Faculty Bibliography

Regional variations exist in the epidemiology of peripheral artery disease (PAD), in comorbidities, use of secondary prevention, and outcomes. Large studies of these variations in worldwide populations are rare. The EUCLID (Examining Use of tiCagreLor In peripheral artery Disease) trial included 13,885 patients with PAD from four geographical regions (Central/South America, Europe, Asia, North America) and compared monotherapy with ticagrelor and clopidogrel. Inclusion criteria were either an ankle-brachial index < 0.80 or a prior revascularization. The primary efficacy endpoint was time to first occurrence of any event in the composite of cardiovascular death, myocardial infarction, or ischemic stroke and did not differ between the study arms. This post hoc analysis of EUCLID confirmed that regional differences occurred in the inclusion criteria with more prior revascularization in North America (73.9%) and Asia (72.5%) compared with Central/South America (34.0%) and Europe (51.6%). The characteristics of patients also differed. Prior amputation at baseline was most frequent in Central/South America (6.3%) compared with other regions (1.6-2.8%). A history of stroke was most common in Asia, coronary heart disease in North America, and diabetes in Central/South America compared with other regions. The incidence of outcomes in patients with PAD varied by region. North America had the highest rate of the primary combined endpoint (5.97 events/100 patient-years). Corresponding rates were 4.80, 3.95, and 3.87 for Asia, Europe, and Central/South America, respectively. Hospitalization for acute limb ischemia (events/100 patient-years) was most frequent in Europe (0.75) and North America (0.74) compared with Asia (0.60) and Central/South America (0.33). Adjustment for inclusion criteria and relevant PAD characteristics did not have a major impact on these regional differences. Further adjustment for concomitant disease, risk factors, and preventive medication modified the regional differences only marginally. In conclusion, substantial regional differences were found in cardiovascular and limb outcomes in patients with PAD and were not explained by variation in the category of included patients, concomitant disease, risk factors, and prevention. Such differences, which may be due to variation in other factors such as background population rates or clinical care, need to be considered when designing and interpreting large international studies (ClinicalTrials.gov Identifier: NCT01732822).

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PURPOSE OF REVIEW/OBJECTIVE:Psoriasis is a chronic inflammatory skin condition that is associated with increased cardiovascular risk compared to those without psoriasis. This review will cover emerging mechanisms of cardiovascular risk, key pathways targeted with biologic therapies, and the current evidence on therapies to modulate this risk in patients with psoriasis. RECENT FINDINGS/RESULTS:Recent scientific work has highlighted mechanisms that contribute to this enhanced risk, including the role of vascular endothelial dysfunction, platelet activation, dyslipidemia, and increased cardiometabolic comorbidities. Newer biologic and targeted synthetic therapies have transformed psoriasis treatment with high rates of clinical remission and durable skin disease control now possible. Epidemiological evidence suggests that many of these therapies may lower cardiovascular risk in psoriasis, although prospective interventional data is lacking (or mixed). Recently, caution has also been raised that some treatments may negatively affect cardiovascular risk. Overall, the current data suggests a positive or neutral ability to reduce cardiovascular risk for TNF, IL-17A, and IL-12/23p40 inhibitors, but current evidence remains conflicting for anti-IL-23/p19 and JAK inhibitors. More studies that include prospective cohorts, larger number of patients, treatment duration, and validated surrogate outcomes are needed to better evaluate the role of biologic therapies on cardiovascular risk in psoriasis.

Importance/UNASSIGNED:Traditional time-to-event analyses rate events occurring early as more important than later events, even if later events are more severe, eg, death. Days alive out of hospital (DAOH) adds a patient-focused perspective beyond trial end points. Objective/UNASSIGNED:To compare DAOH between invasive management and conservative management, including invasive protocol-assigned stays, in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) randomized clinical trial. Design, Setting, and Participants/UNASSIGNED:In this prespecified analysis of the ISCHEMIA trial, DAOH was compared between 5179 patients with stable coronary disease and moderate or severe ischemia randomized to invasive management or conservative management. Participants were recruited from 320 sites in 37 countries. Stays included overnight stays in hospital or extended care facility (skilled nursing facility, rehabilitation, or nursing home). DAOH was separately analyzed excluding invasive protocol-assigned procedures. Data were collected from July 2012 to June 2019, and data were analyzed from July 2020 to April 2021. Interventions/UNASSIGNED:Invasive management with angiography and revascularization if feasible or conservative management, with both groups receiving optimal medical therapy. Main Outcomes and Measures/UNASSIGNED:The hypothesis was formulated before data lock in July 2020. The primary end point was mean DAOH per patient between randomization and 4 years. Initial stays for invasive protocol-assigned procedures were prespecified to be excluded. Results/UNASSIGNED:Of 5179 included patients, 1168 (22.6%) were female, and the median (interquartile range) age was 64 (58-70) years. The average DAOH was higher in the conservative management group compared with the invasive management group at 1 month (30.8 vs 28.4 days; P < .001), 1 year (362.2 vs 355.9 days; P < .001), and 2 years (718.4 vs 712.1 days; P = .001). At 4 years, the 2 groups' DAOH were not significantly different (1415.0 vs 1412.2 days; P = .65). In the invasive management group, 2434 of 4002 stays (60.8%) were for protocol-assigned procedures. There were no clear differences at any time point in DAOH when protocol-assigned procedures were excluded from the invasive management group. There were more hospital and extended care stays in the invasive management vs conservative management group during follow-up (4002 vs 1897; P < .001). Excluding protocol-assigned procedures, there were fewer stays in the invasive vs conservative group (1568 vs 1897; P = .001). Cardiovascular stays following the initial assigned procedures were lower in the invasive management group (685 of 4002 [17.1%] vs 1095 of 1897 [57.8%]; P < .001) due to decreased spontaneous myocardial infarction stays (65 [1.6%] vs 123 [6.5%]; P < .001) and unstable angina stays (119 [3.0%] vs 216 [11.4%]; P < .001). Conclusions and Relevance/UNASSIGNED:DAOH was higher for patients in the conservative management group in the first 2 years but not different at 4 years. DAOH was decreased early in the invasive management group due to protocol-assigned procedures. Hospital stays for myocardial infarction and unstable angina during follow-up were lower in the invasive management group. DAOH provides a patient-focused metric that can be used by clinicians and patients in shared decision-making for management of stable coronary artery disease. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01471522.

BACKGROUND:Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS:In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS:The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS:In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

BACKGROUND:Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS:In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS:The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio <1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS:In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).

OBJECTIVE:To better characterize COVID-19 patients most at risk for severe, outpatient thrombosis by defining patients hospitalized with COVID-19 with an arterial or venous thrombosis diagnosed at admission METHODS AND RESULTS: We conducted a single center retrospective analysis of COVID-19 patients. There was a shift in the proportions of thrombosis subtypes from 2019 to 2020, with declines in STEMI (from 22.0% to 10.1% of thrombotic events) and stroke (from 48.6% to 37.2%), and an increase in the proportion of patients with VTE (29.4% to 52.7%). COVID-associated thrombosis were younger (58 years vs. 64 years, p=0.043), trended to be less frequently female (31.3% vs. 43.9%, p =0.16), but there was no difference body mass index or major comorbidities between those with and without COVID-19. COVID-19-associted thrombosis was correlated with a higher mortality (15.2% vs. 4.3%, p=0.016). The biometric profile of patients admitted with COVID-associated thrombosis compared to regular thrombosis had significant changes in the complete blood count, liver function tests, d-dimer, c-related protein, ferritin, and coagulation panels. CONCLUSIONS:Outpatients with COVID-19 who developed thrombosis requiring hospitalization have an increased mortality over non-COVID-19 outpatients who develop thrombosis requiring hospitalization. Given the significantly higher inflammatory markers, it is possible this is related to different mechanisms of thrombotic disease in these patients. The inflammation may be a target to reduce the risk of or aid in the treatment of thrombosis. We call for more studies elucidating the role immunothrombosis maybe playing in COVID.

INTRODUCTION:Current evidence indicates that rivaroxaban may be a safe and effective alternative to warfarin among patients with nonvalvular atrial fibrillation (NVAF) and obesity. However, evidence regarding the impact of polypharmacy is limited in this population. The present study evaluated the effectiveness and safety of rivaroxaban versus warfarin among NVAF patients with obesity and polypharmacy in the US. METHODS:) and polypharmacy (≥ 5 medications) initiated on rivaroxaban or warfarin. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances between groups. Study outcomes were evaluated up to 36 months post-treatment initiation and included the composite of stroke or systemic embolism (stroke/SE) and major bleeding. Subgroup analyses were conducted stratified by polypharmacy category (5-9 or ≥ 10 medications). Outcomes were assessed using Cox proportional hazards regression models with hazard ratios (HR) and 95% confidence intervals (CIs). RESULTS:A total of 7000 and 3920 NVAF patients with obesity and polypharmacy were initiated on rivaroxaban and warfarin, respectively. At 36 months of follow-up, rivaroxaban was associated with a 29% lower risk of stroke/SE relative to warfarin (HR 0.71, 95% CI 0.57, 0.90). Major bleeding risk was not significantly different among rivaroxaban- compared to warfarin-treated patients (HR 0.85, 95% CI 0.70, 1.03). Subgroup analyses yielded results that were largely consistent with the overall polypharmacy analysis. CONCLUSIONS:These results suggest that rivaroxaban is an effective and safe treatment option among NVAF patients with obesity and polypharmacy in a commercially-insured US population.