Using logistic regression models to investigate the effects of high-sensitivity cardiac troponin T confounders on ruling in acute myocardial infarction.

OBJECTIVES: Confounding factors, including sex, age, and renal dysfunction, affect high-sensitivity cardiac troponin T (hs-cTnT) concentrations and the acute myocardial infarction (AMI) diagnosis. This study assessed the effects of these confounders through logistic regression models and evaluated the diagnostic performance of an optimized, integrated prediction model. METHODS: This retrospective study included a primary derivation cohort of 18,022 emergency department (ED) patients at a US medical center and a validation cohort of 890 ED patients at a Canadian medical center. Hs-cTnT was measured with 0/3 h sampling. The primary outcome was index AMI diagnosis. Logistic regression models were optimized to predict AMI using delta hs-cTnT and its confounders as covariates. The diagnostic performance of model cutoffs was compared to that of the hs-cTnT delta thresholds. Serial logistic regressions were carried out to evaluate the relationship between covariates. RESULTS: The area under the curve of the best-fitted model was 0.95. The model achieved a 90.0% diagnostic accuracy in the validation cohort. The optimal model cutoff yielded comparable performance (90.5% accuracy) to the optimal sex-specific delta thresholds (90.3% accuracy), with 95.8% agreement between the two diagnostic methods. Serial logistic regressions revealed that delta hs-cTnT played a more predominant role in AMI prediction than its confounders, among which sex is more predictive of AMI (total effect coefficient 1.04) than age (total effect coefficient 0.05) and eGFR (total effect coefficient -0.008). CONCLUSIONS: The integrated prediction model incorporating confounding factors does not outperform hs-cTnT delta thresholds. Sex-specific hs-cTnT delta thresholds remain to provide the highest diagnostic accuracy.

Outcomes Associated with Introduction of the 5th Generation High-Sensitivity Cardiac Troponin in Patients Presenting with Cardiovascular Disorders.

BACKGROUND: The new high-sensitivity cardiac troponin T (hs-cTnT) is now widely used in the United States. OBJECTIVES: We aimed to examine outcomes associated with the introduction of the new 5th generation hs-cTnT assay among patients presenting to the emergency department (ED) with cardiovascular (CV) disorders. METHODS: The study comprised 5377 patients presenting to the ED with CV disorders between January and September 2018. Outcomes included rates of direct ED discharge, cardiac testing/procedures, and mortality. CV indications for troponin testing were categorized as rule-out acute coronary syndrome (RO-ACS) and other-CV (O-CV). RESULTS: Mean age was 62 ± 17 years, and 47% were female. Demographics and medical history did not differ significantly between the troponin groups. The use of hs-cTnT was associated with increased rates of direct discharge from the ED in the RO-ACS (48% vs. 37%; p < 0.01), but not in the O-CV (25% vs. 25%) cohort. Cardiac tests/procedures were more often performed after hs-cTnT vs. cTnT testing in both cohorts (45% vs. 41% for RO-ACS, and 33% vs. 28% for O-CV; p < 0.05 for both). Multivariate analysis demonstrated that hs-cTnT was not associated with a significant increase in postdischarge mortality in both cohorts (RO-ACS: hazard ratio = 1.47 [p = 0.13], O-CV: hazard ratio = 0.97 [p = 0.87]). CONCLUSIONS: Among patients with RO-ACS, hs-cTnT implementation resulted in increased rates of direct home discharge from the ED, without a significant increase in postdischarge mortality. Among patients presenting with O-CV indication, hs-cTnT implementation resulted in increased rates of cardiac testing procedures without an effect of ED discharge rates or long-term mortality.

Outcomes associated with the high sensitivity cardiac troponin testing in patients presenting with non-cardiovascular disorders.

There are limited data regarding the utility of troponin testing in patients presenting with non-cardiovascular (CV) symptoms as the primary manifestation. The study population comprised 2057 patients who presented to the emergency department (ED) of a US healthcare system with non-CV symptoms as the primary manifestation between January and September 2018. We compared the effect of high-sensitivity cardiac troponin T (hs-cTnT) (n = 901) after its introduction vs. 4th generation cTnT (n = 1156) on the following outcomes measures: ED length of stay (LOS), coronary tests/procedures (angiography or stress test), and long-term mortality. Mean age was 64 ± 17 yrs., and 47% were female. Primary non-CV manifestations included pneumonia, obstructive pulmonary disease, infection, abdominal-complaint, and renal failure. Mean follow up was 9 ± 4 months. Patients' demographics and medical history were clinically similar between the two troponin groups. A second cTn test was obtained more frequently in the hs-cTnT than cTnT (84% vs. 32%; p < 0.001), possibly leading to a longer ED stay (8.1 ± 8.2 h vs 5.6 ± 3.4 h, respectively; p < 0.001). Coronary tests/procedures were performed at a significantly higher rate in the hs-cTnT than cTnT following the introduction of the hs-cTnT test (28% vs. 22%, p < 0.001). Multivariate analysis showed that following the introduction of hs-cTnT testing, there was a significant 27% lower risk of long-term mortality from ED admission through follow-up (HR = 0.73, 95%CI 0.54-0.98; p = 0.035). In conclusion, we show that in patients presenting primarily with non-CV disorders, the implementation of the hs-cTnT was associated with a higher rate of diagnostic coronary procedures/interventions, possibly leading to improved long-term survival rates.

Sex-Specific Absolute Delta Thresholds for High-Sensitivity Cardiac Troponin T.

BACKGROUND: Sex differences in high-sensitivity cardiac troponin (hs-cTn) concentrations from healthy populations have led to the establishment of sex-specific upper reference limits for hs-cTn assays. This study assessed the performance of sex-specific delta (i.e., changes in concentrations) thresholds for the hs-cTnT assay for ruling in acute myocardial infarction (AMI) in different emergency department (ED) populations. METHODS: This retrospective study consisted of 2 cohorts (Cohort 1 derivation and Cohort 2 validation). Cohort 1 consisted of 18 056 ED patients who had serial hs-cTnT measured using a 0-h/3-h algorithm at a US medical center, with Cohort 2 consisting of 1137 ED patients with 0-h/3-h sampling at a Canadian medical center. The primary outcome was AMI diagnosis with sex-specific deltas derived based on the Youden index and specificity estimates (i.e., ≥90%) in Cohort 1 and validated in Cohort 2. RESULTS: In Cohort 1, 42% of all patients had 0-h hs-cTnT above the sex-specific 99th percentile. Males had higher 0-h hs-cTnT (median 17 ng/L) and absolute deltas (median 2 ng/L) than females (0-h median 11 ng/L, P < 0.0001; deltas median 1 ng/L, P < 0.0001) in non-AMI patients but not in patients with AMI. For ruling in AMI, the sex-specific delta thresholds based on 90% specificity (14 ng/L for males, 11 ng/L for females) performed best and resulted in 91% diagnostic accuracy in both males and females. The sex-specific delta thresholds yielding high specificity estimates were confirmed in the validation data set. CONCLUSIONS: Sex-specific absolute delta thresholds can be used to rule in AMI and are robust across different study populations.

Impact of non-cardiovascular disease burden on thirty-day hospital readmission in heart failure patients.

BACKGROUND: Little is known about the impact of non-cardiovascular disease (CVD) burden on 30- -day readmission in heart failure (HF) patients. The aim of the study was to assess the role of non-CVD burden on 30-day readmission in HF patients. \ METHODS: We analyzed the effect of non-CVD burden by frequency of ICD-9 code categories on readmis-sions of patients discharged with a primary diagnosis of HF. We first modeled the probability of readmis-sion within 30 days as a function of demographic and clinical covariates in a randomly selected training dataset of the total cohort. Variable selection was carried out using a bootstrap LASSO procedure with 1000 bootstrap samples, the final model was tested on a validation dataset. Adjusted odds ratios and confidence intervals were reported in the validation dataset. RESULTS: There were a total of 6228 HF hospitalizations, 1523 (24%) with readmission within 30 days of discharge. The strongest predictor for 30-day readmissions was any hospital admission in the prior year (p < 0.001). Cardiovascular risk factors did not enter the final model. However, digestive system diseases increased the risk for readmission by 17% for each diagnosis (p = 0.046), while respiratory diseases and genitourinary diseases showed a trend toward a higher risk of readmission (p = 0.07 and p = 0.09, respectively). Non-CVDs out-competed cardiovascular covariates previously reported to predict readmission. CONCLUSIONS: In patients with HF hospitalization, prior admissions predicted 30-day readmission. Diseases of the digestive system also increase 30-day readmission rates. Assessment of non-CVD burden in HF patients could serve as an important risk marker for 30-day readmissions.

Clinical Implications of Complete Left-Sided Reverse Remodeling With Cardiac Resynchronization Therapy: A MADIT-CRT Substudy.

BACKGROUND: Clinical implications of complete left-sided reverse remodeling due to cardiac resynchronization therapy with a defibrillator (CRT-D), defined as reduction in both left ventricular end-systolic volume (LVESV) and left atrial volume (LAV), are unknown. OBJECTIVES: This study aimed to evaluate the rate and predictive value of complete left-sided reverse remodeling on heart failure (HF) and death events in CRT-D patients with left bundle branch block (LBBB) enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). METHODS: The study population comprised 533 CRT-D patients with LBBB, 212 (40%) with complete left-sided reverse remodeling (above-median change in both LAV and LVESV), 115 (22%) with discordant reverse remodeling (above-median change in only LAV or LVESV), and 206 (38%) with lesser reverse remodeling (below-median LAV and LVESV change). The primary endpoint was HF or death; secondary endpoints included HF alone and death alone during long-term follow-up. RESULTS: Patients with complete left-sided reverse remodeling had a significantly lower rate of HF or death than those with discordant reverse remodeling or lesser reverse remodeling (p < 0.001). Multivariate Cox proportional hazard models consistently showed a decreased risk for HF and death in patients with complete reverse remodeling compared with discordant reverse remodeling or lesser reverse remodeling (hazard ratio: 0.66 per each group; 95% CI: 0.50 to 0.85; p = 0.002). This finding was similar for HF alone and death alone. CONCLUSIONS: In MADIT-CRT, >20% of CRT-D patients exhibited discordant reverse remodeling in the left ventricle and the left atrium. CRT-D patients with LBBB and complete left-sided reverse remodeling had a significantly lower risk of HF and death, HF alone, and death alone during long-term follow-up than patients with discordant or lesser reverse remodeling. (MADIT-CRT: Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

Inverse Relationship of Blood Pressure to Long-Term Outcomes and Benefit of Cardiac Resynchronization Therapy in Patients With Mild Heart Failure: A Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy Long-Term Follow-Up Substudy.

BACKGROUND: Previous studies have shown that low blood pressure is associated with increased mortality and heart failure (HF) in patients with left ventricular dysfunction. Cardiac resynchronization therapy (CRT) was shown to increase systolic blood pressure (SBP). Therefore, we hypothesized that treatment with CRT would provide incremental benefit in patients with lower SBP values. METHODS AND RESULTS: The independent contribution of SBP to outcome was analyzed in 1267 patients with left bundle brunch block enrolled in Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). SBP was assessed as continuous measures and further categorized into approximate quintiles. The risk of long-term HF or death and CRT with defibrillator versus implantable cardioverter defibrillator benefit was assessed in multivariate Cox proportional hazards regression models. Multivariate analysis showed that in the implantable cardioverter defibrillator arm, each 10-mm Hg decrement of SBP was independently associated with a significant 21% (P<0.001) increased risk for HF or death, and patients with lower quintile SBP (<110 mm Hg) experienced a corresponding >2-fold risk-increase. CRT with defibrillator provided the greatest HF or mortality risk reduction in patients with SBP<110 mm Hg hazard ratio of 0.34, P<0.001, when compared with hazard ratio of 0.52, P<0.001, in those with 110>SBP≥136 mm Hg and hazard ratio of 0.94, P=0.808, with SBP>136 mm Hg (P for trend=0.001). CONCLUSIONS: In patients with mild HF, prolonged QRS, and left bundle brunch block, low SBP is related to higher risk of mortality or HF with implantable cardioverter defibrillator therapy alone. Treatment with CRT is associated with incremental clinical benefits in patients with lower baseline SBP values. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Atrioventricular delay programming and the benefit of cardiac resynchronization therapy in MADIT-CRT.

BACKGROUND: The optimal atrioventricular pacing delay (AVD) in cardiac resynchronization therapy (CRT) remains to be determined. OBJECTIVE: To determine whether programming CRT devices to short AVD (S-AVD) will improve clinical response secondary to greater reductions in dyssynchrony. METHODS: The study population comprised 1235 patients with left bundle branch block enrolled in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy (MADIT-CRT). We assessed the relationship between AVD and outcomes. Patients programmed to S-AVD (median value of <120 ms; n = 337) vs long AVD (L-AVD; ≥120 ms; n = 390) were assessed for the end points of heart failure (HF) or death, death alone, and echocardiographic response to the CRT at 1-year follow-up. Outcomes were also compared to the left bundle branch block implantable cardioverter-defibrillator-only group (n = 508). RESULTS: Multivariate analysis showed that patients programmed to S-AVD experienced a significant 33% (hazard ratio [HR] 0.67; 95% confidence interval [CI] 0.44-0.85; P = .037) reduction in the risk of HF or death and a 47% (HR 0.53; 95% CI 0.29-0.94; P = .031) reduction in death alone as compared with those programmed to L-AVD. Patients with CRT-programmed S-AVD and L-AVD experienced 63% (HR 0.37; 95% CI 0.26-0.53; P < .001) and 46% (HR 0.54; 95% CI 0.31-0.96; P < .001) reduction, respectively, in the risk of HF or death compared to patients with implantable cardioverter-defibrillator alone. At 1 year of follow-up, S-AVD vs L-AVD was associated with a greater reduction in left ventricular end-systolic volume (34.2% vs 30.8%; P = .002) along with a significantly greater improvement in dyssynchrony (22.3% vs 9.4%; P = .036). CONCLUSIONS: Our findings indicate that in MADIT-CRT programming, the CRT AVD <120 ms was associated with a greater clinical and echocardiographic response to CRT.

Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome.

BACKGROUND: Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. OBJECTIVES: To hypothesize that the assessment of QTc variance in patients with congenital LQTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. METHODS: The study population comprised 1206 patients with LQTS with 95 different mutations and ≥ 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. RESULTS: Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P = .002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P = .95; P value for QTcSD-by-genotype interaction = .002). CONCLUSIONS: Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype.