Novel purine derivatives as selective CDK2 inhibitors with potential anticancer activities: Design, synthesis and biological evaluation.

Purine analogues were discovered to be inhibitors of CDK2, suggesting a potential therapeutic scaffold. This paper addresses the design, synthesis, and anticancer evaluation of purine analogues as kinase inhibitors. In the early stages of the investigation, the designed compounds demonstrated a promising docking score and greater protein-ligand stability in MD simulation than the standard, indicating a higher affinity against CDK2. Thus, we synthesised new purine analogues under simple and optimised reaction conditions. Among the studies under NCI-60, 5g and 5i were the most effective, with a percentage GI of 98.09 and 90 against OVCAR-4 and SNB-75, respectively, at a dose of 10 µM. Additionally, 5g and 5i demonstrated 7.80-fold and 1.54-fold greater cytotoxicity against PA-1 and MCF-7, with IC50s of 1.08 µM and 3.54 µM, respectively, compared to seliciclib (8.43 µM and 5.46 µM). In addition, 5g and 5i showed selective cytotoxicity against PA-1 and MCF-7 than normal cells, with selectivity indexes of 26.40 and 15.45, respectively, as compared to the standard (SI=3.83 and 5.91). In the kinase selectivity assay, both compounds demonstrated greater affinity against CDK2 than other kinases, with IC50 of 0.21 µM and 0.59 µM, in contrast to the standard (IC50 = 0.63 µM). Furthermore, 5g confirmed kinase inhibition in the western blot by lowering CDK2, cyclin A2, and other downstream substrates. Moreover, it triggered cell death by apoptosis and cell cycle arrest in G2/M. Taken together, 5g merits further investigation in PKPD research to discover a potential therapeutic candidate against cancer.

Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).

The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signaling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signaling and inhibit the proliferation of RTK-driven cancer cell lines. Here, we describe the first reported fragment-to-lead campaign against SHP2, where X-ray crystallography and biophysical techniques were used to identify fragments binding to multiple sites on SHP2. Structure-guided optimization, including several computational methods, led to the discovery of two structurally distinct series of SHP2 inhibitors binding to the previously reported allosteric tunnel binding site (Tunnel Site). One of these series was advanced to a low-nanomolar lead that inhibited tumor growth when dosed orally to mice bearing HCC827 xenografts. Furthermore, a third series of SHP2 inhibitors was discovered binding to a previously unreported site, lying at the interface of the C-terminal SH2 and catalytic domains.

Percutaneous coronary intervention before transcatheter aortic valve implantation: A propensity score matched analysis.

BACKGROUND: The role of percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) who subsequently undergo transcatheter aortic valve replacement (TAVR) remains uncertain. Therefore, we conducted this study to assess the association of PCI before TAVR with mortality and cardiovascular outcomes. METHODS: We used the TriNetX database (Jan 2012 - Aug 2022) and grouped patients into PCI (3 months or less) before TAVR and no PCI. We performed propensity score matched (PSM) analyses for outcomes at 30 days and 1 year. RESULTS: Of 17,120 patients undergoing TAVR, 2322 (14 %) had PCI, and 14,798 (86 %) did not have PCI before TAVR. In the PSM cohort (2026 patients in each group), PCI was not associated with lower all-cause mortality at 30 days (HR: 1.25, 95 % CI: 0.82-1.90) or 1 year (HR: 1.02, 95 % CI: 0.83-1.24). Frequency of repeat PCI after TAVR was low in both no PCI vs. PCI (2.4 % vs. 1.2 %) at 1 year; PCI was associated with a lower rate of repeat PCI (HR: 0.49, 95 % CI: 0.30-0.80). Sensitivity analysis revealed an E-value of 3.5 for repeat PCI (E-value for lower CI for HR: 1.81). PCI was not linked to reductions in MI, heart failure exacerbation, all-cause hospitalization, major bleeding, or permanent pacemaker/implantable cardioverter defibrillator. CONCLUSION: This analysis showed that PCI prior to TAVR was not associated with improvement in all-cause mortality. However, PCI was associated with a reduced rate of repeat PCI at 1 year.

Intravascular imaging guided versus coronary angiography guided percutaneous coronary intervention: systematic review and meta-analysis.

OBJECTIVE: To assess the absolute treatment effects of intravascular imaging guided versus angiography guided percutaneous coronary intervention in patients with coronary artery disease, considering their baseline risk. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed/Medline, Embase, and Cochrane Library databases up to 31 August 2023. STUDY SELECTION: Randomized controlled trials comparing intravascular imaging (intravascular ultrasonography or optical coherence tomography) guided versus coronary angiography guided percutaneous coronary intervention in adults with coronary artery disease. MAIN OUTCOME MEASURES: Random effect meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) were used to assess certainty of evidence. Data included rate ratios and absolute risks per 1000 people for cardiac death, myocardial infarction, stent thrombosis, target vessel revascularization, and target lesion revascularization. Absolute risk differences were estimated using SYNTAX risk categories for baseline risks at five years, assuming constant rate ratios across different cardiovascular risk thresholds. RESULTS: In 20 randomized controlled trials (n=11 698), intravascular imaging guided percutaneous coronary intervention was associated with a reduced risk of cardiac death (rate ratio 0.53, 95% confidence interval 0.39 to 0.72), myocardial infarction (0.81, 0.68 to 0.97), stent thrombosis (0.44, 0.27 to 0.72), target vessel revascularization (0.74, 0.61 to 0.89), and target lesion revascularization (0.71, 0.59 to 0.86) but not all cause death (0.81, 0.64 to 1.02). Using SYNTAX risk categories, high certainty evidence showed that from low risk to high risk, intravascular imaging was likely associated with 23 to 64 fewer cardiac deaths, 15 to 19 fewer myocardial infarctions, 9 to 13 fewer stent thrombosis events, 28 to 38 fewer target vessel revascularization events, and 35 to 48 fewer target lesion revascularization events per 1000 people. CONCLUSIONS: Compared with coronary angiography guided percutaneous coronary intervention, intravascular imaging guided percutaneous coronary intervention was associated with significantly reduced cardiac death and cardiovascular outcomes in patients with coronary artery disease. The estimated absolute effects of intravascular imaging guided percutaneous coronary intervention showed a proportional relation with baseline risk, driven by the severity and complexity of coronary artery disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023433568.

Outcomes With Intravascular Ultrasound and Optical Coherence Tomography Guidance in Percutaneous Coronary Intervention.

Intracoronary imaging has become an important tool in the treatment of complex lesions with percutaneous coronary intervention (PCI). This retrospective cohort study identified 1,118,475 patients with PCI from the Nationwide Readmissions Database from 2017 to 2019. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) were identified with appropriate International Classification of Diseases, Tenth Revision codes. The primary outcome was major adverse cardiac events. The secondary outcomes include net adverse clinical events (NACEs), all-cause mortality, myocardial infarction (MI) readmission, admission for stroke, and emergency revascularization. The multivariate Cox proportional hazard regression was used to adjust for demographic and co-morbid confounders. Of 1,118,475 PCIs, 86,140 (7.7%) used IVUS guidance and 5,617 (0.5%) used OCT guidance. The median follow-up time was 184 days. The primary outcome of major adverse cardiac events was significantly lower for the IVUS (6.5% vs 7.6%; hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.86 to 0.91, p <0.001) and OCT (4.4% vs 7.6%; HR 0.69, 95% CI 0.61 to 0.79, p <0.001) groups. IVUS was associated with significantly lower rates of NACEs (8.4% vs 9.4%; HR 0.92, 95% CI 0.89 to 0.94, p <0.001), all-cause mortality (3.5% vs 4.3%; HR 0.85, 95% CI 0.82 to 0.88, p <0.001), readmission for MI (2.7% vs 3.0%; HR 0.95, 95% CI 0.91 to 0.99, p = 0.012), and admission for stroke (0.5% vs 0.6%; HR 0.86, 95% CI 0.78 to 0.95, p = 0.002). OCT was associated with significantly lower rates of NACEs (6.6% vs 9.4%; HR 0.81, 95% CI 0.73 to 0.89, p <0.001) and all-cause mortality (1.8% vs 4.3%; HR 0.51, 95% CI 0.42 to 0.63, p <0.001). Emergency revascularization was not significantly different with IVUS guidance. Readmission for MI, stroke, and emergency revascularization were not significantly different with OCT guidance. A subgroup analysis of patients with ST-elevation MI and non-ST-elevation MI showed similar results. In conclusion, the use of IVUS and OCT guidance with PCI were associated with significantly lower rates of morbidity and mortality in real-world practice.

Site-level variability in the processes of care and outcomes over time among patients with COVID-19 and myocardial injury: Insights from the American Heart Association's COVID-19 Cardiovascular Disease Registry.

Background: Elevated cardiac troponin (cTn) levels in patients with COVID-19 has been associated with worse outcomes. Guidelines on best practices of those patients remain uncertain. Methods: We included patients with COVID-19 and cTn above the assay-specific upper limit of normal (ULN) enrolled in the American Heart Association's COVID-19 registry between March 2020-January 2021. Site-level variability in invasive coronary angiography, LVEF assessment, ICU utilization, and inpatient mortality were determined by calculating adjusted median odds ratio (MOR) using hierarchical logistic regression models. Temporal trends were assessed with Cochran-Armitage trend test. Results: Among 32,636 patients, we included 6234 (19.4 %) with cTn above ULN (age 68.7 ± 16.0 years, 56.5 % male, 51.5 % Caucasian), of whom 1365 (21.6 %) had ≥5-fold elevations. Across 55 sites, the median rate of invasive coronary angiography was 0.1 % with adjusted MOR 1.5(1.0,2.3), median LVEF assessment was 25.5 %, MOR 3.0(2.2,3.9), ICU utilization was 41.7 %, MOR 2.2(1.8,2.6), and mortality was 20.9 %, MOR 1.7(1.5,2.0). Over time, we noted a significant increase in invasive coronary angiography (p-trend = 0.001), and LVEF assessment (p-trend<0.001), and reduction in mortality (p-trend<0.001), without significant change in ICU admissions (p-trend = 0.08). Similar variability and temporal trends were seen among patients with ≥5-fold cTn elevation. Conclusions: The use of invasive coronary angiography among patients with COVID-19 and myocardial injury was very low during the early pandemic. We found moderate institutional variability in processes of care with an uptrend in invasive catheterization and LVEF assessment, and downtrend in mortality. Comparative effectiveness studies are needed to examine whether variability in care is associated with differences in outcomes.

Assessment of Repeat Revascularization in Percutaneous Coronary Intervention Randomized Controlled Trials as a Surrogate for Mortality: A Meta-Regression Analysis.

The association of repeat revascularization after percutaneous coronary intervention (PCI) with mortality is uncertain. To assess the association of repeat revascularization after PCI with mortality in patients with coronary artery disease (CAD). We identified randomized controlled trials comparing PCI with coronary artery bypass graft (CABG) or optimal medical therapy (OMT) using electronic databases through January 1, 2022. We performed a random-effects meta-regression between repeat revascularization rates after PCI (absolute risk difference [%] between PCI and CABG or OMT) with the relative risks (RR) of mortality. We assessed surrogacy of repeat revascularization for mortality using the coefficient of determination (R2), with threshold of 0.80. In 33 trials (21,735 patients), at median follow-up of 4 (2-7) years, repeat revascularization was higher after PCI than CABG [RR: 2.45 (95% confidence interval, 1.99-3.03)], but lower vs OMT [RR: 0.64 (0.46-0.88)]. Overall, meta-regression showed that repeat revascularization rates after PCI had no significant association with all-cause mortality [RR: 1.01 (0.99-1.02); R2=0.10) or cardiovascular mortality [RR: 1.01 (CI: 0.99-1.03); R2=0.09]. In PCI vs CABG (R2=0.0) or PCI vs OMT trials (R2=0.28), repeat revascularization did not meet the threshold for surrogacy for all-cause or cardiovascular mortality (R2=0.0). We observed concordant results for subgroup analyses (enrollment time, follow-up, sample size, risk of bias, stent types, and coronary artery disease), and multivariable analysis adjusted for demographics, comorbidities, risk of bias, MI, and follow-up duration. In summary, this meta-regression did not establish repeat revascularization after PCI as a surrogate for all-cause or cardiovascular mortality.

Three-Year Outcomes After Bifurcation Stenting With Zotarolimus-Eluting Stents: Final Results From the RESOLUTE ONYX Postapproval Study.

Background: Bifurcation represents a challenging lesion subset for percutaneous coronary intervention. Methods: In this prospective study of the Resolute Onyx zotarolimus-eluting stent (ZES), patients with a single bifurcation target lesion who underwent planned treatment using a provisional stenting technique were enrolled at 25 centers in the United States and Europe. The primary end point was target-vessel failure (TVF) at 1 year, and follow-up was performed through 3 years. Results: A total of 205 patients were enrolled. Mean age was 66.6 ± 10.7 years, 21.5% of patients were female, and diabetes mellitus was present in 30.2%. A provisional approach with a single stent was performed in 96.6% of patients. The rate of TVF at 1 year was 7.4%, fulfilling the prespecified performance criterion (upper 1-sided 95% CI of 11.1%, compared with the performance goal of 24.5%). At 3-year follow-up, the rate of TVF was 12.1%, the rate of clinically driven target-lesion revascularization was 6.0%, and there were no episodes of stent thrombosis related to the target lesion. Event rates were consistent among the cohort of patients with angiographic core laboratory-confirmed bifurcation lesions. Conclusions: In this prospective, multicenter study, bifurcation lesion treatment with Resolute Onyx ZES using a planned provisional stent approach was associated with favorable clinical outcomes through 3 years. These results support the longer-term safety and effectiveness of Resolute Onyx ZES to treat bifurcation lesions that are amenable to a planned provisional stenting technique.

A commentary on the use of pharmacoenhancers in the pharmaceutical industry and the implication for DMPK drug discovery strategies.

Paxlovid, a drug combining nirmatrelvir and ritonavir, was designed for the treatment of COVID-19 and its rapid development has led to emergency use approval by the FDA to reduce the impact of COVID-19 infection on patients.In order to overcome potentially suboptimal therapeutic exposures, nirmatrelvir is dosed in combination with ritonavir to boost the pharmacokinetics of the active product.Here we consider examples of drugs co-administered with pharmacoenhancers.Pharmacoenhancers have been adopted for multiple purposes such as ensuring therapeutic exposure of the active product, reducing formation of toxic metabolites, changing the route of administration, and increasing the cost-effectiveness of a therapy.We weigh the benefits and risks of this approach, examining the impact of technology developments on drug design and how enhanced integration between cross-discipline teams can improve the outcome of drug discovery.

Spontaneous Coronary Artery Dissection: An Elusive Disease of the Coronaries.

The articles in our Points to Remember column highlight important "need to know" facts about conditions that cardiovascular healthcare professionals may encounter. These may come from any medical specialty, such as nephrology or neurology. The article in this issue is provided by Swaminathan Perinkulam Sathyanarayanan, MD, Department of Internal Medicine, University of South Dakota, and Smitha Narayana Gowda, MD, and Alpesh Shah, MD, Houston Methodist DeBakey Heart & Vascular Center, Houston Methodist.

Outcomes of patients with moderate-to-severe Ischemia excluded from the ischemia trial.

BACKGROUND: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial showed no difference in outcomes between medical therapy vs coronary revascularization in the management of patients with stable coronary artery disease. We aimed to determine the percentage of patients with at least moderate ischemia that would have been eligible for enrollment and evaluate the outcomes of those who would not. METHODS: Consecutive patients who underwent cardiac single-photon emission computed tomography (SPECT) between April 2016 and September 2019 were identified and all-cause mortality was determined. RESULTS: There were a total of 1508 patients (mean age 67 ± 11.6 years, 69.5% males) with any perfusion defect on SPECT. Patients had a high prevalence of cardiac risk factors (73.4% with hypertension and 54.4% with diabetes mellitus.) Nearly half (709, 47%) had moderate-to-severe ischemia but over two-thirds (479/709, 66.3%) had at least one ISCHEMIA trial exclusion criteria. Patients meeting ISCHEMIA enrollment criteria had a significantly lower all-cause mortality than those who would have been excluded (3.91% vs. 11.3%, respectively, P < .001). CONCLUSION: Our results show that ISCHEMIA selected a relatively small subset of lower risk patients among the larger higher risk group of patients with moderate-to-severe ischemia typical to most cardiology centers.

Impact of network performance on remote robotic-assisted endovascular interventions in porcine model.

Remote robotic-assisted endovascular interventions require real-time control of the robotic system to conduct precise device navigation. The delay (latency) between the input command and the catheter response can be affected by factors such as network speed and distance. This study evaluated the effect of network latency on robotic-assisted endovascular navigation in three vascular beds using in-vivo experimental model. Three operators performed femoral, carotid, and coronary endovascular robotic navigation blinded from the hybrid room with the prototype remote-enabled CorPath GRX system in a porcine model. Navigation was performed to different targets with randomly assigned network latencies from 0 to 1000 ms. Outcome measurements included navigation success, navigation time, perceived lag (1 = imperceptible, 5 = too long), and procedural impact scored by the operators (1 = no impact, 5 = unacceptable). Robotic-assisted remote endovascular navigation was successful in all 65 cases (9 femoral, 38 external carotid, 18 coronary). Guidewire times were not significantly different across the simulated network latency times. Compared to 0 ms added latency, both the procedural impact and perceived lag scores were significantly higher when the added latency was 400 ms or greater (< 0.01). Remote endovascular intervention was feasible in all studied anatomic regions. Network latency of 400 ms or above is perceptible, although acceptable to operators, which suggests that remote robotic-assisted femoral, carotid or coronary arterial interventions should be performed with network latency below 400 ms to provide seamless remote device control.

Discovery of ASTX029, A Clinical Candidate Which Modulates the Phosphorylation and Catalytic Activity of ERK1/2.

Aberrant activation of the mitogen-activated protein kinase pathway frequently drives tumor growth, and the ERK1/2 kinases are positioned at a key node in this pathway, making them important targets for therapeutic intervention. Recently, a number of ERK1/2 inhibitors have been advanced to investigational clinical trials in patients with activating mutations in B-Raf proto-oncogene or Ras. Here, we describe the discovery of the clinical candidate ASTX029 (15) through structure-guided optimization of our previously published isoindolinone lead (7). The medicinal chemistry campaign focused on addressing CYP3A4-mediated metabolism and maintaining favorable physicochemical properties. These efforts led to the identification of ASTX029, which showed the desired pharmacological profile combining ERK1/2 inhibition with suppression of phospho-ERK1/2 (pERK) levels, and in addition, it possesses suitable preclinical pharmacokinetic properties predictive of once daily dosing in humans. ASTX029 is currently in a phase I-II clinical trial in patients with advanced solid tumors.

Clinical Positioning of the IAP Antagonist Tolinapant (ASTX660) in Colorectal Cancer.

Inhibitors of apoptosis proteins (IAPs) are intracellular proteins, with important roles in regulating cell death, inflammation, and immunity. Here, we examined the clinical and therapeutic relevance of IAPs in colorectal cancer. We found that elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in patients with microsatellite stable (MSS) stage III colorectal cancer treated with 5-fluorouracil (5FU)-based adjuvant chemotherapy, suggesting their involvement in promoting chemoresistance. A novel IAP antagonist tolinapant (ASTX660) potently and rapidly downregulated cIAP1 in colorectal cancer models, demonstrating its robust on-target efficacy. In cells co-cultured with TNFα to mimic an inflammatory tumor microenvironment, tolinapant induced caspase-8-dependent apoptosis in colorectal cancer cell line models; however, the extent of apoptosis was limited because of inhibition by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinapant-induced apoptosis was augmented by FOLFOX in human colorectal cancer and murine organoid models in vitro and in vivo, due (at least in part) to FOLFOX-induced downregulation of class I histone deacetylases (HDAC), leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, the effects of FOLFOX could be phenocopied using the clinically relevant class I HDAC inhibitor, entinostat, which also induced acetylation of Ku70 and FLIP downregulation. Further analyses revealed that caspase-8 knockout RIPK3-positive colorectal cancer models were sensitive to tolinapant-induced necroptosis, an effect that could be exploited in caspase-8-proficient models using the clinically relevant caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX in poor prognosis MSS colorectal cancer with elevated cIAP1/2 expression.

ASTX029, a Novel Dual-mechanism ERK Inhibitor, Modulates Both the Phosphorylation and Catalytic Activity of ERK.

The MAPK signaling pathway is commonly upregulated in human cancers. As the primary downstream effector of the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers and for overcoming resistance to upstream inhibition. ASTX029 is a highly potent and selective dual-mechanism ERK inhibitor, discovered using fragment-based drug design. Because of its distinctive ERK-binding mode, ASTX029 inhibits both ERK catalytic activity and the phosphorylation of ERK itself by MEK, despite not directly inhibiting MEK activity. This dual mechanism was demonstrated in cell-free systems, as well as cell lines and xenograft tumor tissue, where the phosphorylation of both ERK and its substrate, ribosomal S6 kinase (RSK), were modulated on treatment with ASTX029. Markers of sensitivity were highlighted in a large cell panel, where ASTX029 preferentially inhibited the proliferation of MAPK-activated cell lines, including those with BRAF or RAS mutations. In vivo, significant antitumor activity was observed in MAPK-activated tumor xenograft models following oral treatment. ASTX029 also demonstrated activity in both in vitro and in vivo models of acquired resistance to MAPK pathway inhibitors. Overall, these findings highlight the therapeutic potential of a dual-mechanism ERK inhibitor such as ASTX029 for the treatment of MAPK-activated cancers, including those which have acquired resistance to inhibitors of upstream components of the MAPK pathway. ASTX029 is currently being evaluated in a first in human phase I-II clinical trial in patients with advanced solid tumors (NCT03520075).

Impact of adherence to the hybrid algorithm for initial crossing strategy selection in chronic total occlusion percutaneous coronary intervention.

INTRODUCTION AND OBJECTIVES: The hybrid algorithm was designed to assist with initial and subsequent crossing strategy selection in chronic total occlusion (CTO) percutaneous coronary interventions (PCIs). However, the success of the initially selected strategy has received limited study. METHODS: We examined the impact of adherence to the hybrid algorithm recommendation for initial CTO crossing technique selection in 4178 CTO PCIs from a large multicenter registry. RESULTS: The initial crossing strategy was concordant with the hybrid algorithm recommendation in 1833 interventions (44%). Patients in the concordant group had a similar age to those in the discordant group but a lower mean J-CTO score (2.0 ± 1.4 vs 2.8 ± 1.1; P < .01). The concordant group showed higher technical success with the first crossing strategy (68% vs 48%; P < .01) and higher overall technical success (88% vs 83%; P < .01) with no difference in the incidence of in-hospital major adverse events (1.8% vs 2.3%; P = .26). In multivariable analysis, after adjustment for age, prior myocardial infarction, prior PCI, prior coronary artery bypass grafting, J-CTO score, and scheduled CTO PCI, nonadherence to the hybrid algorithm was independently associated with lower technical success of the initial crossing strategy (odds ratio, 0.55; 95% confidence interval, 0.48-0.64; P < .01). CONCLUSIONS: Adherence to the hybrid algorithm for initial crossing strategy selection is associated with higher CTO PCI success but similar in-hospital major adverse cardiac events.

Follow-up Outcomes After Chronic Total Occlusion Percutaneous Coronary Intervention in Patients With and Without Prior Coronary Artery Bypass Graft Surgery: Insights From the PROGRESS-CTO Registry.

BACKGROUND: Long-term outcomes of patients with prior coronary artery bypass graft (CABG) surgery undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI) have received limited study. METHODS: We compared the clinical and angiographic characteristics and procedural and follow-up outcomes of patients with and without prior CABG in a multicenter international registry. RESULTS: Of the 1572 patients included in this analysis, a total of 498 (32%) had prior CABG. Prior CABG patients had higher J-CTO scores (2.9 ± 1.1 vs 2.2 ± 1.3; P<.001) and were less likely to undergo PCI of the left anterior descending artery (16.7% vs 29.6%; P<.001). The retrograde technique was used more often (47.4% vs 28.2%; P<.001) and was successful more often (27.4% vs 17.1%; P<.001) in the prior CABG group vs the non-prior CABG group. Technical success was lower in prior CABG patients (82.6% vs 87.9%; P<.01) with similar incidence of in-hospital major adverse cardiovascular events (3.4% vs 3%; P=.65), although in-hospital mortality was higher in the prior CABG group (2.4% vs 1.0%; P=.04). At 1-year follow-up, the composite endpoint of death, myocardial infarction, and revascularization was higher in prior CABG patients (21.79% vs 12.73%; hazard ratio, 1.76; 95% confidence interval, 1.27-2.45; P<.001). CONCLUSION: Compared with non-prior CABG patients, prior CABG patients undergoing CTO-PCI had lower technical success and higher incidence of acute and follow-up adverse cardiovascular events.

C-reactive protein and prognosis after percutaneous coronary intervention and bypass graft surgery for left main coronary artery disease: Analysis from the EXCEL trial.

BACKGROUND: The prognostic impact of high-sensitivity C-reactive protein (CRP) levels in patients with left main coronary artery disease (LMCAD) treated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) is unknown. We sought to determine the effect of elevated baseline CRP levels on the 3-year outcomes after LMCAD revascularization and to examine whether CRP influenced the relative outcomes of PCI versus CABG. METHODS: In the EXCEL trial, patients with LMCAD and Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) scores ≤32 were randomized to PCI versus CABG. The primary composite outcome of death, myocardial infarction (MI), or stroke was analyzed according to baseline CRP levels. RESULTS: Among 999 patients with available CRP levels, median CRP was 3.10 mg/L (interquartile range 1.12-6.40 mg/L). The rate of the primary composite end point of death, MI, or stroke at 3 years steadily increased with greater baseline CRP levels. The adjusted relationship between the 3-year composite rate of death, MI, or stroke and baseline CRP modeled as a continuous log-transformed variable demonstrated steadily increasing event rates with greater CRP levels (adjusted hazard ratio, 1.26, 95% CI 1.10-1.44, P = .0008). Similarly, patients with CRP ≥10 mg/L had a 3-fold higher risk of the 3-year primary end point compared to patients with lower CRP levels (adjusted hazard ratio 2.92, 95% CI 1.88-4.54, P < .0001). The association between an elevated CRP level and the adjusted 3-year risk of the primary composite end point did not differ according to revascularization strategy (Pinteraction = .75). CONCLUSIONS: In patients with LMCAD undergoing revascularization, elevated baseline CRP levels were strongly associated with subsequent death, MI, and stroke at 3 years, irrespective of the mode of revascularization. Further studies are warranted to determine whether anti-inflammatory therapies may improve the prognosis of high-risk patients with LMCAD following revascularization.

Chronic Total Occlusion Coronary Intervention: In Search of a Definitive Benefit.

Percutaneous coronary intervention (PCI) of chronic coronary total occlusion is the latest frontier in percutaneous intervention. There are vast improvements in the initial success and safety of the procedure as well as a better understanding of appropriateness and benefits. Advances in technology and skill allow for increased utilization of PCI in cases of chronic coronary total occlusion, with benefits regarding symptoms and quality of life. Percutaneous coronary intervention for chronic coronary total occlusion can correct ischemia and achieve complete revascularization while avoiding traditional coronary bypass grafting, although survival benefits remain unclear.