Nicholas Amoroso

Short- and Long-Term Outcomes With Drug-Eluting and Bare-Metal Coronary Stents A Mixed-Treatment Comparison Analysis of 117 762 Patient-Years of Follow-Up From Randomized Trials

Background— Drug-eluting stents (DES) have been in clinical use for nearly a decade; however, the relative short- and long-term efficacy and safety of DES compared with bare-metal stents (BMS) and among the DES types are less well defined. Methods and Results— PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials, until March 2012, that compared any of the Food and Drug Administration–approved durable stent and polymer DES (sirolimus-eluting stent [SES], paclitaxel-eluting stent [PES], everolimus-eluting stent [EES], zotarolimus-eluting stent [ZES], and ZES-Resolute [ZES-R]) with each other or against BMS for de novo coronary lesions, enrolling at least 100 patients and with follow-up of at least 6 months. Short-term (⩽1 year) and long-term efficacy (target-vessel revascularization, target-lesion revascularization) and safety (death, myocardial infarction, stent thrombosis) outcomes were evaluated and trial-level data pooled by both mixed-treatment comparison and direct comparison analyses. From 76 randomized clinical trials with 117 762 patient-years of follow-up, compared with BMS, each DES reduced long-term target-vessel revascularization (39%–61%), but the magnitude varied by DES type (EES∼SES∼ZES-R>PES∼ZES>BMS), with a >42% probability that EES had the lowest target-vessel revascularization rate. There was no increase in the risk of any long-term safety outcomes, including stent thrombosis, with any DES (versus BMS). In addition, there was reduction in myocardial infarction (all DES except PES versus BMS) and stent thrombosis (with EES versus BMS: Rate ratio, 0.51; 95% credibility interval, 0.35–0.73). The safest DES appeared to be EES (>86% probability), with reduction in myocardial infarction and stent thrombosis compared with BMS. Short-term outcomes were similar to long-term outcomes, with SES, ZES-R, and everolimus-eluting stent being the most efficacious and EES being the safest stent. Conclusions— DES are highly efficacious at reducing the risk of target-vessel revascularization without an increase in any safety outcomes, including stent thrombosis. However, among the DES types, there were considerable differences, such that EES, SES, and ZES-R were the most efficacious and EES was the safest stent.Background— Drug-eluting stents (DES) have been in clinical use for nearly a decade; however, the relative short- and long-term efficacy and safety of DES compared with bare-metal stents (BMS) and among the DES types are less well defined. Methods and Results— PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials, until March 2012, that compared any of the Food and Drug Administration–approved durable stent and polymer DES (sirolimus-eluting stent [SES], paclitaxel-eluting stent [PES], everolimus-eluting stent [EES], zotarolimus-eluting stent [ZES], and ZES-Resolute [ZES-R]) with each other or against BMS for de novo coronary lesions, enrolling at least 100 patients and with follow-up of at least 6 months. Short-term (≤1 year) and long-term efficacy (target-vessel revascularization, target-lesion revascularization) and safety (death, myocardial infarction, stent thrombosis) outcomes were evaluated and trial-level data pooled by both mixed-treatment comparison and direct comparison analyses. From 76 randomized clinical trials with 117 762 patient-years of follow-up, compared with BMS, each DES reduced long-term target-vessel revascularization (39%–61%), but the magnitude varied by DES type (EES∼SES∼ZES-R>PES∼ZES>BMS), with a >42% probability that EES had the lowest target-vessel revascularization rate. There was no increase in the risk of any long-term safety outcomes, including stent thrombosis, with any DES (versus BMS). In addition, there was reduction in myocardial infarction (all DES except PES versus BMS) and stent thrombosis (with EES versus BMS: Rate ratio, 0.51; 95% credibility interval, 0.35–0.73). The safest DES appeared to be EES (>86% probability), with reduction in myocardial infarction and stent thrombosis compared with BMS. Short-term outcomes were similar to long-term outcomes, with SES, ZES-R, and everolimus-eluting stent being the most efficacious and EES being the safest stent. Conclusions— DES are highly efficacious at reducing the risk of target-vessel revascularization without an increase in any safety outcomes, including stent thrombosis. However, among the DES types, there were considerable differences, such that EES, SES, and ZES-R were the most efficacious and EES was the safest stent. # Clinical Perspective {#article-title-141}

Bare metal stents, durable polymer drug eluting stents, and biodegradable polymer drug eluting stents for coronary artery disease: mixed treatment comparison meta-analysis

Objective To compare the efficacy and safety of biodegradable polymer drug eluting stents with those of bare metal stents and durable polymer drug eluting stents. Design Mixed treatment comparison meta-analysis of 258 544 patient years of follow-up from randomized trials. Data sources and study selection PubMed, Embase, and Central were searched for randomized trials comparing any of the Food and Drug Administration approved durable polymer drug eluting stents (sirolimus eluting, paclitaxel eluting, cobalt chromium everolimus eluting, platinum chromium everolimus eluting, zotarolimus eluting-Endeavor, and zotarolimus eluting-Resolute) or biodegradable polymer drug eluting stents, with each other or against bare metal stents. Outcomes Long term efficacy (target vessel revascularization, target lesion revascularization) and safety (death, myocardial infarction, stent thrombosis). Landmark analysis at more than one year was evaluated to assess the potential late benefit of biodegradable polymer drug eluting stents. Results From 126 randomized trials and 258 544 patient years of follow-up, for long term efficacy (target vessel revascularization), biodegradable polymer drug eluting stents were superior to paclitaxel eluting stents (rate ratio 0.66, 95% credibility interval 0.57 to 0.78) and zotarolimus eluting stent-Endeavor (0.69, 0.56 to 0.84) but not to newer generation durable polymer drug eluting stents (for example: 1.03, 0.89 to 1.21 versus cobalt chromium everolimus eluting stents). Similarly, biodegradable polymer drug eluting stents were superior to paclitaxel eluting stents (rate ratio 0.61, 0.37 to 0.89) but inferior to cobalt chromium everolimus eluting stents (2.04, 1.27 to 3.35) for long term safety (definite stent thrombosis). In the landmark analysis after one year, biodegradable polymer drug eluting stents were superior to sirolimus eluting stents for definite stent thrombosis (rate ratio 0.29, 0.10 to 0.82) but were associated with increased mortality compared with cobalt chromium everolimus eluting stents (1.52, 1.02 to 2.22). Overall, among all stent types, the newer generation durable polymer drug eluting stents (zotarolimus eluting stent-Resolute, cobalt chromium everolimus eluting stents, and platinum chromium everolimus eluting stents) were the most efficacious (lowest target vessel revascularization rate) stents, and cobalt chromium everolimus eluting stents were the safest with significant reductions in definite stent thrombosis (rate ratio 0.35, 0.21 to 0.53), myocardial infarction (0.65, 0.55 to 0.75), and death (0.72, 0.58 to 0.90) compared with bare metal stents. Conclusions Biodegradable polymer drug eluting stents are superior to first generation durable polymer drug eluting stents but not to newer generation durable polymer stents in reducing target vessel revascularization. Newer generation durable polymer stents, and especially cobalt chromium everolimus eluting stents, have the best combination of efficacy and safety. The utility of biodegradable polymer stents in the context of excellent clinical outcomes with newer generation durable polymer stents needs to be proven.

Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22 844 patient years of follow-up from randomised trials

Objectives To evaluate the efficacy and safety of currently used drug eluting stents compared with each other and compared with bare metal stents in patients with diabetes. Design Mixed treatment comparison meta-analysis. Data sources and study selection PubMed, Embase, and CENTRAL were searched for randomised clinical trials, until April 2012, of four durable polymer drug eluting stents (sirolimus eluting stents, paclitaxel eluting stents, everolimus eluting stents, and zotarolimus eluting stents) compared with each other or with bare metal stents for the treatment of de novo coronary lesions and enrolling at least 50 patients with diabetes. Primary outcomes Efficacy (target vessel revascularisation) and safety (death, myocardial infarction, stent thrombosis). Results From 42 trials with 22 844 patient years of follow-up, when compared with bare metal stents (reference rate ratio 1) all of the currently used drug eluting stents were associated with a significant reduction in target vessel revascularisation (37% to 69%), though the efficacy varied with the type of stent (everolimus eluting stents∼sirolimus eluting stents>paclitaxel eluting stents∼zotarolimus eluting stent>bare metal stents). There was about an 87% probability that everolimus eluting stents were the most efficacious compared with all others, though there were limited usable data for the zotarolimus eluting Resolute stent in patients with diabetes. Moreover, there was no increased risk of any safety outcome (including very late stent thrombosis) with any drug eluting stents compared with bare metal stents. There was about a 62% probability that the everolimus eluting stent was the safest stent for the outcome of “any” stent thrombosis. Conclusions Among patients with diabetes treated with coronary stents all currently available drug eluting stents were efficacious without compromising safety compared with bare metal stents. There were relative differences among the drug eluting stents, such that the everolimus eluting stent was the most efficacious and safe.

Outcomes With Various Drug-Eluting or Bare Metal Stents in Patients With ST-Segment–Elevation Myocardial Infarction A Mixed Treatment Comparison Analysis of Trial Level Data From 34 068 Patient-Years of Follow-Up From Randomized Trials

Background—The efficacy and safety of drug-eluting stents (DES) in patients with ST-segment–elevation myocardial infarction (STEMI) is controversial. Consequently, DES implantation has a class IIa indication in the American College of Cardiology/American Heart Association and the European Society of Cardiology STEMI guidelines. Methods and Results—PUBMED, EMBASE, and CENTRAL were searched for randomized clinical trials, until March 2013, comparing any of the 5 Food and Drug Administration–approved durable stent and polymer DES (sirolimus eluting stent, paclitaxel eluting stent, everolimus-eluting stent [EES], zotarolimus-eluting stent, and zotarolimus-eluting stent resolute), against each other or bare metal stents (BMS), and enrolling ≥50 patients with STEMI. Efficacy (target vessel revascularization) and safety (death, myocardial infarction, and stent thrombosis) outcomes at the longest reported follow-up times were evaluated. Twenty-eight randomized clinical trials with 34 068 patient-years of follow-up on subjects with STEMI fulfilled the inclusion criteria. When compared with BMS (reference rate ratio [RR] of 1), sirolimus eluting stent (RR, 0.46; 95% credibility interval [CrI], 0.36–0.56), paclitaxel eluting stent (RR, 0.69; 95% CrI, 0.53–0.87), and EES (RR, 0.42; 95% CrI, 0.26–0.62) were associated with a statistically significant reduction in rate of target vessel revascularization, with the point estimate for zotarolimus-eluting stent resolute trending in a similar direction. There was no increase in the risk of death, myocardial infarction, or stent thrombosis with any DES compared with BMS. Moreover, EES was associated with a statistically significant reduction in the rate of stent thrombosis when compared with sirolimus eluting stent (RR, 0.38; 95% CrI, 0.21–0.74), paclitaxel eluting stent (RR, 0.39; 95% CrI, 0.21–0.73), and even BMS (RR, 0.42; 95% CrI, 0.23–0.76). There was a 74% probability that EES had the lowest rate of any stent thrombosis when compared with all other stent types (no data on zotarolimus-eluting stent resolute). There was no increase in very late stent thrombosis with EES versus BMS (RR, 0.89; 95% CrI, 0.09–8.67). Conclusions—In patients with STEMI, DES versus BMS was associated with substantial decrease in the risk of target vessel revascularization without compromising safety. EES had the added advantage of substantial reduction in the risk of stent thrombosis when compared with first-generation DES and BMS with no increase in very late stent thrombosis.

Hyperglycemia in Nondiabetic Patients Presenting With Acute Myocardial Infarction

Abstract:Hyperglycemia is common in nondiabetic patients with acute myocardial infarction (AMI). Elevated blood glucose level may reflect a response to stress, an underlying abnormal glucometabolic state or both. Regardless of mechanism, hyperglycemia complicating AMI is associated with an inflammatory and prothrombotic state, depressed myocardial contractility and increased short- and long-term mortality. Studies are needed to define optimal monitoring and management of hyperglycemia in nondiabetic patients with AMI.

Comparison of platelet activity measurements by use of arterial and venous blood sampling

Pathological and clinical studies consistently demonstrate that platelets play a significant role in the pathophysiology of atherothrombosis, and measurement of platelet activity can identify individuals at increased cardiovascular risk. While light transmission aggregation is the historical “gold standard” for platelet activity measurement, the large sample volume and significant sampling time preclude this measurement from being widely used. Other more convenient markers of platelet activity are increasingly being investigated as data demonstrating their association with clinical outcomes emerge [1]. Monocyte (MPA) and leukocyte platelet aggregates (LPA) are robust markers of platelet adhesion and activation measured by flow cytometry, the advantages of which include the use of low sample volumes, standardization of technique, and allowance for whole blood to be immediately fixed and processed at a more suitable time [2–3]. Mean platelet volume (MPV), measured on routine automated hemograms, reflects platelet size. Larger platelets are metabolically and enzymatically more active, with greater prothrombotic potential, and associated with clinical outcomes [4–5]. Finally, soluble markers of activation, such as p-selectin, can be evaluated anytime from stored frozen plasma [6]. Collectively, these data make it pertinent for us to understand these markers of platelet activity, including the effect of blood source sampling on their measurements. In this study, we aim to assess the relationship between arterial and venous sources of different markers of platelet activity. Patients in this study were part of the platelet substudy of a randomized trial evaluating effects of glucose-lowering medications in patients with diabetes mellitus, which included non-diabetic controls [7]. All patients underwent coronary angiography at the Manhattan Veterans Affairs Hospital. Of the 75 patients enrolled in this substudy measuring markers of platelet activity on procedural access, 70 had simultaneous measurements from arterial and venous blood sources. All patients signed informed consent, and the institutional review board approved the study. At the time of coronary angiography, blood samples were collected after an initial 2cc discard simultaneously from the antecubital vein using a minimum 21-guage needle and the radial (n=7) or femoral (n=63) artery using a minimum 5 french sheath. Blood was collected in a 7.2mg K2 ethylenediaminetetraacetic (EDTA) acid tube (BD Vacutainer 4.0mL, BD Franklin Lakes, NJ, USA) and processed within 60 minutes on a Sysmex XE-2100 hematology analyzer (Mundelein, Illinois, USA) for platelet count (reported coefficient of variation (CV) <4.0%), MPV (CV <3.0%), and immature platelet fraction (IPF) (CV not reported) measurements. Additional blood was collected in a 3.2% (0.109 moles/L) sodium citrate tube (BD Vacutainer 2.7mL, BD Franklin Lakes, NJ, USA) and processed within 25 minutes for measurement of MPA, LPA, and sP-selectin (sP-selectin) levels. MPA and LPA were measured via an Accuri C6 flow cytometer using directly conjugated CD14-PE or CD45-PE and CD42a-FITC antibodies. Citrate-anticoagulated blood was centrifuged at 8°C for 10 min at 2500×g, plasma was stored at −80°C, and measurements of sP-selectin were made using commercial enzyme-linked immunosorbent assay (ELISA) (eBioscience, CV 7.8%). Measures of platelet activity are presented as median [interquartile range] given their skewed distribution (Shapiro-Wilk). Reproducibility and agreement of each platelet measure between the arterial and venous source was assessed by intraclass correlation coefficient (ICC) and the Bland-Altman analysis of agreement, respectively. ICC was defined as a variance ratio (ρ=σb2σb2+σw2), the proportion of between subject variation, which was estimated using the differences of between subject variance and within subject variance over the total variation (Sb2−Sw2Sb2+Sw2), where Sb2 represents the between subject variance and Sw2 represents within subjects variance [8]. The corresponding variance components were estimated in the framework of one-way ANOVA model. Plots are presented with 95% limits of agreement (precision ± 2 standard deviations) and bias (mean difference) [9]. Correlation of platelet measures between the arterial and venous source was performed using the Spearman’s test [10]. Statistical analysis was conducted using the R program for Scientific Computing (available at www.r-project.org). The median age (n=70) was 65 years (interquartile range 63−72), 99% male, and 80% White. Medical history was significant for known coronary artery disease in 59%, diabetes mellitus in 69%, peripheral artery disease in 14%, and tobacco use in 76%. Measures of platelet activity using an arterial versus venous blood source were reproducible by varying degrees (Table 1). The limits of agreement for arterial versus venous measurement of MPV, IPF, MPA, LPA, and sP-selectin were 0.38 fL to −0.59 fL, 2.0% to −2.39%, −19.0% to −22.2%, 5.7% to −6.5%, and 36.5 ng/mL to −56.6 ng/mL, respectively (Figure S1). The bias for the hematology analysis markers ranged from −0.11 to −0.17, the flow cytometric markers ranged from −0.4% to −1.6%, and sP-selectin was −10.1 ng/mL. Table 1 Markers of platelet activity measured using arterial and venous blood sources Platelet activity is increasingly investigated as a surrogate end-point in the setting of percutaneous coronary intervention (PCI) [11]. Arterial access obtained during PCI provides for a convenient source of blood sampling, whereas venous sampling is more convenient outside the procedural time period. Therefore, when there is a need to compare time-related changes in platelet activity in the PCI population, it is necessary to understand whether venous samples obtained pre- or post-procedure can be compared with arterial samples obtained during the procedure. In the current study, markers of platelet size and activity measured on an automated hematology analyzer and using flow cytometry demonstrated excellent to good agreement between arterial and venous samples, while plasma markers measured by ELISA less so. Jaumdally and colleagues demonstrated no difference in sP-selectin levels from the coronary ostium, aorta, coronary sinus and right femoral vein [12]. They did note a difference in MPV measurements between the coronary ostium and coronary sinus or femoral vein. However, the flow patterns between the aorta and the coronary ostium are markedly different, and the difference in MPV measurements was attenuated when those from the aorta and femoral vein were compared. Furthermore, the study did not provide measures of reliability. Similarly, Chen and colleagues demonstrated significantly higher levels of sP-selectin in the left atrium of 16 patients compared with levels from the right atrium, femoral vein and femoral artery, but similar levels between the femoral vein and artery [13]. In both studies, arterial and venous samples were collected from introducer sheaths, whereas in our study, venous samples were collected from the antecubital vein, a common source of blood sampling post-procedure. Some of the limitations of the current study include the predominately male cohort and small sample size, although this cohort represents one of the larger studies published and is one of the very few studies to evaluate the agreement and correlation between samples obtained via an arterial versus venous blood source.

Impact of Aortic Root Anatomy and Geometry on Paravalvular Leak in Transcatheter Aortic Valve Replacement With Extremely Large Annuli Using the Edwards SAPIEN 3 Valve

OBJECTIVES The aim of this study was to determine factors affecting paravalvular leak (PVL) in transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN 3 (S3) valve in extremely large annuli. BACKGROUND The largest recommended annular area for the 29-mm S3 is 683 mm2. However, experience with S3 TAVR in annuli >683 mm2 has not been widely reported. METHODS From December 2013 to July 2017, 74 patients across 16 centers with mean area 721 ± 38 mm2 (range: 684 to 852 mm2) underwent S3 TAVR. The transfemoral approach was used in 95%, and 39% were under conscious sedation. Patient, anatomic, and procedural characteristics were retrospectively analyzed. Valve Academic Research Consortium-2 outcomes were reported. RESULTS Procedural success was 100%, with 2 deaths, 1 stroke, and 2 major vascular complications at 30 days. Post-dilatation occurred in 32%, with final balloon overfilling (1 to 5 ml extra) in 70% of patients. Implantation depth averaged 22.3 ± 12.4% at the noncoronary cusp and 20.7 ± 9.9% at the left coronary cusp. New left bundle branch block occurred in 17%, and 6.3% required new permanent pacemakers. Thirty-day echocardiography showed mild PVL in 22.3%, 6.9% moderate, and none severe. There was no annular rupture or coronary obstruction. Mild or greater PVL was associated with larger maximum annular and left ventricular outflow tract (LVOT) diameters, larger LVOT area and perimeter, LVOT area greater than annular area, and higher annular eccentricity. CONCLUSIONS TAVR with the 29-mm S3 valve beyond the recommended range by overexpansion is safe, with acceptable PVL and pacemaker rates. Larger LVOTs and more eccentric annuli were associated with more PVL. Longer term follow-up will be needed to determine durability of S3 TAVR in this population.

Response to Letter Regarding Article, “Short- and Long-Term Outcomes With Drug-Eluting and Bare-Metal Coronary Stents: A Mixed-Treatment Comparison Analysis of 117 762 Patient-years of Follow-up From Randomized Trials”

Sharma and Chatterjee compare and contrast our publication1 with a recent publication on stent thrombosis2 and are concerned with “divergent” results of the 2 studies. A thorough reading of both the articles shows that the results of the 2 articles are concordant, demonstrating that everolimus-eluting stents reduce the risk of stent thrombosis compared with other drug-eluting stents and even bare-metal stents. The differences are due largely to the design of the 2 studies. First, the focus of the Palmerini et al2 article was on stent thrombosis, whereas our focus was on not only stent thrombosis, but also other efficacy and safety outcomes, as outlined below. Second, Palmerini et al excluded studies that did not report stent …

Drug-eluting versus bare-metal coronary stents: where are we now?

Drug-eluting stents have dramatically reduced the risk of restenosis, but concerns of an increased risk of stent thrombosis have provided uncertainty about their use. Recent studies have continued to show improved procedural and clinical outcomes with drug-eluting stents both in the setting of acute coronary syndromes and stable coronary artery disease. Newer generation drug-eluting stents (especially everolimus-eluting stents) have been shown to be not only efficacious but also safe with reduced risk of stent thrombosis when compared with bare-metal stents, potentially changing the benchmark for stent safety from bare-metal stents to everolimus-eluting stents. While much progress is being made in the development of bioabsorbable polymer stents, nonpolymer stents and bioabsorbable stent technology, it remains to be seen whether these stents will have superior safety and efficacy outcomes compared with the already much improved rates of revascularization and stent thrombosis seen with newer generation stents (everolimus-eluting stents and resolute zotarolimus-eluting stents).