External validation and updating of prediction models of bleeding risk in patients with cancer receiving anticoagulants.

OBJECTIVE: Patients with cancer are at increased bleeding risk, and anticoagulants increase this risk even more. Yet, validated bleeding risk models for prediction of bleeding risk in patients with cancer are lacking. The aim of this study is to predict bleeding risk in anticoagulated patients with cancer. METHODS: We performed a study using the routine healthcare database of the Julius General Practitioners' Network. Five bleeding risk models were selected for external validation. Patients with a new cancer episode during anticoagulant treatment or those initiating anticoagulation during active cancer were included. The outcome was the composite of major bleeding and clinically relevant non-major (CRNM) bleeding. Next, we internally validated an updated bleeding risk model accounting for the competing risk of death. RESULTS: The validation cohort consisted of 1304 patients with cancer, mean age 74.0±10.9 years, 52.2% males. In total 215 (16.5%) patients developed a first major or CRNM bleeding during a mean follow-up of 1.5 years (incidence rate; 11.0 per 100 person-years (95% CI 9.6 to 12.5)). The c-statistics of all selected bleeding risk models were low, around 0.56. Internal validation of an updated model accounting for death as competing risk showed a slightly improved c-statistic of 0.61 (95% CI 0.54 to 0.70). On updating, only age and a history of bleeding appeared to contribute to the prediction of bleeding risk. CONCLUSIONS: Existing bleeding risk models cannot accurately differentiate bleeding risk between patients. Future studies may use our updated model as a starting point for further development of bleeding risk models in patients with cancer.

Atrial fibrillation: trends in prevalence and antithrombotic prescriptions in the community.

INTRODUCTION: In the past decade, the atrial fibrillation (AF) landscape, including the treatment modalities, has drastically changed. This raises the question how AF prevalence and choices in antithrombotic therapy prescription have developed in the community over time. METHODS: Routine care data from the Julius General Practitioners' Network (JGPN) were used to calculate the yearly prevalence of AF and to quantify the percentage of all patients who were prescribed a platelet inhibitor, vitamin K antagonist (VKA), non-VKA oral anticoagulant (NOAC) or no antithrombotic medication. To explore whether certain patient characteristics are associated with selective prescription of oral anticoagulants (OAC), we applied logistic regression analyses. RESULTS: From 2008 through 2017, the JGPN database included 7459 unique AF patients. During this period, the prevalence of AF increased from 0.4% to 1.4%. The percentage of patients prescribed a VKA declined from 47% to 41%, whereas the percentage of patients prescribed a NOAC rose from 0% to 20%. In patients with new-onset AF, older age, heart failure, diabetes mellitus, vascular disease and dementia were independently associated with a higher likelihood of VKA rather than NOAC prescription. In 2017, 25% of all patients with AF and a CHA2DS2-VASc score ≥ 2 were not prescribed OAC therapy (i.e. 8% with platelet inhibitor monotherapy and 17% without any antithrombotic therapy). CONCLUSION: Between 2008 and 2017, AF prevalence in the community more than tripled. Prescription patterns showed possible 'channelling' of VKAs over NOACs in frailer, elderly patients, whereas still about one in every four AF patients with a CHA2DS2-VASc score ≥ 2 was not prescribed any prophylactic OAC therapy.

Effectiveness of CHA2DS2-VASc based decision support on stroke prevention in atrial fibrillation: A cluster randomised trial in general practice.

BACKGROUND: Guidelines on atrial fibrillation (AF) recommend the CHA2DS2-VASc rule for anticoagulant decision-making, but underuse exists. We studied the impact of an automated decision support on stroke prevention in patients with AF in a cluster randomised trial in general practice. METHODS: Intervention practices were provided with a CHA2DS2-VASc based anticoagulant treatment recommendation. Reference practices provided care as usual. The primary outcome was incidence of ischaemic stroke, transient ischaemic attack (TIA) and/or thromboembolism (TE). Secondary outcomes were bleeding and the proportion of patients on guideline recommended anticoagulant treatment. RESULTS: In total, 1129 AF patients were included in the 19 intervention practices and 1226 AF patients in the 19 reference practices. The median age was 77 (interquartile range (IQR) 68-75) years, the median CHA2DS2-VASc score was 3.0 (IQR 2.0-5.0). Underuse of anticoagulants in patients with CHA2DS2-VASc score ≥ 2 was 6.6%. After a median follow-up of 2.7 years (IQR 2.3-3.0), the incidence rate per 100 person-years of ischaemic stroke/TIA/TE was 1.96 in the intervention group and 1.42 in the reference group (hazard ratio (HR) 1.3, 95% C.I. 0.8-2.1). No difference was observed in the rate of bleeding (0.79 versus 0.82), or in the underuse (7.2% versus 8.2%) or overuse (8.0% versus 7.9%) of anticoagulation. CONCLUSIONS: In this study in patients with AF in general practice, underuse of anticoagulants was relatively low. Providing practitioners with CHA2DS2-VASc based decision support did not result in a reduction in stroke incidence, affect bleeding risk or anticoagulant over- or underuse.

Ruling out pulmonary embolism across different subgroups of patients and healthcare settings: protocol for a systematic review and individual patient data meta-analysis (IPDMA).

BACKGROUND: Diagnosing pulmonary embolism in suspected patients is notoriously difficult as signs and symptoms are non-specific. Different diagnostic strategies have been developed, usually combining clinical probability assessment with D-dimer testing. However, their predictive performance differs across different healthcare settings, patient subgroups, and clinical presentation, which are currently not accounted for in the available diagnostic approaches. METHODS: This is a protocol for a large diagnostic individual patient data meta-analysis (IPDMA) of currently available diagnostic studies in the field of pulmonary embolism. We searched MEDLINE (search date January 1, 1995, till August 25, 2016) to retrieve all primary diagnostic studies that had evaluated diagnostic strategies for pulmonary embolism. Two authors independently screened titles, abstracts, and subsequently full-text articles for eligibility from 3145 individual studies. A total of 40 studies were deemed eligible for inclusion into our IPDMA set, and principal investigators from these studies were invited to participate in a meeting at the 2017 conference from the International Society on Thrombosis and Haemostasis. All authors agreed on data sharing and participation into this project. The process of data collection of available datasets as well as potential identification of additional new datasets based upon personal contacts and an updated search will be finalized early 2018. The aim is to evaluate diagnostic strategies across three research domains: (i) the optimal diagnostic approach for different healthcare settings, (ii) influence of comorbidity on the predictive performance of each diagnostic strategy, and (iii) optimize and tailor the efficiency and safety of ruling out PE across a broad spectrum of patients with a new, patient-tailored clinical decision model that combines clinical items with quantitative D-dimer testing. DISCUSSION: This pre-planned individual patient data meta-analysis aims to contribute in resolving remaining diagnostic challenges of time-efficient diagnosis of pulmonary embolism by tailoring available diagnostic strategies for different healthcare settings and comorbidity. SYSTEMATIC REVIEW REGISTRATION: Prospero trial registration: ID 89366.

Predictive performance of the CHA2DS2-VASc rule in atrial fibrillation: a systematic review and meta-analysis.

Essentials The widely recommended CHA2DS2-VASc shows conflicting results in contemporary validation studies. We performed a systematic review and meta-analysis of 19 studies validating CHA2DS2-VASc. There was high heterogeneity in stroke risks for different CHA2DS2-VASc scores. This was not explained by differences between setting of care, or by performing meta-regression. SUMMARY: Background The CHA2DS2-VASc decision rule is widely recommended for estimating stroke risk in patients with atrial fibrillation (AF), although validation studies show ambiguous and conflicting results. Objectives To: (i) review existing studies validating CHA2DS2-VASc in AF patients who are not (yet) anticoagulated; (ii) meta-analyze estimates of stroke risk per score; and (iii) explore sources of heterogeneity across the validation studies. Methods We performed a systematic literature review and random effects meta-analysis of studies externally validating CHA2DS2-VASc in AF patients not receiving anticoagulants. To explore between-study heterogeneity in stroke risk, we stratified studies to the clinical setting in which patient enrollment started, and performed meta-regression. Results In total, 19 studies were evaluated, with over two million person-years of follow-up. In studies recruiting AF patients in hospitals, stroke risks for scores of 0, 1 and 2 were 0.4% (approximate 95% prediction interval [PI] 0.2-3.2%), 1.2% (95% PI 0.1-3.8%), and 2.2% (95% PI 0.03-7.8%), respectively. These were consistently higher than those in studies recruiting patients from the open general population, with risks of 0.2% (95% PI 0.0-0.9%), 0.7% (95% PI 0.3-1.2%) and 1.5% (95% PI 0.4-3.3%) for scores of 0, 1, and 2, respectively. Heterogeneity, as reflected by the wide PIs, could not be fully explained by meta-regression. Conclusions Studies validating CHA2DS2-VASc show high heterogeneity in predicted stroke risks for different scores.

Adenoma detection with Endocuff colonoscopy versus conventional colonoscopy: a multicentre randomised controlled trial.

BACKGROUND AND AIMS: Colonoscopy is the current reference standard for the detection of colorectal neoplasia, but nevertheless adenomas remain undetected. The Endocuff, an endoscopic cap with plastic projections, may improve colonic visualisation and adenoma detection. The aim of this study was to compare the mean number of adenomas per patient (MAP) and the adenoma detection rate (ADR) between Endocuff-assisted colonoscopy (EAC) and conventional colonoscopy (CC). METHODS: We performed a multicentre, randomised controlled trial in five hospitals and included fecal immonochemical test (FIT)-positive screening participants as well as symptomatic patients (>45 years). Consenting patients were randomised 1:1 to EAC or CC. All colonoscopies were performed by experienced colonoscopists (≥500 colonoscopies) who were trained in EAC. All colonoscopy quality indicators were prospectively recorded. FINDINGS: Of the 1063 included patients (52% male, median age 65 years), 530 were allocated to EAC and 533 to CC. More adenomas were detected with EAC, 722 vs 621, but the gain in MAP was not significant: on average 1.36 per patient in the EAC group versus 1.17 in the CC group (p=0.08). In a per-protocol analysis, the gain was 1.44 vs 1.19 (p=0.02), respectively. In the EAC group, 275 patients (52%) had one or more adenomas detected versus 278 in the CC group (52%; p=0.92). For advanced adenomas these numbers were 109 (21%) vs 117 (22%). The adjusted caecal intubation rate was lower with EAC (94% vs 99%; p<0.001), however when allowing crossover from EAC to CC, they were similar in both groups (98% vs 99%; p value=0.25). INTERPRETATION: Though more adenomas are detected with EAC, the routine use of Endocuff does not translate in a higher number of patients with one or more adenomas detected. Whether increased detection ultimately results in a lower rate of interval carcinomas is not yet known. TRIAL REGISTRATION NUMBER: http://www.trialregister.nl Dutch Trial Register: NTR3962.

The effects of misclassification in routine healthcare databases on the accuracy of prognostic prediction models: a case study of the CHA2DS2-VASc score in atrial fibrillation.

BACKGROUND: Research on prognostic prediction models frequently uses data from routine healthcare. However, potential misclassification of predictors when using such data may strongly affect the studied associations. There is no doubt that such misclassification could lead to the derivation of suboptimal prediction models. The extent to which misclassification affects the validation of existing prediction models is currently unclear.We aimed to quantify the amount of misclassification in routine care data and its effect on the validation of the existing risk prediction model. As an illustrative example, we validated the CHA2DS2-VASc prediction rule for predicting mortality in patients with atrial fibrillation (AF). METHODS: In a prospective cohort in general practice in the Netherlands, we used computerized retrieved data from the electronic medical records of patients known with AF as index predictors. Additionally, manually collected data after scrutinizing all complete medical files were used as reference predictors. Comparing the index with the reference predictors, we assessed misclassification in individual predictors by calculating Cohen's kappas and other diagnostic test accuracy measures. Predictive performance was quantified by the c-statistic and by determining calibration of multivariable models. RESULTS: In total, 2363 AF patients were included. After a median follow-up of 2.7 (IQR 2.3-3.0) years, 368 patients died (incidence rate 6.2 deaths per 100 person-years). Misclassification in individual predictors ranged from substantial (Cohen's kappa 0.56 for prior history of heart failure) to minor (kappa 0.90 for a history of type 2 diabetes). The overall model performance was not affected when using either index or reference predictors, with a c-statistic of 0.684 and 0.681, respectively, and similar calibration. CONCLUSION: In a case study validating the CHA2DS2-VASc prediction model, we found substantial predictor misclassification in routine healthcare data with only limited effect on overall model performance. Our study should be repeated for other often applied prediction models to further evaluate the usefulness of routinely available healthcare data for validating prognostic models in the presence of predictor misclassification.

Participation, yield, and interval carcinomas in three rounds of biennial FIT-based colorectal cancer screening.

BACKGROUND: The effectiveness of colorectal cancer screening programs based on the fecal immunochemical test (FIT) is influenced by program adherence during consecutive screening rounds. We aimed to evaluate the participation rate, yield, and interval cancers in a third round of biennial CRC screening using FIT and to compare those with the first and the second screening round. METHODS: A total of 3566 average-risk individuals aged 50-75 years were invited to participate in a third round of biennial FIT-based CRC screening. All FIT positives were recommended to undergo colonoscopy. We merged our data with the national cancer registry in the Netherlands to identify all non-screen-detected cancers in our cohort. RESULTS: Of the invitees, 2142 (60%) returned the FIT in this third screening round, compared to 56% in the second round and 57% in the first round. Overall, 153 of the third-round participants (7.1%) had a positive FIT result, versus 7.9% in the second round and 8.1% in the first round (P=0.05). Of all FIT positives, 123 (80%) underwent colonoscopy. Within this group, 33 persons had advanced neoplasia. The predictive value of FIT positivity for advanced neoplasia was 27% (33/123), compared to 42% in the second round and 54% in the first round - a significant decline (P<0.01). CONCLUSION: In an FIT-based screening program, participation rates remained stable over consecutive biennial screening rounds, while the FIT positivity rate and positive predictive value for advanced neoplasia gradually declined. Cancers in non-participants are significantly more advanced in staging than cancers in participants in the first round of screening.