Fausto Feres

Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated Stents in Human Coronary Arteries

Background—Restenosis remains an important limitation of interventional cardiology. Therefore, we aimed to determine the safety and efficacy of sirolimus (a cell-cycle inhibitor)-coated BX Velocity...

Three vs Twelve Months of Dual Antiplatelet Therapy After Zotarolimus-Eluting Stents The OPTIMIZE Randomized Trial

IMPORTANCE The current recommendation is for at least 12 months of dual antiplatelet therapy after implantation of a drug-eluting stent. However, the optimal duration of dual antiplatelet therapy with specific types of drug-eluting stents remains unknown. OBJECTIVE To assess the clinical noninferiority of 3 months (short-term) vs 12 months (long-term) of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) with zotarolimus-eluting stents. DESIGN, SETTING, AND PATIENTS The OPTIMIZE trial was an open-label, active-controlled, 1:1 randomized noninferiority study including 3119 patients in 33 sites in Brazil between April 2010 and March 2012. Clinical follow-up was performed at 1, 3, 6, and 12 months. Eligible patients were those with stable coronary artery disease or history of low-risk acute coronary syndrome (ACS) undergoing PCI with zotarolimus-eluting stents. INTERVENTIONS After PCI with zotarolimus-eluting stents, patients were prescribed aspirin (100-200 mg daily) and clopidogrel (75 mg daily) for 3 months (n = 1563) or 12 months (n = 1556), unless contraindicated because of occurrence of an end point. MAIN OUTCOMES AND MEASURES The primary end point was net adverse clinical and cerebral events (NACCE; a composite of all-cause death, myocardial infarction [MI], stroke, or major bleeding); the expected event rate at 1 year was 9%, with a noninferiority margin of 2.7%. Secondary end points were major adverse cardiac events (MACE; a composite of all-cause death, MI, emergent coronary artery bypass graft surgery, or target lesion revascularization) and Academic Research Consortium definite or probable stent thrombosis. RESULTS NACCE occurred in 93 patients receiving short-term and 90 patients receiving long-term therapy (6.0% vs 5.8%, respectively; risk difference, 0.17 [95% CI, -1.52 to 1.86]; P = .002 for noninferiority). Kaplan-Meier estimates demonstrated MACE rates at 1 year of 8.3% (128) in the short-term group and 7.4% (114) in the long-term group (HR, 1.12 [95% CI, 0.87-1.45]). Between 91 and 360 days, no statistically significant association was observed for NACCE (39 [2.6%] vs 38 [2.6%] for the short- and long-term groups, respectively; HR, 1.03 [95% CI, 0.66-1.60]), MACE (78 [5.3%] vs 64 [4.3%]; HR, 1.22 [95% CI, 0.88-1.70]), or stent thrombosis (4 [0.3%] vs 1 [0.1%]; HR, 3.97 [95% CI, 0.44-35.49]). CONCLUSIONS AND RELEVANCE In patients with stable coronary artery disease or low-risk ACS treated with zotarolimus-eluting stents, 3 months of dual antiplatelet therapy was noninferior to 12 months for NACCE, without significantly increasing the risk of stent thrombosis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01113372.

Two-Year Angiographic and Intravascular Ultrasound Follow-Up After Implantation of Sirolimus-Eluting Stents in Human Coronary Arteries

Background—The safety and efficacy of sirolimus-eluting stenting have been demonstrated, but the outcome of patients treated with this novel technology beyond the first year remains unknown. We sought to evaluate the angiographic, intravascular ultrasound (IVUS), and clinical outcomes of patients treated with sirolimus-eluting stents 2 years after implantation. Methods and Results—This study included 30 patients treated with sirolimus-eluting Bx Velocity stenting (slow release [SR], n=15, and fast release [FR], n=15) in São Paulo, Brazil. Twenty-eight patients underwent 2-year angiographic and IVUS follow-up. No deaths occurred during the study period. In-stent late loss was slightly greater in the FR group (0.28±0.4 mm) than in the SR group (−0.09±0.23 mm, P =0.007). No patient had in-stent restenosis. At 2-year follow-up, only 1 patient (FR group) had a 52% diameter stenosis within the lesion segment, which required repeat revascularization. The target-vessel revascularization rate for the entire cohort was 10% (3/30) at 2 years. All other patients had ≤35% diameter stenosis. Angiographic lumen loss at the stent edges was also minimal (in-lesion late loss was 0.33±0.42 mm [FR] and 0.13±0.29 mm [SR]). In-stent neointimal hyperplasia volume, as detected by IVUS, remained minimal after 2 years (FR= 9.90±9 mm3 and SR=10.35±9.3 mm3). Conclusions—This study demonstrates the safety and efficacy of sirolimus-eluting Bx Velocity stents 2 years after implantation in humans. In-stent lumen dimensions remained essentially unchanged at 2-year follow-up in the 2 groups, although angiographic lumen loss was slightly higher in the FR group. Restenosis “catch-up” was not found in our patient population.

Sirolimus-Eluting Stent for the Treatment of In-Stent Restenosis. A Quantitative Coronary Angiography and Three-Dimensional Intravascular Ultrasound Study

Background—We have previously reported the safety and effectiveness of sirolimus-eluting stents for the treatment of de novo coronary lesions. The present investigation explored the potential of this technology to treat in-stent restenosis. Methods and Results—Twenty-five patients with in-stent restenosis were successfully treated with the implantation of 1 or 2 sirolimus-eluting Bx VELOCITY stents in São Paulo, Brazil. Nine patients received 2 stents (1.4 stents per lesion). Angiographic and volumetric intravascular ultrasound (IVUS) images were obtained after the procedure and at 4 and 12 months. All vessels were patent at the time of 12-month angiography. Angiographic late loss averaged 0.07±0.2 mm in-stent and −0.05±0.3 mm in-lesion at 4 months, and 0.36±0.46 mm in-stent and 0.16±0.42 mm in-lesion after 12 months. No patient had in-stent or stent margin restenosis at 4 months, and only one patient developed in-stent restenosis at 1-year follow-up. Intimal hyperplasia by 3-dimensional IVUS was 0.92±1.9 mm3 at 4 months and 2.55±4.9 mm3 after 1 year. Percent volume obstruction was 0.81±1.7% and 1.76±3.4% at the 4- and 12-month follow-up, respectively. There was no evidence of stent malapposition either acutely or in the follow-up IVUS images, and there were no deaths, stent thromboses, or repeat revascularizations. Conclusion—This study demonstrates the safety and the potential utility of sirolimus-eluting Bx VELOCITY stents for the treatment of in-stent restenosis.

Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials

BACKGROUND Despite recent studies, the optimum duration of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent placement remains uncertain. We performed a meta-analysis with several analytical approaches to investigate mortality and other clinical outcomes with different DAPT strategies. METHODS We searched Medline, Embase, Cochrane databases, and proceedings of international meetings on Nov 20, 2014, for randomised controlled trials comparing different DAPT durations after drug-eluting stent implantation. We extracted study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes. DAPT duration was categorised in each study as shorter versus longer, and as 6 months or shorter versus 1 year versus longer than 1 year. Analyses were done by both frequentist and Bayesian approaches. FINDINGS We identified ten trials published between Dec 16, 2011, and Nov 16, 2014, including 31,666 randomly assigned patients. By frequentist pairwise meta-analysis, shorter DAPT was associated with significantly lower all-cause mortality compared with longer DAPT (HR 0·82, 95% CI 0·69-0·98; p=0·02; number needed to treat [NNT]=325), with no significant heterogeneity apparent across trials. The reduced mortality with shorter compared with longer DAPT was attributable to lower non-cardiac mortality (0·67, 0·51-0·89; p=0·006; NNT=347), with similar cardiac mortality (0·93, 0·73-1·17; p=0.52). Shorter DAPT was also associated with a lower risk of major bleeding, but a higher risk of myocardial infarction and stent thrombosis. We noted similar results in a Bayesian framework with non-informative priors. By network meta-analysis, patients treated with 6-month or shorter DAPT and 1-year DAPT had higher risk of myocardial infarction and stent thrombosis but lower risk of mortality compared with patients treated with DAPT for longer than 1 year. Patients treated with DAPT for 6 months or shorter had similar rates of mortality, myocardial infarction, and stent thrombosis, but lower rates of major bleeding than did patients treated with 1-year DAPT. INTERPRETATION Although treatment with DAPT beyond 1 year after drug-eluting stent implantation reduces myocardial infarction and stent thrombosis, it is associated with increased mortality because of an increased risk of non-cardiovascular mortality not offset by a reduction in cardiac mortality. FUNDING None.

Four-Year Angiographic and Intravascular Ultrasound Follow-Up of Patients Treated With Sirolimus-Eluting Stents

Background—Despite the proven superiority of sirolimus-eluting stents (SESs) compared with bare stents in the first year after implantation, long-term outcomes of patients treated with these novel devices remain unknown. Our goal was to evaluate the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with SESs 4 years after implantation. Methods and Results—The study included 30 patients treated with sirolimus-eluting Bx Velocity stenting (slow release [SR; n=15] and fast release [FR; n=15]). Twenty-six patients underwent 4-year angiographic and IVUS follow-up and had matched assessments at all time points (index and 4-, 12-, 24-, and 48-month follow-up). One death occurred during the study period in a patient with a patent SES. There were no target-vessel revascularizations or thromboses between 2- and 4-year follow-up examinations. There was no stent thrombosis, target-lesion revascularization, death, or myocardial infarction in the SR group up to 4 years. Cumulative event-free survival rate was 87% for the total population (80% in the FR group and 93% in the SR group). In-stent late loss was slightly greater in the FR group (0.41±0.49 mm) than the SR group (0.09±0.23) after 4 years. One patient in the FR group had a 52% in-stent restenosis lesion. Percent neointimal hyperplasia volume, as detected by IVUS, remained minimal after 4 years (FR=9.1% and SR=5.7%). Conclusions—This study confirms the longevity of the optimal outcomes observed in patients treated with sirolimus-eluting Bx Velocity stents 4 years after implantation. In-stent lumen dimensions remained essentially unchanged at 4-year follow-up, particularly in the population treated with the currently available SES (SR formulation).

Short- Versus Long-Term Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation: An Individual Patient Data Pairwise and Network Meta-Analysis

BACKGROUND Randomized controlled trials comparing short- (≤6 months) with long-term (≥1 year) dual antiplatelet therapy (DAPT) after drug-eluting stent(s) (DES) placement have been insufficiently powered to detect significant differences in the risk of major adverse cardiac events (MACE). OBJECTIVES This study sought to compare clinical outcomes between short- (≤6 months) and long-term (1 year) DAPT and among 3 months, 6 months, and 1 year of DAPT post-DES placement by performing an individual patient data pairwise and network meta-analysis. METHODS Randomized controlled trials comparing DAPT durations after DES placement were searched through the MEDLINE, EMBASE, and Cochrane databases and in international meeting proceedings. The primary study outcome was 1-year risk of MACE (cardiac death, myocardial infarction, or definite/probable stent thrombosis). RESULTS Four trials including 8,180 randomized patients were identified. At 1-year follow-up, short-term DAPT was associated with similar rates of MACE (hazard ratio [HR]: 1.11; 95% confidence interval [CI]: 0.86 to 1.43; p = 0.44), but significantly lower rates of bleeding (HR: 0.66; 95% CI: 0.46 to 0.94; p = 0.03) versus prolonged DAPT. Comparable results were apparent in the landmark period between DAPT discontinuation and 1-year follow-up (for MACE: HR: 1.20; 95% CI: 0.77 to 1.89; p = 0.42) (for bleeding: HR: 0.44; 95% CI: 0.21 to 0.91; p = 0.03). There were no significant differences in 1-year rates of MACE among 3-month versus 1-year DAPT, 6-month versus 1-year DAPT, or 3-month versus 6-month DAPT. CONCLUSIONS Compared with prolonged DAPT, short-term DAPT is associated with similar rates of MACE but lower rates of bleeding after DES placement.

Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials

BACKGROUND Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor prevents ischaemic events after coronary stenting, but increases bleeding. Guidelines support weighting bleeding risk before the selection of treatment duration, but no standardised tool exists for this purpose. METHODS A total of 14 963 patients treated with DAPT after coronary stenting-largely consisting of aspirin and clopidogrel and without indication to oral anticoagulation-were pooled at a single-patient level from eight multicentre randomised clinical trials with independent adjudication of events. Using Cox proportional hazards regression, we identified predictors of out-of-hospital Thrombosis in Myocardial Infarction (TIMI) major or minor bleeding stratified by trial, and developed a numerical bleeding risk score. The predictive performance of the novel score was assessed in the derivation cohort and validated in patients treated with percutaneous coronary intervention from the PLATelet inhibition and patient Outcomes (PLATO) trial (n=8595) and BernPCI registry (n=6172). The novel score was assessed within patients randomised to different DAPT durations (n=10 081) to identify the effect on bleeding and ischaemia of a long (12-24 months) or short (3-6 months) treatment in relation to baseline bleeding risk. FINDINGS The PRECISE-DAPT score (age, creatinine clearance, haemoglobin, white-blood-cell count, and previous spontaneous bleeding) showed a c-index for out-of-hospital TIMI major or minor bleeding of 0·73 (95% CI 0·61-0·85) in the derivation cohort, and 0·70 (0·65-0·74) in the PLATO trial validation cohort and 0·66 (0·61-0·71) in the BernPCI registry validation cohort. A longer DAPT duration significantly increased bleeding in patients at high risk (score ≥25), but not in those with lower risk profiles (pinteraction=0·007), and exerted a significant ischaemic benefit only in this latter group. INTERPRETATION The PRECISE-DAPT score is a simple five-item risk score, which provides a standardised tool for the prediction of out-of-hospital bleeding during DAPT. In the context of a comprehensive clinical evaluation process, this tool can support clinical decision making for treatment duration. FUNDING None.

Very late thrombosis after drug-eluting stents.

Stent thrombosis is a rare but potentially fatal complication of percutaneous treatment of coronary disease. Its occurrence after drug eluting stent (DES) placement has raised concerns, especially when it occurs late after the stent implantation. The mechanisms of late thrombosis after DES have yet to be completely understood. By means of serial angiography and intravascular (IVUS) images we described a relatively new and unusual vessel response to drug‐eluting stents (e.g. huge positive remodeling in all vessel extension), leading to impressive late‐acquired incomplete stent apposition and finally causing stent thrombosis and acute myocardial infarction. After describing the two cases, one after Cypher stent implantation and one after Taxus stent implantation, we briefly reviewed the literature available on stent thrombosis with special emphasis on its late occurrence.

1-year results of the hydroxyapatite polymer-free sirolimus-eluting stent for the treatment of single de novo coronary lesions: the VESTASYNC I trial.

OBJECTIVES We sought to assess the safety and efficacy of the novel VESTAsync-eluting stent (MIV Therapeutics, Atlanta, Georgia) combining a stainless steel platform with a nanothin-microporous hydroxyapatite surface coating impregnated with a polymer-free low-dose of sirolimus (55 microg). BACKGROUND Durable polymers in first-generation drug-eluting stents (DES) have been linked to local inflammatory reaction leading to a positive vessel remodeling, late incomplete stent apposition, and in some cases, stent thrombosis. The removal of the polymer from the DES system could increase the safety profile of this novel technology. METHODS A total of 15 patients with single de novo lesions in native coronary arteries with 3.0- to 3.5-mm diameter and <or=14-mm length were enrolled in this first-in-man study. Primary end point was in-stent late lumen loss (LL) at 4 and 9 months. RESULTS Baseline characteristics included mean age of 63 years and 33% of diabetics. Reference vessel diameter and lesion length were 2.7 +/- 0.3 mm and 10 +/- 2.0 mm, respectively. Procedure success was obtained in all cases. Lifelong aspirin and 5-month clopidogrel treatment were prescribed to all patients. At 4 months, in-stent LL and percentage of neointimal hyperplasia were 0.3 +/- 0.25 mm and 2.6 +/- 2.2%, respectively, with a nonsignificant increase at 9 months (0.36 +/- 0.23 mm and 4.0 +/- 2.2%, respectively). Serial intravascular ultrasound did not show late incomplete stent apposition. There were no major adverse cardiac events within 1 year of follow-up. CONCLUSIONS The novel VESTAsync-eluting stent was effective in reducing LL and neointimal hyperplasia at 4 and 9 months, with no evidence of late catch-up by quantitative coronary angiography or intravascular ultrasound.