Eugene McFadden

Clinical End Points in Coronary Stent Trials A Case for Standardized Definitions

Background— Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end points, differences in definitions and timing of assessment have created confusion in interpretation. Methods and Results— The Academic Research Consortium is an informal collaboration between academic research organizations in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006, sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs, were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of considerations from historical legacy to key pathophysiological mechanisms and relevance to clinical interpretability, criteria for assessment of death, myocardial infarction, repeat revascularization, and stent thrombosis were developed. The broadly based consensus end point definitions in this document may be usefully applied or recognized for regulatory and clinical trial purposes. Conclusion— Although consensus criteria will inevitably include certain arbitrary features, consensus criteria for clinical end points provide consistency across studies that can facilitate the evaluation of safety and effectiveness of these devices.

Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy

Although the safety profiles of coronary stents eluting sirolimus or paclitaxel do not seem to differ from those of bare metal stents in the short-to-medium term, concern has arisen about the potential for late stent thromboses related to delayed endothelialisation of the stent struts. We report four cases of angiographically-confirmed stent thrombosis that occurred late after elective implantation of polymer-based paxlitaxel-eluting (343 and 442 days) or sirolimus-eluting (335 and 375 days) stents, and resulted in myocardial infarction. All cases arose soon after antiplatelet therapy was interrupted. If confirmed in systematic long-term follow-up studies, our findings have potentially serious clinical implications.

Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial

BACKGROUND Everolimus-eluting and paclitaxel-eluting stents, compared with bare metal stents, reduced the risk of restenosis in clinical trials with strict inclusion and exclusion criteria. We compared the safety and efficacy of the second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice. METHODS We randomly assigned 1800 consecutive patients (aged 18-85 years) undergoing percutaneous coronary intervention at one centre to treatment with everolimus-eluting or paclitaxel-eluting stents. The primary endpoint was a composite of safety and efficacy (all-cause mortality, myocardial infarction, and target vessel revascularisation) within 12 months. Patients were not told which stent they had been allocated. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01016041. FINDINGS Follow-up was completed in 1797 patients. The primary endpoint occurred in 56 (6%) of 897 patients in the everolimus-eluting stent group versus 82 (9%) of 903 in the paclitaxel-eluting stent group (relative risk 0.69 [95% CI 0.50-0.95], p value for superiority=0.02). The difference was attributable to a lower rate of stent thrombosis (6 [<1%] vs 23 [3%], 0.26 [0.11-0-64], p=0.002), myocardial infarction (25 [3%] vs 48 [5%], 0.52 [0.33-0.84], p=0.007), and target vessel revascularisation (21 [2%] vs 54 [6%], 0.39 [0.24-0.64], p=0.0001). Cardiac death, non-fatal myocardial infarction, or target lesion revascularisation occurred in 44 [5%] patients in the everolimus-eluting stent group versus 74 [8%] patients in the paclitaxel-eluting stent group, p value for superiority was 0.005. INTERPRETATION The everolimus-eluting stent is better than the second generation paclitaxel-eluting stent in unselected patients in terms of safety and efficacy. On the basis of our results, we suggest that paclitaxel-eluting stents should no longer be used in everyday clinical practice. FUNDING Unrestricted grants from Abbott Vascular and Boston Scientific.

Unrestricted Utilization of Sirolimus-Eluting Stents Compared With Conventional Bare Stent Implantation in the “Real World” The Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Registry

Background—The effectiveness of sirolimus-eluting stents in unselected patients treated in the daily practice is currently unknown. Methods and Results—Sirolimus-eluting stent implantation has been used as the default strategy for all percutaneous procedures in our hospital as part of the R apamycin-E luting S tent E valuated A t R otterdam C ardiology H ospital (RESEARCH) registry. Consecutive patients with de novo lesions (n=508) treated exclusively with sirolimus-eluting stents (SES group) were compared with 450 patients who received bare stents in the period just before (pre-SES group). Patients in the SES group more frequently had multivessel disease, more type C lesions, received more stents, and had more bifurcation stenting. At 1 year, the cumulative rate of major adverse cardiac events (death, myocardial infarction, or target vessel revascularization) was 9.7% in the SES group and 14.8% in the pre-SES group (hazard ratio [HR], 0.62 [95% CI, 0.44 to 0.89]; P =0.008). The 1-year risk of clinically driven target vessel revascularization in the SES group and in the pre-SES group was 3.7% versus 10.9%, respectively (HR, 0.35 [95% CI, 0.21 to 0.57]; P <0.001). Conclusions—Unrestricted utilization of sirolimus-eluting stents in the “real world” is safe and effective in reducing both repeat revascularization and major adverse cardiac events at 1 year compared with bare stent implantation.

Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: a randomised study.

BACKGROUND Although both prehospital fibrinolysis and primary angioplasty provide a clinical benefit over in-hospital fibrinolysis in acute myocardial infarction, they have not been directly compared. Our aim was to find out whether primary angioplasty was better than prehospital fibrinolysis. METHODS We did a randomised multicentre trial of 840 patients (of 1200 planned) who presented within 6 h of acute myocardial infarction with ST-segment elevation, initially managed by mobile emergency-care units. We assigned patients to prehospital fibrinolysis (n=419) with accelerated alteplase or primary angioplasty (n=421), and transferred all to a centre with access to emergency angioplasty. Our primary endpoint was a composite of death, non-fatal reinfarction, and non-fatal disabling stroke at 30 days. Analyses were by intention to treat. FINDINGS The median delay between onset of symptoms and treatment was 130 min in the prehospital-fibrinolysis group and 190 min (time to first balloon inflation) in the primary-angioplasty group. Rescue angioplasty was done in 26% of the patients in the fibrinolysis group. The rate of the primary endpoint was 8.2% (34 patients) in the prehospital-fibrinolysis group and 6.2% (26 patients) in the primary-angioplasty group (risk difference 1.96, 95% CI -1.53 to 5.46). 16 (3.8%) patients assigned prehospital fibrinolysis and 20 (4.8%) assigned primary angioplasty died (p=0.61). INTERPRETATION A strategy of primary angioplasty was not better than a strategy of prehospital fibrinolysis (with transfer to an interventional facility for possible rescue angioplasty) in patients presenting with early myocardial infarction.

Short- and Long-Term Clinical Outcome After Drug-Eluting Stent Implantation for the Percutaneous Treatment of Left Main Coronary Artery Disease Insights From the Rapamycin-Eluting and Taxus Stent Evaluated At Rotterdam Cardiology Hospital Registries (RESEARCH and T-SEARCH)

Background—The impact of drug-eluting stent (DES) implantation on the incidence of major adverse cardiovascular events in patients undergoing percutaneous intervention for left main (LM) coronary disease is largely unknown. Methods and Results—From April 2001 to December 2003, 181 patients underwent percutaneous coronary intervention for LM stenosis at our institution. The first cohort consisted of 86 patients (19 protected LM) treated with bare metal stents (pre-DES group); the second cohort comprised 95 patients (15 protected LM) treated exclusively with DES. The 2 cohorts were well balanced for all baseline characteristics. At a median follow-up of 503 days (range, 331 to 873 days), the cumulative incidence of major adverse cardiovascular events was lower in the DES cohort than in patients in the pre-DES group (24% versus 45%, respectively; hazard ratio [HR], 0.52 [95% CI, 0.31 to 0.88]; P=0.01). Total mortality did not differ between cohorts; however, there were significantly lower rates of both myocardial infarction (4% versus 12%, respectively; HR, 0.22 [95% CI, 0.07 to 0.65]; P=0.006) and target vessel revascularization (6% versus 23%, respectively; HR, 0.26 [95% CI, 0.10 to 0.65]; P=0.004) in the DES group. On multivariate analysis, use of DES, Parsonnet classification, troponin elevation at entry, distal LM location, and reference vessel diameter were independent predictors of major adverse cardiovascular events. Conclusions—When percutaneous coronary intervention is undertaken at LM lesions, routine DES implantation, which reduces the cumulative incidence of myocardial infarction and the need for target vessel revascularization compared with bare metal stents, should currently be the preferred strategy.

Clinical, Angiographic, and Procedural Predictors of Angiographic Restenosis After Sirolimus-Eluting Stent Implantation in Complex Patients An Evaluation From the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Study

Background—The factors associated with the occurrence of restenosis after sirolimus-eluting stent (SES) implantation in complex cases are currently unknown. Methods and Results—A cohort of consecutive complex patients treated with SES implantation was selected according to the following criteria: (1) treatment of acute myocardial infarction, (2) treatment of in-stent restenosis, (3) 2.25-mm diameter SES, (4) left main coronary stenting, (5) chronic total occlusion, (6) stented segment >36 mm, and (7) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis (OR 4.16, 95% CI 1.63 to 11.01; P <0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P <0.01), diabetes (OR 2.63, 95% CI 1.14 to 6.31; P =0.02), total stented length (per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P <0.01), reference diameter (per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P =0.03), and left anterior descending artery (OR 0.30, 95% CI 0.10 to 0.69; P <0.01). Conclusions—Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.

Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina

BACKGROUND Serotonin, a major product of platelet activation, has potent vasoactive effects in animal models, but its role in human coronary artery disease remains largely speculative. METHODS Using quantitative coronary angiography, we compared the effects of the intracoronary infusion of graded concentrations of serotonin (10(-7) to 10(-4) mol per liter) on coronary vessels in two groups of patients with different clinical presentations of coronary disease (nine with stable angina and five with variant angina), with the effects in a control group of eight subjects with normal vessels on angiography. RESULTS Normal coronary vessels had a biphasic response to intracoronary serotonin: dilation at concentrations up to 10(-5) mol per liter, but constriction at 10(-4) mol per liter. Vessels in patients with stable angina constricted at all concentrations, with mean (+/- SEM) maximal decreases in diameter of 23.9 +/- 3.6, 33.1 +/- 3.9, and 41.7 +/- 3.1 percent from base line in proximal, middle, and distal segments at a serotonin concentration of 10(-4) mol per liter. Smooth segments constricted more than irregular segments (42.0 +/- 4.6 vs. 21.1 +/- 1.6 percent). Four patients with stable angina had a marked reduction in collateral filling. All the patients with stable angina had angina during the intracoronary infusion of serotonin, and electrocardiographic changes were noted in six. All the patients with variant angina had angina, electrocardiographic changes, and localized occlusive epicardial coronary-artery spasm at concentrations of 10(-6) (n = 2) or 10(-5) (n = 3) mol per liter. CONCLUSIONS Patients with stable coronary disease do not have the normal vasodilator response to intracoronary serotonin, but rather have progressive constriction, which is particularly intense in small distal and collateral vessels. Patients with variant angina have occlusive coronary-artery spasm at a dose that dilates normal vessels and causes only slight constriction in vessels from patients with stable angina. These findings suggest that serotonin, released after the intracoronary activation of platelets, may contribute to or cause myocardial ischemia in patients with coronary artery disease.

Coronary Restenosis After Sirolimus-Eluting Stent Implantation Morphological Description and Mechanistic Analysis From a Consecutive Series of Cases

Background We describe the clinical and morphological patterns of restenosis after sirolimus‐eluting stent (SES) implantation. Methods and Results From 121 patients with coronary angiography obtained >30 days after SES implantation, restenosis (diameter stenosis >50%) was identified in 19 patients and 20 lesions (located at the proximal 5‐mm segment in 30% or within the stent in 70%). Residual dissection after the procedure or balloon trauma outside the stent was identified in 83% of the proximal edge lesions. Lesions within the stent were focal, and stent discontinuity was identified in some lesions evaluated by intravascular ultrasound. Conclusions Sirolimus‐eluting stent edge restenosis is frequently associated with local trauma outside the stent. In‐stent restenosis occurs as a localized lesion, commonly associated with a discontinuity in stent coverage. Local conditions instead of intrinsic drug‐resistance to sirolimus are likely to play a major role in post‐SES restenosis. (Circulation. 2003; 108:257‐260.)

Predictors of Restenosis After Coronary Stent Implantation

OBJECTIVES We sought to determine predictors of restenosis after coronary stenting (CS) in a consecutive series of patients. BACKGROUND Although stenting in highly selected patient groups reduces restenosis, the results of stenting in a heterogeneous patient group and the effects of clinical and procedural factors on stent restenosis are currently unclear. METHODS We analyzed the 6-month angiographic outcome of 500 lesions in 463 consecutive patients undergoing successful CS. Clinical, qualitative and quantitative angiographic variables were correlated with restenosis assessed as both a binary and a continuous variable. RESULTS Restenosis, defined as the presence of >50% diameter stenosis in the dilated segment, was present in 105 (26%) of the 405 lesions with angiographic follow-up. The mean late lumen loss during the follow-up period was 0.79+/-0.64 mm. Implantation of multiple stents (p < 0.0001) and a high acute gain (p < 0.0002) were independently associated with a higher late lumen loss. In contrast, the use of high inflation pressure (p < 0.02) and Palmaz-Schatz stents (p < 0.005) was independently associated with a lower late lumen loss. When restenosis was defined as a qualitative variable, implantation of multiple stents (p < 0.001), stenosis length (p < 0.01), small reference diameter (p < 0.02) and stent type other than Palmaz-Schatz (p < 0.01) were independent predictors of restenosis. None of the clinical variables tested was associated with restenosis. CONCLUSIONS Coronary stenting in an unselected patient group is associated with an acceptable restenosis rate. Although some risk factors were identified, the risk of restenosis was not related to most of the variables tested. This suggests that the superiority of CS over balloon angioplasty, in terms of restenosis, might also apply to subgroups of patients that were not included in the recent randomized studies.