Current and Future Roles of Glycoprotein IIb-IIIa Inhibitors in Primary Angioplasty for ST-Segment Elevation Myocardial Infarction.

Acute myocardial infarction still represents the major cause of mortality in high-income countries. Therefore, considerable efforts have been focused on the treatment of myocardial infarctions in the acute and long-term phase, with special attention being paid to reperfusion strategies and adjunctive antithrombotic therapies. In fact, despite the successful mechanical recanalization of the epicardial conduit, a substantial percentage of patients still experience poor myocardial reperfusion or acute/subacute in-stent thrombosis. Due the delayed onset of action of currently available oral antiplatelet therapies, glycoprotein (GP) IIb-IIIa inhibitors could be expected to improve clinical outcomes, especially when administrated in the early phase of the infarction, due to the larger platelet composition of fresh thrombi, the dynamic nature of early thrombi, and the larger amount of viable myocardium existing in the early, as compared to a delayed, phase. Considerable evidence has accumulated regarding the benefits from GP IIb-IIIa inhibitors on mortality, especially among high-risk patients and when administered as an upstream strategy. Therefore, based on currently available data, GP IIb-IIIa inhibitors can be considered when the drug can be administered within the first 3 h of symptom onset and among high-risk patients (e.g., those with advanced Killip class or an anterior myocardial infarction). Even though it is not universally accepted, in our opinion, this strategy should be implemented in a pre-hospital setting (in an ambulance) or as soon as possible when arriving at the hospital (at the Emergency Room or Coronary Care Unit, irrespective of whether they are in spoke or hub hospitals). A new, second-generation GP IIb-IIIa inhibitor (zalunfiban) appears to be highly suitable as a pre-hospital pharmacological facilitation strategy at the time of first medical contact due to its favourable features, including its simple subcutaneous administration, rapid onset of action (15 min), and limited time of action (with a half-life of ~1 h), which is likely to minimize the risk of bleeding. The ongoing CELEBRATE trial, including 2499 STEMI patients, may potentially provide compelling data to support the upstream treatment of STEMI patients undergoing mechanical reperfusion. In fact, although the current therapeutic target of increased rates of timely reperfusion has been achieved, the future goal in myocardial infarction treatment should be to achieve the most rapid reperfusion prior to primary percutaneous coronary intervention, thus further minimizing myocardial damage, or, in some cases, even preventing it completely, and improving survival.

Long-Term Outcomes of Transcatheter vs Surgical Aortic Valve Replacement: Meta-analysis of Randomized Trials.

Background: We aimed to perform a meta-analysis of randomized trials comparing long-term outcomes of patients undergoing transcatheter aortic valve replacement (TAVR) vs surgical aortic valve replacement (SAVR) for severe aortic stenosis. The short-term efficacy and safety of TAVR are proven, but long-term outcomes are unclear. Methods: We included randomized controlled trials comparing TAVR vs SAVR at the longest available follow-up. The primary end point was death or disabling stroke. Secondary end points were all-cause mortality, cardiac mortality, stroke, pacemaker implantation, valve thrombosis, valve gradients, and moderate-to-severe paravalvular leaks. The study is registered with PROSPERO (CRD42023481856). Results: Seven trials (N = 7785 patients) were included. Weighted mean trial follow-up was 5.76 ± 0.073 years. Overall, no significant difference in death or disabling stroke was observed with TAVR vs SAVR (HR, 1.02; 95% CI, 0.93-1.11; P = .70). Mortality risks were similar. TAVR resulted in higher pacemaker implantation and moderate-to-severe paravalvular leaks compared to SAVR. Results were consistent across different surgical risk profiles. As compared to SAVR, self-expanding TAVR had lower death or stroke risk (P interaction = .06), valve thrombosis (P interaction = .06), and valve gradients (P interaction < .01) but higher pacemaker implantation rates than balloon-expandable TAVR (P interaction < .01). Conclusions: In severe aortic stenosis, the long-term mortality or disabling stroke risk of TAVR is similar to SAVR, but with higher risk of pacemaker implantation, especially with self-expanding valves. As compared with SAVR, the relative reduction in death or stroke risk and valve thrombosis was greater with self-expanding than with balloon-expandable valves.

Coronary intravascular lithotripsy for severe coronary artery calcification: The Disrupt CAD I-IV trials.

Coronary artery calcification (CAC) severity is associated with increased vessel inflammation, atherosclerosis, stent failure, and risk of percutaneous coronary intervention-related complications. Current modalities for CAC modification include atherectomy techniques (rotational, orbital, and laser) and balloon modification (cutting and scoring). However, these methods are limited by their risk of slow flow/no reflow, coronary dissection, perforation, and myocardial infarction. Intravascular lithotripsy (IVL) emits high-energy sonic waves that induce calcium fractures within a target lesion to improve vessel compliance for stent placement. Low rates of major cardiac adverse events (MACE) and high rates of procedural and angiographic success were observed with IVL in the Disrupt CAD I-IV trials. Optical coherence tomography sub-studies identified calcium fracture as the likely etiology of improved vessel compliance and increased luminal diameter post-IVL. Rates of MACE, procedural, and angiographic success were consistent across the Disrupt CAD trials, suggesting IVL is less operator-dependent compared to other calcium-modifying techniques. Coronary IVL offers interventional cardiologists a safe and effective method of severe CAC modification, while providing reproducible outcomes.

Management strategies and prognosis of patients ineligible for transcatheter mitral valve replacement.

BACKGROUND: Transcatheter mitral valve replacement (TMVR) faces anatomical challenges, currently limiting widespread adoption. OBJECTIVES: To describe the natural history and prognosis of patients ineligible for various TMVR devices. METHODS: During a 4-year period (2019-2023) 3 TMVR devices (SAPIEN M3, Intrepid and Alta Valve) became available at a single institution (The Christ Hospital, Cincinnati, OH) in the setting of pivotal clinical trials or early feasibility study. Consenting patients who were deemed ineligible ≥1 of these trials were prospectively studied to capture anatomical reasons for ineligibility, cross-over to alternative mitral valve therapies (surgery or high-risk mitral transcatheter edge to edge repair [M-TEER]), and clinical events. RESULTS: A total of 61 patients (out of 71 consenting patients or 85.9 %) were deemed ineligible for TMVR during the study period. The mean age was 79.2 ± 8.8 years, 65.6 % were female, with elevated surgical risk (median STS 4.3, IQR: 2.7-7.3). The 2 most common anatomical reasons for ineligibility were increased risk of left ventricular outflow tract obstruction (LVOTO) (n = 24, 39.3 %) and annular size (n = 29, 47.5 %). During follow-up (median 277 [162-555] days) there were 7 deaths (11.5 %) and 12 (19.7 %) hospitalizations for heart failure. Management strategies included high-risk M-TEER in 11 patients (1 death [9.0 %], 0 HF hospitalizations [0 %]), surgery in 9 patients (0 deaths, 1 HF hospitalizations [11.1 %]), and medical management in 41 patients (6 deaths [14.6 %], 11 HF hospitalizations [26.8 %]) (p = 0.715 for mortality and p = 0.093 for HF hospitalizations). Residual MR ≥ moderate was 0 %, 50 %, and 100 % for surgery, M-TEER and medical treatment, respectively (p < 0.001). CONCLUSIONS: One third of patients deemed ineligible for TMVR are candidates for high-risk M-TEER or surgery with acceptable morbidity and mortality. Our results have practical implications for patient management.

Critical Analysis of Thrombocytopenia Associated With Glycoprotein IIb/IIIa Inhibitors and Potential Role of Zalunfiban, a Novel Small Molecule Glycoprotein Inhibitor, in Understanding the Mechanism(s).

Thrombocytopenia is a rare but serious complication of the intravenous glycoprotein IIb/IIIa (GPIIb/IIIa; integrin αIIbß3) receptor inhibitors (GPIs), abciximab, eptifibatide, and tirofiban. The thrombocytopenia ranges from mild (50 000-100 000 platelets/µL), to severe (20 000 to <50 000/µL), to profound (<20 000/µL). Profound thrombocytopenia appears to occur in <1% of patients receiving their first course of therapy. Thrombocytopenia can be either acute (<24 hours) or delayed (up to ~14 days). Both hemorrhagic and thrombotic complications have been reported in association with thrombocytopenia. Diagnosis requires exclusion of pseudothrombocytopenia and heparin-induced thrombocytopenia. Therapy based on the severity of thrombocytopenia and symptoms may include drug withdrawals and treatment with steroids, intravenous IgG, and platelet transfusions. Abciximab-associated thrombocytopenia is most common and due to either preformed antibodies or antibodies induced in response to abciximab (delayed). Readministration of abciximab is associated with increased risk of thrombocytopenia. Evidence also supports an immune basis for thrombocytopenia associated with the 2 small molecule GPIs. The latter bind αIIbß3 like the natural ligands and thus induce the receptor to undergo major conformational changes that potentially create neoepitopes. Thrombocytopenia associated with these drugs is also immune-mediated, with antibodies recognizing the αIIbß3 receptor only in the presence of the drug. It is unclear whether the antibody binding depends on the conformational change and whether the drug contributes directly to the epitope. Zalunfiban, a second-generation subcutaneous small molecule GPI, does not induce the conformational changes; therefore, data from studies of zalunfiban will provide information on the contribution of the conformational changes to the development of GPI-associated thrombocytopenia.

Impact of Calcium Eccentricity on the Safety and Effectiveness of Coronary Intravascular Lithotripsy: Pooled Analysis From the Disrupt CAD Studies.

BACKGROUND: Coronary intravascular lithotripsy (IVL) safely facilitates successful stent implantation in severely calcified lesions. This analysis sought to determine the relative impact of lesion calcium eccentricity on the safety and effectiveness of IVL using high-resolution optical coherence tomography imaging. METHODS: Individual patient-level data (n=262) were pooled from 4 distinct international prospective studies (Disrupt CAD I, II, III, and IV) and analyzed by an independent optical coherence tomography core laboratory. IVL performance in eccentric versus concentric calcification was analyzed by dividing calcified lesions into quartiles (≤180° [most eccentric], 181°-270°, 271°-359°, and 360° [concentric]) by maximum continuous calcium arc. RESULTS: In the 230 patients with clear imaging field on optical coherence tomography, there were no differences in preprocedure minimum lumen area, diameter stenosis, or maximum calcium thickness. The calcium length and volume index increased progressively with increasing mean and maximum continuous calcium arc (ie, concentricity). Conversely, the minimum calcium thickness decreased progressively with increasing concentricity. Post-procedure, the number of calcium fractures, fracture depth, and fracture width increased with increasing concentricity, with a 4-fold increase in the number of fractures in lesions with 360° of calcium arc compared with ≤180°. This increase in IVL-induced calcium fracture with increasing calcium burden and concentricity facilitated stent expansion and luminal gain such that there were no significant differences across quartiles. CONCLUSIONS: IVL induced calcium fractures proportional to the magnitude of coronary artery calcium, including in eccentric calcium, leading to consistent improvements in stent expansion and luminal gain in both eccentric and concentric calcified coronary lesions.

Bleeding and Ischemic Risk Prediction in Patients With High Bleeding Risk (an EVOLVE Short DAPT Analysis).

The EVOLVE Short DAPT study demonstrated the safety of truncated dual antiplatelet therapy (DAPT) in patients with a high bleeding risk (HBR) treated with SYNERGY stent(s) (Boston Scientific Company, Marlborough, Massachusetts). In this population, bleeding and ischemic risk prediction may further inform DAPT decisions. This post hoc analysis of the EVOLVE Short DAPT study identified predictors of ischemic and bleeding events up to 15 months using Cox proportional hazard models. The predicted probabilities of bleeding were calculated using the Breslow method. Of 2,009 enrolled patients, 96.9% of the patients met at least 1 HBR criteria. At 15 months, the cumulative incidences of bleeding and ischemic events were 6.3% and 6.0%, respectively. The risk of bleeding was increased in patients who received oral anticoagulants (hazard ratio [HR] 2.24, 95% confidence interval [CI] 1.50 to 3.36, p <0.001) or had peripheral vascular disease (HR 1.61, 95% CI 1.01 to 2.56, p = 0.045). The risk of ischemic events was increased in patients with diabetes (HR 1.86, 95% CI 1.24 to 2.78, p <0.01) or congestive heart failure (HR 2.06, 95% CI 1.39 to 3.04, p <0.001). Renal insufficiency/failure was associated with both endpoints. There was a strong positive correlation between the predicted probability of ischemic and bleeding events (R = 0.77, p <0.001). In 617 patients with a predicted bleeding risk <4%, ischemic events predominated, and the ischemic and bleeding rates were higher in patients with a predicted bleeding risk ≥4%. Within an HBR cohort, specific characteristics identify patients at a higher risk for ischemic and separately, bleeding events. Increased bleeding risk is tied to increased ischemic risk. In conclusion, standardized risk models are needed to inform DAPT decisions in patients with a higher risk. Clinical Trial Registration: NCT02605447.

Effects of Elective Coronary Revascularization vs Medical Therapy Alone on Noncardiac Mortality: A Meta-Analysis.

BACKGROUND: Uncertainty exists whether coronary revascularization plus medical therapy (MT) is associated with an increase in noncardiac mortality in chronic coronary syndrome (CCS) when compared with MT alone, particularly following recent data from the ISCHEMIA-EXTEND (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. OBJECTIVES: This study conducted a large-scale meta-analysis of trials comparing elective coronary revascularization plus MT vs MT alone in patients with CCS to determine whether revascularization has a differential impact on noncardiac mortality at the longest follow-up. METHODS: We searched for randomized trials comparing revascularization plus MT vs MT alone in patients with CCS. Treatment effects were measured by rate ratios (RRs) with 95% CIs, using random-effects models. Noncardiac mortality was the prespecified endpoint. The study is registered with PROSPERO (CRD42022380664). RESULTS: Eighteen trials were included involving 16,908 patients randomized to either revascularization plus MT (n = 8,665) or to MT alone (n = 8,243). No significant differences were detected in noncardiac mortality between the assigned treatment groups (RR: 1.09; 95% CI: 0.94-1.26; P = 0.26), with absent heterogeneity (I2 = 0%). Results were consistent without the ISCHEMIA trial (RR: 1.00; 95% CI: 0.84-1.18; P = 0.97). By meta-regression, follow-up duration did not affect noncardiac death rates with revascularization plus MT vs MT alone (P = 0.52). Trial sequential analysis confirmed the reliability of meta-analysis, with the cumulative Z-curve of trial evidence within the nonsignificance area and reaching futility boundaries. Bayesian meta-analysis findings were consistent with the standard approach (RR: 1.08; 95% credible interval: 0.90-1.31). CONCLUSIONS: In patients with CCS, noncardiac mortality in late follow-up was similar for revascularization plus MT compared with MT alone.

5-Year Outcomes After Bioresorbable Coronary Scaffolds Implanted With Improved Technique.

BACKGROUND: Bioresorbable vascular scaffolds (BVS) were designed to improve late event-free survival compared with metallic drug-eluting stents. However, initial trials demonstrated worse early outcomes with BVS, in part due to suboptimal technique. In the large-scale, blinded ABSORB IV trial, polymeric everolimus-eluting BVS implanted with improved technique demonstrated noninferior 1-year outcomes compared with cobalt chromium everolimus-eluting stents (CoCr-EES). OBJECTIVES: This study sought to evaluate the long-term outcomes from the ABSORB IV trial. METHODS: We randomized 2,604 patients at 147 sites with stable or acute coronary syndromes to BVS with improved technique vs CoCr-EES. Patients, clinical assessors, and event adjudicators were blinded to randomization. Five-year follow-up was completed. RESULTS: Target lesion failure at 5 years occurred in 216 (17.5%) patients assigned to BVS and 180 (14.5%) patients assigned to CoCr-EES (P = 0.03). Device thrombosis within 5 years occurred in 21 (1.7%) BVS and 13 (1.1%) CoCr-EES patients (P = 0.15). Event rates were slightly greater with BVS than CoCr-EES through 3-year follow-up and were similar between 3 and 5 years. Angina, also centrally adjudicated, recurred within 5 years in 659 patients (cumulative rate 53.0%) assigned to BVS and 674 (53.3%) patients assigned to CoCr-EES (P = 0.63). CONCLUSIONS: In this large-scale, blinded randomized trial, despite the improved implantation technique, the absolute 5-year rate of target lesion failure was 3% greater after BVS compared with CoCr-EES. The risk period for increased events was limited to 3 years, the time point of complete scaffold bioresorption; event rates were similar thereafter. Angina recurrence after intervention was frequent during 5-year follow-up but was comparable with both devices.(Absorb IV Randomized Controlled Trial; NCT02173379).

Transcatheter Treatment of Native Aortic Valve Regurgitation: The North American Experience With a Novel Device.

BACKGROUND: Transcatheter treatment of patients with native aortic valve regurgitation (AR) has been limited by anatomical factors. No transcatheter device has received U.S. regulatory approval for the treatment of patients with AR. OBJECTIVES: The aim of this study was to describe the compassionate-use experience in North America with a dedicated transcatheter device (J-Valve). METHODS: A multicenter, observational registry was assembled of compassionate-use cases of J-Valve implantation for the treatment of patients with severe symptomatic AR and elevated surgical risk in North America. The J-Valve consists of a self-expanding Nitinol frame, bovine pericardial leaflets, and a valve-locating feature. The available size matrix (5 sizes) can treat a wide range of anatomies (minimum and maximum annular perimeters 57-104 mm). RESULTS: A total of 27 patients (median age 81 years [IQR: 72-85 years], 81% at high surgical risk, 96% in NYHA functional class III or IV) with native valve AR were treated with the J-Valve during the study period (2018-2022). Procedural success (J-Valve delivered to the intended location without the need for surgical conversion or a second transcatheter heart valve) was 81% (22 of 27 cases) in the overall experience and 100% in the last 15 cases. Two cases required conversion to surgery in the early experience, leading to changes in valve design. At 30 days, there was 1 death, 1 stroke, and 3 new pacemakers (13%), and 88% of patients were in NYHA functional class I or II. No patient had residual AR of moderate or greater degree at 30 days. CONCLUSIONS: The J-Valve appears to provide a safe and effective alternative to surgery in patients with pure AR and elevated or prohibitive surgical risk.

Novel Lithotripsy-Assisted Transcatheter Aortic Valve Replacement May Reduce Risk of Aortic Root Rupture.

Background: Severe calcific aortic stenosis (AS) can be successfully treated with transcatheter aortic valve replacement (TAVR) using both balloon-expandable valves (BEV) and self-expanding valves. Challenges remain for treatment of AS with TAVR in relation to the severity of calcification involving valve leaflets, aortic annulus, and/or left ventricular outflow tract. Severe calcification presents challenges to TAVR with respect to aortic root/annular rupture and risk for peri-valve leak (PVL). Methods: Three separate patients with symptomatic severe AS and severely calcified valves underwent TAVR with BEV. Case 1 underwent TAVR without preceding intravascular lithotripsy (IVL) of the native valve and developed annular rupture requiring surgical rescue. Following this experience, TAVR in 2 subsequent cases was preceded by Shockwave IVL using a novel 12-mm × 30-mm L6 balloon placed across the native valve prior to BEV implantation. Results: Following IVL, cases 2 and 3 had uncomplicated TAVR with excellent valve frame expansion, and no significant residual gradient or PVL. Conclusions: Severely calcified aortic valves increase the risk of aortic annular rupture and PVL following TAVR. IVL prior to TAVR may enhance leaflet/ annular compliance with the potential to improve the safety and effectiveness of TAVR.

Coronary Intravascular Lithotripsy for Treatment of Severely Calcified Lesions: Long-Term Sex-Specific Outcomes.

Background: Intravascular lithotripsy (IVL) for calcified lesion preparation prior to drug-eluting stent placement has high procedural success and safety, especially in women, whereas other atheroablative approaches are associated with increased procedural complications. We sought to investigate long-term sex-based outcomes of IVL-facilitated stenting. Methods: We performed a patient-level pooled analysis of the single-arm Disrupt CAD III and IV studies. Patient baseline, procedural characteristics, and outcomes were examined according to sex at 30 days and 1 year. The primary end point was major adverse cardiac events (a composite of cardiac death, all myocardial infarction, or target vessel revascularization). Target lesion failure was defined as cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization. Results: A total of 448 patients, 106 (24%) women, were included. Women were older and less likely to be smokers. Women had smaller reference vessel diameters (2.8 mm vs 3.1 mm), shorter lesion length (23.6 mm vs 27.1 mm), and shorter total calcified length (44.4 mm vs 49.3 mm) compared with men. Post-IVL angiographic outcomes and complications were similar between women and men. At 1 year, major adverse cardiac event rates (12.3% vs 13.2%, P = .52) were not different between women and men. There were no differences between women and men (10.4% vs 11.2%; P = .43) in target lesion failure at 1 year. Conclusions: Use of IVL in the treatment of severely calcified lesions is associated with low rates of adverse clinical events and with similar safety and effectiveness in women and men at 1 year.