Increased HIV Incidence in Men Who Have Sex with Men Despite High Levels of ART-Induced Viral Suppression: Analysis of an Extensively Documented Epidemic

Background: There is interest in expanding ART to prevent HIV transmission, but in the group with the highest levels of ART use, men-who-have-sex-with-men (MSM), numbers of new infections diagnosed each year have not decreased as ART coverage has increased for reasons which remain unclear. Methods: We analysed data on the HIV-epidemic in MSM in the UK from a range of sources using an individual-based simulation model. Model runs using parameter sets found to result in good model fit were used to infer changes in HIV-incidence and risk behaviour. Results: HIV-incidence has increased (estimated mean incidence 0.30/100 person-years 1990–1997, 0.45/100 py 1998–2010), associated with a modest (26%) rise in condomless sex. We also explored counter-factual scenarios: had ART not been introduced, but the rise in condomless sex had still occurred, then incidence 2006–2010 was 68% higher; a policy of ART initiation in all diagnosed with HIV from 2001 resulted in 32% lower incidence; had levels of HIV testing been higher (68% tested/year instead of 25%) incidence was 25% lower; a combination of higher testing and ART at diagnosis resulted in 62% lower incidence; cessation of all condom use in 2000 resulted in a 424% increase in incidence. In 2010, we estimate that undiagnosed men, the majority in primary infection, accounted for 82% of new infections. Conclusion: A rise in HIV-incidence has occurred in MSM in the UK despite an only modest increase in levels of condomless sex and high coverage of ART. ART has almost certainly exerted a limiting effect on incidence. Much higher rates of HIV testing combined with initiation of ART at diagnosis would be likely to lead to substantial reductions in HIV incidence. Increased condom use should be promoted to avoid the erosion of the benefits of ART and to prevent other serious sexually transmitted infections

Machine Learning Predicting Atrial Fibrillation as an Adverse Event in the Warfarin and Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial

Background: Atrial fibrillation and heart failure commonly coexist due to shared pathophysiological mechanisms. Prompt identification of patients with heart failure at risk of developing atrial fibrillation would allow clinicians the opportunity to implement appropriate monitoring strategy and timely treatment, reducing the impact of atrial fibrillation on patients’ health. Methods: Four machine learning models combined with logistic regression and cluster analysis were applied post hoc to patient-level data from the Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm (WARCEF) trial to identify factors that predict development of atrial fibrillation in patients with heart failure. Results: Logistic regression showed that White divorced patients have a 1.75-fold higher risk of atrial fibrillation than White patients reporting other marital statuses. By contrast, similar analysis suggests that non-White patients who live alone have a 2.58-fold higher risk than those not living alone. Machine learning analysis also identified “marital status” and “live alone” as relevant predictors of atrial fibrillation. Apart from previously well-recognized factors, the machine learning algorithms and cluster analysis identified 2 distinct clusters, namely White and non-White ethnicities. This should serve as a reminder of the impact of social factors on health. Conclusion: The use of machine learning can prove useful in identifying novel cardiac risk factors. Our analysis has shown that “social factors,” such as living alone, may disproportionately increase the risk of atrial fibrillation in the under-represented non-White patient group with heart failure, highlighting the need for more studies focusing on stratification of multiracial cohorts to better uncover the heterogeneity of atrial fibrillation

Machine learning for stroke in heart failure with reduced ejection fraction but without atrial fibrillation: A post-hoc analysis of the WARCEF trial

Background: The prediction of ischaemic stroke in patients with heart failure with reduced ejection fraction (HFrEF) but without atrial fibrillation (AF) remains challenging. Our aim was to evaluate the performance of machine learning (ML) in identifying the development of ischaemic stroke in this population. Methods: We performed a post-hoc analysis of the WARCEF trial, only including patients without a history of AF. We evaluated the performance of 9 ML models for identifying incident stroke using metrics including area under the curve (AUC) and decision curve analysis. The importance of each feature used in the model was ranked by SAPley Additive exPlanations (SHAP) values. Results: We included 2213 patients with HFrEF but without AF (mean age 58 ± 11 years; 80% male). Of these, 74 (3.3%) had an ischaemic stroke in sinus rhythm during a mean follow-up of 3.3 ± 1.8 years. Out of the 29 patient-demographics variables, 12 were selected for the ML training. Almost all ML models demonstrated high AUC values, outperforming the CHA2DS2-VASc score (AUC: 0.643, 95% confidence interval [CI]: 0.512–0.767). The Support Vector Machine (SVM) and XGBoost models achieved the highest AUCs, with 0.874 (95% CI: 0.769–0.959) and 0.873 (95% CI: 0.783–0.953), respectively. The SVM and LightGBM consistently provided significant net clinical benefits. Key features consistently identified across these models were creatinine clearance (CrCl), blood urea nitrogen (BUN) and warfarin use. Conclusions: Machine-learning models can be useful in identifying incident ischaemic strokes in patients with HFrEF but without AF. CrCl, BUN and warfarin use were the key features

Abstract 192: Stroke in the WARCEF Trial

Background The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference between warfarin and aspirin in heart failure patients in sinus rhythm for the outcome of first to occur of 84 ischemic strokes (IS), 7 intracerebral hemorrhages or 531 deaths. Pre-specified secondary analysis showed a 48% HR reduction (p=0.005) in IS risk for warfarin vs. aspirin. We examined this IS benefit for warfarin in post-hoc analyses. Methods We used the Wilcoxon rank sum test, stratified by prior IS or TIA, to compare the distributions of mRS among warfarin and aspirin IS patients in WARCEF. Median (md) scores and interquartile ranges (IQR) are shown for warfarin and aspirin arms, respectively. We used Fisher’s exact test to compare the effect of warfarin vs. aspirin on fatal IS; a stratified exact test to compare proportions of severe (mRS 3-5) IS; and stratified Poisson regression to compare IS subtypes. Results Twenty-nine (2.5%) of 1142 patients on warfarin and 55 (4.7%) of 1163 on aspirin had IS. The warfarin IS rate (0.72 per 100 patient years [/100PY]) was lower than for aspirin (1.36/100PY). There were no differences between warfarin and aspirin IS patients in baseline mRS (md 1, IQR, 2, N=29 vs. md 1, IQR 2, N=55); fatal IS (3/29, 10.3% vs. 6/55, 10.9%, p=1.0), or post-IS (after 90+30 days) mRS (md 2, IQR 3, n=23 vs. md 2, IQR 3, n=48, p=0.437). There were also no differences between warfarin and aspirin in change from baseline to post-IS mRS (md 1, IQR 3, n=23 vs. md 1, IQR 3, n=48, p=0.884). Cardioembolic IS was significantly less frequent on warfarin than on aspirin (9 [0.22/100PY] vs. 22 [0.55/100PY], p=0.012). The warfarin arm showed trends to fewer severe (mRS 3-5) IS (3/23 [13.0%] vs. 16/48 [33.3%], p=0.086) and a lower rate of IS of potential cardioembolic etiology (15 [0.37/100PY] vs. 27 [0.67/100PY] p=0.063). There was no difference between warfarin and aspirin in rate of non-cardioembolic IS (5 [0.12/100PY] vs. 6 [0.15/100PY], p=0.768). Conclusions Warfarin appears superior to aspirin in reducing the frequency of cardioembolic IS in heart failure patients in sinus rhythm. This is supported by trends to lower frequencies of severe IS and potentially cardioembolic IS in patients on warfarin compared to aspirin. </jats:p

Abstract 192: Stroke in the WARCEF Trial

Background The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference between warfarin and aspirin in heart failure patients in sinus rhythm for the outcome of first to occur of 84 ischemic strokes (IS), 7 intracerebral hemorrhages or 531 deaths. Pre-specified secondary analysis showed a 48% HR reduction (p=0.005) in IS risk for warfarin vs. aspirin. We examined this IS benefit for warfarin in post-hoc analyses. Methods We used the Wilcoxon rank sum test, stratified by prior IS or TIA, to compare the distributions of mRS among warfarin and aspirin IS patients in WARCEF. Median (md) scores and interquartile ranges (IQR) are shown for warfarin and aspirin arms, respectively. We used Fisher’s exact test to compare the effect of warfarin vs. aspirin on fatal IS; a stratified exact test to compare proportions of severe (mRS 3-5) IS; and stratified Poisson regression to compare IS subtypes. Results Twenty-nine (2.5%) of 1142 patients on warfarin and 55 (4.7%) of 1163 on aspirin had IS. The warfarin IS rate (0.72 per 100 patient years [/100PY]) was lower than for aspirin (1.36/100PY). There were no differences between warfarin and aspirin IS patients in baseline mRS (md 1, IQR, 2, N=29 vs. md 1, IQR 2, N=55); fatal IS (3/29, 10.3% vs. 6/55, 10.9%, p=1.0), or post-IS (after 90+30 days) mRS (md 2, IQR 3, n=23 vs. md 2, IQR 3, n=48, p=0.437). There were also no differences between warfarin and aspirin in change from baseline to post-IS mRS (md 1, IQR 3, n=23 vs. md 1, IQR 3, n=48, p=0.884). Cardioembolic IS was significantly less frequent on warfarin than on aspirin (9 [0.22/100PY] vs. 22 [0.55/100PY], p=0.012). The warfarin arm showed trends to fewer severe (mRS 3-5) IS (3/23 [13.0%] vs. 16/48 [33.3%], p=0.086) and a lower rate of IS of potential cardioembolic etiology (15 [0.37/100PY] vs. 27 [0.67/100PY] p=0.063). There was no difference between warfarin and aspirin in rate of non-cardioembolic IS (5 [0.12/100PY] vs. 6 [0.15/100PY], p=0.768). Conclusions Warfarin appears superior to aspirin in reducing the frequency of cardioembolic IS in heart failure patients in sinus rhythm. This is supported by trends to lower frequencies of severe IS and potentially cardioembolic IS in patients on warfarin compared to aspirin

Warfarin and aspirin in patients with heart failure and sinus Rhythm

BACKGROUND: It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS: We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS: The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82). CONCLUSIONS: Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized