Arrival by ambulance in acute heart failure: insights into the mode of presentation from Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF).

OBJECTIVES: Limited data exist assessing the relationship between ambulance versus self-presentation and outcomes in patients with acute heart failure (AHF). SETTING: Clinical trial sites in North America. PARTICIPANTS: 1068 patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. PRIMARY AND SECONDARY OUTCOME MEASURES: The association between ambulance use and dyspnoea improvement, 30-day mortality or HF rehospitalisation and 180-day mortality. RESULTS: Of the 1068 patients in the substudy, 832 (78%) self-presented (SP) and 236 (22%) patients presented via ambulance. Patients presenting via ambulance were older, more likely to be female, have a higher ejection fraction but similar natriuretic peptide levels as patients who SP. Patients presenting by ambulance (compared with SP) trended towards more dyspnoea improvement at 6 (p=0.09) and 24 h (p=0.10). The co-primary end point (30-day mortality or HF rehospitalisation) was similar between groups (ambulance 12.2% vs SP 11.4%, p=0.74). Patients who presented by ambulance had a higher 30-day and 180-day mortality rate than those who SP (30-day: 4.3% vs 2.2%, p=0.08; 180-day: 15.1% vs 10.3%, p=0.04). After adjustment for baseline characteristics, patients arriving by ambulance (compared with SP) had a 2-fold high risk of 30-day mortality (OR 2.12, 95% CI 0.94 to 4.79), but no relationship to the composite of 30-day mortality/HF rehospitalisation (OR 1.01, 95% CI 0.63 to 1.63). CONCLUSIONS: Among patients with AHF, 30-day and 180-day mortality is 1.5-2 times higher for those with presenting via ambulance compared with patients who self-present. Understanding patient-related and system-related factors of ambulance use for patients with AHF is important. TRIAL REGISTRATION NUMBER: NCT00475852.

Arterial access site and outcomes in patients undergoing percutaneous coronary intervention with and without vorapaxar.

OBJECTIVES: We evaluated outcomes associated with transradial vs. transfemoral approaches and vorapaxar in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in the TRACER trial. BACKGROUND: Vorapaxar reduces ischemic events but increases the risk of major bleeding. METHODS: We compared 30-day and 2-year major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization) and noncoronary artery bypass graft (CABG)-related bleedings in 2,192 transradial and 4,880 transfemoral patients undergoing PCI after adjusting for confounding variables, including propensity for transradial access. RESULTS: Overall, 30-day GUSTO moderate/severe and non-CABG TIMI major/minor bleeding occurred less frequently in transradial (0.9% vs. 2.0%, P = 0.001) vs. transfemoral (1.1% vs. 2.5%, P = 0.005) patients. A similar reduction was seen at 2 years (3.3% vs. 4.7%, P = 0.008; 3.3% vs. 4.9%, P < 0.001, respectively). Transradial was associated with an increased risk of ischemic events at 30 days (OR 1.38, 95% CI 1.11-1.72; P = 0.004), driven primarily by increased periprocedural myocardial infarctions. At 2 years, rates of MACE were comparable (HR 1.14, 95% CI 0.98-1.33; P = 0.096). Although bleeding rates were higher with vorapaxar in transfemoral vs. transradial patients, there was no significant treatment interaction. Also, the access site did not modulate the association between vorapaxar and MACE. CONCLUSIONS: Transradial access was associated with lower bleeding rates and similar long-term ischemic outcomes, suggesting transradial access is safer than transfemoral access among ACS patients receiving potent antiplatelet therapies. Because of the nonrandomized allocation of arterial access, these results should be considered exploratory. © 2015 Wiley Periodicals, Inc.

Efficacy and Safety of Vorapaxar in Non-ST-Segment Elevation Acute Coronary Syndrome Patients Undergoing Noncardiac Surgery.

BACKGROUND: Perioperative antiplatelet agents potentially increase bleeding after non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). The protease-activated receptor 1 antagonist vorapaxar reduced cardiovascular events and was associated with increased bleeding versus placebo in NSTE ACS, but its efficacy and safety in noncardiac surgery (NCS) remain unknown. We aimed to evaluate ischemic, bleeding, and long-term outcomes of vorapaxar in NCS after NSTE ACS. METHODS AND RESULTS: In the TRACER trial, 2202 (17.0%) patients underwent major or minor NCS after NSTE ACS over 1.5 years (median); continuing study treatment perioperatively was recommended. The primary ischemic end point for this analysis was cardiovascular death, myocardial infarction, stent thrombosis, or urgent revascularization within 30 days of NCS. Safety outcomes included 30-day NCS bleeding and GUSTO moderate/severe bleeding. Overall, 1171 vorapaxar and 1031 placebo patients underwent NCS. Preoperative aspirin and thienopyridine use was 96.8% versus 97.7% (P=0.235) and 89.1% versus 86.1% (P=0.036) for vorapaxar versus placebo, respectively. Within 30 days of NCS, no differences were observed in the primary ischemic end point between vorapaxar and placebo groups (3.4% versus 3.9%; adjusted odds ratio 0.81, 95% CI 0.50 to 1.33, P=0.41). Similarly, no differences in NCS bleeding (3.9% versus 3.4%; adjusted odds ratio 1.41, 95% CI 0.87 to 2.31, P=0.17) or GUSTO moderate/severe bleeding (4.2% versus 3.7%; adjusted odds ratio 1.15, 95% CI, 0.72 to 1.83, P=0.55) were observed. In a 30-day landmarked analysis, NCS patients had a higher long-term risk of the ischemic end point (adjusted hazard ratio 1.62, 95% CI 1.33 to 1.97, P<0.001) and GUSTO moderate/severe bleeding (adjusted hazard ratio 5.63, 95% CI 3.98 to 7.97, P<0.001) versus patients who did not undergo NCS, independent of study treatment. CONCLUSION: NCS after NSTE ACS is common and associated with more ischemic outcomes and bleeding. Vorapaxar after NSTE ACS was not associated with increased perioperative ischemic or bleeding events in patients undergoing NCS.

Acute Heart Failure and Atrial Fibrillation: Insights From the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) Trial.

BACKGROUND: Patients with acute heart failure (AHF) frequently have atrial fibrillation (AF), but how this affects patient-reported outcomes has not been well characterized. METHODS AND RESULTS: We examined dyspnea improvement and clinical outcomes in 7007 patients in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. At baseline, 2677 (38.2%) patients had current or a history of AF and 4330 (61.8%) did not. Patients with a history of AF were older than those without (72 vs. 63 years) and had more comorbidities and a higher median left ventricular ejection fraction (31% vs. 27%, P<0.001). Compared to those without AF, patients with AF had a similar mean ventricular rate on admission (81 vs. 83 beats per minute [bpm]; P=0.138) but a lower rate at discharge (75 vs. 78 bpm; P<0.001). There was no difference in dyspnea improvement between patients with and without AF at 6 hours (P=0.087), but patients with AF had less dyspnea improvement at 24 hours (P<0.001). Compared to patients without AF, patients with AF had a higher 30-day all-cause mortality rate (4.7% vs. 3.3%; P=0.005), a higher 30-day HF rehospitalisation rate (7.2% vs. 5.3%; P=0.001), and a higher coprimary composite outcome of 30-day death or readmission (11.6% vs. 8.6%; P<0.001). This difference persisted after adjustment for prognostic variables (adjusted odds ratio=1.19; (95% confidence interval, 1.02 to 1.38; P=0.029). CONCLUSIONS: Among patients admitted to the hospital with AHF, current or a history of AF is associated with less dyspnea improvement and higher morbidity and mortality at 30-days, compared to those not in AF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852.

Acute decompensated heart failure patients admitted to critical care units: insights from ASCEND-HF.

BACKGROUND: Little is known about global patterns of critical care unit (CCU) care and the relationship with outcomes in patients with acute decompensated heart failure (ADHF). Whether a ward or a CCU admission is associated with better outcomes is unclear. METHODS: Patients in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial were initially hospitalized in a ward or CCU (coronary or intensive care unit). Sites were geographically classified: Asia-Pacific (AP), Central Europe (CE), Latin America (LA), North America (NA), and Western-Europe (WE). The primary outcome of 30-day all-cause mortality or all-cause hospital readmission was adjusted using a two-stage multivariable logistic regression model with a generalized estimated equation that took sites within each country as a nested random factor. RESULTS: Overall, 1944 (38.2%) patients were admitted to a CCU and 3150 (61.8%) to a ward, and this varied by region: 50.6% AP, 63.3% CE, 60.7% WE, 22.1% LA, and 28.6% NA. The 30-day death or readmission rate was 15.2% in ward patients and 17.0% in CCU patients (risk-adjusted Odds Ratio [OR] 1.44: 95% CI, 1.14-1.82). Compared with CCU patients in NA (24.1% 30-day event rate), the primary outcomes were: AP (10.4%, Odds Ratio [OR] 0.63; 95% confidence Interval [CI], 0.35 to 1.15), CE (10.4%, OR 0.56: 95% CI, 0.31 to 1.02), LA (22.4%, OR 0.60: 95% CI, 0.11 to 3.32), and WE (11.2%, OR 0.63, 95% CI, 0.25 to 1.56). No regional differences in 30-day mortality were observed; however, 30-day readmission rates were highest in NA sites. CONCLUSIONS: Management of patients with ADHF varies significantly, and after adjustment, CCU care was associated with higher risk of early mortality, not explained by international differences. These findings may help to improve the early decisions regarding risk stratification of patients hospitalized with ADHF.

Rates and reasons for device-based guideline eligibility in patients with heart failure.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT) are recommended by guidelines for patients with heart failure (HF) meeting specific criteria. Uncertainty exists regarding estimates of device eligibility, related in part to the method of assessing for guideline nonadherence. OBJECTIVE: The aim of this study was to identify the rates of guideline eligibility and device utilization after accounting for reasons for not receiving an ICD or CRT. METHODS: Patients were identified from 2006 to 2011 in a tertiary Heart Function Clinic in Canada. The chart-level data were collected that would indicate guideline eligibility and nonadherence. RESULTS: A total of 762 patients with HF were included (mean age 66 years; 527 (69%) were males; median left ventricular ejection fraction 33%). Over follow-up, 331 patients (43%) were never guideline eligible whereas 431 (57%) were guideline eligible for a device. Yearly rates for ICD and CRT adherence in "guideline-eligible" patients ranged from 59% to 68% and from 66% to 81%, respectively. "Patient preference" was the most commonly documented reason for guideline nonadherence in eligible patients. After removal of patients with reasons for nonadherence, rates of ICD and CRT adherence in the "truly eligible" patients were found to be higher (70%-81% and 71%-88%, respectively) than those in guideline-eligible patients. Independent predictors of device nonadherence in truly eligible patients were age >75 years, QRS duration <120 ms, left ventricular ejection fraction <30%, and female sex. CONCLUSION: Based on chart-level data, utilization rates of device-based therapies in patients with HF appear much higher than those of prior registry-based estimates. Given the importance of patient preferences for lack of device use, future quality-of-care metrics based on guideline adherence should capture detailed chart-level data and patient preferences.

Global variation in quality of care among patients hospitalized with acute heart failure in an international trial: findings from the acute study clinical effectiveness of nesiritide in decompensated heart failure trial (ASCEND-HF).

BACKGROUND: Translation of evidence-based heart failure (HF) therapies to clinical practice is incomplete and may vary internationally. We examined common measures of quality of care in patients enrolled in the international Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial. METHODS AND RESULTS: Patients were admitted to 398 hospitals for acute HF in 5 regions (North America, n=3149; Latin America, n=658; Asia Pacific, n=1744; Central Europe, n=966; and Western Europe, n=490). Predefined quality indicators assessed at hospital discharge included the following: medications (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, ß-blockers, aldosterone antagonists, hydralazine/nitrates, statin therapy, and warfarin), use (or planned use) of implantable intracardiac devices, and blood pressure control (<140/90 mm Hg). We determined regional variations in quality indicators as well as the temporal variation of these indicators during the course of the trial. There was significant variation in conformity among different quality indicators, ranging from 0% to 89%. Of all potential performance opportunities, 19 076 of 32 268 (59%) were met, with Central Europe highest at 64%, followed by North America (63%), Western Europe (61%), Latin America (56%), and Asia Pacific (51%; P<0.0001). North America, Central Europe, and Asia Pacific regions demonstrated a modest increase in quality indicator conformity over time, although there was no significant change in other regions. CONCLUSIONS: Quality of care for patients hospitalized with acute HF varies and remains suboptimal even within a randomized clinical trial, which included quality improvement interventions. Specific measures designed to improve performance measures should be implemented even within multicenter clinical trials.

Combined polymorphisms in oxidative stress genes predict coronary artery disease and oxidative stress in coronary angiography patients.

Oxidative stress has been implicated in all stages of atherosclerosis, but how inherited variations in oxidative stress genes influence the severity of cardiovascular disease is not known. We tested associations between polymorphisms in candidate oxidative stress genes, plasma oxidative stress biomarkers, and cardiovascular mortality in an angiography cohort. Single nucleotide polymorphisms (SNPs) across 15 genes were selected by linkage disequilibrium tagging. Genotyping was performed using customized arrayed primer extension micro-arrays, with automated genotype calling methods. Effects of SNPs and haplotypes on plasma oxidative stress and coronary artery disease (CAD) were estimated using a stochastic estimation maximization algorithm. Proportionate hazards analyses were used to determine effects of single and combined genetic markers on cardiovascular mortality risk, and on the following oxidative stress biomarkers: myeloperoxidase (MPO), nitrotyrosine, oxidized low-density lipoprotein, and antioxidant capacity. Oxidative stress gene SNPs associated with CAD were combined into an oxidative stress risk allele score, which predicted disease presence (1.5-fold risk increase per allele, P < 0.001). Combined risk alleles were also associated with elevated plasma MPO (P < 0.003), an oxidative stress biomarker that predicts cardiovascular mortality. Genetic markers that represent lifetime oxidative stress burden may implicate specific oxidative stress pathways in the pathogenesis of atherosclerosis, and offer therapeutic opportunities.

Robust SNP genotyping by multiplex PCR and arrayed primer extension.

BACKGROUND: Arrayed primer extension (APEX) is a microarray-based rapid minisequencing methodology that may have utility in 'personalized medicine' applications that involve genetic diagnostics of single nucleotide polymorphisms (SNPs). However, to date there have been few reports that objectively evaluate the assay completion rate, call rate and accuracy of APEX. We have further developed robust assay design, chemistry and analysis methodologies, and have sought to determine how effective APEX is in comparison to leading 'gold-standard' genotyping platforms. Our methods have been tested against industry-leading technologies in two blinded experiments based on Coriell DNA samples and SNP genotype data from the International HapMap Project. RESULTS: In the first experiment, we genotyped 50 SNPs across the entire 270 HapMap Coriell DNA sample set. For each Coriell sample, DNA template was amplified in a total of 7 multiplex PCRs prior to genotyping. We obtained good results for 41 of the SNPs, with 99.8% genotype concordance with HapMap data, at an automated call rate of 94.9% (not including the 9 failed SNPs). In the second experiment, involving modifications to the initial DNA amplification so that a single 50-plex PCR could be achieved, genotyping of the same 50 SNPs across each of 49 randomly chosen Coriell DNA samples allowed extremely robust 50-plex genotyping from as little as 5 ng of DNA, with 100% assay completion rate, 100% call rate and >99.9% accuracy. CONCLUSION: We have shown our methods to be effective for robust multiplex SNP genotyping using APEX, with 100% call rate and >99.9% accuracy. We believe that such methodology may be useful in future point-of-care clinical diagnostic applications where accuracy and call rate are both paramount.

Dynamic variable selection in SNP genotype autocalling from APEX microarray data.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are DNA sequence variations, occurring when a single nucleotide--adenine (A), thymine (T), cytosine (C) or guanine (G)--is altered. Arguably, SNPs account for more than 90% of human genetic variation. Our laboratory has developed a highly redundant SNP genotyping assay consisting of multiple probes with signals from multiple channels for a single SNP, based on arrayed primer extension (APEX). This mini-sequencing method is a powerful combination of a highly parallel microarray with distinctive Sanger-based dideoxy terminator sequencing chemistry. Using this microarray platform, our current genotype calling system (known as SNP Chart) is capable of calling single SNP genotypes by manual inspection of the APEX data, which is time-consuming and exposed to user subjectivity bias. RESULTS: Using a set of 32 Coriell DNA samples plus three negative PCR controls as a training data set, we have developed a fully-automated genotyping algorithm based on simple linear discriminant analysis (LDA) using dynamic variable selection. The algorithm combines separate analyses based on the multiple probe sets to give a final posterior probability for each candidate genotype. We have tested our algorithm on a completely independent data set of 270 DNA samples, with validated genotypes, from patients admitted to the intensive care unit (ICU) of St. Paul's Hospital (plus one negative PCR control sample). Our method achieves a concordance rate of 98.9% with a 99.6% call rate for a set of 96 SNPs. By adjusting the threshold value for the final posterior probability of the called genotype, the call rate reduces to 94.9% with a higher concordance rate of 99.6%. We also reversed the two independent data sets in their training and testing roles, achieving a concordance rate up to 99.8%. CONCLUSION: The strength of this APEX chemistry-based platform is its unique redundancy having multiple probes for a single SNP. Our model-based genotype calling algorithm captures the redundancy in the system considering all the underlying probe features of a particular SNP, automatically down-weighting any 'bad data' corresponding to image artifacts on the microarray slide or failure of a specific chemistry. In this regard, our method is able to automatically select the probes which work well and reduce the effect of other so-called bad performing probes in a sample-specific manner, for any number of SNPs.