Assessment of Days Alive Out of Hospital as a Possible End Point in Trials of Stroke Prevention for Atrial Fibrillation: A ROCKET AF Analysis.

BACKGROUND: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. METHODS AND RESULTS: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). CONCLUSIONS: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Lung function trajectories in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterised by decline in lung function. We evaluated trajectories of forced vital capacity (FVC) and diffusing capacity (DLco) in a cohort of patients with IPF. METHODS: Patients with IPF that was diagnosed or confirmed at the enrolling centre in the previous 6 months were enrolled into the IPF-PRO Registry between June 2014 and October 2018. Patients were followed prospectively, with lung function data collected as part of routine clinical care. Mean trajectories of FVC and DLco % predicted in all patients and in subgroups by characteristics assessed at enrolment were estimated using a joint model that accounted for factors such as disease severity and visit patterns. RESULTS: Of 1002 patients in the registry, 941 had ≥ 1 FVC and/or DLco measurement after enrolment. The median (Q1, Q3) follow-up period was 35.1 (18.9, 47.2) months. Overall, mean estimated declines in FVC and DLco % predicted were 2.8% and 2.9% per year, respectively. There was no evidence that the mean trajectories of FVC or DLco had a non-linear relationship with time at the population level. Patients who were male, white, had a family history of ILD, were using oxygen, or had prior/current use of antifibrotic therapy at enrolment had greater rates of decline in FVC % predicted. Patients who were male or white had greater rates of decline in DLco % predicted. CONCLUSIONS: Data from the IPF-PRO Registry suggest a constant rate of decline in lung function over a prolonged period, supporting the inexorably progressive nature of IPF. A graphical abstract summarising the data in this manuscript is available at: https://www.usscicomms.com/respiratory/IPF-PRORegistry_LungFunctionTrajectories . TRIAL REGISTRATION: NCT01915511.

Effect of Antifibrotic Therapy on Survival in Patients With Idiopathic Pulmonary Fibrosis.

PURPOSE: Real-world studies have reported reduced mortality in patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotic therapy; however, the initiation or discontinuation of therapy during these studies may have introduced bias. This study investigated the effect of antifibrotic therapy on mortality and other outcomes in patients with IPF using causal inference methodology. METHODS: Data from a multicenter US registry of patients with IPF were used to assess the effect of antifibrotic therapy (nintedanib or pirfenidone) on death, death or lung transplant, respiratory-related hospitalization, and acute worsening of IPF (defined as any health care encounter deemed due to acute worsening of IPF). This study used the Gran method, which accounts for differences in patient characteristics and for treatment initiations and discontinuations during follow-up. The analysis cohort was limited to patients who started antifibrotic therapy on or after the day of enrollment or had never taken it. FINDINGS: Among the 499 patients analyzed, 352 (70.5%) received antifibrotic therapy. Estimated event rates of death at 1 year were 6.6% (95% CI, 6.1-7.1) for treated patients and 10.2% (95% CI, 9.5-10.9) for control patients. There was a numerical reduction in the risk of death (hazard ratio [HR], 0.53; 95% CI, 0.28-1.03; P = 0.060) but numerical increases in risks of respiratory-related hospitalization (HR, 1.88; 95% CI, 0.90-3.92; P = 0.091) and acute worsening of IPF (HR, 1.71; 95% CI, 0.36-8.09; P = 0.496) in treated versus control patients. IMPLICATIONS: Analyses based on causal inference methodology suggest that patients with IPF who receive antifibrotic therapy have improved survival.

Validation of the WATCH-DM and TRS-HFDM Risk Scores to Predict the Risk of Incident Hospitalization for Heart Failure Among Adults With Type 2 Diabetes: A Multicohort Analysis.

Background The WATCH-DM (weight [body mass index], age, hypertension, creatinine, high-density lipoprotein cholesterol, diabetes control [fasting plasma glucose], ECG QRS duration, myocardial infarction, and coronary artery bypass grafting) and TRS-HFDM (Thrombolysis in Myocardial Infarction [TIMI] risk score for heart failure in diabetes) risk scores were developed to predict risk of heart failure (HF) among individuals with type 2 diabetes. WATCH-DM was developed to predict incident HF, whereas TRS-HFDM predicts HF hospitalization among patients with and without a prior HF history. We evaluated the model performance of both scores to predict incident HF events among patients with type 2 diabetes and no history of HF hospitalization across different cohorts and clinical settings with varying baseline risk. Methods and Results Incident HF risk was estimated by the integer-based WATCH-DM and TRS-HFDM scores in participants with type 2 diabetes free of baseline HF from 2 randomized clinical trials (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin], N=12 028; and Look AHEAD [Look Action for Health in Diabetes] trial, N=4867). The integer-based WATCH-DM score was also validated in electronic health record data from a single large health care system (N=7475). Model discrimination was assessed by the Harrell concordance index and calibration by the Greenwood-Nam-D'Agostino statistic. HF incidence rate was 7.5, 3.9, and 4.1 per 1000 person-years in the TECOS, Look AHEAD trial, and electronic health record cohorts, respectively. Integer-based WATCH-DM and TRS-HFDM scores had similar discrimination and calibration for predicting 5-year HF risk in the Look AHEAD trial cohort (concordance indexes=0.70; Greenwood-Nam-D'Agostino P>0.30 for both). Both scores had lower discrimination and underpredicted HF risk in the TECOS cohort (concordance indexes=0.65 and 0.66, respectively; Greenwood-Nam-D'Agostino P<0.001 for both). In the electronic health record cohort, the integer-based WATCH-DM score demonstrated a concordance index of 0.73 with adequate calibration (Greenwood-Nam-D'Agostino P=0.96). TRS-HFDM score could not be validated in the electronic health record because of unavailability of data on urine albumin/creatinine ratio in most patients in the contemporary clinical practice. Conclusions The WATCH-DM and TRS-HFDM risk scores can discriminate risk of HF among intermediate-risk populations with type 2 diabetes.

Angiotensin Receptor Neprilysin Inhibition and Associated Outcomes by Race and Ethnicity in Patients With Heart Failure With Reduced Ejection Fraction: Data From CHAMP-HF.

Background There are limited data on the use of angiotensin receptor neprilysin inhibitors (ARNIs) in minority populations with heart failure (HF) with reduced ejection fraction. We used data from the CHAMP-HF (Change the Management of Patients With Heart Failure) registry to evaluate ARNI initiation and associated changes in health status and clinical outcomes across different races and ethnicities. Methods and Results CHAMP-HF was a prospective, observational registry of US outpatients with chronic HF with reduced ejection fraction. We compared patients starting ARNI with patients not starting ARNI using a propensity-matched analysis. Patients were grouped as Hispanic, non-Hispanic Black, non-Hispanic White, or non-Hispanic other individuals, where "non-Hispanic other" consists of all patients who did not identify as Hispanic, Black, or White. Health status was assessed using the 12-item Kansas City Cardiomyopathy Questionnaire. Outcomes were analyzed with multivariable models that included race and ethnicity, ARNI initiation, and an interaction term between race and ethnicity and ARNI initiation. Cox proportional hazards models were used for death/HF hospitalization, and multiple regression was used for change in Kansas City Cardiomyopathy Questionnaire score. The analysis included 1516 patients, with 758 patients in each group (ARNI and no ARNI). Changes in Kansas City Cardiomyopathy Questionnaire score after ARNI initiation were similar among all race and ethnicity groups (mean [SD], non-Hispanic White individuals, 3.5 [19.0]; non-Hispanic Black individuals, 2.0 [17.0]; non-Hispanic other individuals, 5.5 [20.3]; and Hispanic individuals, 3.2 [20.1]), with no statistically significant interaction between race and ethnicity and ARNI initiation (P=0.21). There was similarly no statistically significant interaction between race and ethnicity and ARNI initiation for HF hospitalization (P=0.82) or all-cause mortality (P=0.92). Conclusions In a large registry of outpatients with HF with reduced ejection fraction, the association between ARNI initiation and outcomes did not differ by race and ethnicity. These data support the use of ARNI therapy for chronic HF with reduced ejection fraction irrespective of race and ethnicity.

The association of improvement in left ventricular ejection fraction with outcomes in patients with heart failure with reduced ejection fraction: data from CHAMP-HF.

AIMS: We assessed for an association between improvements in left ventricular ejection fraction (LVEF) and future outcomes, including health status, in routine clinical practice. METHODS AND RESULTS: CHAMP-HF was a registry of outpatients with heart failure (HF) and LVEF ≤40%. Enrolled participants completed the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) at regular intervals and were followed as part of routine care. We assessed for associations between improvements in LVEF (≥10%) over time and concurrent changes in KCCQ-12, as well as the subsequent risk of poor outcomes. We included 2092 participants in the study. They had the following characteristics: median age 67 years (25th-75th percentile 58-75), 29% female, median duration of HF 2.7 years (0.6-6.8), and median baseline LVEF 30% (23-35). Of the study participants, 689 (33%) had a ≥10% absolute improvement in LVEF. Participants with an LVEF improvement also had an improvement in KCCQ-12 overall summary score compared with participants without an LVEF improvement (+7.6 vs. +3.5, adjusted effect estimate +4.01 [95% confidence interval CI 2.3-5.7]). Similarly, subsequent all-cause death or HF hospitalization occurred in 12% in the LVEF improvement group versus 25% in the group without an LVEF improvement (adjusted hazard ratio 0.50, 95% confidence interval 0.41-0.61). CONCLUSION: In a large cohort of outpatients with chronic HF, improvements in LVEF were associated with improved health status and a reduced risk for future clinical events. These data underscore the importance of improvement in LVEF as a treatment target for medical interventions for patients with chronic HF.

Associations between resources and practices of ILD centers and outcomes in patients with idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

BACKGROUND: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes. METHODS: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient case mix by adjusting for known predictors of each outcome. We assessed whether site-level heterogeneity existed for each patient-level outcome, and if so, we investigated potential drivers of the heterogeneity. RESULTS: All 27 sites that enrolled ≥ 10 patients returned the questionnaire. Most sites were actively following > 100 patients with IPF (70.4%), had a lung transplant program (66.7%), and had a dedicated ILD nurse leader (77.8%). Substantial heterogeneity was observed in the event rates of clinically relevant outcomes across the sites. After controlling for patient case mix, there were no outcomes for which the site variance component was significantly different from 0, but the p-value for hospitalization was 0.052. Starting/completing an ILD-related quality improvement project in the previous 2 years was associated with a lower risk of hospitalization (HR 0.60 [95% CI 0.44, 0.82]; p = 0.001). CONCLUSIONS: Analyses of data from patients with IPF managed at sites across the US found no site-specific characteristics or practices that were significantly associated with clinically relevant outcomes after adjusting for patient case mix. Trial registration ClinicalTrials.gov, NCT01915511. Registered 5 August 2013, https://clinicaltrials.gov/ct2/show/NCT01915511.

Clinical Outcomes of Patients with Combined Idiopathic Pulmonary Fibrosis and Emphysema in the IPF-PRO Registry.

PURPOSE: To assess the impact of concomitant emphysema on outcomes in patients with idiopathic pulmonary fibrosis (IPF). METHODS: The IPF-PRO Registry is a US registry of patients with IPF. The presence of combined pulmonary fibrosis and emphysema (CPFE) at enrollment was determined by investigators' review of an HRCT scan. Associations between emphysema and clinical outcomes were analyzed using Cox proportional hazards models. RESULTS: Of 934 patients, 119 (12.7%) had CPFE. Compared with patients with IPF alone, patients with CPFE were older (median 72 vs 70 years); higher proportions were current/former smokers (88.2% vs 63.7%), used oxygen with activity (49.6% vs 31.9%) or at rest (30.8% vs 18.4%), had congestive heart failure (13.6% vs 4.8%) and had prior respiratory hospitalization (25.0% vs 16.7%); they had higher FVC (median 71.8 vs 69.4% predicted) and lower DLco (median 35.3 vs 43.6% predicted). In patients with CPFE and IPF alone, respectively, at 1 year, rates of death or lung transplant were 17.5% (95% CI: 11.7, 25.8) and 11.2% (9.2, 13.6) and rates of hospitalization were 21.6% (14.6, 29.6) and 20.6% (17.9, 23.5). There were no significant associations between emphysema and any outcome after adjustment for baseline variables. No baseline variable predicted outcomes better in IPF alone than in CPFE. CONCLUSION: Approximately 13% of patients in the IPF-PRO Registry had CPFE. Physiologic characteristics and comorbidities of patients with CPFE differed from those of patients with IPF alone, but the presence of emphysema did not drive outcomes after adjustment for baseline covariates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01915511; registered August 5, 2013.

Disparities in Lung Transplant among Patients with Idiopathic Pulmonary Fibrosis: An Analysis of the IPF-PRO Registry.

Rationale: Lung transplant offers the potential to extend life for patients with idiopathic pulmonary fibrosis (IPF); yet, this therapeutic modality is only available to a small proportion of patients. Objectives: To identify clinical characteristics and social determinants of health that differentially associate with lung transplant compared with death in patients with IPF. Methods: We evaluated data from the Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry, a multicenter U.S. registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were enrolled between June 2014 and October 2018. Patients who were listed for lung transplant were not eligible to enroll in the registry, but patients could be listed for transplant after enrollment. We performed a multivariable time-to-event analysis incorporating competing risks methodology to examine differential associations between prespecified covariates and the risk of lung transplant versus death. Covariates included factors related to lung transplant eligibility, clinical characteristics of IPF, and social determinants of health. Covariates were modeled as time independent or time dependent as appropriate. Results: Among 955 patients with IPF, event rates of lung transplant and death were 7.4% and 16.3%, respectively, at 2 years. Covariates with the strongest differential association were age, median zip code income, and enrollment at a center with a lung transplant program. Lung transplant was less likely (hazard ratio [HR], 0.13 [95% confidence interval (CI), 0.06-0.28] per 5-yr increase) and death more likely (HR, 1.41 [95% CI, 1.22-1.64] per 5-yr increase) among those older than 70 years of age. Higher median zip code income was associated with lung transplant (HR, 1.22 [95% CI, 1.13-1.31] per $10,000 increase) but not death (HR, 0.99 [95% CI, 0.94-1.04] per $10,000 increase). Enrollment at a center with a lung transplant program was associated with lung transplant (HR, 4.31 [95% CI, 1.76-10.54]) but not death (HR, 0.99 [95% CI, 0.69-1.43]). Oxygen use with activity was associated with both lung transplant and death, but more strongly with lung transplant. A higher number of comorbidities was associated with an increased likelihood of death but not lung transplant. Conclusions: For patients in the Idiopathic Pulmonary Fibrosis Prospective Outcomes Registry, median zip code income and access to a lung transplant center differentially impact the risk of lung transplant compared with death, regardless of disease severity measures or other transplant eligibility factors. Interventions are needed to mitigate inequalities in lung transplantation based on socioeconomic status. Clinical trial registered with www.clinicaltrials.gov (NCT01915511).

Comparative Effectiveness of Dosing of Medical Therapy for Heart Failure: From the CHAMP-HF Registry.

BACKGROUND: The comparative effectiveness of differing dosages of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) on clinical and patient-reported outcomes in clinical practice in the United States is unknown. This study sought to characterize associations between the dosing of GDMT and outcomes for patients with HFrEF in U.S. clinical practice. METHODS: This analysis included 4832 outpatients who had chronic HFrEF across 150 practices in the U.S. in the Change the Management of Patients with Heart Failure (CHAMP-HF) registry with no contraindication and available dosing data for at least 1 GDMT at baseline. Baseline dosing of angiotensin-converting enzyme (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) therapies were examined. For each medication class, multivariable models assessed associations between medication dosing and clinical outcomes over 24 months (all-cause mortality, HF hospitalization) and patient-reported outcomes at 12 months (change in the Kansas City Cardiomyopathy Questionnaire Overall Summary score [KCCQ-OS]). RESULTS: After adjustment, compared with target dosing, lower dosing was associated with higher all-cause mortality for ACEIs/ARBs/ARNIs (50% to < 100% target dosage, HR 1.16 [95% CI 0.87-1.55]; < 50% target dosage, HR 1.37 [95% CI 1.05-1.79]; none, HR 1.75 [95% CI 1.32-2.34; overall P< 0.001) and beta-blockers (50% to < 100% target dosage, HR 1.30 [95% CI 1.00-1.69]; < 50% target dosage, HR 1.41 [95% CI 1.11-1.79; none, HR 1.24 [95% CI 0.92-1.67]; overall P= 0.042). Lower dosing of ACEIs/ARBs/ARNIs was independently associated with higher risk of HF hospitalization (50% to < 100% target dosage, HR 1.08 [95% CI 0.90-1.30]; < 50% target dosage, HR 1.23 [1.04-1.47]; none, HR 1.29 [1.04-1.60]; overall P= 0.046), but beta-blocker dosing was not (overall P= 0.085). Target dosing of MRAs was not associated with risk of mortality or HF hospitalization. For each GDMT, compared with target dosing, lower dosing was not associated with change in the KCCQ-OS at 12 months, with the potential exception of worsening KCCQ-OS scores with lower dosing of ACEIs/ARBs/ARNIs. CONCLUSIONS: In this contemporary U.S. outpatient HFrEF registry, target dosing of ACEI/ARB/ARNI and beta-blocker therapy was associated with reduced mortality and was variably associated with HF hospitalization and patient-reported outcomes. MRA dosing was not associated with outcomes. The totality of these findings support the benefits of target dosing of GDMT in routine practice, as tolerated, with unmeasured differences among patients receiving differing dosages potentially explaining the differing results seen here compared with randomized clinical trials.

Implementation of guideline recommendations and outcomes in patients with idiopathic pulmonary fibrosis: Data from the IPF-PRO registry.

BACKGROUND: Few data are available on the extent to which clinical practice is aligned with international guidelines for the management of idiopathic pulmonary fibrosis (IPF). We investigated the extent to which management guidelines for IPF have been implemented in the US IPF-PRO Registry and associations between implementation of guidelines and clinical outcomes. METHODS: We assessed the implementation of eight recommendations in clinical practice guidelines within the 6 months after enrollment: visit to a specialized clinic; pulmonary function testing; use of oxygen in patients with resting hypoxemia and exercise-induced hypoxemia; referral for pulmonary rehabilitation; treatment of gastro-esophageal reflux disease; initiation of anti-fibrotic therapy; referral for lung transplant evaluation. An implementation score was calculated as the number of recommendations achieved divided by the number for which the patient was eligible. Associations between implementation score and outcomes were analyzed using logistic regression and Cox proportional hazards models. RESULTS: Among 727 patients, median (Q1, Q3) implementation score was 0.6 (0.5, 0.8). Patients with an implementation score >0.6 had greater disease severity than those with a lower score. Implementation was lowest for referral for pulmonary rehabilitation (19.5%) and lung transplant evaluation (22.3%). In unadjusted models, patients with higher implementation scores had a greater risk of death, death or lung transplant, and hospitalization, but no significant associations were observed in adjusted models. CONCLUSIONS: Management guidelines were more likely to be implemented in patients with IPF with greater disease severity. When adjusted for disease severity, no association was found between implementation of management guidelines and clinical outcomes.

Diuretic Changes, Health Care Resource Utilization, and Clinical Outcomes for Heart Failure With Reduced Ejection Fraction: From the Change the Management of Patients With Heart Failure Registry.

BACKGROUND: Diuretics are a mainstay therapy for the symptomatic treatment of heart failure. However, in contemporary US outpatient practice, the degree to which diuretic dosing changes over time and the associations with clinical outcomes and health care resource utilization are unknown. METHODS: Among 3426 US outpatients with chronic heart failure with reduced ejection fraction in the Change the Management of Patients with Heart Failure registry with complete medication data and who were prescribed a loop diuretic, diuretic dose increase was defined as: (1) change to a total daily dose higher than their previous total daily dose, (2) addition of metolazone to the regimen, (3) change from furosemide to either bumetanide or torsemide, and the change persists for at least 7 days. Adjusted hazard ratios or rate ratios along with 95% CIs were reported for clinical outcomes among patients with an increase in oral diuretic dose versus no increase in diuretic dose. RESULTS: Overall, 796 (23%) had a diuretic dose increase (18 episodes per 100 patient-years). The proportion of patients with dyspnea at rest (38% versus 26%), dyspnea at exertion (79% versus 67%), orthopnea (32% versus 21%), edema (60% versus 43%), and weight gain (40% versus 23%) were significantly (all P <0.001) higher in the diuretic increase group. Baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (hazard ratio, 0.75 [95% CI, 0.65-0.87]) use were associated with lower likelihood of diuretic increase over time. Patients with a diuretic dose increase had a significantly higher number of heart failure hospitalizations (rate ratio, 2.53 [95% CI, 2.10-3.05]), emergency department visits (rate ratio, 1.84 [95% CI, 1.56-2.17]), and home health visits (rate ratio, 1.88 [95% CI, 1.39-2.54]), but not all-cause mortality (hazard ratio, 1.10 [95% CI, 0.89-1.36]). Similarly, greater furosemide dose equivalent increases were associated with greater resource utilization but not with mortality, compared with smaller increases. CONCLUSIONS: In this contemporary US registry, 1 in 4 patients with heart failure with reduced ejection fraction had outpatient escalation of diuretic therapy over longitudinal follow-up, and these patients were more likely to have sign/symptoms of congestion. Outpatient diuretic dose escalation of any magnitude was associated with heart failure hospitalizations and resource utilization, but not all-cause mortality.

Termination Based on Event Accrual in Per Protocol Versus Intention to Treat in the ROCKET AF Trial.

Background In event-driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy-event tracking in the per-protocol cohort during the on-treatment period versus the intention-to-treat (ITT) cohort during the ITT period. Methods and Results ROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per-protocol cohort during the on-treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62-0.96; P<0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68-0.99; P=0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points. Conclusions Clinical trial termination based on event accrual in the ITT cohort versus the per-protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.

Outcomes for patients with anterior myocardial infarction and prior cardiac arrest in the home automated external defibrillator trial (HAT).

BACKGROUND: Patients with sudden cardiac arrest occurring in the acute phase of myocardial infarction (MI-SCA) are believed to be at similar risk of death after revascularization compared with MI patients without SCA (MI-no SCA). Among patients with anterior MI, we examined whether those with MI-SCA were at greater risk of all-cause mortality or sudden cardiac death (SCD) than MI-no SCA patients. METHODS: The Home Automated External Defibrillator Trial enrolled patients with anterior MI who had not received or were candidates for an implantable cardioverter defibrillator (ICD). Our cohort included patients with a reported SCA event, in the acute phase of an MI, prior to HAT trial enrollment. Cox proportional hazards models examined the adjusted association between MI-SCA versus MI-no SCA patients and all-cause mortality and sudden cardiac death (SCD). We also determined whether the relationship between prior SCA and outcomes changed with subsequent events (syncope, revascularization, and recurrent MI) during follow-up. RESULTS: Of 6849 patients, 650 (9.5%) had MI-SCA before trial enrollment. Approximately 48% of patients had the MI-SCA event ≤1 year prior to enrollment; 71% of SCA events were in-hospital. MI-SCA patients were younger, more frequently white, and had higher rates of prior PCI versus MI-no SCA patients. There were no differences in adjusted all-cause mortality (hazard ratio [HR 0.95; 95% CI 0.65-1.38]) or SCD (HR 1.12; 95% CI 0.68-1.83) for MI-SCA vs. MI-no SCA. After ICD implantation, MI-SCA patients experienced higher all-cause mortality risk (HR 5.01, 95% CI 1.05-23.79) versus MI-no SCA patients; there was no mortality difference between MI-SCA and MI-no SCA patients without ICD implantation (HR 0.89, 95% CI 0.60-1.31), [interaction p = 0.035]. CONCLUSIONS: Patients with MI-SCA had similar adjusted risk of all-cause mortality and SCD compared with MI-no SCA. After ICD implantation, MI-SCA patients had higher mortality compared with MI-no SCA patients.

Pharmacotherapy for diabetes and stroke risk: Results from ROCKET AF.

BACKGROUND: Insulin use may be a better predictor of stroke risk and morbidity and mortality than diabetes in patients with atrial fibrillation (AF). OBJECTIVES: Determine if the increased risk of stroke observed in patients with AF and diabetes is restricted to those treated with insulin. METHODS: We analyzed the association between diabetes and treatment and the occurrence of stroke/systemic embolism, myocardial infarction (MI), all-cause death, vascular death, composite outcomes, and bleeding risk in the ROCKET AF trial. RESULTS: In a cohort of 14,264 patients, there were 40.3% (n = 5746) with diabetes, 5.9% (n = 842) on insulin, 18.9% (n = 2697) on oral medications, and 11.9% (n = 1703) diet-controlled. Compared to those without diabetes, patients with non-insulin-treated diabetes had increased risks of stroke (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.06-1.68), MI (HR 1.64, 95% CI 1.17-2.30), all-cause death (HR 1.26, 95% CI 1.08-1.46), vascular death (HR 1.33, 95% CI 1.11-1.60), and composite outcomes (HR 1.37, 95% CI 1.18-1.157). Patients with insulin-treated diabetes had a significantly higher risk of MI (HR 2.31, 95% CI 1.33-4.01) and composite outcomes (HR 1.57, 95% CI 1.19-2.08) compared to those without diabetes. There were no significant differences between insulin-treated and non-insulin-treated diabetes for any outcome. CONCLUSION: Among patients with AF and diabetes, there were no significant differences in outcomes in insulin-treated diabetes compared to non-insulin-treated diabetes.

Variability of discharge medical therapy for secondary prevention among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) in the United States.

BACKGROUND: Optimal medical therapy after myocardial infarction with nonobstructive coronary arteries (MINOCA; <50% stenosis) is uncertain. We evaluated variability in discharge prescription of angiotensin-converting enzyme inhibitors / angiotensin receptor blockers (ACEI/ARB) and beta-blockers (BB) to MINOCA patients between hospitals to assess physician equipoise about secondary prevention. METHODS: Patients with MINOCA between 2007-2014 were identified in the NCDR Chest Pain-MI Registry. Those with prior revascularization or missing demographic, angiographic, or medication data were excluded. Analysis was limited to high-volume hospitals with ≥20 MINOCA total discharges. Discharge prescriptions for ACEI/ARB and BB after MINOCA were analyzed for each hospital. Clinical data on left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR), and diabetes mellitus status were extracted to identify other indications for ACEI/ARB or BB. RESULTS: Clinical data were available for 17,849 MINOCA patients, of whom 8,752 (49%) had LVEF <40%, GFR ≤60 mL/min, and/or diabetes. 5,913 patients without one of these indications for ACEI/ARB or BB were discharged from 156 high-volume hospitals. At discharge, ACEI/ARB was prescribed to between 16.0% and 88.8% of MINOCA patients (median 45.6%, IQR 38.0%-56.5%) and BB to between 28.0% and 97.5% (median 74.1%, IQR 64.7%-80.0%). CONCLUSION: There is marked variability between hospitals in the proportions of patients receiving ACEI/ARB and BB after hospitalization for MINOCA, suggesting clinical equipoise about the routine use of these agents. Randomized clinical trials are necessary to establish the benefit of ACEI/ARB and BB to improve outcomes after MINOCA.

Association Between Hospital Volumes and Clinical Outcomes for Patients With Nontraumatic Subarachnoid Hemorrhage.

Background Previous studies of patients with nontraumatic subarachnoid hemorrhage (SAH) suggest better outcomes at hospitals with higher case and procedural volumes, but the shape of the volume-outcome curve has not been defined. We sought to establish minimum volume criteria for SAH and aneurysm obliteration procedures that could be used for comprehensive stroke center certification. Methods and Results Data from 8512 discharges in the National Inpatient Sample (NIS) from 2010 to 2011 were analyzed using logistic regression models to evaluate the association between clinical outcomes (in-hospital mortality and the NIS-SAH Outcome Measure [NIS-SOM]) and measures of hospital annual case volume (nontraumatic SAH discharges, coiling, and clipping procedures). Sensitivity and specificity analyses for the association of desirable outcomes with different volume thresholds were performed. During 8512 SAH hospitalizations, 28.7% of cases underwent clipping and 20.1% underwent coiling with rates of 21.2% for in-hospital mortality and 38.6% for poor outcome on the NIS-SOM. The mean (range) of SAH, coiling, and clipping annual case volumes were 30.9 (1-195), 8.7 (0-94), and 6.1 (0-69), respectively. Logistic regression demonstrated improved outcomes with increasing annual case volumes of SAH discharges and procedures for aneurysm obliteration, with attenuation of the benefit beyond 35 SAH cases/year. Analysis of sensitivity and specificity using different volume thresholds confirmed these results. Analysis of previously proposed volume thresholds, including those utilized as minimum standards for comprehensive stroke center certification, showed that hospitals with more than 35 SAH cases annually had consistently superior outcomes compared with hospitals with fewer cases, although some hospitals below this threshold had similar outcomes. The adjusted odds ratio demonstrating lower risk of poor outcomes with SAH annual case volume ≥35 compared with 20 to 34 was 0.82 for the NIS-SOM (95% CI, 0.71-094; P=0.0054) and 0.80 (95% CI, 0.68-0.93; P=0.0055) for in-hospital mortality. Conclusions Outcomes for patients with SAH improve with increasing hospital case volumes and procedure volumes, with consistently better outcomes for hospitals with more than 35 SAH cases per year.

Association of Heart Failure With Outcomes Among Patients With Peripheral Artery Disease: Insights From EUCLID.

Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5 years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76 kg, HR, 0.77; 95% CI, 0.64-0.93; <76 kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF.

Assessment of Common Comorbidity Phenotypes Among Older Adults With Knee Osteoarthritis to Inform Integrated Care Models.

OBJECTIVE: To establish the frequency of concordant, discordant, and clinically dominant comorbidities among Medicare beneficiaries with knee osteoarthritis (KOA) and to identify common concordant condition subgroups. PARTICIPANTS AND METHODS: We used a 5% representative sample of Medicare claims data to identify beneficiaries who received a diagnosis of KOA between January 1, 2012, and September 30, 2015, and matched control group without an osteoarthritis (OA) diagnosis. Frequency of 34 comorbid conditions was categorized as concordant, discordant, or clinically dominant among those with KOA and a matched sample without OA. Comorbid condition phenotypes were characterized by concordant conditions and derived using latent class analysis among those with KOA. RESULTS: The study sample included 203,361 beneficiaries with KOA and 203,361 non-OA controls. The largest difference in frequency between the two cohorts was for co-occurring musculoskeletal conditions (23.7% absolute difference), chronic pain syndromes (6.5%), and rheumatic diseases (4.5%), all with a higher frequency among those with knee OA. Phenotypes were identified as low comorbidity (53% of cohort with classification), hypothyroid/osteoporosis (27%), vascular disease (10%), and high medical and psychological comorbidity (10%). CONCLUSIONS: Approximately 47% of Medicare beneficiaries with KOA in this sample had a phenotype characterized by one or more concordant conditions, suggesting that existing clinical pathways that rely on single or dominant providers might be insufficient for a large proportion of older adults with KOA. These findings could guide development of integrated KOA-comorbidity care pathways that are responsive to emerging priorities for personalized, value-based health care.

Comparison of New York Heart Association Class and Patient-Reported Outcomes for Heart Failure With Reduced Ejection Fraction.

Importance: It is unclear how New York Heart Association (NYHA) functional class compares with patient-reported outcomes among patients with heart failure (HF) in contemporary US clinical practice. Objective: To characterize longitudinal changes and concordance between NYHA class and the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS), and their associations with clinical outcomes. Design, Setting, and Participants: This cohort study included 2872 US outpatients with chronic HF with reduced ejection fraction across 145 practices enrolled in the CHAMP-HF registry between December 2015 and October 2017. All patients had complete NYHA class and KCCQ-OS data at baseline and 12 months. Longitudinal changes and correlations between the 2 measure were examined. Multivariable models landmarked at 12 months evaluated associations between improvement in NYHA and KCCQ-OS from baseline to 12 months with clinical outcomes occurring from months 12 through 24. Statistical analyses were performed from March to August 2020. Exposure: Change in health status, as defined by 12-month change in NYHA class or KCCQ-OS. Main Outcomes and Measures: All-cause mortality, HF hospitalization, and mortality or HF hospitalization. Results: In total, 2872 patients were included in this analysis (median [interquartile range] age, 68 [59-75] years; 872 [30.4%] were women; and 2156 [75.1%] were of White race). At baseline, 312 patients (10.9%) were NYHA class I, 1710 patients (59.5%) were class II, 804 patients (28.0%) were class III, and 46 patients (1.6%) were class IV. For KCCQ-OS, 1131 patients (39.4%) scored 75 to 100 (best health status), 967 patients (33.7%) scored 50 to 74, 612 patients (21.3%) scored 25 to 49, and 162 patients (5.6%) scored 0 to 24 (worst health status). At 12 months, 1002 patients (34.9%) had a change in NYHA class (599 [20.9%] with improvement; 403 [14.0%] with worsening) and 2158 patients (75.1%) had a change of 5 or more points in KCCQ-OS (1388 [48.3%] with improvement; 770 [26.8%] with worsening). The most common trajectory for NYHA class was no change (1870 [65.1%]), and the most common trajectory for KCCQ-OS was an improvement of at least 10 points (1047 [36.5%]). After adjustment, improvement in NYHA class was not associated with subsequent clinical outcomes, whereas an improvement of 5 or more points in KCCQ-OS was independently associated with decreased mortality (hazard ratio, 0.59; 95% CI, 0.44-0.80; P < .001) and mortality or HF hospitalization (hazard ratio, 0.73; 95% CI, 0.59-0.89; P = .002). Conclusions and Relevance: Findings of this cohort study suggest that, in contemporary US clinical practice, compared with NYHA class, KCCQ-OS is more sensitive to clinically meaningful changes in health status over time. Changes in KCCQ-OS may have more prognostic value than changes in NYHA class.