An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial.

BACKGROUND: Bleeding rates on dual antiplatelet therapy (DAPT) within 1 month after percutaneous coronary intervention (PCI) remain high in clinical practice, particularly in patients with acute coronary syndrome or high bleeding risk. Aspirin-free strategy might result in lower bleeding early after PCI without increasing cardiovascular events, but its efficacy and safety have not yet been proven in randomized trials. METHODS: We randomly assigned 6002 patients with acute coronary syndrome or high bleeding risk just before PCI either to prasugrel (3.75 mg/day) monotherapy or to DAPT with aspirin (81-100 mg/day) and prasugrel (3.75 mg/day) after loading of 20 mg of prasugrel in both groups. The coprimary end points were major bleeding (Bleeding Academic Research Consortium 3 or 5) for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) for noninferiority with a relative 50% margin. RESULTS: The full analysis set population consisted of 5966 patients (no-aspirin group, 2984 patients; DAPT group, 2982 patients; age, 71.6±11.7 years; men, 76.6%; acute coronary syndrome, 75.0%). Within 7 days before randomization, aspirin alone, aspirin with P2Y12 inhibitor, oral anticoagulants, and intravenous heparin infusion were given in 21.3%, 6.4%, 8.9%, and 24.5%, respectively. Adherence to the protocol-specified antiplatelet therapy was 88% in both groups at 1 month. At 1 month, the no-aspirin group was not superior to the DAPT group for the coprimary bleeding end point (4.47% and 4.71%; hazard ratio, 0.95 [95% CI, 0.75-1.20]; Psuperiority=0.66). The no-aspirin group was noninferior to the DAPT group for the coprimary cardiovascular end point (4.12% and 3.69%; hazard ratio, 1.12 [95% CI, 0.87-1.45]; Pnoninferiority=0.01). There was no difference in net adverse clinical outcomes and each component of coprimary cardiovascular end point. There was an excess of any unplanned coronary revascularization (1.05% and 0.57%; hazard ratio, 1.83 [95%CI, 1.01-3.30]) and subacute definite or probable stent thrombosis (0.58% and 0.17%; hazard ratio, 3.40 [95% CI, 1.26-9.23]) in the no-aspirin group compared with the DAPT group. CONCLUSIONS: The aspirin-free strategy using low-dose prasugrel compared with the DAPT strategy failed to attest superiority for major bleeding within 1 month after PCI but was noninferior for cardiovascular events within 1 month after PCI. However, the aspirin-free strategy was associated with a signal suggesting an excess of coronary events. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04609111.

Plasma ANGPTL8 Levels and Risk for Secondary Cardiovascular Events in Japanese Patients With Stable Coronary Artery Disease Receiving Statin Therapy.

BACKGROUND: The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients. METHODS: We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization. RESULTS: Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166

Dual Antiplatelet Therapy Duration After Multivessel Optimal Intravascular Ultrasound-Guided Percutaneous Coronary Intervention.

BACKGROUND: There is a scarcity of data evaluating contemporary real-world dual antiplatelet therapy (DAPT) strategies after percutaneous coronary intervention (PCI).Methods and Results: In the OPTIVUS-Complex PCI study multivessel cohort enrolling 982 patients undergoing multivessel PCI, including left anterior descending coronary artery using intravascular ultrasound (IVUS), we conducted 90-day landmark analyses to compare shorter and longer DAPT. DAPT discontinuation was defined as withdrawal of P2Y12inhibitors or aspirin for at least 2 months. The prevalence of acute coronary syndrome and high bleeding risk by the Bleeding Academic Research Consortium were 14.2% and 52.5%, respectively. The cumulative incidence of DAPT discontinuation was 22.6% at 90 days, and 68.8% at 1 year. In the 90-day landmark analyses, there were no differences in the incidences of a composite of death, myocardial infarction, stroke, or any coronary revascularization (5.9% vs. 9.2%, log-rank P=0.12; adjusted hazard ratio, 0.59; 95% confidence interval, 0.32-1.08; P=0.09) and BARC type 3 or 5 bleeding (1.4% vs. 1.9%, log-rank P=0.62) between the off- and on-DAPT groups at 90 days. CONCLUSIONS: The adoption of short DAPT duration was still low in this trial conducted after the release of the STOPDAPT-2 trial results. The 1-year incidence of cardiovascular events was not different between the shorter and longer DAPT groups, suggesting no apparent benefit of prolonged DAPT in reducing cardiovascular events even in patients who undergo multivessel PCI.

1-Year Safety of 3-Month Dual Antiplatelet Therapy Followed by Aspirin or P2Y12 Receptor Inhibitor Monotherapy Using a Bioabsorbable Polymer Sirolimus-Eluting Stent.

BACKGROUND: This study evaluated the safety of 3-month dual antiplatelet therapy (DAPT) after implantation of a bioresorbable polymer sirolimus-eluting stent (BP-SES) and compared P2Y12inhibitor with aspirin monotherapy 3 months after DAPT.Methods and Results:Patients who underwent percutaneous coronary intervention using BP-SES were enrolled and followed for 1 year. Patients with a history of stent thrombosis were excluded. The primary endpoint was a composite of all-cause death, myocardial infarction, stroke (ischemic and hemorrhagic), definite or probable stent thrombosis, and severe bleeding at 12 months. The BP-SES arm of the CENTURY II trial was used as a conventional DAPT group for comparison. After DAPT, patients were maintained on either aspirin (n=846) or a P2Y12inhibitor (n=674 patients).In all, 1,695 patients were enrolled in the study across 65 centers. The primary endpoint occurred in 4.3% of patients at 1 year. After propensity score adjustment, the incidence of the primary endpoint was not inferior in those receiving DAPT for 3 months compared with conventional DAPT (5.5%; Pnon-inferiority<0.0001). The incidence of the primary endpoint and severe bleeding did not differ between the aspirin and P2Y12inhibitor monotherapy groups. CONCLUSIONS: After adjustment, 3-month DAPT was not inferior to longer DAPT after BP-SES implantation in terms of net adverse clinical events. There was no difference in bleeding and thrombotic events between P2Y12inhibitor and aspirin monotherapy after 3 months DAPT.

Prognostic Significance of a Combination of QRS Score and E/e' Obtained 2 Weeks After the Onset of ST-Elevation Myocardial Infarction.

BACKGROUND: The early mitral inflow velocity to mitral early diastolic velocity ratio (E/e') and electrocardiogram (ECG) determination of QRS score are useful for risk stratification in patients with ST-elevation myocardial infarction (STEMI).Methods and Results:In this study, 420 consecutive patients (357 male; mean [±SD] age 63.6±12.2 years) with first-time STEMI who successfully underwent primary percutaneous coronary intervention within 12 h of symptom onset were followed-up for 5 years (median follow-up 67 months). Echocardiography, ECG, and blood samples were obtained 2 weeks after onset. Infarct size was estimated by the QRS score after 2 weeks (QRS-2wks) and creatine phosphokinase-MB concentrations (peak and area under the curve). The primary endpoint was death from cardiac causes or rehospitalization for heart failure (HF). During follow-up, 21 patients died of cardiac causes and 62 had HF. Multivariate Cox proportional hazard analysis showed that mean E/e' (hazard ratio [HR] 1.152; 95% confidence interval [CI] 1.088-1.215; P<0.0001), QRS-2wks (HR 1.153; 95% CI 1.057-1.254; P<0.0001), and hypertension (HR 1.702; 95% CI 1.040-2.888; P=0.03) were independent predictors of the primary endpoint. Kaplan-Meier curve analysis showed that patients with QRS-2wks >4 and mean E/e' >14 were at an extremely high risk of cardiac death or HF (log rank, χ2=116.3, P<0.0001). CONCLUSIONS: In patients with STEMI, a combination of QRS-2wks and mean E/e' was a simple but useful predictor of cardiac death and HF.

Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients With Acute Coronary Syndrome　- The ODYSSEY J-IVUS Trial.

BACKGROUND: In patients with acute coronary syndrome (ACS), alirocumab reduced the risk of recurring ischemic events. ODYSSEY J-IVUS assessed the effect of alirocumab on coronary atheroma volume in Japanese patients recently hospitalized with ACS and hypercholesterolemia, using intravascular ultrasound imaging analysis.Methods and Results:Patients (n=206) who at index ACS diagnosis either had low-density lipoprotein cholesterol (LDL-C) ≥2.59 mmol/L (≥100 mg/dL) despite stable statin therapy, or were not on statins with LDL-C levels above target after statin initiation, were randomized (1:1) to alirocumab (75 mg every 2 weeks [Q2 W]/up to 150 mg Q2 W), or standard of care (SoC; atorvastatin ≥10 mg/day or rosuvastatin ≥5 mg/day) for 36 weeks. The primary efficacy endpoint (week [W] 36 mean [standard error] percent change in normalized total atheroma volume [TAV] from baseline) was -3.1 (1.0)% with SoC vs. -4.8 (1.0)% with alirocumab (between-group difference: -1.6 [1.4]; P=0.23). W36 absolute change from baseline in percent atheroma volume was -1.3 (0.4)% (SoC) and -1.4 (0.4)% (alirocumab; nominal P=0.79). At W36, LDL-C was reduced from baseline by 13.4% (SoC) vs. 63.9% (alirocumab; nominal P<0.0001). In total, 61.8% (SoC) and 75.7% (alirocumab) of patients reported treatment-emergency adverse events. CONCLUSIONS: In Japanese patients with ACS and hypercholesterolemia inadequately controlled despite statin therapy, from baseline to W36, a numerically greater percent reduction in normalized TAV was observed with alirocumab vs. SoC, which did not reach statistical significance.

Second-Generation vs. First-Generation Drug-Eluting Stents in Patients With Calcified Coronary Lesions　- Pooled Analysis From the RESET and NEXT Trials.

BACKGROUND: The comparative efficacy of second-generation (G2) vs. first-generation (G1) drug-eluting stents (DES) for calcified coronary lesions is unknown.Methods and Results:We compared the 3-year clinical outcomes of patients with G1- or G2-DES according to the presence or absence of calcified coronary lesions as assessed in an angiographic core laboratory using data from 2 large-scale prospective multicenter randomized trials, RESET and NEXT. G1-DES and G2-DES were implanted in 299 and 1,033 patients, respectively, in the Calc stratum (≥1 lesion with moderate/severe calcification), and 1,208 and 3,550 patients, respectively, in the Non-calc stratum (no/mild calcification). The patients in the Calc stratum had a significantly higher adjusted risk for the primary outcome measure (any target-lesion revascularization (TLR)) than those in the Non-calc stratum (HR: 1.38, 95% CI: 1.11-1.71, P=0.004). The cumulative 3-year incidence of any TLR was not significantly different between the G1-DES and G2-DES groups in both the Calc and Non-calc strata (12.1% vs. 9.7%, P=0.22, and 6.8% vs. 6.1%, P=0.44, respectively). After adjusting for confounders, the effect of G2DES relative to G1-DES for any TLR remained insignificant in both the Calc and Non-calc strata (HR: 0.78, 95% CI: 0.48-1.25, P=0.3, and HR: 0.84, 95% CI: 0.61-1.17, P=0.31, respectively, P interaction=0.55). CONCLUSIONS: The effect of G2-DES relative to G1-DES for TLR was not significantly different regardless of the presence or absence of lesion calcification.

Clopidogrel vs Aspirin Monotherapy Beyond 1 Year After Percutaneous Coronary Intervention.

BACKGROUND: It remains unclear whether clopidogrel is better suited than aspirin as the long-term antiplatelet monotherapy following dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). OBJECTIVES: This study compared clopidogrel monotherapy following 1 month of DAPT (clopidogrel group) with aspirin monotherapy following 12 months of DAPT (aspirin group) after PCI for 5 years. METHODS: STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy 2) is a multicenter, open-label, adjudicator-blinded, randomized clinical trial conducted in Japan. Patients who underwent PCI with cobalt-chromium everolimus-eluting stents were randomized in a 1-to-1 fashion either to clopidogrel or aspirin groups. The primary endpoint was a composite of cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) or major bleeding (TIMI major or minor bleeding). RESULTS: Among 3,005 study patients (age: 68.6 ± 10.7 years; women: 22.3%; acute coronary syndrome: 38.3%), 2,934 patients (97.6%) completed the 5-year follow-up (adherence to the study drugs at 395 days: 84.7% and 75.9%). The clopidogrel group compared with the aspirin group was noninferior but not superior for the primary endpoint (11.75% and 13.57%, respectively; HR: 0.85; 95% CI: 0.70-1.05; Pnoninferiority < 0.001; Psuperiority = 0.13), whereas it was superior for the cardiovascular outcomes (8.61% and 11.05%, respectively; HR: 0.77; 95% CI: 0.61-0.97; P = 0.03) and not superior for major bleeding (4.44% and 4.92%, respectively; HR: 0.89; 95% CI: 0.64-1.25; P = 0.51). By the 1-year landmark analysis, clopidogrel was numerically, but not significantly, superior to aspirin for cardiovascular events (6.79% and 8.68%, respectively; HR: 0.77; 95% CI: 0.59-1.01; P = 0.06) without difference in major bleeding (3.99% and 3.32%, respectively; HR: 1.23; 95% CI: 0.84-1.81; P = 0.31). CONCLUSIONS: Clopidogrel might be an attractive alternative to aspirin with a borderline ischemic benefit beyond 1 year after PCI.

Evolocumab for prevention of microvascular dysfunction in patients undergoing percutaneous coronary intervention: the randomised, open-label EVOCATION trial.

BACKGROUND: Statins have been shown to prevent microvascular dysfunction that may cause periprocedural myocardial infarction after percutaneous coronary intervention (PCI). Evolocumab has more potent lipid-lowering properties than statins.  Aims: The aims of this study were to investigate whether evolocumab pretreatment on top of statin therapy could prevent periprocedural microvascular dysfunction.  Methods: This study included 100 patients with stable coronary artery disease who were scheduled to undergo PCI and had high low-density lipoprotein cholesterol (LDL-C) under statin therapy. Patients were randomised to receive evolocumab 140 mg every 2 weeks for 2 to 6 weeks before PCI (evolocumab group: N=54) or not (control group: N=46). The primary endpoint was the index of microvascular resistance (IMR) after PCI. Troponin T was measured before and 24 hours after PCI.  Results: Geometric mean LDL-C was 94.1 (95% confidence interval [CI]: 86.8-102.1) mg/dl and 89.4 (95% CI: 83.5-95.7) mg/dl at baseline, and 25.6 (95% CI: 21.9-30.0) mg/dl and 79.8 (95% CI: 73.9-86.3) mg/dl before PCI, in the evolocumab group and in the control group, respectively. PCI was performed 22.1±8.5 days after allocation. Geometric mean IMR was 20.6 (95% CI: 17.2-24.6) in the evolocumab group and 20.6 (95% CI: 17.0-25.0) in the control group (p=0.98). There was no significant difference in the geometric mean of post-PCI troponin T (0.054, 95% CI: 0.041-0.071 ng/ml vs 0.054, 95% CI: 0.038-0.077 ng/ml; p=0.99) and in the incidence of major periprocedural myocardial infarction between the 2 groups (44.4% vs 44.2%; p=1.00).  Conclusions: Evolocumab pretreatment did not prevent periprocedural microvascular dysfunction in patients on modern medical management with statins.

Details on the effect of very short dual antiplatelet therapy after drug-eluting stent implantation in patients with high bleeding risk: insight from the STOPDAPT-2 trial.

Previously we briefly reported the effect of 1-month dual antiplatelet therapy (DAPT) for patients with high bleeding risk (HBR) receiving percutaneous coronary intervention (PCI) in the STOPDAPT-2 trial, but full analysis data have not been available. We conducted post hoc subgroup analysis regarding the effect of very short DAPT for HBR patients in STOPDAPT-2 trial. The primary endpoint was a 1-year composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) and bleeding (TIMI major/minor bleeding) outcomes. Major secondary endpoints were 1-year cardiovascular composite endpoint and bleeding endpoint. HBR was defined by the academic research consortium (ARC) HBR criteria. Among the 3009 study patients, 1054 (35.0%) were classified as HBR and 1955 (65.0%) were as non-HBR. There were no significant interactions between HBR/non-HBR subgroups and the assigned DAPT group on the primary endpoint (HBR; 3.48% vs. 5.98%, HR 0.57, 95% CI 0.32-1.03, and non-HBR; 1.81% vs. 2.36%, HR 0.78, 95% CI 0.42-1.45; P for interaction = 0.48), the major secondary cardiovascular endpoint (HBR; 3.07% vs. 4.03%, HR 0.77, 95% CI 0.40-1.48, and non-HBR; 1.41% vs. 1.61%, HR 0.89, 95% CI 0.43-1.84; P for interaction = 0.77), and the major secondary bleeding endpoint (HBR; 0.41% vs. 2.71%, HR 0.15, 95% CI 0.03-0.65, and non-HBR; 0.40% vs. 0.85%, HR 0.48, 95% CI 0.14-1.58; P for interaction = 0.22). In conclusion, the effects of 1-month DAPT for the primary and major secondary endpoints were consistent in HBR and non-HBR patients without any significant interactions. The benefit of 1-month DAPT in reducing major bleeding was numerically greater in HBR patients.Clinical trial registration Short and optimal duration of dual antiplatelet therapy after everolimus-eluting cobalt-chromium stent-2 [STOPDAPT-2]; NCT02619760.

Long-term use of carvedilol in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention.

BACKGROUND: Despite its recommendation by the current guidelines, the role of long-term oral beta-blocker therapy has never been evaluated by randomized trials in uncomplicated ST-segment elevation myocardial infarction (STEMI) patients without heart failure, left ventricular dysfunction or ventricular arrhythmia who underwent primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: In a multi-center, open-label, randomized controlled trial, STEMI patients with successful primary PCI within 24 hours from the onset and with left ventricular ejection fraction (LVEF) ≥40% were randomly assigned in a 1-to-1 fashion either to the carvedilol group or to the no beta-blocker group within 7 days after primary PCI. The primary endpoint is a composite of all-cause death, myocardial infarction, hospitalization for heart failure, and hospitalization for acute coronary syndrome. Between August 2010 and May 2014, 801 patients were randomly assigned to the carvedilol group (N = 399) or the no beta-blocker group (N = 402) at 67 centers in Japan. The carvedilol dose was up-titrated from 3.4±2.1 mg at baseline to 6.3±4.3 mg at 1-year. During median follow-up of 3.9 years with 96.4% follow-up, the cumulative 3-year incidences of both the primary endpoint and any coronary revascularization were not significantly different between the carvedilol and no beta-blocker groups (6.8% and 7.9%, P = 0.20, and 20.3% and 17.7%, P = 0.65, respectively). There also was no significant difference in LVEF at 1-year between the 2 groups (60.9±8.4% and 59.6±8.8%, P = 0.06). CONCLUSION: Long-term carvedilol therapy added on the contemporary evidence-based medications did not seem beneficial in selected STEMI patients treated with primary PCI. TRIAL REGISTRATION: CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial) ClinicalTrials.gov.number, NCT 01155635.

Impact of statin pretreatment on the incidence of plaque rupture in ST-elevation acute myocardial infarction.

OBJECTIVE: Several studies in experimental animals have shown that statins stabilize atheromatous plaques by increasing fibrous-cap thickness. However, direct evidence linking the use of statins to the incidence of plaque rupture in humans is lacking. We investigated whether statin treatment before the onset of ST-elevation myocardial infarction (STEMI) influences the incidence of plaque rupture detected by intravascular ultrasound (IVUS). METHODS: The study enrolled 458 patients with STEMI who were admitted within 6h from symptom onset. IVUS interrogation was performed before percutaneous coronary intervention. RESULTS: Plaque ruptures were detected in 262 patients (57%). Patients with statin pretreatment (n=68) had a lower incidence of plaque rupture than those without (37% vs. 61%, p<0.001). Univariate analysis revealed that smoking (p=0.003), lower high-density lipoprotein cholesterol (p=0.001), and a lack of statin pretreatment (p<0.001) were associated with a higher incidence of plaque rupture. Multivariate logistic regression analysis identified statin pretreatment as a negative determinant of plaque rupture independent of age, gender, coronary risk factors, and all other medications (odds ratio 0.35; 95% CI 0.19-0.66, p=0.001). Positive remodeling was also associated with plaque rupture (p<0.001), and the relationship between statin pretreatment and a lower incidence of plaque rupture persisted after adjustment for positive remodeling (odds ratio 0.42; 95% CI 0.22-0.80, p=0.009). CONCLUSIONS: Statin treatment before the onset of STEMI is associated with a lower incidence of plaque rupture, suggesting that the prevention of plaque rupture may be a crucial mechanism underlying clinical benefits associated with statins.