Clinical outcomes in 2481 unselected real-world patients treated with a polymer-free sirolimus-eluting stent: 3 years results from the NANO multicenter Registry

Objectives To evaluate the 3-year clinical outcomes of a polymer-free sirolimus-eluting, Nano plus stent for the treatment of coronary artery disease in the NANO multicenter Registry. Background The long-term clinical data evaluating the safety and efficacy of the novel polymer-free sirolimus-eluting Nano plus stent (Lepu Medical, Beijing, China) is limited. Methods The NANO all-comers Registry trial was a prospective, multicenter clinical registry conducted in 26 centers in China between August 2016 and January 2017. A total of 2481 consecutive patients were exclusively treated with the Nano plus stent. The primary clinical endpoint, target lesion failure (TLF, defined as cardiac death, target vessel nonfatal myocardial infarction, and clinically driven target lesion revascularization [CD-TLR]), was analyzed at 3 years. Results At 3 years, 2295 patients (92.5%) were followed. The incidence of TLF was 6.8% (168/2481). The rate of cardiac death was 3.8% (94/2481), target vessel nonfatal myocardial infarction 0.7% (18/2481), and CD-TLR 2.9% (68/2481). The rate of definite/probable stent thrombosis was 0.5% (13/2481). The risk factors of diabetes mellitus, acute myocardial infarction, age, chronic renal failure, in-stent restenosis, chronic total occlusion, and left ventricular ejection fraction < 40% were the independent predictors of 3-year TLF. Conclusions At three years, the rate of TLF was relatively low in patients treated with the polymer-free Nano plus stent. The polymer-free Nano plus stent showed a favorable safety and efficacy profile in real-world patients. Clinical trial registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02929030.

Benefits of Icosapent Ethyl Across the Range of Kidney Function in Patients with Established Cardiovascular Disease or Diabetes: REDUCE-IT RENAL

Background: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. Methods: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) was a multicenter, double-blind, placebo-controlled trial that randomized statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and one additional risk factor to treatment with icosapent ethyl (4 grams daily) or placebo. Patients from REDUCE-IT were categorized by prespecified eGFR categories to analyze the effect of icosapent ethyl on the primary endpoint (composite of cardiovascular [CV] death, nonfatal myocardial infarction nonfatal stroke, coronary revascularization, or unstable angina) and key secondary endpoint (a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke). Results: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL/min/1.73m 2 (range: 17 to 123 mL/min/1.73m 2 ). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and secondary composite endpoints across baseline eGFR categories. Patients with eGFR<60 mL/min/1.73m 2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite endpoint (icosapent ethyl versus placebo, 21.8% versus 28.9%, hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.59-0.85, P=0.0002) and key secondary composite endpoints (16.8% versus 22.5%, HR 0.71, 95% CI 0.57-0.88, p=0.001). The numerical reduction in CV death was greatest in the eGFR <60 mL/min/1.73m 2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR 0.70, 95% CI 0.51-0.95, P=0.02). While patients with eGFR <60 mL/min/1.73m 2 treated with icosapent ethyl had the highest numerical rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42, 95% CI 0.86-2.32, P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR 1.40, 95% CI 0.90-2.18, P=0.13), hazard ratios for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter = 0.92; P-interaction for serious bleeding = 0.76). Conclusions: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01492361

Effect of endothelial nitric oxide synthase gene polymorphism on cardiovascular death and nonfatal myocardial infarction in Japanese general population

Introduction Single nucleotide polymorphisms (SNP) of endothelial nitric oxide synthase (NOS3) have been reported to be associated with diabetes mellitus and myocardial infarction. However, few reports have prospectively investigated the effects of NOS3 SNP on cardiovascular death and nonfatal myocardial infarction. Purpose The purpose of this study was to investigate the impact of NOS3 SNP on cardiovascular death and the development of nonfatal myocardial infarction. Methods This prospective cohort study included 2,752 subjects (aged ≥40) who participated in a community based health checkup. We genotyped two SNPs within NOS3 (rs1808593, rs1799983). All subjects were prospectively followed during the median follow-up period of 15.4 years with the end point of cardiovascular death and nonfatal myocardial infarction. Results The homozygous G-allele (GG), heterozygous (GT), and homozygous T-allele (TT) carriers of rs1808593 were identified in 60 (2%), 706 (26%), and 1,986 (72%) subjects, respectively. Kaplan-Meier analysis demonstrated that homozygous G-allele carriers of rs1808593 had the greater risk than those without. Multivariate Cox proportional hazard regression analysis revealed that the homozygous G allele of rs1808593 was associated with cardiovascular death and the development of nonfatal myocardial infarction after adjusting for confounding risk factors. Conclusions NOS3 gene polymorphism could be a genetic risk factor for cardiovascular death and nonfatal myocardial infarction in the Japanese general population. FUNDunding Acknowledgement Type of funding sources: None. Figure 1

Associations of Serum Nonesterified Fatty Acids With Coronary Heart Disease Mortality and Nonfatal Myocardial Infarction: The CHS (Cardiovascular Health Study) Cohort

Background Significant associations have been reported between serum total nonesterified fatty acid (NEFA) concentrations and coronary heart disease (CHD) mortality and incident nonfatal myocardial infarction (MI) in some prospective cohort studies. Little is known about whether individual or subclasses (saturated, polyunsaturated [n‐6 and n‐3], and trans fatty acids) of serum NEFAs relate to CHD mortality and nonfatal MI. Methods and Results CHS (Cardiovascular Health Study) participants (N=1681) who had no history of MI, angina, or revascularization or were free of MI at baseline (1996–1997) were included. NEFAs were quantified using gas chromatography. Cox regression analysis was used to evaluate associations of 5 subclasses and individual NEFAs with CHD composite (CHD mortality and nonfatal MI), CHD mortality, and incident nonfatal MI. During a median follow‐up of 11.7 years, 266 cases of CHD death and 271 cases of nonfatal MI occurred. In the fully adjusted model, no significant associations were identified between individual NEFA and CHD composite. Exploratory analyses indicated that lauric acid (12:0) was negatively associated (hazard ratio [HR], 0.76; 95% CI, 0.59–0.98; P =0.0328) and dihomo‐γ‐linolenic acid (20:3n‐6) was positively associated with CHD mortality (HR, 1.34; 95% CI, 1.02–1.76; P =0.0351). Elaidic acid (18:1n‐7 t ) was positively associated with incident nonfatal MI (HR, 1.46; 95% CI, 1.01–2.12; P =0.0445). No significant associations were observed for NEFA subclass and any outcomes. Conclusions In CHS participants, 2 NEFAs, dihomo‐γ‐linolenic and elaidic acids, were positively associated with CHD mortality and nonfatal MI, respectively, suggesting potential susceptibility biomarkers for risks of CHD mortality and nonfatal MI.

Patients With LDLR and PCSK9 Gene Variants Experienced Higher Incidence of Cardiovascular Outcomes in Heterozygous Familial Hypercholesterolemia

Background Patients with familial hypercholesterolemia who harbored both low‐density lipoprotein receptor ( LDLR ) and PCSK9 (proprotein convertase subtilisin/kexin type 9) gene variants exhibit severe phenotype associated with substantially high levels of low‐density lipoprotein cholesterol. In this study, we investigated the cardiovascular outcomes in patients with both LDLR and PCSK9 gene variants. Methods and Results A total of 232 unrelated patients with LDLR and/or PCSK9 gene variants were stratified as follows: patients with LDLR and PCSK9 ( LDLR/PCSK9 ) gene variants, patients with LDLR gene variant, and patients with PCSK9 gene variant. Clinical demographics and the occurrence of primary outcome (nonfatal myocardial infarction) were compared. The observation period of primary outcome started at the time of birth and ended at the time of the first cardiac event or the last visit. Patients with LDLR/PCSK9 gene variants were identified in 6% of study patients. They had higher levels of low‐density lipoprotein cholesterol ( P =0.04) than those with LDLR gene variants. On multivariate Cox regression model, they experienced a higher incidence of nonfatal myocardial infarction (hazard ratio, 4.62; 95% CI, 1.66–11.0; P =0.003 versus patients with LDLR gene variant). Of note, risk for nonfatal myocardial infarction was greatest in male patients with LDLR/PCSK9 gene variants compared with those with LDLR gene variant (86% versus 24%; P <0.001). Conclusions Patients with LDLR/PCSK9 gene variants were high‐risk genotype associated with atherogenic lipid profiles and worse cardiovascular outcomes. These findings underscore the importance of genetic testing to identify patients with LDLR/PCSK9 gene variants, who require more stringent antiatherosclerotic management.

Clinical Outcomes in 2481 Unselected Real-World Patients Treated With a Polymer-Free Sirolimus-Eluting Stent: 3 Years Results From the NANO Multicenter Registry

The long-term clinical data evaluating the safety and efficacy of the novel polymer-free sirolimus-eluting Nano plus stent (Lepu Medical, Beijing, China) is limited. We evaluated the 3-year clinical outcomes of a polymer-free sirolimus-eluting, Nano plus stent for the treatment of coronary artery disease in the NANO multicenter Registry. The NANO all-comers Registry trial was a prospective, multicenter clinical registry conducted in 26 centers between August 2016 and January 2017. A total of 2481 consecutive patients were exclusively treated with the Nano plus stent. The main clinical endpoint, target lesion failure (TLF, defined as cardiac death, target vessel nonfatal myocardial infarction, and clinically driven target lesion revascularization [CD-TLR]), was analyzed at 3 years. The incidence of TLF was 6.8% (168/2481). The rates of its individual components were as follows: cardiac death 3.8% (94/2481), target vessel nonfatal myocardial infarction 0.7% (18/2481), and CD-TLR 2.9% (68/2481). The rate of definite/probable stent thrombosis was 0.5% (13/2481). Diabetes mellitus, acute myocardial infarction, age, chronic renal failure, in-stent restenosis, chronic total occlusion and left ventricular ejection fraction <40% were the independent predictors of 3-year TLF. The TLF was relatively low in patients treated with polymer-free Nano plus stent at 3 years. The polymer-free Nano plus stent showed a favorable safety and efficacy profile in the real-world patients.Clinical trial registrationURL: https://www.clinicaltrials.gov/. Unique identifier: NCT02929030.

Efficacy of betablockers in patients with acute coronary syndrome: a systematic review and meta analysis of randomized trials

Background Since the inception of clinical guidelines on the management of patients with acute coronary syndrome (ACS), betablocker therapy has been included as a class I recommendation. However, most studies evaluating betablockers in ACS were conducted in the pre-reperfusion era. Currently, the great majority of patients undergo reperfusion and secondary prevention therapy has evolved; the impact of treatment with a betablocker in these patients may be different. Purpose We conducted a systematic review and meta-analysis to evaluate the impact of betablockers on mortality in patients after an ACS in the reperfusion era. Methods We searched MEDLINE, EMBASE, and Cochrane Central Registry of Controlled Trials for RCTs from inception to September 2019. We included randomized controlled trials comparing betablockers to no betablockers in adult patients presenting with an ACS. Independently and in duplicate, we screened titles and abstracts, reviewed the full-text report of potentially eligible studies and extracted data. Two reviewers also evaluated the risk of bias in duplicate. Disagreements were addressed by consensus. We considered trials to be conducted in the reperfusion era if reperfusion was attempted in more than 50% of patients, either with thrombolytics or primary angioplasty. Our primary outcome of interest was all-cause mortality. Secondary outcomes included hospitalization for heart failure, nonfatal myocardial infarction, stroke and cardiogenic shock. We pooled trial outcomes using a fixed effects model. The study protocol is registered with PROSPERO (CRD42019143158). Results After the initial screening of 10,969 references and full-text review of 176 articles, nine RCTs comprising a total of 49,639 patients with ACS were eligible for the final analysis. Predominantly, these patients presented with ST elevation myocardial infarction. Treatment with a betablocker did not improve all-cause mortality at 30 days (risk ratio (RR) 0.98 [95% CI 0.92–1.04], I2=44%), or at longest follow up (up to three years) with RR 0.97 ([95% CI 0.91–1.03], I2=0%). Betablocker therapy was associated with an increased risk of HF hospitalization (RR 1.10 [95% CI 1.05–1.15], I2=52%) and cardiogenic shock during index hospitalization (RR 1.29, [95% CI 1.18–1.40], I2=0%). However, betablocker therapy reduced the risk of nonfatal myocardial infarction (RR 0.72 [95% CI 0.63–0.83], I2=0%); it did not impact the risk of stroke (RR 1.13 [95% CI 0.95–1.35], I2=0%). Conclusion In the reperfusion era, betablocker therapy after an ACS does not appear to improve short or long-term survival. Although betablocker therapy was associated with a reduction in nonfatal myocardial infarction, it increased the risk of heart failure hospitalization and cardiogenic shock. In light of these findings, clinical guidelines should reconsider the strength of their recommendation for betablocker use in the ACS population until further contemporary evidence is available. Funding Acknowledgement Type of funding source: None

Cardiovascular and safety events of PCSK9 inhibitors in statin-treated patients with cardiovascular risk: A Systematic Review and Meta-Analysis

Objectives: To evaluate whether proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) is associated with cardiovascular and safety events in statin-treated patients with cardiovascular risk. Methods: Electronic databases (Pubmed, Cochrane, MEDLINE, EMBASE, ClinicalTrials.gov) were searched through March 31, 2020. Included randomized clinical trials (RCTs) compared PCSK9i use with no PCSK9i in statin treated patients. Two investigators abstracted data and appraised risks of bias. A meta-analysis was performed to calculate risk ratios (RRs) and 95% CIs using fix-effects models. Adjudicated cardiovascular events (CVE) and adverse drug events (ADE) were defined as the primary outcome. Secondary outcomes were cardiovascular (CV) death, all-cause death, nonfatal myocardial infarction, ischemic stroke, serious ADE and injection-site reaction. Results: A total of 10 RCTs 50 053 participants were included. PCSK9i use was associated with signigicant reductions in the CVE (RR, 0.87 [95%CI, 0.83-0.91]; NNT, 54; P<0.00001; I2=0%, heterogeneity P=0.86), nonfatal myocardial infarction (RR, 0.86 [95% CI, 0.78-0.96]; NNT, 95; P=0.005; I2=0%, heterogeneity P=0.88), and ischemic stroke (RR, 0.75 [95%CI 0.64-0.87]; NNT, 244; P=0.00; I2=0%, heterogeneity P=0.82) compared with no PCSK9i in statin-treated patients with CV risk. No significant associations were found between PCSK9i use and no PCSK9i in ADE and serious ADE. PCSK9i use was associated with signigicant increasing in injection-site reaction (RR, 1.55 [95%CI 1.38-1.75]; NNT, 101; P<0.00001; I2=0%, heterogeneity P=0.44). Conclusions: Among statin-treated patients with CV risk, the use of PCSK9i was associated with improving CV outcomes. The use of PCSK9i was well tolerated, but had significantly injection-site reactions.

One-year Results of a Factorial Randomized Trial of Aspirin versus Placebo and Clonidine versus Placebo in Patients Having Noncardiac Surgery

Background The authors previously reported that perioperative aspirin and/or clonidine does not prevent a composite of death or myocardial infarction 30 days after noncardiac surgery. Moreover, aspirin increased the risk of major bleeding and clonidine caused hypotension and bradycardia. Whether these complications produce harm at 1 yr remains unknown. Methods The authors randomized 10,010 patients with or at risk of atherosclerosis and scheduled for noncardiac surgery in a 1:1:1:1 ratio to clonidine/aspirin, clonidine/aspirin placebo, clonidine placebo/aspirin, or clonidine placebo/aspirin placebo. Patients started taking aspirin or placebo just before surgery; those not previously taking aspirin continued daily for 30 days, and those taking aspirin previously continued for 7 days. Patients were also randomly assigned to receive clonidine or placebo just before surgery, with the study drug continued for 72 h. Results Neither aspirin nor clonidine had a significant effect on the primary 1-yr outcome, a composite of death or nonfatal myocardial infarction, with a 1-yr hazard ratio for aspirin of 1.00 (95% CI, 0.89 to 1.12; P = 0.948; 586 patients [11.8%] vs. 589 patients [11.8%]) and a hazard ratio for clonidine of 1.07 (95% CI, 0.96 to 1.20; P = 0.218; 608 patients [12.1%] vs. 567 patients [11.3%]), with effect on death or nonfatal infarction. Reduction in death and nonfatal myocardial infarction from aspirin in patients who previously had percutaneous coronary intervention at 30 days persisted at 1 yr. Specifically, the hazard ratio was 0.58 (95% CI, 0.35 to 0.95) in those with previous percutaneous coronary intervention and 1.03 (95% CI, 0.91to 1.16) in those without (interaction P = 0.033). There was no significant effect of either drug on death, cardiovascular complications, cancer, or chronic incisional pain at 1 yr (all P &gt; 0.1). Conclusions Neither perioperative aspirin nor clonidine have significant long-term effects after noncardiac surgery. Perioperative aspirin in patients with previous percutaneous coronary intervention showed persistent benefit at 1 yr, a plausible sub-group effect. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Primary Prevention of Cardiovascular Events with Aspirin: Toward More Harm than Benefit—A Systematic Review and Meta-Analysis

Primary prevention of cardiovascular events with aspirin remains controversial, as the risk of bleeding might outweigh the benefits. Recently, new evidence has emerged from the ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events), ASCEND (A Study of Cardiovascular Events in Diabetes), and ASPREE (Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly) trials. The aim of this study was to perform a systematic review and meta-analysis of aspirin's efficacy and safety in the primary prevention of cardiovascular events in healthy individuals and in individuals with cardiovascular risk factors, and separately in those with diabetes. The Medline database was searched, without time restrictions, for relevant human trials published in English up to December 10, 2018, and additional trials were identified from reference lists. Data on efficacy (cardiovascular death and nonfatal myocardial infarction) and safety (major bleeding) were extracted for analysis. In total, 20 randomized trials were identified. Separate meta-analyses were performed on 10 trials including 144,930 individuals, who were healthy or had cardiovascular risk factors, and on 4 trials including 20,326 individuals with diabetes. In healthy individuals and individuals with cardiovascular risk factors, aspirin reduced the risk of nonfatal myocardial infarction by 21% (p < 0.001), but had no effect on cardiovascular death (p = 0.52), and increased the risk of major bleeding by 48% (p < 0.001). In individuals with diabetes, aspirin had no effect on nonfatal myocardial infarction (p = 0.93) or cardiovascular death (p = 0.92) and increased the risk of bleeding by 49% (p = 0.13). This meta-analysis suggests that aspirin should not be used on a routine basis in the primary prevention of cardiovascular events, especially in individuals with diabetes.