Publications by authors named "Jan Westerink"

85 Publications

End-stage kidney disease in patients with clinically manifest vascular disease; incidence and risk factors: results from the UCC-SMART cohort study.

J Nephrol 2021 Mar 13. Epub 2021 Mar 13.

Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Patients with cardiovascular disease (CVD) are at increased risk of end-stage kidney disease (ESKD). Insights into the incidence and role of modifiable risk factors for end-stage kidney disease may provide means for prevention in patients with cardiovascular disease.

Methods: We included 8402 patients with stable cardiovascular disease. Incidence rates (IRs) for end-stage kidney disease were determined stratified according to vascular disease location. Cox proportional hazard models were used to assess the risk of end-stage kidney disease for the different determinants.

Results: Sixty-five events were observed with a median follow-up of 8.6 years. The overall incidence rate of end-stage kidney disease was 0.9/1000 person-years. Patients with polyvascular disease had the highest incidence rate (1.8/1000 person-years). Smoking (Hazard ratio (HR) 1.87; 95% CI 1.10-3.19), type 2 diabetes (HR 1.81; 95% CI 1.05-3.14), higher systolic blood pressure (HR 1.37; 95% CI 1.24-1.52/10 mmHg), lower estimated glomerular filtration rate (eGFR) (HR 2.86; 95% CI 2.44-3.23/10 mL/min/1.73 m) and higher urine albumin/creatinine ratio (uACR) (HR 1.19; 95% CI 1.15-1.23/10 mg/mmol) were independently associated with elevated risk of end-stage kidney disease. Body mass index (BMI), waist circumference, non-HDL-cholesterol and exercise were not independently associated with risk of end-stage kidney disease.

Conclusions: Incidence of end-stage kidney disease in patients with cardiovascular disease varies according to vascular disease location. Several modifiable risk factors for end-stage kidney disease were identified in patients with cardiovascular disease. These findings highlight the potential of risk factor management in patients with manifest cardiovascular disease.
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http://dx.doi.org/10.1007/s40620-021-00996-1DOI Listing
March 2021

Impaired Cytoskeletal and Membrane Biophysical Properties of Acanthocytes in Hypobetalipoproteinemia - A Case Study.

Front Physiol 2021 23;12:638027. Epub 2021 Feb 23.

CELL Unit & PICT Imaging Platform, de Duve Institute, UCLouvain, Brussels, Belgium.

Familial hypobetalipoproteinemia is a metabolic disorder mainly caused by mutations in the gene. In its homozygous form it can lead without treatment to severe ophthalmological and neurological manifestations. In contrast, the heterozygous form is generally asymptomatic but associated with a low risk of cardiovascular disease. Acanthocytes or thorny red blood cells (RBCs) are described for both forms of the disease. However, those morphological changes are poorly characterized and their potential consequences for RBC functionality are not understood. Thus, in the present study, we asked whether, to what extent and how acanthocytes from a patient with heterozygous familial hypobetalipoproteinemia could exhibit altered RBC functionality. Acanthocytes represented 50% of the total RBC population and contained mitoTracker-positive surface patches, indicating the presence of mitochondrial fragments. While RBC osmotic fragility, calcium content and ATP homeostasis were preserved, a slight decrease of RBC deformability combined with an increase of intracellular free reactive oxygen species were observed. The spectrin cytoskeleton was altered, showing a lower density and an enrichment in patches. At the membrane level, no obvious modification of the RBC membrane fatty acids nor of the cholesterol content were detected but the ceramide species were all increased. Membrane stiffness and curvature were also increased whereas transversal asymmetry was preserved. In contrast, lateral asymmetry was highly impaired showing: (i) increased abundance and decreased functionality of sphingomyelin-enriched domains; (ii) cholesterol enrichment in spicules; and (iii) ceramide enrichment in patches. We propose that oxidative stress induces cytoskeletal alterations, leading to increased membrane stiffness and curvature and impaired lipid lateral distribution in domains and spicules. In addition, ceramide- and spectrin-enriched patches could result from a RBC maturation defect. Altogether, the data indicate that acanthocytes are associated with cytoskeletal and membrane lipid lateral asymmetry alterations, while deformability is only mildly impaired. In addition, familial hypobetalipoproteinemia might also affect RBC precursors leading to disturbed RBC maturation. This study paves the way for the potential use of membrane biophysics and lipid vital imaging as new methods for diagnosis of RBC disorders.
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http://dx.doi.org/10.3389/fphys.2021.638027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940373PMC
February 2021

Cost-effectiveness of magnetic resonance imaging for diagnosing recurrent ipsilateral deep vein thrombosis.

Blood Adv 2021 Mar;5(5):1369-1378

Department of Thrombosis and Hemostasis and.

The diagnostic workup of recurrent ipsilateral deep vein thrombosis (DVT) using compression ultrasonography (CUS) can be complicated by persistent intravascular abnormalities after a previous DVT. We showed that magnetic resonance direct thrombus imaging (MRDTI) can exclude recurrent ipsilateral DVT. However, it is unknown whether the application of MRDTI in daily clinical practice is cost effective. The aim of this study was to evaluate the cost effectiveness of MRDTI-based diagnosis for suspected recurrent ipsilateral DVT during first year of treatment and follow-up in the Dutch health care setting. Patient-level data of the Theia study (NCT02262052) were analyzed in 10 diagnostic scenarios, including a clinical decision rule and D-dimer test and imaging with CUS and/or MRDTI. The total costs of diagnostic tests and treatment during 1-year follow-up, including costs of false-positive and false-negative diagnoses, were compared and related to the associated mortality. The 1-year health care costs with MRDTI (range, €1219-1296) were generally lower than strategies without MRDTI (range, €1278-1529). This was because of superior specificity, despite higher initial diagnostic costs. Diagnostic strategies including CUS alone and CUS followed by MRDTI in case of an inconclusive CUS were potential optimal cost-effective strategies, with estimated average costs of €1529 and €1263 per patient and predicted mortality of 1 per 737 patients and 1 per 609 patients, respectively. Our model shows that diagnostic strategies with MRDTI for suspected recurrent ipsilateral DVT have generally lower 1-year health care costs than strategies without MRDTI. Therefore, compared with CUS alone, applying MRDTI did not increase health care costs.
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http://dx.doi.org/10.1182/bloodadvances.2020003849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948280PMC
March 2021

Bempedoic acid: Everything with a place and purpose.

Authors:
Jan Westerink

Eur J Prev Cardiol 2020 Jun 6. Epub 2020 Jun 6.

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http://dx.doi.org/10.1177/2047487320929779DOI Listing
June 2020

Applicability of Blood Pressure-Lowering Drug Trials to Real-World Patients With Cardiovascular Disease.

Hypertension 2021 Feb 21;77(2):357-366. Epub 2020 Dec 21.

From the Department of Vascular Medicine (N.E.B., W.S., F.L.J.V., J.W.), University Medical Center Utrecht, the Netherlands.

This study aimed to assess applicability of blood pressure-lowering drug trials to real-world secondary preventive care. We applied the eligibility criteria of the landmark blood pressure-lowering drug trials (EUROPA, PEACE, HOPE-peripheral arterial disease [PAD], PRoFESS, and PROGRESS) to patients with coronary artery disease (CAD; n=5155), peripheral arterial disease (PAD; n=1487), and cerebrovascular disease (n=2515) participating in the UCC-SMART cohort. Baseline differences according to trial eligibility were assessed. Differences in risk of all-cause mortality and a composite of cardiovascular death, myocardial infarction, and stroke (major adverse cardiovascular event) were calculated using Cox proportional hazard models, adjusted for age, sex, and cardiovascular risk factors. Seventy-five percent of UCC-SMART patients with CAD would have been eligible for EUROPA, 84% for PEACE, 59% of patients with PAD for HOPE-PAD, 17% of patients with cerebrovascular disease for PRoFESS, and 100% for PROGRESS. Eligible patients were older (average difference ranging 1.4-14.6 years across trials). Eligible patients with CAD were at lower risk of major adverse cardiovascular event after adjustment for age, sex, and cardiovascular risk factors in PEACE (hazard ratio, 0.65 [95% CI, 0.53-0.79]) and of mortality in both EUROPA (hazard ratio, 0.72 [95% CI, 0.62-0.82]) and PEACE (0.63 [95% CI, 0.51-0.78]). Adjusted mortality and major adverse cardiovascular event risks were not different between eligible and ineligible patients with PAD and cerebrovascular disease in HOPE-PAD, PRoFESS, and PROGRESS. The majority of real-world patients with CAD, PAD, or cerebrovascular disease would be eligible for landmark trials on blood pressure-lowering drugs. Patients with CAD ineligible for the EUROPA and PEACE trials are at higher adjusted mortality and major adverse cardiovascular event risks, which may limit applicability of their results to ineligible patients.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15965DOI Listing
February 2021

Associations Between Systolic Interarm Differences in Blood Pressure and Cardiovascular Disease Outcomes and Mortality: Individual Participant Data Meta-Analysis, Development and Validation of a Prognostic Algorithm: The INTERPRESS-IPD Collaboration.

Hypertension 2021 Feb 21;77(2):650-661. Epub 2020 Dec 21.

From the Primary Care Research Group, Institute of Health Services Research (C.E.C., F.C.W., S.T.J.M., S.F.M., R.S.T., J.L.C.), University of Exeter Medical School, College of Medicine & Health, Devon, England.

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803446PMC
February 2021

No benefit of HDL mimetic CER-001 on carotid atherosclerosis in patients with genetically determined very low HDL levels.

Atherosclerosis 2020 10 29;311:13-19. Epub 2020 Aug 29.

Department of Vascular Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands. Electronic address:

Background And Aims: Infusion of high-density lipoprotein (HDL) mimetics failed to induce regression of atherosclerosis in recent randomized clinical trials. However, patients in these previous trials had normal levels of HDL-cholesterol, which potentially limited efficacy. Patients with very low levels of HDL-cholesterol and impaired cholesterol efflux capacity can be expected to derive the most potential benefit from infusion of HDL mimetics. This randomized clinical trial evaluated the efficacy of infusions of the HDL mimetic CER-001 in patients with genetically determined very low levels of HDL cholesterol.

Methods: In this multicenter, randomized clinical trial, we recruited patients with familial hypoalphalipoproteinemia (due to ABCA1 and/or APOA1 loss-of-function variants). Participants were randomized to intravenous infusions of 8 mg/kg CER-001 or placebo (2:1 ratio), comprising 9 weekly infusions followed by infusions every two weeks. Patients underwent repeated 3T-MRI to assess mean vessel wall area and F-FDG PET/CT to quantify arterial wall inflammation.

Results: A total of 30 patients with a mean age of 52.7 ± 7.4 years and HDL-cholesterol of 0.35 ± 0.25 mmol/L were recruited. After 24 weeks, the absolute change in mean vessel wall area was not significantly different in the CER-001 group compared with placebo (n = 27; treatment difference: 0.77 mm, p = 0.21). Furthermore, there was no significant difference in carotid arterial wall inflammation (n = 24, treatment difference: 0.10 target-to-background ratio of the most diseased segment, p = 0.33) after 24 weeks.

Conclusion: In patients with genetically determined very low HDL-cholesterol, 24 weeks of treatment with HDL mimetic CER-001 did not reduce carotid vessel wall dimensions or arterial wall inflammation, compared with placebo.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.08.004DOI Listing
October 2020

A Pathophysiological Perspective on the SARS-CoV-2 Coagulopathy.

Hemasphere 2020 Aug 10;4(4):e457. Epub 2020 Aug 10.

Van Creveldkliniek, Benign Hematology Center, University Medical Center Utrecht, Utrecht, The Netherlands.

Recent evidence is focusing on the presence of a hypercoagulable state with development of both venous and arterial thromboembolic complications in patients infected with SARS-CoV-2. The ongoing activation of coagulation related to the severity of the illness is further characterized by thrombotic microangiopathy and endotheliitis. These microangiopathic changes cannot be classified as classical disseminated intravascular coagulation (DIC). In this short review we describe the interaction between coagulation and inflammation with focus on the possible mechanisms that might be involved in SARS-CoV-2 infection associated coagulopathy in the critically ill.
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http://dx.doi.org/10.1097/HS9.0000000000000457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430228PMC
August 2020

Standardized reporting of co-morbidity outcome after bariatric surgery: low compliance with the ASMBS outcome reporting standards despite ease of use.

Surg Obes Relat Dis 2020 Nov 19;16(11):1673-1682. Epub 2020 Jul 19.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: Despite the publication of the American Society for Metabolic and Bariatric Surgery (ASMBS) Outcome Reporting Standards in 2015, there is still a great variety in definitions used for reporting remission of co-morbidities after bariatric surgery. This hampers meaningful comparison of results.

Objective: To assess compliance with the ASMBS standards in current literature, and to evaluate use of the standards by applying them in a report on the outcomes of 5 co-morbidities after bariatric surgery.

Setting: Two clinics of the Dutch Obesity Clinic, location Den Haag and Velp, and three affiliated hospitals: Haaglanden Medical Center in Den Haag, Groene Hart Hospital in Gouda, and Vitalys Clinic in Velp.

Methods: A systematic search in PubMed was conducted to identify studies using the ASMBS standards. Besides, the standards were applied to a cohort of patients who underwent a primary bariatric procedure between November 2016 and June 2017. Outcomes of co-morbidities were determined at 6 and 12 months after surgery.

Results: Ten previous studies applying ASMBS definitions were identified by the search, including 6 studies using portions of the definitions, and 4 using complete definitions for 3 co-morbidities or in a small population. In this study, the standards were applied to 1064 patients, of whom 796 patients (75%) underwent Roux-en-Y gastric bypass and 268 patients (25%) underwent sleeve gastrectomy. At 12 months, complete remission of diabetes (glycosylated hemoglobin <6%, off medication) was reached in 63%, partial remission (glycosylated hemoglobin 6%-6.4%, off medication) in 7%, and improvement in 28% of patients (n = 232/248, 94%). Complete remission of hypertension (normotensive, off medication) was noted in 8%, partial remission (prehypertensive, off medication) in 23% and improvement in 63% (n = 397/412, 96%). Remission rate for dyslipidemia (normal nonhigh-density lipoprotein, off medication) was 57% and improvement rate was 19% (n = 129/133, 97%). Resolution of gastroesophageal reflux disease (no symptoms, off medication) was observed in 54% (n = 265/265). Obstructive sleep apnea syndrome improved in 90% (n = 157/169, 93%).

Conclusions: Compliance with the ASMBS standards is low, despite ease of use. Standardized definitions provided by the ASMBS guideline could be used in future research to enable comparison of outcomes of different studies and surgical procedures.
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http://dx.doi.org/10.1016/j.soard.2020.07.011DOI Listing
November 2020

Prevalence of Nonalcoholic Fatty Liver Disease (NAFLD) in Patients With Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

J Clin Endocrinol Metab 2020 12;105(12)

Department of Internal Medicine, Diabetology and Vascular Medicine, University Medical Center Utrecht, GA Utrecht, the Netherlands.

Context: Nonalcoholic fatty liver disease (NAFLD) prevalence is high, especially in patients with obesity and type 2 diabetes, and is expected to rise steeply in the coming decades.

Objective: We estimated NAFLD prevalence in patients with type 1 diabetes and explored associated characteristics and outcomes.

Data Sources: We reviewed PubMed and Embase for studies on NAFLD and type 1 diabetes to March 2020. We screened references of included articles.

Study Selection: Two authors independently screened titles/abstracts. One author screened full text articles. NAFLD was defined as described in the individual studies: steatosis and/or fibrosis. Studies not reporting alternative causes of hepatic steatosis or defining NAFLD only as elevated liver enzymes, were excluded. Initially, 919 articles met the selection criteria.

Data Extraction: One researcher performed data extraction and risk of bias assessment using standardized tables.

Data Synthesis: We assessed pooled prevalence rates by meta-analysis using a random-effects model, subsequently exploring heterogeneity by subgroup-, meta-regression-, and sensitivity analysis. Twenty studies between 2009 and 2019 were included (n = 3901). Pooled NAFLD prevalence was 19.3% (95% CI, 12.3%-27.5%), increasing to 22.0% (95% CI, 13.9%-31.2%) in adults only. Pooled prevalence of ultrasound studies was high (27.1%, 95% CI, 18.7%-36.3%) compared to studies using magnetic resonance imaging (8.6%, 95% CI, 2.1%-18.6%), liver biopsy (19.3%, 95% CI, 10.0%-30.7%), or transient elastography (2.3%, 95% CI, 0.6%-4.8%).

Conclusion: NAFLD prevalence in patients with type 1 diabetes is considerable and is highly dependent on the specific diagnostic modality and NAFLD definition used. These data are helpful in directing actions to standardize NAFLD diagnosis, which will help defining contributing mechanisms and outcomes.
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http://dx.doi.org/10.1210/clinem/dgaa575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526735PMC
December 2020

The relation between VLDL-cholesterol and risk of cardiovascular events in patients with manifest cardiovascular disease.

Int J Cardiol 2021 Jan 15;322:251-257. Epub 2020 Aug 15.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Introduction: Apolipoprotein B containing lipoproteins are atherogenic. There is evidence that with low plasma low density lipoprotein cholesterol (LDL-C) levels residual vascular risk might be caused by triglyceride rich lipoproteins such as very-low density lipoproteins (VLDL), chylomicrons and their remnants. We investigated the relationship between VLDL-cholesterol (VLDL-C) and recurrent major adverse cardiovascular events (MACE), major adverse limb events (MALE) and all-cause mortality in a cohort of patients with cardiovascular disease.

Methods: Prospective cohort study in 8057 patients with cardiovascular disease from the UCC-SMART study. The relation between calculated VLDL-C levels and the occurrence of MACE, MALE and all-cause mortality was analyzed with Cox regression models.

Results: Patients mean age was 60 ± 10 years, 74% were male, 4894 (61%) had coronary artery disease, 2445 (30%) stroke, 1425 (18%) peripheral arterial disease and 684 (8%) patients had an abdominal aorta aneurysm at baseline. A total of 1535 MACE, 571 MALE and 1792 deaths were observed during a median follow up of 8.2 years (interquartile range 4.512.2). VLDL-C was not associated with risk of MACE or all-cause mortality. In the highest quartile of VLDL-C the risk was higher for major adverse limb events (MALE) (HR 1.49; 95%CI 1.16-1.93) compared to the lowest quartile, after adjustment for confounders including LDL-C and lipid lowering medication.

Conclusion: In patients with clinically manifest cardiovascular disease plasma VLDL-C confers an increased risk for MALE, but not for MACE and all-cause mortality, independent of established risk factors including LDL-C and lipid-lowering medication.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.030DOI Listing
January 2021

Intimal and medial calcification in relation to cardiovascular risk factors.

PLoS One 2020 13;15(7):e0235228. Epub 2020 Jul 13.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Purpose: To assess specific risk factors and biomarkers associated with intimal arterial calcification (IAC) and medial arterial calcification (MAC).

Methods: We conducted a cross-sectional study in patients with or at risk of vascular disease from the SMART study(n = 520) and the DCS cohort(n = 198). Non-contrast computed tomography scanning of the lower extremities was performed and calcification in the femoral and crural arteries was scored as absent, predominant IAC, predominant MAC or indistinguishable. Multinomial regression models were used to assess the associations between cardiovascular risk factors and calcification patterns. Biomarkers for inflammation, calcification and vitamin K status were measured in a subset of patients with IAC(n = 151) and MAC(n = 151).

Results: Femoral calcification was found in 77% of the participants, of whom 38% had IAC, 28% had MAC and 11% were scored as indistinguishable. The absolute agreement between the femoral and crural arteries was high(69%). Higher age, male sex, statin use and history of coronary artery disease were associated with higher prevalences of femoral IAC and MAC compared to absence of calcification. Smoking and low ankle-brachial-index (ABI) were associated with higher prevalence of IAC and high ABI was associated with less IAC. Compared to patients with IAC, patients with MAC more often had diabetes, have a high ABI and were less often smokers. Inactive Matrix-Gla Protein was associated with increased MAC prevalence, while osteonectin was associated with decreased risk of MAC, compared to IAC.

Conclusions: When femoral calcification is present, the majority of the patients have IAC or MAC throughout the lower extremity, which have different associated risk factor profiles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235228PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357737PMC
September 2020

Outcomes of second opinions in general internal medicine.

PLoS One 2020 9;15(7):e0236048. Epub 2020 Jul 9.

Department of Internal Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: To date, the outcomes of second opinions in internal medicine in terms of diagnostic yield and patient benefit have not been studied extensively. This retrospective study explores the outcomes of second opinions at a general internal medicine outpatient clinic in an academic hospital.

Methods: A register of all patients referred to the general internal medicine outpatient clinic of the University Medical Center in Utrecht for a second opinion, was kept. All 173 patients referred between June 2016 and August 2018 were selected. Case records were analyzed for patient characteristics, referring doctor, chief complaint, performed investigations, follow-up time and, established diagnosis, additional diagnoses, initiated treatment and reported benefit.

Results: A new diagnosis was established in 13% of all patients. A new treatment was initiated in 56% of all patients: 91% and 51% of patients with and without a new diagnosis respectively (p < 0.001). Of all patients, 19% received an effective treatment (52% vs 14% of patients with vs without a new diagnosis, p < 0.001). Regardless of treatment, resolution or improvement of the chief complaint was achieved in 28% of all patients (52% vs 25% of patients with vs without a new diagnosis, p = 0.006). Regarding diagnostics, 23-33% of radiology, endoscopy and pathology tests performed during second opinion were a repetition of previously conducted investigations. Conventional blood tests were a repetition in 89% of cases. Median time to diagnosis was 64 days (IQR: 25-128 days) and median time to discharge was 75 days (IQR: 31-144 days).

Conclusion: Second opinions in general internal medicine lead to the establishment of a new diagnosis in a small proportion of patients. However, the value of second opinions may not be limited to the establishment of diagnoses, as new treatments are often initiated and overall patients report improved symptomatology in 28% of cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236048PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347190PMC
September 2020

Safety of using the combination of the Wells rule and D-dimer test for excluding acute recurrent ipsilateral deep vein thrombosis.

J Thromb Haemost 2020 09 21;18(9):2341-2348. Epub 2020 Jul 21.

Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.

Background: The diagnostic accuracy of clinical probability assessment and D-dimer testing for clinically suspected recurrent deep vein thrombosis (DVT) is largely unknown.

Aim: To evaluate the safety of ruling out acute recurrent DVT based on an unlikely Wells score for DVT and a normal D-dimer test.

Methods: This was a predefined endpoint of the Theia study in which the diagnostic accuracy of magnetic resonance direct thrombus imaging in acute recurrent ipsilateral DVT was validated. The Wells rule and D-dimer test, performed as part of the study protocol, were not used for management decisions. The primary outcome of this analysis was the incidence of recurrent DVT at baseline or during 3-month follow-up for patients with an unlikely Wells score and a normal D-dimer test.

Results: Results of both Wells score and D-dimer tests were available in 231 patients without anticoagulant treatment. The recurrent DVT prevalence was 45% (103/231). Forty-nine patients had an unlikely Wells score and normal D-dimer test, of whom 3 (6.1%, 95% confidence interval [CI] 1.3%-18%) had recurrent DVT at baseline/follow-up, yielding a sensitivity of 97% (95% CI 92%-99%) and specificity of 36% (95% CI 28%-45%). Thus, if clinical probability scoring and D-dimer testing would have been applied, radiological imaging could have been omitted in 21% of patients with a diagnostic failure rate of 6.1%.

Conclusion: By applying clinical probability scoring and D-dimer testing, radiological imaging could be spared in one fifth of patients with suspected recurrent ipsilateral DVT. However, the high failure rate does not support implementation of this strategy in daily practice.
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http://dx.doi.org/10.1111/jth.14986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497055PMC
September 2020

Bempedoic acid: Everything with a place and purpose.

Authors:
Jan Westerink

Eur J Prev Cardiol 2020 Jun 6:2047487320929779. Epub 2020 Jun 6.

Department of Vascular Medicine, University Medical Center Utrecht, the Netherlands.

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http://dx.doi.org/10.1177/2047487320929779DOI Listing
June 2020

Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS-CoV-2.

Int J Lab Hematol 2020 10 22;42(5):e211-e212. Epub 2020 May 22.

Department of Intensive Care, University Medical Center Utrecht and University Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1111/ijlh.13244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280565PMC
October 2020

Development of a clinical decision tool to reduce diagnostic testing for primary aldosteronism in patients with difficult-to-control hypertension.

BMC Endocr Disord 2020 Apr 29;20(1):56. Epub 2020 Apr 29.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, 85500, 3508 GA, Utrecht, The Netherlands.

Background: Satisfactory tools to preclude low-risk patients from intensive diagnostic testing for primary aldosteronism (PA) are lacking. Therefore, we aimed to develop a decision tool to determine which patients with difficult-to-control hypertension have a low probability of PA, thereby limiting the exposure to invasive testing while at the same time increasing the efficiency of testing in the remaining patients.

Methods: Data from consecutive patients with difficult-to-control hypertension, analysed through a standardized diagnostic protocol between January 2010 and October 2017 (n = 824), were included in this cross-sectional study. PA was diagnosed by a combined approach: 1) elevated aldosterone-to-renin ratio (> 5.0 pmol/fmol/s), confirmed with 2) non-suppressible aldosterone after standardized saline infusion (≥280 pmol/L). Multivariable logistic regression analyses including seven pre-specified clinical variables (age, systolic blood pressure, serum potassium, potassium supplementation, serum sodium, eGFR and HbA1c) was performed. After correction for optimism, test reliability, discriminative performance and test characteristics were determined.

Results: PA was diagnosed in 40 (4.9%) of 824 patients. Predicted probabilities of PA agreed well with observed frequencies and the c-statistic was 0.77 (95% confidence interval (95%CI) 0.70-0.83). Predicted probability cut-off values of 1.0-2.5% prevented unnecessary testing in 8-32% of the patients with difficult-to-control hypertension, carrying sensitivities of 0.98 (95%CI 0.96-0.99) and 0.92 (0.83-0.97), and negative predictive values of 0.99 (0.98-1.00) and 0.99 (0.97-0.99).

Conclusions: With a decision tool, based on seven easy-to-measure clinical variables, patients with a low probability of PA can be reliably selected and a considerable proportion of patients with difficult-to-control hypertension can be spared intensive diagnostic testing.
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http://dx.doi.org/10.1186/s12902-020-0528-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191700PMC
April 2020

Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2.

Int J Lab Hematol 2020 06;42 Suppl 1:19-20

Department of Clinical Chemistry and Laboratory Medicine, University Medical Center Utrecht and University Utrecht, Utrecht, the Netherlands.

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http://dx.doi.org/10.1111/ijlh.13230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264532PMC
June 2020

Cardiovascular risk factors and the risk of major adverse limb events in patients with symptomatic cardiovascular disease.

Heart 2020 Nov 13;106(21):1686-1692. Epub 2020 Mar 13.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands

Aim: To determine the relationship between non-high-density lipoprotein cholesterol (non-HDL-c), systolic blood pressure (SBP) and smoking and the risk of major adverse limb events (MALE) and the combination with major adverse cardiovascular events (MALE/MACE) in patients with symptomatic vascular disease.

Methods: Patients with symptomatic vascular disease from the Utrecht Cardiovascular Cohort - Secondary Manifestations of ARTerial disease (1996-2017) study were included. The effects of non-HDL-c, SBP and smoking on the risk of MALE were analysed with Cox proportional hazard models stratified for presence of peripheral artery disease (PAD). MALE was defined as major amputation, peripheral revascularisation or thrombolysis in the lower limb.

Results: In 8139 patients (median follow-up 7.8 years, IQR 4.0-11.8), 577 MALE (8.7 per 1000 person-years) and 1933 MALE/MACE were observed (29.1 per 1000 person-years). In patients with PAD there was no relation between non-HDL-c and MALE, and in patients with coronary artery disease (CAD), cerebrovascular disease (CVD) or abdominal aortic aneurysm (AAA) the risk of MALE was higher per 1 mmol/L non-HDL-c (HR 1.14, 95% CI 1.01 to 1.29). Per 10 mm Hg SBP, the risk of MALE was higher in patients with PAD (HR 1.06, 95% CI 1.01 to 1.12) and in patients with CVD/CAD/AAA (HR 1.15, 95% CI 1.08 to 1.22). The risk of MALE was higher in smokers with PAD (HR 1.45, 95% CI 0.97 to 2.14) and CAD/CVD/AAA (HR 7.08, 95% CI 3.99 to 12.57).

Conclusions: The risk of MALE and MALE/MACE in patients with symptomatic vascular disease differs according to vascular disease location and is associated with non-HDL-c, SBP and smoking. These findings confirm the importance of MALE as an outcome and underline the importance of risk factor management in patients with vascular disease.
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http://dx.doi.org/10.1136/heartjnl-2019-316088DOI Listing
November 2020

Timing of Thoracic Outlet Decompression after Thrombolysis for Primary Upper Extremity Deep Venous Thrombosis: A Systematic Review.

Ann Vasc Surg 2020 Jul 6;66:654-661. Epub 2020 Feb 6.

Department of Vascular Surgery, University Medical Center, Utrecht, the Netherlands. Electronic address:

Background: The optimal timing of decompression surgery after thrombolysis in patients with primary upper extremity deep vein thrombosis (UEDVT) is still a matter of debate. This systematic review compares the safety and efficacy of early intervention versus postponed intervention in patients with primary UEDVT.

Methods: A structured PUBMED, EMBASE, and COCHRANE search was performed for studies reporting on the timing of surgical intervention for primary UEDVT. Studies reporting on timing of decompression surgery in combination with recurrent thrombosis, bleeding complications, and symptom-free survival were included. Two treatment groups were defined; group A received surgical decompression within two weeks after thrombolysis and group B after two weeks or more. All end points were assessed in accordance with the reported outcomes in the included articles. Mean percentages were calculated using descriptive statistics.

Results: Six articles (126 patients) were included: 87 patients in group A versus 39 in group B. In group A, bleeding complications occurred in 7% of patients versus 5% in group B. Two-third of the bleeding complications in group A occurred in patients receiving surgical decompression within 24 hr after thrombolysis while kept on intravenous heparin both preoperatively and postoperatively. Reported preoperative recurrent thrombosis was 7% in group A versus 11% in group B, another 13% had postoperative recurrent thrombosis versus 21% in group B. The effectiveness of both treatment strategies was comparable with a total of 89% of patients in group A with minimal or no symptoms at final follow-up compared with 90% in group B. The mean follow-up in group A was 35 months (1-168 months) and 28 months (1-168 months) in group B.

Conclusions: Based on the limited available data presented in this review, early decompression surgery within two weeks after catheter-directed thrombolysis seems as safe and effective as postponed surgical intervention in patients with primary UEDVT.
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http://dx.doi.org/10.1016/j.avsg.2020.01.083DOI Listing
July 2020

Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis.

Blood 2020 04;135(16):1377-1385

Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.

The diagnosis of recurrent ipsilateral deep vein thrombosis (DVT) is challenging, because persistent intravascular abnormalities after previous DVT often hinder a diagnosis by compression ultrasonography. Magnetic resonance direct thrombus imaging (MRDTI), a technique without intravenous contrast and with a 10-minute acquisition time, has been shown to accurately distinguish acute recurrent DVT from chronic thrombotic remains. We have evaluated the safety of MRDTI as the sole test for excluding recurrent ipsilateral DVT. The Theia Study was a prospective, international, multicenter, diagnostic management study involving patients with clinically suspected acute recurrent ipsilateral DVT. Treatment of the patients was managed according to the result of the MRDTI, performed within 24 hours of study inclusion. The primary outcome was the 3-month incidence of venous thromboembolism (VTE) after a MRDTI negative for DVT. The secondary outcome was the interobserver agreement on the MRDTI readings. An independent committee adjudicated all end points. Three hundred five patients were included. The baseline prevalence of recurrent DVT was 38%; superficial thrombophlebitis was diagnosed in 4.6%. The primary outcome occurred in 2 of 119 (1.7%; 95% confidence interval [CI], 0.20-5.9) patients with MRDTI negative for DVT and thrombophlebitis, who were not treated with any anticoagulant during follow-up; neither of these recurrences was fatal. The incidence of recurrent VTE in all patients with MRDTI negative for DVT was 1.1% (95% CI, 0.13%-3.8%). The agreement between initial local and post hoc central reading of the MRDTI images was excellent (κ statistic, 0.91). The incidence of VTE recurrence after negative MRDTI was low, and MRDTI proved to be a feasible and reproducible diagnostic test. This trial was registered at www.clinicaltrials.gov as #NCT02262052.
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http://dx.doi.org/10.1182/blood.2019004114DOI Listing
April 2020

Normal-range thyroid-stimulating hormone levels and cardiovascular events and mortality in type 2 diabetes.

Diabetes Res Clin Pract 2019 Nov 16;157:107880. Epub 2019 Oct 16.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University, P.O. Box 85500, 3508 GA Utrecht, the Netherlands. Electronic address:

Aims: Thyroid dysfunction is a risk factor for cardiovascular disease. Whether thyroid function within the normal range is a risk factor for cardiovascular disease remains uncertain. The aim of this study is to evaluate whether plasma thyroid-stimulating hormone (TSH) levels in the normal range are a risk factor for cardiovascular disease and mortality in participants with type 2 diabetes mellitus with high cardiovascular risk.

Methods: We included 1265 participants with high cardiovascular risk, type 2 diabetes, and TSH within the normal range (0.35-5.00 mIU/L) from the Second Manifestations of ARTerial disease cohort. The primary outcome was major cardiovascular events (MACE; vascular death, stroke and myocardial infarction). Secondary outcomes of interest were the separate vascular outcomes and all-cause mortality. Cox proportional hazard models were used to evaluate the risk of plasma TSH levels on all outcomes.

Results: A total of 191 MACE occurred during a total follow-up of 8183 years. Plasma TSH levels were not associated with MACE (hazard ratio (HR) per mIU/L TSH increase 0.93; 95% confidence interval (95%CI) 0.80-1.08). With a total of 54 strokes during the study period, plasma TSH was associated with a lower risk of stroke (HR per mIU/L 0.64, 95% CI 0.45-0.89). There was no association between plasma TSH levels and risk of myocardial infarction, vascular death, or all-cause mortality.

Conclusions: Higher TSH levels within the normal range are associated with a lower risk of stroke in high-risk patients with type 2 diabetes, but not associated with the risk of other cardiovascular events or mortality.
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http://dx.doi.org/10.1016/j.diabres.2019.107880DOI Listing
November 2019

Apparent therapy-resistant hypertension as risk factor for the development of type 2 diabetes mellitus.

J Hypertens 2020 01;38(1):45-51

Department of Vascular Medicine Department of Cardiology Department of Vascular Surgery Department of Neurology and Neurosurgery Department of Diabetology, University Medical Centre Utrecht, Utrecht, The Netherlands.

Objective: To evaluate whether the relationship between hypertension and type 2 diabetes mellitus (T2DM) is different for patients with uncontrolled hypertension, controlled hypertension or patients with apparent therapy-resistant hypertension (aTRH), compared with patients without hypertension.

Methods: Using Cox proportional hazard models we evaluated the risk of new-onset T2DM in 8756 patients, at high risk for vascular disease. Hypertensive patients were subdivided according to blood pressure (BP) and use of BP-lowering drugs. BP ≥ 140/90 mmHg was defined as uncontrolled BP. aTRH was defined as uncontrolled BP despite being treated with at least three BP-lowering drugs including a diuretic, or the use at least four BP-lowering drugs irrespective of BP levels. Further analysis evaluated the risk of new-onset T2DM for patients with uncontrolled hypertension and for patients with aTRH, compared with patients with controlled hypertension and without hypertension, respectively.

Results: Forty-five percent had controlled hypertension, 20% had uncontrolled hypertension, 5.7% had aTRH, and 29% were nonhypertensive. During a follow-up of 7.0 (interquartile range: 0-14) years there were 705 new cases of T2DM. Patients with hypertension had a 1.48 (95% confidence interval 1.22-1.80) times higher risk of new-onset T2DM than nonhypertensive patients. There was no significant difference in risk among different hypertension groups.

Conclusion: Patients at high risk for cardiovascular disease with hypertension have a 1.48 times higher risk of new-onset T2DM than nonhypertensive counterparts. The risk did not differ between patients with controlled hypertension, uncontrolled hypertension, or aTRH.
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http://dx.doi.org/10.1097/HJH.0000000000002227DOI Listing
January 2020

The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study.

Eur Heart J 2019 12;40(48):3901-3909

Department of Vascular Medicine, UMCU, 3584 CX Utrecht, the Netherlands.

Aims: Low-grade inflammation, measured by elevated plasma concentrations of high-sensitive C-reactive protein (CRP), is a risk factor for cardiovascular disease (CVD). There is evidence that low-grade inflammation is also related to a higher risk of cancer. The present prospective cohort study evaluates the relation between low-grade systemic inflammation and risk of cancer in patients with stable CVD.

Methods And Results: In total, 7178 patients with stable CVD and plasma CRP levels ≤10 mg/L were included. Data were linked to the Dutch national cancer registry. Cox regression models were fitted to study the relation between CRP and incident CVD and cancer. After a median follow-up time of 8.3 years (interquartile range 4.6-12.3) 1072 incident cancer diagnoses were observed. C-reactive protein concentration was related to total cancer [hazard ratio (HR) 1.35; 95% confidence interval (CI) 1.10-1.65] comparing last quintile to first quintile of CRP. Especially lung cancer, independent of histopathological subtype, was related to CRP (HR 3.39; 95% CI 2.02-5.69 comparing last to first quintile of CRP). Incidence of epithelial neoplasms and especially squamous cell neoplasms were related to CRP concentration, irrespective of anatomical location. Sensitivity analyses after excluding patients with a cancer diagnosis within 1, 2, and 5 years of follow-up showed similar results. No effect modification was observed by smoking status or time since smoking cessation (P-values for interaction > 0.05).

Conclusion: Chronic systemic low-grade inflammation, measured by CRP levels ≤10 mg/L, is a risk factor for incident cancer, markedly lung cancer, in patients with stable CVD. The relation between inflammation and incident cancer is seen in former and current smokers and is uncertain in never smokers.
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http://dx.doi.org/10.1093/eurheartj/ehz587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925382PMC
December 2019

Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial.

Eur Heart J 2019 12;40(46):3771-3778a

Department of Vascular Medicine, University Medical Center Utrecht, University Utrecht, GA Utrecht, The Netherlands.

Aims: Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease.

Methods And Results: Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months).

Conclusion: There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.
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http://dx.doi.org/10.1093/eurheartj/ehz404DOI Listing
December 2019

Heterogeneity of Treatment Effects From an Intensive Lifestyle Weight Loss Intervention on Cardiovascular Events in Patients With Type 2 Diabetes: Data From the Look AHEAD Trial.

Diabetes Care 2019 10 15;42(10):1988-1994. Epub 2019 Aug 15.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands

Objective: To explore the presence of heterogeneity of treatment effect (HTE) of an intensive lifestyle intervention on the occurrence of major cardiovascular events (MACE) in overweight or obese patients with type 2 diabetes, and to identify patient characteristics associated with individual treatment effect.

Research Design And Methods: In 4,901 participants from the Action for Health in Diabetes (Look AHEAD) trial, a penalized Cox regression model to predict treatment effect of intensive lifestyle intervention for the risk of MACE was derived, including all possible treatment-by-covariate interaction terms. The ability of the model to predict HTE was confirmed by calculating hazard ratios (HRs) and absolute risk change in quartiles of predicted treatment effect, and baseline patient characteristics were compared between quartiles.

Results: In quartile 1 of predicted treatment effect, with the highest predicted risk reduction, there was a significant treatment benefit of intensive lifestyle intervention (HR 0.64 [95% CI 0.49-0.83]), whereas there was no effect from treatment in quartiles 2 and 3 (HR 0.81 [95% CI 0.58-1.14] and 1.13 [95% CI 0.80-1.60], respectively) and a detrimental effect in quartile 4 (HR 1.37 [95% CI 1.09-1.73]). Several patient characteristics in demographics, medical history, physical examination, and laboratory values were associated with the level of treatment effect.

Conclusions: This post hoc analysis of the Look AHEAD trial showed that an intensive lifestyle intervention aimed at weight loss may reduce cardiovascular events in selected patients but may have a detrimental treatment effect in others.
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http://dx.doi.org/10.2337/dc19-0776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364666PMC
October 2019

Transcranial Doppler 24 Hours after Carotid Endarterectomy Accurately Identifies Patients Not at Risk of Cerebral Hyperperfusion Syndrome.

Eur J Vasc Endovasc Surg 2019 Sep 24;58(3):320-327. Epub 2019 Jul 24.

Vascular Surgery, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address:

Objectives: Intra-operative transcranial Doppler (TCD) is the gold standard for prediction of cerebral hyperperfusion syndrome (CHS) in patients after carotid endarterectomy (CEA) under general anaesthesia. However, post-operative cerebral perfusion patterns may result in a shift in risk assessment for CHS. This is a study of the predictive value of additional post-operative TCD measurements for prediction of CHS after CEA.

Methods: This was a retrospective analysis of prospectively collected data in patients undergoing CEA with available intra- and post-operative TCD measurements between 2011 and 2016. The mean blood flow velocity in the middle cerebral artery (MCAV) was measured pre-operatively, intra-operatively, and post-operatively at two and 24 h. Intra-operative MCAV increase was compared with MCAV increase two and 24 h post-operatively in relation to CHS. Cerebral hyperperfusion (CH) was defined as MCAV increase ≥ 100%, and CHS as CH with the presence of headache or neurological symptoms. Positive (PPV) and negative predictive values (NPV) of TCD measurements were calculated to predict CHS.

Results: Of 257 CEA patients, 25 (9.7%) had CH intra-operatively, 45 (17.5%) 2 h post-operatively, and 34 (13.2%) 24 h post-operatively. Of nine patients (3.5%) who developed CHS, intra-operative CH was diagnosed in two and post-operative CH in eight (after 2 h [n = 5] or after 24 h [n = 6]). This resulted in a PPV of 8%, 11%, and 18%, and a NPV of 97%, 98%, and 99% for intra-operative, 2 h and 24 h post-operative TCD, respectively.

Conclusions: TCD measurement of the MCAV 24 h after CEA under general anaesthesia is most accurate to identify patients who are not at risk of CHS.
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http://dx.doi.org/10.1016/j.ejvs.2019.04.033DOI Listing
September 2019

Mediation analysis of the relationship between type 2 diabetes and cardiovascular events and all-cause mortality: Findings from the SMART cohort.

Diabetes Obes Metab 2019 08 23;21(8):1935-1943. Epub 2019 May 23.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

Aim: To quantify the magnitude and specific contributions of known cardiovascular risk factors leading to higher cardiovascular risk and all-cause mortality caused by type 2 diabetes (T2D).

Methods: Mediation analysis was performed to assess the relative contributions of known classical risk factors for vascular disease in T2D (insulin resistance, systolic blood pressure, renal function, LDL-cholesterol, triglycerides and micro-albuminuria), and what proportion of the effect of T2D on cardiovascular events and all-cause mortality these factors mediate in the Second Manifestations of ARTerial disease (SMART) cohort consisting of 1910 T2D patients.

Results: Only 35% (95% CI 15-71%) of the excess cardiovascular risk caused by T2D is mediated by the classical cardiovascular risk factors. The largest mediated effect was through insulin resistance [proportion of mediated effect (PME) 18%, 95% CI 3-37%], followed by elevated triglycerides (PME 8%, 95% CI 4-14%) and micro-albuminuria (PME 7%, 95% CI 3-17%). Only 42% (95% CI 18-73%) of the excess mortality risk was mediated by the classical risk factors considered. The largest mediated effect was by micro-albuminuria (PME 18%, 95% CI 10-29%) followed by insulin resistance (PME 15%, 95% CI 1-33%).

Conclusion: A substantial amount of the increased cardiovascular risk and all-cause mortality caused by T2D cannot be explained by traditional vascular risk factors. Future research should focus on identifying non-classical pathways that might further explain the increased cardiovascular and mortality risk caused by T2D.
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http://dx.doi.org/10.1111/dom.13759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767388PMC
August 2019

The effect of stopping phenprocoumon 5 days preoperatively: A retrospective study.

Res Pract Thromb Haemost 2019 Jan 9;3(1):85-88. Epub 2018 Nov 9.

Department of Internal Medicine Diakonessenhuis Utrecht The Netherlands.

Background: Clinicians lack substantiated guidance on when vitamin K antagonist (VKA) treatment should be interrupted preoperatively, especially with regard to phenprocoumon, with its long half-life of 5.5 days.

Objective: To evaluate the efficacy of discontinuing phenprocoumon 5 days preoperatively and determine whether a safe international normalized ratio (INR) was reached.

Methods: This was a retrospective review of 118 patients using phenprocoumon prior to elective surgery. Preoperative INRs and factors that could potentially influence these values were identified and described. A safe preoperative INR was defined as <1.8.

Results: Of the 118 included patients, 42 patients (35.6%) had an off-target INR. The male sex was significantly and independently associated with an off-target INR (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.022-5.445). A high American Society of Anesthesiologists (ASA) classification was also significantly and independently associated with an off-target INR (OR 2.3, 95% CI: 1.029-5.173).

Conclusion: Discontinuation of phenprocoumon 5 days preoperatively resulted in an INR < 1.8 in more than one-third of patients. Individualizing or extending the period of phenprocoumon discontinuation may be a necessary treatment option.
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http://dx.doi.org/10.1002/rth2.12159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332713PMC
January 2019

Overcoming Obstacles in Lipid-lowering Therapy in Patients with HIV - A Systematic Review of Current Evidence.

AIDS Rev 2018 ;20(4):205-219

Department of Internal Medicine and Infectious Diseases. University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.

Cardiovascular risk management in human immunodeficiency virus (HIV)-infected individuals is gaining increased attention due to the rising incidence and prevalence of cardiovascular disease in this population. Despite the availability of efficacious treatment strategies, implementation of guideline advocated preventive therapy, such as lipid-lowering therapy with statins, is hampered by perceived, expected, and real side effects as well as by expected interactions with combination antiretroviral therapy. These obstacles to optimal treatment have resulted in a large gap between the number of patients in whom lipid-lowering therapy is indicated and those actually taking lipid-lowering medication. In the past few years, research has shown that the majority of patient-reported side effects is not causally related to statin therapy but is attributable to the nocebo effect. Furthermore, excessive caution due to expected drug interactions between statins and antiretroviral therapy is often unnecessary, especially with novel classes of antiretroviral therapy. The main aim of this review is to discuss the causes and consequences of this lipid-lowering treatment gap in HIV-infected patients together with a practical guide on how to overcome these obstacles. In addition, new treatment options on the optimal cardiovascular management focusing primarily on novel classes of antiretroviral therapy and lipid-lowering medication will be discussed.
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http://dx.doi.org/10.24875/AIDSRev.18000016DOI Listing
May 2019