Publications by authors named "Shaun G Goodman"

375 Publications

Contemporary use of guideline-based higher potency P2Y12 receptor inhibitor therapy in patients with moderate-to-high risk non-ST-segment elevation myocardial infarction: Results from the Canadian ACS reflective II cross-sectional study.

Clin Cardiol 2021 May 13. Epub 2021 May 13.

Terrence Donnelly Heart Centre, St Michael's Hospital, University of Toronto, Toronto, Canada.

Background: After myocardial infarction, guidelines recommend higher-potency P2Y12 receptor inhibitors, namely ticagrelor and prasugrel, over clopidogrel.

Hypothesis: We aimed to determine the contemporary use of higher-potency antiplatelet therapy in Canadian patients with non-ST-elevation myocardial infarction (NSTEMI).

Methods: A total of 684 moderate-to-high risk NSTEMI patients were enrolled in the prospective Canadian ACS Reflective II registry at 12 Canadian hospitals and three clinics in five provinces between July 2016 and May 2018. Multivariable logistic regression modeling was performed to assess factors independently associated with higher-potency P2Y12 receptor inhibitor use at discharge.

Results: At hospital discharge, 78.3% of patients were treated with a P2Y12 receptor inhibitor. Among patients discharged on a P2Y12 receptor inhibitor, use of higher-potency P2Y12 receptor inhibitor was 61.4%. After adjustment, treatment in-hospital with PCI (OR 4.48, 95%CI 3.34-6.03, p < .0001) was most strongly associated with higher use of higher-potency P2Y12 receptor inhibitor, while oral anticoagulant use at discharge (OR 0.03, 95%CI 0.01-0.12, p < .0001), and atrial fibrillation (OR 0.40, 95%CI 0.17-0.98, p = .046) were most strongly associated with lower use of higher-potency P2Y12 receptor inhibitor. Use of higher-potency P2Y12 receptor inhibitor varied across provinces (range, 21.6%-78.9%).

Discussion: In contemporary Canadian practice, approximately 60% of moderate-to-high risk NSTEMI patients discharged on a P2Y12 receptor inhibitor are treated with a higher-potency P2Y12 receptor inhibitor. In addition to factors that increase risk of bleeding, interprovincial differences in practice patterns were associated with use of higher-potency P2Y12 receptor inhibitor at discharge. Opportunities remain for further optimization of evidence-based, guideline-recommended antiplatelet therapy use.
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http://dx.doi.org/10.1002/clc.23618DOI Listing
May 2021

Glycemic Control and Cardiovascular Risk Factor Management in Adults With Type 2 Diabetes With and Without Chronic Kidney Disease Before Sodium-Glucose Cotransporter Protein 2 Inhibitors: Insights From the Diabetes Mellitus Status in Canada Survey.

Can J Diabetes 2021 Feb 24. Epub 2021 Feb 24.

Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objectives: Optimal control of cardiovascular risk factors in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD) is challenging. Limited data are available from the primary care setting on achievement of guideline-recommended targets in this population before the use of sodium-glucose cotransporter protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

Methods: The Diabetes Mellitus Status in Canada survey included 5,172 patients with T2D seen by primary care physicians (PCPs) in November 2012. We compared treatment targets and therapeutic interventions in patients with and without CKD.

Results: Compared with those without CKD (n=3,804), patients with CKD (n=1,368) were older, more likely to be female, had a longer duration of diabetes and had more vascular complications. CKD patients more frequently had a less stringent glycated hemoglobin (A1C) target of ≤8.0% set by PCPs (10.3% vs 20%, p<0.001), and fewer CKD patients met the A1C target of ≤7.0% (50.9% vs 47.1%, p=0.016) than those without CKD. Both groups had a similar likelihood of achieving the blood pressure (BP) target of ≤130/80 mmHg (36.8% vs 34.8%, p=0.20), whereas CKD patients more frequently achieved a low-density lipoprotein cholesterol target of ≤2.0 mmol/L (54.8% vs 61.3%, p<0.001). Overall, only 12.5% in both groups achieved all 3 targets (12.3% vs 13.3%, p=0.33).

Conclusions: Only 1 of 8 T2D patients achieved optimal glycemic, BP and cholesterol targets, regardless of the presence or absence of CKD. Although more medical interventions were used in CKD patients, a lower proportion achieved guideline-recommended targets for A1C. These findings provide a benchmark for future comparison.
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http://dx.doi.org/10.1016/j.jcjd.2021.02.003DOI Listing
February 2021

Lipid Testing, Lipid-Modifying Therapy, and PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Eligibility in 27 979 Patients With Incident Acute Coronary Syndrome.

Circ Cardiovasc Qual Outcomes 2021 Apr 5;14(4):e006646. Epub 2021 Apr 5.

St Michael's Hospital, University of Toronto, Canada (B.S., A.T.Y., S.G.G.).

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 <0.0001). Of the 24 229 tested, 18 767 (77.5%) had at least one lipid value above guideline-recommended threshold (LDL [low-density lipoprotein] ≥1.8 mmol/L [70 mg/dL] and non-HDL [high-density lipoprotein] ≥2.6 mmol/L [100 mg/dL]), of which 7284 (38.8%) did not have repeat testing within the year after discharge. Lipid testing in hospital was associated with higher rates of initiation or escalation of statin therapy within 90 days of their ACS (adjusted odds ratio, 2.13 [95% CI, 1.97-2.30). In total, 9592 patients (39.6% of the tested cohort) would be eligible for PCSK9i use, which could result in 184 fewer cardiovascular events over 3.4 years, including cardiovascular death, nonfatal ACS (myocardial infarction or unstable angina requiring hospitalization), and ischemic stroke.

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.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.006646DOI Listing
April 2021

Intensity of statin treatment after acute coronary syndrome, residual risk, and its modification by alirocumab: insights from the ODYSSEY OUTCOMES trial.

Eur J Prev Cardiol 2021 03 27;28(1):33-43. Epub 2020 Jul 27.

Université de Paris, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, FACT (French Alliance for Cardiovascular Trials), and INSERM, France.

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 < 0.001) in these statin treatment categories, respectively. Alirocumab produced similar relative reductions in low-density lipoprotein cholesterol from baseline across statin treatment subgroups, but the mean absolute reductions differed (52.9, 56.7 and 86.1 mg/dL, respectively; P < 0.001). With placebo, the incidence of major adverse cardiovascular events was highest in the no statin subgroup (10.8%, 10.7% and 26.0% respectively). Alirocumab reduced major adverse cardiovascular events in each statin subgroup (hazard ratio 0.88, 95% confidence interval (CI) 0.80-0.96; 0.68, 0.49-0.94; and 0.65, 0.44-0.97, respectively; Pinteraction = 0.14) with a gradient of absolute risk reduction: 1.25%, 95% CI 0.34-2.16; 3.16%, 0.38-5.94; 7.97%, 0.42-15.51; Pinteraction = 0.106).

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.
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http://dx.doi.org/10.1177/2047487320941987DOI Listing
March 2021

Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y Inhibitor Therapy: A Meta-Analysis.

JACC Cardiovasc Interv 2021 Apr 17;14(7):739-750. Epub 2021 Mar 17.

Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada.

Objectives: 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.

Background: The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear.

Methods: 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 P2Y inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype.

Results: Of 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).

Conclusions: 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 inhibitor therapy.
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http://dx.doi.org/10.1016/j.jcin.2021.01.024DOI Listing
April 2021

Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment.

Diabetes Care 2021 May 15;44(5):1219-1227. Epub 2021 Mar 15.

Green Lane Cardiovascular Services, Auckland City Hospital, Auckland, New Zealand.

Objective: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.

Research Design And Methods: In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.

Results: Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes 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 1.04 (95% CI 1.02-1.06, < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; = 0.0002) for incident type 2 diabetes.

Conclusions: In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
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http://dx.doi.org/10.2337/dc20-2842DOI Listing
May 2021

Clinical risk prediction models for the prognosis and management of acute coronary syndromes.

Eur Heart J Qual Care Clin Outcomes 2021 May;7(3):222-228

Division of Cardiology, Department of Medicine, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto M5B 1W8,Ontario, Canada.

Patients with acute coronary syndromes (ACS), particularly non-ST-segment elevation ACS, represent a spectrum of patients at variable risk of short- and long-term adverse clinical outcomes. Accurate prognostic assessment in this population requires the simultaneous consideration of multiple clinical and laboratory variables which may be under-recognized by the treating physicians, leading to an observed risk-treatment paradox in the use of invasive and pharmacological therapies. The routine application of established clinical risk scores, such as the Global Registry of Acute Coronary Events risk score, is recommended by major international clinical practice guidelines for structured risk stratification at the time of presentation, but uptake remains inconsistent. This article discusses the methodology of designing, deriving, and validating clinical risk scores, reviews the major validated risk scores for assessing prognosis in ACS, and examines their role in guiding clinical decision-making in ACS management, especially the timing of invasive coronary angiography. We also discuss emerging data on the impact of the routine use of such risk scores on patient management and clinical outcomes, as well as future directions for investigation in this field.
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http://dx.doi.org/10.1093/ehjqcco/qcab018DOI Listing
May 2021

Predicting major adverse limb events in individuals with type 2 diabetes: Insights from the EXSCEL trial.

Diabet Med 2021 Mar 10:e14552. Epub 2021 Mar 10.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.

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 4.83, 95% CI: 3.94-5.92), prior foot ulcer (HR 2.16, 95% CI: 1.63-2.87), prior amputation (HR 2.00, 95% CI: 1.53-2.64), current smoking (HR 2.00, 95% CI: 1.54-2.61), insulin use (HR 1.86, 95% CI: 1.52-2.27), coronary artery disease (HR 1.67, 95% CI: 1.38-2.03) and male sex (HR 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 to 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.
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http://dx.doi.org/10.1111/dme.14552DOI Listing
March 2021

Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective: 2021 Update.

Circulation 2021 Feb 8;143(6):583-596. Epub 2021 Feb 8.

Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA (D.L.B., C.P.C., D.P.F.).

A growing number of patients undergoing percutaneous coronary intervention (PCI) with stent implantation also have atrial fibrillation. This poses challenges for their optimal antithrombotic management because patients with atrial fibrillation undergoing PCI require oral anticoagulation for the prevention of cardiac thromboembolism and dual antiplatelet therapy for the prevention of coronary thrombotic complications. The combination of oral anticoagulation and dual antiplatelet therapy substantially increases the risk of bleeding. Over the last decade, a series of North American Consensus Statements on the Management of Antithrombotic Therapy in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention have been reported. Since the last update in 2018, several pivotal clinical trials in the field have been published. This document provides a focused updated of the 2018 recommendations. The group recommends that in patients with atrial fibrillation undergoing PCI, a non-vitamin K antagonist oral anticoagulant is the oral anticoagulation of choice. Dual antiplatelet therapy with aspirin and a P2Y inhibitor should be given to all patients during the peri-PCI period (during inpatient stay, until time of discharge, up to 1 week after PCI, at the discretion of the treating physician), after which the default strategy is to stop aspirin and continue treatment with a P2Y inhibitor, preferably clopidogrel, in combination with a non-vitamin K antagonist oral anticoagulant (ie, double therapy). In patients at increased thrombotic risk who have an acceptable risk of bleeding, it is reasonable to continue aspirin (ie, triple therapy) for up to 1 month. Double therapy should be given for 6 to 12 months with the actual duration depending on the ischemic and bleeding risk profile of the patient, after which patients should discontinue antiplatelet therapy and receive oral anticoagulation alone.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050438DOI Listing
February 2021

Non-vitamin K antagonist oral anticoagulant (NOAC) use and dosing in Canadian practice: Insights from the optimising pharmacotherapy in the management approach to lowering risk in atrial fibrillation (OPTIMAL AF) Programme.

Int J Clin Pract 2020 Dec 27;74(12):e13625. Epub 2020 Aug 27.

University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1111/ijcp.13625DOI Listing
December 2020

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

Circulation 2021 Mar 13;143(11):1109-1122. Epub 2021 Jan 13.

Division of Cardiology, School of Medicine, University of Colorado, Aurora (G.G.S., M.S.).

Background: Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score-matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment.

Methods: Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25 to 50 (n=3692), or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching.

Results: Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (hazard ratio, 0.74 [95% CI, 0.62-0.89]; absolute risk reduction, 0.92) or 25 to 50 mg/dL (hazard ratio, 0.74 [95% CI, 0.64-0.87]; absolute risk reduction, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73-1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL.

Conclusions: After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL had a reduction in the risk of MACE that was similar to that of patients who achieved LDL-C levels of 25 to 50 mg/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969166PMC
March 2021

Objective Risk Assessment vs Standard Care for Acute Coronary Syndromes: A Randomized Clinical Trial.

JAMA Cardiol 2021 Mar;6(3):304-313

Cardiology Department, Concord Repatriation General Hospital, Sydney, Australia.

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.au Identifier: ACTRN12614000550606.
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http://dx.doi.org/10.1001/jamacardio.2020.6314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726696PMC
March 2021

Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients With High-risk Cardiovascular Disease: A Randomized Clinical Trial.

JAMA 2021 01;325(1):39-49

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness.

Objective: To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease.

Design, Setting, And Participants: Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible.

Interventions: Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons.

Main Outcomes And Measures: The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed.

Results: Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17]; P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants.

Conclusions And Relevance: In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population.

Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.
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http://dx.doi.org/10.1001/jama.2020.23649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718608PMC
January 2021

Is There a Sex Gap in Surviving an Acute Coronary Syndrome or Subsequent Development of Heart Failure?

Circulation 2020 Dec 30;142(23):2231-2239. Epub 2020 Nov 30.

Canadian VIGOUR Centre (J.A.E., A.S., R.C.W., F.A.M., S.G.G., P.K.), University of Alberta, Edmonton.

Background: We hypothesized that disparities between sexes in the management of myocardial infarction (MI) may have changed over time, and thus altered the prognoses after MI, especially the risk for the development of heart failure.

Methods: Using a large population-based cohort of patients with MI between April 1, 2002, and March 31, 2016, we examined the incidence, angiographic findings, treatment (including revascularization), and clinical outcomes of patients with a first-time MI. To elucidate the differences between sexes, a series of multivariable models were created to explore all MI and non-ST-segment-elevation MI (NSTEMI) versus ST-segment-elevation MI (STEMI) over time.

Results: Between 2002 and 2016, 45 064 patients (13 878 [30.8%] women) were hospitalized with a primary diagnosis of first-time MI (54.9% NSTEMI and 45.1% STEMI). Women were older (median age, 72 versus 61 years), had more comorbidities, and had lower rates of diagnostic angiography than did men (women, 74%, versus men, 87%). When angiography was performed, women had a lower proportion of left main, 2-vessel disease with proximal left anterior descending or 3-vessel disease compared with men (33.4% versus 40.9%, <0.0001), and a higher frequency of 1-vessel disease or nonobstructive coronary artery disease (39.6% versus 29.1%, <0.0001). Women had a higher unadjusted rate of in-hospital mortality than did men in both patients with STEMI (women, 9.4%, versus men, 4.5%) and patients with NSTEMI (women, 4.7%, versus men, 2.9%). After adjustment, this difference remained significant in STEMI (adjusted odds ratio, 1.42 [95% CI, 1.24-1.64]) but not in NSTEMI (adjusted odds ratio, 0.97 [95% CI, 0.83-1.13]). After discharge, women developed heart failure after STEMI (women, 22.5%, versus men, 14.9%) as well as after NSTEMI (women, 23.2%, versus men, 15.7%). The adjusted relative risk for women versus men of developing the outcomes of mortality and heart failure remained similar across years, although the differences were nonsignificantly attenuated over 5 years of follow-up.

Conclusions: Although some attenuation of differences in clinical outcomes over time has occurred, women remain at higher risk than men of dying or developing heart failure in the subsequent 5 years after STEMI or NSTEMI, even after accounting for differences in angiographic findings, revascularization, and other confounders.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048015DOI Listing
December 2020

Does management of lipid lowering differ between specialists and primary care: Insights from GOAL Canada.

Int J Clin Pract 2021 Apr 14;75(4):e13861. Epub 2020 Dec 14.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.

Background: We studied whether significant differences in care gaps exist between specialists and primary care physicians (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 FH, 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 = .0002) and other therapies such as niacin or fibrate (10% vs 6%, P = .0006) but similar use of ezetimibe (24% vs 27%, P = .15). At the end of follow-up, specialists used less statins (70% vs 77%, P = .0005) and other therapies (6% vs 10%, P = .007) but more ezetimibe (45% vs 38%, P = .01) and the same frequency of PCSK9i (28% vs 27%, P = .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 = .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.
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http://dx.doi.org/10.1111/ijcp.13861DOI Listing
April 2021

Meta-Analysis of Safety and Efficacy of Direct Oral Anticoagulants Versus Warfarin According to Time in Therapeutic Range in Atrial Fibrillation.

Am J Cardiol 2021 02 12;140:62-68. Epub 2020 Nov 12.

Department of Medicine, University of Toronto, Toronto, Canada; Departments of Critical Care and Medicine, St. Michael's Hospital, Toronto, Canada.

Among atrial fibrillation (AF) patients, it is unclear whether the efficacy and safety of direct oral anticoagulants (DOAC) relative to warfarin is consistent across various levels of international normalized ratio (INR) control. To determine the efficacy and safety of DOAC agents compared with warfarin for patients with various levels of anticoagulation control as reflected by their time in therapeutic range (TTR), we conducted a systematic review and meta-analysis of published randomized controlled trials of DOAC versus (vs) warfarin which reported outcomes stratified by TTR. Based on reported center-based TTR (cTTR) ranges, degrees of INR control were categorized into 3 cTTR strata: low (<60%), intermediate (60% to 66%), and high (>66%). Pooled hazard ratios (HR) and 95% confidence intervals (CI) were determined for stroke or systemic embolism (SSE), major bleeding, and intracranial hemorrhage (ICH). Across all cTTR strata, DOAC-treated patients had lower risk of SSE versus warfarin, with a HR of 0.73 (95% CI 0.61 to 0.88) for the low, 0.76 (95% CI 0.59 to 0.98) intermediate; and 0.78 (95% CI 0.63 to 0.96) high cTTR subgroups. Compared with warfarin, DOAC-treated patients had lower risk of major bleeding in the low and intermediate cTTR strata, and similar risk in the highest cTTR stratum (HR 1.00, 95% CI 0.80 to 1.26). Patients treated with DOAC had lower risk of ICH compared with warfarin (HR 0.55, 95% CI; 0.40 to 0.74) which was observed across all cTTR strata. In conclusion, regardless of the degree of INR control, DOAC agents are preferable over warfarin as stroke prevention therapy for patients with AF.
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http://dx.doi.org/10.1016/j.amjcard.2020.10.064DOI Listing
February 2021

Diabetes association with self-reported health, resource utilization, and prognosis post-myocardial infarction.

Clin Cardiol 2020 Dec 4;43(12):1352-1361. Epub 2020 Nov 4.

London School of Hygiene and Tropical Medicine, London, UK.

Background: Diabetes mellitus (DM) is associated with increased cardiovascular (CV) risk. We compared health-related quality of life (HRQoL), healthcare resource utilization (HRU), and clinical outcomes of stable post-myocardial infarction (MI) patients with and without DM.

Hypothesis: In post-MI patients, DM is associated with worse HRQoL, increased HRU, and worse clinical outcomes.

Methods: The prospective, observational long-term risk, clinical management, and healthcare Resource utilization of stable coronary artery disease study obtained data from 8968 patients aged ≥50 years 1 to 3 years post-MI (369 centers; 25 countries). Patients with ≥1 of the following risk factors were included: age ≥65 years, history of a second MI >1 year before enrollment, multivessel coronary artery disease, creatinine clearance ≥15 and <60 mL/min, and DM treated with medication. Self-reported health status was assessed at baseline, 1 and 2 years and converted to EQ-5D scores. The main outcome measures were baseline HRQoL and HRU during follow-up.

Results: DM at enrollment was 33% (2959 patients, 869 insulin treated). Mean baseline EQ-5D score (0.86 vs 0.82; P < .0001) was higher; mean number of hospitalizations (0.38 vs 0.50, P < .0001) and mean length of stay (LoS; 9.3 vs 11.5; P = .001) were lower in patients without vs with DM. All-cause death and the composite of CV death, MI, and stroke were significantly higher in DM patients, with adjusted 2-year rate ratios of 1.43 (P < .01) and 1.55 (P < .001), respectively.

Conclusions: Stable post-MI patients with DM (especially insulin treated) had poorer EQ-5D scores, higher hospitalization rates and LoS, and worse clinical outcomes vs those without DM. Strategies focusing specifically on this high-risk population should be developed to improve outcomes.

Trial Registration: ClinicalTrials.gov: NCT01866904 (https://clinicaltrials.gov).
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http://dx.doi.org/10.1002/clc.23476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724227PMC
December 2020

Rationale and design of the TAILOR-PCI digital study: Transitioning a randomized controlled trial to a digital registry.

Am Heart J 2021 02 31;232:84-93. Epub 2020 Oct 31.

University of California San Francisco, San Francisco, CA. Electronic address:

Background: Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention (TAILOR-PCI) is the largest cardiovascular genotype-based randomized pragmatic trial (NCT#01742117) to evaluate the role of genotype-guided selection of oral P2Y inhibitor therapy in improving ischemic outcomes after PCI. The trial has been extended from the original 12- to 24-month follow-up, using study coordinator-initiated telephone visits. TAILOR-PCI Digital Study tests the feasibility of extending the trial follow-up in a subset of patients for up to 24 months using state-of-the-art digital solutions. The rationale, design, and approach of extended digital study of patients recruited into a large, international, multi-center clinical trial has not been previously described.

Methods: A total of 930 patients from U.S. and Canadian sites previously enrolled in the 5,302 patient TAILOR-PCI trial within 23 months of randomization are invited by mail to the Digital Study website (http://tailorpci.eurekaplatform.org) and by up to 2 recruiting telephone calls. Eureka, a direct-to-participant digital research platform, is used to consent and collect prospective data on patients for the digital study. Patients are asked to answer health-related surveys at fixed intervals using the Eureka mobile app and or desktop platform. The likelihood of patients enrolled in a randomized clinical trial transitioning to a registry using digital technology, the reasons for nonparticipation and engagement rates are evaluated. To capture hospitalizations, patients may optionally enable geofencing, a process that allows background location tracking and triggering of surveys if a hospital visit greater than 4 hours is detected. In addition, patients answer digital hospitalization surveys every month. Hospitalization data received from the Digital Study will be compared to data collected from study coordinator telephone visits during the same time frame.

Conclusions: The TAILOR-PCI Digital Study evaluates the feasibility of transitioning a large multicenter randomized clinical trial to a digital registry. The study could provide evidence for the ability of digital technology to follow clinical trial patients and to ascertain trial-related events thus also building the foundation for conducting digital clinical trials. Such a digital approach may be especially pertinent in the era of COVID-19.
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http://dx.doi.org/10.1016/j.ahj.2020.10.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833248PMC
February 2021

Association between levosimendan, postoperative AKI, and mortality in cardiac surgery: Insights from the LEVO-CTS trial.

Am Heart J 2021 01 28;231:18-24. Epub 2020 Oct 28.

Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.

Objectives: We aimed to evaluate the association between levosimendan treatment and acute kidney injury (AKI) as well as assess the clinical sequelae of AKI in cardiac surgery patients with depressed left ventricular function (ejection fraction <35%).

Methods: Patients in the LEVO-CTS trial undergoing on-pump coronary artery bypass grafting (CABG), valve, or CABG/valve surgery were stratified by occurrence and severity of postoperative AKI using the AKIN classification. The association between levosimendan infusion and AKI was modeled using multivariable regression.

Results: Among 854 LEVO-CTS patients, 231 (27.0%) experienced postoperative AKI, including 182 (21.3%) with stage 1, 35 (4.1%) with stage 2, and 14 (1.6%) with stage 3 AKI. The rate of AKI was similar between patients receiving levosimendan or placebo. The odds of 30-day mortality significantly increased by AKI stage compared to those without AKI (stage 1: adjusted odds ratio [aOR] 2.0, 95% confidence interval [CI] 0.8-4.9; stage 2: aOR 9.1, 95% CI 3.2-25.7; stage 3: aOR 12.4, 95% CI 3.0-50.4). No association was observed between levosimendan, AKI stage, and odds of 30-day mortality (interaction P = .69). Factors independently associated with AKI included increasing age, body mass index, diabetes, and increasing baseline systolic blood pressure. Increasing baseline eGFR and aldosterone antagonist use were associated with a lower risk of AKI.

Conclusions: Postoperative AKI is common among high-risk patients undergoing cardiac surgery and associated with significantly increased risk of 30-day death or dialysis. Levosimendan was not associated with the risk of AKI.
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http://dx.doi.org/10.1016/j.ahj.2020.10.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755750PMC
January 2021

Rationale and design of ApoA-I Event Reducing in Ischemic Syndromes II (AEGIS-II): A phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group study to investigate the efficacy and safety of CSL112 in subjects after acute myocardial infarction.

Am Heart J 2021 01 13;231:121-127. Epub 2020 Oct 13.

Cardiovascular Institute, Mount Sinai, New York, NY.

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.
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http://dx.doi.org/10.1016/j.ahj.2020.10.052DOI Listing
January 2021

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial.

Eur Heart J 2020 11;41(44):4245-4255

Division of Cardiology, University of Colorado School of Medicine, Box B130, Aurora, CO 80045, USA.

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 Ptrend = 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.
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http://dx.doi.org/10.1093/eurheartj/ehaa649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724642PMC
November 2020

Update to Evidence-Based Secondary Prevention Strategies After Acute Coronary Syndrome.

CJC Open 2020 Sep 10;2(5):402-415. Epub 2020 Apr 10.

St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

A recent acute coronary syndrome provides an opportunity to optimise secondary prevention strategies to reduce the risk of future cardiovascular events. This review provides an updated synopsis of current evidence-based approaches. New clinical trial data on the use of antiplatelet and anticoagulants allow choices of the selection and duration of treatment. Lipid lowering after an acute coronary syndrome is now enhanced, with proprotein convertase subtilisin-kexin type 9 inhibitors providing added benefit on top of statin and ezetimibe treatment in high-risk patients. In addition, a recent trial of icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid, addresses residual risk in patients with elevated triglycerides already treated with statins. The use of both sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes reduces cardiovascular events independently of glucose lowering.
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http://dx.doi.org/10.1016/j.cjco.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499366PMC
September 2020

Cardiac Stress Testing After Coronary Revascularization.

Am J Cardiol 2020 12 16;136:9-14. Epub 2020 Sep 16.

Terrence Donnelly Heart Centre, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.amjcard.2020.08.051DOI Listing
December 2020

Relation of High Lipoprotein (a) Concentrations to Platelet Reactivity in Individuals with and Without Coronary Artery Disease.

Adv Ther 2020 11 5;37(11):4568-4584. Epub 2020 Sep 5.

Faculdade de Medicina, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, São Paulo, SP, Brazil.

Introduction: Lipoprotein (a) [Lp(a)] is a risk factor for coronary artery disease (CAD). To the best of our knowledge, this is the first study addressing the relationship between Lp(a) and platelet reactivity in primary and secondary prevention.

Methods: Lp(a) was evaluated in 396 individuals with (82.3%) and without (17.7%) obstructive CAD. The population was divided into two groups according to Lp(a) concentrations with a cutoff value of 50 mg/dL. The primary objective was to evaluate the association between Lp(a) and adenosine diphosphate (ADP)-induced platelet reactivity using the VerifyNow™ P2Y assay. Platelet reactivity was also induced by arachidonic acid and collagen-epinephrine (C-EPI) and assessed by Multiplate™, platelet function analyzer™ 100 (PFA-100), and light transmission aggregometry (LTA) assays. Secondary objectives included the assessment of the primary endpoint in individuals with or without CAD.

Results: Overall, 294 (74.2%) individuals had Lp(a) < 50 mg/dL [median (IQR) 13.2 (5.8-27.9) mg/dL] and 102 (25.8%) had Lp(a) ≥ 50 mg/dL [82.5 (67.6-114.5) mg/dL], P < 0.001. Univariate analysis in the entire population revealed no differences in ADP-induced platelet reactivity between individuals with Lp(a) ≥ 50 mg/dL (249.4 ± 43.8 PRU) versus Lp(a) < 50 mg/dL (243.1 ± 52.2 PRU), P = 0.277. Similar findings were present in individuals with (P = 0.228) and without (P = 0.669) CAD, and regardless of the agonist used or method of analysis (all P > 0.05). Finally, multivariable analysis did not show a significant association between ADP-induced platelet reactivity and Lp(a) ≥ 50 mg/dL [adjusted OR = 1.00 [(95% CI 0.99-1.01), P = 0.590].

Conclusion: In individuals with or without CAD, Lp(a) ≥ 50 mg/dL was not associated with higher platelet reactivity.
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http://dx.doi.org/10.1007/s12325-020-01483-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547998PMC
November 2020

Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial.

JAMA 2020 08;324(8):761-771

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-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 in CYP2C19 LOF 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. CYP2C19 LOF 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 with CYP2C19 LOF 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 with CYP2C19 LOF 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 903 CYP2C19 LOF 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 in CYP2C19 LOF 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: Among CYP2C19 LOF 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.
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http://dx.doi.org/10.1001/jama.2020.12443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448831PMC
August 2020

Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial.

Eur Heart J 2020 11;41(42):4114-4123

Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.

Aims: Statins reduce cardiovascular risk in patients with acute coronary syndrome (ACS) and normal-to-moderately impaired renal function. It is not known whether proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide similar benefit across a range of renal function. We determined whether effects of the PCSK9 inhibitor alirocumab to reduce cardiovascular events and death after ACS are influenced by renal function.

Methods And Results: ODYSSEY OUTCOMES compared alirocumab with placebo in patients with recent ACS and dyslipidaemia despite intensive statin treatment. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 was exclusionary. In 18 918 patients, baseline eGFR was 82.8 ± 17.6 mL/min/1.73 m2, and low-density lipoprotein cholesterol (LDL-C) was 92 ± 31 mg/dL. At 36 months, alirocumab decreased LDL-C by 48.5% vs. placebo but did not affect eGFR (P = 0.65). Overall, alirocumab reduced risk of the primary outcome (coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization) with fewer deaths. There was no interaction between continuous eGFR and treatment on the primary outcome or death (P = 0.14 and 0.59, respectively). Alirocumab reduced primary outcomes in patients with eGFR ≥90 mL/min/1.73 m2 (n = 7470; hazard ratio 0.784, 95% confidence interval 0.670-0.919; P = 0.003) and 60 to <90 (n = 9326; 0.833, 0.731-0.949; P = 0.006), but not in those with eGFR < 60 (n = 2122; 0.974, 0.805-1.178; P = 0.784). Adverse events other than local injection-site reactions were similar in both groups across all categories of eGFR.

Conclusions: In patients with recent ACS, alirocumab was associated with fewer cardiovascular events and deaths across the range of renal function studied, with larger relative risk reductions in those with eGFR > 60 mL/min/1.73 m2.
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http://dx.doi.org/10.1093/eurheartj/ehaa498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700757PMC
November 2020

Improving the Design of Future PCI Trials for Stable Coronary Artery Disease: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 07;76(4):435-450

Terrence Donnelly Heart Centre, St. Michael's Hospital, University of Toronto and Canadian Heart Research Centre, Toronto, Ontario, Canada; Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

The role of percutaneous coronary interventions in addition to medical therapy for patients with stable coronary artery disease continues to be debated in routine clinical practice, despite more than 2 decades of randomized controlled trials. The residual uncertainty arises from particular challenges facing revascularization trials. Which endpoint do doctors care about, and which do patients care about? Which participants should be enrolled? What background medical therapy should we use? When is placebo control relevant? In this paper, we discuss how these questions can be approached and examine the merits and disadvantages of possible options. Engaging multiple stakeholders, including patients, researchers, regulators, and funders, to ensure the design elements are methodologically valid and clinically meaningful should be an aspirational goal in the development of future trials.
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http://dx.doi.org/10.1016/j.jacc.2020.05.060DOI Listing
July 2020

Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI.

J Am Coll Cardiol 2020 07;76(2):162-171

Duke Clinical Research Institute, Durham, North Carolina; Division of Cardiology, Duke University School of Medicine, Durham, North Carolina. Electronic address:

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jacc.2020.05.031DOI Listing
July 2020

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics.

Cardiovasc Drugs Ther 2021 Jun;35(3):549-559

Department of Cardiovascular Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

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.
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http://dx.doi.org/10.1007/s10557-020-06988-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779664PMC
June 2021

Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial.

J Am Coll Cardiol 2020 05;75(18):2297-2308

Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Université de Paris, French Alliance for Cardiovascular Trials, Institut National de la Santé et de la Recherche Médicale U1148, Paris, France; National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom. Electronic address: https://twitter.com/gabrielsteg.

Background: Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.

Objectives: This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.

Methods: A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl.

Results: Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.

Conclusions: In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).
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http://dx.doi.org/10.1016/j.jacc.2020.03.029DOI Listing
May 2020