M.L. Bots's research while affiliated with Utrecht University and other places

Introduction The American Heart Association (AHA) introduced the concept of Life’s Essential 8 (LE8) to measure and monitor cardiovascular health (CVH) to prevent cardiovascular diseases. Purpose This study aims to identify the association between LE8 and the risk of incident total stroke, ischemic stroke, and haemorrhagic stroke. Methods We included 37,358 participants from the EPIC-NL (European Prospective Investigation Into Cancer and Nutrition- Netherlands) population-based cohort. The LE8 score was calculated according to the AHA’s definition using the LE8 metrics; diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood pressure, and blood glucose. The overall LE8 score (range 0-100) was categorised into low (0-49), moderate (50-79), and high (80-100) CVH. A Cox proportional hazard model adjusted for age, sex, educational levels, alcohol consumption and history of atrial fibrillation, was used to assess the association between LE8 and the risk of stroke. Results The mean age of participants was 49 years ± 12 years and 75% of participants were female. The mean LE8 score of the participants was 72 ± 11. During the median follow-up of 15.3 years (interquartile range: 14.1-16.5 years), 1323 (3.5%) total stroke, 873 (2.3%) ischemic stroke, and 247 (0.7%) haemorrhagic stroke cases occurred. Moderate and high CVH scores were associated with a lower risk of total stroke compared with low CVH scores: hazard ratio (HR) 0.52 [95% confidence interval (95%CI) 0.41-0.65] for moderate and HR 0.33 [95%CI 0.25-0.43] for high CVH). For ischemic stroke we observed similar associations (HR 0.46 [95%CI 0.35-0.61] for moderate and HR 0.31 [95%CI 0.23-0.44] for high CVH) as well as for haemorrhagic stroke (HR 0.68 [95%CI 0.37-1.25] for moderate and HR 0.38 [95%CI 0.19-0.75] for high CVH). Conclusions Our findings suggest an inverse graded relationship between LE8 and stroke. A higher baseline LE8 score was associated with an impressive lower risk of total stroke, ischemic stroke, and haemorrhagic stroke among Dutch adults. Improving the LE8 score could therefore potentially be a valuable tool to prevent the risk of stroke.

Introduction The American Heart Association (AHA) introduced the concept of Life’s Essential 8 (LE8) to measure and monitor cardiovascular health (CVH) to prevent cardiovascular diseases. Purpose This study examined the association between LE8 and the incidence of atrial fibrillation (AF). Methods In total, 37,807 participants from the population-based European Prospective Investigation Into Cancer and Nutrition-Netherlands (EPIC-NL) cohort were included. The components diet, physical activity, sleep health, nicotine exposure, body mass index, blood glucose, blood lipids, blood pressure were all given a score between 0 and 100 and an overall LE8 score was created by averaging the component scores. The overall LE8 score was categorized into low cardiovascular health (CVH, 0-49), moderate CVH (50-79), and high CVH (80-100). AF cases were obtained through linkage with registries. A Cox proportional hazards model adjusted for age, sex, education level, heart failure, coronary heart disease, and alcohol consumption, was used to assess the association between LE8 and AF. Results The mean age of participants was 49 years ± 12 years and 75% of participants were female. During a median follow-up of 15.3 years (interquartile range: 14.1 – 26.5 years), 833 AF cases (2.3%) were identified. Compared to the participants with a high CVH score (19.5%), participants with a low CVH score (5%) had a 2 times higher hazard for incident AF (hazard ratio (HR) 1.99 [95% confidence interval (95%CI) 1.49 – 2.65]). Furthermore, a decrease in the number of ideal components was associated with a higher risk for incident AF (HR 1.11 [95%CI 1.05 – 1.18]). Conclusions The results show that a worse CVH, indicated by a lower LE8 score, is associated with an increased risk for incident AF. Preventing AF could potentially be achieved by implementing the LE8 score in clinical practice. Especially since LE8 is a tool that is easy to interpret and can be applied by healthcare providers to encourage patients to make improvements in the risk factors for AF.

Background: Unhealthy dietary habits are an important risk factor for cardiovascular disease (CVD) and adopting a healthy diet is a central recommendation in CVD prevention. This study assessed the dietary habits of patients with established CVD, their compliance to dietary guidelines, and the relationship between guideline-compliance and recurrent cardiovascular event risk. Methods: 2656 patients with established CVD from the Utrecht Cardiovascular Cohort-Secondary Manifestations of ARTerial disease (UCC-SMART) prospective cohort study, were included between 1996 and 2022. Data on dietary intake was retrospectively collected for all participants in December 2022 using a 160-item food frequency questionnaire. Compliance with dietary guidelines was quantified using an amended version of the Dutch Healthy Diet 2015 (DHD-15) index (range: 0-135). Cox proportional hazard models were used to quantify the relationship with cardiovascular events (stroke and myocardial infarction). Results: Among 2656 CVD patients (77% male, mean age 59 ± 9 years), median energy intake was 1922 [IQR: 1536-2351] kcal/day. The median DHD-15 index was 81.7 [IQR 71.2-92.0], with high compliance scores for recommendations on legumes and fish, and low scores for recommendations on whole grains, red meat, processed meat, and dairy. A higher DHD-15 score was associated with lower stroke risk (HR 0.78, 95% CI 0.66-0.92 per 10-point increase) but not with myocardial infarction. Conclusion: Compliance with dietary guidelines was suboptimal in patients with established CVD. High compliance was associated with a clinically significant reduction in stroke risk in patients with established CVD, emphasizing the importance of dietary counseling.

Background and purpose Risk factors for stroke differ between women and men in general populations. However, little is known about sex differences in secondary prevention. We investigated if sex interacted with modifiable risk factors for stroke in a large arterial disease cohort. Methods Within the prospective UCC-SMART study, 13,898 patients (35% women) with atherosclerotic disease or high-risk factor profile were followed up to 23 years for stroke incidence or recurrence. Hypertension, smoking, diabetes, overweight, dyslipidemia, high alcohol use, and physical inactivity were studied as risk factors. Association between these factors and ischemic and hemorrhagic stroke incidence or recurrence was studied in women and men using Cox proportional hazard models and Poisson regression models. Women-to-men relative hazard ratios (RHR) and rate differences (RD) were estimated for each risk factor. Left-truncated age was used as timescale. Results The age-adjusted stroke incidence rate was lower in women than men (3.9 vs 4.4 per 1000 person-years), as was the age-adjusted stroke recurrence rate (10.0 vs 11.7). Hypertension and smoking were associated with stroke risk in both sexes. HDL cholesterol was associated with lower stroke incidence in women but not in men (RHR 0.49; CI 0.27–0.88; and RD 1.39; CI − 1.31 to 4.10). Overweight was associated with a lower stroke recurrence in women but not in men (RHR 0.42; CI 0.23–0.80; and RD 9.05; CI 2.78–15.32). Conclusions In high-risk population, sex modifies the association of HDL cholesterol on stroke incidence, and the association of overweight on stroke recurrence. Our findings highlight the importance of sex-specific secondary prevention.

Background Clinical Decision Support Systems (CDSSs) based on routine care data using artificial intelligence (AI) are increasingly deployed. CDSSs, however, may affect patient-physician relationships (Figure 1) and potentially result in a decrease in treatment adherence. Communication about these systems has mostly focused on technical aspects and less on their acceptance and trust. We aimed to investigate whether patient trust in physicians is affected when supported by a CDSS. Methods We conducted a vignette study among the patient panel (N=860) of a University Medical Center. Patients were presented either a high-risk or a low-risk vignette. For both vignettes, a physician made a treatment decision with (intervention group) or without (control group) the use of a CDSS. Using a questionnaire with a 1-7 point Likert scale (1 = strongly disagree, 7 = strongly agree), we collected data on patient trust in physicians in three dimensions: competence, integrity and benevolence, and trust in technology in general. We assessed differences between the control and intervention groups using Mann-Whitney U tests and potential effect modification by sex, age and education level using multivariate analyses. Results In total, 398 individuals participated. Trust in general was high (5.8 in the high-risk case and 6.0 in the low-risk case). Figure 2 illustrates the distribution of the dimensions of trust, by case and group. In the high-risk case, perceived competence and integrity was lower in the intervention group compared to the control group (5.8 vs. 5.6 and 6.3 vs. 6.0, respectively). In the intervention group, perception of the physician’s competence and integrity was significantly lower in women than in men. No differences between the groups were found in the trust dimensions within the low-risk case. Participants with higher trust in technology in general also showed a higher confidence in physicians using a CDSS in terms of benevolence and integrity (P=.009 and P=.044, respectively). Conclusion We found that, in general, trust in physicians was high. However, our findings indicate a potentially negative effect of AI applications on the patient-physician relationship, especially in women and high-risk situations. Trust in technology in general might increase the likelihood of embracing the use of CDSSs by the treating professional.

Background People with chronic kidney disease (CKD) have a markedly higher risk for cardiovascular disease. Systematic underrepresentation of people with CKD in cardiovascular randomised controlled trials (RCTs) limits evidence to guide cardiovascular risk management (CVRM). Purpose In this systematic review we aimed to identify evidence gaps regarding CVRM medication for people with CKD and evaluated the prevalence of exclusion of people with CKD from cardiovascular RCTs. Method We searched Clinicaltrials.gov through the Cochrane Central Register of Controlled Trials from inception until October 2021. Eligible studies were randomised controlled trials (RCTs) that investigate the efficacy of guideline-recommended CVRM medications on (cardiovascular) mortality, cardiovascular morbidity, and end-stage kidney disease in adults with a history of cardiovascular disease or one or more major risk factors for cardiovascular disease. Two reviewers independently determined the eligibility of references and extracted data. Outcomes were an overview of studies that report results for people with CKD, evidence gaps in results, and the rate of exclusion of people with CKD. Results We included 1180 of the 2794 eligible RCTs involving 2,158,869 participants (mean age 63±6 years, 36% female). Overall, 841 (71%) RCTs excluded (subgroups of) people with CKD based on heterogenous exclusion criteria. Since 2000, this prevalence has increased from 70% to 75%. Of included RCTs, only 157 (13%) reported results for people with CKD (again in heterogenous subgroups). The prevalence of RCTs with results for people with CKD has increased since 2000 from 10% to 23%. Nevertheless, significant evidence gaps remain for most CVRM interventions, particularly for those with an eGFR <30 ml/min/1.73m2 (22 RCTs), and people who are treated with dialysis (14 RCTs) or received a kidney transplant (1 RCTs). Conclusion(s) The majority of cardiovascular RCTs continues to exclude (subgroups of) people with CKD and this has only increased over the years. Although more RCTs report results for people with CKD, evidence gaps for the efficacy most CVRM medications persist, particularly for those with severe CKD.Figure 1:Heat map (subgroup) analyses for MACE for people with different stages CKD. Panel A illustrates analyses for hypertension, panel B for antiplatelets and anticoagulants, panel C for cholesterol-lowering drugs, panel D for glucose-lowering drugs, and panel E for combinations of interventions.

Background Computer-aided clinical decision support algorithms require continuous adjustments (learning) to account for changes in patient-characteristics, treatment(s), and outcomes, also referred to as a "Learning Healthcare System" (LHS). A LHS’s accuracy depends on adequate reflection of all patients, and participation bias may distort its effectiveness substantially. Therefore, we studied participation bias in a single center cardiovascular cohort study. Methods The cardiovascular cohort was set up as a LHS aiming for guideline-based treatment according to the individual risk profile for all cardiovascular disease patients in routine clinical care. Patients visiting an outpatient clinic for first time evaluation of a cardiovascular disease or risk factor received information on the cardiovascular cohort prior to their visit. During visit, cardiovascular risk management (CVRM) data was collected in the electronic health record (EHR) and informed consent was asked. We studied differences in characteristics between consenting, non-consenting and non-responding patients, and used multivariable logistic regression to identify determinants of non-consent. Multinomial regression was used for exploratory analyses of non-response determinants. A waiver (19/641) was obtained from the institutional review board for this study. Results In total, 2378 patients were consenting, 1907 non-consenting, and 1445 non-responding. In short, non-consent was related to higher cardiovascular risk (e.g., a cardiovascular disease history (OR 1.43, 95%CI 1.23-1.66)) and lower education (OR 0.76, 95%CI 0.60-0.97) than consent (Figure 1). Non-response, in contrast, was associated with higher physical activity (OR 1.04, 95%CI 1.01-1.08) and education level (OR 1.43, 95%CI 1.04-1.98) compared to consent. Non-consent and non-response patients were, respectively, younger and older. Presence of CVRM indicators in the EHR was 5-30% lower in non-consenting and 37-69% lower in non-responding patients compared to consenting patients. Conclusion A traditional informed consent procedure leads to participation bias in a LHS. Furthermore, it affects structured registration of CVRM indicators in the EHR, which is detrimental for the LHS feedback loop, and potentially leads to suboptimal cardiovascular risk management in patients not willing to participate. This study underlines the importance of reassessing the need of a traditional informed consent procedure for the use of routine care data in learning healthcare systems. Open in new tabDownload slide

Background Management of asymptomatic patients with severe mitral regurgitation (MR) and preserved left ventricular function is still a challenging clinical entity. According to international guidelines, early mitral valve repair (MVR) surgery and active surveillance with facilitated surgery are both possible treatment strategies. Conflicting evidence is available on the number of patients that reach an indication for facilitated surgery during follow-up in the active surveillance strategy group [1, 2]. In the multicenter Dutch AMR registry, asymptomatic MR patients were allocated to either strategy according to the heart team decision [3]. In this registry there was a low threshold to perform additional testing (i.e. cardiac magnetic resonance imaging, holter monitoring and/or cardiopulmonary exercise testing). Purpose To prospectively assess the percentage of MR patients undergoing facilitated surgery during a long-term active surveillance strategy. Methods Since 2013, 99 patients with severe primary MR were included in the Dutch AMR Registry in 5 medical centers. Enrollment for early surgery or active surveillance was based on ESC guidelines and heart team decision. During long term follow-up, we assessed primary endpoints for both groups; occurrence of atrial fibrillation, cerebrovascular accident, heart failure, MVR surgery and cardiovascular/non-cardiovascular death. In particular, we assessed the number and timing of patients that underwent facilitated surgery in the active surveillance group. Results In total, 71 patients were allocated to the active surveillance and 28 to the early surgery group. 39 Patients in the active surveillance group reached a primary endpoint including 3 deaths (2 cardiovascular and 1 non-cardiovascular) (Figure 1). In the early surgery group, 4 patients reached a primary endpoint including 2 cardiovascular deaths. Over a mean follow-up time of 4.4 years, 36 patients (51%) of the active surveillance population underwent facilitated surgery due to either symptomatic or asymptomatic triggers (Table 1). Conclusions In the Dutch AMR registry, 51% of MR patients under active surveillance needed facilitated surgery within 4.4 years. Approximately half of these patients were still asymptomatic when developing an indication for surgery. Cardiovascular mortality rates were similar between the two treatment strategies. This result shows that active surveillance can be safely accomplished in asymptomatic severe MR patients. The Dutch AMR registry will further elucidate 1) whether MR patients can be stratified at baseline to either strategy based on additional testing and 2) whether facilitated surgery is non-inferior to early surgery in terms of surgical outcome, quality of life and long-term survival. For now, the current results support an active surveillance strategy in selected asymptomatic MR patients based on guidelines since half of patients are still free of symptoms without guideline indications for surgery.Figure 1Table 1

Introduction Lifetime risk of aneurysmal subarachnoid haemorrhage (aSAH) is high (7%) in persons ⩾35 years with hypertension who smoke(d). Whether screening for intracranial aneurysms (IAs) to prevent aSAH is effective in these patients is unknown. Patients and methods Participants were retrieved from a cohort of patients with clinically manifest atherosclerotic vascular disease included between 2012 and 2019 at the University Medical Centre Utrecht (SMART-ORACLE, NCT01932671) in whom CT-angiography (CTA) of intracranial arteries was performed. We selected patients ⩾35 years with hypertension who smoke(d). CTAs were reviewed for the presence of IAs by experienced neuroradiologists. Patients with IAs were offered follow-up imaging to detect aneurysmal growth. We determined aneurysm prevalence and developed a diagnostic model for IA risk at screening using multivariable logistic regression. Results IA were found in 25 of 500 patients (5.0% prevalence, 95%CI: 3.3%–7.3%). Median 5 year risk of rupture assessed with the PHASES score was 0.9% (IQR: 0.7%–1.3%). During a median follow-up of 57 months (IQR: 39–83 months) no patients suffered from aSAH. Aneurysmal growth was detected in one patient for whom preventive treatment was advised. IA risk at screening ranged between 1.6% and 13.4% with predictors being age, female sex and current smoking. Discussion and conclusion IA prevalence in persons ⩾35 years with hypertension and atherosclerotic vascular disease who smoke(d) was 5%. Given the very small proportion of IA that needed preventive treatment, we currently do not advise screening for Caucasian persons older than 35 years of age who smoke and have hypertension in general. Whether screening may be effective for certain subgroups (e.g. women older than 50 years of age) or other ethnic populations should be the subject of future studies.

Introduction High convection volumes in hemodiafiltration (HDF) result in improved survival; however, it remains unclear whether it is achievable in all patients. Methods CONVINCE, a randomized controlled trial, randomized patients with end-stage kidney disease 1:1 to high-dose HDF versus high-flux hemodialysis (HD) continuation. We evaluated the proportion of patients achieving high-dose HDF target: convection volume per visit of ≥23 l (range ±1 l) at baseline, month 3, and month 6. We compared baseline characteristics in the following 2 ways: (i) patients on target for all 3 visits versus patients who missed target on ≥1 visits and (ii) patients on target for all 3 visits or missing it once versus patients who missed target on ≥2 visits. Results A total of 653 patients were randomized to HDF. Their mean age was 62.2 (SD 13.5) years, 36% were female, 81% had fistula vascular access, and 33% had diabetes. Across the 3 visits, 75 patients (11%), 27 patients (4%), and 11 patients (2%) missed the convection volume target once, twice, and thrice, respectively. Apart from diabetes, there were no apparent differences in patient characteristics between patients who always achieved the high-dose target (83%) and those who missed the target either once or more (17%) or twice or more (6%). Conclusion Achieving high-dose HDF is feasible for nearly all patients in CONVINCE and could be maintained during the 6-month follow-up period. Apart from diabetes, there were no other indications for confounding by indication on multivariable analyses that may explain the potential survival advantage for patients receiving high-dose HDF.