Assessing the external validity of the VALIDATE-SWEDEHEART trial.
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ABSTRACT: Aims
The VALIDATE-SWEDEHEART trial was a registry-based randomized trial comparing bivalirudin and heparin in patients with acute myocardial infarction undergoing percutaneous coronary intervention. It showed no differences in mortality at 30 or 180 days. This study examines how well the trial population results may generalize to the population of all screened patients with fulfilled inclusion criteria in regard to mortality at 30 and 180 days.Methods
The standardized difference in the mean propensity score for trial inclusion between trial population and the screened not-enrolled with fulfilled inclusion criteria was calculated as a metric of similarity. Propensity scores were then used in an inverse-probability weighted Cox regression analysis using the trial population only to estimate the difference in mortality as it would have been had the trial included all screened patients with fulfilled inclusion criteria. Patients who were very likely to be included were weighted down and those who had a very low probability of being in the trial were weighted up.Results
The propensity score difference was 0.61. There were no significant differences in mortality between bivalirudin and heparin in the inverse-probability weighted analysis (hazard ratio 1.11, 95% confidence interval (0.73, 1.68)) at 30 days or 180 days (hazard ratio 0.98, 95% confidence interval (0.70, 1.36)).Conclusion
The propensity score difference demonstrated that the screened not-enrolled with fulfilled inclusion criteria and trial population were not similar. The inverse-probability weighted analysis showed no significant differences in mortality. From this, we conclude that the VALIDATE results may be generalized to the screened not-enrolled with fulfilled inclusion criteria.
SUBMITTER: Rylance RT
PROVIDER: S-EPMC8290983 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:OBJECTIVE:We aimed to assess the patient experience of informed consent (IC) during acute myocardial infarction (AMI) in a sub-study of the VALIDATE-SWEDEHEART trial. The original trial compared two anticoagulant agents in patients undergoing coronary intervention. A witnessed oral IC was required prior to randomization in patients with ST-segment elevation myocardial infarction, which was subsequently complemented with a written IC after percutaneous coronary intervention. Written consent was obtained before angiography in patients with non-ST-segment elevation myocardial infarction. BACKGROUND:The IC process in patients with AMI is under debate. Earlier trials in this population have required prospective consent before randomization. A trial published some years ago used deferred consent, but the patient experience of this process is poorly studied. METHODS:A total of 414 patients who participated in the main trial were enrolled and asked the following questions: (1) Do you remember being asked to participate in a study? (2) How was your experience of being asked to participate; do you remember it being positive or negative? (3) Would you have liked more information about the study? (4) Do you think it would have been better if you were included in the study without being informed until a later time? RESULTS:Of these patients, 94% remembered being included; 85% of them experienced this positively, 12% were neutral and 3% negative. Regarding more information, 88% did not want further information, and 68% expressed that they wanted to be consulted before inclusion. Of the patients, 5% thought it would have been better to have study inclusion without consent, and 27% considered it of no importance. CONCLUSION:It is reasonable to ask patients for verbal IC in the acute phase of AMI. Most patients felt positively about being asked to participate and had knowledge of being enrolled in a scientific study. In addition they objected to providing IC after randomization and treatment. TRIAL REGISTRATION:VALIDATE-SWEDEHEART European Union Clinical Trials Register: 2012-005260-10. ClinicalTrials.gov: NCT02311231. Registered on 8 Dec 2014.
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Project description:BACKGROUND:Microsimulation models are increasingly being used to inform colorectal cancer (CRC) screening recommendations. MISCAN-Colon is an example of such a model, used to inform the Dutch CRC screening program and US Preventive Services Task Force guidelines. Assessing the validity of these models is essential to provide transparency regarding their performance. In this study, we tested the external and predictive validity of MISCAN-Colon. METHODS:We validated MISCAN-Colon using the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, a randomized controlled trial that examined the effectiveness of once-only flexible sigmoidoscopy (FS) screening. We simulated the study population and design of the NORCCAP trial in MISCAN-Colon and compared 10- to 12-year model-predicted hazard ratios (HRs) for overall and distal CRC incidence and mortality to those observed. In addition, we compared the numbers of screen-detected neoplasia. Finally, we predicted the trial's future results to allow for the assessment of predictive validity. RESULTS:MISCAN-Colon predicted an HR for overall CRC incidence (0.85), distal CRC incidence (0.82), overall CRC mortality (0.68), and distal CRC mortality (0.62). These were within the limits of the 95% confidence intervals of the NORCCAP trial results. Similar results were observed for the number of screen-detected cancers. The model significantly underestimated the number of screen-detected adenomas. Model-predicted HRs for CRC incidence and mortality up to 15- to 17-year follow-up were 0.84 and 0.72, respectively. CONCLUSION:Although the underestimation of screen-detected adenomas requires further investigation, MISCAN-Colon is able to make a valid replication of the CRC incidence and mortality reduction of an FS screening trial, which suggests that it can be considered a useful tool to support decision making on CRC screening.
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Project description:Background The impact of baseline anemia in a contemporary acute coronary syndrome (ACS) population undergoing percutaneous coronary intervention in the era of predominant radial artery access, potent P2Y12 inhibition, and rare use of glycoprotein IIb/IIIa inhibitors has not been adequately studied. Methods and Results ACS patients who underwent percutaneous coronary intervention between 2014 and 2016 in the VALIDATE-SWEDEHEART (Bivalirudin Versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies Registry) trial without missing values for hemoglobin were included (n=5482). Mortality, myocardial reinfarction, and major bleeding at 180 days were assessed using Cox regression models and propensity score matching. All studied comorbidities were more common in ACS patients who had anemia (n=792). ACS patients with anemia had higher rates of 180-day mortality (6.9% versus 2.1%; hazard ratio, 1.9; 95% CI, 1.3-2.7; P<0.001), myocardial reinfarction (4.3% versus 1.9%; hazard ratio, 1.7; 95% CI, 1.1-2.7; P=0.013), and major bleeding (13.4% versus 8.2%; hazard ratio, 1.3; 95% CI, 1.0-1.6; P=0.041). The results were most evident in patients with a hemoglobin value <100 g/L, who had a nearly 10 times higher mortality rate. Conclusions Baseline anemia in ACS patients undergoing percutaneous coronary intervention, treated according to current practice including routine radial artery access, constitutes a high-risk feature for both ischemic events, bleeding events, and mortality. A multidisciplinary approach is warranted to maximize benefit and minimize patient risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02311231.
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Project description:BackgroundRandomized controlled trials (RCT) are regarded as the gold standard for effect evaluation in clinical interventions. However, RCTs may not produce relevant results to all patient groups. We aimed to assess the external validity of a multicenter RCT (DelPhi trial).MethodsThe DelPhi RCT investigated whether elderly patients with displaced proximal humeral fractures (PHFs) receiving reversed total shoulder prosthetic replacement (RTSA) gained better functional outcomes compared to open reduction and internal fixation (ORIF) using an proximal humerus locking plate (PHILOS). Eligible patients were between 65 and 85 years old with severely displaced 11-B2 or 11-C2 fractures (AO/OTA-classification, 2007). We compared baseline and follow-up data of patients for two of the seven hospitals that were included in the DelPhi trial (n = 54) with non-included patients (n = 69). Comparisons were made based on reviewing medical records regarding demographic, health and fracture parameters.ResultsForty-four percent of the eligible patients were included in the DelPhi trial. Comparing included and non-included patients indicated higher incidences of serious heart disease (P = 0.044) and a tendency toward higher tobacco intake (P = 0.067) in non-included patients. Furthermore, non-included patients were older (P = 0.040) and had higher ASA classification (P < 0.001) and were in more need for resident aid (in-home assistance) (P = 0.022) than included patients. The cause of PHF was more frequently related to fall indoors in non-included vs. included patients (P = 0.018) and non-included patients were more prone to other concomitant fractures (P = 0.004). Having concomitant fractures was associated with osteoporosis (P = 0.014). We observed no significant differences in rates of complications or deaths between included and non-included patients within 3 months after treatment. In descending order, non-included patients were treated conservatively, with PHILOS, RTSA, anatomic hemi-prothesis or an alternative type of ORIF. RTSA was the preferred treatment choice for C2-type fractures (P < 0.001).ConclusionsResults from the DelPhi RCT may not directly apply to older PHFs patients with lower health status or concomitant fractures.Level of evidenceLevel 4.
| S-EPMC8783856 | biostudies-literature
Project description:Transforming growth factor beta (TGFβ) promotes tumorigenesis by suppressing immune surveillance and inducing epithelial to mesenchymal transition (EMT). TGFβ may augment tumorigenesis by activating autophagy, which protects cancer cells from chemotherapy and promotes invasive and anti-apoptotic properties. Here, we assess how TGFβ1 modulates autophagy related (ATG) gene expression and ATG protein levels. We also assessed microtubule-associated protein light chain 3 (LC3) lipidation, LC3 puncta formation and autophagosome-lysosome co-localization in non-small cell lung cancer (NSCLC) cell lines. These experimental approaches were validated using pharmacological autophagy inhibitors (chloroquine and spautin-1) and an autophagy activator (MG132). We found that TGFβ1, chloroquine and MG132 had little effect on ATG protein levels but increased LC3 lipidation, LC3 puncta formation and autophagosome-lysosome co-localization. Since similar outcomes were observed using chloroquine and MG132, we concluded that several techniques employed to assess TGFβ-dependent autophagy may not differentiate between the activation of autophagy versus lysosomal inhibition. Thus, NSCLC cell lines stably expressing a GFP-LC3-RFP-LC3ΔG autophagic flux probe were used to assess TGFβ-mediated autophagy. Using this approach, we observed that TGFβ, MG132 and serum starvation increased autophagic flux, whereas chloroquine and spautin-1 decreased autophagic flux. Finally, we demonstrated that ATG5 and ATG7 are critical for TGFβ-dependent autophagy in NSCLC cells. The application of this model will fuel future experiments to characterize TGFβ-dependent autophagy, which is necessary to understand the molecular processes that link, TGFβ, autophagy and tumorigenesis.
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Project description:ObjectiveThe objective of the current study was to quantitatively explore aspects of external validity, both researcher's choices (eligibility) and patient's choices (consent), of a recently conducted clinical trial.MethodsA cohesive comparison between the MEDACIS trial (NCT02451293) database and a national quality and research database was conducted. Comparisons between both participants and nonconsenting patients (patient consent) and participants and noneligible patients (researcher selection) were performed. Comparisons of outcomes were depressive and anxiety symptoms, demographics, and somatic or psychiatric comorbidity.ResultsNoneligible patients had significantly higher levels of depressive symptoms and anxiety and were older and more likely to suffer from unstable angina pectoris. Furthermore, noneligible patients were less likely to be married, had a lower educational level, used more medication, and had a higher frequency of comorbidity. Nonconsenting patients had significantly higher levels of depressive symptoms and anxiety and were older and more likely to be females compared to participants.ConclusionSignificant differences were present between noneligible patients and participants; however, more troublingly significant differences were shown between nonconsenting patients and participants. The presence of depressive symptoms and anxiety has a significant impact on patients' willingness to give informed consent in clinical trials in cardiology with a focus on psychological outcomes.
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Project description:Background The clinical importance of intraprocedural stent thrombosis (IPST) during percutaneous coronary intervention in the contemporary era of potent oral P2Y12 inhibitors is not established. The aim of this study was to assess IPST and its association with clinical outcome in patients with myocardial infarction undergoing percutaneous coronary intervention with contemporary antithromboticmedications. Methods and Results The VALIDATE-SWEDEHEART study (Bivalirudin Versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies Registry Trial) included 6006 patients with myocardial infarction, treated with potent P2Y12 inhibitors during percutaneous coronary intervention. IPST, defined as a new or worsening thrombus related to a stent deployed during the procedure, was reported by the interventional cardiologist in 55 patients (0.9%) and was significantly associated with ST-segment elevation myocardial infarction presentation, longer stents, bailout glycoprotein IIb/IIIa inhibitors, and final Thrombolysis in Myocardial Infarction flow <3. The primary composite end point included cardiovascular death, myocardial infarction, out-of-laboratory definite stent thrombosis and target vessel revascularization within 30 days. Secondary end points were major bleeding and the individual components of the primary composite end point. Patients with versus without IPST had significantly higher rates of the primary composite end point (20.0% versus 4.4%), including higher rates of cardiovascular death, target vessel revascularization, and definite stent thrombosis, but not myocardial infarction or major bleeding. By multivariable analysis, IPST was independently associated with the primary composite end point (hazard ratio, 3.82; 95% CI, 2.05-7.12; P<0.001). Conclusions IPST is a rare but dangerous complication during percutaneous coronary intervention, independently associated with poor prognosis, even in the current era of potent antiplatelet agents. Future treatment studies are needed to reduce the rate of IPST and to improve the poor outcome among these patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02311231.
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Project description:The arrival of modern brain imaging technologies has provided new opportunities for examining the biological essence of human intelligence as well as the relationship between brain size and cognition. Thanks to these advances, we can now state that the relationship between brain size and intelligence has never been well understood. This view is supported by findings showing that cognition is correlated more with brain tissues than sheer brain size. The complexity of cellular and molecular organization of neural connections actually determines the computational capacity of the brain. In this review article, we determine that while genotypes are responsible for defining the theoretical limits of intelligence, what is primarily responsible for determining whether those limits are reached or exceeded is experience (environmental influence). Therefore, we contend that the gene-environment interplay defines the intelligent quotient of an individual.
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Project description:BackgroundRandomized controlled trials (RCTs) are the most reliable way of evaluating the effect of new treatments by comparing them with previously accepted treatment regimens. The results obtained from an RCT are extrapolated from the study environment to the general health care system. The ability to do so is called external validity. We sought to evaluate the external validity of an RCT comparing the results of total hip arthroplasty with those of hemiarthroplasty for the treatment of displaced femoral neck fractures in patients ≥80 years of age.MethodsThis prospective, single-center cohort study included 183 patients ≥80 years of age who had a displaced femoral neck fracture. All patients were screened according to the inclusion and exclusion criteria for an RCT comparing total hip arthroplasty and hemiarthroplasty. The population for this study consisted of patients who gave their informed consent and were randomized into the RCT (consenting group, 120 patients) as well as those who declined to give their consent to participate (non-consenting group, 63 patients). The outcome measurements were mortality, complications, and patient-reported outcome measures. Follow-up was carried out postoperatively with use of a mailed survey that included patient-reported outcome questionnaires.ResultsWe found a statistically significant and clinically relevant difference between the groups, with the non-consenting group having a higher risk of death compared with the consenting group. (hazard ratio, 4.6; 95% confidence interval, 1.9 to 11.1). No differences were found between the groups in terms of patient-reported outcome measures or surgical complications.ConclusionsThis cohort study indicates a higher mortality rate but comparable hip function and quality of life among eligible non-consenters as compared with eligible consenters when evaluating the external validity of an RCT in patients ≥80 years of age with femoral neck fracture.Level of evidenceTherapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
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Project description:PurposeReal-world data from large administrative claims databases in Japan have recently become available, but limited evidence exists to support their validity. VALIDATE-J validated claims-based algorithms for selected cancers in Japan.MethodsVALIDATE-J was a multicenter, cross-sectional, retrospective study. Disease-identifying algorithms were used to identify cancers diagnosed between January or March 2012 and December 2016 using claims data from two hospitals in Japan. Positive predictive values (PPVs), specificity, and sensitivity were calculated for prevalent (regardless of baseline cancer-free period) and incident (12-month cancer-free period; with claims and registry periods in the same month) cases, using hospital cancer registry data as gold standard.Results22 108 cancers were identified in the hospital claims databases. PPVs (number of registry cases) for prevalent/incident cases were: any malignancy 79.0% (25 934)/73.1% (18 119); colorectal 84.4% (3519)/65.6% (2340); gastric 87.4% (3534)/76.8% (2279); lung 88.1% (2066)/79.9% (1636); breast 86.4% (4959)/59.9% (3185); pancreatic 87.1% (582)/80.4% (508); melanoma 48.7% (46)/42.9% (36); and lymphoma 83.6% (1457)/77.8% (1035). Specificity ranged from 98.3% to 100% (prevalent)/99.5% to 100% (incident); sensitivity ranged from 39.1% to 67.6% (prevalent)/12.5% to 31.4% (incident). PPVs of claims-based algorithms for several cancers in patients ≥66 years of age were slightly higher than those in a US Medicare population.ConclusionsVALIDATE-J demonstrated high specificity and modest-to-moderate sensitivity for claims-based algorithms of most malignancies using Japanese claims data. Use of claims-based algorithms will enable identification of patient populations from claims databases, while avoiding direct patient identification. Further research is needed to confirm the generalizability of our results and applicability to specific subgroups of patient populations.
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