Ticagrelor With or Without Aspirin in High-Risk Patients With Diabetes Mellitus Undergoing Percutaneous Coronary Intervention

BackgroundP2Y₁₂ inhibitor monotherapy with ticagrelor after a brief period of dual antiplatelet therapy can reduce bleeding without increasing ischemic harm after percutaneous coronary intervention (PCI). The impact of this approach among patients with diabetes mellitus (DM) remains unknown.ObjectivesThe purpose of this study was to examine the effect of ticagrelor monotherapy versus ticagrelor plus aspirin among patients with DM undergoing PCI.MethodsThis was a pre-specified analysis of the DM cohort in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial. After 3 months of ticagrelor plus aspirin, patients were maintained on ticagrelor and randomized to aspirin or placebo for 1 year. The primary endpoint was Bleeding Academic Research Consortium 2, 3, or 5 bleeding. The composite ischemic endpoint was all-cause death, myocardial infarction, or stroke.ResultsPatients with DM comprised 37% (n = 2,620) of the randomized cohort and were characterized by more frequent comorbidities and a higher prevalence of multivessel disease. The incidence of Bleeding Academic Research Consortium 2, 3, or 5 bleeding was 4.5% and 6.7% among patients with DM randomized to ticagrelor plus placebo versus ticagrelor plus aspirin (hazard ratio: 0.65; 95% confidence interval: 0.47 to 0.91; p = 0.012). Ticagrelor monotherapy was not associated with an increase in ischemic events compared with ticagrelor plus aspirin (4.6% vs. 5.9%; hazard ratio: 0.77; 95% confidence interval: 0.55 to 1.09; p = 0.14). In the overall trial population, there was no significant interaction between DM status and treatment group for the primary bleeding or ischemic endpoints.ConclusionsCompared with ticagrelor plus aspirin, the effect of ticagrelor monotherapy in reducing the risk of clinically relevant bleeding without any increase in ischemic events was consistent among patients with or without DM undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)     

Multimodality Intravascular Imaging of High-Risk Coronary Plaque

The majority of coronary atherothrombotic events presenting as myocardial infarction (MI) occur as a result of plaque rupture or erosion. Understanding the evolution from a stable plaque into a life-threatening, high-risk plaque is required for advancing clinical approaches to predict atherothrombotic events, and better treat coronary atherosclerosis. Unfortunately, none of the coronary imaging approaches used in clinical practice can reliably predict which plaques will cause an MI. Currently used imaging techniques mostly identify morphological features of plaques, but are not capable of detecting essential molecular characteristics known to be important drivers of future risk. To address this challenge, engineers, scientists, and clinicians have been working hand-in-hand to advance a variety of multimodality intravascular imaging techniques, whereby 2 or more complementary modalities are integrated into the same imaging catheter. Some of these have already been tested in early clinical studies, with other next-generation techniques also in development. This review examines these emerging hybrid intracoronary imaging techniques and discusses their strengths, limitations, and potential for clinical translation from both an engineering and clinical perspective.     

Effects of Methylnaltrexone on Ticagrelor-Induced Antiplatelet Effects in Coronary Artery Disease Patients Treated With Morphine

ObjectivesThe aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor.BackgroundMorphine delays the onset of action of oral P2Y₁₂ receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia.MethodsIn this prospective, randomized, double-blind, placebo-controlled, crossover study, aspirin-treated patients with stable coronary artery disease (n = 30) were randomized to receive methylnaltrexone (0.3 mg/kg intravenous) or matching placebo. After methylnaltrexone or placebo administration, all patients received morphine (5 mg intravenous). This was followed 15 min later by a 180-mg loading dose of ticagrelor. Patients crossed over to the alternative study treatment after 7 ± 2 days of washout. PK and PD assessments were performed at 12 time points (6 pre- and 6 post-crossover). PK analysis included measurement of plasma levels of ticagrelor and its major active metabolite (AR-C124910XX). PD assessments included VerifyNow P2Y₁₂, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein.ResultsOnly marginal changes in plasma levels of ticagrelor (and its major active metabolite) were observed with ticagrelor: maximum plasma concentration and area under the plasma concentration versus time curve from time 0 to the last measurable concentration were 38% and 30% higher, respectively, in patients receiving methylnaltrexone compared with those receiving placebo, but no differences in time to maximum plasma concentration were observed. There were no differences in P2Y₁₂ reaction units by VerifyNow P2Y₁₂ between groups at each time point, including 2 h (the primary endpoint; p = 0.261). Similarly, there were no differences in PD markers assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein.ConclusionsIn patients with coronary artery disease receiving morphine, intravenous administration of the peripheral opioid receptor antagonist methylnaltrexone leads to only marginal changes in plasma levels of ticagrelor and its major metabolite, without affecting levels of platelet reactivity. (Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine; NCT02403830)     

Prognostic Implications of Plaque Characteristics and Stenosis Severity in Patients With Coronary Artery Disease

BackgroundAlthough the presence of ischemia is a key prognostic factor in patients with coronary artery disease, the presence of high-risk plaque characteristics (HRPC) is also associated with increased risk of cardiovascular events. Limited data exist regarding the prognostic implications of combined information on physiological stenosis severity assessed by fractional flow reserve (FFR) and plaque vulnerability by coronary computed tomography angiography (CTA)–defined HRPC.ObjectivesThe current study aimed to evaluate the: 1) association between physiological stenosis severity and coronary CTA-defined HRPC; and 2) prognostic implications of coronary CTA-defined HRPC according to physiological stenosis severity in patients with coronary artery disease.MethodsA total of 772 vessels (299 patients) evaluated by both coronary CTA and FFR were analyzed. The presence and number of HRPC (minimum lumen area <4 mm², plaque burden ≥70%, low attenuating plaque, positive remodeling, napkin-ring sign, or spotty calcification) were assessed using coronary CTA images. The risk of vessel-oriented composite outcome (VOCO) (a composite of vessel-related ischemia-driven revascularization, vessel-related myocardial infarction, or cardiac death) at 5 years was compared according to the number of HRPC and FFR categories.ResultsThe proportion of lesions with ≥3 HRPC was significantly decreased according to the increase in FFR values (58.6%, 46.5%, 36.8%, 15.7%, and 3.5% for FFR ≤0.60, 0.61 to ≤0.70, 0.71 to ≤0.80, 0.81 to ≤0.90, and >0.90, respectively; overall p value <0.001). Both FFR and number of HRPC showed significant association with the estimated risk of VOCO (p = 0.008 and p = 0.023, respectively). In the FFR >0.80 group, lesions with ≥3 HRPC showed significantly higher risk of VOCO than those with <3 HRPC (15.0% vs. 4.3%; hazard ratio: 3.964; 95% confidence interval: 1.451 to 10.828; p = 0.007). However, there was no significant difference in the risk of VOCO according to HRPC in the FFR ≤0.80 group. By multivariable analysis, the presence of ≥3 HRPC was independently associated with the risk of VOCO in the FFR >0.80 group.ConclusionsPhysiological stenosis severity and the number of HRPC were closely related, and both components had significant association with the risk of clinical events. However, the prognostic implication of HRPC was different according to FFR. Integration of both physiological stenosis severity and plaque vulnerability would provide better prognostic stratification of patients than either individual component alone, especially in patients with FFR >0.80. (Clinical Implication of 3-vessel Fractional Flow Reserve [3V FFR-FRIENDS study]; NCT01621438)     

Myocardial Flow Reserve and Coronary Calcification in Prognosis of Patients With Suspected Coronary Artery Disease

ObjectivesThe aim of this analysis is to examine the incremental prognostic value of coronary artery calcium (CAC) score and myocardial flow reserve (MFR) in patients with suspected coronary artery disease (CAD) undergoing positron emission tomography (PET) myocardial perfusion imaging (MPI).BackgroundAdvances in cardiac PET and computed tomography imaging enabled the simultaneous acquisition of anatomic and physiological data for patients suspected of CAD.MethodsConsecutive patients who underwent PET MPI and CAC score calculation at King Abdulaziz Cardiac Center, Riyadh, Saudi Arabia, between May 2011 and May 2018 were included in the study. MPI and CAC images were obtained in the same setting. The primary endpoint of the study was a composite of cardiac death and nonfatal myocardial infarction. Cox proportional hazard regression was used to assess the incremental prognostic value of CAC and MFR by sequentially adding the variables to a model that included clinical and PET variables.ResultsA total of 4,008 patients (mean age 59.7 ± 11.6 years, 55% women) were included in the analysis. Risk factors were prevalent (77.6% hypertension, 58.1% diabetes). In total, 35.9% of the cohort had CAC of 0, 16.5% had CAC ≥400, and 43.9% had MFR <2. Over a median follow up of 1.9 years, 130 (3.2%) patients had cardiac death/nonfatal myocardial infarction. CAC and MFR score added incremental prognostic value over clinical and perfusion variables (base model: c-index 0.8137; Akaike information criterion [AIC]: 1,865.877; p = 0.0011; CAC model: c-index = 0.8330; AIC: 1,850.810; p = 0.045 vs. base model; MFR model: c-index = 0.8279; AIC: 1,859.235; p = 0.024). Combining CAC and MFR did not enhance risk prediction (c-index = 0.8435; AIC: 1,846.334; p = 0.074 vs. MFR model; p = 0.21 vs. CAC model.)ConclusionsIn this large cohort of patients referred for PET MPI, both CAC and MFR independently added incremental prognostic value over clinical and MPI variables. Although combining both may have synergetic prognostic effect, this relation was not shown in multivariable model of this analysis.     

Sex Differences in Compositional Plaque Volume Progression in Patients With Coronary Artery Disease

ObjectivesThis study sought to explore sex-based differences in total and compositional plaque volume (PV) progression.BackgroundIt is unclear whether sex has an impact on PV progression in patients with coronary artery disease (CAD).MethodsThe study analyzed a prospective multinational registry of consecutive patients with suspected CAD who underwent 2 or more clinically indicated coronary computed tomography angiography (CTA) at ≥2-year intervals. Total and compositional PV at baseline and follow-up were quantitatively analyzed and normalized using the analyzed total vessel length. Multivariate linear regression models were constructed.ResultsOf the 1,255 patients included (median coronary CTA interval 3.8 years), 543 were women and 712 were men. Women were older (62 ± 9 years of age vs. 59 ± 9 years of age; p < 0.001) and had higher total cholesterol levels (195 ± 41 mg/dl vs. 187 ± 39 mg/dl; p = 0.002). Prevalence of hypertension, diabetes, and family history of CAD were not different (all p > 0.05). At baseline, men possessed greater total PV (31.3 mm³ [interquartile range (IQR): 0 to 121.8 mm³] vs. 56.7 mm³ [IQR: 6.8 to 152.1 mm³] p = 0.005), and there was an approximately 9-year delay in women in developing total PV than in men. The prevalence of high-risk plaques was greater in men than women (31% vs. 20%; p < 0.001). In multivariate analysis, after adjusting for age, clinical risk factors, medication use, and total PV at baseline, despite similar total PV progression rates, female sex was associated with greater calcified PV progression (β = 2.83; p = 0.004) but slower noncalcified PV progression (β = –3.39; p = 0.008) and less development of high-risk plaques (β = –0.18; p = 0.049) than in men.ConclusionsThe compositional PV progression differed according to sex, suggesting that comprehensive plaque evaluation may contribute to further refining of risk stratification according to sex. (NCT02803411).     

Intravascular Polarimetry in Patients With Coronary Artery Disease

ObjectivesThe aims of this first-in-human pilot study of intravascular polarimetry were to investigate polarization properties of coronary plaques in patients and to examine the relationship of these features with established structural characteristics available to conventional optical frequency domain imaging (OFDI) and with clinical presentation.BackgroundPolarization-sensitive OFDI measures birefringence and depolarization of tissue together with conventional cross-sectional optical frequency domain images of subsurface microstructure.MethodsThirty patients undergoing polarization-sensitive OFDI (acute coronary syndrome, n = 12; stable angina pectoris, n = 18) participated in this study. Three hundred forty-two cross-sectional images evenly distributed along all imaged coronary arteries were classified into 1 of 7 plaque categories according to conventional OFDI. Polarization features averaged over the entire intimal area of each cross section were compared among plaque types and with structural parameters. Furthermore, the polarization properties in cross sections (n = 244) of the fibrous caps of acute coronary syndrome and stable angina pectoris culprit lesions were assessed and compared with structural features using a generalized linear model.ResultsThe median birefringence and depolarization showed statistically significant differences among plaque types (p < 0.001 for both, one-way analysis of variance). Depolarization differed significantly among individual plaque types (p < 0.05), except between normal arteries and fibrous plaques and between fibrofatty and fibrocalcified plaques. Caps of acute coronary syndrome lesions and ruptured caps exhibited lower birefringence than caps of stable angina pectoris lesions (p < 0.01). In addition to clinical presentation, cap birefringence was also associated with macrophage accumulation as assessed using normalized SD.ConclusionsIntravascular polarimetry provides quantitative metrics that help characterize coronary arterial tissues and may offer refined insight into coronary arterial atherosclerotic lesions in patients.     

Cangrelor in Patients With Coronary Artery Disease Pretreated With Ticagrelor: The Switching Antiplatelet (SWAP)-5 Study

BackgroundThere are no studies specifically designed to rule out a drug-drug interaction (DDI) when cangrelor is used among patients who have been pretreated with ticagrelor.ObjectivesThis study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor.MethodsIn this prospective, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (N = 20) were pretreated with a 180-mg ticagrelor loading dose and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1 to 4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included VerifyNow P2Y₁₂ reaction units (PRU), light transmittance aggregometry, vasodilator-stimulated phosphoprotein, and Total Thrombus-Formation Analysis System. PK/PD assessments were performed at 7 time points.ResultsCompared with placebo, adding cangrelor to patients pretreated with ticagrelor resulted in a significant reduction in PRU at 30 minutes and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU were low and similar in both groups (16.9 vs 12.6; mean difference: 4.3; 95% CI: ?28.6 to 37.3), meeting the noninferiority primary endpoint (predefined noninferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite.ConclusionsCompared with placebo, the use of cangrelor in patients pretreated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI. (PD and PK Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment [SWAP-5]; NCT04634162)     

A Boosted Ensemble Algorithm for Determination of Plaque Stability in High-Risk Patients on Coronary CTA

ObjectivesThis study sought to identify culprit lesion (CL) precursors among acute coronary syndrome (ACS) patients based on qualitative and quantitative computed tomography–based plaque characteristics.BackgroundCoronary computed tomography angiography (CTA) has been validated for patient-level prediction of ACS. However, the applicability of coronary CTA to CL assessment is not known.MethodsUtilizing the ICONIC (Incident COroNary Syndromes Identified by Computed Tomography) study, a nested case-control study of 468 patients with baseline coronary CTA, the study included ACS patients with invasive coronary angiography–adjudicated CLs that could be aligned to CL precursors on baseline coronary CTA. Separate blinded core laboratories adjudicated CLs and performed atherosclerotic plaque evaluation. Thereafter, the study used a boosted ensemble algorithm (XGBoost) to develop a predictive model of CLs. Data were randomly split into a training set (80%) and a test set (20%). The area under the receiver-operating characteristic curve of this model was compared with that of diameter stenosis (model 1), high-risk plaque features (model 2), and lesion-level features of CL precursors from the ICONIC study (model 3). Thereafter, the machine learning (ML) model was applied to 234 non-ACS patients with 864 lesions to determine model performance for CL exclusion.ResultsCL precursors were identified by both coronary angiography and baseline coronary CTA in 124 of 234 (53.0%) patients, with a total of 582 lesions (containing 124 CLs) included in the analysis. The ML model demonstrated significantly higher area under the receiver-operating characteristic curve for discriminating CL precursors (0.774; 95% confidence interval [CI]: 0.758 to 0.790) compared with model 1 (0.599; 95% CI: 0.599 to 0.599; p < 0.01), model 2 (0.532; 95% CI: 0.501 to 0.563; p < 0.01), and model 3 (0.672; 95% CI: 0.662 to 0.682; p < 0.01). When applied to the non-ACS cohort, the ML model had a specificity of 89.3% for excluding CLs.ConclusionsIn a high-risk cohort, a boosted ensemble algorithm can be used to predict CL from non-CL precursors on coronary CTA.     

Coronary 18F-Sodium Fluoride Uptake Predicts Outcomes in Patients With Coronary Artery Disease

BackgroundReliable methods for predicting myocardial infarction in patients with established coronary artery disease are lacking. Coronary ¹⁸F-sodium fluoride (¹⁸F-NaF) positron emission tomography (PET) provides an assessment of atherosclerosis activity.ObjectivesThis study assessed whether ¹⁸F-NaF PET predicts myocardial infarction and provides additional prognostic information to current methods of risk stratification.MethodsPatients with known coronary artery disease underwent ¹⁸F-NaF PET computed tomography and were followed up for fatal or nonfatal myocardial infarction over 42 months (interquartile range: 31 to 49 months). Total coronary ¹⁸F-NaF uptake was determined by the coronary microcalcification activity (CMA).ResultsIn a post hoc analysis of data collected for prospective observational studies, the authors studied 293 study participants (age: 65 ± 9 years; 84% men), of whom 203 (69%) showed increased coronary ¹⁸F-NaF activity (CMA >0). Fatal or nonfatal myocardial infarction occurred only in patients with increased coronary ¹⁸F-NaF activity (20 of 203 with a CMA >0 vs. 0 of 90 with a CMA of 0; p < 0.001). On receiver operator curve analysis, fatal or nonfatal myocardial infarction prediction was highest for ¹⁸F-NaF CMA, outperforming coronary calcium scoring, modified Duke coronary artery disease index and Reduction of Atherothrombosis for Continued Health (REACH) and Secondary Manifestations of Arterial Disease (SMART) risk scores (area under the curve: 0.76 vs. 0.54, 0.62, 0.52, and 0.54, respectively; p < 0.001 for all). Patients with CMA >1.56 had a >7-fold increase in fatal or nonfatal myocardial infarction (hazard ratio: 7.1; 95% confidence interval: 2.2 to 25.1; p = 0.003) independent of age, sex, risk factors, segment involvement and coronary calcium scores, presence of coronary stents, coronary stenosis, REACH and SMART scores, the Duke coronary artery disease index, and recent myocardial infarction.ConclusionsIn patients with established coronary artery disease, ¹⁸F-NaF PET provides powerful independent prediction of fatal or nonfatal myocardial infarction.     

Identification of Myocardial Disarray in Patients With Hypertrophic Cardiomyopathy and Ventricular Arrhythmias

BackgroundMyocardial disarray is a likely focus for fatal arrhythmia in hypertrophic cardiomyopathy (HCM). This microstructural abnormality can be inferred by mapping the preferential diffusion of water along cardiac muscle fibers using diffusion tensor cardiac magnetic resonance (DT-CMR) imaging. Fractional anisotropy (FA) quantifies directionality of diffusion in 3 dimensions. The authors hypothesized that FA would be reduced in HCM due to disarray and fibrosis that may represent the anatomic substrate for ventricular arrhythmia.ObjectivesThis study sought to assess FA as a noninvasive in vivo biomarker of HCM myoarchitecture and its association with ventricular arrhythmia.MethodsA total of 50 HCM patients (47 ± 15 years of age, 77% male) and 30 healthy control subjects (46 ± 16 years of age, 70% male) underwent DT-CMR in diastole, cine, late gadolinium enhancement (LGE), and extracellular volume (ECV) imaging at 3-T.ResultsDiastolic FA was reduced in HCM compared with control subjects (0.49 ± 0.05 vs. 0.52 ± 0.03; p = 0.0005). Control subjects had a mid-wall ring of high FA. In HCM, this ring was disrupted by reduced FA, consistent with published histology demonstrating that disarray and fibrosis invade circumferentially aligned mid-wall myocytes. LGE and ECV were significant predictors of FA, in line with fibrosis contributing to low FA. Yet FA adjusted for LGE and ECV remained reduced in HCM (p = 0.028). FA in the hypertrophied segment was reduced in HCM patients with ventricular arrhythmia compared to patients without (n = 15; 0.41 ± 0.03 vs. 0.46 ± 0.06; p = 0.007). A decrease in FA of 0.05 increased odds of ventricular arrhythmia by 2.5 (95% confidence interval: 1.2 to 5.3; p = 0.015) in HCM and remained significant even after correcting for LGE, ECV, and wall thickness (p = 0.036).ConclusionsDT-CMR assessment of left ventricular myoarchitecture matched patterns reported previously on histology. Low diastolic FA in HCM was associated with ventricular arrhythmia and is likely to represent disarray after accounting for fibrosis. The authors propose that diastolic FA could be the first in vivo marker of disarray in HCM and a potential independent risk factor.     

Ticagrelor or Prasugrel in Patients With Acute Coronary Syndrome in Relation to Estimated Glomerular Filtration Rate

ObjectivesThe aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs).BackgroundThe outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined.MethodsPatients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m²), intermediate eGFR (≥60 and <90 mL/min/1.73 m²), and high eGFR (≥90 mL/min/1.73 m²). The primary endpoint was a composite of all-cause death, myocardial infarction, and stroke; the secondary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding, both at 1 year.ResultsPatients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding.ConclusionsThese results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)     

Nonculprit Lesion Myocardial Infarction Following Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome

BackgroundRecent emphasis on reduced duration and/or intensity of antiplatelet therapy following percutaneous coronary intervention (PCI) irrespective of indication for PCI may fail to account for the substantial risk of subsequent nontarget lesion events in acute coronary syndrome (ACS) patients.ObjectivesThe authors sought to examine the effect of more potent antiplatelet therapy on the basis of the timing and etiology of recurrent myocardial infarction (MI) or cardiovascular death following PCI for ACS.MethodsIn the TRITON-TIMI 38 study (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38), which randomized patients to prasugrel or clopidogrel, 12,844 patients with ACS received at least 1 stent. MI and cardiovascular death were categorized as: 1) procedural (related to revascularization); 2) definite or probable stent thrombosis (ST); or 3) spontaneous (non-ST or non–procedure-related). Median follow-up was 14.5 months.ResultsAmong the first events occurring within 30 days, 584 (69.0%) were procedural, 126 (14.9%) ST-related, and 136 (16.1%) spontaneous. After 30 days, 22 (4.7%) were procedural, 63 (13.5%) were ST-related, and 383 (81.8%) spontaneous. Prasugrel significantly reduced the incidence of MI or cardiovascular death for ST-related (1.0% vs. 2.1%; p < 0.001) and spontaneous events (3.9% vs. 4.8%; p = 0.012), with a directionally consistent numerical reduction for procedural events (4.4% vs. 5.1%; p = 0.078). Prasugrel increased spontaneous, but not procedural, major bleeding.ConclusionsLong-term potent antithrombotic therapy reduces de novo (spontaneous) atherothrombotic events in addition to preventing complications associated with stenting of the culprit lesion following ACS. In patients undergoing PCI for ACS, spontaneous events predominate after 30 days, with the later-phase cardiovascular benefit of potent dual antiplatelet therapy driven largely by reducing de novo atherothrombotic ischemic events. (Comparison of Prasugrel [CS-747] and Clopidogrel in Acute Coronary Syndrome Subjects Who Are to Undergo Percutaneous Coronary Intervention; NCT00097591)     

Prognostic Role of CMR and Conventional Risk Factors in Myocardial Infarction With Nonobstructed Coronary Arteries

ObjectivesThis study sought to assess the prognostic impact of cardiac magnetic resonance (CMR) and conventional risk factors in patients with myocardial infarction with nonobstructed coronaries (MINOCA).BackgroundMyocardial infarction with nonobstructed coronary arteries (MINOCA) represents a diagnostic dilemma, and the prognostic markers have not been clarified.MethodsA total of 388 consecutive patients with MINOCA undergoing CMR assessment were identified retrospectively from a registry database and prospectively followed for a primary clinical endpoint of all-cause mortality. A 1.5-T CMR was performed using a comprehensive protocol (cines, T2-weighted, and late gadolinium enhancement sequences). Patients were grouped into 4 categories based on their CMR findings: myocardial infarction (MI) (embolic/spontaneous recanalization), myocarditis, cardiomyopathy, and normal CMR.ResultsCMR (performed at a median of 37 days from presentation) was able to identify the cause for the troponin rise in 74% of the patients (25% myocarditis, 25% MI, and 25% cardiomyopathy), whereas a normal CMR was identified in 26%. Over a median follow-up of 1,262 days (3.5 years), 5.7% patients died. The cardiomyopathy group had the worst prognosis (mortality 15%; log-rank test: 19.9; p < 0.001), MI had 4% mortality, and 2% in both myocarditis and normal CMR. In a multivariable Cox regression model (including clinical and CMR parameters), CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation electrocardiogram (ECG) remained the only 2 significant predictors of mortality. Using presentation with ECG ST-segment elevation and CMR diagnosis of cardiomyopathy as risk markers, the mortality risk rates were 2%, 11%, and 21% for presence of 0, 1, and 2 factors, respectively (p < 0.0001).ConclusionsIn a large cohort of patients with MINOCA, CMR (median 37 days from presentation) identified a final diagnosis in 74% of patients. Cardiomyopathy had the highest mortality, followed by MI. The strongest predictors of mortality were a CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation ECG.     

Ticagrelor or Prasugrel in Patients With Acute Coronary Syndromes and Diabetes Mellitus

ObjectivesThe aim of this study was to assess the efficacy and safety of ticagrelor versus prasugrel in patients with diabetes mellitus (DM) presenting with acute coronary syndromes (ACS) in whom invasive therapy was planned.BackgroundThe efficacy and safety of ticagrelor versus prasugrel in patients with ACS with DM undergoing invasive treatment remain unknown.MethodsThis pre-specified analysis of the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) 5 trial included 892 patients with ACS with DM and 3,124 patients with ACS without DM randomized to prasugrel or ticagrelor. The primary endpoint was a composite of death, myocardial infarction, or stroke; the safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding (both assessed 12 months after randomization).ResultsThe primary endpoint occurred in 51 patients (11.2%) in the ticagrelor group and 55 patients (13.0%) in the prasugrel group in the DM cohort (hazard ratio: 0.84; 95% confidence interval: 0.58 to 1.24; p = 0.383) and in 132 patients (8.6%) in the ticagrelor group and 81 patients (5.2%) in the prasugrel group in the non-DM cohort (hazard ratio: 1.70; 95% confidence interval: 1.29 to 2.24; p < 0.001). There was a significant treatment arm–by–diabetic status interaction (p_int = 0.0035). Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 27 patients (6.9%) in the ticagrelor group and 19 patients (5.5%) in the prasugrel group (p = 0.425) in the DM cohort and in 68 patients (5.2%) in the ticagrelor group and 60 patients (4.6%) in the prasugrel group in the non-DM cohort (p = 0.500).ConclusionsDM seems to affect the efficacy of ticagrelor and prasugrel in patients with ACS. In patients with DM, the efficacy of ticagrelor was comparable with that of prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)     

Differences in Progression to Obstructive Lesions per High-Risk Plaque Features and Plaque Volumes With CCTA

ObjectivesThis study explored whether the pattern of nonobstructive lesion progression into obstructive lesions would differ according to the presence of high-risk plaque (HRP).BackgroundIt is still debatable whether HRP simply represents a certain phase during the natural history of coronary atherosclerotic plaques or if disease progression would differ according to the presence of HRP.MethodsPatients with nonobstructive coronary artery disease, defined as percent diameter stenosis (%DS) <50%, were enrolled from a prospective, multinational registry of consecutive patients who underwent serial coronary computed tomography angiography at an interscan interval of ≥2 years. HRP was defined as lesions with ≥2 features of positive remodeling, spotty calcification, or low-attenuation plaque. Quantitative total and compositional percent atheroma volume (PAV) at baseline and annualized PAV change were compared between non-HRP and HRP lesions.ResultsA total of 3,049 nonobstructive lesions were identified from 1,297 patients (mean age 60.3 ± 9.3 years; 56.8% men). There were 2,624 non-HRP and 425 HRP lesions. HRP lesions had a greater total PAV and all noncalcified components of PAV and %DS at baseline compared with non-HRP lesions. However, the annualized total PAV changes were greater in non-HRP lesions than in HRP lesions. On multivariate analysis adjusted for clinical risk factors, drug use, change in lipid level, total PAV, %DS, and HRP, only the baseline total PAV and %DS independently predicted the development of obstructive lesions (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 1.02 to 1.07, and HR: 1.07; 95% CI: 1.04 to 1.10, respectively, all p < 0.05), whereas the presence of HRP did not (p > 0.05).ConclusionsThe pattern of individual coronary atherosclerotic plaque progression differed according to the presence of HRP. Baseline PAV, not the presence of HRP features, was the most important predictor of lesions developing into obstructive lesions. (Progression of Atherosclerotic Plaque Determined By Computed Tomographic Angiography Imaging [PARADIGM]; NCT02803411)     

Effect of Ticagrelor on Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction (HEALING-AMI)

ObjectivesThe aim of this study was to evaluate the effect of ticagrelor versus clopidogrel on left ventricular (LV) remodeling after reperfusion of ST-segment elevation myocardial infarction (STEMI) in humans.BackgroundAnimal studies have demonstrated that ticagrelor compared with clopidogrel better protects myocardium against reperfusion injury and improves remodeling after myocardial infarction.MethodsIn this investigator-initiated, randomized, open-label, assessor-blinded trial performed at 10 centers in Korea, patients were enrolled if they had naive STEMI successfully treated with primary percutaneous coronary intervention (PCI) and at least 6-month planned duration of dual-antiplatelet treatment. The coprimary endpoints were LV remodeling index (LVRI) (a relative change of LV end-diastolic volume) measured on 3-dimensional echocardiography and N-terminal pro–B-type natriuretic peptide level at 6 months.ResultsAmong initially enrolled patients with STEMI (n = 336), 139 in each group completed the study. LVRI at 6 months was numerically lower with ticagrelor versus clopidogrel (0.6 ± 18.6% vs. 4.5 ± 16.5%; p = 0.095). Ticagrelor significantly reduced the 6-month level of N-terminal pro–B-type natriuretic peptide (173 ± 141 pg/ml vs. 289 ± 585 pg/ml; p = 0.028). These differences were prominent in patients with pre-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade 0. By multivariate analysis, ticagrelor versus clopidogrel reduced the risk for positive LV remodeling (LVRI >0%) (odds ratio: 0.56; 95% confidence interval: 0.33 to 0.95; p = 0.030). The LV end-diastolic volume index remained unchanged during ticagrelor treatment (from 54.7 ± 12.2 to 54.2 ± 12.2 ml/m²; p = 0.629), but this value increased over time during clopidogrel treatment (from 54.6 ± 11.3 to 56.4 ± 13.9 ml/m²; p = 0.056) (difference −2.3 ml/m²; 95% confidence interval: −4.8 to 0.2 ml/m²; p = 0.073). Ticagrelor reduced LV end-systolic volume index (from 27.0 ± 8.5 to 24.7 ± 8.4 ml/m²; p < 0.001), whereas no reduction was seen with clopidogrel (from 26.2 ± 8.9 to 25.6 ± 11.0 ml/m²; p = 0.366) (difference −1.8 ml/m²; 95% confidence interval: −3.5 to −0.1 ml/m²; p = 0.040).ConclusionsTicagrelor was superior to clopidogrel for LV remodeling after reperfusion of STEMI with primary PCI. (High Platelet Inhibition With Ticagrelor to Improve Left Ventricular Remodeling in Patients With ST Segment Elevation Myocardial Infarction [HEALING-AMI]; NCT02224534)     

Ticagrelor Monotherapy After PCI in High-Risk Patients With Prior MI: A Prespecified TWILIGHT Substudy

ObjectivesThe aim of this study was to evaluate if patients with prior myocardial infarction (MI) could benefit from ticagrelor monotherapy in terms of bleeding reduction without any compromise in ischemic event prevention.BackgroundPatients with history of MI who undergo percutaneous coronary intervention (PCI) remain at risk for recurrent ischemic events. The optimal antithrombotic strategy for this cohort remains debated.MethodsIn this prespecified analysis of the randomized TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial, the authors evaluated the impact of history of MI on treatment effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients undergoing PCI with drug-eluting stent with at least 1 clinical and 1 angiographic high-risk feature and free from adverse events at 3 months after index PCI. The primary endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, and the key secondary endpoint was the composite of all-cause death, MI, or stroke, both at 12 months after randomization.ResultsA total of 1,937 patients (29.7%) with and 4,595 patients (70.3%) without prior MI were randomized to ticagrelor and placebo or ticagrelor and aspirin. At 1 year after randomization, patients with prior MI experienced higher rates of death, MI, or stroke (5.7% vs 3.2%; P < 0.001) but similar BARC types 2 to 5 bleeding (5.0% vs 5.5%; P = 0.677) compared with patients without prior MI. Ticagrelor monotherapy consistently reduced the risk for the primary bleeding outcome in patients with (3.4% vs 6.7%; HR: 0.50; 95% CI: 0.33-0.76) and without (4.2% vs 7.0%; HR: 0.58; 95% CI: 0.45-0.76; P_interaction = 0.54) prior MI. Rates of the key secondary ischemic outcome were not significantly different between treatment groups irrespective of history of MI (prior MI, 6.0% vs 5.5% [HR: 1.09; 95% CI: 0.75-1.58]; no prior MI, 3.1% vs 3.3% [HR: 0.92; 95% CI: 0.67-1.28]; P_interaction = 0.52).ConclusionsTicagrelor monotherapy is associated with significantly lower risk for bleeding events compared with ticagrelor plus aspirin, without any compromise in ischemic prevention, among high-risk patients with history of MI undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)     

Myocardial Fibrosis as a Predictor of Sudden Death in Patients With Coronary Artery Disease

BackgroundThe “gray zone” of myocardial fibrosis (GZF) on cardiovascular magnetic resonance may be a substrate for ventricular arrhythmias (VAs).ObjectivesThe purpose of this study was to determine whether GZF predicts sudden cardiac death (SCD) and VAs (ventricular fibrillation or sustained ventricular tachycardia) in patients with coronary artery disease (CAD) and a wide range of left ventricular ejection fractions (LVEFs).MethodsIn this retrospective study of CAD patients, the presence of myocardial fibrosis on visual assessment (MF_VA) and GZF mass in patients with MF_VA were assessed in relation to SCD and the composite, arrhythmic endpoint of SCD or VAs.ResultsAmong 979 patients (mean age [± SD]: 65.8 ± 12.3 years), 29 (2.96%) experienced SCD and 80 (8.17%) met the arrhythmic endpoint over median 5.82 years (interquartile range: 4.1 to 7.3 years). In the whole cohort, MF_VA was strongly associated with SCD (hazard ratio: 10.1; 95% confidence interval [CI]: 1.42 to 1,278.9) and the arrhythmic endpoint (hazard ratio: 28.0; 95% CI: 4.07 to 3,525.4). In competing risks analyses, associations between LVEF <35% and SCD (subdistribution hazard ratio [sHR]: 2.99; 95% CI: 1.42 to 6.31) and the arrhythmic endpoint (sHR: 4.71; 95% CI: 2.97 to 7.47) were weaker. In competing risk analyses of the MF_VA subcohort (n = 832), GZF using the 3SD method (GZF_3SD) >5.0 g was strongly associated with SCD (sHR: 10.8; 95% CI: 3.74 to 30.9) and the arrhythmic endpoint (sHR: 7.40; 95% CI: 4.29 to 12.8). Associations between LVEF <35% and SCD (sHR: 2.62; 95% CI: 1.24 to 5.52) and the arrhythmic endpoint (sHR: 4.14; 95% CI: 2.61 to 6.57) were weaker.ConclusionsIn CAD patients, MF_VA plus quantified GZF_3SD mass was more strongly associated with SCD and VAs than LVEF. In selecting patients for implantable cardioverter-defibrillators, assessment of MF_VA followed by quantification of GZF_3SD mass may be preferable to LVEF.     

Enhanced Diagnosis of Plaque Erosion by Deep Learning in Patients With Acute Coronary Syndromes

BackgroundAcute coronary syndromes caused by plaque erosion might be potentially managed conservatively without stenting. Currently, the diagnosis of plaque erosion requires expertise in optical coherence tomographic (OCT) image interpretation. In addition, the current deep learning (DL) approaches for OCT image interpretation are based on a single frame, without integrating the information from adjacent frames.ObjectivesThe aim of this study was to develop a novel DL model to facilitate an accurate diagnosis of plaque erosion.MethodsA novel “Transformer”-based DL model was developed that integrates information from adjacent frames emulating the cardiologists who review consecutive OCT frames to make a diagnosis and compared with the standard convolutional neural network (CNN) DL model. A total of 237,021 cross-sectional OCT images from 581 patients were used for training and internal validation, and 65,394 images from 292 patients from another dataset were used for external validation. Model performances were evaluated using the area under the receiver-operating characteristic curve (AUC).ResultsFor the frame-level diagnosis of plaque erosion, the Transformer model showed superior performance than the CNN model, with an AUC of 0.94 compared with 0.85 in the external validation. For the lesion-level diagnosis, the Transformer model showed improved diagnostic performance compared with the CNN model, with an AUC of 0.91 compared with 0.84 in the external validation.ConclusionsThis newly developed Transformer model will help cardiologists diagnose plaque erosion with high accuracy in patients with acute coronary syndromes.