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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).

The association between frailty and health status in patients with heart failure with preserved ejection fraction (HFpEF) is not well known.

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The effect of vericiguat on sequential N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and influence of this relationship on clinical outcomes is unknown.

Background: Baseline Q waves may provide additional value compared with time from the onset of symptoms in predicting outcomes for patients with ST-segment elevation. We evaluated whether baseline Q waves superseded time from symptom onset as a prognostic marker of one-year mortality in patients with ST-segment elevation acute coronary syndrome. Our study was derived from data from patients undergoing primary percutaneous coronary intervention within 24 hours in the PLATelet inhibition and patient Outcomes trial Methods: Q waves on the baseline electrocardiogram were evaluated by a blinded core laboratory. We assessed the associations between baseline Q waves and time from symptom onset to percutaneous coronary intervention with peak biomarkers, ST-segment resolution on the discharge electrocardiogram, and one-year all-cause and vascular mortality. Results: Of 4341 patients with ST-segment elevation, 46% had baseline Q waves. Compared to those without Q waves, those with baseline Q waves were older, more frequently male, had higher heart rates, more advanced Killip class and had a longer time between the onset of symptoms and percutaneous coronary intervention. They also had higher one-year all-cause mortality than patients without baseline Q waves (baseline Q waves: 4.9%; no baseline Q waves: 2.8%; hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.29-2.45, p < 0.001). Complete ST-segment resolution was greatest and all-cause mortality lowest among those with symptom onset three hours or less before percutaneous coronary intervention and no baseline Q waves. After multivariable adjustment, baseline Q waves, but not time from symptom onset, were associated with a significant increase in all-cause mortality (adjusted HR 1.42, 95% CI 1.10-2.01, p = 0.046) and vascular mortality (adjusted HR 1.58, 95% CI 1.09-2.28, p = 0.02). Interpretation: The presence of baseline Q waves provides useful additional prognostic insight into the clinical outcome of patients with ST-segment elevation. Clinical Trials.gov registration no. NCT00391872, The clinical outcome of patients with ST-segment elevation myocardial infarction (STEMI) is directly related to the extent of myocardial necrosis. (1) Because the extent of necrosis is strongly influenced by [...]

Abstract Background: Previous studies examining sex-related differences in the treatment of coronary artery disease have focused on patients in hospital. We sought to examine sex-related differences at an earlier point [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjmed.2006.05.056 Byline: Wei-Ching Chang, Padma Kaul, Cynthia M. Westerhout, Michelle M. Graham, Paul W. Armstrong Keywords: Acute myocardial infarction; Socioeconomic status; Emergency department; Revascularization Abstract: To assess the effects of socioeconomic status on mortality in patients with acute myocardial infarction. Author Affiliation: University of Alberta, Edmonton, Alberta, Canada. Article Note: (footnote) This study was supported by a grant from the Canadian Institute of Health Research. Although the study is based in part on data provided by Alberta Health and Wellness, the interpretation and conclusions contained herein are those of the researchers and do not necessarily represent the views of the Government of Alberta. Neither the Government nor Alberta Health and Wellness express any opinion in relation to this study.

IMPORTANCE: Conducting a clinical trial involves significant risks, time, and resources. The return on investment for these trials, measured by advancing health care and contributions to the scientific literature, is often uncertain. OBJECTIVE: To assess the long-term effects of major clinical trials of acute coronary syndromes contemporary to the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial, which did not achieve its primary objective. EVIDENCE REVIEW: The Cochrane Central Register of Controlled Trials database was screened for clinical trials of acute coronary syndromes (including unstable angina, ST-elevation myocardial infarction, and non–ST-elevation myocardial infarction) with more than 1000 participants and primary results published between January 1, 2005, and December 31, 2009, in Circulation, European Heart Journal, JAMA, Journal of the American College of Cardiology, The Lancet, and The New England Journal of Medicine. For identified trials, bibliographic information, citations, trial name, registration, inclusion diagnosis, intervention type, sample size, primary outcome result, sponsor information, and academic involvement were extracted. To identify secondary analyses, bibliographic information for citing articles, their citations, and their abstracts were extracted. Clinical practice guideline bibliographies for citations of trial publications were reviewed, and the class and level of evidence of resulting recommendations were extracted. FINDINGS: Of 784 records screened, 30 were primary publications of 25 clinical trials. Through December 31, 2018, these trials were cited a median of 497 times (interquartile range [IQR], 424-931 citations). Trials that did not achieve their primary objective had fewer primary citations (the number of times that each published journal article with the primary [main] results of a trial was cited) (median, 443 [IQR, 396-468] vs 868 [IQR, 645-1774] citations, P = .006). The frequency of secondary analyses peaked within 5 years of the primary trial at 643. Trials that did not achieve the primary objective had fewer secondary analyses (median, 15 [IQR, 5-31] vs 18 [IQR, 10-43] analyses, P = .44) that were not cited significantly less often (median, 484 [IQR, 191-1299] vs 1124 [IQR, 410-4283] citations, P = .16). All trials were cited by at least 1 clinical practice guideline. CONCLUSIONS AND RELEVANCE: This review found that trials that achieved the primary objective were frequently cited. Secondary research activity did not differ by primary result, and the primary trials and secondary analyses contributed to clinical practice recommendations. These data show the long-term importance of clinical trials regardless of primary outcome result.

The purpose of this study was to examine the treatment effect of vericiguat in relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at randomization.

IMPORTANCE: Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in patients with heart failure (HF) and reduced ejection fraction, many patients are undertreated. The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial tested whether a strategy of using target concentrations of N-terminal pro–brain natriuretic peptide (NT-proBNP) to guide optimization of GDMT could improve outcomes. OBJECTIVE: To examine medical therapy for HF in GUIDE-IT and potential reasons why the intervention did not produce improvements in medical therapy. DESIGN, SETTING, AND PARTICIPANTS: GUIDE-IT, a randomized clinical trial performed at 45 sites in the United States and Canada, was conducted from January 16, 2013, to September 20, 2016. A total of 894 patients with HF and reduced ejection fraction (≤40%) were randomized to NT-proBNP−guided treatment with a goal to suppress NT-proBNP concentrations to less than 1000 pg/mL vs usual care. This secondary analysis examined the medical therapy titration and reasons why the intervention did not produce improvements in care and outcomes. Data were analyzed March 27 to June 28, 2019. MAIN OUTCOMES AND MEASURES: For each encounter, medication titrations were captured. A reason was requested if a modification was not made. A Cox proportional hazards regression model was used to assess the independent association of drug class with outcomes. RESULTS: Among the 838 patients available for analysis (566 men [67.5%]; median age, 62.0 years), 6223 visits occurred during 24 months. Adjustments of HF medication were made during 2847 of 5218 qualified visits (54.6%) (all usual care visits and all guided care visits with NT-proBNP level ≥1000 pg/mL) in 862 patients (96.4%). Most adjustments occurred within the first 6 months, primarily within the first 6 weeks. The most common reasons for not adjusting were “clinically stable” and “already at maximally tolerated therapy.” Only 130 patients (15.5%) achieved optimal GDMT (≥50% of the target dose of β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or any dose of mineralocorticoid antagonists) at 6 months, an increase from the baseline (79 of 891 [8.9%]) but not different by treatment arm. Higher doses of β-blockers were associated with reduced risk of the composite outcome of HF hospitalization and cardiovascular death (hazard ratio [HR], 0.98; 95% CI, 0.97-1.00; P = .008) and of all-cause death (HR, 0.97; 95% CI, 0.95-0.99; P = .01). Higher doses of angiotensin-converting enzyme inhibitors (HR, 0.84; 95% CI, 0.75-0.93; P &lt; .001) and angiotensin receptor blockers (HR, 0.84; 95% CI, 0.71-0.99; P = .04) were associated with reduced risk of all-cause death. Increasing doses of mineralocorticoid antagonists did not appear to be associated with improved outcomes. CONCLUSIONS AND RELEVANCE: Despite a protocol-driven approach, many patients in GUIDE-IT did not receive medication adjustments and did not achieve optimal GDMT, including those with known elevated NT-proBNP concentrations. These results suggest that opportunities exist to titrate medications for maximal benefit in HF. GUIDE-IT may have failed to achieve treatment benefit because of therapeutic inertia in clinical practice, or current GDMT goals may be unrealistic. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01685840

Aims: The STREAM study randomly assigned ST-elevation myocardial infarction (STEMI) patients to receive a pharmacoinvasive versus primary percutaneous coronary intervention reperfusion strategy. We assessed whether there was an association between outcomes based on randomisation at a community hospital versus a prehospital location.Methods/results: Community hospital patients (358/1866 (19.2%)) were compared to prehospital patients and their outcomes categorised into pharmacoinvasive according to their treatment assignment. Compared to prehospital patients, community hospital patients had more diabetes (17.8% vs. 11.5%, P=0.001), higher Killip Class >1 (9.4% vs. 5.0%, P=0.002) and thrombolysis in myocardial infarction risk scores ⩾5 (18.2% vs. 12.4%, P=0.005). The 30-day primary endpoint (death, shock, congestive heart failure and re-infarction) for community hospital patients was 14.9% versus 13.2% for prehospital patients (P=0.403). Community hospital pharmacoinvasive patients tended to receive less rescue (35.1% vs. 42.8%, P=0.062); when deployed their rescue was delayed 43 minutes. Community hospital patients undergoing primary percutaneous coronary intervention experienced a delay of 31 minutes versus prehospital patients. Pharmacoinvasive patients receiving scheduled angiography from a community hospital and prehospital patients had comparable times to angiography (17.7 vs. 18.7 hours) and low event rates (6.2% vs. 8.0%). Although the interaction between randomisation location and treatment received on the primary endpoint was not significant (Pinteraction=0.065) those pharmacoinvasive patients requiring rescue from community hospitals had worse outcomes than prehospital rescue patients (odds ratio 2.28, 95% confidence interval 1.16–4.49).Conclusion: Within STREAM, STEMI patients randomly assigned at community hospitals had a higher baseline risk but similar outcomes compared to those studied prehospital patients irrespective of successful pharmacoinvasive therapy or primary percutaneous coronary intervention. However, worse outcomes in the pharmacoinvasive patients requiring rescue in community hospitals emphasises their need for immediate transfer to a percutaneous coronary intervention-capable hospital.

Supplemental Digital Content is available in the text.Advances in cardiovascular medicine fueled by innovative clinical trials have dramatically improved the lives of patients worldwide. Commensurate with this progress has been a decline in morbid and mortal events. Accordingly, an increased propensity to collate patient outcomes in clinical trials has emerged that combines death and nonfatal complications into a single composite event. Despite the acknowledged benefits in trial efficiency from such an approach, this method assumes uniform directionality of each component, does not distinguish the relative clinical significance of each, and counts only the first occurrence of any event in the final tally within a conventional time to first event analysis. In this article, we evaluate the criticisms that have been leveled at this approach and provide an overview of recently published phase III cardiovascular trials using primary composite end points. We then explore what to anticipate from the large cohort of as-yet unpublished clinical trials in this arena. Last, we propose a variety of novel approaches that use composite end points and suggest a path forward to enhancing their use in future clinical trials.

Background:Both patient age and sex influence heart failure (HF) treatment and outcomes. Given women are generally older in HF trials, we examined the associations of age and sex with clinical characteristics, background HF therapy, and response to vericiguat in VICTORIA. VICTORIA enrolled 5050 patients with HF with reduced ejection fraction (HFrEF) and recent worsening HF, was broadly inclusive without an upper age limit, and included 28% women (n=1208), and 31% (1568 ) were ≥75 years old with event rates exceeding most HF trials.Methods:Clinical characteristics were compared across age groups (<65, 65 to <75, ≥75 and <75, ≥75 years) and sex (Table).Results:More women (37%) than men (29%) were age ≥75 years. Compared with younger patients, those ≥75 had higher EF and class III/IV symptoms, more comorbidities, higher NT-proBNP and lower eGFR, indicative of more advanced disease; however, this age group had the lowest use of triple therapy. Within each age group, women had higher EF and lower burden of some comorbidities (atrial fibrillation, hyperlipidemia, coronary artery disease) compared with men, but similar functional status and NT-proBNP. There were no sex differences in the use of triple therapy by age group; however, women ≥75 years less often achieved target doses of triple therapy than men of similar age. Women were also less likely to receive HF devices across all ages. The incidence of the primary composite endpoint (cardiovascular death or HF hospitalization) increased across age groups and was higher in men than women. Compared with the pre-specified age subgroup analysis (i.e., <75, ≥75 years), the beneficial effect of vericiguat on the primary endpoint was not modified by age (continuous) and sex (3-way interaction; p=0.847).Conclusions:Women in VICTORIA were older than men, and while elderly women received less intense background HF therapy, their prognosis was nominally better than elderly men. Vericiguat’s benefit was independent of age and sex.

Background:In the VICTORIA trial in patients with heart failure with reduced ejection fraction, vericiguat (V) versus placebo (P) reduced the primary composite outcome (heart failure hospitalization [HFH] or cardiovascular death [CVD]) from 38.5 to 35.5% (1869 events: V=897, P=972) (Fig A). In this prespecified analysis, we assessed vericiguat’s treatment effect using weighted composite endpoint (WCEP) and win-ratio (WR) methods.Methods:Clinical events were centrally adjudicated. A survey of 37 international trial leaders conducted before database lock led to the derivation of relative weights of subtypes of HFH (mild [change in therapy] 0.39; moderate [requiring IV diuresis] 0.50; severe [urgent deterioration requiring inotropic support] 0.67) and CVD (1.0). A WCEP model estimated the effect of vericiguat on mean survival after severity-weighting recurrent HFH events and CVD. The unmatched WR approach, which accounted for recurrent HFH events, was applied with the hierarchy of HFH

Background:Patients with chronic heart failure with reduced ejection fraction (HFrEF) and recent decompensation are at high risk of cardiovascular (CV) events including mortality; risk stratification remains challenging. To further assess risk in this population, we characterized their baseline 12-lead ECGs and their prognostic value in 4880 patients (24% female) from the VICTORIA study.Methods:Baseline ECG parameters were interpreted in a core laboratory blinded to centrally adjudicated clinical outcomes. There were 1799 primary composite events (time to first HF hospitalization (HFH) or CV death) and 1005 total all-cause deaths (21% sudden). The MAGGIC-adjusted association between baseline ECG parameters and outcomes are presented as hazard ratio (HR) and 95% confidence intervals (CIs).Results:Incidence rates of baseline ECG parameters and their association with all-cause death and the primary composite outcome are shown below. The median MAGGIC score was 24 (19, 28) points. Higher heart rate, greater QRS duration, and prolonged QTc were significantly associated with the primary composite and all-cause death (Table), as well as for CV death ([HR 1.04, 95% CI 1.02-1.07; p<0.001] [HR 1.02, 1.00-1.04; p=0.015] [HR 1.16, 1.00-1.34; p=0.049]), respectively. Sex-based interactions were evident for contiguous Q waves on all-cause death (male: HR 0.98, 0.82-1.17; female: HR 1.56, 1.15-2.12; interaction p=0.010) and CV death (male: HR 1.03, 0.85-1.25; female: HR 1.66, 1.17-2.34; interaction p=0.019). Additionally, contiguous Q-waves were associated with sudden death (HR 1.45, 1.05-2.00; p=0.022) and appeared to double the risk in females (male: HR 1.25, 0.87-1.79; female: HR 2.50, 1.23-5.06; interaction p= 0.087).Conclusion:Routine ECG parameters are associated with worse outcomes in high risk HFrEF patients—particularly in females with contiguous Q waves.

Aims: Little is known regarding consequences of frailty in patients with acute coronary syndrome (ACS). We assessed the associations of frailty and outcomes in ACS patients who were participating in a clinical trial.Methods and results: The TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial randomized 9326 patients planned for medical management to prasugrel or clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), or stroke over a period of 30 months. A frailty score based upon the Fried score was self-reported at baseline in patients aged ?65 years. Five frailty questions were recorded for 4996/5102 (97.9%) patients: 72.3% were classified as not-frail (0 items), 23.0% as pre-frail (1–2 items), and 4.7% as frail (?3 items). Increasing frailty score was associated with older age, diabetes, and higher Global Registry of Acute Coronary Events (GRACE) scores. Frailty was associated with a higher unadjusted incidence of the primary endpoint (pre-frail vs not-frail: 29.2% vs 23.1%; hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.19–1.61; p<0.001; frail vs not-frail: 39.7% vs 23.1%; HR: 1.76; 95% CI: 1.36–2.28; p<0.001), and all-cause mortality (pre-frail vs not-frail: 21.7% vs 15.0%; HR: 1.45; 95% CI: 1.22–1.73; p<0.001; frail vs not-frail: 30.2% vs 15.0%; HR: 1.98; 95% CI: 1.47–2.68; p<0.001). After adjustment for baseline characteristics and GRACE covariates, frailty remained independently associated with the primary endpoint: pre-frail vs not-frail, HR: 1.33; 95% CI: 1.15–1.54; p<0.001; frail vs not-frail, HR: 1.52; 95% CI: 1.18–1.98; p=0.002. There was no association of frailty with bleeding.Conclusion: Frailty is associated with the composite of cardiovascular death, MI, or stroke. Frailty assessment contributes to risk prediction and adds to the GRACE score.

The outcomes of acute cardiovascular symptom presentations are potentially modifiable with the use of biomarkers to accelerate accurate diagnosis. This randomized trial tested troponin and B-type natriuretic peptide before hospital guidance in patients with acute cardiovascular symptoms.

Randomized controlled trials (RCT) are limited by their generalizability to the broader nontrial population. To provide a context for Acute Study of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, we designed a complementary registry to characterize clinical characteristics, practice patterns, and in-hospital outcomes of acute heart failure patients.

Recent research and contemporary ST elevation myocardial infarction guidelines emphasize the importance of prompt reperfusion and have redefined the traditional time to treatment metric to include prehospital paramedical staff as the point of first medical contact. However, an important knowledge gap exists relating to data systematically addressing the impact of arrival at the hospital by ambulance and the delays inherent in transfer from a community hospital to tertiary centres for percutaneous coronary intervention (PCI).

Four intravenous glycoprotein IIb/IIIa receptor inhibitors (GPIs) (abciximab, eptifibatide, tirofiban and lamifiban) have been tested extensively over the last decade for their efficacy and safety in patients with acute coronary syndromes (ACS). GPIs are well-established adjunct agents for patients undergoing percutaneous coronary intervention, and considerable effort has gone into evaluating these agents in patients who are not scheduled to undergo coronary revascularisation. In the current article, six major randomised clinical trials conducted in the latter patient population are reviewed. Based on a recent meta-analysis of these trials, GPIs reduced the incidence of death or myocardial infarction in patients not scheduled for early revascularisation, with the greatest reduction observed in patients at high risk of thrombotic complications. Major bleeding complications were more frequent in those receiving GPIs, however, the incidences of intracranial haemorrhage and stroke were similar in both treatment groups. Despite these risks, the benefits of GPI therapy in addition to conventional treatment, such as aspirin and heparin, should be considered for these high-risk patients.

Supplemental Digital Content is available in the text.

Introduction:ST elevation resolution following primary percutaneous coronary intervention (PCI) in ST segment elevation myocardial infarction (STEMI) identifies a spectrum of myocardial reperfusion. The pathophysiologic basis for this heterogenous response is unclear and may be mediated by several interlinked processes.Objective:To use a multiple biomarker strategy to identify novel proteins and thereby provide mechanistic insights into the variability of myocardial reperfusion in STEMI following PCIMethods:We evaluated novel proteomic biomarkers associated with ST elevation resolution using a high throughput ?targeted discovery? approach in APEX AMI trial patients undergoing primary PCI <6 hours from symptom onset. Patients were divided according to presence (n=861) or absence (n=299) of ?50% ST-segment resolution, assessed a median of 40 min (IQR 23-70 min) after PCI. Serum drawn prior to PCIwas analyzed for 91 biomarkers (Olink Proseek Multiplex CVD III panel). Expression levels were compared according to ST resolution and adjusted for false discovery rate (FDR). Multivariable analysis was performed adjusted for baseline clinical factors and time to PCI.Results:A total of 11 biomarkers discriminated between those with and without ST resolution: 5 remained significant after FDR adjustment including NT-proBNP, ST2 protein, transferrin receptor protein 1, platelet derived growth factor subunit A, and secretoglobin family 3A member 2 (Figure A). After multivariable adjustment, all 5 remained significant (Figure B)Conclusions:This exploratory analysis identifies five discovery proteins associated with ST elevation resolution after primary PCI, and provides an opportunity to understand the heterogeneity of myocardial reperfusion and explore novel mechanisms aimed at improving outcomes in STEMI.

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