Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial.

Importance: The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. Objective: To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments. Design, Setting, and Participants: This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024. Exposure: Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg). Main Outcomes and Measures: Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity. Results: Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure. Conclusions and Relevance: In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04593940.

Leveraging Clinical Digitized Data to Understand Temporal Characteristics and Outcomes of Acute Myocardial Infarctions at a Tertiary Care Medical Centre in Pakistan from 1988-2018 - Methods and Results.

Background and Objective: Few data exist on trends in acute myocardial infarction (AMI) patterns spanning recent epidemiological shifts in low middle-income countries (LMICs). To understand temporal disease patterns of AMI characteristics and outcomes between 1988-2018, we used digitized legacy clinical data at a large tertiary care centre in Pakistan. Methods: We reviewed digital health information capture systems maintained across the Aga Khan University Hospital and obtained structured elements to create a master dataset. We included index admissions of patients >18 years that were discharged between January 1, 1988, and December 31, 2018, with a primary discharge diagnosis of AMI (using ICD-9 diagnoses). The outcome evaluated was in-hospital mortality.Clinical characteristics derived from the electronic database were validated against chart review in a random sample of cases (k 0.53-1.00). Results: The final population consisted of 14,601 patients of which 30.6% (n = 4,470) were female, 52.4% (n = 7,651) had ST elevation MI and 47.6% (n = 6,950) had non-ST elevation MI. The median (IQR) age at presentation was 61 (52-70) years. Overall unadjusted in-hospital mortality was 10.3%. Across the time period, increasing trends were noted for the following characteristics: age, proportion of women, prevalence of hypertension, diabetes, proportion with NSTEMI (all ptrend < 0.001). In-hospital mortality rates declined significantly between 1988-1997 and 2008-2018 (13.8% to 9.2%, p < 0.001). Conclusions: The patterns of AMI have changed over the last three decades with a concomitant decline in in-hospital mortality at a tertiary care centre in Pakistan. Clinical digitized data presents a unique opportunity for gaining insights into disease patterns in LMICs.

Estimated Glomerular Filtration Rate Variability in Patients With Heart Failure and Chronic Kidney Disease.

BACKGROUND: Greater variability in the estimated glomerular filtration rate (eGFR) is associated with higher mortality in patients with chronic kidney disease (CKD). Heart failure (HF) is common in CKD and may increase variability through changes in hemodynamic and volume regulation. We sought to determine if patients with vs without HF have higher kidney function variability in CKD, and to define the association with mortality. METHODS AND RESULTS: Patients undergoing coronary angiography from 2003 to 2013 with an eGFR of less than 60 mL/min/1.73 m2 were evaluated from the Duke Databank for Cardiovascular Disease. Variability in the eGFR, measured as the coefficient of variation (CV) of residuals from the regression of eGFR vs time, was calculated spanning 3 months to 2 years after catheterization. Mortality was assessed 2 to 7 years after catheterization. Patients were grouped into 3 HF phenotypes: HF with reduced ejection fraction, HF with preserved ejection, and no HF. Regression was used to evaluate associations between HF phenotypes and variability in the eGFR and between variability in the eGFR and mortality rate with stratification by HF phenotype. Among 3767 participants, the median eGFR at baseline was 45 mL/min/1.73 m2 (interquartile range 33-53 mL/min/1.73 m2), and longitudinal measures of eGFR over 21 months had within-patient residual variability (CV) of 14% (9%-20%). In adjusted analyses, variability in the eGFR was greater in those with HF with preserved ejection (n = 695, CV difference 0.98%, 95% confidence interval 0.14%-1.81%) or HF with reduced ejection fraction (n = 800, CV difference 2.51%, 95% confidence interval 1.66%-3.37%) relative to no HF (n = 2272). In 3068 participants eligible for mortality analysis, the presence of HF and greater variability in the eGFR were each associated independently with higher mortality, but there was no evidence of interaction between variability in the eGFR and any HF phenotype (all P for interaction ≥.49). CONCLUSIONS: Variability in the eGFR is greater in patients with HF and associated with mortality. Prediction algorithms and classification schemes should consider not only static, but also dynamic eGFR variability in HF and CKD prognostication.

Modulation of Small Artery Function by Insulin in Young Women: Role of Adiposity.

OBJECTIVES: Vascular dysfunction is common in obesity. Insulin can directly modulate arterial function, but its role is unclear in obesity. We examined the influence of adiposity on direct effects of insulin on human artery responses. METHODS: 22 healthy women were stratified by median BMI into lower (LA) (n=11) and higher adiposity (HA) (n=11). Small arteries from gluteal biopsies were tested for contractile responses to Noradrenaline (NA), the endothelium-dependent dilator Carbachol and the endothelium-independent dilator sodium nitroprusside were examined before and after incubation with 100 mU/ml human insulin. RESULTS: Contractile responses were similar in the two groups. Insulin reduced NA-induced contraction in HA [3.5 (2.4-4.6) vs. 2.4 (1.4-3.4) mN/mm: p=0.004] but not those from LA [4.1 (2.8-5.3) vs. 3.7 (2.5-5.0) mN/mm: p=0.33]. Endothelium-dependent dilation (EDD) was significantly reduced in arteries from women in the HA (34.7 (18.8-50.6%)) compared to those from women in the LA (62.3 (46.2- 78.4); p=0.013). Insulin improved EDD (change in maximal dilation before/after insulin (%)) in arteries from the HA (37.7 (18.0 to 57.3) but not the LA (6.3 (-6.5 to 19.1), p=0.007. CONCLUSION: Reduced EDD evident in arteries from HA subjects improve by incubating in insulin. Hyperinsulinaemia may be necessary in maintaining endothelial function in obesity.

The prognostic value of diastolic and systolic mechanical left ventricular dyssynchrony among patients with coronary artery disease and heart failure.

BACKGROUND: Prevalence and prognostic value of diastolic and systolic dyssynchrony in patients with coronary artery disease (CAD) + heart failure (HF) or CAD alone are not well understood. METHODS: We included patients with gated single-photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI) between 2003 and 2009. Patients had at least one major epicardial obstruction ≥ 50%. We assessed the association between dyssynchrony and outcomes, including all-cause and cardiovascular death. RESULTS: Of the 1294 patients, HF was present in 25%. Median follow-up was 6.7 years (IQR 4.9-9.3) years with 537 recorded deaths. Patients with CAD + HF had a higher incidence of dyssynchrony than patients with CAD alone (diastolic BW 28.8% for the HF + CAD vs 14.7% for the CAD alone). Patients with CAD + HF had a lower survival than CAD alone at 10 years (33%; 95% CI 27-40 vs 59; 95% CI 55-62, P < 0.0001). With one exception, HF was found to have no statistically significant interaction with dyssynchrony measures in unadjusted and adjusted survival models. CONCLUSIONS: Patients with CAD + HF have a high prevalence of mechanical dyssynchrony as measured by GSPECT MPI, and a higher mortality than CAD alone. However, clinical outcomes associated with mechanical dyssynchrony did not differ in patients with and without HF.

Pulmonary Hypertension Subtypes and Mortality in CKD.

RATIONALE & OBJECTIVE: Pulmonary hypertension (PH) contributes to cardiovascular disease and mortality in patients with chronic kidney disease (CKD), but the pathophysiology is mostly unknown. This study sought to estimate the prevalence and consequences of PH subtypes in the setting of CKD. STUDY DESIGN: Observational retrospective cohort study. SETTING & PARTICIPANTS: We examined 12,618 patients with a right heart catheterization in the Duke Databank for Cardiovascular Disease from January 1, 2000, to December 31, 2014. EXPOSURES: Baseline kidney function stratified by CKD glomerular filtration rate category and PH subtype. OUTCOMES: All-cause mortality. ANALYTICAL APPROACH: Multivariable Cox proportional hazards analysis. RESULTS: In this cohort, 73.4% of patients with CKD had PH, compared with 56.9% of patients without CKD. Isolated postcapillary PH (39.0%) and combined pre- and postcapillary PH (38.3%) were the most common PH subtypes in CKD. Conversely, precapillary PH was the most common subtype in the non-CKD cohort (35.9%). The relationships between mean pulmonary artery pressure, pulmonary capillary wedge pressure, and right atrial pressure with mortality were similar in both the CKD and non-CKD cohorts. Compared with those without PH, precapillary PH conferred the highest mortality risk among patients without CKD (HR, 2.27; 95% CI, 2.00-2.57). By contrast, in those with CKD, combined pre- and postcapillary PH was associated with the highest risk for mortality in CKD in adjusted analyses (compared with no PH, HRs of 1.89 [95% CI, 1.57-2.28], 1.87 [95% CI, 1.52-2.31], 2.13 [95% CI, 1.52-2.97], and 1.63 [95% CI, 1.12-2.36] for glomerular filtration rate categories G3a, G3b, G4, and G5/G5D). LIMITATIONS: The cohort referred for right heart catheterization may not be generalizable to the general population. Serum creatinine data in the 6 months preceding catheterization may not reflect true baseline CKD. Observational design precludes assumptions of causality. CONCLUSIONS: In patients with CKD referred for right heart catheterization, PH is common and associated with poor survival. Combined pre- and postcapillary PH was common and portended the worst survival for patients with CKD.

Percutaneous coronary intervention outcomes in patients with stable coronary disease and left ventricular systolic dysfunction.

AIMS: We sought to better understand the role of percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) and moderate or severe left ventricular systolic dysfunction. METHODS AND RESULTS: Using data from the Duke Databank for Cardiovascular Disease, we analysed patients who underwent coronary angiography at Duke University Medical Center (1995-2012) that had stable CAD amenable to PCI and left ventricular ejection fraction ≤35%. Patients with acute coronary syndrome or Canadian Cardiovascular Society class III or IV angina were excluded. We used propensity-matched Cox proportional hazards to evaluate the association of PCI with mortality and hospitalizations. Of 901 patients, 259 were treated with PCI and 642 with medical therapy. PCI propensity scores created from 24 variables were used to assemble a matched cohort of 444 patients (222 pairs) receiving PCI or medical therapy alone. Over a median follow-up of 7 years, 128 (58%) PCI and 125 (56%) medical therapy alone patients died [hazard ratio 0.87 (95% confidence interval 0.68, 1.10)]; there was also no difference in the rate of a composite endpoint of all-cause mortality or cardiovascular hospitalization [hazard ratio 1.18 (95% confidence interval 0.96, 1.44)] between the two groups. CONCLUSIONS: In this well-profiled, propensity-matched cohort of patients with stable CAD amenable to PCI and moderate or severe left ventricular systolic dysfunction, the addition of PCI to medical therapy did not improve long-term mortality, or the composite of mortality or cardiovascular hospitalization. The impact of PCI on other outcomes in these high-risk patients requires further study.

Echocardiographic Assessment of Right Ventricular Function and Response to Therapy in Pulmonary Arterial Hypertension.

Echocardiography is a key tool in the management of patients with pulmonary arterial hypertension (PAH), but many potential parameters could be used to assess response to therapy. In this retrospective study of 48 patients with severe PAH at baseline, we examined echocardiographic variables before and after initiation of PAH-specific therapy to evaluate which measures of right ventricular (RV) function best correlated with clinical response to therapy as assessed by 6-minute walk distance (6MWD) and 3-year all-cause mortality. Tricuspid annular plane systolic excursion (TAPSE), mid-RV and basal-RV diameters, RV systolic pressure, and RV global longitudinal strain were all found to significantly improve after initiation of a PAH therapy. Decreases in right atrial area (r = -0.50, p = 0.002) and mid-RV diameter (r = -0.36, p = 0.03) were most strongly correlated with improvement in 6MWD. Pretreatment values of RA area (hazard ratio [HR] per 1 SD: 2.72; 95% confidence interval [CI] 1.58, 4.69), mid-RV diameter (HR 2.03; 1.20, 3.45), basal-RV diameter (HR 2.27; 1.40, 3.70), and RV global longitudinal strain (HR 2.36; 1.22, 4.56) were all associated with mortality risk. 6MWD and TAPSE were the 2 variables for which pretreatment measures (6MWD - HR 0.35; 0.17, 0.72; TAPSE - HR 0.41; 0.21, 0.82) and change with treatment (6MWD - HR 0.26; 0.10, 0.64; TAPSE - HR 0.40; 0.21, 0.77) were both significantly associated with 3-year mortality. Change in RV systolic pressure with treatment was significantly associated with mortality (HR 2.55; 1.23, 5.28,) but pretreatment baseline had no association (HR 1.48; 0.72, 3.06). Although many echocardiographic parameters change with initiation of PAH treatment, the strong association of both baseline TAPSE and change in TAPSE with mortality supports the ongoing use of TAPSE as an important measure in the assessment of disease severity and treatment response in PAH.

Racial differences in long-term outcomes among black and white patients with drug-eluting stents.

BACKGROUND: Some studies suggest that black patients may have worse outcomes after drug-eluting stent (DES) placement. There are limited data characterizing long-term outcomes by race. The objective was to compare long-term outcomes between black and white patients after percutaneous coronary intervention (PCI) with DES implantation. METHODS: We analyzed 915 black and 3,559 white (n = 4,474) consecutive patients who underwent DES placement at Duke University Medical Center from 2005 through 2013. Over 6-year follow up, we compared rates of myocardial infarction (MI), all-cause mortality, revascularization, and major bleeding between black and white patients. A multivariable Cox regression model was fit to adjust for potentially confounding variables. Dual-antiplatelet therapy use over time was determined by patient follow-up surveys and compared by race. RESULTS: Black patients were younger; were more often female; had higher body mass indexes; had more diabetes mellitus, hypertension, and renal disease; and had lower median household incomes than white patients (P < .001). At 6 years after DES placement, black relative to white patients had higher unadjusted rates of MI (12.1% vs 10.1%, hazard ratio 1.25, 95% CI 1.00-1.57, P = .05) and major bleeding (17.8% vs 14.3%, hazard ratio 1.28, 95% CI 1.07-1.54, P = .01), but there were no significant differences in other outcomes. After multivariable adjustment, there were no statistically significant racial differences in any of these outcomes at 6 years. Similarly, dual-antiplatelet therapy use was comparable between racial groups. CONCLUSIONS: Unadjusted rates of MI and major bleeding over long-term follow up were higher among black patients compared to white patients, but these differences may be explained by racial differences in comorbid disease.

Trends in cardiorespiratory fitness: The evolution of exercise treadmill testing at a single Academic Medical Center from 1970 to 2012.

OBJECTIVE: To identify temporal trends in the use of exercise treadmill testing (ETT) and cardiorespiratory fitness (CRF) estimated by ETT in metabolic equivalents (METs). PATIENTS AND METHODS: We compiled an ETT database of all available treadmill tests-including those with concomitant stress echocardiography and nuclear perfusion imaging studies-performed at Duke University Hospital from January 1, 1970- December 31, 2012. Six different ramp protocols were used in these combined modalities. CRF at maximal exertion was estimated using established metrics. Eligible patients were required to have no missing data on maximal treadmill speed, grade, and protocol. RESULTS: The most commonly used ETT protocol was the Bruce (n = 28,877), followed by manual test (n = 7390). Since the 1980's, the use of ETT for clinical purposes declined substantially; there was a decreased trend in utilization of 9.4% over the decades 1990-1999 and 2000-2009. When standard protocol (Bruce) was assessed in isolation, trends in CRF decreased progressively from 1970 to 2012 (mean METs (standard deviation): 11.7 (4.3) to 10.5 (3.5)). After adjusting for baseline comorbidities, the trend was reduced to a lesser degree. CONCLUSIONS: The use of ETT at our institution has declined over time, perhaps due to changes in clinical practice. In patients undergoing ETT using the standard Bruce protocol, CRF decreased progressively over the last five decades. Future studies are needed to clarify the etiology of the decrease in use of such a powerful predictor of clinical outcomes in our medical care environment.

The Prognostic Value of Diastolic and Systolic Mechanical Left Ventricular Dyssynchrony Among Patients With Coronary Heart Disease.

OBJECTIVES: The goal of this study was to examine whether diastolic dyssynchrony, measured by using gated single-photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI) in patients with coronary artery disease (CAD), is independently associated with adverse outcomes. BACKGROUND: Systolic left ventricular dyssynchrony is known to be associated with worse clinical outcome in patients with CAD. METHODS: This study included patients who presented to Duke University for GSPECT MPI between 2003 and 2009. Patients had at least 1 major epicardial obstruction ≥50%. Dyssynchrony was assessed by using Emory Cardiac Toolbox software and compared with a control population without CAD. Abnormal degree of diastolic/systolic dyssynchrony was defined as values above 2 SDs above mean of mechanical dyssynchrony parameters. Using Cox proportional hazards modeling, the adjusted association between dyssynchrony and outcomes, including all-cause and cardiovascular death, was assessed. RESULTS: Among 1,310 patients with a median age of 64 years (interquartile range: 55 to 72 years), 69.7% were male and 2.6% had left bundle branch block. Overall, 241 (18.4%) and 238 (18.2%) patients had significant systolic and diastolic mechanical dyssynchrony, respectively, and 211 (16.1%) had both. After a median follow-up of 7.1 years, 543 deaths occurred. At 5 years, the mortality estimate was 21.2% among patients with a normal degree of diastolic left ventricular mechanical dyssynchrony (LVMD) and 41.7% among those with an abnormal degree of LVMD (p < 0.001). When added to clinical comorbidities, electrical dyssynchrony, and systolic LVMD, diastolic dyssynchrony was incrementally associated with cardiovascular mortality (global chi-square statistic of 211.9 vs. 222.8; 2 degrees of freedom; p = 0.004). In a model that also includes left ventricular ejection fraction, the addition of diastolic dyssynchrony to systolic dyssynchrony maintained an incremental prognostic benefit (global chi-square statistic of 234.8 vs. 241.8; p = 0.030). Adjustment for baseline ischemia and scar burden did not change this relationship. CONCLUSIONS: Systolic and diastolic left ventricular dyssynchrony, as measured by using GSPECT MPI, were associated with adverse outcomes. Moreover, diastolic dyssynchrony appears to provide incremental predictive value to clinical history, electrical dyssynchrony, and left ventricular function.

Tricuspid Valve Regurgitation Immediately After Heart Transplant and Long-Term Outcomes.

BACKGROUND: Tricuspid valve regurgitation (TR) is a common finding immediately after cardiac transplantation. However, there is a scarcity of data regarding its implication if left untreated on long-term outcomes and the role of early surgical repair. METHODS: We retrospectively reviewed the Duke University Medical Center transplant database from January 2000 to June 2012 and identified 542 patients who underwent orthotropic heart transplantation. Patients were excluded if they underwent surgical repair for TR during the transplant or if the transplant was part of a multiorgan transplant or redo heart transplantation. TR was assessed intraoperatively after weaning from cardiopulmonary bypass. Independent variables were grade of TR and changes in TR grade during follow-up. TR grades were classified as insignificant (none or mild) versus significant (moderate or severe). Survival and need for posttransplant valve repair during follow-up were assessed. RESULTS: Significant TR was detected in 114 patients (21%) after weaning from cardiopulmonary bypass, with no significant difference in preoperative recipient pulmonary vascular resistance. Significant TR was associated with increased maximum postoperative plasma creatinine (median [interquartile range], 2.2 [1.5 to 3.2] mg/dL vs 1.8 [1.4 to 2.6] mg/dL, p = 0.008), prolonged postoperative stay (median [interquartile range], 12 [9 to 21] days vs 10 [8 to 14] days; p < 0.001), and decreased adjusted survival. Significant TR regressed to insignificant in 91% of recipients by 1 year after transplant. Six recipients (1%) who had significant TR after cardiopulmonary bypass underwent delayed tricuspid valve repair for significant TR during follow-up. CONCLUSIONS: Significant TR is a common finding immediately after transplant and is associated with early morbidity and reduced adjusted survival. Most significant TR resolves by 1 year after transplant. Optimal algorithms for follow-up and treatment of significant TR after heart transplantation need to be defined.

Clinical Utility and Prognostic Value of Right Atrial Function in Pulmonary Hypertension.

Background Although right atrial (RA) enlargement is an established marker for adverse outcomes, the prognostic importance of RA dysfunction independent of RA size in pulmonary arterial hypertension is not known. Methods and Results Study subjects with pulmonary arterial hypertension were prospectively enrolled from 2010 to 2014. RA function was measured using RA speckle-tracking longitudinal strain and strain rate (SR) during each phase of the cardiac cycle: (1) RA reservoir (peak longitudinal strain, peak systolic SR), (2) RA conduit (peak early diastolic SR), and (3) RA active contraction (peak active contraction strain, peak contraction SR). The primary outcome was a composite of time to hospitalization or death assessed on follow-up. A total of 63 subjects had complete echocardiographic data. Of these, 91% were females, and the mean age was 58±12 years. During the follow-up period (range: 1-58 months), 39 were hospitalized or had died. After multivariable adjustment for age, sex, and left atrial size, peak longitudinal strain, peak active contraction strain, and peak early diastolic SR were significantly associated with increased risk of the composite outcome ( P=0.0005, P=0.0167, and P=0.0054, respectively). Conclusions RA dysfunction independently predicts mortality and hospitalizations in patients with pulmonary arterial hypertension.

Long-term outcomes of mitral regurgitation by type and severity.

BACKGROUND: We aimed to determine the association of MR severity and type with all-cause death in a large, real-world, clinical setting. METHODS: We reviewed full echocardiography studies at Duke Echocardiography Laboratory (01/01/1995-12/31/2010), classifying MR based on valve morphology, presence of coronary artery disease, and left ventricular size and function. Survival was compared among patients stratified by MR type and baseline severity. RESULTS: Of 93,007 qualifying patients, 32,137 (34.6%) had ≥mild MR. A total of 8094 (8.7%) had moderate/severe MR, which was primary myxomatous (14.1%), primary non-myxomatous (6.2%), secondary non-ischemic (17.0%), and secondary ischemic (49.4%). At 10 years, patients with primary myxomatous MR or MR due to indeterminate cause had survival rates of >60%; primary non-myxomatous, secondary ischemic, and non-ischemic MR had survival rates <50%. While mild (HR 1.06, 95% CI 1.03-1.09), moderate (HR 1.31, 95% CI 1.27-1.37), and severe (HR 1.55, 95% CI 1.46-1.65) MR were independently associated with all-cause death, the relationship of increasing MR severity with mortality varied across MR types (P ≤ .001 for interaction); the highest risk associated with worsening severity was seen in primary myxomatous MR followed by secondary ischemic MR and primary non-myxomatous MR. CONCLUSIONS: Although MR severity is independently associated with increased all-cause death risk for most forms of MR, the absolute mortality rates associated with worse MR severity are much higher for primary myxomatous, non-myxomatous, and secondary ischemic MR. The findings from this study support carefully defining MR by type and severity.

The relationship between baseline and follow-up left ventricular ejection fraction with adverse events among primary prevention ICD patients.

BACKGROUND: Left ventricular ejection fraction (LVEF) is used to select patients for primary prevention implantable cardioverter defibrillators (ICDs). The relationship between baseline and long-term follow-up LVEF and clinical outcomes among primary prevention ICD patients remains unclear. METHODS: We studied 195 patients with a baseline LVEF ≤35% ≤6 months prior to ICD implantation and follow-up LVEF 1-3 years after ICD implantation without intervening left ventricular assist device (LVAD) or transplant. The co-primary study endpoints were: (1) a composite of time to death, LVAD, or transplant and (2) appropriate ICD therapy. We examined multivariable Cox proportional hazard models with a 3-year post-implant landmark view; the LVEF closest to the 3-year mark was considered the follow-up LVEF for analyses. Follow-up LVEF was examined using 2 definitions: (1) ≥10% improvement compared to baseline or (2) actual value of ≥40%. RESULTS: Fifty patients (26%) had a LVEF improvement of ≥10% and 44 (23%) had a follow-up LVEF ≥40%. Neither baseline nor follow-up LVEF was significantly associated with the composite endpoint. In contrast, both baseline and follow-up LVEF were associated with risk for long-term ICD therapies, whether follow-up LVEF was modeled as a ≥10% absolute improvement (baseline LVEF HR 0.87, CI 0.91-0.93, P < .001; follow-up LVEF HR 0.18, CI 0.06-0.53, P = .002) or a ≥40% follow-up value (baseline LVEF HR 0.89, CI 0.83-0.96, P = .001, follow-up LVEF HR 0.26, CI 0.08-0.87, P = .03). CONCLUSIONS: Among primary prevention ICD recipients, both baseline and follow-up LVEF were independently associated with long-term risk for appropriate ICD therapy, but they were not associated with time to the composite of LVAD, transplant, or death.

Predicting risk of cardiac events among ST-segment elevation myocardial infarction patients with conservatively managed non-infarct-related artery coronary artery disease: An analysis of the Duke Databank for Cardiovascular Disease.

BACKGROUND: Recent randomized evidence has demonstrated benefit with complete revascularization during the index hospitalization for multivessel coronary artery disease ST-segment elevation myocardial infarction (STEMI) patients; however, this benefit likely depends on the risk of future major adverse cardiovascular events (MACE). METHODS: Using data from Duke University Medical Center (2003-2012), we identified those at high risk for 1-year MACE among 664 STEMI patients with conservatively managed non-infarct-related artery (non-IRA) lesions. Using multivariable logistic regression, we identified clinical and angiographic characteristics associated with MACE (death, myocardial infarction, urgent revascularization) to 1 year and developed an integer-based risk prediction model for clinical use. RESULTS: In this cohort (median age 60 years, 30% female), the unadjusted Kaplan-Meier rates for MACE at 30 days and 1 year were 10% and 28%, respectively. Characteristics associated with MACE at 1 year included reduced left ventricular ejection fraction, hypertension, heart failure, higher-risk non-IRA vessels (left main), renal insufficiency, and greater % stenosis of non-IRA lesions. A 15-point risk score including these variables had modest discrimination (C-index 0.67) across a spectrum of subsequent risk (4%-88%) for 1-year MACE. CONCLUSIONS: There is a wide spectrum of risk following primary percutaneous coronary intervention for STEMI patients with multivessel disease. Using readily available clinical characteristics, the expected incidence of MACE by 1 year can be calculated with a simplified risk score, facilitating a tailored approach to clinical care.

Comparison of Clinical Characteristics and Outcomes of Patients With Versus Without Diabetes Mellitus and With Versus Without Angina Pectoris (from the Duke Databank for Cardiovascular Disease).

Angina pectoris (AP) has different prognostic implications in various populations. Patients with diabetes mellitus (DM) may experience neuropathy such that AP may not be perceived in the setting of coronary artery disease (CAD). The prognostic utility of AP in DM patients with CAD is not well known. We analyzed patients with CAD who underwent coronary angiography at Duke University from 2002 to 2011 and compared patients with and without AP within the previous 6 weeks stratified by DM status. We used multivariable Cox regression to assess the association between AP and the outcomes of cardiovascular (CV) hospitalization/revascularization, all-cause mortality/myocardial infarction/revascularization, and all-cause mortality. Of 17,211 patients with CAD, 5,284 (31%) had DM and AP was present in 69% of DM and 67% of non-DM. After risk adjustment, the risk of CV hospitalization/revascularization and all-cause mortality/myocardial infarction/revascularization in patients with and without AP was similar regardless of DM status (all p ≥0.05). In patients with or without DM, AP was associated with lower all-cause mortality compared with no AP (adjusted hazard ratio 0.89, 95% confidence interval 0.82 to 0.97, p = 0.005 for DM patients). The relation between AP status and clinical outcomes was not dependent on DM status (all interaction p >0.10). In conclusion, in patients with CAD, AP was associated with similar risk for CV hospitalization and revascularization and lower all-cause mortality compared with patients without AP regardless of DM status. Future studies are needed to assess whether these findings are related to increased severity of disease in those without AP or whether AP leads to differential management that improves survival.

Race and Sex Differences in QRS Interval and Associated Outcome Among Patients with Left Ventricular Systolic Dysfunction.

BACKGROUND: Prolonged QRS duration is associated with increased mortality among heart failure patients, but race or sex differences in QRS duration and associated effect on outcomes are unknown. METHODS AND RESULTS: We investigated QRS duration and morphology among 2463 black and white patients with heart failure and left ventricular ejection fraction ≤35% who underwent coronary angiography and 12-lead electrocardiography at Duke University Hospital from 1995 through 2011. We used multivariable Cox regression models to assess the relationship between QRS duration and all-cause mortality and investigate race-QRS and sex-QRS duration interaction. Median QRS duration was 105 ms (interquartile range [IQR], 92-132) with variation by race and sex (P<0.001). QRS duration was longest in white men (111 ms; IQR, 98-139) followed by white women (108 ms; IQR, 92-140), black men (100 ms; IQR, 91-120), and black women (94 ms; IQR, 86-118). Left bundle branch block was more common in women than men (24% vs 14%) and in white (21%) versus black individuals (12%). In black patients, there was a 16% increase in risk of mortality for every 10 ms increase in QRS duration up to 112 ms (hazard ratio, 1.16; 95% CI, 1.07, 1.25) that was not present among white patients (interaction, P=0.06). CONCLUSIONS: Black individuals with heart failure had a shorter QRS duration and more often had non-left bundle branch block morphology than white patients. Women had left bundle branch block more commonly than men. Among black patients, modest QRS prolongation was associated with increased mortality.

Comparative Efficacy of Coronary Revascularization Procedures for Multivessel Coronary Artery Disease in Patients With Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease and death, yet little data exist regarding the comparative efficacy of coronary revascularization procedures in CKD patients with multivessel disease. We created a cohort of 4,687 adults who underwent cardiac catheterization, had a serum creatinine value measured within 30 days, and had more than one vessel with ≥50% stenosis. We used Cox proportional hazard regression modeling weighted by the inverse probability of treatment to examine the association between 4 treatment strategies (medical management, percutaneous coronary intervention [PCI] with bare metal stent, PCI with drug-eluting stent, and coronary artery bypass grafting [CABG]) and mortality among patients across categories of estimated glomerular filtration rate; secondary outcome was a composite of mortality, myocardial infarction, or revascularization. Compared with medical management, CABG was associated with a reduced risk of death for patients of any nondialysis CKD severity (hazard ratio [HR] range 0.43 to 0.59). There were no significant mortality differences between CABG and PCI, except a decreased death risk in CABG-treated CKD patients (HR range 0.54 to 0.55). Compared with medical management and PCI, CABG was associated with a lower risk of death, myocardial infarction, or revascularization in nondialysis CKD patients (HR range 0.41 to 0.64). There were similar associations between decreased estimated glomerular filtration rate and increased mortality across all multivessel coronary artery disease patient treatment groups. When accounting for treatment propensity, surgical revascularization was associated with improved outcomes in patients of all CKD severities. A prospective randomized trial in CKD patients is required to confirm our findings.

Revascularization Strategies and Outcomes in Elderly Patients With Multivessel Coronary Disease.

BACKGROUND: Balancing risks and benefits of revascularization in elderly patients with multivessel coronary artery disease (CAD) is challenging. The appropriate revascularization strategy for elderly patients with multivessel CAD is unclear. METHODS: We used the Duke Databank for Cardiovascular Disease to identify patients aged 75 years or more who had multivessel disease and treatment with percutaneous coronary intervention or coronary artery bypass graft surgery (CABG) within 30 days of the index catheterization between October 1, 2003, and June 30, 2013. The primary outcome was a composite of all-cause death, myocardial infarction, and coronary revascularization through latest follow-up. Associations between bare-metal stents (BMS), drug-eluting stents (DES), CABG, and outcomes were determined using multivariable Cox proportional hazards modeling, adjusting for potential confounders with CABG as the reference. Comparisons between BMS and DES were done using BMS as the reference. RESULTS: We identified 763 patients who met the criteria (BMS, n = 202; DES, n = 411; CABG, n = 150). The median age was 79 years (interquartile range, 76 to 82), and the median follow-up was 6.28 years. After adjustment, both BMS and DES were associated with a higher risk of the primary outcome. The BMS versus CABG hazard ratio was 1.58 (95% confidence interval: 1.15 to 2.19, p = 0.01). The DES versus CABG hazard ratio was 1.45 (95% confidence interval: 1.08 to 1.95, p = 0.01). The adjusted hazard ratio for DES versus BMS (0.92, 95% confidence interval: 0.71 to 1.19, p = 0.51) was not statistically significant. CONCLUSIONS: In this single-center analysis of 763 elderly patients with multivessel disease, CABG was associated with the best overall clinical outcomes, but was selected for a minority of patients. An adequately powered, randomized trial should be considered to define the best treatment strategy for this population.