ABSTRACT
Cardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial results may not be generalisable and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored generalisability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), and secondary outcomes. As the pre-specified criteria were met confirming trial emulation, we then explored treatment heterogeneity among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease (CKD). In the trial-eligible population (n=137,155), results for the primary outcome demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]), meeting the pre-specified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age and CKD. This suggests that ONTARGET trial findings are generalisable to trial-underrepresented subgroups.
ABSTRACT
AIM: This prospective cohort study investigated the association between periodontal diseases (PDs) and all-cause and cause-specific mortality. MATERIALS AND METHODS: We utilized adult participants recruited from six National Health and Nutrition Examination Survey cycles (1999-2014) and linked mortality data from the National Death Index up to December 2019. Baseline clinical periodontal examinations were performed by trained and calibrated examiners. All-cause and cause-specific mortality was modelled through multivariable Cox proportional hazards and Fine-Gray models to account for competing risks. All models were adjusted for demographic and lifestyle variables, clinical measurements and comorbidities. RESULTS: Overall, 15,030 participants were included, with a median length of follow-up of 9 years. Risk of all-cause mortality was 22% greater in people with PD than the control group (adjusted hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.12-1.31). Risks of mortality by cardiovascular diseases (CVD), respiratory disease and diabetes were highest in participants with severe PD (CVD-sub-distribution HR [SHR]: 1.38, 95% CI: 1.16-1.64; respiratory-SHR: 1.62, 95% CI: 1.07-2.45; diabetes-SHR: 1.68, 95% CI: 1.12-2.53). CONCLUSIONS: Severe PD is associated with all-cause and cause-specific mortality among US adults after multivariable adjustment.
ABSTRACT
INTRODUCTION: Cardiovascular disease is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based on evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those aged ≥75 years, from ethnic minority backgrounds or with low kidney function may be limited.Using individual anonymised data from the Ongoing Telmisartan Alone and the Ramipril Global Endpoint Trial (ONTARGET) trial, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within a real-world setting in the area of cardiovascular disease. If the original trial results are replicable, we will estimate treatment effects and risk in groups underrepresented and excluded from the original clinical trial. METHODS AND ANALYSIS: We will develop a cohort analogous to the ONTARGET trial within the Clinical Practice Research Datalink between 1 January 2001 and 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome is a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for congestive heart failure. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include under represented and excluded groups. ETHICS AND DISSEMINATION: Ethical approval has been granted by the London School of Hygiene & Tropical Medicine Ethics Committee (Ref: 22658). The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency (protocol no. 20_012). Access to the individual patient data from the ONTARGET trial was obtained by the trial investigators. Findings will be submitted to peer-reviewed journals and presented at conferences.
