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The role of Helicobacter pylori (H. pylori) screening and eradication on reducing upper gastrointestinal bleeding (UGIB) complications after acute myocardial infarction (MI) is uncertain. The HELicobacter pylori screening to prevent gastrointestinal bleeding in patients with acute MI (HELP-MI SWEDEHEART) trial aims to determine whether systematic H. pylori screening compared to usual care reduces UGIB, mortality, and cardiovascular outcomes after MI. A cluster randomized, crossover, registry-based clinical trial using SWEDEHEART as trial platform for study population definition and source for data collection in combination with nationwide Swedish health data registries. Thirty-five Swedish hospitals, organized into 18 clusters based on percutaneous coronary intervention networks, were randomized to either routine H. pylori screening for adults with acute type-1 MI or usual care. After 1 year, a 2-month blanking period was followed by a crossover to the alternate allocation for 1 year. The trial enrolment was concluded after one additional year of registry-based follow-up. The primary endpoint is UGIB. Secondary endpoints include all-cause death, cardiovascular death, readmission for MI, stroke, or heart failure. Endpoints will be reported combined (Net Adverse Clinical Events; Major Adverse Cardiac or Cerebrovascular Events) and separately. The primary analysis will include all available follow-up time corresponding to a maximum follow-up time of 3 years and 2 months. HELP-MI SWEDEHEART aims to determine the utility of routine H. pylori screening to reduce UGIB and improve cardiovascular outcomes after MI. By integrating national registry follow-up data with a pragmatic trial design, it has the potential to provide evidence for the effect of the implementation of routine H. pylori screening as part of acute MI care. ClinicalTrials.gov, NCT05024864.

Purpose of Review Randomized controlled trials (RCTs) in heart failure (HF) are becoming increasingly complex and expensive to conduct and if positive deliver expensive therapy tested only in selected populations. Recent Findings Electronic health records and clinical cardiovascular quality registries are providing opportunities for pragmatic and registry-based prospective randomized clinical trials (RRCTs). Simplified regulatory, ethics, and consent procedures; recruitment integrated into real-world care; and simplified or automated baseline and outcome collection allow assessment of study power and feasibility, fast and efficient recruitment, delivery of generalizable findings at low cost, and potentially evidence-based and novel use of generic drugs with low costs to society. Summary There have been no RRCTs in HF to date. Major challenges include generating funding, international collaboration, and the monitoring of safety and adherence for chronic HF treatments. Here, we use the Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF), to be conducted in the Swedish Heart Failure Registry, to exemplify the advantages and challenges of HF RRCTs.

To investigate if addition of metformin to standard care (life-style advice) reduces the occurrence of cardiovascular events and death after myocardial infarction (MI) in patients with newly detected prediabetes. The Myocardial Infarction and new treatment with Metformin study (MIMET) is a large multicentre registry-based randomised clinical trial (R-RCT) within the SWEDEHEART registry platform expected to include 5160 patients with MI and newly detected prediabetes (identified with fasting blood glucose, HbA1c or 2-h glucose on oral glucose tolerance test) at ∼20 study sites in Sweden. Patients 18–80 years, without known diabetes and naïve to glucose lowering therapy, will be randomised 1:1 to open-label metformin therapy plus standard care or standard care alone. Patients will be followed for 2 years for the primary outcome new cardiovascular event (first of death, non-fatal MI, hospitalisation for heart failure or non-fatal stroke). Secondary endpoints include individual components of the primary endpoint, diabetes diagnosis, initiation of any glucose lowering therapy, cancer, and treatment safety. Events will be collected from national healthcare registries. The MIMET study will investigate if metformin is superior to standard care after myocardial infarction in preventing cardiovascular events in patients with prediabetes (Clinicaltrials.gov identifier: NCT05182970; EudraCT No: 2019-001487-30). •In patients with AMI prediabetes is common and associated with an increased risk of worse outcome.•Metformin is an effective glucose-lowering agent, inexpensive, widely available and safe.•There is a gap of knowledge regarding favourable cardiovascular effects of metformin.•MIMET is the first ongoing RRCT analysing CV outcome of metformin in prediabetes in AMI patients.•A pragmatic RRCT based on routine care enables a high inclusion rate, a more complete follow-up at a lower cost.

Background: After decades of ubiquitous oxygen therapy in all patients with acute myocardial infarction (MI), recent guidelines are more restrictive based on lack of efficacy in contemporary trials evaluating hard clinical outcomes in patients without hypoxemia at baseline. However, no evidence regarding treatment effects on health-related quality of life (HRQoL) exists. In this study, we investigated the impact of routine oxygen supplementation on HRQoL 6–8 weeks after hospitalization with acute MI. Secondary objectives included analyses of MI subtypes, further adjustment for infarct size, and oxygen saturation at baseline and 1-year follow-up. Methods: In the DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial, 6,629 normoxemic patients with suspected MI were randomized to oxygen at 6 L/min for 6–12 h or ambient air. In this prespecified analysis, patients younger than 75 years of age with confirmed MI who had available HRQoL data by European Quality of Life Five Dimensions questionnaire (EQ-5D) in the national registry were included. Primary endpoint was the EQ-5D index assessed by multivariate linear regression at 6–10 weeks after MI occurrence. Results: A total of 3,086 patients (median age 64, 22% female) were eligible, 1,518 allocated to oxygen and 1,568 to ambient air. We found no statistically significant effect of oxygen therapy on EQ-5D index (−0.01; 95% CI: −0.03–0.01; p = 0.23) or EQ-VAS score (−0.57; 95% CI: −1.88–0.75; p = 0.40) compared to ambient air after 6–10 weeks. Furthermore, no significant difference was observed between the treatment groups in EQ-5D dimensions. Results remained consistent across MI subtypes and at 1-year follow-up, including further adjustment for infarct size or oxygen saturation at baseline. Conclusions: Routine oxygen therapy provided to normoxemic patients with acute MI did not improve HRQoL up to 1 year after MI occurrence. Clinical Trial Registration: ClinicalTrials.gov number, NCT01787110.

Abstract Real world data (RWD) refers to healthcare information that is routinely collected in electronic healthcare records (EHR), hospital and pharmacy records, patient and disease registries, and health insurance databases. The collection and analysis of this vast amount of data is an important complement to that obtained from conventional randomised controlled trials (RCT). Real world data has been used for healthcare quality improvements, to conduct clinical trials, to support drug and device development, and to inform medical guidelines. The utility of RWD may be facilitated by common data models, which standardise format and content, and allow data from different health systems to be analysed together. The European Society of Cardiology (ESC) supports the use of RWD in collaboration with national cardiac societies, regulatory authorities, and industry to encourage continuous quality of care improvements at the hospital and country level, to conduct registry-based randomised clinical trials (R-RCT) and to facilitate safety surveillance of novel drugs and devices. The European Medicines Agency (EMA) is developing systems and processes to enable the use of RWD that can help in trial planning, defining clinical contexts, and enhancing outcome assessments. RWD can also contribute to the measurement of the impact of regulatory actions, such as contraindications or restriction of indications by looking at medicines use patterns over time across European Member States. A number of other initiatives from the European Commission and the EMA are underway to strengthen the EU's health security framework, and foster the collection and utilisation of RWD. Graphical Abstract Graphical Abstract Examples of types of data that can be collected as part of routine care.

During the last decade Sweden has invested in a national infrastructure for collection of structured clinical data in the form of healthcare registries (in Sweden known as Kvalitetsregister). These data can be combined with other public data using the national personal identifiers that are issued to Swedish citizens. The healthcare registries have an almost complete coverage of Swedish healthcare, and a large network of clinicians is involved in the quality assurance and continuous improvement of healthcare using these registries. Uppsala Clinical Research Center (UCR) has been a technology provider of large-scale national registries and has a strong background in clinical trial management. This effort combines the areas of healthcare registries and clinical trials into a novel way of performing clinical trials to be able to: 1) run clinical trials as an integrated part of normal clinic workflow; and 2) leverage the nationwide network of outcome reporting. This strategy was shown to be successful in the TASTE (Thrombus Aspiration in Myocardial Infarction) study. When TASTE had been published, the New England Journal of Medicine wrote a perspective on the study calling it 'The randomized registry trial-the next disruptive technology in clinical research?' Since then several studies have been conducted in this way with great success. UCR has been appointed, by Clinical Studies Sweden and the Swedish Research Council, to develop the Swedish national guidelines for registry-based randomized clinical trials in order to ensure the possibility for more organizations to run this kind of study. This paper describes key concepts of register-based randomized clinical trials and the development of Swedish national guidelines.

Registry-based randomized controlled trials are defined as pragmatic trials that use registries as a platform for case records, data collection, randomization, and follow-up. Recently, the application of registry-based randomized controlled trials has attracted increasing attention in health research to address comparative effectiveness research questions in real-world settings, mainly due to their low cost, enhanced generalizability of findings, rapid consecutive enrollment, and the potential completeness of follow-up for the reference population, when compared with conventional randomized effectiveness trials. However several challenges of registry-based randomized controlled trials have to be taken into consideration, including registry data quality, ethical issues, and methodological challenges. In this article, we summarize the advantages, challenges, and areas for future research related to registry-based randomized controlled trials.

Registry-based randomized controlled trials (RRCTs) can provide internally valid results in a real-world context at relatively low effort and cost. However, the main characteristics, the extent to which the registry is utilized (eg, proportion of data from registry) and registry-related limitations are not well characterized. This methodological review of RRCTs aims to analyze the trial design features, investigate potential usage options, and identify possible limitations of using registry data for randomized controlled trials (RCTs). A systematic search in PubMed for ongoing and published RRCTs was conducted up to February 2, 2023. Studies that reported at least one outcome derived from a registry were included. Study selection was independently performed by two reviewers. All data were extracted into a standardized table, and descriptive statistics were generated. We included 162 RRCTs (41 protocols and 121 studies). Most RRCTs were multicenter trials (n = 127; 78.4%) comprising a large number of participants (median = 1787; range = 41 to 683,927) and a long follow-up period (median = 60 months; range = 1 to 367 months) with a minimal loss to follow-up. The inclusion criteria of participants were mostly broadly defined. Types of interventions ranged from surgical procedures to behavioral interventions, and almost half of the interventions (46.9%) had a preventive purpose. The main registry outcome was mostly a clinical endpoint (40.1%) or a composite endpoint of major clinical events (30.9%) that was objectively measurable. We found different degrees of registry utilization, ranging from the exclusive use of long-term monitoring of previously published data to the more comprehensive registry utilization for patient recruitment, endpoint collection, and long-term follow-up. Limitations related to the use of registry data comprised potential coding errors or incomplete data (eg, due to under-recording of mild cases). In addition, technical challenges must be considered (eg, failed linkages or time-delayed data entry). A broad spectrum of potential usage options and usage extent of registry data exist. Our analysis suggests that in many cases, the potential of using registry data and thus their benefits were not fully utilized. In addition, the study illustrates that there is not a single, unified methodology for designing RRCTs but that registries can support RCTs in various ways. Therefore, future RRCTs should specify for what purposes and to what extent registries were utilized. Moreover, a clear definition and taxonomy of RRCTs appears necessary for facilitating future dialogue and research on RRCTs.

The objective of this study was to analyze the features of registry-based randomized trials (rRCTs). We systematically searched PubMed for rRCTs. Study selection was performed independently by two reviewers. We extracted all data in standardized tables and prepared descriptive summary statistics. The search resulted in 1,202 hits. We included 71 rRCTs. Most rRCTs were from Denmark and Sweden. Chronic conditions were considered in 82.2%. A preventive intervention was examined in 45.1%. The median of included patients was 2,000 (range: 69–246,079). Definition of the study population was mostly broad. Study procedures were regularly little standardized. The number of included and analyzed patients was the same in 82.1%. In half of the rRCTs, more than one registry was utilized. Various linkage techniques were used. In median, two outcomes were collected from the registry/ies. The median follow-up of the rRCTs was 5.3 years (range: 6 weeks to 27 years). Information on quality of registry data was reported in 11.3%. rRCTs can provide valid (randomization, low lost-to-follow-up rates, generalizable) patient important long-term comparative-effectiveness data for relative little effort. Researchers planning an RCT should always check whether existing registries can be used for data collection. Reporting on data quality must be improved for use in evidence synthesis.

Registry-based randomized controlled trials (RRCTs) have potential to address limitations of traditional clinical trials. To describe their current use, information on planned and published RRCTs was identified and synthesized. A scoping review of published RRCT protocols and reports was conducted. Articles published between 2010 and 2021 identified from electronic database searching, a recent review of RRCTs, and targeted searching for recent RRCT protocols (2018–2021) were screened. Data on trial data sources, types of primary outcomes, and how these primary outcomes were described, selected, and reported were extracted. Ninety RRCT articles (77 reports; 13 protocols) were included. Forty nine (54%) used or planned to rely on registry data for their trial, 26 (29%) used both registry and additional data, and 15 (17%) used the registry solely for recruitment. Primary outcomes were routinely collected from the registry for 66 articles (73%). Only 28 articles (31%) described any methods to promote outcome data quality during or after data collection. Core outcome sets were not used in any of the trials. With improvements in registry design, outcome selection, measurement, and reporting, future RRCTs may deliver on promises of efficient, high-quality trials that address clinically relevant questions. •Most current registry-based randomized controlled trials (RRCTs) are conducted in adult populations in cardiology and oncology, with no examples identified in rare diseases.•Primary outcomes assessed in RRCTs are mostly routinely collected and assessed directly from the registry, but patient-reported outcomes or core outcome sets are rarely used.•Omission of key information on the selection and measurement of primary trial outcomes and handling of missing trial data is consistent with well-documented reports of poor reporting of RRCTs, which impairs use of RRCT results.•Consideration of the data needs of an RCT when designing new patient registries and use of reporting guidance such as CONSORT-ROUTINE can improve and advance future RRCTs and reduce research waste.