may be a driver of practice indicator outcomes. Additional investigations are warranted to more precisely estimate clinical outcomes in patients attending facilities enrolling into the bundle 100% relative to the previous fee-for-service framework.

Red blood cell transfusion, hyperkalemia, and heart failure in advanced chronic kidney disease.

PURPOSE: In recent years, the use of red blood cell (RBC) transfusion for the treatment of chronic kidney disease (CKD)-related anemia has increased. We used the OptumInsight medical claims database to study the association between receiving a transfusion and hyperkalemia and heart failure events. METHODS: Persons 18-64 years of age with diagnosed stage 4 or 5 CKD (not requiring dialysis) between 2006 and 2010 were followed until their first hospitalization or emergency room visit with a diagnosis of hyperkalemia or heart failure, termination of insurance coverage, or death. We used a case-only design and conditional logistic regression to estimate rate ratios (RR) and 95% confidence intervals (CIs) describing associations between RBC transfusion and the risks of hyperkalemia or heart failure. We used single (1:1) and variable (1:m) self-control matching intervals, with adjustment for time-varying confounders. RESULTS: Seven thousand eight hundred twenty-nine individuals met our inclusion criteria; two-thirds were age 50 years or older; 43% were women and 51% had diabetes. Rates of hyperkalemia and heart failure were 7.9/100 person-years (95%CI: 7.3, 8.5) and 16.3/100 person-years (95%CI: 15.5, 17.2), respectively. RBC transfusion was associated with an increased risk of both hyperkalemia (single interval matched RR = 12.0, 95%CI: 1.3, 109; multiple interval matched RR = 6.1, 95%CI: 2.5, 15.1) and heart failure (single interval matched RR = 1.7, 95%CI: 0.3, 9.2; multiple interval matched RR = 3.8, 95%CI: 1.4, 10.3). CONCLUSION: In patients with advanced CKD, RBC transfusion appears to be associated with an elevated risk of hyperkalemia and heart failure; further investigation into these risks is warranted.

Effect of facility-level hemoglobin concentration on dialysis patient risk of transfusion.

BACKGROUND: Changes in anemia management practices due to concerns about erythropoiesis-stimulating agent safety and Medicare payment changes may increase patient risk of transfusion. We examined anemia management trends in hemodialysis patients and risk of red blood cell (RBC) transfusion according to dialysis facility-level hemoglobin concentration. STUDY DESIGN: Retrospective follow-up study; 6-month study period (January to June), 3-month exposure/follow-up. SETTING & PARTICIPANTS: For each year in 2007-2011, annual cohorts of point-prevalent Medicare primary payer patients receiving hemodialysis on January 1 with one or more hemoglobin measurements during the study period. Annual cohorts averaged 170,000 patients, with 130,000 patients and 3,100 facilities for the risk analysis. PREDICTOR: Percentage of facility patient-months with hemoglobin level<10 g/dL. OUTCOME: Patient-level RBC transfusion rates. MEASUREMENTS: Monthly epoetin alfa and intravenous iron doses, mean hemoglobin levels, and RBC transfusion rates; percentage of facility patient-months with hemoglobin levels<10 g/dL (exposure) and patient-level RBC transfusion rates (follow-up). RESULTS: Percentages of patients with hemoglobin levels<10 g/dL increased every year from 2007 (6%) to 2011 (~11%). Epoetin alfa doses, iron doses, and transfusion rates remained relatively stable through 2010 and changed in 2011. Median monthly epoetin alfa and iron doses decreased 25% and 43.8%, respectively, and monthly transfusion rates increased from 2.8% to 3.2% in 2011, a 14.3% increase. Patients in facilities with the highest prevalence of hemoglobin levels<10 g/dL over 3 months were at ~30% elevated risk of receiving RBC transfusions within the next 3 months (relative risk, 1.28; 95% CI, 1.22-1.34). LIMITATIONS: Possibly incomplete claims data; smaller units excluded; hemoglobin levels reported monthly for patients receiving epoetin alfa; transfusions usually not administered in dialysis units. CONCLUSIONS: Dialysis facility treatment practices, as assessed by percentage of patient-months with hemoglobin levels<10 g/dL over 3 months, were associated significantly with risk of transfusions in the next 3 months for all patients in the facility, regardless of patient case-mix.

RBC transfusions among hemodialysis patients (1999-2010): influence of hemoglobin concentrations below 10 g/dL.

BACKGROUND: Changes in anemia management over the past decade have produced downward shifts in hemoglobin concentrations. We aimed to examine the effect on use of red blood cell (RBC) transfusions. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We identified point prevalent Medicare hemodialysis patients as of January 1 of each year (1999-2010) and categorized them based on 3-month (April to June) mean hemoglobin levels (<10 or ≥10 g/dL) in each year. PREDICTORS: Hemoglobin patterns over time and clinical profiles based on achieved hemoglobin concentrations. OUTCOMES: RBC transfusion use. MEASUREMENTS: We used negative binomial modeling to examine the effect of hemoglobin level <10 g/dL on transfusion use, adjusting for case-mix differences. RESULTS: Proportions of patients with mean hemoglobin levels <10 g/dL decreased from 10% (1999) to ~4% (2005), but began increasing after 2006 and reached 6% by 2010. Accounting for case-mix differences, transfusion rates remained relatively constant at approximately 7.9 per 100 person-months for patients with hemoglobin levels <10 g/dL and 2 per 100 person-months for patients with hemoglobin levels ≥10 g/dL. Patients with average hemoglobin levels <10 g/dL were more likely to receive transfusions (risk ratio, 2.2; 95% CI, 2.1-2.2) even after adjustment; the risk ratio doubled if hemoglobin levels remained <10 g/dL for 6 months (4.4; 95% CI, 3.7-5.2). LIMITATIONS: Limited in generalizability to patients with Medicare as primary payer; residual confounding from factors such as frailty and chronic inflammation cannot be excluded; categorizing patients based on an average of 3 outpatient hemoglobin measurements may introduce some misclassification. CONCLUSIONS: Risk of transfusion increases substantially with hemoglobin concentrations <10 g/dL; risk appears to be independent of other clinical factors. If anemia management patterns shift toward lower hemoglobin concentrations, RBC transfusion use likely will increase in dialysis patients.

Early trends from the Study to Evaluate the Prospective Payment System Impact on Small Dialysis Organizations (STEPPS).

BACKGROUND: Launched in January 2011, the prospective payment system (PPS) for the US Medicare End-Stage Renal Disease Program bundled payment for services previously reimbursed independently. Small dialysis organizations may be particularly susceptible to the financial implications of the PPS. The ongoing Study to Evaluate the Prospective Payment System Impact on Small Dialysis Organizations (STEPPS) was designed to describe trends in care and outcomes over the period of PPS implementation. This report details early results between October 2010 and June 2011. STUDY DESIGN: Prospective observational cohort study of patients from a sample of 51 small dialysis organizations. SETTING & PARTICIPANTS: 1,873 adult hemodialysis and peritoneal dialysis patients. OUTCOMES: Secular trends in processes of care, anemia, metabolic bone disease management, and red blood cell transfusions. MEASUREMENTS: Facility-level data are collected quarterly. Patient characteristics were collected at enrollment and scheduled intervals thereafter. Clinical outcomes are collected on an ongoing basis. RESULTS: Over time, no significant changes were observed in patient to staff ratios. There was a temporal trend toward greater use of peritoneal dialysis (from 2.4% to 3.6%; P = 0.09). Use of cinacalcet, phosphate binders, and oral vitamin D increased; intravenous (IV) vitamin D use decreased (P for trend for all <0.001). Parathyroid hormone levels increased (from 273 to 324 pg/dL; P < 0.001). Erythropoiesis-stimulating agent doses decreased (P < 0.001 for IV epoetin alfa and IV darbepoetin alfa), particularly high doses. Mean hemoglobin levels decreased (P < 0.001), the percentage of patients with hemoglobin levels <10 g/dL increased (from 12.7% to 16.8%), and transfusion rates increased (from 14.3 to 19.6/100 person-years; P = 0.1). Changes in anemia management were more pronounced for African American patients. LIMITATIONS: Limited data were available for the prebundle period. Secular trends may be subject to the ecologic fallacy and are not causal in nature. CONCLUSIONS: In the period after PPS implementation, IV vitamin D use decreased, use of oral therapies for metabolic bone disease increased, erythropoiesis-stimulating agent use and hemoglobin levels decreased, and transfusion rates increased numerically.