Hemoglobin and Clinical Outcomes in the Vericiguat Global Study in Patients With Heart Failure and Reduced Ejection Fraction (VICTORIA).

BACKGROUND: In the VICTORIA trial (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction), anemia occurred more often in patients treated with vericiguat (7.6%) than with placebo (5.7%). We explored the association between vericiguat, randomization hemoglobin, development of anemia, and whether the benefit of vericiguat related to baseline hemoglobin. METHODS: Anemia was defined as hemoglobin <13.0 g/dL in men and <12.0 g/dL in women (World Health Organization Anemia). Adverse events reported as anemia were also evaluated. We assessed the risk-adjusted relationship between hemoglobin and hematocrit with the primary outcome (composite of cardiovascular death or heart failure hospitalization) and the time-updated hemoglobin relationship to outcomes. RESULTS: At baseline, 1719 (35.7%) patients had World Health Organization anemia; median hemoglobin was 13.4 g/L (25th, 75th percentile: 12.1, 14.7 g/dL). At 16 weeks from randomization, 1643 patients had World Health Organization anemia (284 new for vericiguat and 219 for placebo), which occurred more often with vericiguat than placebo (P<0.001). After 16 weeks, no further decline in hemoglobin occurred over 96 weeks of follow-up and the ratio of hemoglobin/hematocrit remained constant. Overall, adverse event anemia occurred in 342 patients (7.1%). A lower hemoglobin was unrelated to the treatment benefit of vericiguat (versus placebo) on the primary outcome. In addition, analysis of time-updated hemoglobin revealed no association with the treatment effect of vericiguat (versus placebo) on the primary outcome. CONCLUSIONS: Anemia was common at randomization and lower hemoglobin was associated with a greater frequency of clinical events. Although vericiguat modestly lowered hemoglobin by 16 weeks, this effect did not further progress nor was it related to the treatment benefit of vericiguat. Registration: URL: https://www.clinicaltrials.gov: Unique identifier: NCT02861534.

Associated factors and clinical outcomes in mechanical circulatory support use in patients undergoing high risk on-pump cardiac surgery: Insights from the LEVO-CTS trial.

BACKGROUND: We describe variables and outcomes associated with peri-operative mechanical circulatory support (MCS) utilization among patients enrolled in the Levosimendan in patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial. METHODS: In the LEVO-CTS trial, MCS utilization (defined as intra-aortic balloon pump, extracorporeal membrane oxygenation, or surgical ventricular assist device) within 5 days of surgery was examined. The association between MCS use and outcomes including 90-day mortality, 30-day renal-replacement therapy, and hospital and critical stay length of stay were determined. RESULTS: Among the 849 patients from 70 centers randomized to levosimendan or placebo, 85 (10.0%) patients were treated with MCS (71 intra-aortic balloon pump, 7 extracorporeal membrane oxygenation, 7 ventricular assist device); with 89.4% started on post-operative day 0. Inter-institutional use ranged from 0% to 100%. Variables independently associated with MCS utilization included combined coronary artery bypass grafting and valve surgery (adjusted odds ratio [OR] 2.73, 95% confidence interval [CI] 1.70-4.37, P < .001), history of lung disease (OR 1.70, 95% CI 1.06-2.70, P = .029), and history of heart failure (OR 2.44, 95% CI 1.10-5.45, P = .027). Adjusted 90-day mortality (22.4% vs 4.1%, hazard ratio 6.11, 95% CI 3.95-9.44, P < .001) was higher, and median critical care length of stay (8.0 vs 4.0 days, P < .001) was longer in patients managed with MCS. CONCLUSIONS: In a randomized controlled trial of high-risk cardiac surgical patients in North America, we observed patient, and surgical variables associated with MCS utilization. MCS use was associated with a higher risk of post-operative mortality.

Association of obesity with cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease: Insights from TECOS.

BACKGROUND: Obesity is a risk factor for type 2 diabetes (T2D) and cardiovascular disease (CVD). Whether obesity affects outcomes among those with T2D and atherosclerotic CVD (ASCVD) remains uncertain. Our objective was to investigate the relationship between body mass index (BMI) and ASCVD outcomes among TECOS participants with T2D and ASCVD. METHODS: BMI categories were defined as underweight/normal weight (BMI <25 kg/m2), overweight (25-29.9 kg/m2), obese class I (30-34.9 kg/m2), obese class II (35-39.9 kg/m2), and obese class III (≥ 40 kg/m2). Asian-specific BMI categories were applied to Asian participants. Kaplan-Meier survival analysis and Cox proportional hazards models were used to examine associations between baseline BMI and a composite CV outcome (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina). RESULTS: For 14,534 TECOS patients with available BMI, mean age was 65.5 years; 29.3% were female, 32.0% non-White, and 23.1% insulin-treated, with median 3 years' follow-up. At baseline, 11.6% (n = 1686) were underweight/normal weight, 38.1% (n = 5532) overweight, 32.2% (n = 4683) obese class I, 12.4% (n = 1806) obese class II, and 5.7% (n = 827) obese class III. The composite CV outcome occurred in 11.4% (n = 1663) of participants; the outcome risk was lower, compared with under/normal weight, in overweight (HR 0.83, 95% CI 0.71-0.98) and obese class I (HR 0.79, 95% CI 0.67-0.93) individuals. Obesity was not associated with worse glycemic control. CONCLUSIONS: The majority of TECOS participants with ASCVD and T2D were overweight or obese, yet overweight or obese class I individuals had lower CV risk than those who were under/normal weight. These results suggest the presence of an obesity paradox, but this paradox may reflect an epidemiological artifact rather than a true negative association between normal weight and clinical outcomes.

Associations between ß-blocker therapy and cardiovascular outcomes in patients with diabetes and established cardiovascular disease.

BACKGROUND: The effects of ß-blocker therapy in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) are unclear. We sought to evaluate associations between ß-blocker use in T2D with ASCVD and cardiovascular (CV) outcomes. METHODS: In patients with T2D and ASCVD enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), an inverse probability of treatment-weighted Cox proportional hazards model was used to examine the association between baseline ß-blocker therapy (at randomization) and the primary CV composite (defined as CV death, non-fatal myocardial infarction [MI], non-fatal stroke, or hospitalization for unstable angina), including in subgroups with prior MI and heart failure (HF); other outcomes evaluated included individual components of the primary composite, hospitalization for HF, and severe hypoglycemic events. RESULTS: Of the 14,671 patients randomized, 9322 (64%) were on a ß-blocker at baseline; these patients were more likely to have prior MI or HF. Over a median 3.0 (25th, 75th percentile: 2.2, 3.6) years, the risk of the primary CV composite was significantly higher with baseline ß-blocker use versus no ß-blocker use (4.5 vs. 3.4 events/100-patient years, adjusted hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.05-1.29); no significant interaction was noted for patients with versus without prior MI or HF. Baseline ß-blocker use was not associated with risks for severe hypoglycemic events (HR 1.14, 95% CI 0.88-1.48). CONCLUSIONS: In this observational analysis of T2D and ASCVD, baseline ß-blocker use was not associated with risks for severe hypoglycemia yet also was not associated with CV risk reduction over 3 years of follow-up, supporting a randomized examination of chronic ß-blocker therapy in this patient population. (TECOS ClinicalTrials.gov number, NCT00790205).

Sitagliptin and risk of fractures in type 2 diabetes: Results from the TECOS trial.

AIM: To examine fracture incidence among participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). RESEARCH DESIGN AND METHODS: We used data from 14 671 participants in the TECOS study who were randomized double-blind to sitagliptin (n = 7332) or placebo (n = 7339). Cumulative fracture incidence rates were calculated and their association with study treatment assignment was examined using multivariable Cox proportional hazards regression. RESULTS: The baseline mean (standard deviation) participant age was 65.5 (8.0) years, diabetes duration was 11.6 (8.1) years and glycated haemoglobin level was 7.2 (0.5)% [55.2 (5.5) mmol/mol], and 29.3% of participants were women and 32.1% were non-white. During 43 222 person-years' follow-up, 375 (2.6%; 8.7 per 1000 person-years) had a fracture; 146 were major osteoporotic fractures (hip, n = 34; upper extremity, n = 81; and clinical spine, n = 31). Adjusted analyses showed fracture risk increased independently with older age (P < .001), female sex (P < .001), white race (P < .001), lower diastolic blood pressure (P < .001) and diabetic neuropathy (P = .003). Sitagliptin, compared with placebo, was not associated with a higher fracture risk [189 vs 186 incident fractures: unadjusted hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.82 to 1.23, P = .944; adjusted HR 1.03, P = .745], major osteoporotic fractures (P = .673) or hip fractures (P = .761). Insulin therapy was associated with a higher fracture risk (HR 1.40, 95% CI 1.02-1.91; P = .035), and metformin with a lower risk (HR 0.76, 95% CI 0.59-0.98; P = .035). CONCLUSION: Fractures were common among people with diabetes in the TECOS study, but were not related to sitagliptin therapy. Insulin and metformin treatment were associated with higher and lower fracture risks, respectively.

Alignment of site versus adjudication committee-based diagnosis with patient outcomes: Insights from the Providing Rapid Out of Hospital Acute Cardiovascular Treatment 3 trial.

BACKGROUND: Adjudication by an adjudication committee in clinical trials plays an important role in the assessment of outcomes. Controversy exists regarding the utility of adjudication committee versus site-based assessments and their relationship to subsequent clinical events. METHODS: This study is a secondary analysis of the Providing Rapid Out of Hospital Acute Cardiovascular Treatment-3 trial, which randomized patients with chest pain or shortness of breath for biomarker testing in the ambulance. The emergency department physician diagnosis at the time of emergency department disposition was compared with an adjudicated diagnosis assigned by an adjudication committee. The level of agreement between emergency department and adjudication committee diagnosis was evaluated using kappa coefficient and compared to clinical outcomes (30-day re-hospitalization, 30-day and 1-year mortality). RESULTS: Of the 477 patients, 49.3% were male with a median age of 70 years; hospital admission rate was 31.2%. The emergency department physicians and the adjudication committee disagreed in 55 cases (11.5%) with a kappa of 0.71 (95% confidence interval: 0.64, 0.78). The 30-day re-hospitalization, 30-day mortality, and 1-year mortality were 22%, 1.9%, and 9.4%, respectively. Although there were similar rates of re-hospitalization irrespective of adjudication, in cases of disagreement compared to agreement between adjudication committee and emergency department diagnosis, there was a higher 30-day (7.3% vs 1.2%, p = 0.002) and 1-year mortality (27.3% vs 7.1%, p < 0.001). CONCLUSION: Despite substantial agreement between the diagnosis of emergency department physicians and adjudication committee, in the subgroup of patients where there was disagreement, there was significantly worse short-term and long-term mortality.

Temporal changes in biomarkers and their relationships to reperfusion and to clinical outcomes among patients with ST segment elevation myocardial infarction.

Coronary plaque rupture mediating acute ST segment elevation myocardial infarction (STEMI) is associated with a systemic inflammatory response. Whether early temporal changes in inflammatory biomarkers are associated with angiographic and electrocardiographic markers of reperfusion and subsequent clinical outcomes is unclear. In the APEX-AMI biomarker substudy, 376 patients with STEMI had inflammatory biomarkers measured at the time of hospital presentation and 24 h later. The primary outcome was the 90-day composite of death, shock, or heart failure. Secondary reperfusion outcomes were (1) worst least residual ST segment elevation (ST-E: <1 mm, 1 to <2 mm, ≥2 mm) and (2) post-percutaneous coronary intervention (PCI) TIMI flow grade (0/1/2 vs 3) and TIMI myocardial perfusion grade (TMPG 0/1 vs 2/3). The 90-day incidence of death, shock or heart failure was 21.3 % in this cohort. Electrocardiographic reperfusion (worst residual ST-E <1 mm, 1 to <2 mm, ≥2 mm) was associated with differences in 24 h change in N-terminal proB-type natriuretic peptide (NT-proBNP) (1192.8, 1332.5, 1859.0 ng/mL; p = 0.043) and the pro-inflammatory cytokines Interleukin (IL)-6 (14.0, 13.6, 22.1 pg/mL; p = 0.016), IL-12 (-0.5, -0.9, -0.1 pg/mL; p = 0.013), and tumor necrosis factor α (TNFα) (1.0, 0.6, 3.6 pg/mL; p = 0.023). Angiographic reperfusion (TMPG 0/1 vs 2/3) was associated with changes in median NT-proBNP (2649.3, 1382.7 ng/mL; p = 0.002) and IL-6 (28.7, 15.1; p = 0.040). After adjustment for baseline covariates, the 24 h change in the pro-inflammatory cytokine TNFα [hazard ratio (HR) 0.49; 95 % CI 0.26-0.95; p = 0.035] and the anti-inflammatory cytokine IL 10 (HR 1.41; 95 % CI 1.06-1.87; p = 0.018) were independently associated with the primary composite outcome. Successful coronary reperfusion was associated with less systemic inflammatory response and greater temporal inflammatory changes were independently associated with higher 90-day composite of death, shock, or heart failure. These findings provide support for an association between success of reperfusion, an acute STEMI inflammatory response and subsequent clinical outcomes.

Applying novel methods to assess clinical outcomes: insights from the TRILOGY ACS trial.

AIMS: Several methods provide new insights into understanding clinical trial composite endpoints, using both conventional and novel methods. The TRILOGY ACS trial is used as a contemporary example to prospectively compare these methods side by side. METHODS AND RESULTS: The traditional time-to-first-event, Andersen-Gill recurrent events method, win ratio, and a weighted composite endpoint (WCE) are compared using the randomized, active-control TRILOGY ACS trial. This trial had a neutral result and randomized 9326 patients managed without coronary revascularization within 10 days of their acute coronary syndrome to receive either prasugrel or clopidogrel and followed them for up to 30 months. The traditional composite, win ratio, and WCE demonstrated no significant survival advantage for prasugrel, whereas the Andersen-Gill method demonstrated a statistical advantage for prasugrel [hazard ratio (HR), 0.86 (95% CI, 0.72-0.97)]. The traditional composite used 73% of total patient events; 40% of these were derived from the death events. The win ratio used 66% of total events; deaths comprised 57% of these. Both Andersen-Gill and WCE methods used all events in all participants; however, with the Andersen-Gill method, death comprised 41% of the proportion of events, whereas with the WCE method, death comprised 64% of events. CONCLUSION: This study addresses the relative efficiency of various methods for assessing clinical trial events comprising the composite endpoint. The methods accounting for all events, in particular those incorporating their clinical relevance, appear most advantageous, and may be useful in interpreting future trials. This clinical and statistical advantage is especially evident with long-term follow-up where multiple non-fatal events are more common. CLINICAL TRIAL REGISTRATION: NCT00699998.

The long-term effects of dietary sodium restriction on clinical outcomes in patients with heart failure. The SODIUM-HF (Study of Dietary Intervention Under 100 mmol in Heart Failure): a pilot study.

AIMS: To determine the feasibility of conducting a randomized controlled trial comparing a low-sodium to a moderate-sodium diet in heart failure (HF) patients. METHODS AND RESULTS: Patients with HF (New York Heart Association classes II-III) were randomized to low (1500 mg/d) or moderate-sodium (2300 mg/d) diet. Dietary intake was evaluated using 3-day food records. The end points were changes in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores and B-type natriuretic peptide (BNP) levels from baseline to 6 months of follow-up presented as medians [25th, 75th percentiles]. Thirty-eight patients were enrolled (19/group). After 6 months, median sodium intake declined from 2137 to 1398 mg/d in the low-sodium and from 2678 to 1461 mg/d in the moderate-sodium diet group. Median BNP levels in the low-sodium diet group declined (216-71 pg/mL, P = .006), whereas in the moderate-sodium diet group, there was no change in BNP (171-188 pg/mL, P = .7; P = .17 between groups). For 6 months, median KCCQ clinical score increased in both groups (63-75 [P = .006] in the low-sodium diet group and 66-73 [P = .07] in the moderate-sodium group; P = .4 between groups). At 6 months, a post hoc analysis based on the dietary sodium intake achieved (> or ≤ 1,500 mg/d) in all patients showed an association between a sodium intake ≤ 1,500 mg/d and improvement in BNP levels and KCCQ scores. CONCLUSIONS: A dietary intervention restricting sodium intake was feasible, and achievement of this sodium goal was associated with lower BNP levels and improved quality of life in patients with HF.

Reduced dose tenecteplase and outcomes in elderly ST-segment elevation myocardial infarction patients: Insights from the STrategic Reperfusion Early After Myocardial infarction trial.

BACKGROUND: Elderly patients with ST-segment elevation myocardial infarction (STEMI) have worse outcomes and a greater risk of intracranial bleeding than nonelderly patients. Baseline characteristics, clinical outcomes, and the relationship of the tenecteplase (TNK) dose reduction to the efficacy, safety, and electrocardiographic indicators of reperfusion efficacy were evaluated in STEMI patients ≥75 years. METHODS: The STREAM trial evaluated early presenting STEMI patients who could not undergo primary percutaneous coronary intervention within 1 hour of first medical contact. Because of excess intracranial hemorrhage (ICH) in patients ≥75 years, the dose of TNK was reduced by 50%. RESULTS: Before dose amendment, there were 3 (7.1%) of 42 elderly patients with ICH; 2 of these were fatal, whereas no ICH occurred in the 93 elderly patients who received half-dose TNK postamendment. The median extent of ST-segment elevation resolution (≥50%) and proportion of patients with ≥2 mm in the electrocardiogram lead with greatest ST-segment elevation was comparable in elderly patients preamendment and postamendment (63.2% vs 56.0% and 43.6% vs 40.0%, respectively). Patients requiring rescue coronary intervention after TNK was also similar (42.9% vs 44.1%). The primary composite end point (30-day all-cause death, cardiogenic shock, congestive heart failure, and reinfarction) was 31.0% before versus 24.7% postamendment. CONCLUSIONS: Our data, from a modest-sized population of elderly STEMI patients, indicate that half-dose TNK reduces the likelihood of ICH without compromising reperfusion efficacy. These observations are hypothesis generating and warrant further confirmation in randomized clinical trials in the elderly.

Association of metabolic syndrome and its individual components with outcomes among patients with high-risk non-ST-segment elevation acute coronary syndromes.

BACKGROUND: The relationship of metabolic syndrome and its individual components (obesity, hypertension, glucose intolerance, high triglycerides, and low high-density lipoprotein cholesterol) with 1-year mortality in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients is not known. METHODS: The association of metabolic syndrome (and its individual components) with all-cause mortality within 1 year was assessed in NSTE ACS patients enrolled in the EARLY ACS trial. Adjusted hazard ratio (HR) and 95% CIs are reported. RESULTS: Of 9,406 patients, 2,596 (27.6%) had metabolic syndrome. Compared with those without metabolic syndrome, patients with this syndrome were younger, were more often female, and had a higher prevalence of comorbid conditions and higher-risk presenting features. Metabolic syndrome was not associated with increased 1-year mortality (HR 1.20, 95% CI 0.97-1.47; P = .09). The risk of 1-year mortality varied across the individual components: high-density lipoprotein <40 mg/dL (men)/<50 mg/dL (women; or dyslipidemia) was associated with higher risk (HR 1.52, 95% CI 1.15-2.02), and triglycerides >150 mg/dL (or dyslipidemia) was associated with lower risk (HR 0.66, 95% CI 0.54-0.81), whereas the other components (ie, body mass index >30 kg/m(2), fasting plasma glucose >100 mg/dL or diabetes, systolic blood pressure >130 mm Hg or diastolic >85 mm Hg [or hypertension]) were associated with neutral risk of this event. CONCLUSIONS: The individual components of metabolic syndrome had varying associations with 1-year mortality, and as an integrated diagnosis, metabolic syndrome was not significantly associated with 1-year mortality. Thus, patient case-mix of the studied NSTE ACS population may influence the observed relationship of metabolic syndrome with subsequent cardiovascular events.

An assessment of ST-segment measurement variability between two core electrocardiogram laboratories.

OBJECTIVES: We evaluated inter-reader agreement of the ST-segment between two electrocardiogram (ECG) core laboratories. BACKGROUND: Accurate measurement of the ST-segment is key to diagnosis and management of acute coronary syndromes (ACS). Clinical trials also rely on adherence to the pre-specified ECG eligibility criteria. METHODS: 150 patients (100 ST-segment elevation (STE)-ACS, 50 non-STE-ACS) were selected. An experienced ECG reader from each laboratory measured ST-segment deviation on the baseline ECGs (nearest 0.1mm). RESULTS: ∑ST-segment deviation showed excellent inter-reader agreement (R=0.965, intraclass correlation coefficient (ICC) 0.949, 95% CI (0.930-0.963)). Similar agreement was observed when ∑ST-segment elevation (∑STE) and ∑ST-segment depression (∑STD) were assessed separately. Better agreement was evident in STE-ACS cohort (ICC (95% CI): 0.968 (0.953-0.978, 0.969 (0.954-0.979), 0.931 (0.899-0.953)) compared to NSTE-ACS patients (ICC (95% CI): 0.860 (0.768-0.917), 0.816 (0.699-0.890), 0.753 (0.605-0.851) across measurement of ∑ST-segment deviation, ∑STE, and ∑STD. CONCLUSIONS: We demonstrated excellent agreement on ST-segment measurements between two experienced readers from two ECG core laboratories.

Prognostic implications of quantitative evaluation of baseline Q-wave width in ST-segment elevation myocardial infarction.

OBJECTIVES: To evaluate quantitative relationships between baseline Q-wave width and 90-day outcomes in ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Baseline Q-waves are useful in predicting clinical outcomes after MI. METHODS: 3589 STEMI patients were assessed from a multi-centre study. RESULTS: 1156 patients of the overall cohort had pathologic Q-waves. The 90-day mortality and the composite of mortality, congestive heart failure (CHF), or cardiogenic shock (p<0.001 for both outcomes) rose as Q-wave width increased. After adapting a threshold ≥40ms for inferior and ≥20ms for lateral/apical MI in all patients (n=3065) with any measureable Q-wave we found hazard ratios (HR) for mortality (HR: 2.44, 95% confidence interval (CI) (1.54-3.85), p<0.001) and the composite (HR: 2.32, 95% CI (1.70-3.16), p<0.001). This improved reclassification of patients experiencing the composite endpoint versus the conventional definition (net reclassification index (NRI): 0.23, 95% CI (0.09-0.36), p<0.001) and universal MI definition (NRI: 0.15, 95% CI (0.02-0.29), p=0.027). CONCLUSIONS: The width of the baseline Q-wave in STEMI adds prognostic value in predicting 90-day clinical outcomes. A threshold of ≥40ms in inferior and ≥20ms for lateral/apical MI enhances prognostic insight beyond current criteria.

Reperfusion in Patients With ST-Segment-Elevation Myocardial Infarction With Cardiogenic Shock and Prolonged Interhospital Transport Times.

BACKGROUND: In patients with ST-segment-elevation myocardial infarction complicated by cardiogenic shock, primary percutaneous coronary intervention (pPCI) is the preferred revascularization option. Little is known about the efficacy and safety of a pharmacoinvasive approach for patients with cardiogenic shock presenting to a non-PCI hospital with prolonged interhospital transport times. METHODS: In a retrospective analysis of geographically extensive ST-segment-elevation myocardial infarction network (2006-2021), 426 patients with cardiogenic shock and ST-segment-elevation myocardial infarction presented to a non-PCI-capable hospital and underwent reperfusion therapy (53.8% pharmacoinvasive and 46.2% pPCI). The primary clinical outcome was a composite of in-hospital mortality, renal failure requiring dialysis, cardiac arrest, or mechanical circulatory support, and the primary safety outcome was major bleeding defined as an intracranial hemorrhage or bleeding that required transfusion was compared in an inverse probability weighted model. The electrocardiographic reperfusion outcome of interest was the worst residual ST-segment-elevation. RESULTS: Patients with pharmacoinvasive treatment had longer median interhospital transport (3 hours versus 1 hour) and shorter median symptom-onset-to-reperfusion (125 minute-to-needle versus 419 minute-to-balloon) times. ST-segment resolution ≥50% on the postfibrinolysis ECG was 56.6%. Postcatheterization, worst lead residual ST-segment-elevation <1 mm (57.3% versus 46.3%; P=0.01) was higher in the pharmacoinvasive compared with the pPCI cohort, but no differences were observed in the worst lead ST-segment-elevation resolution ≥50% (77.4% versus 81.8%; P=0.57). The primary clinical end point was lower in the pharmacoinvasive cohort (35.2% versus 57.0%; inverse probability weighted odds ratio, 0.44 [95% CI, 0.26-0.72]; P<0.01) compared with patients who received pPCI. An interaction between interhospital transfer time and reperfusion strategy with all-cause mortality was observed, favoring a pharmacoinvasive approach with transfer times >60 minutes. The incidence of the primary safety outcome was 10.1% in the pharmacoinvasive arm versus 18.7% in pPCI (adjusted odds ratio, 0.41 [95% CI, 0.14-1.09]; P=0.08). CONCLUSIONS: In patients with ST-segment-elevation myocardial infarction presenting with cardiogenic shock and prolonged interhospital transport times, a pharmacoinvasive approach was associated with improved electrocardiographic reperfusion and a lower rate of death, dialysis, or mechanical circulatory support without an increase in major bleeding.

Relationship between baseline electrocardiographic measurements and outcomes in patients with high-risk heart failure: Insights from the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial.

AIMS: Whether electrocardiographic (ECG) measurements predict mortality in chronic heart failure with reduced ejection fraction (HFrEF) is unknown. METHODS AND RESULTS: We studied 4880 patients from the Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial with a baseline 12-lead ECG. Associations between ECG measurements and mortality were estimated as hazard ratios (HR) and adjusted for the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score, N-terminal pro-B-type natriuretic peptide, and index event. Select interactions between ECG measurements, patient characteristics and mortality were examined. Over a median of 10.8 months, there were 824 cardiovascular (CV) deaths (214 sudden) and 1005 all-cause deaths. Median age was 68 years (interquartile range [IQR] 60-76), 24% were women, median ejection fraction was 30% (IQR 23-35), 41% had New York Heart Association class III/IV, and median MAGGIC score was 24 (IQR 19-28). After multivariable adjustment, significant associations existed between heart rate (per 5 bpm: HR 1.02), QRS duration (per 10 ms: HR 1.02), absence of left ventricular hypertrophy (HR 0.64) and CV death, and similarly so with all-cause death (HR 1.02; HR 1.02; HR 0.61, respectively). Contiguous pathologic Q waves were significantly associated with sudden death (HR 1.46), and right ventricular hypertrophy with all-cause death (HR 1.44). The only sex-based interaction observed was for pathologic Q waves on CV (men: HR 1.05; women: HR 1.64, pinteraction = 0.024) and all-cause death (men: HR 0.99; women: HR 1.57; pinteraction = 0.010). Whereas sudden death doubled in females, it did not differ among males (male: HR 1.25, 95% confidence interval [CI] 0.87-1.79; female: HR 2.50, 95% CI 1.23-5.06; pinteraction = 0.141). CONCLUSION: Routine ECG measurements provide additional prognostication of mortality in high-risk HFrEF patients, particularly in women with contiguous pathologic Q waves.

Age, Sex, and Outcomes in Heart Failure With Reduced EF: Insights From the VICTORIA Trial.

BACKGROUND: Age and sex influence treatment and outcomes in patients with heart failure (HF). OBJECTIVES: The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women. METHODS: Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression. RESULTS: Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, Pinteraction = 0.169; categorical age, Pinteraction = 0.189); and sex (3-way interaction; P = 0.847). CONCLUSIONS: Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).

Evolution of NT-proBNP During Prerandomization Screening in VICTORIA: Implications for Clinical Outcomes and Efficacy of Vericiguat.

BACKGROUND: Selecting high-risk patients with heart failure with potentially modifiable cardiovascular events is a priority. Our objective was to evaluate NT-proBNP (N-terminal pro-B-type natriuretic peptide) changes during a 30-day screening to establish (1) the frequency and direction of changes; (2) whether a relationship exists between changes in NT-proBNP and the primary composite outcome of cardiovascular death and heart failure hospitalization; and (3) whether changes in NT-proBNP relate to vericiguat's clinical benefit. METHODS: VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) randomized 5050 patients with heart failure with reduced ejection fraction and a recent worsening heart failure event. We studied 3821 patients who had NT-proBNP measured during screening and at randomization. RESULTS: Sixteen hundred exhibited a >20% reduction, 1412 had ≤20% change, and 809 showed a >20% rise in NT-proBNP levels. As compared with the primary composite outcome of 28.4/100 patient-years (497 events; 31.1%) in patients with a >20% decline in NT-proBNP, those with >20% during screening had worse outcomes; 48.8/100 patient-years (359 events; 44.4%); adjusted hazard ratio, 1.61 (95% CI, 1.39-1.85). Those patients with a ≤20% change in NT-proBNP had intermediate outcomes; 39.2/100 patient-years (564 events; 39.9%); adjusted hazard ratio, 1.33 (95% CI, 1.17-1.51). No relationship existed between NT-proBNP changes during screening and vericiguat's effect on cardiovascular death and heart failure hospitalization. CONCLUSIONS: Substantial differences occurred in the rates of cardiovascular death and heart failure hospitalization, especially in patients with a >20% change in NT-proBNP levels during screening interval. Sequential NT-proBNP levels add important prognostic information meriting consideration in future heart failure trials. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

Effect of vericiguat on left ventricular structure and function in patients with heart failure with reduced ejection fraction: The VICTORIA echocardiographic substudy.

AIM: Vericiguat significantly reduced the primary composite outcome of heart failure (HF) hospitalization or cardiovascular death in the VICTORIA trial. It is unknown if these outcome benefits are related to reverse left ventricular (LV) remodelling with vericiguat in patients with HF with reduced ejection fraction (HFrEF). The aim of this study was to compare the effects of vericiguat versus placebo on LV structure and function after 8 months of therapy in patients with HFrEF. METHODS AND RESULTS: Standardized transthoracic echocardiography (TTE) was performed at baseline and after 8 months of therapy in a subset of HFrEF patients in VICTORIA. The co-primary endpoints were changes in LV end-systolic volume index (LVESVI) and LV ejection fraction (LVEF). Quality assurance and central reading were performed by an echocardiographic core laboratory blinded to treatment assignment. A total of 419 patients (208 vericiguat, 211 placebo) with high-quality paired TTE at baseline and 8 months were included. Baseline clinical characteristics were well balanced between treatment groups and echocardiographic characteristics were representative of patients with HFrEF. LVESVI significantly declined (60.7 ± 26.8 to 56.8 ± 30.4 ml/m2 ; p < 0.01) and LVEF significantly increased (33.0 ± 9.4% to 36.1 ± 10.2%; p < 0.01) in the vericiguat group, but similarly in the placebo group (absolute changes for vericiguat vs. placebo: LVESVI -3.8 ± 15.4 vs. -7.1 ± 20.5 ml/m2 ; p = 0.07 and LVEF +3.2 ± 8.0% vs. +2.4 ± 7.6%; p = 0.31). The absolute rate per 100 patient-years of the primary composite endpoint at 8 months tended to be lower in the vericiguat group (19.8) than the placebo group (29.6) (p = 0.07). CONCLUSIONS: In this pre-specified echocardiographic study, significant improvements in LV structure and function occurred over 8 months in both vericiguat and placebo in a high-risk HFrEF population with recent worsening HF. Further studies are warranted to define the mechanisms of vericiguat's benefit in HFrEF.

Ejection Fraction, Biomarkers, and Outcomes and Impact of Vericiguat on Outcomes Across EF in VICTORIA.

BACKGROUND: Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF). OBJECTIVES: The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial. METHODS: Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and >33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro-B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined. RESULTS: The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and >33; P < 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF. CONCLUSIONS: Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%). (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534).

Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.