Late Outcomes of the RAPID-TnT Randomized Controlled Trial: 0/1-Hour High-Sensitivity Troponin T Protocol in Suspected ACS.

BACKGROUND: High-sensitivity troponin assays are increasingly being adopted to expedite evaluation of patients with suspected acute coronary syndromes. Few direct comparisons have examined whether the enhanced performance of these assays at low concentrations leads to changes in care that improves longer-term outcomes. This study evaluated late outcomes of participants managed under an unmasked 0/1-hour high-sensitivity cardiac troponin T (hs-cTnT) protocol compared with a 0/3-hour masked hs-cTnT protocol. METHODS: We conducted a multicenter prospective patient-level randomized comparison of care informed by unmasked 0/1-hour hs-cTnT protocol (reported to <5 ng/L) versus standard practice masked hs-cTnT testing (reported to ≤29 ng/L) assessed at 0/3 hours and followed participants for 12 months. Participants included were those presenting to metropolitan emergency departments with suspected acute coronary syndromes, without ECG evidence of coronary ischemia. The primary end point was time to all-cause death or myocardial infarction using Cox proportional hazards models adjusted for clustering within hospitals. RESULTS: Between August 2015 and April 2019, we randomized 3378 participants, of whom 108 withdrew, resulting in 12-month follow-up for 3270 participants (masked: 1632; unmasked: 1638). Among these, 2993 (91.5%) had an initial troponin concentration of ≤29 ng/L. Deployment of the 0/1-hour hs-cTnT protocol was associated with reductions in functional testing. Over 12-month follow-up, there was no difference in invasive coronary angiography (0/1-hour unmasked: 232/1638 [14.2%]; 0/3-hour masked: 202/1632 [12.4%]; P=0.13), although an increase was seen among patients with hs-cTnT levels within the masked range (0/1-hour unmasked arm: 168/1507 [11.2%]; 0/3-hour masked arm: 124/1486 [8.3%]; P=0.010). By 12 months, all-cause death and myocardial infarction did not differ between study arms overall (0/1-hour: 82/1638 [5.0%] versus 0/3-hour: 62/1632 [3.8%]; hazard ratio, 1.32 [95% CI, 0.95-1.83]; P=0.10). Among participants with initial troponin T concentrations ≤29 ng/L, unmasked hs-cTnT reporting was associated with an increase in death or myocardial infarction (0/1-hour: 55/1507 [3.7%] versus 0/3-hour: 34/1486 [2.3%]; hazard ratio, 1.60 [95% CI, 1.05-2.46]; P=0.030). CONCLUSIONS: Unmasked hs-cTnT reporting deployed within a 0/1-hour protocol did not reduce ischemic events over 12-month follow-up. Changes in practice associated with the implementation of this protocol may be associated with an increase in death and myocardial infarction among those with newly identified troponin elevations. Registration: URL: https://www.anzctr.org.au; Unique identifier: ACTRN12615001379505.

Faecal immunochemical test mitigates risk of delayed colonoscopy in people with elevated risk of colorectal neoplasia.

BACKGROUND AND AIM: Surveillance colonoscopies may be delayed because of pressure on resources, such as the COVID-19 pandemic. This study aimed to determine whether delayed surveillance colonoscopy increases the risk for advanced neoplasia and whether interval screening with faecal immunochemical tests (FITs) and other known risk factors can mitigate this risk. METHODS: A retrospective cohort study of individuals undergoing surveillance colonoscopy for personal or family history of colorectal neoplasia was being provided with FIT between colonoscopies. Colonoscopy ≥ 6 months after the guideline-recommended interval was considered "delayed." Individuals were stratified based on prime colonoscopy findings to nonneoplastic findings, non-advanced adenoma, and advanced adenoma. The relative risk (RR) for developing advanced neoplasia was determined using a robust multivariable modified Poisson regression. RESULTS: Of 2548 surveillance colonoscopies, 1457 (57.18%) were delayed. Prior advanced adenoma, older age (> 60 years) and nonparticipation in interval FIT were associated with increased risk for advanced neoplasia (P < 0.05). There was a trend to increased risk in those with prior advanced adenoma with an increasing colonoscopy delay (P trend = 0.01). In participants who did not complete interval FIT and having advanced adenoma in the prime colonoscopy, risk of advanced neoplasia was 2.48 times higher (RR = 2.48, 95% confidence interval: 1.20-5.13) in participants who had beyond 2 years of delayed colonoscopy compared with those with on-time colonoscopy. Colonoscopy delay did not increase the risk of advanced neoplasia in participants with negative interval FIT results. CONCLUSION: Surveillance colonoscopy can be safely extended beyond 6 months in elevated colorectal cancer risk patients who do not have prior advanced adenoma diagnosis, particularly if interval FIT is negative.

A Randomized Trial of a 1-Hour Troponin T Protocol in Suspected Acute Coronary Syndromes: The Rapid Assessment of Possible Acute Coronary Syndrome in the Emergency Department With High-Sensitivity Troponin T Study (RAPID-TnT).

BACKGROUND: High-sensitivity troponin assays promise earlier discrimination of myocardial infarction. Yet, the benefits and harms of this improved discriminatory performance when incorporated within rapid testing protocols, with respect to subsequent testing and clinical events, has not been evaluated in an in-practice patient-level randomized study. This multicenter study evaluated the noninferiority of a 0/1-hour high-sensitivity cardiac troponin T (hs-cTnT) protocol in comparison with a 0/3-hour masked hs-cTnT protocol in patients with suspected acute coronary syndrome presenting to the emergency department (ED). METHODS: Patients were randomly assigned to either a 0/1-hour hs-cTnT protocol (reported to the limit of detection [<5 ng/L]) or masked hs-cTnT reported to ≤29 ng/L evaluated at 0/3-hours (standard arm). The 30-day primary end point was all-cause death and myocardial infarction. Noninferiority was defined as an absolute margin of 0.5% determined by Poisson regression. RESULTS: In total, 3378 participants with an emergency presentation were randomly assigned between August 2015 and April 2019. Ninety participants were deemed ineligible or withdrew consent. The remaining participants received care guided either by the 0/1-hour hs-cTnT protocol (n=1646) or the 0/3-hour standard masked hs-cTnT protocol (n=1642) and were followed for 30 days. Median age was 59 (49-70) years, and 47% were female. Participants in the 0/1-hour arm were more likely to be discharged from the ED (0/1-hour arm: 45.1% versus standard arm: 32.3%, P<0.001) and median ED length of stay was shorter (0/1-hour arm: 4.6 [interquartile range, 3.4-6.4] hours versus standard arm: 5.6 (interquartile range, 4.0-7.1) hours, P<0.001). Those randomly assigned to the 0/1-hour protocol were less likely to undergo functional cardiac testing (0/1-hour arm: 7.5% versus standard arm: 11.0%, P<0.001). The 0/1-hour hs-cTnT protocol was not inferior to standard care (0/1-hour arm: 17/1646 [1.0%] versus 16/1642 [1.0%]; incidence rate ratio, 1.06 [ 0.53-2.11], noninferiority P value=0.006, superiority P value=0.867), although an increase in myocardial injury was observed. Among patients discharged from ED, the 0/1-hour protocol had a negative predictive value of 99.6% (95% CI, 99.0-99.9%) for 30-day death or myocardial infarction. CONCLUSIONS: This in-practice evaluation of a 0/1-hour hs-cTnT protocol embedded in ED care enabled more rapid discharge of patients with suspected acute coronary syndrome. Improving short-term outcomes among patients with newly recognized troponin T elevation will require an evolution in management strategies for these patients. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au. Unique identifier: ACTRN12615001379505.

High-sensitivity troponin in chronic kidney disease: Considerations in myocardial infarction and beyond.

Acute myocardial infarction (MI) represents one of the most common hospital encounters, with significant short-term and long-term morbidity and mortality, and frequently occurs in patients with chronic kidney disease (CKD). Cardiac troponin is an exquisitely sensitive biomarker for myocardial injury and plays an essential role in the diagnosis, risk-stratification, and management of MI. In 2017, the United States Food and Drug Administration approved Roche Diagnostics' 5th generation high-sensitivity cardiac troponin (hs-cTn) for clinical use. Whilst the improved analytical sensitivity of these new high-sensitivity troponin assays facilitate early diagnosis of MI, it also frequently identifies troponin elevations above the conventional reference threshold in the context of non-coronary conditions such as renal dysfunction, and can represent a major diagnostic challenge to clinicians. Furthermore, the optimal management strategy of patients with troponin elevation and high comorbidity burden, a common issue in patients with CKD, remains undefined. In recent years, there has been substantial research and progress undertaken in this rapidly evolving area. In this review, we aim to provide clinicians with an overview of hs-cTn in the setting of CKD as well as an update on its application and the particular considerations involved in the management of myocardial infarction, stable coronary artery disease and myocardial injury in this high risk population.

Effect of Balloon Aortic Valvuloplasty on Mortality in Patients With Severe Aortic Stenosis Prior to Conservative Treatment and Surgical or Transcatheter Aortic Valve Replacement.

BACKGROUND: Outcomes following an initial strategy of balloon aortic valvuloplasty (BAV) prior to medical therapy or intervention with surgical or transcatheter aortic valve replacement (SAVR or TAVR) are unclear in the modern transcatheter intervention era. METHODS: A retrospective, observational cohort study of the echocardiography, cardiothoracic surgery and TAVR databases between 1 January 2006 and 31 December 2016 was performed to compare outcomes between all patients with severe aortic stenosis (AS) treated with or without BAV prior to medical or invasive therapy. RESULTS: 3,142 patients were available for analysis. 223 BAV treated patients had lower mortality relative to medically treated patients, particularly early (20.1% v. 7.6% at 6 months, 58.1% v. 52.5% at 5 years). Over 5 years, the adjusted hazard ratio (HR) was 0.62 (95% CI 0.48-0.80, p < 0.001). Compared with 630 patients proceeding directly to intervention, 75 patients receiving BAV experienced a higher mortality (HR = 2.76, 95% CI 2.07-3.66, p < 0.001). No subsequent excess perioperative mortality was observed with BAV compared with those receiving surgery directly (HR = 1.45, 95% CI 0.91-2.31, p = 0.117). CONCLUSIONS: The risk associated with BAV is low, and improves mortality compared with medical therapy. Balloon aortic valvuloplasty treated patients have poorer outcomes, but treatment with BAV does not increase perioperative mortality and may lessen it.

The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design.

BACKGROUND: Elevated troponin level findings among patients presenting with suspected acute coronary syndrome (ACS) or another intercurrent illness undeniably identifies patients at increased risk of mortality. Whilst enhancing our capacity to discriminate risk, the use of high-sensitivity troponin assays frequently identifies patients with myocardial injury (i.e. troponin rise without acute signs of myocardial ischemia) or type 2 myocardial infarction (T2MI; oxygen supply-demand imbalance). This leads to the clinically challenging task of distinguishing type 1 myocardial infarction (T1MI; coronary plaque rupture) from myocardial injury and T2MI in the context of concurrent acute illness. Diagnostic discernment in this context is crucial because MI classification has implications for further investigation and care. Early invasive management is of well-established benefit among patients with T1MI. However, the appropriateness of this investigation in the heterogeneous context of T2MI, where there is high competing mortality risk, remains unknown. Although coronary angiography in T2MI is advocated by some, there is insufficient evidence in existing literature to support this opinion as highlighted by current national guidelines. OBJECTIVE: The objective is to evaluate the clinical and economic impact of early invasive management with coronary angiography in T2MI in terms of all-cause mortality and cost effectiveness. DESIGN: This prospective, pragmatic, multicenter, randomized trial among patients with suspected supply demand ischemia leading to troponin elevation (n=1,800; T2MI [1,500], chronic myocardial injury [300]) compares the impact of invasive angiography (or computed tomography angiography as per local preference) within 5 days of randomization versus conservative management (with or without functional testing at clinician discretion) on all-cause mortality by 2 years. Randomized treatment allocation will be stratified by baseline estimated risk of mortality using the Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III risk score. Cost-effectiveness will be evaluated by follow-up on clinical events, quality of life, and resource utilization over 24 months. SUMMARY: Ascertaining the most appropriate first-line investigative strategy for these commonly encountered high-risk T2MI patients in a randomized comparative study will be pivotal in informing evidence-based guidelines that lead to better patient and health care outcomes.

A randomized trial of a 1-hour troponin T protocol in suspected acute coronary syndromes: Design of the Rapid Assessment of Possible ACS In the emergency Department with high sensitivity Troponin T (RAPID-TnT) study.

BACKGROUND: Protocols incorporating high-sensitivity troponin to guide decision making in the disposition of patients with suspected acute coronary syndromes (ACS) in the emergency department have received a lot of attention. Traditionally, patients with chest pain have required long periods of observation in emergency department before being deemed safe for discharge. In an era of limited health service resources, a protocol that could discharge patients safely within an hour of presentation is extremely attractive. Unfortunately, despite incorporation into some guidelines, these protocols have not been subjected to randomized comparisons evaluating safety, effectiveness, and cost-effectiveness. OBJECTIVE: This study is designed to provide the evidence required to allow key decision makers to implement these protocols: specifically, to provide evidence that a decision rule based on 0- and 1-hour high-sensitivity troponin T (hs-TnT) is safe, provides noninferior outcomes in all patients with suspected ACS, and that implementation of a rapid troponin protocol leads to efficient care. DESIGN: This prospective pragmatic trial (n=5,400, 5 hospitals) randomly allocates patients with suspected ACS to either a 0/1-hour hs-TnT protocol as advocated in clinical guidelines, versus usual care of standard troponin reporting evaluated at 3 and 6hours. The primary effectiveness composite end points of this study are all-cause death and new/recurrent ACS within 30days. To evaluate cost-effectiveness, follow-up will determine clinical events, quality of life, and resource utilization within 12 months. SUMMARY: Demonstrating that a 0/1-hour hs-TnT protocol improves the effectiveness and efficiency of care within a robust comparative study will fill an evidence gap that currently limits the translation of more precise hs-TnT testing into better patient and health service outcomes.

Impacts of high sensitivity troponin T reporting on care and outcomes in clinical practice: Interactions between low troponin concentrations and participant sex within two randomized clinical trials.

BACKGROUND: The impacts of high sensitivity cardiac troponin (hs-cTn) reporting on downstream interventions amongst suspected acute coronary syndrome (ACS) in the emergency department (ED), especially amongst those with newly identified hs-cTn elevations and in consideration of well-established sex-related disparities, has not been critically evaluated to date. This investigation explores the impact of hs-cTnT reporting on care and outcomes, particularly by participant sex. METHODS: Two similarly ED-based randomized controlled trials conducted between July 2011 to March 2013 (n = 1988) and August 2015 to April 2019 (n = 3378) were comparatively evaluated. Clinical outcomes were adjudicated to the Fourth Universal Definition of MI. Changes in practice were assessed at 30 days, and death or MI were explored to 12 months. RESULTS: The HS-Troponin study demonstrated no difference in death or MI with unmasking amongst those with hs-cTnT <30 ng/L, whereas the RAPID TnT study demonstrated a significantly higher rate. In RAPID TnT, there was significant increase in death or MI associated with unmasking for females with hs-cTnT <30 ng/L (masked: 11[1.5%], unmasked: 25[3.4%],HR: 2.27,95%C.I.:1.87-2.77,P < 0.001). Less cardiac stress testing with unmasking amongst those <30 ng/L was observed in males in both studies, which was significant in RAPID TnT (masked: 92[12.0%], unmasked: 55[7.0%], P = 0.008). In RAPID TnT, significantly higher rates of angiography in males were observed with unmasking, with no such changes amongst females <30 ng/L (masked: 28[3.7%], unmasked: 51[6.5%],P = 0.01). CONCLUSION: Compared with males, there were no evident impacts on downstream practices for females with unmasking in RAPID TnT, likely representing missed opportunities to reduce late death or MI.

One-Year Outcomes of Early, Compassionate Use of the PASCAL Ace Implant System for Transcatheter Mitral Valve Repair.

Background: Continued development of transcatheter mitral repair technologies is needed to address the large and diverse population of high-risk patients with symptomatic mitral regurgitation (MR). The new PASCAL Ace implant system, with its narrower profile, complements the original PASCAL transcatheter valve repair system. The aim of this study is to report 1-year outcomes from the early, compassionate-use observational experience with the novel PASCAL Ace implant system. Methods: After heart team assessment, adults with symptomatic moderate-to-severe (3+) or severe (4+) MR despite optimal medical therapy were treated under compassionate use at 3 hospitals internationally. Data were prospectively collected, and outcomes were assessed over a 12-month follow-up period. Results: Seventeen patients (mean age 76 years, 65% male, mean Society of Thoracic Surgeons Predicted Risk of Operative Mortality score 9.6) were treated. MR etiology was degenerative in 29%, functional in 65%, and mixed in 6%; 59% were in New York Heart Association (NYHA) class III-IV. Technical success was achieved in 100%, and procedural success in 94%. At 1 year, MR grade ≤2+ was achieved in 93% (p < 0.001) with 88% survival rate and 94% free from heart failure hospitalization. The composite major adverse event rate was 6% and 100% of patients had ≤NYHA class II symptoms (p < 0.001). Conclusions: At 1 year, the PASCAL Ace implant system demonstrated feasibility in this early, compassionate use experience in a small group of symptomatic patients with anatomically complex MR. The unique features of the PASCAL Ace implant may expand the treatable MR population.

Implementation of more sensitive cardiac troponin T assay in a state-wide health service.

AIMS: Explore the impact of deploying high-sensitivity (hs) cardiac troponin T (cTnT) assay across a state-wide health service. METHODS AND RESULTS: Presentations to emergency departments of six tertiary hospitals between January 2008 and August 2019 were included; standard cTnT assay was superseded by hs-cTnT in June 2011 without changing the reference range (≥30 ng/L reported as elevated), despite cTnT level of 30 ng/L being equivalent to ∼44 ng/L with hs-cTnT. Clinical outcomes were captured using state-wide linked health records. Interrupted time series analyses were used adjusted for seasonality and multiple co-morbidities using propensity score matching allowing for correlation within hospitals. In total, 614,847 presentations had ≥1 troponin measurement. Clinical ordering of troponin decreased throughout the study with no increase in elevated measurements amongst those tested with hs-cTnT. Small but statistically significant changes in index myocardial infarction (MI) diagnosis (-0.36%/year, 95%CI [confidence interval]:-0.48, -0.24,p < 0.001) and invasive coronary angiography (0.12%/year,95%CI:0, 0.24,p = 0.02) were seen, with no impact on death/MI at 30 days or 3-year survival in episodes of care (EOCs) with elevated cTnT after hs-cTnT implementation. Length of stay (LOS) was shorter among those with an elevated hs-cTnT (-4.44 h/year, 95%CI:-5.27, -3.60, p < 0.001). Non-elevated cTnT EOCs demonstrated shorter total LOS and improved 3-year survival (adjusted hazard ratio:0.90, 95%CI:0.83, 0.97,p = 0.008) although death/MI at 30 days was unchanged using hs-cTnT. CONCLUSION: Widespread implementation of hs-cTnT without altering clinical thresholds reported to clinicians provided significantly shorter LOS without a clinically significant impact on clinical outcomes. A safer cohort with non-elevated cTnT was identified by hs-cTnT compared to the standard cTnT assay.

Transcatheter Tricuspid Valve Replacement With the EVOQUE System: 1-Year Outcomes of a Multicenter, First-in-Human Experience.

OBJECTIVES: The aim of this study was to report the midterm outcomes at 1 year in the expanded first-in-human experience with the transfemoral EVOQUE system (Edwards Lifesciences) for tricuspid regurgitation (TR). BACKGROUND: Untreated TR is associated with excess mortality and morbidity. The first-in-human experience with the EVOQUE tricuspid valve replacement system reported favorable 30-day outcomes with no mortality in a compassionate use population. METHODS: Twenty-seven patients with severe TR were treated with the EVOQUE system in a compassionate use experience at 7 centers between May 2019 and July 2020. All patients had clinical right-sided heart failure (HF) and were deemed inoperable and unsuitable for transcatheter edge-to-edge repair by the institutional heart teams. The clinical outcomes collected included all-cause mortality, symptom status, TR severity, HF hospitalization, and major adverse cardiovascular events. RESULTS: At baseline, all patients (age: 77 ± 8 years, 89% female) were at high surgical risk (mean Society of Thoracic Surgeons score: 8.6% ± 5.5%), with 89% New York Heart Association functional class III/IV. TR was predominantly functional in etiology (19/27, 70%). At 1 year, mortality was 7% (2/27), 70% of patients were New York Heart Association functional class I/II, and 96% and 87% of patients had a TR grade ≤2+ and ≤1+, respectively. Between 30 days and 1 year, 2 patients experienced HF hospitalizations, and 1 patient required a new pacemaker implantation. CONCLUSIONS: In this early, compassionate use experience, the transfemoral transcatheter EVOQUE tricuspid valve replacement system demonstrated durable efficacy, persistent improvement in symptom status, and low rates of mortality and HF hospitalizations at a 1-year follow-up. Further studies are underway to validate its efficacy.

Same-Day Discharge Post-Transcatheter Aortic Valve Replacement During the COVID-19 Pandemic: The Multicenter PROTECT TAVR Study.

OBJECTIVES: The aim of this study was to determine the safety and efficacy of same-day discharge (SDD) after transcatheter aortic valve replacement (TAVR) during the COVID-19 pandemic. BACKGROUND: The COVID-19 pandemic has placed significant stress on health care systems worldwide. SDD in highly selected TAVR patients can facilitate the provision of essential cardiovascular care while managing competing COVID-19 resource demands. METHODS: Patient selection for SDD was at the discretion of the local multidisciplinary heart team, across 7 international sites. The primary outcome was a composite of cardiovascular death, stroke, myocardial infarction, all-cause readmission, major vascular complications, and new permanent pacemaker (PPM) implantation. RESULTS: From March 2020 to August 2021, 124 of 2,100 patients who underwent elective transfemoral TAVR were selected for SDD. The average age was 78.9 ± 7.8 years, the median Society of Thoracic Surgeons score was 2.4 (IQR: 1.4-4.2), and 32.3% (n = 40) had preexisting PPMs. There were no major vascular complications, strokes, or deaths during the index admission. One patient (0.8%) required PPM implantation for complete heart block and was discharged the same day. No patient required a PPM between discharge home and 30-day follow-up. The composite of cardiovascular death, stroke, myocardial infarction, all-cause readmission, major vascular complications, and new PPM at 30 days occurred in 5.7% patients (n = 6 of 106). CONCLUSIONS: SDD post-TAVR is safe and feasible in selected patients at low risk for adverse clinical events postdischarge. This strategy may have a potential role in highly selected patients even when the COVID-19 pandemic abates.

Transcatheter solutions for transcatheter aortic valve replacement dysfunction: is redo transcatheter aortic valve replacement a durable option?

As transcatheter aortic valve replacement (TAVR) expands into a younger and lower risk cohort of patients, many important clinical questions are raised, including the one of overall valve durability. Bioprosthetic valve dysfunction (BVD) is a complex clinical issue, of which structural valve deterioration (SVD) is a subcategory. Similar to surgical bioprosthesis, transcatheter heart valves (THVs) can fail over the years however, data on long-term THVs durability is lacking, especially in the lower risk cohort. Surgical explant with open aortic surgery or a second THV, described as redo-TAVR, are feasible options when the first THV fails. However long-term data in these patients is even more limited. Important clinical considerations such as the mechanism(s) of THV dysfunction, the type and timing of the second procedure must be carefully considered. There are also inherently important clinical concerns regarding redo-TAVR, such as coronary access and higher post procedure gradients. In the present keynote lecture, we review the diagnosis of THV dysfunction and transcatheter options available when SVD occurs.

Troponin elevation pattern and subsequent cardiac and non-cardiac outcomes: Implementing the Fourth Universal Definition of Myocardial Infarction and high-sensitivity troponin at a population level.

BACKGROUND: The Fourth Universal Definition of Myocardial Infarction (MI) differentiates MI from myocardial injury. We characterised the temporal course of cardiac and non-cardiac outcomes associated with MI, acute and chronic myocardial injury. METHODS: We included all patients presenting to public emergency departments in South Australia between June 2011-Sept 2019. Episodes of care (EOCs) were classified into 5 groups based on high-sensitivity troponin-T (hs-cTnT) and diagnostic codes: 1) Acute MI [rise/fall in hs-cTnT and primary diagnosis of acute coronary syndrome], 2) Acute myocardial injury with coronary artery disease (CAD) [rise/fall in hs-cTnT and diagnosis of CAD], 3) Acute myocardial injury without CAD [rise/fall in hs-cTnT without diagnosis of CAD], 4) Chronic myocardial injury [elevated hs-cTnT without rise/fall], and 5) No myocardial injury. Multivariable flexible parametric models were used to characterize the temporal hazard of death, MI, heart failure (HF), and ventricular arrhythmia. RESULTS: 372,310 EOCs (218,878 individuals) were included: acute MI (19,052 [5.12%]), acute myocardial injury with CAD (6,928 [1.86%]), acute myocardial injury without CAD (32,231 [8.66%]), chronic myocardial injury (55,056 [14.79%]), and no myocardial injury (259,043 [69.58%]). We observed an early hazard of MI and HF after acute MI and acute myocardial injury with CAD. In contrast, subsequent MI risk was lower and more constant in patients with acute injury without CAD or chronic injury. All patterns of myocardial injury were associated with significantly higher risk of all-cause mortality and ventricular arrhythmia. CONCLUSIONS: Different patterns of myocardial injury were associated with divergent profiles of subsequent cardiac and non-cardiac risk. The therapeutic approach and modifiability of such excess risks require further research.

Redistribution of terbium ions across acetylcholine receptor-enriched membranes induced by agonist desensitization.

Using small-angle x-ray diffraction from centrifugally oriented acetylcholine receptor (AChR) enriched membranes coupled with anomalous scattering from terbium ions (Tb3+) titrated into presumed Ca2+ binding sites, we have mapped the distribution of Tb3+ perpendicular to the membrane plane using a heavy atom refinement algorithm. We have compared the distribution of Tb3+ in the closed resting state with that in the carbamylcholine-desensitized state. In the closed resting state we find 45 Tb3+ ions distributed in 10 narrow peaks perpendicular to the membrane plane. Applying the same refinement procedure to the data from carbamylcholine desensitized AChR we find 18 fewer Tb3+ ions in eight peaks, and slight rearrangements of Tb3+ density in the peaks near the ends of the AChR ion channel pore. These agonist dependent changes in the Tb3+ stoichiometry and distribution suggest a likely role for multivalent cations in stabilizing the different functional states of the AChR, and the changes in the Tb3+ distribution at the two ends of the pore suggest a potential role for multivalent cations in the gating of the ion channel.

Multidisciplinary transcatheter aortic valve replacement heart team programme improves mortality in aortic stenosis.

Objectives: To analyse the effect of the implementation of a transcatheter aortic valve replacement (TAVR) and multidisciplinary heart team programme on mortality in severe aortic stenosis (AS). Methods: A retrospective, observational cohort study was performed using the echocardiography, cardiothoracic surgery and TAVR databases between 1 January 2006 and 31 December 2016. Outcomes were compared between the pre- and post-TAVR programme eras in a tertiary referral centre providing transcatheter and surgical interventions for AS.All-cause mortality within 5 years from diagnosis was determined for 3399 patients with echocardiographically defined severe AS. Results: Of 3399 patients, there were 210 deaths (6.2%) at 30 days and 1614 deaths (47.5%) at 5 years.Overall, patients diagnosed in the post-TAVR programme era were older, with a lower ejection fraction and more severe AS, but were less comorbid.Among 705 patients undergoing intervention, those in the post-TAVR programme era were older, with a lower ejection fraction and more severe AS but no significant differences in comorbidities.Using an inverse probability weighted cohort and a Cox proportional hazards model, a significant mortality benefit was noted between eras alone (HR=0.86, 95% CI 0.77 to 0.97, p=0.015). When matching for age, comorbidities and valve severity, this benefit was more evident (HR=0.82, 95% CI 0.73 to 0.92, p=0.001).After adjusting for the presence of aortic valve intervention, a significant benefit persisted (HR=0.84, 95% CI 0.75 to 0.95, p=0.005). Conclusion: The implementation of a TAVR programme is associated with a mortality benefit in the population with severe AS, independent of the expansion of access to intervention.

Invasive management of acute coronary syndrome: Interaction with competing risks.

BACKGROUND: The aim of this study was to characterise the interaction between ACS- and non-ACS-risk on the benefits of invasive management in patients presenting with acute coronary syndrome (ACS). METHODS: Consecutive patients admitted to a tertiary hospital's Cardiac Care Unit in the months of July-December, 2003-2011 with troponin elevation (>30 ng/L) were included. "ACS-specific-risk" was estimated using the GRACE score and "non-ACS-risk" was estimated using the Charlson-Comorbidity-Index (CCI). Inverse-probability-of-treatment weighting was used to adjust for baseline differences between patients who did or did not receive invasive management. A multivariable flexible parametric model was used to characterise the time-varying hazard. RESULTS: In total, 3057 patients were included with a median follow-up of 9.0 years. Based on CCI, 1783 patients were classified as 'low-non-ACS risk' (CCI ≤ 1; invasive management 81%; 12-month mortality 5%), 820 as 'medium-non-ACS risk' (CCI 2-3; invasive management 68%; 12-month mortality 13%), and 468 as 'high-non-ACS risk' (CCI ≥ 4; invasive management 47%; 12-month mortality 29%). After adjustment, invasive management was associated with a significant reduction in one-year overall-mortality in the 'low-risk' and 'medium-risk' groups (HR = 0.38, 95%CI:0.26-0.56; HR = 0.46, 95%CI:0.32-0.67); but not in the 'high-risk' group (HR = 1.02, 95%CI:0.67-1.56). The absolute benefit of invasive management was greatest with higher baseline ACS-risk, with a non-linear interaction between ACS- and non-ACS-risk. CONCLUSIONS: There is a complex interaction between ACS- and non-ACS-risk on the benefit of invasive management. These results highlight the need to develop robust methods to objectively quantify risk attributable to non-ACS comorbidities in order to make informed decisions regarding the use of invasive management in individuals with numerous comorbidities.

A Prospective Randomised Controlled Trial of a Single Intravenous Infusion of Ferric Carboxymaltose vs Single Intravenous Iron Polymaltose or Daily Oral Ferrous Sulphate in the Treatment of Iron Deficiency Anaemia in Pregnancy.

Iron deficiency anaemia (IDA) is the most common nutritional deficiency affecting pregnant women worldwide. This study aims to compare the efficacy and safety of a newly available intravenous (IV) iron preparation, ferric carboxymaltose (FCM), against IV iron polymaltose (IPM), and standard oral iron (ferrous sulphate) for the treatment of IDA in pregnancy. This is an open-labelled prospective randomised controlled trial (RCT) with intention-to-treat analysis conducted at a primary health care facility with a single tertiary referral centre in Launceston. Tasmania, Australia. A 3-arm randomised controlled trial was conducted comparing a single IV infusion of 1000mg of FCM (n = 83 patients) over 15 minutes against a single IV infusion of 1000mg of IPM (n = 82) over 2 hours against 325mg daily oral ferrous sulphate (n = 81) until delivery, for the treatment of IDA in pregnancy. A total of 246 consecutive pregnant women were recruited between September 2013 and July 2014. The median age was 28 years, with a median and mean gestation of 27 weeks. The median serum ferritin was 9µg/L, with a mean of 13µg/L. The mean haemoglobin (Hb) was 114g/L. The primary outcome was the change in ferritin and Hb levels at 4 weeks after intervention. Secondary outcomes included ferritin and Hb improvements at predelivery, safety, tolerability, quality of life (QoL), cost utility, and fetal outcomes. The mean Hb level differences between the baseline intervention time point and 4 weeks thereafter were significantly higher in the FCM versus the oral group by 4.35g/L (95% CI: 1.64-7.05; P = 0.0006) and in the IPM vs the oral group by 4.08g/L (95% CI: 1.57-6.60; P = 0.0005), but not different between the FCM and IPM groups (0.26g/L; 95% CI: -2.59 to 3.11; P = 0.9740). The mean ferritin level differences were significantly higher at 4 weeks in the FCM vs oral iron group by 166µg/L (95% CI: 138-194; P < 0.0001) and in the IPM vs oral iron group by 145µg/L (95% CI: 109-1180, P < 0.0001), but not between the 2 IV groups (21.5µg/L; 95% CI: -23.9 to 66.9; P = 0.4989). Administration of IV FCM during pregnancy was safe and better tolerated than IV IPM or oral iron. Compliance to oral iron was the lowest amongst treatment groups with one-third of the patients missing doses of daily iron tablets. Significant improvement in overall QoL scores was observed in both IV iron supplement groups by achieving normal ferritin following effective and prompt repletion of iron stores, compared to the oral iron group (P = 0.04, 95% CI: 21.3, 1.8). The overall cost utility of IV FCM and IV IPM appear to be similar to oral iron. There were no differences in the fetal outcomes between the 3 trial arms. In conclusion, this study demonstrates that a single IV iron infusion is an effective and safe option for treatment of IDA during pregnancy. FCM was more convenient than other treatments. Rapid parenteral iron repletion can improve iron stores, Hb levels and QoL in pregnant women, with ongoing benefits until delivery. Integration of IV iron for IDA in pregnancy can potentially improve pregnancy outcomes for the mother. Update of guidelines to integrate the use of new IV iron preparations in pregnancy is warranted.

P2Y12 Inhibitor Pre-Treatment in Non-ST-Elevation Acute Coronary Syndrome: A Decision-Analytic Model.

Current guidelines recommend initiation of a P2Y12 inhibitor for all patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) at the time of diagnosis (pre-treatment); however, there are no randomized trials directly comparing pre-treatment with initiation at the time of angiography to support this practice. We explore clinical and institutional parameters potentially associated with benefit with this strategy in a decision-analytic model based on available evidence from randomised trials. A decision analysis model was constructed comparing three P2Y12 inhibitors in addition to aspirin in patients with NSTE-ACS. Based on clinical trial data, the cumulative probability of 30 day mortality, myocardial infarction (MI) and major bleeding were determined, and used to calculate the net clinical benefit (NCB) with and without pre-treatment. Sensitivity analysis was performed to assess the relationship between NCB and baseline ischemic risk, bleeding risk, time to angiography and local surgical revascularization rates. Pre-treatment with ticagrelor and clopidogrel was associated with a greater than 50% likelihood of providing a >1% increase in 30 day NCB when baseline estimated ischemic risk exceeds 11% and 14%, respectively. Prasugrel pre-treatment did not achieve a greater than 50% probability of an increase in NCB regardless of baseline ischemic risk. Institutional surgical revascularization rates and time to coronary angiography did not correlate with the likelihood of benefit from P2Y12 pre-treatment. In conclusion, pre-treatment with P2Y12 inhibition is unlikely to be beneficial to the majority of patients presenting with NSTE-ACS. A tailored assessment of each patient's individual ischemic and bleeding risk may identify those likely to benefit.