Interleukin-1 blockade with anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials.

AIMS: ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study, we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF. METHODS AND RESULTS: We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1-year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analysed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs. 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs. 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs. 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs. 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-reactive protein between baseline and 14 days (75.48 [41.7-147.47] vs. 222.82 [117.22-399.28] mg day/L, P < 0.001). CONCLUSION: IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new-onset HF or hospitalization for HF at 1 year following STEMI.

Interleukin-1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST-Segment-Elevation Myocardial Infarction.

Background ST-segment-elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin-1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C-reactive protein) levels during the first 14 days in patients with ST-segment-elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo-controlled, double-blind, clinical trial in 99 patients with ST-segment-elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39-120] versus 214 [interquartile range, 131-394] mg·day/L; P<0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end-systolic volume (median, 1.4 [interquartile range, -9.8 to 9.8] versus -3.9 [interquartile range, -15.4 to 1.4] mL; P=0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, -1.6% to 10.2%] versus 2.7% [interquartile range, -1.8% to 9.3%]; P=0.61) at 12 months. The incidence of death or new-onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [P=0.046] and 0% versus 11.4% [P=0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P=0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P=0.016). Conclusions In patients presenting with ST-segment-elevation myocardial infarction, interleukin-1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01950299.

Efficacy and Safety of Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Stents Versus Thin, Durable-Polymer Everolimus-Eluting Stents for Coronary Revascularization of Patients With Diabetes Mellitus.

Patients with diabetes mellitus are prone to increased adverse outcomes after percutaneous coronary intervention, even with contemporary drug-eluting stents. Randomized controlled trials have demonstrated comparable clinical outcomes between an ultrathin bioresorbable-polymer sirolimus-eluting stent (BP-SES) and a thin-strut durable-polymer everolimus-eluting stent (DP-EES) that has specific labeling for patients with diabetes. We aimed to evaluate the safety and efficacy of the BP-SES in patients with diabetes mellitus. To determine the performance of the BP-SES in diabetic patients, patient-level data from the BIOFLOW II, IV, and V randomized controlled trials were pooled. The primary end point was target lesion failure (TLF), defined as the composite of cardiovascular death, target-vessel myocardial infarction, ischemia-driven target lesion revascularization, and definite or probable stent thrombosis, at 1 year. Among 1,553 BP-SES and 791 DP-EES patients, 757 diabetic patients were identified. Of the diabetic patients included in this analysis (494 BP-SES vs 263 DP-EES), the proportion of insulin- and noninsulin-treated patients was similar between groups. The 1-year TLF rate in the diabetic population was 6.3% in the BP-SES group and 8.7% in the DP-EES group (hazard ratio 0.82, 95% confidence interval 0.047 to 1.43, p = 0.493). There were no significant differences, based on stent type or diabetes treatment regimen, in TLF hazards. In a patient-level pooled analysis of the diabetic population from randomized trials, 1-year clinical safety and efficacy outcomes were similar in patients treated with ultrathin BP-SES and thin-strut DP-EES.

Acute thrombogenicity of fluoropolymer-coated versus biodegradable and polymer-free stents.

AIMS: Durable fluoropolymer-coated everolimus-eluting stents (FP-EES) have shown lower rates of stent thrombosis (ST) versus bare metal stents (BMS) and first-generation bioabsorbable polymer (BP) DES. The aim of the study was to evaluate the specific role of the FP in thromboresistance. METHODS AND RESULTS: A total of 57 stents were assessed in three separate ex vivo swine arteriovenous shunt model experiments (first shunt experiment, custom-made fluoropolymer-coated BMS [FP-only] vs. BMS [n=8 each]; second shunt experiment, FP-EES vs. abluminally coated biodegradable polymer sirolimus-eluting stents [BP-SES] vs. BMS [n=8 each]; and third shunt experiment, FP-EES vs. polymer-free Biolimus A9-coated stents [PF-BCS] vs. BMS [n=6 each]). After one hour of circulation, stents were bisected, and each half was dual-immunostained using a platelet cocktail and a marker for inflammation. Antibody staining was visualised by confocal microscopy. In addition, stents were evaluated by scanning electron microscopy. FP-only stents showed significantly lower platelet adherence compared with BMS (% fluorescence-positive area: FP-only=1.8%, BMS=5.6%, p=0.047) with similar inflammatory cell density. FP-EES also demonstrated the lowest platelet adherence compared with BP-SES (p=0.056), PF-BCS (p=0.013) and BMS (p=0.003) with the significantly lowest inflammatory cell density. CONCLUSIONS: Fluoropolymer coating imparts greater thromboresistance relative to BMS and to polymer-free DES designs, which reflects an unique phenomenon known as fluoropassivation, representing one proposed mechanism for clinically observed low ST rates in FP-EES.

Comparison of acute thrombogenicity for magnesium versus stainless steel stents in a porcine arteriovenous shunt model.

AIMS: The present study aimed to investigate whether the Magmaris resorbable magnesium scaffold (RMS) has platelet-repelling properties by comparing its acute thrombogenicity with an equivalent stainless steel stent in an arteriovenous shunt model. METHODS AND RESULTS: An ex vivo porcine carotid jugular arteriovenous shunt was established and connected to Sylgard tubing containing the Magmaris RMS with sirolimus-eluting PLLA coating and an equivalent 316L stainless steel stent with sirolimus-eluting PLLA coating. Six shunts (two shunt runs per pig) were run comparing the two scaffolds (n=9) in alternating order. Nested generalised linear mixed models were employed to compare variables between scaffold groups. Confocal fluorescent microscopy containing CD61/CD42b demonstrated that the 316L equivalent stent had significantly greater platelet coverage of the total scaffold compared with Magmaris (5.8% vs. 2.8%, adjusted rate ratio 2.21 [1.41, 3.47], p=0.012). Scanning electron microscopy demonstrated significantly greater thrombus deposition on the 316L equivalent stent as a percentage of the total scaffold compared with Magmaris (8.0% vs. 5.3%, p=0.009). Magmaris also had significantly less CD14 positive monocyte deposition and a trend towards less PM-1 positive neutrophil compared with the 316L equivalent stent. CONCLUSIONS: Magmaris has less thrombogenicity and inflammatory cell deposition compared with the equivalent 316L stainless steel (in geometry and design) stent in a porcine arteriovenous shunt model. These data suggest that resorbable magnesium scaffolds may have inherent properties that reduce adhesion of platelets and inflammatory cells.

Meta-Analysis of the Impact of Strut Thickness on Outcomes in Patients With Drug-Eluting Stents in a Coronary Artery.

The aim of this network meta-analysis is to assess the impact of strut thickness on clinical outcomes in patients who underwent percutaneous coronary intervention. We searched Medline/PubMed and performed a Bayesian network meta-analysis to compare outcomes of patients who underwent percutaneous coronary intervention with drug-eluting stents (DES) of different strut thicknesses (ultrathin 60 to 80 µm; thin 81 to 100 µm; intermediate 101 to 120 µm; thick ≥120 µm). Studies comparing DES with similar strut thickness, bare metal stents, and fully bioresorbable scaffolds were excluded. Odds ratios with credible intervals (OR [CrIs]) were generated with random-effects models to compare outcomes. Our primary end point was stent thrombosis (ST). We identified 69 RCTs including 80,885 patients (ultrathin group = 10,219; thin group = 36,575; intermediate group = 11,399; thick group = 22,692). Mean age was 64 ± 11 years and 75% were male gender. When compared with thick-strut DES, ultrathin struts had significant less ST and myocardial infarction (OR 0.43 [CrI 0.27 to 0.68]; and OR 0.73 [CrI 0.62 to 0.92], respectively). Sensitivity analysis including only studies with permanent polymer DES gave similar results. Improvement in DES technology with thinner struts is associated with significant reduction in ST and myocardial infarction compared with thicker struts.

Rationale and design of the Virginia Commonwealth University-Anakinra Remodeling Trial-3 (VCU-ART3): A randomized, placebo-controlled, double-blinded, multicenter study.

There is clear association between the intensity of the acute inflammatory response during acute myocardial infarction (AMI) and adverse prognosis after AMI. Interleukin-1 (IL-1) is a pro-inflammatory cytokine released during AMI and involved in adverse remodeling and heart failure (HF). We describe a study to evaluate the safety and efficacy of IL-1 blockade using an IL-1 receptor antagonist (anakinra) during the acute phase of ST-segment elevation myocardial infarction (STEMI). The Virginia Commonwealth University-Anakinra Remodeling Trial-3 (VCU-ART3; http://www.ClinicalTrials.gov NCT01950299) is a phase 2, multicenter, double-blinded, randomized, placebo-controlled clinical trial comparing anakinra 100 mg once or twice daily vs matching placebo (1:1:1) for 14 days in 99 patients with STEMI. Patients who present to the hospital with STEMI within 12 hours of symptom onset will be eligible for enrollment. Patients will be excluded for a history of HF (functional class III-IV), severe valvular disease, severe kidney disease (stage 4-5), active infection, recent use of immunosuppressive drugs, active malignancy, or chronic autoimmune/auto-inflammatory diseases. We will measure the difference in the area under the curve for C-reactive protein between admission and day 14, separately comparing each of the anakinra groups with the placebo group. The P value will be considered significant if <0.025 to adjust for multiple comparisons. Patients will also be followed for up to 12 months from enrollment to evaluate cardiac remodeling (echocardiography), cardiac function (echocardiography), and major adverse cardiovascular outcomes (cardiovascular death, MI, revascularization, and new onset of HF).

Biologics and Cardiovascular Disease.

The advent of biologic therapy has enhanced our ability to augment disease in an increasingly targeted manner. The use of biologics in cardiovascular disease (CVD) has steadily increased over the past several decades. Much of the early data on biologics and CVD were derived from their use in rheumatologic populations. Atherosclerosis, myocardial infarction, and heart failure have been closely linked to the inflammatory response. Accordingly, cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 have been targeted. Noninflammatory mediators, such as proprotein convertase subtilisin kexin type 9 (PCSK9), have been selected for therapeutic intervention as well. Furthermore, RNA interference (RNAi) therapy has emerged and may serve as another targeted therapeutic mechanism. Herein, we will review the history, obstacles, and advances in using biologic therapy for CVD.

Inflammation and atherosclerosis: Cardiovascular evaluation in patients with autoimmune diseases.

Evidence now indicates that inflammation contributes considerably to the initiation and progression of atherosclerosis and active inflammatory processes may trigger plaque rupture and enhance the risk of coronary thrombosis leading to a clinical ischemic event. Interest in characterizing inflammatory markers that predict clinical events have dominated clinical investigation. Such markers include C-reactive protein, Fibrinogen and a number of interleukins. Human macrophages avidly phagocytize cholesterol crystals. These cholesterol crystals induce a dose-dependent secretion of mature Interleukin 1-beta (IL-1ß) from human monocytes and macrophages (an NLRP3 inflammasome-mediated pathway). Since IL-1ß production leads to increased levels of IL-6 and C-reactive protein, this could be a mechanistic link between early deposition of cholesterol crystals within the vessel wall to the macrophage-monocyte interactions that initiate fatty streaks and promote local atherosclerotic progression. We have entered a time where a pure anti-inflammatory drug without significant effects on lipids or any other traditional cardiovascular risk factor decreased cardiovascular events. Patients with autoimmune diseases are at increase cardiovascular risk. In this review we describe the link between inflammation and atherosclerosis. Furthermore we explore the data regarding primary prevention, cardiac imaging for risk stratification and the implications of targeting inflammation in patients with autoimmune disease.

Utility of Invasive Electrophysiology Studies in Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation.

Permanent pacemaker (PPM) implantation remains common after transcatheter aortic valve implantation (TAVI). Invasive electrophysiology studies (EPSs) may reduce PPM implantation rates by identifying patients who do not require long-term pacing. At our institution, a new strategy in which patients with equivocal indications for pacing underwent EPSs to determine the need for PPM implantation was adopted. We compared baseline demographics, TAVI procedural details, and outcomes in patients without any conduction disturbance after TAVI, patients with new PPM implantation, and patients with EPS ± new PPM implantation. After exclusion for preexisting PPMs, of a total of 614 consecutive TAVI patients, 117 (19.1%) required new PPM implantation for unequivocal pacing indications, and 95 (15.5%) underwent EPSs. Of those patients who underwent EPSs, 28 (29.5%) required PPM implantation and 67 (70.5%) did not. The overall rate of new PPM implantation was higher for self-expanding versus balloon-expandable valves (34.0% vs 19.9%, p = 0.0011). PPM implantation increased intensive care and hospital length of stay compared with patients without any conduction disturbance (10.7 ± 8.3 vs 8.5 ± 6.4 days, p = 0.003). A negative EPS did not prolong length of stay. There were no significant differences in 30-day and 1-year mortality between groups. In conclusion, among TAVI patients with new-onset conduction disturbance, EPS is a safe strategy to identify those who require PPM implantation and those in whom PPMs can be avoided.

CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis.

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non-foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1α and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1α via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1α/VEGF-A pathway.

Comparison of treatment strategies for femoro-popliteal disease: A network meta-analysis.

OBJECTIVES: We sought to compare treatment strategies in a Bayesian network meta-analysis of randomized controlled trials. BACKGROUND: Peripheral artery disease (PAD) is a prevalent morbidity that is treated with various strategies. METHODS: We performed a MEDLINE search for randomized studies comparing at least 2 treatment strategies, including bypass surgery, percutaneous transluminal angioplasty (PTA) balloons, stents, covered stents, drug-eluting stents (DES), and drug-coated balloons (DCB), in patients with native femoro-popliteal disease. Mixed treatment comparison model generation was performed to directly and indirectly compare the strategies in terms of restenosis and target lesion revascularization (TLR) presented as odds ratios (OR, [95% credible intervals]). RESULTS: Twenty-nine studies with 4,820 patients were included in the present study. PTA was the largest group with 1,900 patients, followed by DCB (n = 1,343), bare metal stents (n = 941), covered stents (n = 304), DES (n = 236), and bypass (n = 92). Mean age was 68 ± 9 years, 64% were male, 37% diabetic, and 55% smokers. Mean lesion length was 77 ± 44 mm, and 39% were total occlusions. Bayesian hierarchical random-effects model demonstrated all treatments were significantly better than, or had a trend toward superiority over, PTA, with DCB ranking well in both restenosis (OR = 0.29, [0.17-0.47]) and TLR (OR = 0.31, [0.20-0.46]). Nonetheless, none of the therapies showed superiority in terms of survival or amputations. CONCLUSION: Treatment of femoro-popliteal disease has significantly evolved in recent years, with higher rates of patency and freedom from TLR. However, the utility of these treatment strategies in terms of reduction of amputations and overall survival remains in question.

Evolving Electrocardiographic Indications for Emergent Reperfusion.

Chest pain or other symptoms concerning for acute coronary syndrome continues to remain a major reason for presentation to the emergency department. However, there is significant heterogeneity in the spectrum of risk severity of these patients. The electrocardiogram (ECG) remains a critically valuable tool in the physician's arsenal to diagnose patients and help with risk stratification. There are multiple high-risk ECG findings that are suggestive of adverse outcome and may benefit from rapid transfer for coronary angiography. This article reviews specific high-risk ECG patterns that may represent acute myocardial infarction or identify impending acute myocardial infarction that benefit from early diagnostic coronary angiography.

Optical coherence tomography-guided percutaneous coronary intervention compared with other imaging guidance: a meta-analysis.

The use of optical coherence tomography (OCT) in PCI guidance is limited perhaps by the lack of adequately powered studies which compare its efficacy and outcomes to the other more popular imaging modalities. We therefore performed a meta-analysis to compare clinical outcomes following OCT-guided PCI with the other imaging modalities in two separate comparisons. We abstracted data from randomized control trials and observational comparative studies focusing on OCT versus either angiography- or IVUS-guided PCI outcomes identified following a systematic search (April 2006 and May 2017). This meta-analysis included a total of 2781 patients; OCT-guidance versus Angiography guidance (n = 1753) and OCT-guidance versus IVUS-guidance (n = 1028). Pooled estimates of outcomes, presented as odds ratios (OR) [95% confidence intervals], were generated with random-effect models. OCT guidance showed lower rates of MACE (OR 0.70 [0.49, 1.00] p = 0.05) and cardiac deaths (OR 0.40 [0.18, 0.90] p = 0.03) compared to Angiography-guidance alone but no statistical significant results for myocardial infarction (OR 0.70 [0.42, 1.16] p = 0.17), stent thrombosis (OR 1.17 [0.40, 3.43] p = 0.77) and target lesion revascularizations (OR 1.07 [0.48, 2.38] p = 0.86).No statistical significance was observed in the OCT versus IVUS comparison; MACE (OR 0.89 [0.46, 1.73] p = 0.73), cardiac deaths (OR 0.56 [0.12, 2.70] p = 0.47), MI (OR 0.56 [0.12, 2.70] p = 0.47), ST (OR 0.43 [0.06, 2.95] p = 0.39), and TLR(OR 0.99 [0.45, 2.18] p = 0.99). OCT-guided PCI in comparison with angiography-guided was associated with reduction in adverse events for the composite of cardiac deaths, myocardial infarction and repeat revascularizations. There was no statistically significant difference in clinical outcomes observed in the comparison between OCT- and IVUS-guidance.

A comparison of the ultrathin Orsiro Hybrid sirolimus-eluting stent with contemporary drug-eluting stents: A meta-analysis of randomized controlled trials.

BACKGROUND: Recent studies suggest the Orsiro sirolimus-eluting stent (O-SES), which has ultrathin struts with a biodegradable sirolimus-eluting polymer coating, performed better than contemporary drug-eluting stents (DES). We performed a meta-analysis to compare clinical outcomes for all randomized controlled trials (RCTs) of O-SES vs contemporary DES. METHODS/MATERIALS: PubMed, Cochrane CENTRAL, and meeting abstracts were searched for all RCTs comparing O-SES with contemporary DES. Pooled estimates of longest available clinical outcomes at a minimum of one-year follow-up, presented as odds ratios (OR) [95% confidence intervals], were generated with random-effect models. RESULTS: We included 8 RCTs with a total of 11,176 patients (5444 O-SES and 5732 contemporary DES [3537 EES, 1295 ZES, and 1264 BP-BES) with a mean age of 65±11, 74% were male, 40% underwent PCI for stable angina, and 56% for ACS. We assessed outcomes comparing O-SES vs. everolimus-eluting stents, vs. permanent-polymer DES, and vs. all DES including biodegradable-polymer DES. Orsiro performed comparably in all categories with a trend toward a reduction in myocardial infarction (0.83 [0.68, 1.02], p=0.07) and stent thrombosis (0.75 [0.54, 1.04], p=0.08). CONCLUSION: Overall, the Orsiro SES had similar clinical outcomes to contemporary DES with a trend toward reduction in myocardial infarction and stent thrombosis.