Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

BACKGROUND: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. METHODS: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. RESULTS: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, -2.26 to 2.37]; P=0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P=0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, -0.64 to 3.36]; P=0.18) and 6-month follow-up (adjusted mean difference, -0.37 [95% CI, -2.52 to 1.78]; P=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. CONCLUSIONS: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03296813.

Association of Acute Kidney Injury and Cardiovascular Disease Following Percutaneous Coronary Intervention: Assessment of Interactions by Race, Diabetes, and Kidney Function.

RATIONALE & OBJECTIVE: Black patients and those with diabetes or reduced kidney function experience a disproportionate burden of acute kidney injury (AKI) and cardiovascular events. However, whether these factors modify the association between AKI and cardiovascular events after percutaneous coronary intervention (PCI) is unknown and was the focus of this study. STUDY DESIGN: Observational cohort. SETTING & PARTICIPANTS: Patients who underwent PCI at Duke between January 1, 2003, and December 31, 2013, with data available in the Duke Databank for Cardiovascular Disease. EXPOSURE: AKI, defined as ≥1.5-fold relative elevation in serum creatinine within 7 days from a reference value ascertained 30 days before PCI, or a 0.3 mg/dL increase from the reference value within 48 hours. OUTCOME: A composite of all-cause death, myocardial infarction, stroke, or revascularization during the first year after PCI. ANALYTICAL APPROACH: Cox regression models adjusted for potential confounders and with interaction terms between AKI and race, diabetes, or baseline estimated glomerular filtration rate (eGFR). RESULTS: Among 9,422 patients, 9% (n = 865) developed AKI, and the primary composite outcome occurred in 21% (n = 2,017). AKI was associated with a nearly 2-fold higher risk of the primary outcome (adjusted HR, 1.94 [95% CI, 1.71-2.20]). The association between AKI and cardiovascular risk did not significantly differ by race (P interaction, 0.4), diabetes, (P interaction, 0.06), or eGFR (P interaction, 0.2). However, Black race and severely reduced eGFR, but not diabetes, each had a cumulative impact with AKI on risk for the primary outcome. Compared with White patients with no AKI as the reference, the risk for the outcome was highest in Black patients with AKI (HR, 2.27 [95% CI, 1.83-2.82]), followed by White patients with AKI (HR, 1.87 [95% CI, 1.58-2.21]), and was least in patients of other races with AKI (HR, 1.48 [95% CI, 0.88-2.48]). LIMITATIONS: Residual confounding, including the impact of clinical care following PCI on cardiovascular outcomes of AKI. CONCLUSIONS: Neither race, diabetes, nor reduced eGFR potentiated the association of AKI with cardiovascular risk, but Black patients with AKI had a qualitatively greater risk than White patients with AKI or patients of other races with AKI. PLAIN-LANGUAGE SUMMARY: This study examined differences by race, diabetes, or kidney function in the well-known association of AKI with increased risk for cardiovascular outcomes among patients undergoing percutaneous coronary intervention. The authors found that AKI was associated with a greater risk for cardiovascular outcomes, but this risk did not differ by patients' race, diabetes status, or level of kidney function before the procedure. That said, the risk for cardiovascular outcomes was numerically highest among Black patients compared with White patients or those of other races. These study findings suggest that future efforts to prevent AKI among patients undergoing the procedure could reduce racial disparities in risk for unfavorable cardiovascular outcomes afterward.

Morbidity and Mortality Associated With Heart Failure in Acute Coronary Syndrome: A Pooled Analysis of 4 Clinical Trials.

BACKGROUND: Heart failure (HF) may complicate acute coronary syndrome (ACS) and is associated with a high burden of short- and long-term morbidity and mortality. Only limited data regarding future ischemic events and rehospitalization are available for patients who suffer HF before or during ACS. METHODS: A secondary analysis of 4 large ACS trials (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) using Cox proportional hazards models was performed to investigate the association of HF status (no HF, chronic HF, de novo HF) at presentation for ACS with all-cause and cardiovascular death, major adverse cardiovascular event (MACE ), myocardial infarction, stroke, and hospitalization for heart failure (HHF) by 1 year. Cumulative incidence plots are presented at 30 days and 1 year. RESULTS: A total of 11.1% of the 47,474 patients presenting with ACS presented with evidence of acute HF, 55.0% of whom presented with de novo HF. Patients with chronic HF presented with evidence of acute HF at a higher rate than those with no previous HF (40.3% vs 6.9%). Compared to those without HF, those with chronic and de novo HF had higher rates of all-cause mortality (adjusted hazard ratio [aHR] 2.01, 95% confidence interval [CI] 1.72-2.34 and aHR 1.47, 95% CI1.15-1.88, respectively), MACE (aHR 1.47, 95% CI1.31-1-.66 and aHR 1.38, 95% CI1.12-1.69), and HHF (aHR 2.29, 95% CI2.02-2.61 and aHR 1.48, 95% CI 1.20-1.82) at 1 year. CONCLUSION: In this large cohort of patients with ACS, both prior and de novo HF complicating ACS were associated with significantly higher risk-adjusted rates of death, ischemic events and HHF at 30 days and 1 year. Further studies examining the association between HF and outcomes in this high-risk population are warranted, especially given the advent of more contemporary HF therapies.

Trends of blood pressure control in the U.S. during the COVID-19 pandemic.

IMPORTANCE: COVID-19 altered lifestyles and disrupted routine health care. Whether blood pressure (BP) control worsened during COVID-19 is unknown. OBJECTIVE: To understand whether home BP control worsened during COVID-19 across the United States (US) . DESIGN, SETTING, AND PARTICIPANTS: A population-based analysis of home BP data from 72,706 participants enrolled in a digital health hypertension control program. Data was compared before (January 2019 to March 2020) and during (April 2020 to August 2020) COVID-19. MAIN OUTCOMES AND MEASURES: Monthly mean home BP readings, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were quantified before and during the pandemic. Multivariable adjustments were made for age, sex, race, region, and months enrolled. Home BP readings were also classified based on monthly averages and highest home BP readings into risk groups: Stage 2 HTN: BP> = 135 or DBP> = 85; Uncontrolled HTN: SBP> = 145 or DBP> = 95; or Severely uncontrolled HTN: SBP> = 160 or DBP> = 100). RESULTS: Overall, 72,706 participants were enrolled in a digital health hypertension program between 1/1/2019 and 8/31/2020. Compared with participants pre-COVID-19 (n = 33,440), those during COVID-19 (n = 39,266) were of similar age (mean 53.0 ± 10.7 years vs 53.3 ± 10.8 years); sex (46% vs 50.6% female) and race (29.1% vs 34.2% non-white). Relative to pre-Covid (Apr-Aug 2019) the mean monthly number of home BP readings rose during COVID-19 (Apr-Aug, 2020), from 7.3 to 9.3 per month (P < .001). During COVID-19, participants had higher monthly adjusted mean SBP (131.6 mmHg vs. 127.5 mmHg, P < .001); DBP (80.2 mmHg vs. 79.2 mmHg, P < .001); and MAP (97.4 mmHg vs. 95.3 mmHg; P < .001). Relative to the pre-pandemic period, during COVID-19 the proportion of participants with a mean monthly BP classified as uncontrolled or severely uncontrolled hypertension also rose, 15% vs 19% and 4% vs 5%, respectively CONCLUSIONS AND RELEVANCE: Based on home BP readings, mean monthly BP rose modestly after COVID-19, despite increased utilization of home monitoring. Further studies are needed to examine the longitudinal effects of the pandemic on cardiovascular disease risk factors, the impact of these on long-term population health.

Clinical trajectory of patients with a worsening heart failure event and reduced ventricular ejection fraction.

BACKGROUND: Recent data suggest that patients with heart failure with reduced ejection fraction (HFrEF) and worsening heart failure (WHF) have potential for greater benefit from newer HF therapies. We investigated characteristics and outcomes of patients with HFrEF and WHF by severity of left ventricular dysfunction. METHODS: We identified patients with chronic symptomatic HFrEF (left ventricular ejection fraction [LVEF] ≤35%) and evidence of WHF (emergency department visit or hospitalization for acute HF within 12 months of index echocardiogram) treated at Duke University between 1/2009 and 12/2018. Patients were stratified by LVEF≤25% or 26% to35%. Cox models were used to estimate cause-specific hazard ratios and 5-year event incidence of death and hospitalization across the range of LVEF. RESULTS: Of 2823 patients with HFrEF and WHF, 1620 (57.4%) had an LVEF≤25% and 1203 (42.6%) had an LVEF 26% to35%. Compared to patients with LVEF 26% to35%, those with LVEF≤25% were younger and more commonly men with a lower cardiovascular comorbidity burden. Patients with LVEF≤25% were less commonly on beta blockers (85.9% vs 90.5%) but more commonly treated with mineralocorticoid receptor antagonists (49.3% vs 41.1%) and implantable defibrillators (41.3% vs 28.2%). Patients with LVEF≤25% had significantly higher hazards for death (HR 1.24 [95% CI 1.11 - 1.38]), all-cause hospitalization (HR 1.21 [95% CI 1.10 - 1.33]), and HF hospitalization (HR 1.25 [95% CI 1.1 - 1.38]) through 5-years. CONCLUSIONS: More than half of patients with chronic HFrEF and WHF have severe LV dysfunction. Important differences in comorbidities, HF therapies, and outcomes exist between those with LVEF≤25% and those with LVEF 26% to35%.

Polypharmacy in Palliative Care for Advanced Heart Failure: The PAL-HF Experience.

BACKGROUND: Palliative care (PC) in advanced heart failure (HF) aims to improve symptoms and quality of life (QOL), in part through medication management. The impact of PC on polypharmacy (>5 medications) remains unknown. METHODS AND RESULTS: We explored patterns of polypharmacy in the Palliative Care in HF (PAL-HF) randomized controlled trial of standard care vs interdisciplinary PC in advanced HF (N = 150). We describe differences in medication counts between arms at 2, 6, 12, and 24 weeks for HF (12 classes) and PC (6 classes) medications. General linear mixed models were used to evaluate associations between treatment arm and polypharmacy over time. The median age of the patients was 72 years (interquartile range 62-80 years), 47% were female, and 41% were Black. Overall, 48% had ischemic etiology, and 55% had an ejection fraction of 40% or less. Polypharmacy was present at baseline in 100% of patients. HF and PC medication counts increased in both arms, with no significant differences in counts by drug class at any time point between arms. CONCLUSIONS: In a trial of patients with advanced HF considered eligible for PC, polypharmacy was universal at baseline and increased during follow-up with no effect of the palliative intervention on medication counts relative to standard care.

Racial Differences in AKI Incidence Following Percutaneous Coronary Intervention.

BACKGROUND: Undergoing percutaneous coronary intervention (PCI) is a risk factor for AKI development, but few studies have quantified racial differences in AKI incidence after this procedure. METHODS: We examined the association of self-reported race (Black, White, or other) and baseline eGFR with AKI incidence among patients who underwent PCI at Duke University Medical Center between January 1, 2003, and December 31, 2013. We defined AKI as a 0.3 mg/dl absolute increase in serum creatinine within 48 hours, or ≥1.5-fold relative elevation within 7 days post-PCI from the reference value ascertained within 30 days before PCI. RESULTS: Of 9422 patients in the analytic cohort (median age 63 years; 33% female; 75% White, 20% Black, 5% other race), 9% developed AKI overall (14% of Black, 8% of White, 10% of others). After adjustment for demographics, socioeconomic status, comorbidities, predisposing medications, PCI indication, periprocedural AKI prophylaxis, and PCI procedural characteristics, Black race was associated with increased odds for incident AKI compared with White race (odds ratio [OR], 1.79; 95% confidence interval [95% CI], 1.48 to 2.15). Compared with Whites, odds for incident AKI were not significantly higher in other patients (OR, 1.30; 95% CI, 0.93 to 1.83). Low baseline eGFR was associated with graded, higher odds of AKI incidence (P value for trend <0.001); however, there was no interaction between race and baseline eGFR on odds for incident AKI (P value for interaction = 0.75). CONCLUSIONS: Black patients had greater odds of developing AKI after PCI compared with White patients. Future investigations should identify factors, including multiple domains of social determinants, that predispose Black individuals to disparate AKI risk after PCI.

Predicting major adverse limb events in individuals with type 2 diabetes: Insights from the EXSCEL trial.

AIMS: Although models exist to predict amputation among people with type 2 diabetes with foot ulceration or infection, we aimed to develop a prediction model for a broader range of major adverse limb events (MALE)-including gangrene, revascularization and amputation-among individuals with type 2 diabetes. METHODS: In a post-hoc analysis of data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, we compared participants who experienced MALE with those who did not. A multivariable model was constructed and translated into a risk score. RESULTS: Among the 14,752 participants with type 2 diabetes in EXSCEL, 3.6% experienced MALE. Characteristics associated with increased risk of MALE were peripheral artery disease (PAD) (HRadj 4.83, 95% CI: 3.94-5.92), prior foot ulcer (HRadj 2.16, 95% CI: 1.63-2.87), prior amputation (HRadj 2.00, 95% CI: 1.53-2.64), current smoking (HRadj 2.00, 95% CI: 1.54-2.61), insulin use (HRadj 1.86, 95% CI: 1.52-2.27), coronary artery disease (HRadj 1.67, 95% CI: 1.38-2.03) and male sex (HRadj 1.64, 95% CI: 1.31-2.06). Cerebrovascular disease, former smoking, age, glycated haemoglobin, race and neuropathy were also associated significantly with MALE after adjustment. A risk score ranging from 6 to 96 points was constructed, with a C-statistic of 0.822 (95% CI: 0.803-0.841). CONCLUSIONS: The majority of MALE occurred among participants with PAD, but participants without a history of PAD also experienced MALE. A risk score with good performance was generated. Although it requires validation in an external dataset, this risk score may be valuable in identifying patients requiring more intensive care and closer follow-up.

Peripheral blood metabolite profiles associated with new onset atrial fibrillation.

BACKGROUND: Peripheral blood metabolite profiles have yielded mechanistic insights into various cardiovascular disease states. We hypothesized that peripheral blood metabolite profiles would be associated with new onset atrial fibrillation (AF). METHODS AND RESULTS: The study population comprised 1892 patients without AF at baseline, who, as part the MURDOCK Cardiovascular Disease Study molecular profiling cohort (n = 2023), had previously had determination of levels of 69 metabolites from frozen, fasting plasma specimens obtained during coronary angiography. We used Cox proportional hazards models to examine the association of 13 uncorrelated metabolite factors created from these data using principal components analysis (PCA) with new occurrences of AF during a median follow up of 2.8 (0.1-4.9) years. A total of 233 patients developed new AF (12.3%) during follow up. Patients with new onset AF were older (median 67 vs. 60 years); more often white (82 vs. 71%) and male (68 vs. 60%), and had more comorbidities than those who did not develop AF. After adjustment, PCA factor 1 (medium chain acylcarnitines; hazard ratio [HR]: 1.11 [1.01-1.22]), factor 2 (short chain dicarboxylacylcarnitines; HR: 1.21 [1.09-1.34]) and factor 5 (long chain acylcarnitines; HR: 1.19 [1.06-1.34]) were associated with new onset AF. CONCLUSION: Metabolite profiles were associated with new onset AF among patients referred for coronary angiography. Validation of these observations in broader patient populations may provide better mechanistic insight into the development of AF, and may provide new opportunities for prevention and treatment.

Claims-based cardiovascular outcome identification for clinical research: Results from 7 large randomized cardiovascular clinical trials.

BACKGROUND: Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes. METHODS: We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection. RESULTS: Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest. CONCLUSIONS: Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

Discharge timing and outcomes after uncomplicated non-ST-segment elevation acute myocardial infarction.

BACKGROUND: Length of stay after non-ST-segment elevation myocardial infarction (NSTEMI) continues to decrease, but information to guide duration of hospitalization is limited. METHODS: We used landmark analyses, in which the landmark defined potential days of discharge, to estimate complication rates on the first day the patient would have been out of the hospital, and estimated associations between timing of discharge and 30-day and 1-year event-free survival after discharge among NSTEMI patients. RESULTS: Among 20,410 NSTEMI patients, median length of stay was 7 (4, 12) days; 3,209 (15.7%) experienced a cardiac complication on days 0 to 2 and 1,322 (6.5%) were discharged without complications during hospital days 0 to 2. At the start of day 3, 15,879 patients (77.8%) were still hospitalized without complications. Of these, 1,689 (10.6%) were discharged event-free on day 3. Adjusted event-free survival rates of death or myocardial infarction from day 4 to 30 days after among the 1,689 patients was 99.1% compared with 93.1% for the 14,190 who remained hospitalized at the end of day 3. For 1-year mortality, these rates were 98.1% and 96.4%, respectively. Among 13,334 patients hospitalized without complications at the start of day 4, 1,706 were discharged event-free that day. Adjusted survival rates among these patients, compared with those still hospitalized at the end of day 4, were 98.0% versus 93.7% for 30-day death or myocardial infarction and 97.8% versus 96.1% for 1-year mortality. CONCLUSIONS: Patients with NSTEMI who had no serious complications during the first 2 hospital days were at low risk of subsequent short- and intermediate-term death or ischemic events.

Safety of ticagrelor in patients with baseline conduction abnormalities: A PLATO (Study of Platelet Inhibition and Patient Outcomes) analysis.

BACKGROUND: Although bradyarrhythmias have been observed with ticagrelor and its use with advanced atrioventricular block is not recommended, questions arise regarding its use in patients with mild conduction abnormalities. The objectives were to compare rates of clinically relevant arrhythmias in relation to any mild baseline conduction abnormality in patients with acute coronary syndrome randomized to ticagrelor versus clopidogrel. METHODS: We included all subjects in the electrocardiographic (ECG) substudy of the Platelet Inhibition and Patient Outcomes trial, excluding those with missing baseline ECG or with a pacemaker at baseline (N = 15,460). Conduction abnormality was defined as sinus bradycardia, first-degree atrioventricular block, hemiblock, or bundle-branch block. The primary arrhythmic outcome was the composite of any symptomatic brady- or tachyarrhythmia, permanent pacemaker placement, or cardiac arrest through 12 months. RESULTS: Patients with baseline conduction abnormalities (n = 4,256, 27.5%) were older and more likely to experience the primary arrhythmic outcome. There were no differences by ticagrelor versus clopidogrel in the composite arrhythmic end point in those with baseline conduction disease (1-year cumulative incidence rate: 17% for both study arms; hazard ratio: 0.99 [0.86-1.15]) or without baseline conduction disease (1-year cumulative incidence rate: clopidogrel 12.8% vs ticagrelor 12.4%; hazard ratio: 0.98 (0.88-1.09). There were also no statistically significant differences between ticagrelor and clopidogrel in the rates of bradycardic (or any individual arrhythmic) events in patients with baseline conduction abnormalities. CONCLUSIONS: Ticagrelor compared to clopidogrel did not increase arrhythmic events even in subjects with acute coronary syndrome who present with mild conduction abnormalities on their baseline ECG.

Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial.

AIMS: Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS. METHODS AND RESULTS: In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring >30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P < 0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P = 0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P = 0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P < 0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event. CONCLUSION: In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding.

An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome.

BACKGROUND: Studies have suggested a relationship between higher baseline serum uric acid (sUA) levels and an elevated risk of subsequent ischemic cardiovascular outcomes among acute coronary syndrome (ACS) patients; this relationship may be modified by a clinical history of gout and has not been studied in large patient cohorts. We sought to understand the effect of sUA and gout on ACS outcomes. METHODS: Using PLATO and TRACER data on 27,959 ACS patients, we evaluated baseline sUA levels in relation to a composite of cardiovascular death, myocardial infarction (MI), or stroke. We assessed interaction terms to determine if a baseline clinical diagnosis of gout modified this putative relationship; 46% (n=12,882) had sUA levels elevated >6.0 mg/dL. RESULTS: Patients with elevated levels were more often male with a history of prior MI, diabetes, and heart failure compared with those with sUA <6.0 mg/dL. The unadjusted risk of the composite endpoint increased with corresponding elevations in sUA levels (per 1 mg/dL increase) (HR=1.23 [95% CI: 1.20-1.26]) above the statistical inflection point of 5.0 mg/dL. After adjustment, the association between sUA level and the composite outcome remained significant (HR=1.07 [95% CI: 1.04-1.10]), and baseline gout did not modify this relationship. CONCLUSIONS: In patients with ACS, increasing levels of sUA are associated with an elevated risk of cardiovascular events, regardless of a clinical diagnosis of gout. Further investigation is warranted to determine the mechanism behind this relationship and to delineate whether sUA is an appropriate therapeutic target to reduce cardiovascular risk.

Differential occurrence, profile, and impact of first recurrent cardiovascular events after an acute coronary syndrome.

OBJECTIVE: Acute coronary syndrome (ACS) trials typically use a composite primary outcome (myocardial infarction [MI], stroke, or cardiovascular death), but differential patient characteristics, timing, and consequences associated with individual component end points as first events have not been well studied. We compared patient characteristics and prognostic significance associated with first cardiovascular events in the post-ACS setting for initially stabilized patients. METHODS: We combined patient-level data from 4 trials of post-ACS antithrombotic therapies (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) to characterize the timing of and characteristics associated with first cardiovascular events (MI, stroke, or cardiovascular death). Landmark analysis at 7 days after index ACS presentation was used to focus on spontaneous, postdischarge events that were not confounded by in-hospital procedural complications. Using a competing risk framework, we tested for differential associations between prespecified covariates and the occurrence of nonfatal stroke vs MI as the first event, and we examined subsequent events after the first nonfatal event. RESULTS: Among 46,694 patients with a median follow-up of 358 (25th, 75th percentiles 262, 486) days, a first ischemic event occurred in 4,307 patients (9.2%) as follows: MI in 5.8% (n = 2,690), stroke in 1.0% (n = 477), and cardiovascular death in 2.4% (n = 1,140). Older age, prior stroke/transient ischemic attack, prior atrial fibrillation, and higher diastolic blood pressure were associated with a significantly greater risk of stroke vs MI, whereas prior percutaneous coronary intervention was associated with a greater risk of MI vs stroke. Second events occurred in 32% of those with a first nonfatal stroke at a median of 13 (3, 59) days after the first event and in 32% of those with a first nonfatal MI at a median of 35 (5, 137) days after the first event. The most common second event was a recurrent MI among those with MI as the first event and cardiovascular death among those with stroke as the first event. CONCLUSIONS: Approximately 9% of patients experienced a first cardiovascular event in the post-ACS setting during a median follow-up of 1 year. Although the profile and prognostic implications of stroke vs MI as the first nonfatal event differ substantially, approximately one-third of these patients experienced a second event, typically soon after the first event. These findings have implications for improving post-ACS care and influencing the design of future cardiovascular trials.

Renal failure in patients with ST-segment elevation acute myocardial infarction treated with primary percutaneous coronary intervention: Predictors, clinical and angiographic features, and outcomes.

BACKGROUND: Among patients presenting with ST-segment elevation myocardial infarction (STEMI) for primary percutaneous coronary intervention (PCI), the associations between clinical outcomes and both baseline renal function and the development of acute kidney injury (AKI) have not been reported in a trial population with unselected baseline renal function. METHODS: Patients enrolled in the APEX-AMI trial who underwent primary PCI for the treatment of STEMI were categorized according to (a) baseline renal function and (b) the development of AKI. Patient characteristics, clinical outcomes, and treatment patterns were analyzed according to baseline renal function and the development of AKI. A prediction model for AKI after primary PCI for STEMI was also developed. RESULTS: A total of 5,244 patients were included in this analysis and stratified according to baseline estimated glomerular filtration rate (eGFR) (milliliters per minute per 1.73 m(2)) of >90, 60 to 90, 30 to 59, or <30 or as dialysis dependent. Patients with lower eGFR were older, more often female, and less often treated with evidence-based medicines and had worse angiographic outcomes and higher mortality. The rates of AKI for patients with a baseline eGFR of >90, 60 to 90, 30 to 59, and <30 were 2.5%, 4.1%, 8.1%, and 1.6%, respectively (P < .0001). The strongest predictors of AKI were age and presenting in Killip class III or IV. CONCLUSIONS: Among patients undergoing primary PCI for STEMI, impaired renal function at presentation and development of post-PCI AKI were highly associated with worse clinical and angiographic outcomes, including death. The risk of developing AKI was low and only modestly associated with baseline renal function.

Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial.

BACKGROUND: Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes. METHODS: Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (≥30 but <300 mg/dL), or macroalbuminuria (≥300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute ≥0.3 mg/dL or relative ≥50%), was descriptively reported. RESULTS: Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98). CONCLUSIONS: High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.

Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

BACKGROUND: In the PLATO trial, ticagrelor was superior to clopidogrel in reducing cardiovascular events among patients with acute coronary syndrome (ACS) at the expense of increased nonfatal bleeding. Because Asian patients, when compared with non-Asian patients, are believed to be more susceptible to bleeding, we evaluated the effects of ticagrelor compared with clopidogrel in Asian (n=1,106) and non-Asian (n=17,515) patients with acute coronary syndrome enrolled in the PLATO study. METHODS AND RESULTS: Interaction between Asian/non-Asian and primary efficacy end point (a composite of vascular death, myocardial infarction, and stroke) and net clinical benefit (composite of primary efficacy end point and coronary artery bypass graft [CABG] surgery or non-CABG-related major bleeding) were evaluated with a Cox proportional hazards model. Baseline demographics and comorbidities were different between Asians and non-Asians. The overall cardiovascular event rates were higher in Asians, but bleeding rates were similar. Despite these observed differences, the effects of ticagrelor versus clopidogrel were not significantly different between Asians and non-Asians with respect to the primary efficacy outcome (hazard ratio for Asians vs non-Asians, 0.84 [95% CI 0.61-1.17] vs 0.85 [95% CI 0.77-0.93], P=.974), net clinical benefit (0.85 [95% CI 0.65-1.11] vs 0.93 [95% CI 0.86-0.99], P=.521), or individual efficacy end points. There was no significant interaction for bleeding (PLATO major bleeding, 1.02 [95% CI 0.70-1.49] vs 1.04 [95% CI 0.95-1.14], P=.938) and other related adverse events with ticagrelor compared with clopidogrel between Asians and non-Asians. CONCLUSIONS: We observed consistency of effects in Asian patients receiving ticagrelor and clopidogrel in the PLATO study. The relatively modest number of Asian patients in this analysis supports further investigation of larger cohorts to confirm our observations.

Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction.

IMPORTANCE: Little information exists about the anatomical characteristics and clinical relevance of non-infarct-related artery (IRA) disease among patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To investigate the incidence, extent, and location of obstructive non-IRA disease and compare 30-day mortality according to the presence of non-IRA disease in patients with STEMI. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of patients pooled from a convenience sample of 8 independent, international, randomized STEMI clinical trials published between 1993 and 2007. Follow-up varied from 1 month to 1 year. Among 68,765 patients enrolled in the trials, 28,282 patients with valid angiographic information were included in this analysis. Obstructive coronary artery disease was defined as stenosis of 50% or more of the diameter of a major epicardial artery. To assess the generalizability of trial-based results, external validation was performed using observational data for patients with STEMI from the Korea Acute Myocardial Infarction Registry (KAMIR) (between November 1, 2005, and December 31, 2013; n = 18,217) and the Duke Cardiovascular Databank (between January 1, 2005, and December 31, 2012; n = 1812). MAIN OUTCOMES AND MEASURES: Thirty-day mortality following STEMI. RESULTS: Overall, 52.8% (14,929 patients) had obstructive non-IRA disease; 29.6% involved 1 vessel and 18.8% involved 2 vessels. There was no substantial difference in the extent and distribution of non-IRA disease according to the IRA territory. Unadjusted and adjusted rates of 30-day mortality were significantly higher in patients with non-IRA disease than in those without non-IRA disease (unadjusted, 4.3% vs 1.7%, respectively; risk difference, 2.7% [95% CI, 2.3% to 3.0%], P < .001; and adjusted, 3.3% vs 1.9%, respectively; risk difference, 1.4% [95% CI, 1.0% to 1.8%], P < .001). The overall prevalence and association of non-IRA disease with 30-day mortality was consistent with findings from the KAMIR registry (adjusted, 3.6% for patients with non-IRA disease vs 2.5% in those without it; risk difference, 1.1% [95% CI, 0.6% to 1.7%]; P < .001), but not with the Duke database (adjusted, 4.7% with non-IRA disease vs 4.3% without it; risk difference, 0.4% [95% CI, -1.4% to 2.2%], P = .65). CONCLUSIONS AND RELEVANCE: In a retrospective pooled analysis of 8 clinical trials, obstructive non-IRA disease was common among patients presenting with STEMI, and was associated with a modest statistically significant increase in 30-day mortality. These findings require confirmation in prospectively designed studies, but raise questions about the appropriateness and timing of non-IRA revascularization in patients with STEMI.

Natural history of echocardiographic changes in atrial fibrillation: A case-controlled study of longitudinal remodeling.

BACKGROUND: Atrial fibrillation (AF) can be a cause and consequence of cardiac remodeling. The natural history of remodeling associated with AF is incompletely described. OBJECTIVE: The purpose of this study was to describe the frequency and timing of AF-associated echocardiographic changes. METHODS: Patients within the Duke University Health System with ≥2 transthoracic echocardiograms (TTEs) performed between 2005 and 2018 were evaluated. Patients with AF and normal baseline TTEs were matched to patients without AF on year of TTE, age, and CHA2DS2-VASc score. Frequency and timing of changes in chamber size, ventricular function, mitral regurgitation, and all-cause mortality were compared over 5 years of follow-up. RESULTS: The cohort included 3299 patients with AF at baseline and 7613 controls without AF. Normal baseline TTEs were acquired from 730 of patients with AF; 727 of these patients were matched to controls without AF. Patients with AF had higher rates of left atrial enlargement (hazard ratio [HR] 1.53; 95% confidence interval 1.27-1.85; P < .001), left ventricular (LV) systolic dysfunction (HR 1.80; 95% confidence interval 1.00-3.26; P = .045), LV diastolic dysfunction (HR 1.51; 95% confidence interval 1.08-2.10; P = .01), and moderate or greater mitral regurgitation (HR 2.09; 95% confidence interval 1.27-3.43; P = .003) than did controls. Atrial enlargement, systolic dysfunction, and mitral regurgitation surpassed the rates seen in controls within 6-12 months, whereas differences in diastolic dysfunction emerged at 24 months. There were no differences in ventricular sizes or mortality. CONCLUSION: AF is associated with higher rates of left atrial enlargement, LV systolic and diastolic dysfunction, and mitral regurgitation that typically manifest within 6-24 months of diagnosis. The natural history of cardiac remodeling in patients with AF may inform treatment decisions and facilitate patient-tailored care.