Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease | NEJM - nejm.org

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Trial Design, Oversight, and Funding

The SWEDEPAD trial is a pragmatic, multicenter, randomized, parallel-group, open-label, single-blind, registry-based clinical trial. A complete list of the trial personnel is provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. In total, 22 of the 28 vascular centers in Sweden are participating in the trial. Screening, enrollment, randomization, and follow-up of the patients in the trial are being performed with the use of the National Quality Registry for Vascular Surgery (Swedvasc) (details are provided in the Supplementary Appendix).^14,15 The registry is maintained by the Uppsala Clinical Research Center at Uppsala University.

The trial is led by an executive committee with national representation. An independent data and safety monitoring committee periodically evaluates blinded event-rate data and the overall safety of the investigational treatment. The trial protocol (available at NEJM.org) was approved by the Central Ethical Review Authority in Sweden. The trial sponsor is the Institute of Clinical Sciences at the Sahlgrenska Academy, University of Gothenburg, Sweden. Trial management and statistical analyses are performed at the Uppsala Clinical Research Center at Uppsala University.

The trial is funded by grants from the Swedish Research Council, the Swedish Heart–Lung Foundation, and Region Västra Götaland. In addition, all the companies that provide drug-coated balloons and drug-coated stents for patients in Sweden with peripheral artery disease are supporting the trial by providing price discounts on their devices. Neither the trial sponsor nor any of the funding bodies had any influence on the trial design; the preparation of the protocol or statistical analysis plan; the selection of sites or patients; patient enrollment, evaluation, or follow-up; site monitoring or supervision; the collection or storage of the data; the decision to suspend enrollment for this analysis; the analysis or interpretation of the data; the preparation of the manuscript; or the decision to submit the manuscript for publication. The authors vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol, with the exception of the decision to perform this unplanned interim analysis, as noted previously.

Patients

The target population consists of adults with confirmed symptomatic peripheral artery disease that is caused by a new or recurrent flow-limiting stenosis (defined as a loss of >50% of the cross-sectional diameter) or occlusion in infrainguinal arteries and that is eligible for endovascular treatment according to established indications. The trial includes two cohorts of patients who undergo randomization separately: patients with chronic limb-threatening ischemia and patients with intermittent claudication. Exclusion criteria are acute lower-limb ischemia, infrainguinal aneurysmal disease, and either previous participation in the trial or concurrent participation in another interventional trial involving infrainguinal arterial lesions. Patients without a Swedish personal identification number are also excluded. All the patients provide written informed consent.

Trial Procedures

A summary of the trial design and trial procedures is provided in Figure S1 in the Supplementary Appendix. After patients are admitted to the hospital for the scheduled procedure, informed consent is obtained. Randomization occurs during the intervention procedure, after a guide wire has crossed the lesion but before any dilation has been performed. At each trial center, patients are randomly assigned to treatment with either a drug-coated device or an uncoated device. Randomization is performed online with the Swedvasc Web-based platform and a dedicated computerized randomization module that has been introduced in the registry. Randomization is stratified according to disease severity (chronic limb-threatening ischemia or intermittent claudication) and center. To activate the randomization function, information regarding disease severity, the vascular segment to be treated (femoropopliteal, infrapopliteal, or both), and the planned revascularization technique (primary balloon angioplasty or primary stenting) must first be recorded.

All devices with European Union approval (i.e., those that have received the CE mark) for peripheral artery disease interventions are allowed. In case of target lesions in multiple vessel segments, the treatment assignment applies to all the treated lesions. The patient and the ultrasonographer who performs duplex ultrasonography on follow-up are unaware of the treatment assignment, whereas the operator for the revascularization procedure is aware of the treatment assignment. Details of the interventional procedure and the associated antithrombotic treatment are provided in the Supplementary Appendix.

Patients in the trial are followed according to the Swedvasc follow-up procedures, which include patient visits to the center at 30 days and 1 year after the revascularization procedure (details are provided in the Supplementary Appendix). All reinterventions as well as any additional procedures with paclitaxel-coated devices other than the index revascularization are recorded in Swedvasc. Swedvasc is interlinked with the Swedish national population registry, enabling continuous updates regarding all-cause mortality to be made to the trial database. Therefore, the vital status of each patient is known and regularly updated during long-term follow-up.

Trial Outcomes

The end point for this unplanned interim analysis was all-cause mortality. The prespecified primary efficacy end points in the overall trial differ for the two trial cohorts. For the cohort of patients with chronic limb-threatening ischemia, the primary efficacy end point is the incidence of major amputations during follow-up, which is planned to be analyzed when all the patients in that cohort have been followed for at least 1 year. For the cohort of patients with intermittent claudication, the primary efficacy end point is health-related quality of life after 1 year, which is assessed with the use of the Vascular Quality of Life Questionnaire-6. All-cause mortality is a prespecified secondary end point in the trial protocol for both cohorts. A complete list of the trial end points is provided in the Supplementary Appendix.

Statistical Analysis

Baseline characteristics are presented as means and standard deviations or as medians and interquartile ranges for continuous variables and as absolute and relative percentages for categorical variables. A detailed description of the original sample size estimation for the trial is provided in the Supplementary Appendix. In this interim analysis, only the single end point of all-cause mortality was analyzed. The analysis was based on the intention-to-treat population, which included all the patients who underwent randomization, irrespective of their adherence to the protocol and their continued participation in the trial. Comparisons of all-cause mortality between the drug-coated–device group and the uncoated-device group were performed with the use of a Cox proportional hazards model; hazard ratios and 95% confidence intervals were estimated for the overall trial population as well as separately for patients with chronic limb-threatening ischemia and those with intermittent claudication. The hazard ratios and confidence intervals have been adjusted to account for center effects. The confidence intervals have not been adjusted for multiplicity and cannot be used to infer definitive treatment effects. A Kaplan–Meier analysis was used to estimate the cumulative probability of death from any cause in each treatment group during follow-up. All the analyses were performed with the use of R software, version 3.6.¹⁶

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