Edoardo Camenzind

A Cause for Concern

Percutaneous coronary intervention has become the most frequently used method of myocardial revascularization.1,2 The advent of coronary stenting led to a significant decrease in the complications seen after balloon angioplasty, resulting in improved patient outcome.3,4 Yet, stented angioplasty has been plagued from the onset by early stent thrombosis (<30 days after index procedure) and late in-stent restenosis (ISR). Initially, stent thrombosis rates as high as 24% raised serious doubts as to the viability of the therapy.5 With the combined prescription of thienopyridines and aspirin for 4 to 8 weeks,6,7 together with proper stent deployment techniques,8 early stent thrombosis rates decreased to what was felt to be an unavoidable and acceptable 1% to 1.5%. At the same time, efforts to reduce the 30% late ISR rates through systemic pharmacological approaches remained unsuccessful until local radiation, a strong antiproliferative therapy, was applied to prevent or treat ISR.9–13 Vascular brachytherapy was the first illustration that delayed healing might portend an increased risk of thrombosis together with the expected reduction in restenosis. Indeed, stent thrombosis rates increased again up to 5.3%, and the time window of event occurrence was extended beyond 1 year so that the initial clinical benefit would eventually erode as time went by.13,14 Today, first-generation drug-eluting stents (gen1-DES: Cypher, Cordis, Johnson & Johnson, Miami Lakes, Fla [sirolimus-eluting stent, SES] and Taxus, Boston Scientific Corp, Natick, Mass [paclitaxel-eluting stent]) releasing an antiproliferative compound (sirolimus or paclitaxel, respectively) via a nonbioerodable polymer have been proved to reduce the incidence of ISR by up to 75%.15–39 Since the publication in 2002 of the first randomized trial16 comparing DES and bare metal stents (BMS) in highly selected patients and lesions, the use of DES in clinical practice has expanded to the majority of coronary lesion subsets …

Inhibition of restenosis with a paclitaxel-eluting, polymer-free coronary stent: the European evaLUation of pacliTaxel Eluting Stent (ELUTES) trial.

Background—The use of a stent to deliver a drug may reduce in-stent restenosis. Paclitaxel interrupts the smooth muscle cell cycle by stabilizing microtubules, thereby arresting mitosis. Methods and Results—On the basis of prior animal studies, the European evaLUation of the pacliTaxel Eluting Stent (ELUTES) pilot clinical trial (n=190) investigated the safety and efficacy of V-Flex Plus coronary stents (Cook Inc) coated with escalating doses of paclitaxel (0.2, 0.7, 1.4, and 2.7 &mgr;g/mm2 stent surface area) applied directly to the abluminal surface of the stent in de novo lesions compared with bare stent alone. The primary efficacy end point was angiographic percent diameter stenosis at 6 months. At angiographic follow-up, percent diameter stenosis was 33.9±26.7% in controls (n=34) and 14.2±16.6% in the 2.7-&mgr;g/mm2 group (n=31; P =0.006). Late loss decreased from 0.73±0.73 to 0.11±0.50 mm (P =0.002). Binary restenosis (≥50% at follow-up) decreased from 20.6% to 3.2% (P =0.056), with no significant benefit from intermediate paclitaxel doses. Freedom from major adverse cardiac events in the highest (effective) dose group was 92%, 89%, and 86% at 1, 6, and 12 months, respectively (P =NS versus control). No late stent thromboses were seen in any treated group despite clopidogrel treatment for 3 months only. Conclusions—Paclitaxel applied directly to the abluminal surface of a bare metal coronary stent, at a dose density of 2.7 &mgr;g/mm2, reduced angiographic indicators of in-stent restenosis without short- or medium-term side effects.

Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention

IMPORTANCE Dual antiplatelet therapy after percutaneous coronary intervention (PCI) reduces ischemia but increases bleeding. OBJECTIVE To develop a clinical decision tool to identify patients expected to derive benefit vs harm from continuing thienopyridine beyond 1 year after PCI. DESIGN, SETTING, AND PARTICIPANTS Among 11,648 randomized DAPT Study patients from 11 countries (August 2009-May 2014), a prediction rule was derived stratifying patients into groups to distinguish ischemic and bleeding risk 12 to 30 months after PCI. Validation was internal via bootstrap resampling and external among 8136 patients from 36 countries randomized in the PROTECT trial (June 2007-July 2014). EXPOSURES Twelve months of open-label thienopyridine plus aspirin, then randomized to 18 months of continued thienopyridine plus aspirin vs placebo plus aspirin. MAIN OUTCOMES AND MEASURES Ischemia (myocardial infarction or stent thrombosis) and bleeding (moderate or severe) 12 to 30 months after PCI. RESULTS Among DAPT Study patients (derivation cohort; mean age, 61.3 years; women, 25.1%), ischemia occurred in 348 patients (3.0%) and bleeding in 215 (1.8%). Derivation cohort models predicting ischemia and bleeding had c statistics of 0.70 and 0.68, respectively. The prediction rule assigned 1 point each for myocardial infarction at presentation, prior myocardial infarction or PCI, diabetes, stent diameter less than 3 mm, smoking, and paclitaxel-eluting stent; 2 points each for history of congestive heart failure/low ejection fraction and vein graft intervention; -1 point for age 65 to younger than 75 years; and -2 points for age 75 years or older. Among the high score group (score ≥2, n = 5917), continued thienopyridine vs placebo was associated with reduced ischemic events (2.7% vs 5.7%; risk difference [RD], -3.0% [95% CI, -4.1% to -2.0%], P < .001) compared with the low score group (score <2, n = 5731; 1.7% vs 2.3%; RD, -0.7% [95% CI, -1.4% to 0.09%], P = .07; interaction P < .001). Conversely, continued thienopyridine was associated with smaller increases in bleeding among the high score group (1.8% vs 1.4%; RD, 0.4% [95% CI, -0.3% to 1.0%], P = .26) compared with the low score group (3.0% vs 1.4%; RD, 1.5% [95% CI, 0.8% to 2.3%], P < .001; interaction P = .02). Among PROTECT patients (validation cohort; mean age, 62 years; women, 23.7%), ischemia occurred in 79 patients (1.0%) and bleeding in 37 (0.5%), with a c statistic of 0.64 for ischemia and 0.64 for bleeding. In this cohort, the high-score patients (n = 2848) had increased ischemic events compared with the low-score patients and no significant difference in bleeding. CONCLUSION AND RELEVANCE Among patients not sustaining major bleeding or ischemic events 1 year after PCI, a prediction rule assessing late ischemic and bleeding risks to inform dual antiplatelet therapy duration showed modest accuracy in derivation and validation cohorts. This rule requires further prospective evaluation to assess potential effects on patient care, as well as validation in other cohorts. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00977938.

Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy

The mechanisms of immediate and late changes after percutaneous transluminal coronary angioplasty (PTCA) and directional coronary atherectomy (DCA) were assessed by serial ultrasound imaging in 18 patients treated with PTCA and 16 treated with DCA before, immediately after, and 6 months after coronary interventions. A reduction in plaque area was the main operative mechanism of DCA, explaining 66% of lumen enlargement. In the PTCA group, the increase in lumen area was the result of a more balanced combination of plaque reduction (52% of lumen increase) and increase in total lumen area (48%); p < 0.05 versus DCA. In the PTCA group, this last mechanism was prevalent (p < 0.05) in the lesions showing wall fracture or dissection after treatment and in the lesions with a mixed or calcific composition. In the PTCA group, concentric lesions showed a greater plaque compression than eccentric lesions (p < 0.02). Plaque increase was responsible for 92% and 32% of the late lumen loss after DCA and after PTCA, respectively (p < 0.05). In PTCA patients, a chronic reduction in total vessel area was the main operative mechanism of lumen reduction (67%) and was prevalent in lesions with a mixed or calcific composition. (p < 0.05).

Mechanisms of Neointima Formation and Remodeling in the Porcine Coronary Artery

Background —To characterize the cells responsible for neointima formation after porcine coronary artery wall injury, we studied the expression of smooth muscle cell (SMC) differentiation markers in 2 models: (1) self-expanding stent implantation resulting in no or little interruption of internal elastic lamina and (2) percutaneous transluminal coronary angioplasty (PTCA) resulting in complete medial rupture and exposure of adventitia to blood components. Methods and Results —The expression of &agr;-smooth muscle (SM) actin, SM myosin heavy chain isoforms 1 and 2, desmin, and smoothelin was investigated by means of immunohistochemistry and Western blots in tissues of the arterial wall collected at different time points and in cell populations cultured from these tissues. The expression of smoothelin, a marker of late SMC differentiation, was used to discriminate between SMCs and myofibroblasts. Both stent- and PTCA-induced neointimal tissues and their cultured cell populations expressed all 4 markers. The adventitial tissue underlying PTCA-induced lesions temporarily expressed &agr;-SM actin, desmin, and SM myosin heavy chain isoforms, but not smoothelin. When placed in culture, adventitial cells expressed only &agr;-SM actin. Conclusions —Our results suggest that SMCs are the main components of coronary artery neointima after both self-expanding stent implantation and PTCA. The adventitial reaction observed after PTCA evolves with a chronology independent of that of neointima formation and probably corresponds to a myofibroblastic reaction.

Vascular Responses at Proximal and Distal Edges of Paclitaxel-Eluting Stents Serial Intravascular Ultrasound Analysis From the TAXUS II Trial

Background—On the basis of brachytherapy experience, edge stenosis has been raised as a potential limitation for drug-eluting stents. We used serial intravascular ultrasound (IVUS) to prospectively analyze vessel responses in adjacent reference segments after implantation of polymer-controlled paclitaxel-eluting stents. Methods and Results—TAXUS II was a randomized, double-blind trial with 2 consecutive patient cohorts that compared slow-release (SR) and moderate-release (MR) paclitaxel-eluting stents with control bare metal stents (BMS). By protocol, all patients had postprocedure and 6-month follow-up IVUS. Quantitative IVUS analysis was performed by an independent core laboratory, blinded to treatment allocation, in 5-mm vessel segments immediately proximal and distal to the stent. Serial IVUS was available for 106 SR, 107 MR, and 214 BMS patients. For all 3 groups, a significant decrease in proximal-edge lumen area was observed at 6 months. The decrease was comparable (by ANOVA, P =0.194) for patients in the SR (−0.54±2.1 mm2) and MR (−0.88±1.9 mm2) groups compared with the BMS (−1.02±1.9 mm2) group. For the distal edge, a significant decrease in lumen area was only observed with BMS (−0.91±2.0 mm2, P <0.0001); this decrease was significantly attenuated with SR (0.08±2.0 mm2) and MR (−0.19±1.7 mm2) stents (P <0.0001 by ANOVA). Negative vessel remodeling was observed at the proximal (−0.48±2.2 mm2, P =0.011) but not the distal edges of BMS and at neither edge of SR or MR stents. Conclusions—The marked reduction in in-stent restenosis with SR or MR stents is not associated with increased edge stenosis at 6-month follow-up IVUS. In fact, compared with BMS, there is instead a significant reduction in late lumen loss at the distal edge with TAXUS stents.

Stent thrombosis and major clinical events at 3 years after zotarolimus-eluting or sirolimus-eluting coronary stent implantation: a randomised, multicentre, open-label, controlled trial.

BACKGROUND We sought to compare the long-term safety of two devices with different antiproliferative properties: the Endeavor zotarolimus-eluting stent (E-ZES; Medtronic, Inc) and the Cypher sirolimus-eluting stent (C-SES; Cordis, Johnson & Johnson) in a broad group of patients and lesions. METHODS Between May 21, 2007 and Dec 22, 2008, we recruited 8791 patients from 36 recruiting countries to participate in this open-label, multicentre, randomised, superiority trial. Eligible patients were those aged 18 years or older undergoing elective, unplanned, or emergency procedures in native coronary arteries. Patients were randomly assigned to either receive E-ZES and C-SES (ratio 1:1). Randomisation was stratified per centre with varying block sizes of four, six, or eight patients, and concealed with a central telephone-based or web-based allocation service. The primary outcome was definite or probable stent thrombosis at 3 years and was analysed by intention to treat. Patients and investigators were aware of treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00476957. FINDINGS PROTECT randomised 8791 patients, of whom 8709 provided consent to participate and were eligible: 4357 were allocated to the E-ZES group and 4352 patients to the C-SES group. At 3 years, rates of definite or probable stent thrombosis did not differ between groups (1·4% for E-ZES [predicted: 1·5%] vs 1·8% [predicted: 2·5%] for C-SES; hazard ratio [HR] 0·81, 95% CI 0·58-1·14, p=0·22). Dual antiplatelet therapy was used in 8402 (96%) patients at discharge, 7456 (88%) at 1 year, 3041 (37%) at 2 years, and 2364 (30%) at 3 years. INTERPRETATION No evidence of superiority of E-ZES compared with C-SES in definite or probable stent thrombosis rates was noted at 3 years. Time analysis suggests a difference in definite or probable stent thrombosis between groups is emerging over time, and a longer follow-up is therefore needed given the clinical relevance of stent thrombosis. FUNDING Medtronic, Inc.

Heterogeneity of Smooth Muscle Cell Populations Cultured From Pig Coronary Artery

Objective — Heterogeneous smooth muscle cell (SMC) populations have been described in the arteries of several species. We have investigated whether SMC heterogeneity is present in the porcine coronary artery, which is widely used as a model of restenosis. Methods and Results — By using 2 isolation methods, distinct medial populations were identified: spindle-shaped SMCs (S-SMCs) after enzymatic digestion, with a “hill-and-valley” growth pattern, and rhomboid SMCs (R-SMCs) after explantation, which grow as a monolayer. Moreover, the intimal thickening that was induced after stent implantation yielded a large proportion of R-SMCs. R-SMCs exhibited high proliferative and migratory activities and high urokinase activity and were poorly differentiated compared with S-SMCs. Heparin and transforming growth factor-β2 inhibited proliferation and increased differentiation in both populations, whereas fibroblast growth factor-2 and platelet-derived growth factor-BB had the opposite effect. In addition, S-SMCs treated with fibroblast growth factor-2 or platelet-derived growth factor-BB or placed in coculture with coronary artery endothelial cells acquired a rhomboid phenotype. This change was reversible and was also observed with S-SMC clones, suggesting that it depends on phenotypic modulation rather than on selection. Conclusions — Our results show that 2 distinct SMC subpopulations can be recovered from the pig coronary artery media. The study of these subpopulations will be useful for understanding the mechanisms of restenosis.

Phenotypic Modulation of Intima and Media Smooth Muscle Cells in Fatal Cases of Coronary Artery Lesion

Objectives—Characterize the phenotypic features of media and intima coronary artery smooth muscle cells (SMCs) in mildly stenotic plaques, erosions, stable plaques, and in-stent restenosis. Methods and Results—Expression of α-smooth muscle actin (α-SMA), smooth muscle myosin heavy chains (SMMHCs), and smoothelin was investigated by immunohistochemistry followed by morphometric quantification. The cross-sectional area and the expression of cytoskeletal proteins in the media were lower in restenotic lesions and, to a lesser extent, in stable plaques compared with mildly stenotic plaques and erosions. An important expression of α-SMA was detected in the intima of the different lesions; moreover, α-SMA staining was significantly larger in erosions compared with all other conditions. In the same location, a striking decrease of SMMHCs and a disappearance of smoothelin were observed in all situations. Conclusions—Medial atrophy is prevalent in restenotic lesions and stable plaques compared with mildly stenotic plaques and erosions. Intimal SMCs of all situations exhibit a phenotypic profile, suggesting that they have modulated into myofibroblasts (MFs). The high accumulation of α-SMA–positive MFs in erosions compared with stable plaques correlates with the higher appearance of thrombotic complications in this situation.

Safety and efficacy of drug-eluting stents in women: a patient-level pooled analysis of randomised trials

BACKGROUND The safety and efficacy of drug-eluting stents (DES) in the treatment of coronary artery disease have been assessed in several randomised trials. However, none of these trials were powered to assess the safety and efficacy of DES in women because only a small proportion of recruited participants were women. We therefore investigated the safety and efficacy of DES in female patients during long-term follow-up. METHODS We pooled patient-level data for female participants from 26 randomised trials of DES and analysed outcomes according to stent type (bare-metal stents, early-generation DES, and newer-generation DES). The primary safety endpoint was a composite of death or myocardial infarction. The secondary safety endpoint was definite or probable stent thrombosis. The primary efficacy endpoint was target-lesion revascularisation. Analysis was by intention to treat. FINDINGS Of 43,904 patients recruited in 26 trials of DES, 11,557 (26·3%) were women (mean age 67·1 years [SD 10·6]). 1108 (9·6%) women received bare-metal stents, 4171 (36·1%) early-generation DES, and 6278 (54·3%) newer-generation DES. At 3 years, estimated cumulative incidence of the composite of death or myocardial infarction occurred in 132 (12·8%) women in the bare-metal stent group, 421 (10·9%) in the early-generation DES group, and 496 (9·2%) in the newer-generation DES group (p=0·001). Definite or probable stent thrombosis occurred in 13 (1·3%), 79 (2·1%), and 66 (1·1%) women in the bare-metal stent, early-generation DES, and newer-generation DES groups, respectively (p=0·01). The use of DES was associated with a significant reduction in the 3 year rates of target-lesion revascularisation (197 [18·6%] women in the bare-metal stent group, 294 [7·8%] in the early-generation DES group, and 330 [6·3%] in the newer-generation DES group, p<0·0001). Results did not change after adjustment for baseline characteristics in the multivariable analysis. INTERPRETATION The use of DES in women is more effective and safe than is use of bare-metal stents during long-term follow-up. Newer-generation DES are associated with an improved safety profile compared with early-generation DES, and should therefore be thought of as the standard of care for percutaneous coronary revascularisation in women. FUNDING Women in Innovation Initiative of the Society of Cardiovascular Angiography and Interventions.