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Digital, Background Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk. Objectives In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels. Methods ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was 13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43. Conclusions In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402), Ciencias Médicas y de la Salud

Background: Cardiovascular disease is the second-leading cause of death in Canada. However, limited data are available on the prevalence of atherosclerotic cardiovascular disease (ASCVD) in Canada. The study objective was to describe the incidence and prevalence of ASCVD in adult patients in Ontario, Canada, and to evaluate temporal trends for subsequent ASCVD events among those with new-onset ASCVD. Methods: This retrospective, observational study identified ASCVD incidence and prevalence data from the Institute for Clinical Evaluative Sciences Data Repository for adults from Ontario. Overall prevalence was established for the period from 2002 to 2018. Incident cases from April 1, 2005 to March 2016 were then identified, and followed up to 2018. Primary outcomes were date and type of index event/procedure, patient characteristics/baseline demographics, and comorbidities. Secondary outcomes assessed were time from first to second ASCVD event, subsequent event(s) and/or mortality, and type of subsequent event(s) relative to the type of index/primary event. Results: A total of 1,042,621 eligible prevalent ASCVD cases were identified; of these, 743,309 patients (69%) were newly diagnosed with incident ASCVD. The 10-year prevalence rates for all ASCVD subtypes increased over the study period. Overall event incidence rates per 1000 person-years were mostly stable or increased. Among incident cases, 50% experienced subsequent events over the study period. Conclusions: This observational study demonstrated increasing prevalence and high incidence of new ASCVD diagnoses in adults from Ontario, over the study period. These data, together with the substantial number of subsequent events in ASCVD patients, demonstrate significant clinical burden of this disease in Ontario. Résumé: Contexte: Les maladies cardiovasculaires constituent la deuxième cause de décès au Canada. Toutefois, on dispose de peu de données sur la prévalence de la maladie cardiovasculaire athéroscléreuse (MCVAS) au Canada. L’étude avait pour objectifs de décrire l’incidence et la prévalence de la MCVAS chez les patients adultes en Ontario (Canada) et d’évaluer les tendances temporelles des manifestations subséquentes de MCVAS chez les personnes ayant une MCVAS d’apparition récente. Méthodologie: Cette étude observationnelle rétrospective a permis de colliger les données sur l’incidence et la prévalence de la MCVAS chez les adultes ontariens consignées dans le référentiel de l’Institut des sciences cliniques évaluatives. La prévalence globale a été établie pour la période allant de 2002 à 2018. Les cas incidents survenus du 1er avril 2005 à mars 2016 ont ensuite été recensés et suivis jusqu’en 2018. Les paramètres d’évaluation principaux étaient : date et nature de la manifestation index et de l’intervention; caractéristiques des patients et données démographiques initiales; comorbidités. Les éléments suivants constituaient les paramètres d’évaluation secon-daires : temps écoulé entre la première et la deuxième manifestation de MCVAS, la ou les manifestations subséquentes et/ou le décès; nature de la ou des manifestations subséquentes par rapport à celle de la manifestation index ou primaire. Résultats: En tout, 1 042 621 cas de MCVAS prévalents admissibles ont été dénombrés; parmi ceux-ci, il y avait 743 309 (69 %) cas incidents de MCVAS nouvellement diagnostiqués. Les taux de prévalence à 10 ans de tous les sous-types de MCVAS ont augmenté au cours de la période étudiée. Les taux globaux d’incidence des manifestations par 1000 années-personnes étaient généralement stables ou accrus. Cinquante pour cent des cas incidents ont été associés à des manifestations subséquentes au cours de la période étudiée. Conclusions: Cette étude observationnelle a démontré une prévalence croissante et une incidence élevée de nouveaux diagnostics de MCVAS chez les adultes en Ontario au cours de la période étudiée. Les données à cet égard, ainsi que le grand nombre de manifestations subséquentes de la maladie, démontrent que la MCVAS constitue un fardeau clinique considérable en Ontario.

Chronic kidney disease (CKD) increases the risk of adverse outcomes in acute coronary syndrome (ACS). The optimal regimen of dual antiplatelet therapy (DAPT) post-percutaneous coronary intervention (PCI) in CKD poses a challenge due to the increased bleeding and clotting tendencies, particularly since patients with CKD were underrepresented in randomized controlled trials. We examined the practice patterns of DAPT prescription stratified by the presence of CKD. The multicentre prospective Canadian Observational Antiplatelet Study (COAPT) enrolled patients with ACS between December 2011 and May 2013. The present study is a subgroup analysis comparing type and duration of DAPT and associated outcomes among patients with and without CKD (eGFR 60 ml/min/1.73 m

BACKGROUND Although acetylsalicylic acid is the most commonly used antithrombotic agent for the secondary prevention of cardiovascular events, residual atherothrombotic risk has prompted a guideline recommendation for the addition of dual antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) in high vascular risk patients. Accordingly, the CONNECT CVD quality enhancement initiative provides a contemporary "snapshot" of the clinical features and antithrombotic management of atherosclerotic cardiovascular disease (ASCVD) patients in Canada. METHODS Canadian cardiologists (49 cardiologists from six provinces) undertook a retrospective chart audit of 10 ASCVD patients in their outpatient practice who met the Cardiovascular Outcomes for People Using Anticoagulation Strategy-like criteria from May 2018 to April 2019. RESULTS Of the 492 (two cardiologists provided 11 patients) enroled, average age was 70 years, 25% were female, 39% had diabetes and 20% had atrial fibrillation. Prior revascularisation was common (percutaneous coronary artery intervention 61%, coronary artery bypass graft 39%), with 31% having multivessel disease. A total of 47% of patients had a Reduction of Atherothrombosis for Continued Health bleeding score of ≥11 (~2.8% risk of serious bleeding at 2 years). Single antiplatelet therapy (SAPT) alone was most commonly used (62%), while 22% were on DAPT alone. In total, 22% were on oral anticoagulation (OAC), with 16% being on non-vitamin K oral anticoagulant alone, 5% on DPI and 1% received triple therapy. CONCLUSIONS In contemporary Canadian clinical practice of stable ASCVD patients, a large number of patients receive antithrombotic therapy other than SAPT. Further efforts are required to guide the appropriate selection of patients in whom more potent antithrombotic therapies may safely reduce residual risk.

Background We studied care gap in patients with familial hypercholesterolemia (FH) with respect to lipid‐lowering therapy. Methods and Results We enrolled patients with cardiovascular disease (CVD) or FH and low‐density lipoprotein‐cholesterol >2.0 mmol/L despite maximally tolerated statin therapy. During follow‐up physicians received online reminders of treatment recommendations of 2009 patients (median age, 63 years, 42% women), 52.4% had CVD only, 31.7% FH only, and 15.9% both CVD and FH. Patients with FH were younger and more likely to be women and non‐White with significantly higher baseline low‐density lipoprotein‐cholesterol level (mmol/L) as compared with patients with CVD (FH 3.92±1.48 versus CVD 2.96±0.94, P P =0.0001) at baseline but not ezetimibe (28.1% versus 20.4%, P =0.0003). Among patients with FH only, 45.3% were at low‐density lipoprotein target (≥ 50% reduction from pre‐treatment level or low‐density lipoprotein P P Conclusions There is significant treatment inertia in patients with FH including those with CVD. Education focused on patients with FH should continue to be undertaken.

Background: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. Methods: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m 2 . The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). Results: Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m 2 , LV mass indexed to body surface area 60.7 [11.9] g/m 2 ), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m 2 and 0.01 g/m 2 for those assigned empagliflozin and placebo, respectively (adjusted difference −3.35 g/m 2 ; 95% CI, −5.9 to −0.81g/m 2 , P =0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference −6.8mmHg, 95% CI −11.2 to −2.3mmHg, P =0.003), diastolic blood pressure (adjusted difference −3.2mmHg; 95% CI, −5.8 to −0.6mmHg, P =0.02) and elevation of hematocrit ( P =0.0003). Conclusions: Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02998970.

Aims Hypertriglyceridaemia in patients with atherosclerotic cardiovascular disease (ASCVD) has been in focus following the REDUCE-IT trial showing benefit with icosapent ethyl. Among individuals with prevalent ASCVD, we sought to quantify the contemporary, real-world risk of ASCVD events associated with hypertriglyceridaemia, as well as estimate icosapent ethyl eligibility and compare trial participants with REDUCE-IT-like individuals in the population. Methods and results We examined data from 2 424 865 adults with lipid panels in the Ontario population. Among those with prevalent ASCVD, we examined adjusted associations between triglyceride (TG) and ASCVD events (first occurrence of myocardial infarction, unstable angina, stroke or transient ischaemic attack, coronary revascularization, or cardiovascular death). The proportion of patients with ASCVD potentially eligible for icosapent ethyl was estimated as those with TG 135–499 mg/dL (1.52–5.63 mmol/L) and low-density lipoprotein cholesterol (LDLc) 41–100 mg/dL (1.06–2.59 mmol/L), similar to the lipid cut-offs in REDUCE-IT, and their demographics and event rates examined. Among 196 717 individuals with ASCVD, median age was 69 years and 30% were female. A total of 24 097 composite ASCVD events occurred over a mean (standard deviation) 2.9 (0.5) years of follow-up. Increasing TG was associated with a graded, progressively higher hazard of ASCVD events. Twenty-five percent (49 886) of individuals with ASCVD had hypertriglyceridaemia and controlled LDLc; these patients were demographically similar to those in REDUCE-IT with comparable event rates. Conclusions Among patients with ASCVD, hypertriglyceridaemia is common, and is associated with higher ASCVD risk across a range of TG. It is possible that as many as one in four patients with ASCVD may be candidates for emerging therapies.

International audience; Background: Risk prediction tools are lacking for patients with stable disease some years after myocardial infarction (MI).Hypothesis: A practical long‐term cardiovascular risk index can be developed.Methods: The long‐Term rIsk, Clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post‐myocardial infarction patients prospective global registry enrolled patients 1 to 3 years post‐MI (369 centers; 25 countries), all with ≥1 risk factor (age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, or chronic non‐end‐stage kidney disease [CKD]). Self‐reported health was assessed with EuroQoL‐5 dimensions. Multivariable Poisson regression models were used to determine key predictors of the primary composite outcome (MI, unstable angina with urgent revascularization [UA], stroke, or all‐cause death) over 2 years.Results: The primary outcome occurred in 621 (6.9%) of 9027 eligible patients: death 295 (3.3%), MI 195 (2.2%), UA 103 (1.1%), and stroke 58 (0.6%). All events accrued linearly. In a multivariable model, 11 significant predictors of primary outcome (age ≥65 years, diabetes, second prior MI, CKD, history of major bleed, peripheral arterial disease, heart failure, cardiovascular hospitalization (prior 6 months), medical management (index MI), on diuretic, and poor self‐reported health) were identified and combined into a user‐friendly risk index. Compared with lowest‐risk patients, those in the top 16% had a rate ratio of 6.9 for the primary composite, and 18.7 for all‐cause death (overall c‐statistic; 0.686, and 0.768, respectively). External validation was performed using the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events registry (c‐statistic; 0.748, and 0.849, respectively).Conclusions: In patients >1‐year post‐MI, recurrent cardiovascular events and deaths accrue linearly. A simple risk index can stratify patients, potentially helping to guide management.

Supplemental Digital Content is available in the text., Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P

Background: The efficacy of ticagrelor in the long-term post–ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain.Objectives: The purpose o...

Background Although it is known that women do not participate in trials as frequently as men, there are limited recent data examining how women recruitment has changed over time. Methods We conducted MEDLINE search using a validated strategy for randomized trials published in New England Journal of Medicine, Lancet, and Journal of the American Medical Association between 1986 and 2015, and included trials evaluating pharmacologic or nonpharmacologic therapies. We abstracted data on demographics, intervention type, clinical indication, and trial design characteristics, and examined their relationships with women enrollment. Results In total, 598 trials met inclusion criteria. Women enrollment increased significantly over time (21% between 1986 and 1990 to 33% between 2011 and 2015; Pfor trend Conclusions Although enrollment of women has increased over time, it remains lower than the relative proportion in the disease population. Future studies should elucidate the reasons for persistent under-representation of women in clinical trials.

Background: The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18, 924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. Objectives: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. Methods: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. Results: With 3, 064 first and 5, 425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. Conclusions: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.

Background: Registry-based randomized controlled trials allow for outcome ascertainment using routine health data (RHD). While this method provides a potential solution to the rising cost and complexity of clinical trials, comparative analyses of outcome ascertainment by clinical end point committee (CEC) adjudication compared with RHD sources are sparse. Among cardiovascular trials, we set out to systematically compare the incidence of cardiovascular events and estimated randomized treatment effects ascertained from RHD versus traditional clinical evaluation and adjudication. Methods: We searched MEDLINE (1976 to August 2020) for studies where outcome ascertainment was performed by both RHD and CEC adjudication to compare the incidence of cardiovascular events and treatment effects. We derived ratios of hazard ratios to compare treatment effects from RHD and CEC adjudication. We pooled ratios of hazard ratios using an inverse variance random-effects meta-analysis. Results: Nine studies (1988–2020; 32 156 patients) involving 10 randomized control trials compared outcome ascertainment with RHD and CEC in patients with or at risk of cardiovascular disease. There was a high degree of agreement and interrater reliability between CEC and RHD outcome determination for all-cause mortality (agreement percentage: 98.4%–100% and κ: 0.95–1.0) and cardiovascular mortality (agreement percentage: 97.8%–99.9% and κ: 0.66–0.99). For myocardial infarction, the κ values ranged from 0.67–0.98, and for stroke the values ranged from 0.52–0.89. In contrast, the κ value for peripheral artery disease was low (κ: 0.27). There was little difference in the randomized treatment effect derived from CEC and RHD ascertainment of events based on the ratios of hazard ratio, with pooled ratios of hazard ratios ranging from 0.93 (95% CI, 0.63–1.39) for cardiovascular mortality to 1.27 (95% CI, 0.67–2.41) for stroke. Conclusions: Clinical outcome ascertainment using retrospectively acquired RHD displayed high levels of agreement with CEC adjudication for identifying all-cause mortality and cardiovascular outcomes. Importantly, cardiovascular treatment effects in randomized control trials determined from RHD and CEC resulted in similar point estimates. Overall, our review supports the use of RHD as a potential alternative source for clinical outcome ascertainment in cardiovascular trials. Validation studies with prospectively planned linkage are warranted.

BackgroundSociodemographic and clinical factors are emerging as important predictors for developing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.ObjectiveTo determine whether public health interventions that culminated in a stay-at-home lockdown instituted during the first wave of the pandemic in March/April 2020 were effective at mitigating the association of any of these factors with the risk of infection.DesignPopulation-based cohort studySettingOntario, CanadaPatientsAll adults that underwent testing for SARS-CoV-2 between January 1 and June 12, 2020.MeasurementsThe outcome of interest was SARS-CoV-2 infection, determined by reverse transcription polymerase chain reaction testing. Adjusted odds ratios (ORs) were determined for sociodemographic and clinical risk factors before and after the peak of the pandemic to assess for changes in effect sizes.ResultsAmong 578,263 community-dwelling individuals, 20,524 (3.5%) people tested positive. The association between age and SARS-CoV-2 infection risk among tested community-dwelling individuals varied over time (P-interaction ConclusionAfter public health interventions in March/April 2020, people with multiple risk factors residing in the most racially diverse communities of Ontario continued to have the highest likelihood of SARS-CoV-2 infection while risk was mitigated for people with multiple risk factors residing in less racially/ethnically diverse communities. Further efforts are necessary to reduce the risk of SARS-CoV-2 infection among the highest risk individuals residing in these communities.Primary Funding SourceCanadian Institutes of Health Research and the Ted Rogers Centre for Heart Research.

Background: While registry-based studies have shown that as many as 1 in 2 patients with stable atherosclerotic cardiovascular disease would be eligible for PCSK9i (proprotein convertase subtilisin-kexin type 9 inhibitor) therapy, this has not been studied in a large population-based postacute coronary syndrome (ACS) cohort. Methods: We examined lipid testing performed in hospital or within 90 days of discharge and lipid-lowering therapies dispensed within 90 days of discharge in patients surviving for at least 1 year after their first ACS between 2012 and 2018 in the province of Alberta, Canada. We estimated the proportion of patients eligible for PCSK9i and the expected benefits of treatment. Results: Of the 27 979 patients (median age 64.0 years, 29.3% female, 28.0% diabetic), 3750 (13.4%) did not have lipid testing in-hospital or within 90 days postdischarge. Untested patients were more likely to be older, female, from rural areas, to have more comorbidities, to already be on cardioprotective therapies, to present with unstable angina, and were less likely to have invasive interventions (all P Conclusions: Within 90 days of incident ACS, ≈80% of patients did not meet guideline-recommended lipid thresholds and more than one-third would potentially be eligible for PCSK9i.

AIMS: Although models exist to predict amputation among people with type 2 diabetes with foot ulceration or infection, we aimed to develop a prediction model for a broader range of major adverse limb events (MALE)—including gangrene, revascularization, and amputation—among individuals with type 2 diabetes. METHODS: In a post-hoc analysis of data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, we compared participants who experienced MALE with those who did not. A multivariable model was constructed and translated into a risk score. RESULTS: Among the 14,752 participants with type 2 diabetes in EXSCEL, 3.6% experienced MALE. Characteristics associated with increased risk of MALE were peripheral artery disease (PAD) (HR(adj) 4.83, 95% CI 3.94–5.92), prior foot ulcer (HR(adj) 2.16, 95% CI 1.63–2.87), prior amputation (HR(adj) 2.00, 95% CI 1.53–2.64), current smoking (HR(adj) 2.00, 95% CI 1.54–2.61), insulin use (HR(adj) 1.86, 95% CI 1.52–2.27), coronary artery disease (HR(adj) 1.67, 95% CI 1.38–2.03), and male sex (HR(adj) 1.64, 95% CI 1.31–2.06). Cerebrovascular disease, former smoking, age, glycated haemoglobin, race, and neuropathy were also associated significantly with MALE after adjustment. A risk score ranging from 6-96 points was constructed, with a C-statistic of 0.822 (95% CI 0.803–0.841). CONCLUSIONS: The majority of MALE occurred among participants with PAD, but participants without a history of PAD also experienced MALE. A risk score with good performance was generated. Although it requires validation in an external dataset, this risk score may be valuable in identifying patients requiring more intensive care and closer follow-up.

OBJECTIVE Observational data associate greater prevalence of type 2 diabetes (T2D) with lower lipoprotein(a) levels. Whether pharmacologic lowering of lipoprotein(a) influences incident T2D is unknown. We determined the relationship of lipoprotein(a) concentration to incident T2D and effects of treatment with alirocumab, a PCSK9 inhibitor. RESEARCH DESIGN AND METHODS The ODYSSEY OUTCOMES trial compared alirocumab with placebo in patients with acute coronary syndrome (ACS). Incident diabetes was determined from laboratory, medication, and adverse event data. RESULTS Among 13,480 patients without diabetes at baseline, 1324 developed T2D over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio (HR) 1.04 (95% CI 1.02-1.06, PAlirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident T2D (HR 0.95, 95% CI 0.85–1.05). At low baseline lipoprotein(a) levels alirocumab tended to reduce incident T2D, while at high baseline lipoprotein(a) alirocumab tended to increase incident T2D compared to placebo (treatment-baseline lipoprotein(a) interaction P=0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with HR 1.07 (95% CI 1.03−1.12; P=0.0002) for incident T2D. CONCLUSIONS In patients with ACS, baseline lipoprotein(a) concentration associated inversely with incident T2D. Alirocumab had neutral overall effect on incident T2D. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident T2D. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.

BACKGROUND Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality in Canada and worldwide. Laboratory tests, including troponin and low-density lipoprotein cholesterol (LDL-C), are important biomarkers of ASCVD risk. The objective of this study was to investigate patterns of testing for troponin and LDL-C test volumes among Alberta residents during the coronavirus disease 2019 (COVID-19) pandemic. METHODS AND RESULTS A repeated cross-sectional study design captured population-level laboratory test volumes between March 15, 2019 and December 14, 2020. Three-month cross-sections were derived to report laboratory test volumes by different COVID-19 restriction periods during 2020-2021 and using 2019-2020 as a preceding control period. Percent change for troponin and LDL-C test volumes were calculated for both control and COVID-19 periods among adult (≥18 years of age) Alberta residents, and stratified by age (18-49, 50-65, 66-79, and ≥80 years), sex, and geographic zones (urban, rural). This preliminary data is part of an ongoing study for which further troponin and LDL-C test volumes will be available up until March 14, 2021 (representing one year of data throughout the COVID-19 pandemic). Among the Alberta population, 292,836 troponin and 794,789 LDL-C tests were captured between March 15, 2020 and December 14, 2020 (Figure 1). Testing patterns during the COVID-19 restriction period showed marked reduction in test volumes from the previous year. The initial cross-section of the COVID-19 period (March-June 2020) was characterized by the largest overall reduction with troponin test volumes decreasing 18% and LDL-C test volumes decreasing 63%, compared to the year prior. As restrictions eased in the summer months of 2020, testing volumes rebounded to near pre-pandemic volumes for both tests. However, in the fall of 2020, troponin tests decreased again (-15%). Within these drops in utilization, slightly larger relative declines were observed for troponin test volumes in women (-20%) and patients ≥80 years-old (-25%) and for LDL-C test volumes among urban residents (-64%), women (-67%) and patients aged 18-49 (-66%) and 50-65 (-65%) years (Table 1). CONCLUSION This study describes declines in troponin and LDL-C test volumes in the initial and second COVID-19 lockdown periods. Women had overall smaller total troponin and LDL-C test volumes and larger relative declines during the pandemic compared to men. The decrease in these ASCVD-related laboratory test volumes during the pandemic may have been accompanied by other important changes in indicators of healthcare utilization and associated clinical outcomes. Ongoing analyses will further explore the impact of the pandemic.

Background While prior studies have shown racial/ethnic differences in cardiovascular (CV) outcomes within private or mixed health care systems, it remains uncertain whether inequalities in cardiovascular outcomes exist between different races and ethnicities in universal health care contexts. We aimed to determine whether there are racial/ethnicity disparities in long-term CV outcomes within a single-payer universal health care system. Methods The CARTaGENE study is a population-based prospective cohort study with enrollment of 19,996 individuals between 40–69 years in 2009, in the province of Quebec, Canada. Participants residing in four large metropolitan areas were randomly chosen from the provincial health insurance registry by strata of age, sex, and postal codes. Follow-up was available up to 2016. For this analysis, we retained only participants without prior known CV disease. The primary composite endpoint was time to the first CV event or intervention (CV death, acute coronary syndrome, heart failure, coronary revascularization, ischemic stroke, or peripheral vascular event or revascularization). We used unadjusted and adjusted Cox proportional hazard models to evaluate the association of self-defined race/ethnicity with the primary endpoint. Results There were 17,802 eligible participants with a mean age of 51 years (52.5% females) with 111,312 person-years of follow-up (median follow-up of 6.6 years). South Asian (SA) participants had the highest prevalence of diabetes mellitus (29%) and hypertension (32%). After adjustment for age and sex, SA ethnicity was associated with a 95% relative increase in risk for CV events, while East/Southeast Asian (ESA) ethnicity was associated with a 42% relative decrease in risk for CV events compared to White participants. After further adjustment for socioeconomic status and CV risk factors, ESA ethnicity remained associated with a similar decreased CV risk. In contrast, the association of SA ethnicity with increased CV risk was attenuated after full adjustment for baseline characteristics (Table 1). Conclusions Racial/ethnic disparities in long-term CV outcomes are present in a single-payer universal healthcare setting. ESA ethnicity was associated with a lower risk of long-term CV outcomes. Future studies are needed to corroborate the reduced risk of long-term major CV events associated with ESA ethnicity. Understanding the reasons related to potential CV protection with ESA ethnicity could facilitate endeavors to reduce long-term CV outcomes in other races/ethnicities. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): McGill Health University Center

Acute myocardial infarction (MI) patients remain at high risk for recurrent events. Cholesterol efflux, mediated by apolipoprotein A-I, removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion. Impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates among both patients with stable coronary artery disease and recent MI. CSL112, a novel intravenous formulation of apolipoprotein A-I (human) derived from human plasma, increases cholesterol efflux capacity. AEGIS-II is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial investigating the efficacy and safety of CSL112 compared to placebo among high-risk acute MI participants. Eligibility criteria include age ≥ 18 years with type 1 (spontaneous) MI, evidence of multivessel stable coronary artery disease, and presence of diabetes requiring pharmacotherapy, or ≥2 of the following: age ≥ 65 years, prior MI, or peripheral artery disease. A target sample of 17,400 participants will be randomized 1:1 to receive 4 weekly infusions of CSL112 6 g or placebo, initiated prior to or on the day of discharge and within 5 days of first medical contact. The primary outcome is the time to first occurrence of the composite of CV death, MI, or stroke through 90 days. Key secondary outcomes include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia through 90 days and time to first occurrence of the composite primary outcome through 180 and 365 days. AEGIS-II will be the first trial to formally test whether enhancing cholesterol efflux can reduce the rate of recurrent major adverse CV events.

Importance Although international guidelines recommend use of the Global Registries of Acute Coronary Events (GRACE) risk score (GRS) to guide acute coronary syndrome (ACS) treatment decisions, the prospective utility of the GRS in improving care and outcomes is unproven. Objective To assess the effect of routine GRS implementation on guideline-indicated treatments and clinical outcomes of hospitalized patients with ACS. Design, Setting, and Participants Prospective cluster (hospital-level) randomized open-label blinded end point (PROBE) clinical trial using a multicenter ACS registry of acute care cardiology services. Fixed sampling of the first 10 patients within calendar month, with either ST-segment elevation or non–ST-segment elevation ACS. The study enrolled patients from June 2014 to March 2018, and data were analyzed between February 2020 and April 2020. Interventions Implementation of routine risk stratification using the GRS and guideline recommendations. Main Outcomes and Measures The primary outcome was a performance score based on receipt of early invasive treatment, discharge prescription of 4 of 5 guideline-recommended pharmacotherapies, and cardiac rehabilitation referral. Clinical outcomes included a composite of all-cause death and/or myocardial infarction (MI) within 1 year. Results This study enrolled 2318 patients from 24 hospitals and was stopped prematurely owing to futility. Of the patients enrolled, median age was 65 years (interquartile range, 56-74 years), 29.5% were women (n = 684), and 62.9% were considered high risk (n = 1433). Provision of all 3 measures among high-risk patients did not differ between the randomized arms (GRS: 424 of 717 [59.9%] vs control: 376 of 681 [55.2%]; odds ratio [OR], 1.04; 95% CI, 0.63-1.71;P = .88). The provision of early invasive treatment was increased compared with the control arm (GRS: 1042 of 1135 [91.8%] vs control: 989 of 1183 [83.6%]; OR, 2.26; 95% CI, 1.30-3.96;P = .004). Prescription of 4 of 5 guideline-recommended pharmacotherapies (GRS: 864 of 1135 [76.7%] vs control: 893 of 1183 [77.5%]; OR, 0.97; 95% CI, 0.68-1.38) and cardiac rehabilitation (GRS: 855 of 1135 [75.1%] vs control: 861 of 1183 [72.8%]; OR, 0.68; 95% CI, 0.32-1.44) were not different. By 12 months, GRS intervention was not associated with a significant reduction in death or MI compared with the control group (GRS: 96 of 1044 [9.2%] vs control: 146 of 1087 [13.4%]; OR, 0.66; 95% CI, 0.38-1.14). Conclusions and Relevance Routine GRS implementation in cardiology services with high levels of clinical care was associated with an increase in early invasive treatment but not other aspects of care. Low event rates and premature study discontinuation indicates the need for further, larger scale randomized studies. Trial Registration anzctr.org.auIdentifier:ACTRN12614000550606

The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel.The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear.Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2YOf 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction 0.001).The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y

Doi, Yasuji/0000-0002-8368-0827; galvani, marcello/0000-0001-5897-667X; Gislason, Gunnar H/0000-0002-0548-402X; Taskinen, Marja-Riitta/0000-0002-6229-3588; Sherwood, Matthew/0000-0002-4305-5883; Malynovsky, Yaroslav V/0000-0002-9118-1104; Viktorova, vic-inna@mail.ru I.A./0000-0001-8728-2722; bastos, jose/0000-0002-9526-3123; Yang, Eric H/0000-0003-4889-7454; Rudenko, Anatoliy Viktorovich/0000-0003-1099-1613; Novotny, Vojtech/0000-0003-3521-9945; Nikolaev, Konstantin/0000-0003-4601-6203; Reshetko, Olga/0000-0003-3107-7636; Leonardi, Sergio/0000-0002-4800-6132; Muenzel, Thomas/0000-0001-5503-4150; Ushakov, Alexei V/0000-0002-7020-4442; Tse, Hung Fat/0000-0002-9578-7808; Podoleanu, Cristian/0000-0001-9987-2519; Raffel, Owen C/0000-0001-5470-7050; Khasanov, Niiaz/0000-0002-7760-0763; Chumakova, Galina A/0000-0002-2810-6531; Ersanli, Murat/0000-0003-1847-3087; cornel, jan hein/0000-0002-1006-2112; Abbate, Antonio/0000-0002-1930-785X; Racca, Vittorio/0000-0002-4465-3789; Urina-Triana, Miguel A/0000-0001-6003-4622; Rasputina, Lesia/0000-0003-1230-4039; Racca, Vittorio/0000-0002-4465-3789; Reis, Gilmar/0000-0002-4847-1034; Sandhu, Manjinder/0000-0003-2538-2079; Keskin, Kudret/0000-0002-9049-1530; PAREPA, IRINEL/0000-0002-7571-9015; Manakshe, Gajendra/0000-0002-4983-4271; Nicolau, Jose C/0000-0002-9680-3689; Strelnieks, Aldis/0000-0003-3493-2562; Budaj, Andrzej/0000-0002-6395-2098; Marin, Francisco/0000-0001-7246-7708; Wongpraparut, Nattawut/0000-0002-1541-3313; Yuan, Zuyi/0000-0002-4141-0298; Jeong, Myung Ho/0000-0003-2424-810X; Mostovoy, Yuriy/0000-0002-7041-1230; Pepine, Carl/0000-0002-6011-681X; Lopez-Jaramillo, Patricio/0000-0002-9122-8742; Garcia-Lledo, Alberto/0000-0002-8986-2584; Tesloianu, Nicolae-Dan/0000-0002-1007-3022; Kosmacheva, Elena/0000-0001-8600-0199; Kunz Sebba Barroso Souza, Weimar/0000-0002-1265-1930; Katz, Amos/0000-0003-0422-934X; Tunon, Jose/0000-0002-1373-0999; Acevedo, Monica/0000-0002-7989-6633; Hove, Jens/0000-0002-5600-5623; Yakushin, Sergey/0000-0001-7202-742X; Gonzalez Juanatey, Jose Ramon/0000-0001-9681-3388; Lyamina, Nadezhda/0000-0001-6939-3234; Aylward, Philip/0000-0002-5358-8552; Apostolovic, Svetlana/0000-0001-9015-297X; Airaksinen, Juhani/0000-0002-0193-568X; Nahhas, Prof. Dr. Ahmed/0000-0002-2887-8187; Barbarash, Olga/0000-0002-4642-3610, WOS: 000475553300016, PubMed: 31272931, Background After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1.4-1.8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. Methods ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1: 1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0.65-1.30 mmol/L. in this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA(1c) or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. the primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials. gov, number NCT01663402. Findings At study baseline, 5444 patients (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2.20-2.28 mmol/L), after 4 months' treatment with alirocumab (0.80 mmol/L), or after 4 months' treatment with placebo (2.25-2.28 mmol/L). in the placebo group, the incidence of the primary endpoint over a median of 2.8 years was greater in patients with diabetes (16.4%) than in those with prediabetes (9.2%) or normoglycaemia (8.5%); hazard ratio (HR) for diabetes versus normoglycaemia 2.09 (95% CI 1.78-2.46, p, Sanofi; Regeneron Pharmaceuticals, Sanofi and Regeneron Pharmaceuticals.

Aims Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events. Methods and results Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio P trend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median −5.0 [−13.6, 0] mg/dL) and corrected LDL-C (median −51.3 [−67.1, −34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events. Conclusion Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.

Introduction: The relationship between health care utilization and clinical outcomes in patients (pts) with atrial fibrillation (AF) is unknown. The objective of this study was to investigate whether cardiologists’ billing patterns are associated with different patient-level clinical outcomes. Methods: A retrospective cohort study was conducted using claims data in Ontario, Canada between April 1, 2011 and March 31, 2016. This study included all cardiologists who had at least 25 AF pts per year, and whose billings were ≥80% fee-for service. The cardiologists were stratified into quintiles based on their median billing per patient over the study period. The primary outcomes were patient-level receipt of repeat visits, cardiac diagnostic tests, medications ≤1 year of index date. The secondary clinical outcomes were death, emergency department visits and all-cause hospitalization at 1 year post-index visit. Results: The patient cohort was comprised of 182,572 AF pts (median age 74 years, 58% male) from 467 cardiologists. AF pts seen by higher billing cardiologists were more likely to undergo diagnostic tests within the first year of the index visit. Pts were 26% more likely to have an echocardiogram (adjusted odds ratio [aOR] 1.26 [95% CI, 1.13 to 1.39]), 28% a stress test (aOR 1.28 [1.15-1.42]), 25% Holter monitoring (aOR 1.25 [1.10-1.40]), and 80% more likely to get a stress echocardiogram (aOR 1.80 [1.49-2.10]), highest vs quintile 2. (Figure). Pts across billing quintiles received similar medical therapy. AF pts seen by higher billing cardiologists had a higher rate of all-cause hospitalization (aOR 1.13 [1.07- 1.19]); mortality rates were similar across cardiologists billing quintiles (e.g., aOR 0.98 [0.91- 1.04] for quintile 4 vs 2). Conclusion: Cardiologists who bill more per patient tend to order more diagnostic tests per AF patient but these are not associated with lower rates of hospitalization or death.

Background: Managing antithrombotic therapy transitions at hospital admission and discharge in patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) is challenging and is affected by prior treatment. We examined oral anticoagulant (OAC) use prior to enrollment and the relationship with outcomes in the AUGUSTUS trial. Methods: Patients in AUGUSTUS (N=4,614) were analyzed according to whether they were [n=2262] or were not [n=2352] on a prior OAC. Bleeding and clinical outcomes were compared by Kaplan-Meier (KM) estimates at 180 days. For each outcome, KM estimates and treatment interactions were determined by randomized arm and prior OAC status. Results: Those with prior OAC use had higher CHA 2 DS 2 -VASC and HAS-BLED scores and more comorbid medical conditions (hypertension, heart failure, diabetes, prior stroke), and were more likely to have been enrolled following elective PCI. Prior OAC use included vitamin K antagonists (VKAs) 47%, rivaroxaban 22%, apixaban 22%, dabigatran 12%, and edoxaban 1%. There was no difference in combined ISTH major/clinically relevant non-major (CRNM) bleeding with or without prior OAC use (13.5% vs. 13.5%; HR 1.00, 95% CI 0.85-1.18). Patients with prior OAC use had lower risk of death or ischemic events (5.4% vs. 7.6%; HR 0.72, 95% CI 0.57-0.91). No interactions were observed between randomized treatment (apixaban vs. VKA and aspirin vs. placebo) and prior OAC status for outcomes other than MI where apixaban (vs. VKA) was associated with a lower risk of MI in those with prior OAC use (Figure). Conclusion: In AUGUSTUS, OAC prior to enrollment was more common in patients with comorbidities and those enrolled following elective PCI. Prior OAC was associated with fewer ischemic events but not more bleeding. Our results support the use of apixaban plus a P2Y12 inhibitor without aspirin for patients with AF and ACS/PCI, irrespective of prior OAC use.

Background: Cohort studies and clinical trials have shown a greater prevalence of diabetes among subjects with lower levels of lipoprotein(a) [Lp(a)]. Some healthy cohort studies have shown a greater incidence of new onset diabetes (NOD) among those with lower Lp(a). It is unknown whether the risk of NOD associates with Lp(a) levels in patients (pts) with established cardiovascular disease or whether pharmacologic reduction of Lp(a) with PCSK9 inhibitors modulates this risk. Objective: Using data from the ODYSSEY OUTCOMES trial that compared the PCSK9 inhibitor alirocumab (ALI) with placebo (PBO) in pts with recent acute coronary syndrome, we examined whether NOD was related to baseline Lp(a) level and whether any such relationship was modified by ALI treatment. Methods and Results: Lp(a) was measured with a mass assay in 13,480 trial pts without diabetes at baseline; median (IQR) baseline Lp(a) was 21.9 mg/dL (6.9-61.1); median follow-up was 2.7 years. Intensive statin therapy was utilized in 89%. In the PBO group, NOD was greatest in Quartile 1 and least in Quartile 4 of baseline Lp(a) ( Figure , 4.6 vs 3.1 cases per 100 pt-years, P trend 0.0003). ALI lowered Lp(a) by a median of 23% from baseline. Absolute median reduction in Lp(a) with ALI ranged from nil in baseline Lp(a) Quartile 1 to 15 mg/dL in Quartile 4. Treatment HR (ALI/PBO) for NOD was neutral overall (0.95, 95% CI 0.85-1.05) but varied across baseline Lp(a) quartiles from 0.79 (0.64-0.96) in Quartile 1 to 1.09 (0.87-1.38) in Quartile 4 ( Figure , P trend =0.025). Conclusion: In pts with recent acute coronary syndrome, there is greater NOD among those with lower baseline Lp(a) levels. ALI has an overall neutral effect on NOD: In pts with low baseline Lp(a), ALI has minimal effect on Lp(a) levels and tends to reduce NOD. In pts with high baseline Lp(a), ALI reduces Lp(a) levels with a non-significant excess of NOD. The findings may have implications for emerging therapies that reduce Lp(a) more substantially than PCSK9 inhibitors.

Introduction: It is controversial whether triglyceride (TG) levels are independently associated with post-acute coronary syndrome (ACS) major adverse cardiovascular events (MACE) in patients treated with statins. PCSK9 inhibitors such as alirocumab (ALI) produce substantial reductions in LDL-C, modest reductions in lipoprotein(a) and TG-rich lipoproteins, and reduce MACE. Objective: Using data from the ODYSSEY OUTCOMES trial that compared ALI with placebo in 18,924 patients with recent ACS on optimized statin treatment, we performed a prespecified analysis to determine if MACE (death from coronary heart disease, myocardial infarction, ischemic stroke, or unstable angina) was associated with baseline TG levels in patients treated with placebo, and if MACE reduction with ALI was influenced by baseline TG or the change in TG under treatment. Methods and Results: Proportional hazards models relating continuous baseline TG or the change in TG from baseline to Month 4 with MACE were adjusted for baseline variables: age, region, LDL-C, lipoprotein(a), diabetes, hypertension, BMI, heart failure, peripheral artery disease and cerebrovascular disease. At baseline, median TG level was 130 mg/dL. Median absolute change from baseline to month 4 in the ALI group was -17 (-49, 12) mg/dL. Within the placebo group, baseline TG was associated with MACE (HR per 10 mg/dL increment 1.007, 95% CI 1.001–1.014, p=0.03), although spline analysis suggested non-linearity ( Figure ; spline effect p=0.01) with higher risk above approximately 190 mg/dL. MACE reduction by ALI (HR 0.85, 95% CI 0.78–0.93) did not depend on baseline TG (interaction p=0.99). In the ALI group, change in TG from baseline to Month 4 did not predict MACE after Month 4 (p=0.47). Conclusions: Among patients with recent ACS on optimized statin treatment, baseline TG levels are an independent predictor of MACE. The beneficial effect of ALI on MACE did not depend on either baseline or on treatment TG levels .

Background/Introduction Limited real-world data are available on attainment of low-density lipoprotein cholesterol (LDL-C) treatment goals in patients with atherosclerotic cardiovascular disease (ASCVD) in Canada. Purpose A retrospective observational study was conducted to describe types of ASCVD events/procedures, time between events and use of lipid lowering treatment (LLT) in patients who did not achieve LDL-C goal. Methods Patients in Ontario ≥65 years with a primary ASCVD event/procedure between 1 Apr 2005 and 31 Mar 2016, treated with an LLT and with index and follow up LDL-C values were identified from claims data at the Institute for Clinical Evaluative Sciences data repository. Patients were assessed over a 1-year follow up period for LDL-C goal attainment ( Results Overall, 28% of 143,302 patients ≥65 years on LLT failed to attain LDL-C goal at follow up (Figure). The proportion of patients failing to achieve LDL-C goal decreased from 35% to 22% over the 11-year study period. Mean time between index and follow up LDL-C (based on lowest score >2 weeks and up to 1 year after index LDL-C) was 203±97 days. When analysed by low-, moderate- or high-intensity statin, 57%, 30%, and 22% of patients failed to achieve LDL-C goal at follow up, respectively. Conclusions In this study, more than 1 in 4 patients with ASCVD in Ontario failed to achieve guideline recommended LDL-C goal despite treatment. In particular, ∼1 in 3 patients with cerebral and peripheral arterial disease were not at goal. An opportunity exists to better manage these high risk ASCVD patients with further statin intensification and additional LLTs This study made use of de-identified data from the ICES Data Repository, which is managed by the Institute for Clinical Evaluative Sciences with support from its funders and partners: Canada's Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, the Canadian Institutes of Health Research and the Government of Ontario. The opinions, results and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen Canada Inc.

Background The AUGUSTUS trial showed that patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) and/or PCI treated with a P2Y12 inhibitor and apixaban resulted in less bleeding and comparable ischemic events compared with regimens that included a vitamin K antagonist (VKA), aspirin, or both. We assessed the effect of apixaban versus VKA and aspirin versus placebo according to patients' baseline risk of stroke and bleeding. Methods AUGUSTUS randomized 4614 patients in a two-by-two factorial design to open label apixaban or VKA and blinded aspirin or placebo. The primary endpoint was major or clinically relevant nonmajor (CRNM) bleeding over 6 months of follow-up. The effects were assessed stratified by baseline CHA2DS2-VASc and HAS-BLED score using Cox proportional hazards models. Results 4386 patients were included for this analysis. The median age was 71 (64–77) years, 29.4% were female, 81.7% had a CHA2DS2-VASc score≥3, and 66.8% a HAS-BLED score≥3. As shown in the table, rates of bleeding were lower with apixaban (vs VKA) irrespective of baseline bleeding risk (p-value interaction: 0.23). Aspirin (vs placebo) was associated with increased bleeding irrespective of baseline risk (p-value interaction: 0.88). Apixaban use was associated with a lower risk of death or hospitalization without a significant interaction with stroke risk (p-value of interaction=0.53). No differences were found for ischemic outcomes. Conclusion An antithrombotic regimen including a P2Y12 inhibitor and apixaban is associated with less bleeding and hospitalization compared to a regimen with VKA, aspirin, or both with results consistent across CHA2DS2-VASc, and HAS-BLED scores. Our findings support the use of apixaban and a P2Y12 inhibitor without aspirin during the first 6 months for most patients with AF and ACS and/or PCI, regardless of stroke and bleeding risk. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The Augustus trial was sponsored by Bristol-Myers Squibb and Pfizer, Inc

Background AUGUSTUS randomized patients with atrial fibrillation and ACS and/or PCI to apixaban or VKA and aspirin or placebo for 6 months on background P2Y12 inhibitor. Purpose To characterise the clinical outcomes in patients receiving clopidogrel or ticagrelor. Methods Patients enrolled in AUGUSTUS (n=4614) were grouped by P2Y12 inhibitor at randomization. Baseline characteristics were compared among groups. Rates of ISTH major or CRNM bleeding, definite/probable stent thrombosis (ST), stroke, MI, and death or ischaemic event were quantified and treatment groups were compared according to treatment with clopidogrel or ticagrelor. Results At randomization, patients were treated with clopidogrel (n=4165), ticagrelor (n=280), prasugrel (n=51) or no P2Y12 inhibitor (n=118). Median ages were 71, 69, 66 and 72 years (P Conclusions Apixaban is safer than VKA regardless of P2Y12 inhibitor used. Dropping aspirin reduces bleeding but is associated with numerically higher ST rates regardless of P2Y12 inhibitor used. These data support current recommendations for preferential use of NOAC vs. VKA and individualised choice of P2Y12 inhibitor and timing of aspirin cessation after PCI according to the patient's risks of bleeding and stent thrombosis. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Bristol-Myers Squibb/Pfizer

Background Atrial fibrillation (AF) is a marker of risk in patients presenting with acute coronary syndromes (ACS). The potential effect of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) on the incidence of AF is unknown. Methods The ODYSSEY OUTCOMES trial compared randomized treatment with the PCSK9 inhibitor alirocumab or placebo in patients with recent ACS and residual dyslipidaemia despite optimal statin therapy. The current analysis determined: 1) whether alirocumab treatment influenced incident AF; 2) whether a history of AF influenced the risk of major adverse cardiovascular events (MACE); and 3) whether there was interaction between AF at baseline and randomized treatment on MACE. AF was determined from the medical history and investigator reports of adverse events. Results Of 18,924 participants, 662 (3.5%) had a history of AF at randomization and 18,262 (96.5%) had no history of AF. Of the latter category, 499 (2.7%) had incident AF. Older age, randomization in South America or Eastern Europe, history of heart failure or myocardial infarction, and higher body mass index were factors associated with incident AF. Treatment with alirocumab or placebo did not influence incident AF (2.2% vs 2.6%, respectively; hazard ratio 0.90, 95% confidence interval 0.75–1.08; Figure). Patients with a history of AF had a greater burden of comorbidities, including cerebrovascular disease, peripheral artery disease, hypertension and heart failure; they also had higher rates of MACE (Table). There was no significant interaction between AF and randomized treatment on risk of MACE (P interaction=0.78) Conclusions Although treatment with alirocumab did not significantly modify the risk of incident AF after ACS in this analysis, future studies with more sensitive and systematic methods of ascertainment may be warranted. History of AF is a strong predictor of risk of recurrent MACE after ACS. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi, Regeneron Pharmaceuticals, Inc

Background New ESC/EAS guidelines advise a low-density lipoprotein cholesterol (LDL-C) target level Aim To overcome these limitations, we performed a propensity score-matching (PSM) analysis of the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in 18,924 patients with recent ACS. Methods Patients on alirocumab were classified in 1 of 3 pre-specified categories according to Month 4 LDL-C 50 mg/dL (n=2197). Within each category, MACE after Month 4 was compared with patients on placebo using 1:1 PSM on demographic, clinical, and adherence variables. Because the trial design involved blinded substitution of placebo for alirocumab when consecutive LDL-C levels were Results Patients in the three achieved LDL-C categories of the alirocumab group differed by baseline age, sex, geographic region; history of diabetes, smoking, peripheral artery disease, cerebrovascular disease, coronary revascularization, heart failure, obstructive pulmonary disease, or malignancy; type of index ACS event; baseline LDL-C, lipoprotein(a), estimated glomerular filtration rate, body mass index, systolic blood pressure; use of intensive statin therapy; and adherence with study medication. After PSM, patients in each LDL-C category on alirocumab were well matched to patients on placebo for these characteristics. Treatment hazard ratios (HRs) for MACE (Figure) were similar in those with achieved LDL-C 50 mg/dL achieved less benefit. Patients who achieved consecutive LDL-C levels Conclusion After accounting for differences in baseline characteristics and adherence, reduction in risk of MACE with alirocumab was similar in patients who achieved LDL-C Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi and Regeneron Pharmaceuticals, Inc

Background/Introduction The prevalence of ischaemic heart disease is lower in women vs men in Canada. Studies have shown that women are more likely to be underdiagnosed and less likely to receive guideline-recommended treatments than men. Women receiving lipid-lowering therapies (LLTs) are also less likely to attain treatment goals vs men. Purpose We analysed use of LLTs and attainment of low-density lipoprotein cholesterol (LDL-C) treatment goals in a recent longitudinal cohort of patients with ASCVD with public drug coverage in Ontario to describe differences observed between female and male patients. Methods Patients ≥65 years with a primary ASCVD event/procedure between 1 Apr 2005 and 31 Mar 2016, treated with an LLT and with index and follow up LDL-C values were identified from claims data at the Institute for Clinical Evaluative Sciences data repository. Patients were assessed over a 1 year follow up period for LDL-C goal attainment ( Results 143,302 patients with ASCVD ≥65 years on LLTs were identified of which 41% were female. A higher proportion of female vs male patients were prescribed low (3% vs 2%) and medium intensity statins (51% vs 44%) compared with high intensity statins (43% vs 52%). A higher proportion of women failed to attain LDL-C goal compared to men (33% vs 24%) (Figure). When analysed by low, moderate or high intensity statin, 65%, 35%, and 27% of female patients and 49%, 25% and 19% of male patients failed to attain LDL-C goal at follow up. Conclusions In this retrospective study, women with a diagnosis of ASCVD were more frequently treated with low/moderate intensity statins whereas men were more frequently treated with high intensity statins. Approximately 2 of 3 women and 3 of 4 men receiving statin treatment attained LDL-C goal during the 1-year follow up period. Overall, there appear to be treatment differences between female and male patients with ASCVD, with males receiving higher intensity statin therapy and attaining LDL-C goal more frequently. Further research is needed to determine why these discrepancies exist. This study made use of de-identified data from the ICES Data Repository, which is managed by the Institute for Clinical Evaluative Sciences with support from its funders and partners: Canada's Strategy for Patient-Oriented Research (SPOR), the Ontario SPOR Support Unit, the Canadian Institutes of Health Research and the Government of Ontario. The opinions, results and conclusions reported are those of the authors. No endorsement by ICES or any of its funders or partners is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen Canada Inc

ObjectiveTo assess associations of health-related quality of life (HRQoL) with patient profile, resource use, cardiovascular (CV) events and mortality in stable patients post-myocardial infarction (MI).MethodsThe global, prospective, observational TIGRIS Study enrolled 9126 patients 1–3 years post-MI. HRQoL was assessed at enrolment and 6-month intervals using the patient-reported EuroQol-5 dimension (EQ-5D) questionnaire, with scores anchored at 0 (worst possible) and 1 (perfect health). Resource use, CV events and mortality were recorded during 2-years’ follow-up. Regression models estimated the associations of index score at enrolment with patient characteristics, resource use, CV events and mortality over 2-years’ follow-up.ResultsAmong 8978 patients who completed the EQ-5D questionnaire, 52% reported ‘some’ or ‘severe’ problems on one or more health dimensions. Factors associated with a lower index score were: female sex, older age, obesity, smoking, higher heart rate, less formal education, presence of comorbidity (eg, angina, stroke), emergency room visit in the previous 6 months and non-ST-elevation MI as the index event. Compared with an index score of 1 at enrolment, a lower index score was associated with higher risk of all-cause death, with an adjusted rate ratio of 3.09 (95% CI 2.20 to 4.31), and of a CV event, with a rate ratio of 2.31 (95% CI 1.76 to 3.03). Patients with lower index score at enrolment had almost two times as many hospitalisations over 2-years’ follow-up.ConclusionsClinicians managing patients post-acute coronary syndrome should recognise that a poorer HRQoL is clearly linked to risk of hospitalisations, major CV events and death.Trial registration numberClinicalTrials.gov Registry (NCT01866904) (https://clinicaltrials.gov).

OBJECTIVES: Returning to work after an episode of acute coronary syndrome (ACS) is challenging for many patients, and has both personal and social impacts. There are limited data regarding the working status in the very long-term after ACS. METHODS: We retrospectively analyzed 1,632 patients who were working prior to hospitalization for ACS in a quaternary hospital and were followed-up for up to 17 years. Adjusted models were developed to analyze the variables independently associated with actively working at the last contact, and a prognostic predictive index for not working at follow-up was developed. RESULTS: The following variables were significantly and independently associated with actively working at the last contact: age>median (hazard-ratio [HR], 0.76, p

Background We studied whether significant differences in care gaps exist between specialists and PCPs. Methods GOAL Canada enrolled patients with CVD or familial hypercholesterolemia (FH) and LDL-C > 2.0 mmol/L despite maximally tolerated statin therapy. During follow-up, physicians received online reminders of treatment recommendations based on Canadian Guidelines. Results A total of 177 physicians (58% PCPs) enrolled 2009 patients; approximately half of the patients were enrolled by each physician group. Patients enrolled by specialists were slightly older (mean age 63 years vs. 62), female (45% vs. 40%), Caucasian (77% vs. 65%), and had a slightly higher systolic pressure and lower heart rate. Patients enrolled by specialists had less frequent history of familial hypercholesterolemia, diabetes, hypertension, chronic kidney disease and liver disease but more frequent history of coronary artery disease, atrial fibrillation and premature family history of CVD. There was no significant baseline difference in LDL-C, HDL-C, or non-HDL-c, although total cholesterol and triglycerides were slightly higher in patients managed by PCPs. At baseline, PCPs were more likely to use statins (80% vs.73%, p=0.0002) and other therapies such as niacin or fibrate (10% vs. 6%, p=0.0006) but similar use of ezetimibe (24% vs. 27%, p=0.15). At the end of follow up, specialists used less statins (70% vs. 77%, p=0.0005) and other therapies (6% vs. 10%, p=0.007) but more ezetimibe (45% vs. 38%, p=0.01) and the same frequency of PCSK9i (28% vs. 27%, p=0.65). The proportion of patients achieving the recommended LDL-C level of 2.0 mmol/L or below (primary endpoint) was similar at last available visit between specialists and PCPs (44% vs. 42%, p=0.32). Conclusion Despite minor differences in the clinical profile of their patients, both PCPs and specialists actively participate in the management of lipid lowering therapy in high risk CVD patients and experience similar challenges and care gaps.

Aims To estimate the rate of non-vitamin K oral anticoagulant (NOAC) dosing that is lower- and higher-than-recommended and to describe the reasons for NOAC dose discordance with Health Canada prescribing information. Methods The OPTIMAL AF Programme was an observational cohort quality assessment initiative in which primary and specialty care physicians in eight provinces provided a snapshot of their anticoagulated non-valvular atrial fibrillation (NVAF) patients through either an electronic medical record (EMR) system or standardised, paper-based data collection methods. Results Data on 1681 NVAF patients receiving oral anticoagulation (OAC) for stroke prevention was provided by 102 physicians. A NOAC was prescribed in 1379 patients (8%). The standard recommended dose was prescribed in 849 (76%) and reduced dose in 264 (24%). Concordance of the reduced dose with Health Canada prescribing information occurred in 154 patients (58%). The standard dose was concordant in 805 (95%). The main reasons for the use of discordant reduced doses were age of 80 years or more, elevated creatinine, prior bleeding or dose recommended by specialist. Discussion and conclusion The vast majority of Canadian patients meeting the Canadian Cardiovascular Society (CCS) guideline recommendations for OAC to decrease AF-related stroke risk were receiving product monograph-concordant NOAC dosing (85%). Nonetheless, this highlights the fact that an important proportion of patients were prescribed doses that are discordant and opportunities remain to improve NOAC dosing to optimise stroke prevention.

Importance After percutaneous coronary intervention (PCI), patients withCYP2C19*2or*3loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. Objective To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes inCYP2C19LOF carriers after PCI. Design, Setting, and Participants Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. Interventions Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping.CYP2C19LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and Measures The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients withCYP2C19LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. Results Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 withCYP2C19LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903CYP2C19LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02];P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding inCYP2C19LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51];P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07];P = .16). Conclusions and Relevance AmongCYP2C19LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial Registration ClinicalTrials.gov Identifier:NCT01742117

Aims Statins are pivotal to the secondary prevention of major adverse cardiovascular events, but some patients are statin-intolerant. We examined the effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab on the risk of major adverse cardiovascular events according to the intensity of background statin treatment. Methods and results The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with acute coronary syndrome and dyslipidaemia despite intensive or maximum-tolerated statin treatment (including no statin if intolerance was documented). The primary outcome (major adverse cardiovascular events) comprised coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina. Median follow-up was 2.8 years. Baseline statin treatment was high-intensity (88.8%), low/moderate-intensity (8.7%) or none (2.4%). Median baseline low-density lipoprotein cholesterol was 86, 89 and 139 mg/dL (P Conclusions PCSK9 inhibition with alirocumab reduces the relative risk of major adverse cardiovascular events after acute coronary syndrome irrespective of background statin treatment. However, patients on no statin are at high absolute risk for recurrent major adverse cardiovascular events; alirocumab substantially reduces that risk. PCSK9 inhibition may be an important therapeutic strategy for statin-intolerant patients with acute coronary syndrome.

PURPOSE: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies. METHODS: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations. RESULTS: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases. CONCLUSION: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

Unless prompted by symptoms or change in clinical status, the appropriate use criteria consider cardiac stress testing (CST) within 2 years of percutaneous coronary intervention (PCI) and 5 years of coronary artery bypass grafting (CABG) to be rarely appropriate. Little is known regarding use and yield of CST after PCI or CABG. We studied 39,648 patients treated with coronary revascularization (29,497 PCI; 10,151 CABG) between April 2004 and March 2012 in Alberta, Canada. Frequency of CST between 60 days and 2 years after revascularization was determined from linked provincial databases. Yield was defined as subsequent rates of coronary angiography and revascularization after CST. Post PCI, 14,195 (48.1%) patients underwent CST between 60 days and 2 years, while post CABG, 4,469 (44.0%) patients underwent CST. Compared with patients not undergoing CST, patients undergoing CST were more likely to be of younger age, reside in an urban area, have higher neighborhood median household income, but less medical comorbidities. Among PCI patients undergoing CST, 5.2% underwent subsequent coronary angiography, and 2.6% underwent repeat revascularization within 60 days of CST. Rates of coronary angiography and repeat revascularization post-CST among CABG patients were 3.6% and 1.1%, respectively. Approximately one-half of patients undergo CST within 2 years of PCI or CABG in Alberta, Canada. Yield of CST is low, with only 1 out of 38 tested post-PCI patients and 1 out of 91 tested post-CABG patients undergoing further revascularization. In conclusion, additional research is required to determine patients most likely to benefit from CST after revascularization.

Aims Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk irrespective of age, but the evidence is less strong for older patients. Methods and results This prespecified analysis from ODYSSEY OUTCOMES compared the effect of alirocumab vs. placebo in 18 924 patients with recent acute coronary syndrome (ACS) according to age. We examined the effect of assigned treatment on occurrence of the primary study outcome, a composite of coronary heart disease death, myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization [major adverse cardiovascular event (MACE)] and all-cause death. Relative risk reductions were consistent for patients ≥65 vs. Conclusion In patients with recent ACS, alirocumab improves outcomes irrespective of age. Increasing absolute benefit but not harm with advancing age suggests that LDL-C lowering is an important preventive intervention for older patients after ACS.

In clinical practice, cancer management does not consistently encompass screening and identification of cardiovascular (CV) risk. The use of androgen deprivation therapy (ADT) in prostate cancer has been associated with increased CV risk and development of metabolic syndrome, necessitating identification of patients at risk in this population (e.g., those with pre-existing CV disease). A multi-disciplinary team of Canadian physicians was assembled to develop a series of recommendations intended to identify patients who may benefit from optimal management of their cardiovascular disease and/or modification of cardiac risk factors. A key goal was the development of a simple screening tool for identification of patients with pre-existing CV disease. This simple and inclusive set of recommendations are intended for use within urology clinics to facilitate holistic approaches and simplify the management of patients.

Background: Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C. Methods: This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-C corrected ) for cholesterol content in lipoprotein(a). Results: At baseline, median lipoprotein(a) and LDL-C corrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) ( P trend =0.0021), and tended to associate with baseline quartile of LDL-C corrected ( P trend =0.06); VTE tended to associate with baseline quartile of lipoprotein(a) ( P trend =0.06), but not LDL-C corrected ( P trend =0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54–0.89]; P =0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44–1.01]; P =0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) ( P trend =0.03), but not LDL-C corrected ( P trend =0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-C corrected , was associated with the risk of VTE and the composite of VTE and PAD events. Conclusions: In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01663402.

Background: In AUGUSTUS (Open-Label, 2×2 Factorial, Randomized, Controlled Clinical Trial to Evaluate the Safety of Apixaban vs Vitamin K Antagonist and Aspirin vs Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome and/or Percutaneous Coronary Intervention), patients with atrial fibrillation and a recent acute coronary syndrome and those undergoing percutaneous coronary intervention had less bleeding with apixaban than vitamin K antagonist (VKA) and with placebo than aspirin. However, the number of ischemic events was numerically higher with placebo. The aim of this analysis is to assess the tradeoff of risk (bleeding) and benefit (ischemic events) over time with apixaban versus VKA and aspirin versus placebo. Methods: In AUGUSTUS, 4614 patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention on a P2Y 12 inhibitor were randomized to blinded aspirin or placebo and to open-label apixaban or VKA for 6 months. In a post hoc analysis, we compared the risk of 3 composite bleeding outcomes and 3 composite ischemic outcomes from randomization through 30 days and from 30 days to 6 months with apixaban and VKA and with aspirin and placebo. Results: Compared with VKA, apixaban had either a lower or a similar risk of bleeding and ischemic outcomes from randomization to 30 days and from 30 days to 6 months. From randomization to 30 days, aspirin caused more severe bleeding (absolute risk difference, 0.97% [95% CI, 0.23–1.70]) and fewer severe ischemic events (absolute risk difference, −0.91% [95% CI, −1.74 to −0.08]) than placebo. From 30 days to 6 months, the risk of severe bleeding was higher with aspirin than placebo (absolute risk difference, 1.25% [95% CI, 0.23–2.27]), whereas the risk of severe ischemic events was similar (absolute risk difference, −0.17% [95% CI, −1.33 to 0.98]). Conclusions: In patients with atrial fibrillation and recent acute coronary syndrome or percutaneous coronary intervention receiving a P2Y 12 inhibitor, apixaban is preferred over VKA. Use of aspirin immediately and for up to 30 days results in an equal tradeoff between an increase in severe bleeding and a reduction in severe ischemic events. After 30 days, aspirin continues to increase bleeding without significantly reducing ischemic events. These results inform shared, patient-centric decision making on the ideal duration of the use of aspirin after an acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation receiving oral anticoagulation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02415400.

The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher 30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.

BACKGROUND: Evidence is lacking on long-term outcomes in unselected patients surviving the first year following myocardial infarction (MI). METHODS AND RESULTS: The TIGRIS (long-Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients) prospective registry enrolled 9176 eligible patients aged ≥50 years, 1-3 years post-MI, from 25 countries. All had ≥1 risk factor: age ≥ 65 years, diabetes mellitus, second prior MI, multivessel coronary artery disease, chronic kidney disease (CKD). Primary outcome was a composite of MI, unstable angina with urgent revascularization, stroke, or all-cause death at 2-year follow-up. Bleeding requiring hospitalization was also recorded. 9027 patients (98.4%) provided follow-up data: the primary outcome occurred in 621 (7.0%), all-cause mortality in 295 (3.3%), and bleeding in 109 (1.2%) patients. Events accrued linearly over time. In multivariable analyses, qualifying risk factors were associated with increased risk of primary outcome (incidence rate ratio [RR] per 100 patient-years [95% confidence interval]): CKD 2.06 (1.66, 2.55), second prior MI 1.71 (1.38, 2.10), diabetes mellitus 1.63 (1.39, 1.92), age ≥ 65 years 1.53 (1.28, 1.83), and multivessel disease 1.24 (1.05, 1.48). Risk of bleeding events was greater in older patients (vs

Background Glycoprotein IIb/IIIa inhibitors (GPIs) in combination with clopidogrel improve clinical outcome in ST-elevation myocardial infarction (STEMI); however, finding a balance that minimizes both thrombotic and bleeding risk remains fundamental. The efficacy and safety of GPI in addition to ticagrelor, a more potent P2Y12-inhibitor, have not been fully investigated. Methods 1,630 STEMI patients who underwent primary percutaneous coronary intervention (PCI) were analyzed in this subanalysis of the ATLANTIC trial. Patients were divided in three groups: no GPI, GPI administration routinely before primary PCI, and GPI administration in bailout situations. The primary efficacy outcome was a composite of death, myocardial infarction, urgent target revascularization, and definite stent thrombosis at 30 days. The safety outcome was non-coronary artery bypass graft (CABG)-related PLATO major bleeding at 30 days. Results Compared with no GPI (n = 930), routine GPI (n = 525) or bailout GPI (n = 175) was not associated with an improved primary efficacy outcome (4.2% no GPI vs. 4.0% routine GPI vs. 6.9% bailout GPI; p = 0.58). After multivariate analysis, the use of GPI in bailout situations was associated with a higher incidence of non-CABG-related bleeding compared with no GPI (odds ratio [OR] 2.96, 95% confidence interval [CI] 1.32–6.64; p = 0.03). However, routine GPI use compared with no GPI was not associated with a significant increase in bleeding (OR 1.78, 95% CI 0.88–3.61; p = 0.92). Conclusion Use of GPIs in addition to ticagrelor in STEMI patients was not associated with an improvement in 30-day ischemic outcome. A significant increase in 30-day non-CABG-related PLATO major bleeding was seen in patients who received GPIs in a bailout situation.