Extremely Low Activity of Serum Alanine Aminotransferase Is Associated with Long-Term Overall-Cause Mortality in the Elderly Patients Undergoing Percutaneous Coronary Intervention after Acute Coronary Syndrome.

Background and Objectives: Recent studies revealed that the extremely low activity of serum alanine aminotransferase (ALT) is associated with frailty and contributes to increased mortality after acute physical stress. We aimed to investigate whether the extremely low activity of serum ALT (<10 U/L) at the time of diagnosis can be used to predict overall-cause mortality in elderly patients that underwent percutaneous coronary intervention (PCI) after acute coronary syndrome (ACS) diagnosis. Materials and Methods: A retrospective medical record review was performed on 1597 patients diagnosed with ACS who underwent PCI at a single university hospital from February 2014 to March 2020. The associations between the extremely low activity of serum ALT and mortality were assessed using a stepwise Cox regression (forward: conditional). Results: A total of 210 elderly patients were analyzed in this study. The number of deaths was 64 (30.5%), the mean survival time was 25.0 ± 18.9 months, and the mean age was 76.9 ± 7.6 years. The mean door-to-PCI time was 74.0 ± 20.9 min. The results of stepwise Cox regression analysis showed that the extremely low activity of serum ALT (adjusted hazard ratio: 5.157, 95% confidence interval: 3.001-8.862, p < 0.001) was the independent risk factor for long-term overall-cause mortality in the elderly who underwent PCI after ACS diagnosis. Conclusions: The extremely low activity of serum ALT at ACS diagnosis is a significant risk factor for increased long-term overall-cause mortality in the elderly who underwent PCI after ACS diagnosis. It is noteworthy that a simple laboratory test at the time of diagnosis was found to be a significant risk factor for mortality.

BioMatrix Versus Orsiro Stents for Coronary Artery Disease: A Multicenter, Randomized, Open-Label Study.

BACKGROUND: Comparative studies of ultrathin-strut biodegradable polymer sirolimus-eluting stent (BP-SES) have reported promising results and validated its excellent outcomes in terms of safety and efficacy. However, there are limited studies comparing BP drug-eluting stents with struts of different thicknesses. We compared the long-term clinical outcomes of patients treated with an ultrathin-strut BP-SES or a thick-strut biodegradable polymer biolimus-eluting stent (BP-BES). METHODS: The BIODEGRADE trial (Biomatrix and Orsiro Drug-Eluting Stents in Angiographic Result in Patients With Coronary Artery Disease) is a multicenter prospective randomized study comparing coronary revascularization in patients with ultrathin-strut BP-SES and thick-strut BP-BES with the primary end point of target lesion failure at 18 months posttreatment. We performed the prespecified analysis of 3-year clinical outcomes. RESULTS: In total, 2341 patients were randomized to receive treatment with ultrathin-strut BP-SES (N=1175) or thick-strut BP-BES (N=1166). The 3-year incidence rate of target lesion failure was 3.2% for BP-SES and 5.1% for BP-BES (P=0.023). The difference was primarily due to differences in ischemia-driven target lesion revascularization (BP-SES, 1.5%; BP-BES, 2.8%; P=0.035) between groups. A landmark analysis of the late follow-up period showed significant differences in target lesion failure, with outcomes being better in BP-SES. Cardiac death and target lesion revascularization were significantly lower in the BP-SES group. CONCLUSIONS: In a large, randomized trial, the long-term clinical outcome of target lesion failure at 3 years was significantly better among patients treated with the ultrathin-strut BP-SES. The results indicate the superiority of the ultrathin-strut BP-SES compared with the thick-strut BP-BES. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02299011.

BioMatrix versus Orsiro biodegradable polymer stents in all-comer patients with coronary artery disease: the multicentre, randomised BIODEGRADE trial.

AIMS: The aim of this trial was to compare the safety and efficacy of a thin-strut biodegradable polymer sirolimus-eluting cobalt-chromium stent (Orsiro) to a thick-strut biodegradable polymer biolimus-eluting stent (BioMatrix). METHODS AND RESULTS: This randomised, open-label, non-inferiority trial was conducted among patients undergoing percutaneous coronary intervention. The primary endpoint was target lesion failure (TLF). Between July 2014 and September 2017, we randomly assigned 2,341 patients to BioMatrix stents (n=1,166) or Orsiro stents (n=1,175). We analysed 2,327 patients who completed 18-month follow-up. The mean patient age was 63.5 years, and 1,565 (67.3%) patients presented with acute coronary syndrome. At 18 months, 34 (2.9%) patients with BioMatrix stents and 24 (2.1%) with Orsiro stents experienced TLF (hazard ratio [HR] 0.70, upper limit of one-sided 95% confidence interval: 1.18, p for non-inferiority <0.0001). No significant differences were noted in rates of cardiac death (16 [1.4%] vs 12 [1.0%], p=0.558), target lesion-related myocardial infarction (0 [0%] vs 3 [0.3%], p=0.250), target lesion revascularisation (18 [1.6%] vs 10 [0.9%], p=0.124), or stent thrombosis (0 [0%] vs 2 [0.2%], p=0.50). CONCLUSIONS: In patients with a high prevalence of acute coronary syndrome, Orsiro stents were not inferior to BioMatrix stents. Both showed good clinical outcomes.

Valsartan 160 mg/Amlodipine 5 mg Combination Therapy versus Amlodipine 10 mg in Hypertensive Patients with Inadequate Response to Amlodipine 5 mg Monotherapy.

BACKGROUND AND OBJECTIVES: When monotherapy is inadequate for blood pressure control, the next step is either to continue monotherapy in increased doses or to add another antihypertensive agent. However, direct comparison of double-dose monotherapy versus combination therapy has rarely been done. The objective of this study is to compare 10 mg of amlodipine with an amlodipine/valsartan 5/160 mg combination in patients whose blood pressure control is inadequate with amlodipine 5 mg. SUBJECTS AND METHODS: This study was conducted as a multicenter, open-label, randomized controlled trial. Men and women aged 20-80 who were diagnosed as having hypertension, who had been on amlodipine 5 mg monotherapy for at least 4 weeks, and whose daytime mean systolic blood pressure (SBP) ≥135 mmHg or diastolic blood pressure (DBP) ≥85 mmHg on 24-hour ambulatory blood pressure monitoring (ABPM) were randomized to amlodipine (A) 10 mg or amlodipine/valsartan (AV) 5/160 mg group. Follow-up 24-hour ABPM was done at 8 weeks after randomization. RESULTS: Baseline clinical characteristics did not differ between the 2 groups. Ambulatory blood pressure reduction was significantly greater in the AV group compared with the A group (daytime mean SBP change: -14±11 vs. -9±9 mmHg, p<0.001, 24-hour mean SBP change: -13±10 vs. -8±8 mmHg, p<0.0001). Drug-related adverse events also did not differ significantly (A:AV, 6.5 vs. 4.5 %, p=0.56). CONCLUSION: Amlodipine/valsartan 5/160 mg combination was more efficacious than amlodipine 10 mg in hypertensive patients in whom monotherapy of amlodipine 5 mg had failed.

Effect of cilostazol addition or clopidogrel doubling on platelet function profiles in diabetic patients undergoing a percutaneous coronary intervention.

BACKGROUND: We investigated the pharmacodynamic effect of cilostazol addition (100 mg twice, Triple) or clopidogrel doubling (150 mg daily, Double) on standard dual antiplatelet therapy in type 2 diabetes mellitus (T2DM) patients with clopidogrel resistance undergoing a percutaneous coronary intervention. METHODS AND RESULTS: This was a prospective, randomized, cross-over platelet function study. Percent inhibition less than 20% was used as the cutoff value of clopidogrel resistance. After percutaneous coronary intervention, a total of 50 T2DM patients with clopidogrel resistance were assigned to receive cilostazol 100 mg twice daily or clopidogrel 150 mg daily for 28 days; afterwards, they received cross-over treatment for another 28 days. Eight patients were excluded because of side effects and follow-up loss. The platelet function test using VerifyNow was performed at three time points: at baseline (T0), 28 days after randomization (T1), and 28 days after cross-over treatment (T2).A total of 42 T2DM patients completed the study protocol. The clopidogrel resistance improved significantly following cilostazol addition or clopidogrel doubling treatment compared with baseline (52.9±27.0 in Triple, 45.4±16.8% in Double, P<0.001 in both). This effect continued after cross-over treatment (58.1±26.1 and 41.0±20.0%, respectively, both P<0.05). A head-to-head comparison between two groups showed a lower P2Y12 reaction unit (PRU) and higher percentage of platelet inhibition in the Triple than those in the Double group (PRU, 138.7±88.2 vs. 198.8±19.5, P=0.049; %platelet inhibition, 58.1±26.1 vs. 40.97±20.0, P=0.048). CONCLUSION: Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy might be a more effective strategy for overcoming clopidogrel resistance than clopidogrel doubling treatment.

Comparison of resolute zotarolimus-eluting stents and sirolimus-eluting stents in patients with de novo long coronary artery lesions: a randomized LONG-DES IV trial.

BACKGROUND: Procedural and clinical outcomes still remain unfavorable for patients with long coronary lesions who undergo stent-based coronary interventions. Therefore, we compared the relative efficacy and safety of resolute zotarolimus-eluting stents (R-ZES) and sirolimus-eluting stents (SES) for patients with de novo long coronary lesions. METHODS AND RESULTS: This randomized, multicenter, prospective trial, called the Percutaneous Treatment of LONG Native Coronary Lesions With Drug-Eluting Stent-IV (LONG-DES IV) trial, compared long R-ZES and SES in 500 patients with long (≥25 mm) native coronary lesions. The primary end point of the trial was in-segment late luminal loss at 9-month angiographic follow-up. The baseline characteristics were not different between R-ZES and SES groups, including lesion lengths (32.4±13.5 mm versus 31.0±13.5 mm, P=0.27). At 9-month angiographic follow-up, the R-ZES was noninferior to the SES with respect to in-segment late luminal loss, the primary study end point (0.14±0.38 mm versus 0.12±0.43 mm, P for noninferiority=0.03, P for superiority=0.68). In addition, in-stent late luminal loss (0.26±0.36 mm versus 0.24±0.42 mm, P=0.78) and the rates of in-segment (5.2% versus 7.2%, P=0.44) and in-stent (4.0% versus 6.0%, P=0.41) binary restenosis were not significantly different between the 2 groups. There were no significant between-group differences in the rate of adverse clinical events (death, myocardial infarction, stent thrombosis, target-lesion revascularization, and composite outcomes). CONCLUSIONS: For patients with de novo long coronary artery disease, R-ZES implantation showed noninferior angiographic outcomes as compared with SES implantation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01186094.

Outcomes after unrestricted use of everolimus-eluting and sirolimus-eluting stents in routine clinical practice: a multicenter, prospective cohort study.

BACKGROUND: It remains unclear whether there are differences in the safety and efficacy outcomes between everolimus-eluting stents (EES) and sirolimus-eluting stents (SES) in contemporary practice. METHODS AND RESULTS: We prospectively enrolled 6166 consecutive patients who received EES (3081 patients) and SES (3085 patients) between April 2008 and June 2010, using data from the Interventional Cardiology Research In-Cooperation Society-Drug-Eluting Stents Registry. The primary end point was a composite of death, nonfatal myocardial infarction (MI), or target-vessel revascularization (TVR). At 2 years of follow-up, the 2 study groups did not differ significantly in crude risk of the primary end point (12.1% for EES versus 12.4% for SES; HR, 0.97; 95% CI, 0.84-1.12, P=0.66). After adjustment for differences in baseline risk factors, the adjusted risk for the primary end point remained similar for the 2 stent types (HR, 0.96; 95% CI, 0.82-1.12, P=0.60). There were also no differences between the stent groups in the adjusted risks of the individual component of death (HR, 0.93; 95% CI, 0.67-1.30, P=0.68), MI (HR, 0.97; 95% CI, 0.79-1.18, P=0.74), and TVR (HR, 1.10; 95% CI, 0.82-1.49, P=0.51). The adjusted risk of stent thrombosis also was similar (HR, 1.16; 95% CI, 0.47-2.84, P=0.75). CONCLUSIONS: In contemporary practice of percutaneous coronary intervention procedures, the unrestricted use of EES and SES showed similar rates of safety and efficacy outcomes with regard to death, MI, sent thrombosis, and TVR. Future longer-term follow-up is needed to better define the relative benefits of these drug-eluting stents. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01070420.

Preventive effects of exenatide on endothelial dysfunction induced by ischemia-reperfusion injury via KATP channels.

OBJECTIVE: The purpose of this study was to evaluate whether exenatide administration can prevent impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) injury and whether this effect is mediated by K(ATP) channel opening. METHODS AND RESULTS: In a double-blind, placebo-controlled, crossover design, 20 volunteers were randomly assigned to 2 groups: subcutaneous exenatide (10 µg) or placebo administration. At 30 minutes after the study drug administration, endothelium-dependent flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion) injury. Seven days later, both groups were crossed over and received the other treatment (ie, placebo or exenatide) and underwent the same protocol. Pre-IR radial artery diameter, FMD, and baseline radial artery diameter after IR injury were similar between 2 groups (P=no significant difference). After placebo administration, IR significantly blunted FMD (before IR: 12.0±6.23%; after IR: 4.6±3.57%, P=0.02). Exenatide prevented this impairment (FMD before IR: 15.0±7.14%; FMD after IR: 15.0±5.96%, P=no significant difference; P<0.001 compared with placebo). In a separate protocol, this protective effect was completely abolished by pretreatment with glibenclamide (glyburide, 5 mg), a blocker of K(ATP) channels (n=7; FMD before IR: 12.0±2.2%; after IR: 3.2±2.1%, P<0.001). CONCLUSIONS: The present study demonstrates that subcutaneous exenatide protects IR-induced endothelial dysfunction through opening of K(ATP) channels in human IR injury model.

Combined Assessments of Biochemical Markers and ST-Segment Resolution Provide Additional Prognostic Information for Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND AND OBJECTIVES: The prognostic value of biochemical markers and the resolution of ST-segment elevation on electrocardiogram are well established. However, how a combination of these two tools affects the evaluation of risk stratification has not yet been evaluated. SUBJECTS AND METHODS: Between January 2006 and June 2008, 178 consecutive patients treated with primary percutaneous coronary interventions after ST-segment elevation myocardial infarctions (STEMI) were analyzed at two coronary care units. Patients were divided into the following three groups according to ST-segment resolution: complete (≥70% depression of the elevated ST-segment, n=63), partial (30% to 70%, n=90), and incomplete (<30%, n=25). Demographic data, including history, electrocardiography, biochemical markers, initial ejection fraction, and angiographic findings were also evaluated. RESULTS: There were 7 deaths, 3 repeated myocardial infarctions, and 17 readmissions for worsening heart failure during six months of follow-up. In a multivariate analysis to predict clinical outcomes, ejection fraction {hazard ratio (HR): 0.83 (0.76-0.91), p<0.01}, high-sensitivity C-reactive protein {HR: 1.15 (1.05-1.26), p<0.05}, and the degree of ST-segment resolution {HR: 0.96 (0.93-0.09), p<0.05} were independently associated with clinical outcomes. According to the Cox-proportional hazards model, the addition of ST-segment resolution markedly improved the prognostic utility of the model containing biochemical markers and ejection fraction. CONCLUSION: Assessment of biomarkers upon admission and ST-segment resolution are strong predictors of clinical outcomes. The combination of these data provides additive information about prognosis at an early point in the disease progression and further improves risk stratification for STEMI.

Quantification of regional calcium burden in chronic total occlusion by 64-slice multi-detector computed tomography and procedural outcomes of percutaneous coronary intervention.

BACKGROUND: One of the most important reasons for failure of percutaneous coronary intervention (PCI) in chronic total occlusion (CTO) is calcified plaque, which either prevents passage of guide wire or ruptures after balloon inflation. We sought to evaluate whether quantified calcium contents of CTO on multi-detector computed tomography (MDCT) correlate with immediate procedural outcomes. METHODS: Sixty-four patients with 72 CTO lesions who underwent 64-slice MDCT prior to PCI were investigated. The lesions were divided into 2 groups according to procedural outcomes (55 lesions with PCI-success group, 17 lesions with PCI-failure group). Clinical, angiographic and MDCT parameters, including regional calcium volume (RCaV), regional calcium score (RCaS), regional calcium equivalent mass (RCaEq), and relative calcium area at the most calcified cross section of CTO (%CaS/CSA), were compared between the two groups. RESULTS: The duration of CTO was shorter in PCI-success group than PCI-failure group (7.16 ± 10.5 vs 15.59 ± 14.92 months, p=0.011), and the procedural success rate was 76.3%. Regional calcium-related parameters (RCaV 52.86 ± 58.39 vs 7.26 ± 15.27 mm(3), p<0.001; RCaS 72.71 ± 78.4 vs 9.66 ± 20.2, p<0.001; RCaEq 12.58 ± 12.97 vs 1.84 ± 3.716 mgCaHA, p<0.001; %CaS/CSA 53.9 ± 20.3 vs 30.4 ± 17.1%, p=0.009) in the occluded segment were higher and the occlusion length was longer (37.44 ± 27.48 vs 22.00 ± 18.04 mm, p<0.021) in PCI-failure group compared to PCI-success group. Multivariate regression analysis showed that only %CaS/CSA was a significant determinant of PCI-failure. CONCLUSIONS: Precise quantification of regional calcification and measurement of the occluded segment by high resolution MDCT can deliver important information for predicting procedural outcomes in PCI of CTO.

Estrogen receptors alpha and beta mediate contribution of bone marrow-derived endothelial progenitor cells to functional recovery after myocardial infarction.

BACKGROUND: Estradiol (E2) modulates the kinetics of circulating endothelial progenitor cells (EPCs) and favorably affects neovascularization after ischemic injury. However, the roles of estrogen receptors alpha (ER alpha) and beta (ER beta) in EPC biology are largely unknown. METHODS AND RESULTS: In response to E2, migration, tube formation, adhesion, and estrogen-responsive element-dependent gene transcription activities were severely impaired in EPCs obtained from ER alpha-knockout mice (ER alphaKO) and moderately impaired in ER betaKO EPCs. The number of ER alphaKO EPCs (42.4+/-1.5; P<0.001) and ER betaKO EPCs (55.4+/-1.8; P=0.03) incorporated into the ischemic border zone was reduced as compared with wild-type (WT) EPCs (72.5+/-1.3). In bone marrow transplantation (BMT) models, the number of mobilized endogenous EPCs in E2-treated mice was significantly reduced in ER alphaKO BMT (WT mice transplanted with ER alphaKO bone marrow) (2.03+/-0.18%; P=0.004 versus WT BMT) and ER betaKO BMT (2.62+/-0.07%; P=0.02 versus WT) compared with WT BMT (2.87+/-0.13%) (WT to WT BMT as control) mice. Capillary density at the border zone of ischemic myocardium also was significantly reduced in ER alphaKO BMT and ER betaKO BMT compared with WT mice (WT BMT, 1718+/-75/mm2; ER alphaKO BMT, 1107+/-48/mm2; ER betaKO BMT, 1567+/-50/mm2). ER alpha mRNA was expressed more abundantly on EPCs compared with ER beta. Moreover, vascular endothelial growth factor was significantly downregulated on ER alphaKO EPCs compared with WT EPCs both in vitro and in vivo. CONCLUSIONS: Both ER alpha and ER beta contribute to E2-mediated EPC activation and tissue incorporation and to preservation of cardiac function after myocardial infarction. ER alpha plays a more prominent role in this process. Moreover, ER alpha contributes to upregulation of vascular endothelial growth factor, revealing possible mechanisms of an effect of E2 on EPC biology. Finally, these data provide additional evidence of the importance of bone marrow-derived EPC phenotype in ischemic tissue repair.