Comparison of Clinical Outcomes in Patients with Active Cancer Receiving Rivaroxaban or Low-Molecular-Weight Heparin: The OSCAR-UK Study.

BACKGROUND: In most patients with cancer-associated venous thromboembolism (CT), essentially those not at high risk of bleeding, guidelines recommend treatment with direct oral anticoagulants as an alternative to low-molecular-weight heparins (LMWHs). Population-based studies comparing these therapies are scarce. OBJECTIVES: To compare the risk of venous thromboembolism (VTE) recurrences, significant bleeding, and all-cause mortality in patients with CT receiving rivaroxaban or LMWHs. PATIENTS/METHODS: Using UK Clinical Practice Research Datalink data from 2013 to 2020, we generated a cohort of patients with first CT treated initially with either rivaroxaban or LMWH. Patients were observed 12 months for VTE recurrences, significant bleeds (major bleeds or clinically relevant nonmajor bleeding requiring hospitalization), and all-cause mortality. Overlap weighted sub-distribution hazard ratios (SHRs) compared rivaroxaban with LMWH in an intention-to-treat analysis. RESULTS: The cohort consisted of 2,259 patients with first CT, 314 receiving rivaroxaban, and 1,945 LMWH, mean age 72.4 and 66.9 years, respectively. In the 12-month observational period, 184 person-years following rivaroxaban and 1,057 following LMWH, 10 and 66 incident recurrent VTE events, 20 and 102 significant bleeds, and 10 and 133 deaths were observed in rivaroxaban and LMWH users, respectively. The weighted SHR at 12 months for VTE recurrences in rivaroxaban compared with LMWH were 0.80 (0.37-1.73); for significant bleeds 1.01 (0.57-1.81); and for all-cause mortality 0.49 (0.23-1.06). CONCLUSION: Patients with CT, not at high risk of bleeding, treated with either rivaroxaban or LMWH have comparable effectiveness and safety outcomes. This supports the recommendation that rivaroxaban is a reasonable alternative to LMWH for the treatment of CT.

A Novel Risk Prediction Score for Clinically Significant Bleeding in Patients Anticoagulated for Venous Thromboembolism with Active Cancer.

BACKGROUND: Cancer-associated venous thromboembolism (Ca-VTE) treatment with anticoagulation is associated with bleeding complications and there are limited data on risk factors. Current models do not provide accurate bleeding risk prediction. METHODS: UK Clinical Practice Research Datalink data (2008-2020) were used to generate a cohort of patients with anticoagulant initiation for first Ca-VTE. Patients were observed up to 180 days for significant bleeding including major bleeding and clinically relevant nonmajor bleeding requiring hospitalization (CRNMB-H). A scoring scheme was developed from sub-distribution hazard ratios, and its discrimination (expressed by the C-statistic) estimated from cross-validation. RESULTS: A total of 15,749 patients with Ca-VTE and anticoagulant treatment were included. In total, 537 significant bleeding events, 161 major bleeds, and 376 CRNMB-H were identified after adjudicated review in 4,914 person-years of observation. Incidence rates of 3.3 and 7.7 per 100 person-years were noted for major bleeding and CRNMB-H. Independent predictors of significant bleeding included cancer of the bladder, central nervous system, cervix, kidney, melanoma, prostate and upper gastrointestinal tract, metastases, minor surgery, minor trauma, and history of major bleeding or CRNMB (before or after the Ca-VTE diagnosis). Patients recognized as low, medium, and high risk (30.4, 56.8, and 1.7% of the population, respectively) had a 6-month significant bleeding incidence rate of 5.1, 19.0, and 56.5 per 100 person-years, respectively. Overall C-statistic for significant bleeding was 0.70 (95% confidence interval: 0.65-0.75), and 0.76 (0.68-0.84) and 0.67 (0.61-0.73) for major bleeding and for CRNMB-H, respectively. CONCLUSION: This risk score may identify patients at risk of significant bleeding, while also helping to determine treatment duration.

Optimal length and temporal resolution of dynamic contrast-enhanced MR imaging for the differentiation between prostate cancer and normal peripheral zone tissue.

The value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the detection of prostate cancer is controversial. There are currently insufficient peer reviewed published data or expert consensus to support routine adoption of DCE-MRI for clinical use. Thus, the objective of this study was to explore the optimal temporal resolution and measurement length for DCE-MRI to differentiate cancerous from normal prostate tissue of the peripheral zone of the prostate by non-parametric MRI analysis and to compare with a quantitative MRI analysis. Predictors of interest were onset time, relative signal intensity (RSI), wash-in slope, peak enhancement, wash-out and wash-out slope determined from non-parametric characterisation of DCE-MRI intensity-time profiles. The discriminatory power was estimated from C-statistics based on cross validation. We analyzed 54 patients with 97 prostate tissue specimens (47 prostate cancer, 50 normal prostate tissue) of the peripheral zone, mean age 63.8 years, mean prostate-specific antigen 18.9 ng/mL and mean of 10.5 days between MRI and total prostatectomy. When comparing prostate cancer tissue with normal prostate tissue, median RSI was 422% vs 330%, and wash-in slope 0.870 vs 0.539. The peak enhancement of 67 vs 42 was higher with prostate cancer tissue, while wash-out (-30% vs -23%) and wash-out slope (-0.037 vs -0.029) were lower, and the onset time (32 seconds) was comparable. The optimal C-statistics was 0.743 for temporal resolution of 8.0 seconds and measurement length of 2.5 minutes compared with 0.656 derived from a quantitative MRI analysis. This study provides evidence that the use of a non-parametric approach instead of a more established parametric approach resulted in greater precision to differentiate cancerous from normal prostate tissue of the peripheral zone of the prostate.

Atrial Fibrillation Detected by Single Time-Point Handheld Electrocardiogram Screening and the Risk of Ischemic Stroke.

OBJECTIVE: We evaluated stroke risk in patients with single time-point screen-detected atrial fibrillation (AF) and the effect of oral anticoagulants (OACs). METHODS: Consecutive patients aged ≥65 years attending medical outpatient clinics were prospectively enrolled for AF screening using handheld single-lead electrocardiogram (ECG; AliveCor) from December 2014 to December 2017 (NCT02409654). Repeated screening was performed in patients with >1 visit during this period. Three cohorts were formed: screen-detected AF, clinically diagnosed AF, and no AF. Ischemic stroke risk was estimated using adjusted subdistribution hazard ratios (aSHRs) from multivariate regression and no AF as reference, and stratified according to OAC use. RESULTS: Of 11,972 subjects enrolled, 2,238 (18.7%) had clinically diagnosed AF at study enrollment. The yield of screen-detected AF on initial screening was 2.3% (n = 223/9,734). AF was clinically diagnosed during follow-up in 2.3% (n = 216/9,440) and during subsequent screening in 71 initially screen-negative patients. Compared with no AF, patients with screen-detected AF without OAC treatment had the highest stroke risk (aSHR: 2.63; 95% confidence interval: 1.46-4.72), while aSHR for clinically diagnosed AF without OAC use was 2.01 (1.54-2.62). Among screen-detected AF, the risk of stroke was significantly less with OAC (no strokes in 196 person-years) compared with those not given OAC (12 strokes in 429 person-years), p = 0.01. CONCLUSION: The prognosis of single time-point ECG screen-detected AF is not benign. The risk of stroke is high enough to warrant OAC use, and reduced by OAC.

Variation in the Association between Antineoplastic Therapies and Venous Thromboembolism in Patients with Active Cancer.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of death in cancer patients. Although patients with cancer have numerous risk factors for VTE, the relative contribution of cancer treatments is unclear. OBJECTIVE: The objective of this study is to evaluate the association between cancer therapies and the risk of VTE. METHODS: From UK Clinical Practice Research Datalink, data on patients with first cancer diagnosis between 2008 and 2016 were extracted along with information on hospitalization, treatments, and cause of death. Primary outcome was active cancer-associated VTE. To establish the independent effects of risk factors, adjusted subhazard ratios (adj-SHR) were calculated using Fine and Gray regression analysis accounting for death as competing risk. RESULTS: Among 67,801 patients with a first cancer diagnosis, active cancer-associated VTE occurred in 1,473 (2.2%). During a median observation time of 1.2 years, chemotherapy, surgery, hormonal therapy, radiation therapy, and immunotherapy were given to 71.1, 37.2, 17.2, 17.5, and 1.4% of patients with VTE, respectively. The active cancers associated with the highest risk of VTE-as assessed by incidence rates-included pancreatic cancer, brain cancer, and metastatic cancer. Chemotherapy was associated with an increased risk of VTE (adj-SHR: 3.17, 95% confidence interval [CI]: 2.76-3.65) while immunotherapy with a not significant reduced risk (adj-SHR: 0.67, 95% CI: 0.30-1.52). There was no association between VTE and radiation therapy (adj-SHR: 0.91, 95% CI: 0.65-1.27) and hormonal therapies. CONCLUSION: VTE risk varies with cancer type. Chemotherapy was associated with an increased VTE risk, whereas with radiation and immunotherapy therapy, an association was not confirmed.

Prediction of significant bleeding during vitamin K antagonist treatment for venous thromboembolism in outpatients.

Bleeding is the most concerning complication associated with anticoagulant therapy but poorly characterized and important for risk/benefit assessment. We developed a risk stratification score to predict vitamin K antagonist (VKA)-associated bleeding in venous thromboembolism (VTE) using the UK Clinical Practice Research Datalink. Significant bleeding events in outpatients consisted of major bleeding and clinically relevant non-major bleeding requiring hospitalisation (CRNMB-H) within 90 days of VKA initiation. A scoring scheme for predicting bleeding was developed from subhazard ratios, validated using cross-validation and expressed by the C-statistic. The study cohort consisted of 10,010 patients with first VTE receiving initial VKA treatment, mean age 62·2 years. Between 2008 and 2016, 167 significant bleeding events were recorded (1·7%), i.e. incidence rate was 7·4/100 person-years. Independent predictors for community-acquired significant bleeding included active cancer, trauma/surgical procedure, male gender, dementia, liver disease, anaemia, history of bleeding, cerebrovascular, renal and chronic pulmonary disease, VTE presenting as pulmonary embolism and age over 75. The overall C-statistic was 0·68 (95% CI, 0·60-0·76), 0·75 (0·60-0·88) for major bleeding and 0·65 (0·55-0·75) for CRNMB-H, and higher than in other risk schemes applied to our study population. The developed risk score may identify patients having a significant bleeding risk, in particular major bleeding events, in outpatients.

Feasibility and cost-effectiveness of stroke prevention through community screening for atrial fibrillation using iPhone ECG in pharmacies. The SEARCH-AF study.

Atrial fibrillation (AF) causes a third of all strokes, but often goes undetected before stroke. Identification of unknown AF in the community and subsequent anti-thrombotic treatment could reduce stroke burden. We investigated community screening for unknown AF using an iPhone electrocardiogram (iECG) in pharmacies, and determined the cost-effectiveness of this strategy.Pharmacists performedpulse palpation and iECG recordings, with cardiologist iECG over-reading. General practitioner review/12-lead ECG was facilitated for suspected new AF. An automated AF algorithm was retrospectively applied to collected iECGs. Cost-effectiveness analysis incorporated costs of iECG screening, and treatment/outcome data from a United Kingdom cohort of 5,555 patients with incidentally detected asymptomatic AF. A total of 1,000 pharmacy customers aged ≥65 years (mean 76 ± 7 years; 44% male) were screened. Newly identified AF was found in 1.5% (95% CI, 0.8-2.5%); mean age 79 ± 6 years; all had CHA2DS2-VASc score ≥2. AF prevalence was 6.7% (67/1,000). The automated iECG algorithm showed 98.5% (CI, 92-100%) sensitivity for AF detection and 91.4% (CI, 89-93%) specificity. The incremental cost-effectiveness ratio of extending iECG screening into the community, based on 55% warfarin prescription adherence, would be $AUD5,988 (€3,142; $USD4,066) per Quality Adjusted Life Year gained and $AUD30,481 (€15,993; $USD20,695) for preventing one stroke. Sensitivity analysis indicated cost-effectiveness improved with increased treatment adherence.Screening with iECG in pharmacies with an automated algorithm is both feasible and cost-effective. The high and largely preventable stroke/thromboembolism risk of those with newly identified AF highlights the likely benefits of community AF screening. Guideline recommendation of community iECG AF screening should be considered.