Biobanking animal genetic resources: critical infrastructure and growth opportunities.

National animal gene banks have acquired substantial quantities of germplasm that protect and preserve a wide range of livestock breeds. New challenges and growth opportunities are emerging. A key challenge will be increased gene bank use, but this requires increased characterization of phenotypes and genotypes for populations and collections.

Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of 3 Tests.

BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE). METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

High-Sensitivity Troponin I after Cardiac Surgery and 30-Day Mortality.

BACKGROUND: Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to ≥70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS: We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS: Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS: The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.).

Survival After Invasive or Conservative Management of Stable Coronary Disease.

BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes during a median of 3.2 years. Extended follow-up for mortality is ongoing. METHODS: ISCHEMIA participants were randomized to an initial invasive strategy added to guideline-directed medical therapy or a conservative strategy. Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and noncardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models, and Bayesian methods. Undetermined deaths were classified as cardiovascular as prespecified in the trial protocol. RESULTS: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23% women, 16% Hispanic, 4% Black, 42% with diabetes, and median ejection fraction 0.60. A total of 557 deaths accrued during a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 noncardiovascular deaths, and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate, 12.7% in invasive strategy, 13.4% in conservative strategy; adjusted hazard ratio, 1.00 [95% CI, 0.85-1.18]). There was a lower 7-year rate cardiovascular mortality (6.4% versus 8.6%; adjusted hazard ratio, 0.78 [95% CI, 0.63-0.96]) with an initial invasive strategy but a higher 7-year rate of noncardiovascular mortality (5.6% versus 4.4%; adjusted hazard ratio, 1.44 [95% CI, 1.08-1.91]) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. CONCLUSIONS: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of noncardiovascular mortality with an initial invasive strategy during a median follow-up of 5.7 years. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04894877.

Predicting time to asystole following withdrawal of life-sustaining treatment: a systematic review.

The planned withdrawal of life-sustaining treatment is a common practice in the intensive care unit for patients where ongoing organ support is recognised to be futile. Predicting the time to asystole following withdrawal of life-sustaining treatment is crucial for setting expectations, resource utilisation and identifying patients suitable for organ donation after circulatory death. This systematic review evaluates the literature for variables associated with, and predictive models for, time to asystole in patients managed on intensive care units. We conducted a comprehensive structured search of the MEDLINE and Embase databases. Studies evaluating patients managed on adult intensive care units undergoing withdrawal of life-sustaining treatment with recorded time to asystole were included. Data extraction and PROBAST quality assessment were performed and a narrative summary of the literature was provided. Twenty-three studies (7387 patients) met the inclusion criteria. Variables associated with imminent asystole (<60 min) included: deteriorating oxygenation; absence of corneal reflexes; absence of a cough reflex; blood pressure; use of vasopressors; and use of comfort medications. We identified a total of 20 unique predictive models using a wide range of variables and techniques. Many of these models also underwent secondary validation in further studies or were adapted to develop new models. This review identifies variables associated with time to asystole following withdrawal of life-sustaining treatment and summarises existing predictive models. Although several predictive models have been developed, their generalisability and performance varied. Further research and validation are needed to improve the accuracy and widespread adoption of predictive models for patients managed in intensive care units who may be eligible to donate organs following their diagnosis of death by circulatory criteria.

Bioclimatic thermal stress indices and their relationships with andrological characteristics in hair rams.

This study evaluated relationships among reproductive parameters and the bioclimatic indices: temperature and humidity index (THI), equivalent temperature index (ETI), black globe temperature and humidity index (BGTHI), and thermal comfort index (TCI), during the first 45 days of spermatogenesis (SP-45) and during the 15 days of sperm transit through the epididymis (STP-15) that preceded the reproductive assessments (ReA). Such information is useful in determining the optimal breeding season in Northeast Brazil. Santa Inês rams (n = 25) underwent two ReA in three periods of the year (D-P = dry; R-P = rainy and RD-P = rainy/dry transition), and the bioclimatic indices were calculated at the corresponding SP-45 and STP-15 timepoints prior to each ReA. Sperm kinetic parameters in D-P were depressed compared to R-P and RD-P (P < 0.05). The index values had an antagonistic relationship with most parameters and regression analysis demonstrated that the BGTHI and the TCI had a negative association with the progressive motility, curvilinear, straight line, and average path velocities, and a positive association with slow sperm in the ejaculate in SP-45 and STP-15 phases (P < 0.01). Semen quality kinetics is affected throughout the year by the environment and it is apparent that it is impaired in D-P and better in R-P and RD-P seasons. The BGTHI and TCI measured in the sperm production phase classified the environment most coherently and presented better association with the behavior of sperm kinetics.

Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial.

AIMS: Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus PCSK9 inhibitor. METHODS AND RESULTS: In 18,924 patients post-acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score-matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median 8.3 months from randomization, after a median 6.0 months with LDL-C < 0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C versus 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047). CONCLUSIONS: A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01663402.

Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab.

BACKGROUND: Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain. METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score-matched models. RESULTS: Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; Ptrend<0.0001) and after adjustment for low-density lipoprotein cholesterol (Ptrend=0.035). Higher baseline apoB stratum was associated with greater relative (Ptrend<0.0001) and absolute reduction in MACE with alirocumab versus placebo. In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa. CONCLUSIONS: In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of apoB levels as low as ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01663402.

Initial Invasive or Conservative Strategy for Stable Coronary Disease.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Development of a synthetic biosensor for chemical exchange MRI utilizing in silico optimized peptides.

Chemical exchange saturation transfer (CEST) MRI has been identified as a novel alternative to classical diagnostic imaging. Over the last several decades, many studies have been conducted to determine possible CEST agents, such as endogenously expressed compounds or proteins, that can be utilized to produce contrast with minimally invasive procedures and reduced or non-existent levels of toxicity. In recent years there has been an increased interest in the generation of genetically engineered CEST contrast agents, typically based on existing proteins with CEST contrast or modified to produce CEST contrast. We have developed an in silico method for the evolution of peptide sequences to optimize CEST contrast and showed that these peptides could be combined to create de novo biosensors for CEST MRI. A single protein, superCESTide, was designed to be 198 amino acids. SuperCESTide was expressed in E. coli and purified with size exclusion chromatography. The magnetic transfer ratio asymmetry generated by superCESTide was comparable to levels seen in previous CEST reporters, such as protamine sulfate (salmon protamine) and human protamine. These data show that novel peptides with sequences optimized in silico for CEST contrast that utilize a more comprehensive range of amino acids can still produce contrast when assembled into protein units expressed in complex living environments.

Memory support training and lifestyle modifications to promote healthy aging in persons at risk for Alzheimer's disease: a digital application supported intervention (Brain Boosters).

BACKGROUND: Evidence-based interventions to protect against cognitive decline among older adults at risk for Alzheimer's disease and related dementias (ADRD) are urgently needed. Rehabilitation approaches to support memory and behavioral/lifestyle interventions are recognized as promising strategies for preserving or improving cognitive health, although few previous interventions have combined both approaches. This paper describes the protocol of the Brain Boosters intervention, which synergistically combines training in compensatory and healthy lifestyle behaviors and supports implementation and tracking of new behaviors with a digital application. METHODS: The study utilizes a single-site, single-blinded, randomized controlled design to compare a structured lifestyle and compensatory aid intervention to an education-only self-guided intervention. We plan to enroll 225 community-dwelling adults (25% from underrepresented groups) aged 65 + who endorse subjective cognitive decline (SCD) and low baseline levels of healthy lifestyle behaviors. Both interventions will be administered in group format, consisting of 15 two-hour classes that occur weekly for ten weeks and taper to bi-monthly and monthly, for an intervention duration of 6 months. Participants in both interventions will receive education about a variety of memory support strategies and healthy lifestyle behaviors, focusing on physical and cognitive activity and stress management. The structured intervention will also receive support in adopting new behaviors and tracking set goals aided by the Electronic Memory and Management Aid (EMMA) digital application. Primary outcomes include global cognition (composite of memory, attention, and executive function tests) and everyday function (Everyday Cognition Questionnaire). Data will be collected at baseline and outcome visits, at approximately 6, 12, and 18 months. Qualitative interviews, self-report surveys (e.g., indicators of self-determination, health literacy) and EMMA data metrics will also be used to identify what components of the intervention are most effective and for whom they work. DISCUSSION: Successful project completion will provide valuable information about how individuals with SCD respond to a compensation and preventative lifestyle intervention assisted by a digital application, including an understanding of factors that may impact outcomes, treatment uptake, and adherence. The work will also inform development, scaling, and personalization of future interventions that can delay disability in individuals at risk for ADRD. TRIAL REGISTRATION: ClinicalTrials.gov. (NCT05027789, posted 8/30/2021).

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

Alirocumab after acute coronary syndrome in patients with a history of heart failure.

AIMS: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. METHODS AND RESULTS: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (Pinteraction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF. CONCLUSION: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS.

Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial.

AIMS: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. METHODS AND RESULTS: Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. CONCLUSIONS: In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. CLINICAL TRIAL REGISTRATION: ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.

Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial.

BACKGROUND: Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score-matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment. METHODS: Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25 to 50 (n=3692), or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching. RESULTS: Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (hazard ratio, 0.74 [95% CI, 0.62-0.89]; absolute risk reduction, 0.92) or 25 to 50 mg/dL (hazard ratio, 0.74 [95% CI, 0.64-0.87]; absolute risk reduction, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73-1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL. CONCLUSIONS: After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL had a reduction in the risk of MACE that was similar to that of patients who achieved LDL-C levels of 25 to 50 mg/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.

BACKGROUND: In the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI). METHODS: ISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections >National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. RESULTS: Procedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) and secondary (3.48% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI than after no MI using the primary (adjusted HR, 3.38 [95% CI, 2.03-5.61]; P<0.001) or secondary MI definition (adjusted HR, 3.52 [2.11-5.88]; P<0.001). CONCLUSIONS: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and with the use of the secondary MI definition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Morphine and clinical outcomes in patients with ST segment elevation myocardial infarction treated with fibrinolytic and antiplatelet therapy: Insights from the TREAT trial.

BACKGROUND: Morphine is commonly used to relieve pain, anxiety and dyspnea in STEMI but it lowers blood pressure and delays the activity of oral antiplatelet agents. The impact of morphine on clinical outcomes remains unknown. This analysis was performed to determine if morphine use was associated with increased risk of adverse clinical events among STEMI patients treated with fibrinolytic therapy and clopidogrel or ticagrelor. METHODS: In the Ticagrelor in Patients with ST Elevation Myocardial Infarction Treated with Pharmacological Thrombolysis (TREAT) study, 3799 STEMI patients treated with fibrinolysis were randomized to receive clopidogrel or ticagrelor. Morphine use was left to the discretion of the treating physicians. In this pre-specified analysis, we evaluated clinical outcomes based on the use and timing of morphine administration. Outcomes were stratified by randomized treatment group. Multivariable analysis was performed using Inverse Probability Treatment Weighting (IPTW) weighting. RESULTS: Morphine was used in 53% of patients. After adjustment using IPTW weighting, morphine use was associated with higher hazard of reinfarction at 7 days (HR 4.9, P = .0006) and 30 days (HR 1.7, P = .04), and lower hazard of major bleeding (HR 0.37, P = .006). There was no significant difference in mortality at any time point. CONCLUSIONS: Among patients with STEMI treated with fibrinolytic therapy, morphine use was associated with a higher risk of early reinfarction and a lower risk of major bleeding but no difference in mortality. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02298088.