Xiaojuan Mi

Associations Between Aldosterone Antagonist Therapy and Risks of Mortality and Readmission Among Patients With Heart Failure and Reduced Ejection Fraction

CONTEXT Aldosterone antagonist therapy for heart failure and reduced ejection fraction has been highly efficacious in randomized trials. However, questions remain regarding the effectiveness and safety of the therapy in clinical practice. OBJECTIVE To examine the clinical effectiveness of newly initiated aldosterone antagonist therapy among older patients hospitalized with heart failure and reduced ejection fraction. DESIGN, SETTING, AND PARTICIPANTS Using clinical registry data linked to Medicare claims from 2005 through 2010, we examined outcomes of eligible patients hospitalized with heart failure and reduced ejection fraction. We used Cox proportional hazards models and inverse-weighted estimates of the probability of treatment to adjust for treatment selection bias. MAIN OUTCOME MEASURES All-cause mortality, cardiovascular readmission, and heart failure readmission at 3 years, and hyperkalemia readmission at 30 days and 1 year. RESULTS Among 5887 patients who met the inclusion criteria, the mean age was 77.6 years; of those 1070 (18.2%) started aldosterone antagonist therapy at discharge. Cumulative incidence rates among treated and untreated patients were 49.9% vs 51.2% (P = .62) for mortality; 63.8% vs 63.9% (P = .65) for cardiovascular readmission; and 38.7% vs 44.9% (P < .001) for heart failure readmission at 3 years; and 2.9% vs 1.2% (P < .001) for hyperkalemia readmission within 30 days and 8.9% vs 6.3% (P = .002) within 1 year. After inverse weighting for the probability of treatment, there were no significant differences in mortality (hazard ratio [HR], 1.04; 95% CI, 0.96-1.14; P = .32) and cardiovascular readmission (HR, 1.00; 95% CI, 0.91-1.09; P = .94). Heart failure readmission was lower among treated patients at 3 years (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Readmission associated with hyperkalemia was higher with aldosterone antagonist therapy at 30 days (HR, 2.54; 95% CI, 1.51-4.29; P < .001) and 1 year (HR, 1.50; 95% CI, 1.23-1.84; P < .001). CONCLUSIONS Initiation of aldosterone antagonist therapy at hospital discharge was not independently associated with improved mortality or cardiovascular readmission but was associated with improved heart failure readmission among eligible older patients with heart failure and reduced ejection fraction. There was a significant increase in the risk of readmission with hyperkalemia, predominantly within 30 days after discharge.

Initial Trends in the Use of the 21-Gene Recurrence Score Assay for Patients With Breast Cancer in the Medicare Population, 2005-2009

IMPORTANCE In 2006, the Centers for Medicare & Medicaid Services approved coverage for the use of the 21-gene recurrence score (RS) assay in women with early-stage, estrogen receptor-positive, node-negative breast cancers to help guide recommendations for adjuvant chemotherapy. Use of the assay in community settings has not been previously examined in a nationally representative sample of patients. OBJECTIVE To examine trends in the use of the RS assay in routine clinical practice in a nationally representative sample of women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational study of Medicare beneficiaries diagnosed with incident breast cancer between 2005 and 2009, as recorded in a Surveillance, Epidemiology, and End Results data set with linked Medicare claims through 2010. MAIN OUTCOMES AND MEASURES Demographic and clinical variables associated with the use of the assay. RESULTS A total of 70,802 patients met the study criteria. Use of the RS assay increased from 1.1% in 2005 to 10.1% in 2009 (P < .001). The majority of tests (60.9%) occurred in patients with National Comprehensive Cancer Network-defined intermediate-risk disease (ie, estrogen receptor-positive, node-negative tumors >1 cm). Most patients with other than intermediate-risk disease had borderline indications for testing, including T1b (47.5%) or N1 (26.8%) disease. Testing was associated with younger age, fewer comorbid conditions, higher-grade disease, and being married. Among patients younger than 70 years with intermediate-risk disease, testing rates increased from 7.7% in 2005 to 38.8% in 2009 (P < .001). In multivariable analysis, testing was modestly higher in Northeast than in Western registries (odds ratio, 1.83; 95% CI, 1.49-2.26) but was otherwise not associated with region, local census tract demographic characteristics, black race, location in an urban area, or tumor histologic characteristics. CONCLUSIONS AND RELEVANCE The RS assay was adopted quickly in clinical practice after the Medicare coverage decision in 2006, and use appears to be consistent with guidelines and equitable across geographic and racial groups. Factors influencing adoption of the assay and its impact on adjuvant chemotherapy use in clinical practice remain important areas of study.

Association Between Use of the 21-Gene Recurrence Score Assay and Receipt of Chemotherapy Among Medicare Beneficiaries With Early-Stage Breast Cancer, 2005-2009

IMPORTANCE Guidelines recommend consideration of chemotherapy for most patients with early-stage, estrogen receptor-positive, invasive breast cancer in the absence of additional prognostic information. The 21-gene recurrence score (RS) assay has been shown in limited academic settings to reduce physician recommendations for adjuvant chemotherapy. Associations between the adoption of the assay and receipt of chemotherapy in the general population have not been examined. OBJECTIVE To examine whether adoption of the RS assay in a nationally representative sample of patients with early-stage breast cancer was associated with use of chemotherapy. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of Medicare beneficiaries who received a diagnosis of incident breast cancer between 2005 and 2009 using Surveillance, Epidemiology, and End Results data set with linked Medicare claims. MAIN OUTCOMES AND MEASURES Receipt of chemotherapy within 12 months after diagnosis. RESULTS A total of 44,044 patients had low-risk (24.0%), intermediate-risk (51.3%), or high-risk disease (24.6%, lymph node positive) as defined by National Comprehensive Cancer Network (NCCN) guidelines and met the study criteria. We observed no overall association between receipt of the RS assay and chemotherapy (odds ratio [OR], 1.03 [99% CI, 0.88-1.19]). In multivariable analysis, there was a significant interaction between NCCN risk and use of the RS assay, with assay use associated with lower chemotherapy use in high-risk patients (OR, 0.36 [99% CI, 0.26-0.50]) and greater chemotherapy use in low-risk patients (OR, 3.71 [99% CI, 2.30-5.98]), compared with no receipt of the assay (P=.006 for the overall interaction). Results were similar in prespecified subgroup analyses of patients 70 years and younger, with the exception of a shift toward lower chemotherapy use during 2008 (OR, 0.90 [99% CI, 0.77-.1.05]; P=.09) and 2009 (OR, 0.81 [99% CI, 0.66-0.99]; P=.007). In unadjusted analyses, overall chemotherapy use decreased over time in patients 70 years or younger with high-risk disease and those receiving the assay. CONCLUSIONS AND RELEVANCE The impact of the adoption of the RS assay on receipt of chemotherapy was strongly population dependent and was associated with relatively lower chemotherapy use in groups with high-risk disease and relatively higher chemotherapy use in patients with low-risk disease. Overall use of chemotherapy decreased during the study period in patients who were most likely to receive chemotherapy.

Transitional adherence and persistence in the use of aldosterone antagonist therapy in patients with heart failure

BACKGROUND Aldosterone antagonist therapy is recommended for selected patients with heart failure and reduced ejection fraction. Adherence to therapy in the transition from hospital to home is not well understood. METHODS We identified patients with heart failure and reduced ejection fraction who were ≥65 years old, eligible for aldosterone antagonist therapy, and discharged home from hospitals in the Get With the Guidelines-Heart Failure registry between January 1, 2005, and December 31, 2008. We used Medicare prescription drug event data to measure adherence. Main outcome measures were prescription at discharge, outpatient prescription claim within 90 days, discontinuation, and adherence as measured with the medication possession ratio. We used the cumulative incidence function to estimate rates of initiation and discontinuation. RESULTS Among 2,086 eligible patients, 561 (26.9%) were prescribed an aldosterone antagonist at discharge. Within 90 days, 78.6% of eligible patients with a discharge prescription filled a prescription for the therapy, compared with 13.0% of eligible patients without a discharge prescription (P < .001). The median medication possession ratio was 0.63 over 1 year of follow-up. Among 634 patients who filled a prescription within 90 days of discharge, 7.9% discontinued therapy within 1 year. CONCLUSION Most eligible patients were not prescribed aldosterone antagonist therapy at discharge from a heart failure hospitalization. Eligible patients without a discharge prescription seldom initiated therapy as outpatients. Most patients who were prescribed an aldosterone antagonist at discharge filled the prescription within 90 days and remained on therapy.

Implications of M Bias in Epidemiologic Studies: A Simulation Study

Collider-stratification bias arises from conditioning on a variable (collider) which opens a path from exposure to outcome. M bias occurs when the collider-stratification bias is transmitted through ancestors of exposure and outcome. Previous theoretical work, but not empirical data, has demonstrated that M bias is smaller than confounding bias. The authors simulated data for large cohort studies with binary exposure, an outcome, a collider, and 2 predictors of the collider. They created 178 scenarios by changing the frequencies of variables and/or the magnitudes of associations among the variables. They calculated the effect estimate, percentage bias, and mean squared error. M bias in these realistic scenarios ranged from -2% to -5%. When the authors increased one or both relative risks for the relation between the collider and unmeasured factors to ≥8, the negative bias was more substantial (>15%). The result was substantially biased (e.g., >20%) if an unmeasured confounder that was also a collider was not adjusted to avoid M bias. In scenarios resembling those the authors examined, M bias had a small impact unless associations between the collider and unmeasured confounders were very large (relative risk > 8). When a collider is itself an important confounder, controlling for confounding would take precedence over avoiding M bias.

Follow-up of patients with new cardiovascular implantable electronic devices: are experts' recommendations implemented in routine clinical practice?

Background— A 2008 expert consensus statement outlined the minimum frequency of follow-up of patients with cardiovascular implantable electronic devices (CIEDs). Methods and Results— We studied 38 055 Medicare beneficiaries who received a new CIED between January 1, 2005, and June 30, 2009. The main outcome measure was variation of follow-up by patient factors and year of device implantation. We determined the number of patients who were eligible for and attended an in-person CIED follow-up visit within 2 to 12 weeks, 0 to 16 weeks, and 1 year after implantation. Among eligible patients, 42.4% had an initial in-person visit within 2 to 12 weeks. This visit was significantly more common among white patients than black patients and patients of other races (43.0% versus 36.8% versus 40.5%; P <0.001). Follow-up within 2 to 12 weeks improved from 40.3% in 2005 to 55.1% in 2009 ( P <0.001 for trend). The rate of follow-up within 0 to 16 weeks was 65.1% and improved considerably from 2005 to 2009 (62.3%–79.6%; P <0.001 for trend). Within 1 year, 78.0% of the overall population had at least 1 in-person CIED follow-up visit. Conclusions— Although most Medicare beneficiaries who received a new CIED between 2005 and 2009 did not have an initial in-person CIED follow-up visit within 2 to 12 weeks after device implantation, the rate of initial follow-up improved appreciably over time. This CIED follow-up visit was significantly more common in white patients than in patients of other races.Background—A 2008 expert consensus statement outlined the minimum frequency of follow-up of patients with cardiovascular implantable electronic devices (CIEDs). Methods and Results—We studied 38 055 Medicare beneficiaries who received a new CIED between January 1, 2005, and June 30, 2009. The main outcome measure was variation of follow-up by patient factors and year of device implantation. We determined the number of patients who were eligible for and attended an in-person CIED follow-up visit within 2 to 12 weeks, 0 to 16 weeks, and 1 year after implantation. Among eligible patients, 42.4% had an initial in-person visit within 2 to 12 weeks. This visit was significantly more common among white patients than black patients and patients of other races (43.0% versus 36.8% versus 40.5%; P<0.001). Follow-up within 2 to 12 weeks improved from 40.3% in 2005 to 55.1% in 2009 (P<0.001 for trend). The rate of follow-up within 0 to 16 weeks was 65.1% and improved considerably from 2005 to 2009 (62.3%–79.6%; P<0.001 for trend). Within 1 year, 78.0% of the overall population had at least 1 in-person CIED follow-up visit. Conclusions—Although most Medicare beneficiaries who received a new CIED between 2005 and 2009 did not have an initial in-person CIED follow-up visit within 2 to 12 weeks after device implantation, the rate of initial follow-up improved appreciably over time. This CIED follow-up visit was significantly more common in white patients than in patients of other races.

Early intravenous heart failure therapy and outcomes among older patients hospitalized for acute decompensated heart failure: Findings from the Acute Decompensated Heart Failure Registry Emergency Module (ADHERE-EM)

BACKGROUND Timing of initial treatment for acute decompensated heart failure (ADHF) varies across hospitals and its impact on outcomes remains poorly defined. We examined the association between time to first intravenous (IV) heart failure (HF) therapy and patient outcomes. METHODS Using the ADHERE-EM linked to Medicare claims data, we identified patients ≥65 years old who were hospitalized for ADHF and received IV HF therapy during index admission. Cox proportional hazard model was used to assess the association of time to treatment with a composite of 30-day all-cause mortality or re-admission. Generalized linear mixed models were used to examine the association of time to treatment with in-hospital all-cause mortality, index hospitalization length of stay, and total days alive and out-of-hospital at 30 days. RESULTS Of 6,971 patients, the median time to first IV HF therapy was 2.3-hours (interquartile range 1.1, 4.4). The cumulative incidence of 30-day all-cause mortality or readmission was 27.4%. After adjusting for covariates, time to treatment was not associated with increased risk of composite 30-day all-cause mortality or re-admission (HR 1.00; 95% CI 1.00-1.00; P = .221). However, every hour delay in treatment was associated with a modest increased risk of in-hospital mortality (adjusted OR 1.01; 95% CI 1.00-1.02; P = .001) and an approximately 1.4-hour increase in index admission length of stay (P < .001). CONCLUSION Among older patients presenting with ADHF, delay in initiating IV HF therapy was associated with modestly higher risk for in-hospital mortality and longer length of stay, but was not associated with 30-day outcomes.

Comparative effectiveness of cardiac resynchronization therapy with an implantable cardioverter-defibrillator versus defibrillator therapy alone: a cohort study.

Context In randomized, controlled trials, cardiac resynchronization therapy with a defibrillator (CRT-D) decreased mortality in patients with reduced left ventricular ejection fraction and prolonged QRS duration compared with implantable cardioverter-defibrillator (ICD) therapy alone. The relative benefits and harms of these devices in more routine practice settings have not been studied. Contribution The investigators compared CRT-D with ICD in more than 7000 patients enrolled in a patient registry and found that CRT-D decreased mortality more than ICD. Device-related infections were more common with CRT-D. Caution Residual confounding could not be eliminated. Implication Real-world performance of CRT-D versus ICD seems similar to that observed in randomized, controlled trials. The Editors Implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) have changed the management of patients with reduced left ventricular ejection faction (LVEF). Guidelines for device-based treatment recommend ICD therapy for many patients with reduced LVEF (1) on the basis of randomized, controlled trials showing mortality benefits of ICD therapy (27). Cardiac resynchronization therapy with an ICD (CRT-D), which involves the placement of an additional coronary sinus lead capable of pacing the left ventricle, is further recommended for selected patients with an LVEF of 0.35 or less, heart failure, and evidence of ventricular dyssynchrony manifested as QRS prolongation on electrocardiography (1). The recommendations are based on evidence of lower risk for worsening heart failure and, in some cases, lower mortality with CRT-D in these selected groups (1). Although randomized clinical trials have identified important incremental benefits of CRT in selected patients, the comparative effectiveness of CRT-D versus ICD therapy has not been characterized in patients cared for in clinical practice. Clinical trials in patients with cardiovascular disease in general (8, 9) and of device therapy in particular (10, 11) have typically enrolled selected patients who differ from those seen in practice. Device trials are also often performed in sites and by clinicians with substantial expertise, which may reduce complication rates (12). This factor is specifically germane to CRT because implanting the additional left ventricular lead is associated with higher rates of complications than ICD therapy alone (13). Differences in the patients selected for therapy and the centers where the procedures are done could influence the outcomes of device therapy in real-world clinical practice. Given the number of ICD and CRT devices implanted in the United States annually (14), understanding the incremental effectiveness and complications of CRT in patients treated in contemporary practice could have important implications for patients, clinicians, and policymakers. Controversies about the optimum use of CRT persist. Although the benefits are clearest and recommendations for its use are strongest in patients with left bundle branch block (LBBB) and a QRS duration greater than 150 ms, the benefits in patients with other intraventricular conduction delays (for example, right bundle branch block) and less prolonged QRS duration are debated (1). Furthermore, the benefits of CRT have generally been greatest in patients with more severe symptoms of heart failure, but recent trials have suggested meaningful benefits in less symptomatic patients (6, 7, 15). Finally, questions about the effectiveness of CRT according to patient sex (6, 16) or in patients with atrial fibrillation (1) have been raised. We performed an observational comparative effectiveness study of CRT-D versus ICD therapy alone in a contemporary cohort of patients with reduced LVEF and electrocardiographic evidence of ventricular dyssynchrony who were receiving device-based therapy. Our objectives were to characterize the associations between CRT-D versus ICD therapy alone and patient outcomes, including death, hospitalizations, and device-related complications, and to investigate these associations in specific subgroups of clinical interest. Methods Data Sources Data were from the National Cardiovascular Data Registrys ICD Registry and the Centers for Medicare & Medicaid Services Medicare claims data. The ICD Registry was established in 2005 through a partnership of the Heart Rhythm Society and the American College of Cardiology Foundation and became the sole repository of ICD implantation data for Medicare beneficiaries on 1 April 2006. The Centers for Medicare & Medicaid Services mandates that hospitals enter data on all Medicare beneficiaries receiving ICD therapy for primary prevention into the registry (14), which contains patient demographic characteristics, detailed medical history, and clinical and procedural information. The registry uses standardized data definitions and data quality monitoring (17). Medicare data include inpatient and outpatient claims and the corresponding denominator files between 2006 and 2011. We linked the registry data to Medicare claims data using a validated method that involves combinations of indirect identifiers (18). The Institutional Review Board of the Duke University Health System (Durham, North Carolina) approved the study. Study Cohort In the linked data set, we identified patients who were 65 years or older; were admitted specifically for first-time device implantation; were discharged home between 1 April 2006 and 31 December 2009; were enrolled in fee-for-service Medicare at discharge; and might be considered for CRT-D on the basis of a history of heart failure, an LVEF of 0.35 or less, and a QRS duration at least 120 ms. We excluded patients who received device therapy for secondary prevention, received epicardial leads, were admitted for reasons other than device implantation, had coronary revascularization during the index admission, had a prior ICD pacemaker, or had myocardial infarction within 40 days before the index discharge. Treatment The treatments of interest were CRT-D and ICD therapy alone as recorded in the registry. The registry does not include data for patients receiving CRT without a defibrillator; thus, this therapy was not considered. Outcomes The outcomes of interest were the occurrence of and time to all-cause mortality; all-cause readmission; and readmission for cardiovascular disease, heart failure, device-related infection, and mechanical complications requiring system revision for up to 3 years after implantation. We ascertained mortality on the basis of death dates in the Medicare denominator files and readmission on the basis of subsequent Medicare inpatient claims (Appendix Table 1). Appendix Table 1. Definitions of Readmission Outcomes Subgroups We prespecified clinically important subgroupsincluding age, sex, race, and type of intraventricular conduction delaycombined with QRS duration, New York Heart Association class, and the presence or absence of atrial fibrillation and renal dysfunction. We also considered subgroups according to the cause of left ventricular systolic dysfunction (ischemic vs. nonischemic). We combined the type of intraventricular conduction delay and QRS duration and classified patients into 1 of 4 categories according to guidelines for device-based therapy: LBBB and QRS duration 150 ms or greater, LBBB and QRS duration 120 to 149 ms, no LBBB and QRS duration 150 ms or greater, and no LBBB and QRS duration 120 to 149 ms (1). For the purposes of subgroup analysis, we categorized renal function into 4 groups on the basis of estimated glomerular filtration rates of 90 mL/min/1.73 m2 or greater, 60 to 89 mL/min/1.73 m2, 30 to 59 mL/min/1.73 m2, and 29 mL/min/1.73 m2 or less or end-stage renal disease (19). Covariates We obtained covariates of interest from the registry, including demographic characteristics, medical history, results of clinical measures, year of implantation, and discharge medications. We considered patients to be receiving optimal medical therapy if they received a -blocker and an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker in the absence of contraindications. Demographic variables were complete, and the other variables were missing at low rates (<1%). To avoid case-wise deletions, we imputed missing continuous variables to the overall median value and missing categorical variables to the most common response, an approach that is considered appropriate for variables with low rates of missing data (20). Statistical Analysis We described the baseline characteristics of the study population by using frequencies with percentages for categorical variables and means with SDs for continuous variables. We tested for differences between treatment groups using the chi-square test for categorical variables and the t test for continuous variables. We calculated the standardized difference expressed in percentage points between 2 treatment groups as the difference in means or proportions divided by a pooled estimate of the SD. Standardized differences less than 10 percentage points suggest balance in the 2 groups with respect to that variable (21). We estimated the cumulative incidence of each outcome at 1 year and 3 years after device implantation for both treatment groups. Estimates of mortality were based on the KaplanMeier estimator, and differences between groups were assessed using log-rank tests. Estimates of readmission were based on the cumulative incidence function, which accounts for the competing risk for mortality. For patients not having an event, we defined a censoring date as the earliest among the end of follow-up at 1 year or 3 years after the index discharge date, the end of claims data availability on 31 December 2011, or the date on which the patient enrolled in a Medicare managed care plan. We used Gray tests to assess differences between treatment groups (22). We used propensity score matching to account for differenc

Pharmacotherapy in Medicare beneficiaries with atrial fibrillation

BACKGROUND There are limited data regarding national patterns of pharmacotherapy for atrial fibrillation (AF) among older patients. Drug exposure data are now captured for Medicare beneficiaries enrolled in prescription drug plans. OBJECTIVE To describe pharmacotherapy for AF among Medicare beneficiaries. METHODS By using a 5% national sample of Medicare claims data, we compared demographic characteristics, comorbidity, and treatment patterns according to Medicare Part D status among patients with prevalent AF in 2006 and 2007. RESULTS In 2006, 27,174 patients (29.3%) with prevalent AF were enrolled in Medicare Part D. In 2007, enrollment increased to 45,711 (49.1%). Most enrollees were taking rate-control agents (74.0% in 2007). β-Blocker use was higher in those with concomitant AF and heart failure and increased with higher CHADS(2) scores (P <.001). Antiarrhythmic use was 18.7% in 2006 and 19.1% in 2007, with amiodarone accounting for more than 50%. Class Ic drugs were used in 3.2% of the patients in 2007. Warfarin use was <60% and declined with increasing stroke risk (P <.001). CONCLUSION Pharmacotherapy for AF varied according to comorbidity and underlying risk. Amiodarone was the most commonly prescribed antiarrhythmic agent. Postmarketing surveillance using Medicare Part D claims data linked to clinical data may help inform comparative safety, effectiveness, and net clinical benefit of drug therapy for AF in older patients in real-world settings.

Adherence and Persistence in the Use of Warfarin After Hospital Discharge Among Patients With Heart Failure and Atrial Fibrillation

BACKGROUND Postdischarge adherence and long-term persistence in the use of warfarin among patients with heart failure and atrial fibrillation without contraindications have not been fully described. METHODS AND RESULTS We identified patients with heart failure and atrial fibrillation who were ≥ 65 years old, eligible for warfarin, and discharged home from hospitals in the Get With the Guidelines-Heart Failure registry from January 1, 2006, to December 31, 2009. We used linked Medicare prescription drug event data to measure adherence and persistence. The main outcome measures were rates of prescription at discharge, outpatient dispensing, discontinuation, and adherence as measured by the medication possession ratio. We hypothesized that adherence to warfarin would differ according to whether patients received the prescription at discharge. Among 2,691 eligible patients, 1,856 (69.0%) were prescribed warfarin at discharge. Patients prescribed warfarin at discharge had significantly higher prescription fill rates within 90 days (84.5% vs 12.3%; P < .001) and 1 year (91.6% vs 16.8%; P < .001) and significantly higher medication possession ratios (0.78 vs 0.63; P < .001). Among both previous nonusers and existing users, fill rates at 90 days and 1 year and possession ratios were significantly higher among those prescribed warfarin at discharge. CONCLUSIONS One-third of eligible patients with heart failure and atrial fibrillation were not prescribed warfarin at discharge from a heart failure hospitalization, and few started therapy as outpatients. In contrast, most patients who were prescribed warfarin at discharge filled the prescription within 90 days and remained on therapy at 1 year.