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Background: Differences in patient characteristics, changes in treatment algorithms, and advances in medical technology could each influence the applicability of older randomized trial results to contemporary clinical practice. The DAPT Study (Dual Antiplatelet Therapy) found that longer-duration DAPT decreased ischemic events at the expense of greater bleeding, but subsequent evolution in stent technology and clinical practice may attenuate the benefit of prolonged DAPT in a contemporary population. We evaluated whether the DAPT Study population is different from a contemporary population of US patients receiving percutaneous coronary intervention and estimated the treatment effect of extended-duration antiplatelet therapy after percutaneous coronary intervention in this more contemporary cohort. Methods: We compared the characteristics of drug-eluting stent–treated patients randomly assigned in the DAPT Study to a sample of more contemporary drug-eluting stent–treated patients in the National Cardiovascular Data Registry CathPCI Registry from July 2016 to June 2017. After linking trial and registry data, we used inverse-odds of trial participation weighting to account for patient and procedural characteristics and estimated a contemporary real-world treatment effect of 30 versus 12 months of DAPT after coronary stent procedures. Results: The US drug-eluting stent–treated trial cohort included 8864 DAPT Study patients, and the registry cohort included 568 540 patients. Compared with the trial population, registry patients had more comorbidities and were more likely to present with myocardial infarction and receive 2nd-generation drug-eluting stents. After reweighting trial results to represent the registry population, there was no longer a significant effect of prolonged DAPT on reducing stent thrombosis (reweighted treatment effect: –0.40 [95% CI, –0.99% to 0.15%]), major adverse cardiac and cerebrovascular events (reweighted treatment effect, –0.52 [95% CI, –2.62% to 1.03%]), or myocardial infarction (reweighted treatment effect, –0.97% [95% CI, –2.75% to 0.18%]), but the increase in bleeding with prolonged DAPT persisted (reweighted treatment effect, 2.42% [95% CI, 0.79% to 3.91%]). Conclusions: The differences between the patients and devices used in contemporary clinical practice compared with the DAPT Study were associated with the attenuation of benefits and greater harms attributable to prolonged DAPT duration. These findings limit the applicability of the average treatment effects from the DAPT Study in modern clinical practice.

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Background: The Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) provides early drug delivery and mechanical support similar to those of metallic drug-eluting stents, followed by complete resorption in ≈3 years with recovery of vascular structure and function. The ABSORB III trial demonstrated noninferior rates of target lesion failure (cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization) at 1 year with BVS compared with cobalt chromium everolimus-eluting stents. Between 1 and 3 years and cumulative to 3 years, adverse event rates (particularly target vessel myocardial infarction and scaffold thrombosis) were increased after BVS. We sought to assess clinical outcomes after BVS through 5 years, including beyond the 3-year time point of complete scaffold resorption. Methods: Clinical outcomes from ABSORB III were analyzed by randomized device (intention to treat) cumulative to 5 years and between 3 and 5 years. Results: Rates of target lesion failure, target vessel myocardial infarction, and scaffold thrombosis were increased through the 5-year follow-up with BVS compared with everolimus-eluting stents. However, between 3 and 5 years, reductions in the relative hazards of the BVS compared with everolimus-eluting stents were observed, particularly for target lesion failure (hazard ratio, 0.83 [95% CI, 0.55–1.24] versus 1.35 [95% CI, 1.02–1.78]; P int =0.052) and scaffold thrombosis (hazard ratio, 0.26 [95% CI, 0.02–2.87] versus 3.23 [95% CI, 1.25–8.30]; P int =0.056) compared with the 0- to 3-year time period. Conclusions: In the ABSORB III trial, cumulative 5-year adverse event rates were increased after BVS compared with everolimus-eluting stents. However, the period of excess risk for BVS ended at 3 years, coincident with complete scaffold resorption. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT01751906.

Background: Prolonged dual antiplatelet therapy (DAPT) after percutaneous coronary intervention is associated with increased bleeding, despite a reduced incidence of ischemic events. The SYNERGY everolimus-eluting stent is a thin-strut platinum-chromium stent that elutes everolimus from a thin abluminal layer of bioabsorbable polymer. These design elements may facilitate rapid endothelialization and enable shorter-duration DAPT. Methods: EVOLVE Short DAPT prospectively evaluated the safety of 3-month DAPT in high bleeding risk patients treated with the SYNERGY everolimus-eluting stent, enrolling 2009 patients at 110 global sites. Patients with acute myocardial infarction or complex lesions were excluded. After percutaneous coronary intervention, patients were required to take DAPT (aspirin+P2Y 12 inhibitor) for 3 months, except those on chronic anticoagulation in whom aspirin was optional. Patients free of events (stroke, myocardial infarction, revascularization, and stent thrombosis) who discontinued P2Y 12 inhibitor at 3 months, but continued aspirin, and had at least 1 year of follow-up or an end point event were included in the primary analysis. Two powered coprimary end points were (1) death/myocardial infarction compared with a historical control and (2) study stent-related definite/probable stent thrombosis compared to a performance goal. Results: The analysis population consisted of 1487 patients. The adjusted rate of death/myocardial infarction between 3 and 15 months was 5.6% among patients receiving 3-month DAPT versus 5.7% patients in the 12-month DAPT control (propensity adjusted difference=−0.12%; 97.5% upper bound=1.63% which was less than the prespecified margin of 2.52; P non-inferiority =0.0016). The rate of study stent-related stent thrombosis between 3-15 months was 0.2% in the 3-month DAPT group (97.5% upper bound=0.63%; P =0.0005 for comparison to 1% performance goal). Conclusions: Favorable rates of ischemic outcomes were observed among selected high bleeding risk patients undergoing percutaneous coronary intervention with the SYNERGY everolimus-eluting stent who tolerated 3 months of P2Y 12 inhibitor and then discontinued it, supporting the safety of abbreviated DAPT with this stent platform. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02605447.

Introduction: Cell therapy failed to improve global LV ejection fraction (LVEF) in most trials of post-MI LV dysfunction. LVEF does not consider the effect of cell therapy on different segments of the myocardium, which may be heterogeneous across different myocardial regions in patients with regional MI. Hypothesis: Allogeneic cardiosphere-derived cells (CDCs) improve segmental (but not global) myocardial function indexed as circumferential strain by MRI. Methods: In this randomized double-blind trial, 142 post-MI patients with LVEF Results: In total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3(10.8) and 108 (87.1%) males). Segmental Ecc improvement was significantly greater in patients receiving CDC (-0.5%(4.0)) compared to placebo (0.2%(3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of -0.7% (3.5) in patients receiving CDC vs. 0.04% (3.7) in the placebo group, p=0.04). The beneficial effect of CDCs for improving segmental Ecc was greater in patients with LV ejection fraction18.8% or LV end-diastolic volume index>100 [mixed effect regression coefficients of -0.92(p=0.02),-0.78(p=0.03), and -1.16(p=0.004) respectively versus -0.58(p=0.05) for the entire cohort]. Conclusions: In patients with post-MI LV dysfunction, allogeneic CDC administration resulted in improved segmental myocardial function. This CDC induced improvement in segmental myocardial function was greater in patients with severe LV dysfunction, dilated LV and greater infarct size. (clinicaltrials.gov Identifier: NCT01458405).

Background Gait speed is a reliable measure of physical function and frailty in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). Slow gait speed pre‐TAVR predicts worse clinical outcomes post‐TAVR. The consequences of improved versus worsened physical function post‐TAVR are unknown. Methods and Results The REPRISE III (Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System–Randomized Clinical Evaluation) trial randomized high/extreme risk patients to receive a mechanically‐expanded or self‐expanding transcatheter heart valve. Of 874 patients who underwent TAVR, 576 with complete data at baseline and 1 year were included in this analysis. Slow gait speed in the 5‐m walk test was defined as P =0.001). Conclusions Marked heterogeneity exists in the trajectory of physical function after TAVR and this, more than baseline function, has clinical consequences. Identifying and optimizing factors associated with physical resilience after TAVR may improve outcomes. Registration URL: https://www.clini​caltr​ials.gov ; Unique identifier: NCT02202434.

Background: Thienopyridine plus aspirin beyond 1 year after coronary stenting reduces myocardial infarction (MI) risk and increases bleeding risk in comparison with aspirin alone. The hazard associated with late thienopyridine discontinuation and risk factors for MI after discontinuation are poorly defined. Methods: In the DAPT Study (Dual Antiplatelet Therapy), after percutaneous coronary intervention and 12 months of thienopyridine (clopidogrel or prasugrel) plus aspirin, eligible patients remained on aspirin and were randomly assigned to continued thienopyridine versus placebo for 18 months. At 30 months, patients stopped the study drug and were observed for 3 months. Cumulative incidence of MI was assessed over 3 months after randomization (months 12–15) and 3 months after study drug discontinuation (months 30–33). The MI hazard for each of these periods was assessed across randomized treatment arms and by DAPT score values Results: Among the 11 648 randomly assigned patients, the monthly cumulative incidence of MI was lower with continued thienopyridine versus placebo at 12 to 15 months (0.12% versus 0.37%, P P =0.02, in patients not treated with paclitaxel-eluting stents), and higher at 30 to 33 months (0.30% versus 0.15%, P =0.013, in all patients; in patients without paclitaxel-eluting stents, 0.18% versus 0.17%, P =0.91). The majority of MIs in both time periods (74% and 76%) were not related to stent thrombosis. After multivariable adjustment, treatment arm independently predicted MI at months 12 to 15 ( P P =0.011). During months 12 to 15, patients with DAPT scores P P =0.012, for scoresP =0.064). Conclusions: Discontinuing thienopyridine after either 12 or 30 months is associated with an early increase in MI risk, mainly unrelated to stent thrombosis; the magnitude of risk is highest in the earlier time frame, and lower in patients not treated with paclitaxel-eluting stents. Although higher DAPT scores identify patients with greater absolute ischemic benefit (relative to bleeding harm) with continued thienopyridine therapy, discontinuation at 12 months increases MI hazard regardless of DAPT score group. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00977938.

Background As transcatheter aortic valve replacement expands to younger and/or lower risk patients, the long‐term consequences of permanent pacemaker implantation are a concern. Pacemaker dependency and impact have not been methodically assessed in transcatheter aortic valve replacement trials. We report the incidence and predictors of pacemaker implantation and pacemaker dependency after transcatheter aortic valve replacement with the Lotus valve. Methods and Results A total of 912 patients with high/extreme surgical risk and symptomatic aortic stenosis were randomized 2:1 (Lotus:CoreValve) in REPRISE III (The Repositionable Percutaneous Replacement of Stenotic Aortic Valve through Implantation of Lotus Valve System—Randomized Clinical Evaluation) trial. Systematic assessment of pacemaker dependency was pre‐specified in the trial design. Pacemaker implantation within 30 days was more frequent with Lotus than CoreValve. By multivariable analysis, predictors of pacemaker implantation included baseline right bundle branch block and depth of implantation; diabetes mellitus was also a predictor with Lotus. No association between new pacemaker implantation and clinical outcomes was found. Pacemaker dependency was dynamic (30 days: 43%; 1 year: 50%) and not consistent for individual patients over time. Predictors of pacemaker dependency at 30 days included baseline right bundle branch block, female sex, and depth of implantation. No differences in mortality or stroke were found between patients who were pacemaker dependent or not at 30 days. Rehospitalization was higher in patients who were not pacemaker dependent versus patients without a pacemaker or those who were dependent. Conclusions Pacemaker implantation was not associated with adverse clinical outcomes. Most patients with a new pacemaker at 30 days were not dependent at 1 year. Mortality and stroke were similar between patients with or without pacemaker dependency and patients without a pacemaker. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier NCT 02202434.

Background: The thin-strut SYNERGY stent has an abluminal everolimus-eluting bioabsorbable polymer coating designed to facilitate vascular healing and reduce risk of stent thrombosis. In the multicenter, randomized EVOLVE II trial (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]), SYNERGY was noninferior to the durable polymer PROMUS Element Plus everolimus-eluting stent for the primary end point of 1-year target lesion failure. Longer-term clinical follow-up will support the relative efficacy and safety of SYNERGY. Methods: Patients with ≤3 native coronary lesions (reference vessel diameter ≥2.25–≤4.00 mm; length ≤34 mm) in ≤2 major epicardial vessels were randomized 1:1 to SYNERGY (N=838) or PROMUS Element Plus (N=846). EVOLVE II included a Diabetes substudy which pooled patients with diabetes mellitus from the randomized controlled trial (n=263) and from a sequential, single-arm substudy (N=203). Results: The 5-year target lesion failure rate was 14.3% for SYNERGY and 14.2% for PROMUS Element Plus ( P =0.91). Landmark analysis demonstrated similar rates of target lesion failure from discharge to 1-year ( P =0.90) and from 1 to 5 years ( P =0.94). Definite/probable stent thrombosis was infrequent in both arms (SYNERGY 0.7% versus PROMUS Element Plus 0.9%; P =0.75). There were no significant differences in the rates of cardiac death, myocardial infarction, or revascularization. Among patients with diabetes mellitus, the target lesion failure rate to 1-year was noninferior to a prespecified performance goal and to 5 years was 17.0%. Conclusions: SYNERGY demonstrated comparable outcomes to PROMUS Element Plus, with low rates of stent thrombosis and adverse events through 5 years of follow-up. Five-year clinical outcomes were favorable in patients with diabetes mellitus. These data support the long-term safety and effectiveness of SYNERGY in a broad range of patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01665053.

Background: While most self-expanding transcatheter valves are repositionable, only one fully retrievable valve is currently available. The Meridian valve is a new self-expanding valve with full retrievability properties. The objective of our study was to evaluate the early feasibility, preliminary safety, and efficacy of transcatheter aortic valve replacement with the HLT Meridian valve (HLT, Inc). Methods: This was a multicenter early feasibility study including patients with severe aortic stenosis at high surgical risk undergoing transfemoral transcatheter aortic valve replacement with the 25-mm Meridian valve. All serious adverse events were adjudicated by an independent clinical events committee according to Valve Academic Research Consortium-2 criteria. Echocardiography data were assessed by an independent echocardiography core laboratory. Results: A total of 25 patients (mean age, 85±6 years; 80% of men) were included. The valve was successfully implanted in 22 (88%) patients (annulus too large and extreme horizontal aorta in 2 and 1 unsuccessful cases, respectively). Valve retrieval because of an initial nonadequate positioning was attempted and successfully performed in 10 (40%) patients. Echocardiography post-transcatheter aortic valve replacement showed a low mean residual gradient (10±4 mm Hg) and the absence of moderate-severe aortic regurgitation (none-trace and mild aortic regurgitation in 76% and 24% of patients, respectively). Mortality at 30 days was 8%, with no cases of disabling stroke, valve embolization, or major/life-threatening bleeding complications. At 6-month follow-up, the cumulative mortality rate was 12%, with no changes in echocardiographic parameters and no cases of valve dysfunction. The majority of patients (89%) were in New York Heart Association class I-II at 6 months. Conclusions: Transcatheter aortic valve replacement with the Meridian valve was feasible and associated with acceptable early and 6-month clinical results. Valve retrieval after full valve deployment was successfully performed in all attempted cases, and valve performance was excellent, with low residual gradients, no cases of moderate-severe aortic regurgitation, and none-trace residual aortic regurgitation in the majority of patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02838680 (RADIANT-Canada); NCT02799823 (RADIANT-US).

Rationale: Despite direct immediate intervention and therapy, ST-segment–elevation myocardial infarction (STEMI) victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization, and death. Objective: To evaluate the safety and bioactivity of autologous CD34+ cell (CLBS10) intracoronary infusion in patients with left ventricular dysfunction post STEMI. Methods and Results: Patients who underwent successful stenting for STEMI and had left ventricular dysfunction (ejection fraction≤48%) ≥4 days poststent were eligible for enrollment. Subjects (N=161) underwent mini bone marrow harvest and were randomized 1:1 to receive (1) autologous CD34+ cells (minimum 10 mol/L±20% cells; N=78) or (2) diluent alone (N=83), via intracoronary infusion. The primary safety end point was adverse events, serious adverse events, and major adverse cardiac event. The primary efficacy end point was change in resting myocardial perfusion over 6 months. No differences in myocardial perfusion or adverse events were observed between the control and treatment groups, although increased perfusion was observed within each group from baseline to 6 months ( P P =0.05). At 1 year, 3.6% (N=3) and 0% deaths were observed in the control and treatment group, respectively. Conclusions: This PreSERVE-AMI (Phase 2, randomized, double-blind, placebo-controlled trial) represents the largest study of cell-based therapy for STEMI completed in the United States and provides evidence supporting safety and potential efficacy in patients with left ventricular dysfunction post STEMI who are at risk for death and major morbidity. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01495364.

Background: Women may derive differential benefit from prolonged DAPT (dual antiplatelet therapy) after coronary stenting than men. We assessed whether the risks/benefits of prolonged DAPT differ between women and men. Methods and Results: The DAPT study was a randomized double-blind, placebo-controlled trial comparing continued thienopyridine versus placebo beyond 12 months after coronary stenting. We compared rates of myocardial infarction, stent thrombosis, major adverse cardiovascular and cerebrovascular events, and bleeding by sex and randomized treatment. Of 11 648 patients, women (N=2925) were older, with higher prevalence of diabetes mellitus and lower rates of acute coronary syndrome than men. At 12 to 30 months, women had similar adjusted ischemic and bleeding events as men. The effects of continued thienopyridine therapy did not differ significantly by sex for stent thrombosis (women: hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.22–1.36; men: HR, 0.26; 95% CI, 0.15–0.44; interaction P =0.17), myocardial infarction (women: HR, 0.75; 95% CI, 0.50–1.14; men: HR, 0.46; 95% CI, 0.36–0.60; interaction P =0.052), major adverse cardiovascular and cerebrovascular events (women: HR, 0.87; 95% CI, 0.62–1.22; men: HR, 0.70; 95% CI, 0.58–0.85; interaction P =0.26), and bleeding (women: HR, 1.45; 95% CI, 0.88–2.40; men: HR, 1.78; 95% CI, 1.28–2.49; interaction P =0.50). Conclusions: Women had similar late risks of ischemia and bleeding as men after coronary stent procedures. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00977938.

Background— The Dual Antiplatelet Therapy Study is large streamlined clinical trial designed to evaluate antiplatelet treatment strategies in a broadly inclusive population of subjects treated with coronary stents. Whether large streamlined trials can successfully include a representative group of study sites and patients has not been formally assessed. Methods and Results— Within the National Cardiovascular Data Registry CathPCI Registry, we compared characteristics and outcomes of hospitals participating versus not participating in the Dual Antiplatelet Therapy Study. We also compared clinical and procedural characteristics of trial subjects undergoing percutaneous coronary intervention (PCI) with drug-eluting stents to contemporaneous patients within the National Cardiovascular Data Registry CathPCI Registry. Standardized differences between groups were estimated. Between September 2009 and July 2011, 1.1 million PCIs were performed among 1276 hospitals, of which 309 (24.2%) participated in the Dual Antiplatelet Therapy Study. Participating hospitals were larger (468 versus 311 beds), more frequently located in urban settings (61.2% versus 42.6%), and had higher annual PCI volumes (858 versus 378) compared with nonparticipating hospitals, although hospital case mix and procedural outcomes were similar. Compared with CathPCI patients, trial patients undergoing PCI with drug-eluting stents were similar with respect to race, sex, and rates of diabetes mellitus, hypertension, and smoking, although they had lower rates of prior cardiovascular disease. Conclusions— Within the Dual Antiplatelet Therapy Study, clinical trial sites had similar patient case mix and clinical outcomes as nonparticipating sites. Although trial participants were representative of PCI patients with respect to race, sex and most comorbidities, they had a lower prevalence of chronic cardiovascular disease compared with registry patients. Although a streamlined cardiovascular clinical trial may successfully involve a large number of hospitals and rapidly enroll a diverse population of patients, differences between eligible patients and those actually enrolled remained. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00977938.

Background— Effective progenitor cell recruitment to the ischemic injury zone is a prerequisite for any potential therapeutic effect. Cell uptake determinants in humans with recent myocardial infarction are not defined. We tested the hypothesis that myocardial uptake of autologous CD34 + cells delivered via an intracoronary route after recent myocardial infarction is related to left ventricular (LV) ejection fraction (LVEF) and infarct size. Methods and Results— Thirty-one subjects (age, 36–69 years; 28 men) with primary percutaneous coronary intervention–treated anterior ST-segment–elevation myocardial infarction and significant myocardial injury (median peak troponin I, 138 ng/dL [limits, 58–356 ng/dL]) and sustained LVEF depression at ≤45% were recruited. On day 10 (days 7–12), 4.3×10 6 (0.7–9.9×10 6 ) 99m Tc-extametazime–labeled autologous bone marrow CD34 + cells (activity, 77 MBq [45.9–86.7 MBq]) were administered transcoronarily (left anterior descending coronary artery). 99m Tc-methoxyisobutyl isonitrile (99 m Tc-MIBI) single-photon emission computed tomography before cell delivery showed 7 (2–11) (of 17) segments with definitely abnormal/absent perfusion. Late gadolinium-enhanced infarct core mass was 21.7 g (4.4–45.9 g), and infarct border zone mass was 29.8 g (3.9–60.2 g) (full-width at half-maximum, signal intensity thresholding algorithm). One hour after administration, 5.2% (1.7%–9.9%) of labeled cell activity localized in the myocardium (whole-body planar γ scan). Image fusion of labeled cell single-photon emission computed tomography with LV perfusion single-photon emission computed tomography or with cardiac magnetic resonance infarct imaging indicated cell uptake in the peri-infarct zone. Myocardial uptake of labeled cells activity correlated in particular with late gadolinium-enhanced infarct border zone mass ( r =0.84, P r =0.76, P r =0.45, P =0.008) and late gadolinium-enhanced infarct core ( r =0.58 and r =0.84, P r =−0.07, P =0.68) or gated single-photon emission computed tomography LVEF ( r =−0.28, P =0.16). The correlation with cardiac magnetic resonance imaging-LVEF was weak ( r =−0.38; P =0.04). Conclusions— This largest human study with labeled bone marrow CD34 + cell transcoronary transplantation after recent ST-segment–elevation myocardial infarction found that myocardial cell uptake is determined by infarct size rather than LVEF and occurs preferentially in the peri-infarct zone.

Medical therapies and revascularization play complementary roles in the treatment of patients with coronary atherosclerosis. In general, the degree of clinical benefit from percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), or medical therapy is proportional to the acuity of the clinical syndrome being treated. PCI for ST-segment elevation myocardial infarction1 and early angiography and revascularization for non–ST-segment elevation ACS2 have been demonstrated to improve survival and reduce myocardial infarction (MI) compared with medical therapy alone. Conversely, PCI in patients with stable coronary artery disease (CAD) has been proven to reduce symptoms and improve quality of life but has not been shown to prevent death or MI.3,4 Clinical trials and observational registries have demonstrated that objective evidence of myocardial ischemia is both qualitatively and quantitatively related to the subsequent risk of death and MI, and that greater reduction of ischemia with revascularization compared with medical therapy alone may correlate with improved event-free survival.5–7 This report examines the links between ischemia and prognosis, between revascularization and ischemia reduction, and therefore the likely relationship between revascularization and freedom from death/MI in patients with stable CAD. Ischemia documented by single photon emission computed tomography (SPECT) myocardial perfusion scanning (MPS) has been quantitatively correlated with the occurrence of cardiac death/MI.6 Among 10 627 consecutive patients evaluated for CAD by SPECT MPS, quantitative ischemia was directly proportional to 2-year mortality in medically treated patients, and the relative survival advantage provided by coronary revascularization (versus medical therapy alone) was directly related to the magnitude of ischemic burden (Figure 1).6,7 The observation that revascularization above a quantitative ischemic threshold involving 10% of the left ventricle (LV)7 may be associated with an incremental survival advantage has gained acceptance. A graded relationship between …

Background— A consensus definition for periprocedural myocardial infarction (MI) in coronary stent trials has not been established. Differences between a historic definition, based on modified World Health Organization (WHO) criteria, and a proposed universal definition have not been compared in a prospective clinical trial. Methods and Results— We randomly assigned 3687 patients with stable coronary artery disease to undergo stenting with either everolimus-eluting stents (2458 patients) or paclitaxel-eluting stents (1229 patients). Serial creatine kinase (CK) and CKMB or troponin measurements were obtained before and after stenting. MI was classified by protocol according to the WHO definition (total CK >2× normal with elevated CKMB) and post hoc according to the Universal/Academic Research Consortium (ARC) definition (CKMB or troponin >3× normal). Protocol MI was determined in 58 (1.6%) and universal/ARC MI in 287 (7.8%) patients within 48 hours post index procedure. There were substantial differences in frequency of universal/ARC MI if only CKMB (5.4%) or troponin (18.7%) data were included for evaluation. Total stent length was a strong predictor of both protocol and universal/ARC MI. Mortality at 2 years was low (2.3%) and was not different for either MI definition. The mortality rates did not increase with elevations of CKMB or troponin to >10× normal. Conclusions— There was a marked difference in periprocedural MI rates according to protocol or universal/ARC MI definitions. No association was present between periprocedural MI and mortality up to 2 years by either definition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00307047.

Background— Ticagrelor is the first reversibly binding oral P2Y 12 receptor antagonist. This is the first study to compare the onset and offset of platelet inhibition (IPA) with ticagrelor using the PLATO (PLATelet inhibition and patient Outcomes) trial loading dose (180 mg) with a high loading dose (600 mg) of clopidogrel. Methods and Results— In a multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 to 100 mg/d) received ticagrelor (180-mg load, 90-mg BID maintenance dose [n=57]), clopidogrel (600-mg load, 75-mg/d maintenance dose [n=54]), or placebo (n=12) for 6 weeks. Greater IPA (20 μmol/L ADP, final extent) occurred with ticagrelor than with clopidogrel at 0.5, 1, 2, 4, 8, and 24 hours after loading and at 6 weeks ( P 50% IPA (98% versus 31%, P 70% IPA (90% versus 16%, P P P =NS). IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5; IPA on day 5 for ticagrelor was similar to clopidogrel on day 7 and did not differ from placebo ( P =NS). Conclusions— Ticagrelor achieved more rapid and greater platelet inhibition than high-loading-dose clopidogrel; this was sustained during the maintenance phase and was faster in offset after drug discontinuation. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00528411.

Acute hypertension during cardiac surgery can be difficult to manage and may adversely affect patient outcomes. Clevidipine is a novel, rapidly acting dihydropyridine L-type calcium channel blocker with an ultrashort half-life that decreases arterial blood pressure (BP). The Evaluation of CLevidipine In the Perioperative Treatment of Hypertension Assessing Safety Events trial (ECLIPSE) was performed to compare the safety and efficacy of clevidipine (CLV) with nitroglycerin (NTG), sodium nitroprusside (SNP), and nicardipine (NIC) in the treatment of perioperative acute hypertension in patients undergoing cardiac surgery.We analyzed data from three prospective, randomized, open-label, parallel comparison studies of CLV to NTG or SNP perioperatively, or NIC postoperatively in patients undergoing cardiac surgery at 61 medical centers. Of the 1964 patients enrolled, 1512 met postrandomization inclusion criteria of requiring acute treatment of hypertension based on clinical criteria. The patients were randomized 1:1 for each of the three parallel comparator treatment groups. The primary outcome was the incidence of death, myocardial infarction, stroke or renal dysfunction at 30 days. Adequacy and precision of BP control was evaluated and is reported as a secondary outcome.There was no difference in the incidence of myocardial infarction, stroke or renal dysfunction for CLV-treated patients compared with the other treatment groups. There was no difference in mortality rates between the CLV, NTG or NIC groups. Mortality was significantly higher, though, for SNP-treated patients compared with CLV-treated patients (P=0.04). CLV was more effective compared with NTG (P=0.0006) or SNP (P=0.003) in maintaining BP within the prespecified BP range. CLV was equivalent to NIC in keeping patients within a prespecified BP range; however, when BP range was narrowed, CLV was associated with fewer BP excursions beyond these BP limits compared with NIC.CLV is a safe and effective treatment for acute hypertension in patients undergoing cardiac surgery.

Background: The majority of ODYSSEY Phase 3 clinical trials of the PCSK9 inhibitor alirocumab (ALI) utilized a dose increase strategy designed to individualize LDL-C lowering therapy. Objective: To describe dose response in patients on background statin whose ALI dose was increased from 75 to 150 mg every 2 wks (Q2W) at wk 12. Methods: This analysis included 6 Phase 3, randomized, double-blind, double-dummy trials of 24-104 wks duration (N=1291): ALI vs placebo (COMBO I, FH I+II) or vs ezetimibe 10 mg/day (COMBO II, OPTIONS I+II). Patients on background statin with an initial dose of ALI 75 mg Q2W had dose increase to 150 mg SQ Q2W at wk 12, if at wk 8 LDL-C was ≥70 mg/dL (or >100 mg/dl in OPTIONS studies for patients without prior CHD but other risk factors). LDL-C % reductions from baseline were compared at wk 12 (before dose increase) vs wk 24, including only patients receiving study treatment (on-treatment analysis). Results: Majority of FH and high-risk patients (73.7%) achieved LDL-C Conclusions: The 75 mg Q2W dose is sufficient for most patients to achieve risk-specific LDL-C goals. Increasing ALI dose from 75 to 150 mg Q2W at wk 12 was associated with a 14.2% additional reduction in LDL-C at wk 24, more than double the additional LDL-C reduction achieved by doubling a statin dose. The flexible dosing strategy allows the majority of patients to get to LDL-C goals without affecting the safety profile.

Background: Prior studies suggest an association between naturally high circulating levels of CD34+ cells (CD34) and better outcomes following ischemic events. Pts in the treatment arm of the PreSERVE-AMI study were infused with all CD34 yielded from their bone marrow harvest, resulting in pts with naturally higher CD34 cell counts being infused with a higher cell dose. To determine whether selection bias may have influenced results, we performed an analysis of the relationship between BM CD34 content and outcomes in PreSERVE-AMI. Methods: PreSERVE-AMI is a Phase 2, randomized, double-blind, placebo-controlled trial of autologous, BM derived CD34 (CLBS10) in pts with LV dysfunction (LVEF ≤48% by MRI) ≥4 days post-STEMI. All pts underwent mini BM harvest and were randomized 1:1 to intracoronary infusion of CD34 (minimum dose 10M±20% cells) or placebo (cell diluent). Primary safety endpoints included AEs, SAEs and MACE (CV mortality, HF hospitalization, reinfarction, revascularization). Secondary endpoints included LVEF change from baseline. Regression analyses were performed to assess the influence of BM CD34 content on outcomes. Results: 161 patients were randomized and received intracoronary infusion (Jan 2013-Dec 2014). Mean age was 57±10 and 82% were men. Mean follow-up time was 18 mo, and safety data are accruing. BM CD34 content was not associated with differences in baseline characteristics with the exception of diabetes prevalence being higher in those with higher BM CD34 count (p=0.03). In controls, regression analyses showed no association of BM CD34 content with rates of MACE (p=0.2), SAEs (p=0.4), or change in LVEF (p=0.9). However, in CD34 treated pts, there was a dose-dependent improvement in LV function (p=0.045) and dose-dependent trends in MACE and SAE reduction compared to controls. As previously reported SPECT perfusion improved to a similar degree in control and treated pts. Conclusions: These data suggest that intracoronary infusion of CD34 cells, rather than BM CD34 cell content, is responsible for the benefit observed in the CD34 treatment group. The finding of a dose-response relationship is an important advance for defining the CD34 as an active agent for tissue repair. Future studies will further define CD34 dosimetry.

Background In patients with discordance between low‐density lipoprotein ( LDL ) cholesterol and LDL particle ( LDL ‐P) concentrations, cardiovascular risk more closely correlates with LDL −P. Methods and Results We investigated the effect of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentration and size in hypercholesterolemic patients, using nuclear magnetic resonance spectroscopy. Plasma samples were collected from patients receiving alirocumab 150 mg every 2 weeks (n=26) or placebo (n=31) during a phase II , double‐blind, placebo‐controlled trial in patients ( LDL cholesterol ≥100 mg/ dL ) on a stable atorvastatin dose. In this post hoc analysis, percentage change in concentrations of LDL −P, very‐low‐density lipoprotein particles, and high‐density lipoprotein particles from baseline to week 12 was determined by nuclear magnetic resonance. Alirocumab significantly reduced mean concentrations of total LDL ‐P (−63.3% versus −1.0% with placebo) and large (−71.3% versus −21.8%) and small (−54.0% versus +17.8%) LDL ‐P subfractions and total very‐low‐density lipoprotein particle concentrations (−36.4% versus +33.4%; all P P LDL ‐P size remained relatively unchanged in both groups; however, very‐low‐density and high‐density lipoprotein particle sizes increased to a significantly greater extent with alirocumab. Conclusions Alirocumab significantly reduced LDL ‐C and LDL ‐P concentrations in hypercholesterolemic patients receiving stable atorvastatin therapy. These findings may be of particular relevance to patients with discordant LDL ‐C and LDL ‐P concentrations. Clinical Trial Registration URL : https://clinicaltrials.gov . Unique identifier: NCT01288443.

Background— Tricuspid regurgitation (TR) and right ventricular (RV) dysfunction adversely affect outcomes in patients with heart failure or mitral valve disease, but their impact on outcomes in patients with aortic stenosis treated with transcatheter aortic valve replacement has not been well characterized. Methods and Results— Among 542 patients with symptomatic aortic stenosis treated in the Placement of Aortic Transcatheter Valves (PARTNER) II trial (inoperable cohort) with a Sapien or Sapien XT valve via a transfemoral approach, baseline TR severity, right atrial and RV size and RV function were evaluated by echocardiography according to established guidelines. One-year mortality was 16.9%, 17.2%, 32.6%, and 61.1% for patients with no/trace (n=167), mild (n=205), moderate (n=117), and severe (n=18) TR, respectively ( P P P =0.003) and moderate TR (hazard ratio, 1.60; 95% confidence interval, 1.02–2.52; P =0.042) remained associated with increased mortality as did right atrial and RV enlargement, but not RV dysfunction. There was an interaction between TR and mitral regurgitation severity ( P =0.04); the increased hazard of death associated with moderate/severe TR only occurred in those with no/trace/mild mitral regurgitation. Conclusions— In inoperable patients treated with transcatheter aortic valve replacement, moderate or severe TR and right heart enlargement are independently associated with increased 1-year mortality; however, the association between moderate or severe TR and an increased hazard of death was only found in those with minimal mitral regurgitation at baseline. These findings may improve our assessment of anticipated benefit from transcatheter aortic valve replacement and support the need for future studies on TR and the right heart, including whether concomitant treatment of TR in operable but high-risk patients with aortic stenosis is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01314313.

Percutaneous revascularization of left main coronary artery (LMCA) disease has remained controversial for more than 25 years, since LMCA balloon angioplasty was first performed by Andreas Gruentzig in 1978. Summarizing his experience, Gruentzig concluded, “We have not been too successful with dilating left main stems…although the procedure is relatively simple, the potential complications are both sudden and serious.”1 Following the evolution of percutaneous catheter-based therapies to include both bare metal stent and, more recently, drug-eluting stent (DES) platforms in conjunction with advances in periprocedural and postprocedural adjunctive pharmacotherapies, interest in percutaneous LMCA revascularization, particularly unprotected left main, has been renewed. Although studies performed with bare metal stents demonstrated a low rate of in-hospital mortality, the incidence of late coronary restenosis remained high.2–6 In the Unprotected Left Main Trunk Intervention Multi-Center Assessment (ULTIMA) registry, which enrolled 279 patients with unprotected LMCA disease who had percutaneous coronary revascularization (69% bare metal stent), mortality at a 1-year follow-up was proportional to clinical risk stratification (40% in high-risk versus 3.5% in low-risk patient cohorts), and repeated revascularization was required in 34% of cases.6 The experience gleaned from these studies continued to support the American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations that in reasonable surgical candidates with LMCA disease, coronary bypass surgery is the preferred therapeutic option.7 After the introduction of DES, several small clinical series demonstrated the feasibility and short-term safety of LMCA stenting, while late clinical/angiographic outcomes appeared favorable as compared with historical (nonrandomized) patient cohorts treated with bare metal stents.3,8–11 The cumulative experience with DES treatment for LMCA demonstrated an apparent marked reduction in major adverse cardiovascular events, including target vessel revascularization, during 6 to 12 months of follow-up as compared with the precedent experience after bare metal stent deployment. Article p 2542 The clinical …

The development and introduction of new medical devices have radically changed the practice of medicine. No area of medicine has been affected more than cardiology, with new devices facilitating the effective treatment of coronary artery disease (percutaneous coronary interventions [PCIs]/stents), valvular heart disease (mechanical and bioprosthetic valves), and electrophysiological disorders (pacemakers and automatic implantable cardiodefibrillators). In addition to fueling the growth of the medical device industry, this explosion of technology has driven the development of new medical subspecialties, eg, interventional cardiology and electrophysiology. Other areas of medicine, including orthopedics and general surgery, have witnessed similar transformations. The current regulatory pathway for a significant-risk first-in-class medical device is typically a long, expensive, and risky process, culminating in a pivotal trial designed to demonstrate safety and efficacy. The pivotal trial phase is typically the most time-consuming and costly phase of the process. In the United States, medical devices are regulated by the Center for Devices and Radiological Health at the Food and Drug Administration (FDA), which has been charged by Congress to seek the “least burdensome means” when determining the scope of data required to evaluate the safety and efficacy necessary for device approval.1 Thus, pivotal trials by intention are designed to select patient cohorts most likely to demonstrate procedural benefit while limiting patient/study subject risk within the shortest time frame that can provide meaningful data. The realities of logistics, time, and resources limit the size and duration of most new device trials to 800 to 1500 patients, limiting the power of these trials to detect events with an occurrence rate of

Background— Restenosis after implantation of coronary artery stents remains a significant clinical problem. We undertook a randomized, double-blind, placebo-controlled trial to determine whether cilostazol, a drug that suppresses intimal proliferation, would reduce renarrowing in patients after stent implantation in native coronary arteries. Methods and Results— We assigned 705 patients who had successful coronary stent implantation to receive, in addition to aspirin, cilostazol 100 mg BID or placebo for 6 months; clopidogrel 75 mg daily was administered to all patients for 30 days. Restenosis was determined by quantitative coronary angiography at 6 months. The minimal luminal diameter at 6 months for cilostazol-treated patients was 1.77 mm for the analysis segment (stent plus 5-mm borders) compared with 1.62 mm in the placebo group ( P =0.01). Restenosis, defined as ≥50% narrowing, occurred in 22.0% of patients in the cilostazol group and in 34.5% of the placebo group ( P =0.002), a 36% relative risk reduction. Restenosis was significantly lower in cilostazol-treated diabetics (17.7% versus 37.7%, P =0.01) and in those with small vessels (23.6% versus 35.2%, P =0.02), long lesions (29.9% versus 46.6%, P =0.04), and left anterior descending coronary artery site (19.3% versus 39.8%, P =0.001). There was no difference in bleeding, rehospitalization, target-vessel revascularization, myocardial infarction, or death. Conclusions— Treatment with the drug cilostazol resulted in a significantly larger minimal luminal diameter and a significantly lower binary restenosis rate compared with placebo-treated patients. These favorable effects were apparent in patients at high risk for restenosis.

Background— Successful autologous skeletal myoblast transplantation into infarcted myocardium in a variety of animal models has demonstrated improvement in cardiac function. We evaluated the safety and feasibility of transplanting autologous myoblasts into infarcted myocardium of patients undergoing concurrent coronary artery bypass grafting (CABG) or left ventricular assist device (LVAD) implantation. In addition, we sought to gain preliminary information on graft survival and any associated changes in cardiac function. Methods and Results— Thirty patients with a history of ischemic cardiomyopathy participated in a phase I, nonrandomized, multicenter pilot study of autologous skeletal myoblast transplantation concurrent with CABG or LVAD implantation. Twenty-four patients with a history of previous myocardial infarction and a left ventricular ejection fraction Conclusions— These results demonstrate the survival, feasibility, and safety of autologous myoblast transplantation and suggest that this modality offers a potential therapeutic treatment for end-stage heart disease.

Background— Paclitaxel, a microtubule-stabilizing compound with potent antitumor activity, has been shown to inhibit smooth muscle cell proliferation and migration. The DELIVER trial was a prospective, randomized, blinded, multicenter clinical evaluation of the non–polymer-based paclitaxel-coated ACHIEVE stent compared with the stainless steel Multi-Link (ML) PENTA stent. Methods and Results— A total of 1043 patients with focal de novo coronary lesions, P =0.003), stent binary restenosis was 14.9% versus 20.6% ( P =0.076), and target-vessel failure was 11.9% versus 14.5% ( P =0.12) for ACHIEVE and ML PENTA, respectively. Conclusions— The ACHIEVE paclitaxel-coated stent decreased neointimal proliferation compared with the bare-metal PENTA stent; however, this reduction was insufficient to meet the prespecified primary end point of target-vessel failure and the secondary end point of binary restenosis.

Background— Statins primarily metabolized by cytochrome P450 3A4 (CYP3A4) reportedly reduce clopidogrel’s metabolism to active metabolite, thus attenuating its inhibition of platelet aggregation ex vivo. However, the clinical impact of this interaction has not been evaluated. Methods and Results— Clopidogrel for the Reduction of Events During Observation (CREDO) was a double-blind, placebo-controlled, randomized trial comparing pretreatment (300 mg) and 1-year (75 mg/d) clopidogrel therapy (clopidogrel) with no pretreatment and 1-month clopidogrel therapy (75 mg/d) (control) after a planned percutaneous coronary intervention. All patients received aspirin. The 1-year primary end point was a composite of death, myocardial infarction, and stroke. We performed a post hoc analysis to evaluate the clinical efficacy of concomitant clopidogrel and statin administration, categorizing baseline statin use to those predominantly CYP3A4-metabolized (atorvastatin, lovastatin, simvastatin, and cerivastatin) (CYP3A4-MET) or others (pravastatin and fluvastatin) (non-CYP3A4-MET). Of the 2116 patients enrolled, 1001 received a CYP3A4-MET and 158 a non-CYP3A4-MET statin. For the overall study population, the primary end point was significantly reduced in the clopidogrel group (8.5% versus 11.5%, RRR 26.9%; P =0.025). This clopidogrel benefit was similar with statin use, irrespective of treatment with a CYP3A4-MET (7.6% clopidogrel, 11.8% control, RRR 36.4%, 95% CI 3.9 to 57.9; P =0.03) or non-CYP3A4-MET statin (5.4% clopidogrel, 13.6% control, RRR 60.6%, 95% CI −23.9 to 87.4; P =0.11). Patients given atorvastatin or pravastatin had similar 1-year event rates. Additionally, concomitant therapy with statins had no impact on major or minor bleeding rates. Conclusions— Although ex vivo testing has suggested a potential negative interaction when coadministering a CYP3A4-metabolized statin with clopidogrel, this was not clinically observed statistically in a post hoc analysis of a placebo-controlled study.

The past 20 years have witnessed a dramatic evolution in medical care for patients with acute coronary syndromes (ACS). As the vast majority of hospitals lack tertiary invasive cardiac facilities, most therapeutic strategies for acute myocardial infarction have focused on pharmacological reperfusion with intravenous fibrinolytics. In addition, antiplatelet and anticoagulant therapies have gained evidence-based support for early use in patients with non–ST-segment elevation myocardial infarction. Despite the benefit derived from fibrinolysis in randomized clinical trials, many community hospitals in the United States have sought to implement primary angioplasty infarct reperfusion programs in the absence of elective provisions for percutaneous coronary intervention (PCI). In the context of new data from trials of infarct reperfusion, we should at this time examine the issues that have prompted hospitals of limited resources to provide tertiary cardiovascular services and the evidence-based provisions that must be placed on such strategies. Unquestionably, the rapid restoration of normal coronary blood flow via pharmacological or mechanical recanalization of an occluded infarct-related coronary artery limits myocardial necrosis and reduces mortality. Only recently have the time-dependent efficacies for both mechanical and pharmacological reperfusion strategies been closely scrutinized and have relative differences between these treatment modalities become evident. Although the time from infarct symptom onset to initiation of fibrinolytic reperfusion is a critical determinant for successful recanalization as well as survival, the relationship of infarct duration before PCI recanalization with procedural success or survival is less direct.1 Remarkably, few patients receive PCI within 2 hours of symptom onset, even in highly experienced centers. Indeed, in the stent Primary Angioplasty in Myocardial Infarction Study (PAMI) trial only 5.9% of all patients were reperfused within 2 hours.2 Despite time delays incurred during provision of PCI, relative benefits accompany this therapy, including enhanced survival in a meta-analysis of randomized trials of PCI versus …

Background—Plaque disruption is the inciting event for coronary thrombosis and acute coronary syndromes. Multiple factors influence plaque rupture, including the loss of vascular smooth muscle cells (VSMCs). We hypothesized that monocytes/macrophages (MMs) activated by macrophage colony-stimulating factor (M-CSF) are responsible for VSMC death.Methods and Results—VSMC apoptosis was markedly increased in the presence of both M-CSF and MMs (58.8±3.3%) compared with VSMCs plus M-CSF without MMs (15.7±1.5%,P≤0.00005), VSMCs plus MMs without M-CSF (22.7±3.7%,P≤0.0001), or control VSMCs alone (13.2±2.1%,P≤0.0001). MM cell contact was required for M-CSF–stimulated killing of VSMCs, and MMs displayed an M-CSF concentration-dependent killing effect. Abciximab binds Mac-1 (CD11b/CD18) on MMs. When added to VSMCs exposed to MMs and M-CSF, abciximab (7 μg/mL) significantly reduced VSMC apoptosis (19.1±2.2%,P≤0.0003). Therapeutic doses of tirofiban (0.35 μg/mL) and eptifibatide (5 μg/mL), which inhibit platelet glycoprotein (GP) IIb/IIIa but not Mac-1, did not block activated MM-induced VSMC apoptosis (65.0±3.4% and 51.3±2.5%, respectively). A recombinant anti–CD-18 antibody had an effect similar to that of abciximab (16.5±0.4%).Conclusions—These data suggest that monocytes and physiological concentrations of M-CSF trigger VSMC apoptosis. Abciximab and specific inhibitors of the Mac-1 receptor can antagonize this process.

Background — Platelet glycoprotein IIb/IIIa blockade with abciximab (ReoPro) improves the clinical outcomes of percutaneous coronary intervention. This registry was conducted to characterize the effects of repeated administration of abciximab during intervention. Methods and Results — We recruited 500 consecutive patients at 22 centers in the United States who were receiving abciximab for at least a second time during percutaneous coronary intervention. Safety was measured as the incidence of hypersensitivity reactions, major bleeding, and thrombocytopenia. Efficacy was assessed as event-free clinical success. Human antichimeric antibody (HACA) responses were also characterized. There were no cases of hypersensitivity (95% upper confidence bound, 0.3%), major bleeding, or death. Clinical success was 94.4%. Thrombocytopenia occurred in 23 patients (4.6%; 95% CI, 2.8% to 6.4%), including 12 (2.4%; 95% CI, 1.1% to 3.7%) who developed profound thrombocytopenia (9 cells/L). In 2 patients (0.4%), profound thrombocytopenia did not develop until after hospital discharge; in 4 (0.8%), profound thrombocytopenia recurred despite platelet transfusion. Before a first readministration, a positive HACA titer was present in 22 of 454 patients (4.8%); after a first readministration, an additional 82 of 432 (19.0%) became HACA-positive. HACA did not neutralize the in vitro inhibition of platelet aggregation by abciximab or correlate with clinical events. Conclusions — The results, including overall rates of thrombocytopenia, were consistent with randomized clinical trials of first abciximab treatment. However, there was a shift from mild to profound thrombocytopenia, and cases of delayed presentation and of recurrent thrombocytopenia were seen. These findings suggest that indications and guidelines for first-time use apply to retreatment, particularly the systematic monitoring for thrombocytopenia.

Background — Previous investigators have shown that systemic markers of inflammation may be increased in patients with acute ischemic syndromes or after percutaneous coronary revascularization and that persistent elevation in these markers is predictive of excess risk of subsequent adverse cardiac events. By virtue of its cross-reactivity with the glycoprotein IIb/IIIa, avβ3, and αMβ2 receptors, abciximab may reduce inflammatory processes. Methods and Results — Assays for the inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-α were performed on serum samples obtained from 160 patients in a placebo-controlled, randomized trial of abciximab during angioplasty. Eighty patients each had received a placebo or abciximab bolus plus a 12-hour infusion. Serum samples were drawn at baseline (before revascularization), 24 to 48 hours after study drug administration, and 4 weeks after study drug administration. Between baseline and 24 to 48 hours, the increase in C-reactive protein was 32% less in patients receiving abciximab than placebo ( P =0.025); the rise in interleukin-6 levels was 76% less in the abciximab group ( P P =0.112). By 4 weeks, most marker levels had returned to baseline, with no significant differences between placebo and abciximab groups. Conclusions — Systemic markers of inflammation increase in the first 24 to 48 hours after angioplasty, but the magnitude of that rise is diminished by periprocedural abciximab. Some of the long-term clinical benefit derived from this agent may be related to an anti-inflammatory effect.

Background —The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. Methods and Results —Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACEs: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve ≥95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P =0.006). Patients whose platelet function was P =0.009). By multivariate analysis, platelet function inhibition ≥95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P =0.04). Conclusions —Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

Background —Previous in vitro and in vivo studies have suggested an association between thrombus-related events and type of contrast media. Low osmolar contrast agents appear to improve the safety of diagnostic and coronary artery interventional procedures. However, no data are available on PTCA outcomes with an isosmolar contrast agent. Methods and Results —A multicenter prospective randomized double-blind trial was performed in 856 high-risk patients undergoing coronary artery intervention. The objective was to compare the isosmolar nonionic dimer iodixanol (n=405) with the low osmolar ionic agent ioxaglate (n=410). A composite variable of in-hospital major adverse clinical events (MACE) was the primary end point. A secondary objective was to evaluate major angiographic and procedural events during and after PTCA. The composite in-hospital primary end point was less frequent in those receiving iodixanol compared with those receiving ioxaglate (5.4% versus 9.5%, respectively; P =0.027). Core laboratory defined angiographic success was more frequent in patients receiving iodixanol (92.2% versus 85.9% for ioxaglate, P =0.004). There was a trend toward lower total clinical events at 30 days in patients randomized to iodixanol (9.1% versus 13.2% for ioxaglate, P =0.07). Multivariate predictors of in-hospital MACE were use of ioxaglate ( P =0.01) and treatment of a de novo lesion ( P =0.03). Conclusions —In this contemporary prospective multicenter trial of PTCA in the setting of acute coronary syndromes, there was a low incidence of in-hospital clinical events for both treatment groups. The cohort receiving the nonionic dimer iodixanol experienced a 45% reduction in in-hospital MACE when compared with the cohort receiving ioxaglate.

Background —Blockade of the platelet glycoprotein IIb/IIIa receptor with the monoclonal antibody fragment abciximab was shown in a placebo-controlled randomized trial to reduce the incidence of acute ischemic complications within 30 days among a broad spectrum of patients undergoing percutaneous coronary revascularization. The durability of clinical benefit in this setting has not been established. Methods and Results —A total of 2792 patients enrolled in the Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial were followed with maintenance of double-blinding for 1 year. Patients had been assigned at the time of their index coronary interventional procedure to receive placebo with standard-dose, weight-adjusted heparin (100 U/kg initial bolus), abciximab with standard-dose, weight-adjusted heparin, or abciximab with low-dose, weight-adjusted heparin (70 U/kg initial bolus). The primary outcome was the composite of death, myocardial infarction, or urgent repeat revascularization by 30 days; this composite end point and its individual components were also assessed at 6 months and 1 year. Rates of any repeat revascularization (urgent or elective), target vessel revascularization, and a composite of death, myocardial infarction, or any repeat revascularization were also reported. Follow-up at 1 year was 99% complete for survival status and 97% complete for other end points. By 1 year, the incidence of the primary composite end point was 16.1% in the placebo group, 9.6% in the abciximab with low-dose heparin group ( P P Conclusions —Acute reductions in ischemic events after percutaneous coronary intervention by abciximab are sustained over follow-up to at least 1 year. Early periprocedural myocardial infarctions suppressed by this therapy are associated with long-term mortality rates.

Background —Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow more sustained receptor antagonism with the potential for long-term secondary prevention. The pharmacodynamic efficacy, clinical safety, and outcomes after prolonged receptor blockade with an orally active GP IIb/IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit Thrombosis (ORBIT) Trial is a multicenter, placebo-controlled, randomized trial of xemilofiban, an oral platelet GP IIb/IIIa blocking agent, administered to patients after percutaneous coronary intervention. Methods and Results —After successful elective percutaneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in a dose of 15 or 20 mg. Stented patients randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary intervention and who were randomized to receive xemilofiban were administered a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients received 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 μmol/L ADP and 4 μg/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term therapy in 230 patients. All patients were followed clinically for 90 days. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 correlated with the subsequent occurrence of insignificant or mild bleeding events. Although this study was not powered to evaluate differences in clinical outcomes, a trend ( P =0.04) was observed for reduction of cardiovascular events at 3 months in patients not treated with abciximab who received the highest dose (20 mg) of xemilofiban studied. Conclusions —Xemilofiban inhibited platelet aggregation and was well tolerated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress.

Background —After angioplasty, major complications and ischemic events occur more frequently in diabetic than nondiabetic patients. To determine whether treatment with abciximab is effective in reducing these events in diabetics, we analyzed characteristics and outcomes of diabetic patients enrolled in a large multicenter study (EPILOG). Methods and Results —Of 2792 patients enrolled, 638 (23%) were diabetic. Diabetic patients were older, shorter, and heavier; more likely to be female and have three-vessel disease, prior coronary artery bypass graft surgery, a history of hypertension, or a recent myocardial infarction; and less likely to be current smokers than their nondiabetic counterparts. During hospitalization, death, myocardial infarction, or urgent revascularization occurred in 7.1% of diabetics and 7.5% of nondiabetics. By 6 months, the composite of death and myocardial infarction had occurred in 8.8% of diabetic patients and 7.4% of nondiabetics, whereas death, myocardial infarction, or revascularization had occurred in 27.2% and 22.6%, respectively. Abciximab treatment reduced death or myocardial infarction among diabetic and nondiabetic patients (hazard ratios, 0.28 [95% confidence interval (CI), 0.13 to 0.57] and 0.47 [95% CI, 0.33 to 0.70] at 30 days for diabetics and nondiabetics, respectively, and 0.36 [95% CI, 0.21 to 0.61] and 0.60 [95% CI, 0.44 to 0.82] at 6 months for diabetics and nondiabetics, respectively). Abciximab reduced target vessel revascularization among nondiabetic patients (hazard ratio, 0.78 [95% CI, 0.63 to 0.96]) but not among diabetics (hazard ratio, 1.4 [95% CI, 0.94 to 2.08]). When standard- and low-dose heparin adjuncts were compared, diabetics receiving abciximab with standard-dose heparin had marginally greater reductions in the composite of death and myocardial infarction and in target vessel revascularization than diabetics assigned to abciximab with low-dose heparin. Conclusions —Abciximab treatment in diabetic patients led to a reduction in the composite of death and myocardial infarction, which was at least as great as that seen in nondiabetic patients. However, target vessel revascularization was reduced in nondiabetic but not diabetic patients. This effect may be associated in part with lower doses of heparin. These differences may be related to differences in the platelet and coagulation systems between diabetics and nondiabetics, the greater extent of coronary artery disease in diabetics, or patient selection and management factors.

Background —The clinical and angiographic demographics of patients requiring unplanned coronary stent deployment and the optimal adjunct pharmacotherapy in this population are not well described. This report details the EPILOG trial experience with unplanned coronary stent deployment and the effect of abciximab platelet glycoprotein IIb/IIIa blockade to improve clinical outcomes during 6 months of follow-up. Methods and Results —After randomization in the EPILOG double-blind, placebo-controlled trial of abciximab therapy during percutaneous coronary intervention, 326 (12%) of 2792 patients required unplanned coronary stent deployment. Although stented patients were not distinguished by clinical variables, they had greater coronary lesion complexity by American Heart Association/American College of Cardiology criteria ( P =.003) and greater incidence of lesion length >10 mm ( P =.002), lesion eccentricity ( P =.027), irregular lesion contour ( P =.001), and bifurcation involvement ( P =.019) than nonstented patients. Unplanned stents were required less often in patients treated with abciximab and low-dose, weight-adjusted heparin than in patients receiving placebo and standard-dose heparin (9.0% versus 13.7%; P =.001). Although adverse clinical outcomes including target-vessel revascularization and bleeding events were more frequent in patients requiring unplanned coronary stent deployment, abciximab therapy reduced adverse outcomes in these patients at 30 days and 6 months to a greater extent than was observed in patients not requiring stent placement. Among stented patients, abciximab therapy did not increase bleeding events. Conclusions —Patients requiring unplanned coronary stent deployment have more complex coronary lesion morphology and a more complicated clinical course after coronary intervention. Abciximab therapy both reduces the need for unplanned stent deployment and confers clinical benefit to patients requiring an unplanned stent, without increasing bleeding complications.

Background Several biochemical markers have been investigated for the noninvasive assessment of reperfusion after myocardial infarction. Because myoglobin is released very soon after myocardial injury and clears rapidly after reperfusion, it may prove to be an excellent marker of occlusion and reperfusion. Methods and Results We examined the relation between various myoglobin measures and Thrombolysis In Myocardial Infarction (TIMI) flow grade in 96 patients enrolled in a study of front-loaded thrombolysis who underwent 90-minute angiography. We also combined myoglobin measures with models that include clinical and creatine kinase–MB variables. The myoglobin level measured within 10 minutes of acute angiography showed the best overall performance and was used for later analyses. Of the clinical variables examined, only time from symptom onset to thrombolysis and chest pain grade at angiography discriminated among TIMI flow grades. Combining the 90-minute myoglobin level and these clinical variables showed a significant difference ( P P =.044). The area under the receiver operator characteristic curve for this combined model was .88. Conclusions A single myoglobin measurement obtained 90 minutes after the start of thrombolysis, combined with select clinical variables and creatine kinase–MB levels, enhances the noninvasive prediction of reperfusion after myocardial infarction.

Background Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase. Methods and Results We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P =.006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P =.05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively). Conclusions The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.

Background The access to and growth of percutaneous coronary intervention ( PCI ) has not been fully explored with regard to geographic equity and need. Economic factors and timely access to primary PCI provide the impetus for growth in PCI centers, and this is balanced by volume standards and the benefits of regionalized care. Methods and Results Geospatial and statistical analyses were used to model capacity, growth, and access of PCI hospitals relative to population density and myocardial infarction ( MI ) prevalence at the state level. Longitudinal data were obtained for 2003–2011 from the A merican H ospital A ssociation, the U . S . Census, and the C enters for D isease C ontrol and P revention (CDC) with geographical modeling to map PCI locations. The number of PCI centers has grown 21.2% over the last 8 years, with 39% of all hospitals having interventional cardiology capabilities. During the same time, the US population has grown 8.3%, from 217 million to 235 million, and MI prevalence rates have decreased from 4.0% to 3.7%. The most densely concentrated states have a ratio of 8.1 to 12.1 PCI facilities per million of population with significant variability in both MI prevalence and average distance between PCI facilities. Conclusions Over the last decade, the growth rate for PCI centers is 1.5× that of the population growth, while MI prevalence is decreasing. This has created geographic imbalances and access barriers with excess PCI centers relative to need in some regions and inadequate access in others.

Alvin Toffler, a 20th century philosopher and author of the novel Future Shock once said, “As we move into the 21st century, not only will technology advance, but the rate at which technology advances will increase exponentially.”1 Perhaps those technological advances with greatest relevance to the health and welfare of society involve science and healthcare. Indeed, societal demands for new drug and device design and development have never been greater. Because of advances in medical care, the mortality from cardiovascular diseases has progressively declined over the past 2 decades. We currently stand on the threshold of “cures” for several of mankind’s greatest afflictions, including cancer, atherosclerotic cardiovascular disease, and human immunodeficiency disease.2 Obviously, the time efficiency of providing potentially live saving technologies to society is crucial—lives literally depend on this process. Ideally, benchmarks for safety and efficacy of technology should be satisfied before drug/device availability to assure net clinical benefit. The “gatekeeper” for medical technology is the United States Food and Drug Administration (USFDA), whose charge it is to promote and protect the public health by making safe and effective medical technologies available in a timely manner. Furthermore, in the current era of escalating costs for medical technology, the time required for the development-FDA approval-release process (“time to market”) translates directly into drug/device pricing. In recent years, as cardiovascular specialists, we have been fortunate to be provided with both primary preventative therapies (aspirin, statins, angiotensin-converting enzyme inhibitors, etc) that reduce the prevalence of cardiovascular disease, in addition to exciting new technologies (implantable cardiac defibrillators, cardiac resynchronization therapy, drug-eluting stents, etc) that substantially reduce the morbidity and mortality for those in whom this disease is established. As clinical investigators for new technologies, we are acutely aware of a widening time gap between the availability …

The specter of medical malpractice in the United States has assumed crisis proportions. The American Medical Association has declared that malpractice issues are at least “serious and deteriorating” in 44 states.1 Public awareness has been heightened by sporadic reports of physician work stoppages or closures (at least temporary) of hospital high-risk services (eg, emergency rooms, obstetrics).2 In addition, physician outmigration has occurred from the most egregiously affected regions. A crossroads in American medicine has been reached that both threatens public access to quality care and further endangers an already limited supply of subspecialty physician providers.3,4 Conversely, public disclosure of medical error and negligence5,6 has prompted reasonable demands for responsibility among healthcare providers and compensation to the injured parties. The multiple and diverse factors that have contributed to the current crisis, its medical and public ramifications, and potential remedies are detailed in the present issue of Circulation by Donald J. Palmisano, MD, JD, President of the American Medical Association, Robert Cline, MD, a cardiothoracic surgeon, and Carl J. Pepine, MD, Immediate Past President of the American College of Cardiology.7,8 At the heart of the malpractice crisis appears to be a tort system without adequate controls.9 This system has aptly demonstrated its ability to obtain large settlements in the class action case of silicone breast implants without strong scientific evidence for their harm.9 The expert opinions from noted thought leaders expressed in Circulation are remarkably passionate and consistent in their professional pride as well as commitment to compassionate, quality patient care. Our experts express hope that we are on the verge of a meaningful change in the current tort system, as well as fear of the consequences if change does not occur. On the other hand, we also must be mindful of the fact that …

Background Smoking is known to be a strong risk factor for premature atherosclerosis, myocardial infarction, and sudden cardiac death. Unexpectedly, in the reperfusion era, investigators have reported that patients who smoke have a more favorable prognosis after thrombolysis compared with nonsmokers. Since smoking is associated with a relatively hypercoagulable state, we hypothesized that the coronary occlusion responsible for infarction may be primarily thrombotic, with improved outcome relating to enhanced patency or the absence of a residual stenosis after thrombolytic therapy. Methods and Results To examine this issue, we evaluated 1619 patients treated with TPA, urokinase, or both in six consecutive myocardial infarction trials, of whom 878 (54%) were currently smoking. Patients underwent 90-minute and predischarge catheterizations, which were quantified blinded to the patients’ smoking status. As expected, baseline fibrinogen (2.8 [2.5, 3.6] versus 2.7 [2.4, 3.5] g/dL, P =.003) and hematocrit (44% [41%, 47%] versus 43% [40%, 45%], P =.0001) levels were greater in smokers. Although there were no differences between smokers and nonsmokers with regard to 90-minute patency (73% versus 74%), smokers were more likely to have TIMI-3 flow (41.1% versus 34.6%, P =.034), with a larger minimum lumen diameter of the infarct stenosis both acutely (0.82 [0.51, 1.11] versus 0.72 [0.43, 1.04] mm, P =.0432) and at follow-up (1.2 [0.8, 1.74] versus 1.0 [0.7, 1.5], P =.002). Although smokers tended to have reduced in-hospital mortality compared with nonsmokers in univariate analysis (4.0% versus 8.9%, P =.0001), after adjustment for baseline differences between smokers and nonsmokers in age (54 [47, 62] versus 60 [54, 68] years, P P P P =.0069), smoking history was of no independent prognostic significance. Conclusions Therefore, smokers have a relatively hypercoagulable state, documented by increased hematocrit and fibrinogen levels. Quantitative coronary angiographic analysis suggests that the mechanism of infarction in smokers is more often thrombosis of a less critical atherosclerotic lesion compared with nonsmokers. Enhanced perfusion status, as well as favorable baseline clinical and angiographic characteristics, may be responsible for the more benign prognosis of current smokers.

BACKGROUND Thrombosis has been implicated as central to the clinical complications of coronary angioplasty (PTCA). Chimeric monoclonal 7E3 Fab (c7E3 Fab) is the first of a new class of antiplatelet drugs directed at the platelet glycoprotein IIb/IIIa integrin. This study was performed to determine the pharmacodynamics of c7E3 Fab administration during PTCA and to gain an initial clinical experience with this novel agent. METHODS AND RESULTS The study was a multicenter, open-label, dose-escalation study conducted in two stages. Enrollment included 56 patients scheduled for elective PTCA who were estimated to be at moderate to high risk of sustaining ischemic complications. All patients were given aspirin and heparin. The study drug was given at least 10 minutes before PTCA. In stage 1, increasing bolus doses of c7E3 Fab were given to 15 patients; a bolus dose of 0.25 mg/kg was found to result in blockade of > 80% of the receptors and reduce platelet aggregation to < 20% compared with baseline, establishing this dose as that necessary to sufficiently suppress platelet activity. In stage 2, additional c7E3 Fab was administered by continuous infusion to 32 patients for progressively longer periods of time (up to 24 hours) to confirm that platelet inhibition could be maintained with prolonged drug infusion. Also, 9 patients otherwise meeting entry criteria were given placebo. There were no thrombotic events among patients receiving c7E3 Fab. Overall procedural and clinical success and complication rates as well as rates of bleeding were statistically similar among groups. However, minor bleeding was more frequent with administration of the active drug. CONCLUSIONS The novel antiplatelet agent c7E3 Fab can be administered during PTCA in combination with aspirin and heparin. Suppression of platelet activity is dose dependent and can be maintained for up to 24 hours. Further evaluation will be required to determine the extent of improvement in ischemic complication and restenosis rates and to provide additional insight into the safety profile of this potent monoclonal platelet antibody.