Timing of Complete Revascularization Stratified by Index Presentation During On- and Off-Hours.

Recent trials suggested immediate complete revascularization (ICR) as a safe alternative to staged complete revascularization (SCR), but the impact of the respective percutaneous coronary intervention strategies between on- versus off-hours is unclear. On-hours was defined as an index revascularization performed between 8:00 a.m. and 6:00 p.m., Monday to Friday, or else the procedure was defined as performed during off-hours. The primary end point consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia-driven revascularization, and cerebrovascular events at 1-year follow-up. We used Cox regression models to relate randomized treatment with study end points. We evaluated multiplicative and additive interactions between on- versus off-hours and randomized treatment. The BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease) trial enrolled 1,097 and 428 patients during on- and off-hours, respectively. Patients randomized during off-hours were more likely to present with ST-segment elevation myocardial infarction (66.4% vs 29.5%, p <0.001). The composite primary outcome occurred in 8.4% and 10.1% of patients randomized to ICR and SCR, respectively, during on-hours (hazard ratio 0.80, 95% confidence interval 0.54 to 1.19). During off-hours, the primary composite outcome occurred in 5.4% and 7.7% in ICR and SCR (0.69, 95% confidence interval 0.32 to 1.46) with no evidence of a differential effect (interaction pmultiplicative = 0.70, padditive = 0.56). No differential effect was found between treatment allocation and on- versus off-hours in any of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing ICR versus SCR in patients presenting with acute coronary syndrome and multivessel disease during on- or off-hours.

Immediate or staged complete revascularisation in patients presenting with acute coronary syndrome by number of diseased vessels: a substudy of the BIOVASC randomised trial.

BACKGROUND: In patients presenting with acute coronary syndrome (ACS), the number of diseased vessels may affect the efficacy of a complete revascularisation strategy. AIMS: The authors sought to evaluate the safety and efficacy of immediate complete revascularisation (ICR) and staged complete revascularisation (SCR) in patients presenting with ACS stratified by the number of diseased vessels. METHODS: In this prespecified analysis of the BIOVASC trial, ICR was compared with SCR in patients with two-vessel disease (2VD) or three-vessel disease (3VD). The primary endpoint was a composite of all-cause mortality, myocardial infarction (MI), any unplanned ischaemia-driven revascularisation or cerebrovascular events at 1 year after the index procedure. Comparisons were performed using Cox regression. RESULTS: A total of 1,525 patients were enrolled in the BIOVASC trial, of whom 1,177 presented with 2VD and 265 with 3VD. In the 2VD group, 613 patients were assigned to ICR and 564 to SCR. In the 3VD group, 117 patients were assigned to ICR and 148 to SCR. ICR and SCR led to similar results in both the 2VD (hazard ratio [HR] 0.76, 95% confidence interval [CI]: 0.50-1.13; p=0.18) and 3VD groups (HR 0.79, 95% CI: 0.39-1.59; p=0.51) (pinteraction=0.91) in terms of the primary endpoint. ICR was associated with a lower rate of MI in patients with 3VD (HR 0.21, 95% CI: 0.046-0.93; p=0.04) (pinteraction=0.30). CONCLUSIONS: ICR might be an option in patients presenting with extensive 3VD and might be associated with a lower rate of myocardial infarction compared with SCR.

Timing of Complete Multivessel Revascularization in Patients Presenting With Non-ST-Segment Elevation Acute Coronary Syndrome.

BACKGROUND: Complete revascularization of the culprit and all significant nonculprit lesions in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD) reduces major adverse cardiac events, but optimal timing of revascularization remains unclear. OBJECTIVES: This study aims to compare immediate complete revascularization (ICR) and staged complete revascularization (SCR) in patients presenting with NSTE-ACS and MVD. METHODS: This prespecified substudy of the BIOVASC (Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndrome and Multivessel Disease) trial included patients with NSTE-ACS and MVD. Risk differences of the primary composite outcome of all-cause mortality, myocardial infarction (MI), unplanned ischemia-driven revascularization (UIDR), or cerebrovascular events and its individual components were compared between ICR and SCR at 1 year. RESULTS: The BIOVASC trial enrolled 1,525 patients; 917 patients presented with NSTE-ACS, of whom 459 were allocated to ICR and 458 to SCR. Incidences of the primary composite outcome were similar in the 2 groups (7.9% vs 10.1%; risk difference 2.2%; 95% CI: -1.5 to 6.0; P = 0.15). ICR was associated with a significant reduction of MIs (2.0% vs 5.3%; risk difference 3.3%; 95% CI: 0.9 to 5.7; P = 0.006), which was maintained after exclusion of procedure-related MIs occurring during the index or staged procedure (2.0% vs 4.4%; risk difference 2.4%; 95% CI: 0.1 to 4.7; P = 0.032). UIDRs were also reduced in the ICR group (4.2% vs 7.8%; risk difference 3.5%; 95% CI: 0.4 to 6.6; P = 0.018). CONCLUSIONS: ICR is safe in patients with NSTE-ACS and MVD and was associated with a reduction in MIs and UIDRs at 1 year.

Benefits of immediate complete revascularization in patients with acute coronary syndromes.

Acute coronary syndrome is one of the leading causes of death worldwide. Up to 60% of patients present with additional significant non-culprit lesions. Complete revascularization (CR) of all (culprit and non-culprit) lesions is recommended and recent randomized trials showed the benefit of performing complete multivessel percutaneous coronary intervention in a single setting. Immediate CR is associated with a reduced risk of repeat myocardial infarction and unplanned ischemia driven revascularization. Furthermore, immediate CR resulted in less implanted stents, total contrast use and a shorter duration of hospitalization while maintaining a similar success rate of complete revascularization. Further studies need to evaluate the role of coronary physiology and intravascular imaging for enhanced understanding of the pathophysiology of early events in non-culprit lesions.

Complete Revascularization Strategies in Women and Men With Acute Coronary Syndrome and Multivessel Disease.

This prespecified substudy of the randomized Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease (BIOVASC) trial aimed to compare immediate complete revascularization (ICR) and staged complete revascularization (SCR) in patients with acute coronary syndrome and multivessel disease, stratified by gender. The primary end point consisted of a composite of all-cause mortality, myocardial infarction, unplanned ischemia-driven revascularization, and cerebrovascular events at 1-year follow-up. The secondary end points included the individual components of the primary composite and major bleedings. We used Cox regression models to relate randomized treatment with study end points. We evaluated the multiplicative and additive interactions between gender and randomized treatment. The BIOVASC trial enrolled 338 women and 1,187 men. Women were older than men (median age 71.6 vs 63.7 years, p <0.001) and had a higher prevalence of chronic obstructive pulmonary disease (10.1% vs 5.6%, p = 0.003), renal insufficiency (7.7% vs 4.4%, p = 0.015), and hypertension (60.4% vs 51.7%, p = 0.005). In women, the composite primary outcome occurred in 7.3% versus 12.9% (hazard ratio 0.53, 95% confidence interval 0.26 to 1.08) in patients randomly allocated to ICR and SCR, respectively, and in men in 7.7% versus 8.4% (hazard ratio 0.89, 95% confidence interval 0.60 to 1.34), with no evidence of a differential effect (interaction pmultiplicative = 0.20, padditive = 0.87). No evidence of heterogeneity between women and men was found when comparing ICR with SCR in terms of the secondary outcomes. In conclusion, no differential treatment effect was found when comparing ICR versus SCR in women or men presenting with acute coronary syndrome and multivessel disease.

Propensity Matched Comparison of Clinical Outcome After Immediate Versus Staged Complete Revascularization in Patients With Acute Coronary Syndrome and Multivessel Disease.

Complete revascularization (CR) in patients with acute coronary syndromes (ACS) and multivessel disease (MVD) improves clinical outcomes compared with culprit-only revascularization, but the optimal timing for non-culprit lesions treatment remains unclear. This study evaluated patients presenting with ACS and MVD admitted between January 2015 and September 2021 at the Erasmus University Medical Center. Clinical outcomes were compared between immediate and staged CR in terms of major adverse cardiac and cerebrovascular events (MACCEs), a composite of all-cause mortality, myocardial infarction, stroke, and any unplanned revascularization. A total of 1,400 patients presenting with ACS and MVD who underwent immediate or staged CR were included in this study. Using 1/many propensity score matching without replacement, 299 patients in the staged CR group were matched to 598 patients in the immediate CR group (mean 1:2 ratio), rendering a total of 897 patients for analysis. The median follow-up period was 648 days. MACCE rate was significantly higher in the staged CR group than in the immediate CR group (adjusted hazard ratio [95% confidence interval] 1.60 [1.05 to 2.45], p = 0.03). Furthermore, number of stents, stent length, and contrast usage were significantly greater in the staged revascularization group. Immediate CR was associated with less risk of MACCE than was staged CR. Staged CR required overall more contrast and stent material.

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Non-ST-Elevation Coronary Syndromes and Multivessel Disease: A Systematic Review and Meta-Analysis.

There is lack of evidence regarding the optimal revascularization strategy in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and multivessel disease (MVD). This systematic review and meta-analysis compares the clinical impact of percutaneous coronary intervention (PCI) with that of coronary artery bypass graft surgery (CABG) in this subset of patients. EMBASE, MEDLINE, and Web of Knowledge were searched for studies including patients with NSTE-ACS and MVD who underwent PCI or CABG up to September 1, 2021. The primary end point of the meta-analysis was all-cause mortality at 1 year. The secondary end points were myocardial infarction (MI), stroke, or repeat revascularization at 1 year. The analysis was conducted using the Mantel-Haenszel random-effects model to calculate the odds ratio (OR) with 95% confidence interval (CI). Four prospective observational studies met the inclusion criteria, including 1,542 patients who underwent CABG and 1,630 patients who underwent PCI. No significant differences were found in terms of all-cause mortality (OR 0.91, 95% CI 0.68 to 1.21, p = 0.51), MI (OR 0.78, 95% CI 0.40 to 1.51, p = 0.46), or stroke (OR 1.54, 95% CI 0.55 to 4.35, p = 0.42) between PCI and CABG. Repeat revascularization was significantly lower in the CABG group (OR 0.21, 95% CI 0.13 to 0.34, p <0.00001). In patients presenting with NSTE-ACS and MVD, 1-year mortality, MI, and stroke were similar between patients treated with either PCI or CABG, but the repeat revascularization rate was higher after PCI.

Diagnostic accuracy of angiography-based vessel fractional flow reserve after chronic coronary total occlusion recanalization.

BACKGROUND: Angiography-based vessel fractional flow reserve (vFFR) demonstrated a strong correlation with invasive fractional flow reserve (FFR) in both a pre- and post-percutaneous coronary intervention (PCI) setting. However, the role of vFFR and its correlation with post-PCI FFR in chronic coronary occlusions (CTO) has not been evaluated yet. We sought to investigate the diagnostic performance of post-PCI vFFR with post-PCI FFR as a reference in patients undergoing successful CTO PCI. METHODS: Between March 2016 and April 2020, a total of 80 patients from the FFR-SEARCH (prospective registry) and FFR REACT (randomized controlled trial) studies underwent successful CTO recanalization with post-PCI FFR measurements. RESULTS: A total of 50 patients (median age 66 (interquartile range [IQR]: 56-74) years, 76% were male) were eligible for the analysis. Median post-PCI FFR was 0.89 (IQR: 0.84-0.94), while median post-PCI vFFR was 0.91 (IQR: 0.85-0.94) (p 0.10). Suboptimal physiological results, defined as FFR and vFFR <0.90, were identified in 26 (52%) and in 21 (42%) patients, respectively. A strong correlation (r = 0.82) was found between vFFR and FFR with a mean bias of 0.013 ± 0.051. Receiver-operating characteristics curve analysis revealed an excellent accuracy of vFFR in predicting FFR <0.90 (area under the curve: 0.97; 95% confidence interval: 0.93-1.00). CONCLUSION: Post-PCI vFFR shows a good correlation with post-PCI FFR and a high diagnostic accuracy for post-PCI FFR ≤0.90 in patients undergoing successful PCI of a CTO lesion.

Intravascular ultrasound-guided versus coronary angiography-guided percutaneous coronary intervention in patients with acute myocardial infarction: A systematic review and meta-analysis.

BACKGROUND: Intravascular ultrasound (IVUS) can overcome the intrinsic limitations of coronary angiography for lesion assessment and stenting. IVUS improves outcomes of patients presenting with stable or complex coronary artery disease, but dedicated data on the impact of IVUS-guided percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) remains scarce. METHODS: We systematically searched Embase, MEDLINE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials and Google Scholar for studies that compared clinical outcomes for IVUS- versus angio-guided PCI in patients with AMI. The primary endpoint was all-cause mortality and the secondary endpoint major adverse cardiovascular events (MACE). Mantel-Haenszel random-effects model was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). RESULTS: Nine studies (8 observational, 1 RCT) with a total of 838.902 patients (796.953 angio-guided PCI, 41.949 IVUS-guided PCI) were included. In patients with AMI, IVUS-guided PCI was associated with a significantly lower risk of all-cause mortality (pooled RR: 0.70; 95% CI, 0.59-0.82; p < 0.01), MACE (pooled RR: 0.86; 95% CI, 0.74-0.99; p = 0.04) and target vessel revascularization (TVR) (pooled RR: 0.83; 95% CI, 0.73-0.95; p < 0.01). In the subset of patients presenting with ST-segment elevation, IVUS-guided PCI remained associated with a reduced risk for both all-cause mortality (pooled RR: 0.79; 95% CI, 0.66-0.95, p = 0.01) and MACE (pooled RR: 0.86; 95% CI, 0.74-0.99, p = 0.04). CONCLUSIONS: This is the first systematic review and meta-analysis comparing IVUS- versus angio-guided PCI in patients with AMI, showing a beneficial effect of IVUS-guided PCI on all-cause mortality, MACE and TVR. Results of ongoing dedicated prospective studies are needed to confirm these findings.

Periarteriolar Glioblastoma Stem Cell Niches Express Bone Marrow Hematopoietic Stem Cell Niche Proteins.

In glioblastoma, a fraction of malignant cells consists of therapy-resistant glioblastoma stem cells (GSCs) residing in protective niches that recapitulate hematopoietic stem cell (HSC) niches in bone marrow. We have previously shown that HSC niche proteins stromal cell-derived factor-1α (SDF-1α), C-X-C chemokine receptor type 4 (CXCR4), osteopontin (OPN), and cathepsin K (CatK) are expressed in hypoxic GSC niches around arterioles in five human glioblastoma samples. In HSC niches, HSCs are retained by binding of SDF-1α and OPN to their receptors CXCR4 and CD44, respectively. Protease CatK cleaves SDF-1α to release HSCs out of niches. The aim of the present study was to reproduce the immunohistochemical localization of these GSC markers in 16 human glioblastoma samples with the addition of three novel markers. Furthermore, we assessed the type of blood vessels associated with GSC niches. In total, we found seven GSC niches containing CD133-positive and nestin-positive GSCs as a single-cell layer exclusively around the tunica adventitia of 2% of the CD31-positive and SMA-positive arterioles and not around capillaries and venules. Niches expressed SDF-1α, CXCR4, CatK, OPN, CD44, hypoxia-inducible factor-1α, and vascular endothelial growth factor. In conclusion, we show that GSC niches are present around arterioles and express bone marrow HSC niche proteins.

Cathepsin K cleavage of SDF-1α inhibits its chemotactic activity towards glioblastoma stem-like cells.

Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1α (SDF-1α), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1α is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1α cleavage by CatK inactivates SDF-1α and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1α after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1α at 3 sites in the N-terminus, which is the region of SDF-1α that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1α and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1α had chemotactic activity whereas CatK cleavage products of SDF-1α did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1α. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation.