Reality trial cypher

The goal of the trial was to evaluate treatment with sirolimus-eluting stents compared with paclitaxel-eluting stents among patients with de novo coronary lesions. Treatment with sirolimus-eluting stents will be compared to treatment with paclitaxel-eluting stents among patients with de novo coronary lesions.

Presence of one or two de novo lesions in a native coronary artery between 2. Direct stenting was allowed, as was treatment of bifurcation lesions and ostial lesions. Patients underwent angiographic follow-up at eight months. There were 1, lesions in the 1, patients with treatment attempted, with an average of 1. At eight-month angiographic follow-up, the sirolimus-eluting stent group had larger in-stent minimum lumen diameter 2.

Stent thrombosis was higher in the paclitaxel-eluting stent group 1. In addition to uncertain benefit in patients with AMI, transfusion has potential adverse effects, logistical implications particularly for blood supply , and cost.

The protocol and statistical analysis plan are presented in Supplement 1. Patients provided written informed consent. Patients were randomly assigned in a ratio to undergo a restrictive or a liberal transfusion strategy. A web-based randomization system was used, with a centralized block randomization list with blocks of varying size range, , stratified by center. Homologous leukoreduced packed red blood cells were used for transfusion.

Both strategies were to be maintained until patient discharge or 30 days after randomization, whichever occurred first. The protocol allowed transfusion to be administered at any time in the following documented instances: massive overt active bleeding, presumed important decrease in hemoglobin level and no time to wait for hemoglobin measurement indicating suspected massive bleeding , and shock presumably due to blood loss occurring after randomization.

Group assignment was not blinded for data collection. The primary clinical efficacy outcome was a composite of major adverse cardiovascular events MACE at 30 days, defined as all-cause death, nonfatal stroke, nonfatal recurrent myocardial infarction, or emergency revascularization prompted by ischemia. Secondary outcomes included the individual components of the composite MACE outcome at 30 days and 1 year.

Descriptive end points included the baseline characteristics of patients, use of transfusion, hemoglobin values, and bleeding episodes in each group. The current analysis reports day clinical outcomes. The 1-year outcomes and the cost-effectiveness analyses will be reported separately. Adverse events were monitored during hospital stay and included the following potential adverse effects of transfusion: hemolysis, documented bacteremia acquired after transfusion, multiorgan system dysfunction, acute respiratory distress syndrome, acute heart failure, acute kidney failure, and severe allergic reactions.

All components of the primary efficacy clinical outcome as well as acute heart failure were adjudicated by a critical event committee blinded to treatment assignment and hemoglobin levels. The third universal definition of myocardial infarction was used.

Outcome definitions are detailed in eAppendix 1 in Supplement 2. Noninferiority was assessed using a CI method with a 1-sided Because there was no established clinical superiority of either transfusion strategy and no randomized trial of transfusion vs no transfusion, the choice of a noninferiority margin was based on clinical judgment based on what clinicians would be prepared to accept as potential loss of efficacy of a restrictive transfusion strategy compared with a liberal strategy given the expected theoretical benefits of the former of sparing scarce blood resources, 18 reducing transfusion adverse effects, and reducing logistical burden and costs.

A relative margin of 1. Ninety-five percent CIs were estimated using the Wald method. The analysis was performed among both the as-treated population, which included all patients without a major protocol violation including eligibility criteria not fulfilled , and the as-randomized population, which included all randomized patients with the exception of 2 patients 1 without a consent form and 1 who withdrew consent immediately after randomization.

Concordance in the noninferiority analysis between the as-randomized and the as-treated populations was required to establish noninferiority. The use of multiple imputation methods was planned in the statistical analysis plan in the case of missing data for the primary clinical outcome.

Given the absence of missing data at day 30, imputation was not needed. Because the trial was conducted at multiple sites, site effect was accounted for in a post hoc sensitivity analysis using a generalized linear regression mixed model with binary distribution and a log link function with strategy as a fixed effect and center as a random effect.

If clinical noninferiority of the restrictive strategy was established, a test of superiority of the restrictive strategy was planned. All secondary analyses were performed on the as-randomized population with available data. In a secondary analysis of the main outcome, survival was estimated using the Kaplan-Meier method and groups were compared using a log-rank test. Data for patients with no evidence of MACE were censored at 30 days. The risk proportionality hypothesis was verified by testing the interaction between interest variable and time.

No adjustment was planned for multiplicity and there was no prespecified hierarchy for secondary efficacy outcomes. Because of the potential for type I error due to multiple comparisons, analyses of secondary end points should be interpreted as exploratory.

The effect of transfusion strategy on the primary composite outcome was explored in subgroups of clinical interest age, sex, body weight, presence or absence of diabetes, smoking status, presence or absence of hypertension, presence or absence of dyslipidemia, Killip class, kidney function [creatinine clearance], presence or absence of active bleeding, hemoglobin levels at the time of randomization, ST- vs non—ST-segment elevation myocardial infarction, and revascularization by percutaneous coronary intervention for the index event before or after randomization ; the interaction between subgroup and transfusion strategy was tested using logistic regression.

Statistical analyses were performed using SAS version 9. From March to September , a total of patients with AMI and anemia were consecutively enrolled in the trial in 26 centers in France and 9 centers in Spain; Figure 1. Baseline characteristics of the as-randomized population were similar between the groups Table 1. The median age of patients was 77 years, In most patients, the cause of anemia was unknown; 43 patients 6. The qualifying myocardial infarction was non—ST-elevation myocardial infarction in approximately two-thirds of the patients.

A minority of patients had an identified active bleeding site Table 1 ; eTable 1 in Supplement 2. In-hospital management is detailed in eTable 2 in Supplement 2. Most patients underwent coronary angiography Treatments before hospitalization and during the first 24 hours of admission are shown in eTable 3 in Supplement 2.

Most patients received dual antiplatelet therapy for the qualifying myocardial infarction. Baseline characteristics and treatment of the as-treated population are shown in eTable 4 in Supplement 2 and were consistent with the as-randomized population. Hemoglobin levels were similar in both groups at admission and at randomization Table 2. A total of patients The distribution of the number of red blood cell units transfused per patient is shown in Table 2.

In the liberal group, the majority of patients received 2 or more units. The restrictive group used red blood cell units and the liberal group used Few patients received concomitant fresh frozen plasma or platelet transfusion. The in-hospital hemoglobin nadir was lower in the restrictive group than the liberal group. The median interquartile range length of hospitalization was 7. At discharge, mean SD hemoglobin was 9.

Data for the as-treated population are provided in eTable 5 in Supplement 2. Follow-up data for day MACE were complete for all patients who consented and were randomized.

In the as-treated population, day MACE occurred in 36 patients Noninferiority of the restrictive strategy was also achieved in the as-randomized population relative risk, 0.

Similar results were found in post hoc sensitivity analyses accounting for site effects as-treated population: relative risk, 0. In the planned sequential superiority analysis performed among the as-randomized population Figure 2 , the restrictive strategy did not meet criteria for superiority compared with the liberal strategy upper bound of 1-sided In the restrictive group vs the liberal group, all-cause death occurred in 5.

Although the published data support the claim that DES are safe and effective there have been concerns raised about the incidence of very late stent thrombosis more than 1-year after implantation compared with the use of bare metal stents Iakovou et al ; Colombo and Corbett However, despite these concerns over the long-term safety of DES, the actual incidence of stent thrombosis after 1-year is unknown Park et al In the absence of an internationally accepted definition of late stent thrombosis or any fact-based evidence concerning the incidence of stent thrombosis, a review of the literature suggests that the incidence of late stent thrombosis with SES is comparable with that of bare metal stents Bavry et al ; Iakovou et al ; Moreno et al ; Kereiakes et al ; Weisz et al ; Park et al ; Schampaert et al ; Urban et al It has been suggested that treatment with a drug-eluting stent results in delayed arterial healing when compared with bare metal stents of similar implant duration.

It has also been postulated that the cause of late stent thrombosis associated with DES is multifactorial, with delayed healing in combination with other clinical and procedural risk factors playing a role Joner et al The available evidence indicates that the predictors of stent thrombosis are premature anti-platelet therapy interruption, primary stenting in acute MI, and total stent length.

However, if we are to gain a better understanding of the problems of DES thrombosis it would appear that an extended period of follow-up in a randomized, controlled trial or a large registry such as e-SELECT will be necessary.

Thankfully, the incidence of late stent thrombosis appears to be very rare. Nevertheless, its impact can be tragic. The distribution of an eluted drug in the tissue of a vessel wall is not at all homogenous, and this might reflect the pattern of the stent struts.

While the dose distribution may be sub-therapeutic in one spot, it may be toxic in the direct vicinity of the struts.

Homogenous drug distribution would also require a symmetric deployment of a stent, which does not necessarily happen in the real world. Overlapping stents may lead to doubling of the intended dose, and longitudinally the drug tissue levels may vary considerably from proximal to distal end. An open cell versus a closed cell stent design has different characteristic patterns of apposition to the cell wall, leading again to a difference in the delivered dose, with a closed cell design appearing to offer better drug distribution.

With a closed-cell design, when the stent is deployed in a tortuous site, cell size is minimally affected either on the outer aspect or inner aspect of the bend, and uniform vessel coverage and dosing are maintained.

In contrast, with open-cell design, tortuosity can cause dramatic changes in cell sizes. This may result in both excessively large cells on the outer side of the bend and small cell sizes on the inner surface of the bend.

Consequently, there is non-uniform coverage of the vessel wall and non-uniform dosing, both with potential under dosing and over dosing. Closed-cell design results in optimal drug delivery to tortuous anatomy, for example, in lesions of the right coronary artery and in eccentric lesions, as encountered in highly asymmetric proximal left anterior descending plaque.

For drug distribution and safety one needs to consider the relationship between the stent design and the drug tissue concentration. Currently used polymers for stent coatings have been proven safe. They release drugs at predictable rates and it is interesting to observe that fast and slow release polymers lead to similar tissue concentrations.

The tissue penetration depends more on the hydrophobic or hydrophilic properties of the drug. A hydrophobic or lipophilic drug will easily penetrate and be found in high concentrations regardless of slow or fast release. The difference between slow and fast release may lie in the tissue toxicity; a high tissue level, built up quickly, may have toxic necrotic effects, as seen with paclitaxel.

This can lead to thrombus formation; the stent may no longer be adherent to the necrotic wall. Overall, clinical and histological toxicity is a concern.

Controlled release is crucial to the efficacy of DES. The CYPHER stent has a unique polymer coating, which allows for localized delivery of sirolimus precisely to the site of the lesion. It contains a specific concentration of sirolimus and the polymer ensures that the drug does not wash off during the most time-intensive procedures.

Essentially all the drug is delivered in the first 3 months after implantation. Over the past 25 years coronary angioplasty has developed into a highly sophisticated series of techniques that has the potential to match surgery, and in many cases surpass it.

Implantation of SES has revolutionized the field of percutaneous coronary angioplasty with an impressive reduction of in-stent restenosis compared with bare metal stents. This advantage translates into fewer repeat treatments for the patient, a reduction in the need for surgical intervention, and the ability to treat more patients. Thankfully, the incidence of stent thrombosis appears to be in line with that of bare metal stents.

That being said, the ability to identify the patient who is at risk of stent thrombosis is a major and urgent challenge. The introduction of SES was a major breakthrough for interventional cardiology. Many large, randomized, clinical trials using SES have shown a remarkable reduction in angiographic restenosis and target vessel revascularization compared with bare metal stents. The results of these trials also appear to be supported by evidence from everyday practice and non-controlled clinical trials.

However, the expanded applications of SES, especially in treating complex lesions such as left main disease, acute MI, and saphenous vein graft lesions, are still under evaluation with ongoing studies. The adoption of SES in all percutaneous coronary intervention may become a reality in the near future. National Center for Biotechnology Information , U. Vasc Health Risk Manag. Alexandre Abizaid. Author information Copyright and License information Disclaimer.

All rights reserved. This article has been cited by other articles in PMC. Keywords: angioplasty, restenosis, percutaneous coronary intervention, rapamycin, sirolimus-eluting stent. Introduction When the findings from the first 50 patients treated with angioplasty were first published, few would have predicted the dramatic increase in the use of percutaneous coronary interventions PCI with the associated explosion of clinical research and attendant information Gruntzig et al Pathophysiology of restenosis Stent-induced restenosis involves a complex interplay of biological events.

What is sirolimus? Open in a separate window. Figure 1. Among the factors associated with this changing face of interventional cardiology three stand out: The rising epidemic of diabetes, more complex lesions small vessels, more extensive and diffuse disease, multi-vessel disease, total occlusions, left main disease Urban et al Comparative trials More recently, we have had the opportunity to compare the SES and paclitaxel drug-eluting stents PES following the presentation of data from a total of ten head-to-head trials Table 1.

Table 1 Comparative trials: sirolimus-eluting stents and paclitaxel-eluting stents. Table 2 Rate of late-stent thrombosis: sirolimus-eluting, paclitaxel-eluting, drug-eluting, and bare metal stents. Late loss: a key measurement in differentiating drug-eluting stents DES Late loss is the angiographic metric that allows post-stent neointimal hyperplasia to be most accurately and reliably quantified.

Figure 2. Figure 3. Abbreviations : TLR, target lesion revascularization. Sirolimus — safety and tolerability Safety of a broad therapeutic window Sirolimus has been shown to have a broad therapeutic window. Stent thrombosis Since their introduction, more than 2 million patients, often with complex lesions, diabetes, and acute MI, have been treated with an SES. Closed cell design The distribution of an eluted drug in the tissue of a vessel wall is not at all homogenous, and this might reflect the pattern of the stent struts.

Polymer For drug distribution and safety one needs to consider the relationship between the stent design and the drug tissue concentration. Impact on patients Over the past 25 years coronary angioplasty has developed into a highly sophisticated series of techniques that has the potential to match surgery, and in many cases surpass it.

Conclusions and place in therapy The introduction of SES was a major breakthrough for interventional cardiology. J Am Coll Cardiol. Am Heart J. Sirolimus-eluting vs uncoated stents for prevention of restenosis in small coronary arteries: a randomized trial. Risk of thrombosis with the use of sirolimus-eluting stents for percutaneous coronary intervention from registry and clinical trial data Am J Cardiol.

Design and synthesis of a rapamycin-based high affinity binding FKBR12 ligand.