Persistence and Adherence to PCSK9 Inhibitor Monoclonal Antibodies Versus Ezetimibe in Real-World Settings.

INTRODUCTION: The cardiovascular disease risk reduction benefits of proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibodies (PCSK9i mAb) and ezetimibe are dependent on remaining on treatment and being persistent and adherent. We estimated the percentage of patients on therapy, persistent and adherent at 182 and 365 days among US adults with health insurance who initiated a PCSK9i mAb (n = 16,588) or ezetimibe (n = 83,086) between July 2015 and December 2019. METHODS: Using pharmacy fill claims, being on therapy was defined as having a day of medication supply in the last 60 of 182 and 365 days following treatment initiation, being persistent was defined as not having a gap of 60 days or more between the last day of supply from one prescription fill and the next fill, and being adherent was defined by having medication available to take on ≥ 80% of the 182 and 365 days following treatment initiation. We estimated multivariable-adjusted risk ratios for being persistent and adherent comparing patients initiating PCSK9i mAb versus ezetimibe using Poisson regression. RESULTS: At 182 days following initiation, 80% and 68% were on therapy and 76% and 64% were persistent among patients who initiated a PCSK9i mAb and ezetimibe, respectively. Among patients who were on therapy and persistent at 182 days following initiation, 88% and 81% of those who initiated a PCSK9i mAb and ezetimibe, respectively, were on therapy at 365 days. Among those on therapy and persistent at 182 days following initiation, being persistent and being adherent at 365 days were each more common among PCSK9i mAb versus ezetimibe initiators (persistent: 82% versus 76%, multivariable-adjusted risk ratio 1.07; 95% confidence interval [CI] 1.06-1.08; adherent: 74% versus 71%, multivariable-adjusted risk ratio 1.02; 95% CI 1.01-1.03). CONCLUSIONS: These data suggest approaches to increase persistence and adherence to PCSK9i mAb and ezetimibe should be implemented prior to or within 182 days following treatment initiation.

Medical calculators derived synthetic cohorts: a novel method for generating synthetic patient data.

This study shows that we can use synthetic cohorts created from medical risk calculators to gain insights into how risk estimations, clinical reasoning, data-driven subgrouping, and the confidence in risk calculator scores are connected. When prediction variables aren't evenly distributed in these synthetic cohorts, they can be used to group similar cases together, revealing new insights about how cohorts behave. We also found that the confidence in predictions made by these calculators can vary depending on patient characteristics. This suggests that it might be beneficial to include a "normalized confidence" score in future versions of these calculators for healthcare professionals. We plan to explore this idea further in our upcoming research.

Influenza Vaccine Immune Response in Patients With High-Risk Cardiovascular Disease: A Secondary Analysis of the INVESTED Randomized Clinical Trial.

Importance: High-dose trivalent compared with standard-dose quadrivalent influenza vaccine did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations in patients with high-risk cardiovascular disease in the INVESTED trial. Whether humoral immune response to influenza vaccine is associated with clinical outcomes is unknown. Objective: To examine the antibody response to high-dose trivalent compared with standard-dose quadrivalent inactivated influenza vaccine and its associations with clinical outcomes. Design, Setting, and Participants: This secondary analysis is a prespecified analysis of the immune response substudy of the randomized, double-blind, active-controlled INVESTED trial, which was conducted at 157 sites in the United States and Canada over 3 influenza seasons between September 2016 and January 2019. Antibody titers were determined by hemagglutination inhibition assays at randomization and 4 weeks during the 2017-2018 and 2018-2019 seasons. Eligibility criteria included recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor. Data were analyzed from February 2023 to June 2023. Main Outcomes and Measures: Mean antibody titer change, seroprotection (antibody titer level ≥1:40) and seroconversion (≥4-fold increase in titer) at 4 weeks, and the association between seroconversion status and the risk for adverse clinical outcomes. Interventions: High-dose trivalent or standard-dose quadrivalent inactivated influenza vaccine, with revaccination up to 3 seasons. Results: Antibody data were available for 658 of 5260 randomized participants (12.5%; mean [SD] age, 66.2 [11.4] years; 507 male [77.1%], 151 female [22.9%]; 348 with heart failure [52.9%]). High-dose vaccine was associated with an increased magnitude in antibody titers for A/H1N1, A/H3N2, and B-type antigens compared with standard dose. More than 92% of all participants achieved seroprotection for each of the contained antigens, while seroconversion rates were higher in participants who received high-dose vaccine. Seroconversion for any antigen was not associated with the risk for cardiopulmonary hospitalizations or all-cause mortality (hazard ratio, 1.09; 95% CI, 0.79-1.53; P = .59), irrespective of randomized treatment (P = .38 for interaction). Conclusions and Relevance: High-dose vaccine elicited a more robust humoral response in patients with heart failure or prior myocardial infarction enrolled in the INVESTED trial, with no association between seroconversion status and the risk for cardiopulmonary hospitalizations or all-cause mortality. Vaccination to prevent influenza remains critical in high-risk populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

Development and Validation of the CANHEART Population-Based Laboratory Prediction Models for Atherosclerotic Cardiovascular Disease.

BACKGROUND: Prediction of atherosclerotic cardiovascular disease (ASCVD) in primary prevention assessments exclusively with laboratory results may facilitate automated risk reporting and improve uptake of preventive therapies. OBJECTIVE: To develop and validate sex-specific prediction models for ASCVD using age and routine laboratory tests and compare their performance with that of the pooled cohort equations (PCEs). DESIGN: Derivation and validation of the CANHEART (Cardiovascular Health in Ambulatory Care Research Team) Lab Models. SETTING: Population-based cohort study in Ontario, Canada. PARTICIPANTS: A derivation and internal validation cohort of adults aged 40 to 75 years without cardiovascular disease from April 2009 to December 2015; an external validation cohort of primary care patients from January 2010 to December 2014. MEASUREMENTS: Age and laboratory predictors measured in the outpatient setting included serum total cholesterol, high-density lipoprotein cholesterol, triglycerides, hemoglobin, mean corpuscular volume, platelets, leukocytes, estimated glomerular filtration rate, and glucose. The ASCVD outcomes were defined as myocardial infarction, stroke, and death from ischemic heart or cerebrovascular disease within 5 years. RESULTS: Sex-specific models were developed and internally validated in 2 160 497 women and 1 833 147 men. They were well calibrated, with relative differences less than 1% between mean predicted and observed risk for both sexes. The c-statistic was 0.77 in women and 0.71 in men. External validation in 31 697 primary care patients showed a relative difference less than 14% and an absolute difference less than 0.3 percentage points in mean predicted and observed risks for both sexes. The c-statistics for the laboratory models were 0.72 for both sexes and were not statistically significantly different from those for the PCEs in women (change in c-statistic, -0.01 [95% CI, -0.03 to 0.01]) or men (change in c-statistic, -0.01 [CI, -0.04 to 0.02]). LIMITATION: Medication use was not available at the population level. CONCLUSION: The CANHEART Lab Models predict ASCVD with similar accuracy to more complex models, such as the PCEs. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease: Secondary Analysis of a Randomized Clinical Trial.

Importance: Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial. Objective: To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity. Design, Setting, and Participants: This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US. Intervention: Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons. Main Outcomes and Measures: The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state. Results: Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

STICH3C: Rationale and Study Protocol.

BACKGROUND: Coronary artery bypass grafting (CABG) is the recommended mode of revascularization in patients with ischemic left ventricular dysfunction (iLVSD) and multivessel disease. However, contemporary percutaneous coronary intervention (PCI) outcomes have improved with the integration of novel technologies and refinement of revascularization strategies, and PCI is often used in clinical practice in this population. There is a lack of evidence from randomized trials comparing contemporary state-of-the-art PCI versus CABG for the treatment of iLVSD and multivessel disease. This was the impetus for the STICH3C trial (Canadian CABG or PCI in Patients With Ischemic Cardiomyopathy), described here. METHODS: The STICH3C trial is a prospective, unblinded, international, multicenter trial with an expected sample size of 754 participants from ≈45 centers. Patients with multivessel/left main coronary artery disease and iLVSD with left ventricular ejection fraction ≤40% considered by the local Heart Team appropriate for and amenable to revascularization by both modes of revascularization will be randomized in a 1:1 ratio to state-of-the-art PCI or CABG. RESULTS: The primary end point is the composite of death from any cause, stroke, spontaneous myocardial infarction, urgent repeat revascularization, or heart failure readmission, summarized as a time-to-event outcome. The key hierarchical end point is time to death and frequency of hospitalizations for heart failure. The key safety outcome is a composite of major adverse events. Disease-specific quality-of-life and health economics measures will be compared between groups. Participants will be followed for a median of 5 years, with a minimum follow-up of 4 years. CONCLUSIONS: STICH3C will directly inform patients, clinicians, and international practice guidelines about the efficacy and safety of CABG versus PCI in patients with iLVSD. The results will provide novel and broad evidence, including clinical events, health status, and economic assessments, to guide care for patients with iLVSD and severe coronary artery disease. REGISTRATION: URL: https://clinicaltrials.gov/; Unique identifier: NCT05427370.

Dealing With Nonproportional Hazards in Coronary Revascularisation Studies.

The Cox proportional hazards model is one of the most popular statistical tools to model time to event outcomes without the need for specifying the hazards or survival time distributions. The Cox model requires that the ratio of the hazards of the occurrence of the outcome for any 2 individuals remains constant during the entire follow-up. Studies comparing coronary revascularisation strategies, however, might be prone to violations of proportionality by the crossing of the hazard functions over time. Early increases in the risk of cardiovascular outcomes are commonly observed when comparing coronary artery bypass grafting vs percutaneous coronary intervention, whereas decreased risk might be observed later during the follow-up. The same is valid for comparisons between invasive vs conservative coronary revascularisation strategies. In these situations, the statistical power of the Cox model is reduced, and hazard ratios might not be an informative summary measure of treatment effect. In this article, we discuss methods to identify and account for nonproportionality. We illustrate the use of these methods in a case study based on reconstructed data from a coronary revascularisation clinical trial. And finally, we review the cardiovascular literature to estimate how the proportionality assumption has been reported in coronary revascularisation studies recently.

Incident CHD and ischemic stroke associated with lipoprotein(a) by levels of Factor VIII and inflammation.

BACKGROUND: Inflammation and coagulation may contribute to the increased risk for atherosclerotic cardiovascular disease (ASCVD) associated with high lipoprotein(a). The association of lipoprotein(a) with ASCVD is stronger in individuals with high versus low high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation. OBJECTIVES: Determine the association of lipoprotein(a) with incident ASCVD by levels of coagulation Factor VIII controlling for hs-CRP. METHODS: We analyzed data from 6,495 men and women 45 to 84 years of age in the Multi-Ethnic Study of Atherosclerosis (MESA) without prevalent ASCVD at baseline (2000-2002). Lipoprotein(a) mass concentration, Factor VIII coagulant activity, and hs-CRP were measured at baseline and categorized as high or low (≥75th or <75th percentile of the distribution). Participants were followed for incident coronary heart disease (CHD) and ischemic stroke through 2015. RESULTS: Over a median follow-up of 13.9 years, there were 390 CHD and 247 ischemic stroke events. The hazard ratio (95%CI) for CHD associated with high lipoprotein(a) (≥40.1 versus <40.1 mg/dL) including adjustment for hs-CRP among participants with low and high Factor VIII was 1.07 (0.80-1.44) and 2.00 (1.33-3.01), respectively (p-value for interaction 0.016). The hazard ratio (95%CI) for CHD associated with high lipoprotein(a) including adjustment for Factor VIII was 1.16 (0.87-1.54) and 2.00 (1.29-3.09) among participants with low and high hs-CRP, respectively (p-value for interaction 0.042). Lp(a) was not associated with ischemic stroke regardless of Factor VIII or hs-CRP levels. CONCLUSION: High lipoprotein(a) is a risk factor for CHD in adults with high levels of hemostatic or inflammatory markers.

Association of Beta-Blocker Therapy With Cardiovascular Outcomes in Patients With Stable Ischemic Heart Disease.

BACKGROUND: Previous studies have failed to show a cardioprotective benefit of beta-blockers in patients with stable coronary artery disease (CAD). OBJECTIVES: This study sought to determine the association between beta-blockers and cardiovascular events in patients with stable CAD using a new user design. METHODS: All patients aged >66 years undergoing elective coronary angiography in Ontario, Canada, from 2009 to 2019 with diagnosed obstructive CAD were included. Exclusion criteria included heart failure or a recent myocardial infarction, as well as having a beta-blocker prescription claim in the previous year. Beta-blocker use was defined as having at least 1 beta-blocker prescription claim in the 90 days preceding or after the index coronary angiography. The main outcome was a composite of all-cause mortality and hospitalization for heart failure or myocardial infarction. Inverse probability of treatment weighting using the propensity score was used to account for confounding. RESULTS: This study included 28,039 patients (mean age: 73.0 ± 5.6 years; 66.2% male), and 12,695 of those (45.3%) were newly prescribed beta-blockers. The 5-year risks of the primary outcome were 14.3% in the beta-blocker group and 16.1% in the no beta-blocker group (absolute risk reduction: -1.8%; 95% CI: -2.8 to -0.8; HR: 0.92; 95% CI: 0.86-0.98; P = 0.006). This result was driven by reductions in myocardial infarction hospitalization (cause-specific HR: 0.87; 95% CI: 0.77-0.99; P = 0.031), whereas no differences were observed in all-cause death or heart failure hospitalization. CONCLUSIONS: In patients with angiographically documented stable CAD without heart failure or a recent myocardial infarction, beta-blockers were associated with a small but significant reduction in cardiovascular events at 5 years.

Patient-Reported Outcomes After Tetralogy of Fallot Repair.

BACKGROUND: Comprehensive assessment of tetralogy of Fallot (TOF) outcomes extends beyond morbidity and mortality to incorporate patient-reported outcomes (PROs), including quality of life (QOL) and health status (HS). OBJECTIVES: This study explored PROs in adolescents and adults with TOF and delineated variables associated with PROs. METHODS: This was a cross-sectional observational study within a larger prospective registry of adolescents and adults with repaired TOF and moderate or greater pulmonary regurgitation from North America, Europe, and Asia. Participants completed PROs, including a QOL linear analogue scale (QOL-LAS) and an HS visual analogue scale (HS-VAS). Scores were classified according to age cohorts: <18, 18 to 25, 26 to 40, and >40 years. RESULTS: The study included 607 patients (46.3% female; median age 28.5 years). Median QOL-LAS scores (0-100) were similar across age cohorts (85, 80, 80, 80; P = 0.056). Median HS-VAS scores (0-100) were lowest for the oldest cohort (77) compared with the 3 younger cohorts (85, 80, 80) (P = 0.004). With advancing age, there were increased reports of poor mobility (P < 0.001) and pain or discomfort (P = 0.004); problems in these dimensions were reported by 19.1% and 37.2% of patients aged >40 years, respectively. Of factors associated with superior PROs on multivariable regression modeling (ie, being White, being nonsyndromic, having employment, and having better left ventricular function; P < 0.05), asymptomatic status (functional class I) was the variable associated with the greatest number of QOL and HS measures (P < 0.001). CONCLUSIONS: Strategies to improve TOF outcomes should consider PROs alongside conventional clinical variables. Factors associated with poorer PROs represent opportunities to intervene to improve the lives of patients with TOF.

Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial.

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19. Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). Conclusions and Relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

Sex-Based Differences in Severe Outcomes, Including Cardiovascular Hospitalization, in Adults With COVID-19 in Ontario, Canada.

Background: While men have experienced higher risks of SARS-CoV-2 infection compared to women, an analysis of sex differences by age in severe outcomes during the acute phase of infection is lacking. Objectives: The purpose of this study was to assess heterogeneity in severe outcome risks by age and sex by conducting a retrospective cohort study of community-dwelling adults in Ontario who tested positive for SARS-CoV-2 infection during the first 3 waves. Methods: Adjusted odds ratios were estimated using multilevel multivariable logistic regression models including an interaction term for age and sex. The primary outcome was a composite of severe outcomes (hospitalization for a cardiovascular (CV) event, intensive care unit admission, mechanical ventilation, or death) within 30 days. Results: Among 30,736, 199,132, and 186,131 adults who tested positive during the first 3 waves, 1,908 (6.2%), 5,437 (2.7%), and 5,653 (3.0%) experienced a severe outcome within 30 days. For all outcomes, the sex-specific risk depended on age (all P for interaction <0.05). Men with SARS-CoV-2 infection experienced a higher risk of outcomes than infected women of the same age, except for the risk of all-cause hospitalization being higher for young women than men (ages 18-45 years) during waves 2 and 3. The sex disparity in CV hospitalization across all ages either persisted or increased with each subsequent wave. Conclusions: To mitigate risks in subsequent waves, it is helpful to further understand the factors that contribute to the generally higher risks faced by men across all ages, and the persistent or increasing sex disparity in the risk of CV hospitalization.

Effects of Elective Coronary Revascularization vs Medical Therapy Alone on Noncardiac Mortality: A Meta-Analysis.

BACKGROUND: Uncertainty exists whether coronary revascularization plus medical therapy (MT) is associated with an increase in noncardiac mortality in chronic coronary syndrome (CCS) when compared with MT alone, particularly following recent data from the ISCHEMIA-EXTEND (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. OBJECTIVES: This study conducted a large-scale meta-analysis of trials comparing elective coronary revascularization plus MT vs MT alone in patients with CCS to determine whether revascularization has a differential impact on noncardiac mortality at the longest follow-up. METHODS: We searched for randomized trials comparing revascularization plus MT vs MT alone in patients with CCS. Treatment effects were measured by rate ratios (RRs) with 95% CIs, using random-effects models. Noncardiac mortality was the prespecified endpoint. The study is registered with PROSPERO (CRD42022380664). RESULTS: Eighteen trials were included involving 16,908 patients randomized to either revascularization plus MT (n = 8,665) or to MT alone (n = 8,243). No significant differences were detected in noncardiac mortality between the assigned treatment groups (RR: 1.09; 95% CI: 0.94-1.26; P = 0.26), with absent heterogeneity (I2 = 0%). Results were consistent without the ISCHEMIA trial (RR: 1.00; 95% CI: 0.84-1.18; P = 0.97). By meta-regression, follow-up duration did not affect noncardiac death rates with revascularization plus MT vs MT alone (P = 0.52). Trial sequential analysis confirmed the reliability of meta-analysis, with the cumulative Z-curve of trial evidence within the nonsignificance area and reaching futility boundaries. Bayesian meta-analysis findings were consistent with the standard approach (RR: 1.08; 95% credible interval: 0.90-1.31). CONCLUSIONS: In patients with CCS, noncardiac mortality in late follow-up was similar for revascularization plus MT compared with MT alone.

Genetic-Guided Oral P2Y12 Inhibitor Selection and Cumulative Ischemic Events After Percutaneous Coronary Intervention.

BACKGROUND: Genetic-guided P2Y12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y12 inhibitor therapy on cumulative ischemic and bleeding events. OBJECTIVES: Here, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events. METHODS: The TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI's primary analysis was time to first event in LOF carriers. RESULTS: Among 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39). CONCLUSIONS: Among CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI [TAILOR-PCI]; NCT01742117).

Recurrent Atherosclerotic Cardiovascular Disease Events Potentially Prevented with Guideline-Recommended Cholesterol-Lowering Therapy following Myocardial Infarction.

PURPOSE: Many adults with atherosclerotic cardiovascular disease (ASCVD) who are recommended to take a statin, ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) by the 2018 American Heart Association/American College of Cardiology cholesterol guideline do not receive these medications. We estimated the percentage of recurrent ASCVD events potentially prevented with guideline-recommended cholesterol-lowering therapy following a myocardial infarction (MI) hospitalization. METHODS: We conducted simulations using data from US adults with government health insurance through Medicare or commercial health insurance in the MarketScan database. We used data from patients with an MI hospitalization in 2018-2019 to estimate the percentage receiving guideline-recommended therapy. We used data from patients with an MI hospitalization in 2013-2016 to estimate the 3-year cumulative incidence of recurrent ASCVD events (i.e., MI, coronary revascularization or ischemic stroke). The low-density lipoprotein cholesterol (LDL-C) reduction with guideline-recommended therapy was derived from trials of statins, ezetimibe and PCSK9i, and the associated ASCVD risk reduction was estimated from a meta-analysis by the Cholesterol-Lowering Treatment Trialists Collaboration. RESULTS: Among 279,395 patients with an MI hospitalization in 2018-2019 (mean age 75 years, mean LDL-C 92 mg/dL), 27.3% were receiving guideline-recommended cholesterol-lowering therapy. With current cholesterol-lowering therapy use, 25.3% (95%CI: 25.2%-25.4%) of patients had an ASCVD event over 3 years. If all patients were to receive guideline-recommended therapy, 19.8% (95%CI: 19.5%-19.9%) were estimated to have an ASCVD event over 3 years, representing a 21.6% (95%CI: 20.5%-23.6%) relative risk reduction. CONCLUSION: Implementation of guideline-recommended cholesterol-lowering therapy could prevent a substantial percentage of recurrent ASCVD events.