Faculty Bibliography

BACKGROUND:Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD. OBJECTIVES/OBJECTIVE:The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial. METHODS:Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection. RESULTS:EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex. CONCLUSIONS:Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

BACKGROUND & AIMS/OBJECTIVE:Renal disease is a risk factor for peripheral artery disease (PAD), yet its impact on outcomes after lower extremity (LE) revascularization is not well established. We aimed to characterize the association between chronic kidney disease (CKD) and/or end stage renal disease (ESRD) and post-procedural outcomes in PAD patients undergoing LE revascularization in the United States. METHODS:Adults age ≥18 years undergoing surgical or endovascular LE revascularization for PAD with and without CKD or ESRD were identified from the 2014 Nationwide Readmissions Database. Major adverse cardiovascular events (MACE), defined as a composite of death, myocardial infarction or ischemic stroke, were identified for patients with and without renal disease. All-cause hospital readmissions within 6 months of discharge were determined for all survivors. RESULTS:Among 39,441 patients with PAD hospitalized for LE revascularization, 10,530 had renal disease (26.7%), of whom 69% had CKD without ESRD and 31% had ESRD. Patients with renal disease were more likely to have MACE after LE revascularization (5.2% vs. 2.5%; adjusted OR [aOR] 1.74, 95% CI 1.40-2.16), require LE amputation (26.1% vs. 12.2%; aOR 1.33, 95% CI 1.19-1.50), and require hospital readmission within 6 months (61.0% vs. 43.6%; adjusted HR [aHR] 1.38, 95% CI 1.28-1.48) compared to those without renal disease. CONCLUSIONS:Renal disease is common among patients undergoing LE revascularization for PAD and was independently associated with in-hospital MACE, LE amputation, and hospital readmission within 6 months. Additional efforts to improve outcomes of patients with renal disease and PAD requiring LE revascularization are necessary.

INTRODUCTION/BACKGROUND:Collectively, coronary artery disease (CAD) and peripheral artery disease (PAD) are highly prevalent and are associated with increased risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Improved ability to identify those at highest risk of these events may help optimize secondary prevention efforts in this population. METHODS:Using the Optum Integrated Database, a healthcare claims database linked to electronic medical records (EMR), we identified patients with CAD and/or PAD between January 1, 2009, and September 30, 2016. Index date was the earliest date on which chronic and stable disease was established. Follow-up ran from index date until earliest of patient death, plan disenrollment, or end of study. We developed multivariate Cox proportional hazards models to identify predictors of MACE and/or MALE, limited to measures presumed available to clinicians during patient encounters (e.g., age, presence of selected comorbidities). RESULTS: = 0.98), ranging from 2.3 per 100 PYs among those without predictors (4.9% of patients) to 18.7 per 100 PYs among those with ≥ 6 (6.9%). Patients with ≥ 1 predictor experienced 7.4 MACE and/or MALE per 100 PYs. CONCLUSION/CONCLUSIONS:Readily identifiable predictors can be used to identify subgroups with chronic CAD and/or PAD at elevated risk of MACE and/or MALE. Further research is required to understand the degree to which these subgroups may benefit from early identification and treatment with secondary prevention therapies. FUNDING/BACKGROUND:Janssen Pharmaceuticals.

OBJECTIVE:MATERIAL AND METHODS: This is a single tertiary care center retrospective cohort study of all consecutive inpatients diagnosed with acute VTE from June 2015 to December 2015. During this period, 4495 patients underwent venous duplex examination (622 UE and 3873 LE), identifying 83 inpatient DVTs. Chronic DVT as well as those diagnosed in the outpatient population were excluded. DVTs were classified as either provoked or unprovoked. Provoked DVT were defined as the presence of any of the following factors within 30 days prior to diagnosis: major surgery, immobilization (greater than 3 days of bedrest), trauma, infection requiring antibiotics, central venous access, pregnancy, and/or hormonal medication use. Inpatient pulmonary embolisms (PE) detected on chest computed tomography (CT) were also evaluated during this time frame. Patient data were collected including age, gender, race, lifestyle factors, comorbidities, VTE risk factors, symptomatology at presentation, management including anticoagulation choice and filter placement if applicable, as well as discharge disposition. Statistical analysis was performed using GraphPad Prism 8.0 (GraphPad Software, San Diego, California, USA), and a threshold p-value of < 0.05 set for significance. RESULTS:During the study period, 83 DVTs (48 LEDVT, 35 UEDVT) and 24 PE were identified in 96 inpatients. Of these DVTs, 77.1% of these were defined as provoked. Eleven patients had simultaneous DVT and PE, and thirteen patients had PE with presumed occult pelvic or LEDVT. UEDVT patients had a higher proportion of comorbidities than LEDVT patients: coronary artery disease (25.7% vs. 13.1%, p=0.16), congestive heart failure (20% vs. 6.6%, p=0.09), as well as a trend toward higher incidence of malignancy (60% vs. 42.6%, p=0.13). Of provoked VTE, UEDVT correlated more significantly with central venous catheters (88.4% vs. 12.5%, p=<0.0001), but was less commonly associated with prolonged bed rest (19.2% vs. 39.5%, p=0.11). PE was diagnosed in 24/96 (25%) of the study population. Patients with LEDVT were found to have a significantly higher incidence of PE compared to those with UEDVT (34.4% vs. 8.6%, p=0.006). Same-admission mortality for patients with VTE was 13/96 (13.5%). Of these, patients with UEDVT had significantly higher all-cause mortality than patients with LEDVT (28.5% vs. 4.9%, p=0.004). When catheter-related UEDVT were excluded, there remained a significant difference in mortality between non-catheter related UEDVT and LEDVT (33.3% vs. 4.9% p=0.0119). CONCLUSIONS:This study demonstrates a high prevalence of UEDVT in hospitalized patients who experience VTE. Despite a lower incidence of synchronous PE, patients with UEDVT had a higher prevalence of significant medical comorbidities and higher all-cause mortality on the index hospital admission.

The human genome encodes thousands of long non-coding RNAs (lncRNAs), the majority of which are poorly conserved and uncharacterized. Here we identify a primate-specific lncRNA (CHROME), elevated in the plasma and atherosclerotic plaques of individuals with coronary artery disease, that regulates cellular and systemic cholesterol homeostasis. LncRNA CHROME expression is influenced by dietary and cellular cholesterol via the sterol-activated liver X receptor transcription factors, which control genes mediating responses to cholesterol overload. Using gain- and loss-of-function approaches, we show that CHROME promotes cholesterol efflux and HDL biogenesis by curbing the actions of a set of functionally related microRNAs that repress genes in those pathways. CHROME knockdown in human hepatocytes and macrophages increases levels of miR-27b, miR-33a, miR-33b and miR-128, thereby reducing expression of their overlapping target gene networks and associated biologic functions. In particular, cells lacking CHROME show reduced expression of ABCA1, which regulates cholesterol efflux and nascent HDL particle formation. Collectively, our findings identify CHROME as a central component of the non-coding RNA circuitry controlling cholesterol homeostasis in humans.

Background: Hypertension is a risk factor for major adverse cardiac events (MACE) in patients with symptomatic peripheral artery disease (PAD).
Purpose(s): The effects of a history of hypertension and baseline systolic blood pressure (SBP) on MACE and major adverse limb events (MALE), including acute limb ischemia and major amputation, were evaluated in the Examining Use of tiCagreLor In paD (EUCLID) trial.
Method(s): EUCLID randomized 13,885 patients with PAD and found no benefit of ticagrelor compared with clopidogrel on risk of MACE or MALE. The median duration of follow up was approximately 30 months. This post hoc, subgroup analysis evaluated the effects of hypertension history at baseline on the hazard for MACE and MALE. An adjusted restricted cubic spline regression analysis evaluated the association of SBP with MACE and MALE.
Result(s): A clinical history of hypertension was present in 10,857 (78%) patients at baseline and these patients were more likely to be older, female, white or African American, and reside in North America compared with the 3026 without hypertension. Hypertension was associated with a higher prevalence of concomitant cardiovascular diseases, polyvascular disease, diabetes, and prior coronary interventions. MACE occurred at a rate of 4.63 events/100 pt-yrs in participants with hypertension and 3.64 events/100 ptyrs in participants without hypertension, (adjusted hazard ratio [aHR] 0.94, 95% CI 0.82-1.08; p=0.38). MALE occurred at a rate of 1.11 events/100 ptyrs in those with hypertension and 1.38 events/100 pt-yrs in those without hypertension (p=0.054) (aHR 0.93 (95% CI 0.73, 1.18) p=0.55. The adjusted spline model for MACE and SBP demonstrated a significantly nonlinear relationship with a HR 1.08 (95% CI 1.01, 1.15), p=0.0275 for every 10-unit decrease <135 mmHg SBP and HR 1.11 (1.06, 1.16), p<0.0001 for every 10-unit increase >135 mmHg (figure). There was no association between baseline SBP and MALE events.
Conclusion(s): A history of hypertension was not associated with a higher adjusted hazard for MACE or MALE in participants with PAD. In contrast, SBP at baseline was associated with increased risk of MACE at values both above and below 135 mmHg

Introduction - Critical limb ischemia (CLI) implies a heightened risk for cardiovascular morbidity and mortality. Methods - The EUCLID trial (NCT01732822) investigated the effect of antithrombotic monotherapy, ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily, in patients with symptomatic peripheral arterial disease (PAD). Inclusion criteria were previous lower extremity revascularization (LER) or ankle-brachial index (ABI) <=0.80, randomizing 13,885 patients. Ticagrelor was not superior to clopidogrel in the reduction of cardiovascular events, nor did major bleeding differ between groups. The present study focuses on patients with CLI at baseline, defined by rest pain, minor or major tissue loss. Results - At baseline 643 patients (4.6 %) had CLI (Rutherford 4 (58.8%), Rutherford 5-6 (41.2%)). The proportion of patients with CLI in the LER group (351/7873, 4.5%) or low ABI group (292/6009, 4.9%) was similar.Diabetes mellitus was more common in the CLI group (49.3% vs 38.0%, p<0.0001), while a history of coronary artery disease was more common for the non-CLI group (29.2% vs 25.3%, p=0.035). A history of carotid disease was more frequent in non-CLI patients (18.0% vs 12.1%, p=0.0002) and a corresponding relationship was recorded for hypertension (non-CLI 78.4%, CLI 74.2%, p=0.01). Before randomization, more CLI than non-CLI patients were on clopidogrel (40.0% vs 31.8%, p<0.0001) whereas aspirin treatment was more common in the non-CLI group (67.3% vs 55.5%, p<0.0001). Dual antiplatelet therapy (aspirin and clopidogrel) was used by 16.2 % of CLI patients and 16.3 % of the non-CLI group. Statins were used by 73.8% of non-CLI patients, and 64.1% of the CLI group (p<0.0001). A history of major amputation was more common in patients with CLI (10.3%) compared to non-CLI patients (2.1%), p<0.0001. The primary efficacy endpoint, cardiovascular death, MI or ischemic stroke occurred significantly more frequently among CLI patients with a rate of 8.85 versus 4.28 per 100 patient-years (HR 2.07(1.72-2.48), p<0.0001; Fig), and this difference remained significant after adjustment for baseline characteristics (HR 1.43(1.16-1.76), p=0.0009). When including acute limb ischemia requiring hospitalization with MACE, significant differences remained, also after adjustment for baseline characteristics (HR 1.38(1.13-1.69), p=0.0016). LER was more common in CLI compared with non-CLI patients (HR 1.29(1.05-1.59), p=0.018), the difference not remaining significant after adjustment (HR 1.19(0.96-1.49), p=0.12). Bleeding did not differ between patients with and without CLI.The primary efficacy endpoint did not differ between ticagrelor and clopidogrel treated patients in the respective CLI and non-CLI groups, nor did bleeding. [Formula presented] Conclusion - Patients suffering CLI represented nearly 5% of patients enrolled in the EUCLID trial. The low amputation rate at baseline suggests milder forms of CLI dominated. CLI patients had a 2-fold higher rate of cardiovascular mortality and morbidity compared to non-CLI patients. Further efforts are required to reduce the risk for cardiovascular events in PAD, especially in patients with CLI.
Copyright

New-onset heart failure (HF) is associated with cardiovascular morbidity and mortality. It is uncertain to what extent HF confers an increased risk of venous thromboembolism (VTE). Adults ≥65 years old hospitalized with a new diagnosis of HF were identified from Medicare claims from 2007-2013. We identified the incidence, predictors and outcomes of VTE in HF. We compared VTE incidence during follow-up after HF hospitalization with a corresponding period 1-year prior to the HF diagnosis. Among 207,535 patients with a new HF diagnosis, the cumulative incidence of VTE was 1.4%, 2.5%, and 10.5% at 30 days, 1 year, and 5 years, respectively. The odds of VTE were greatest immediately after new-onset HF and steadily declined over time (OR 2.2 [95% CI 2.0-2.3], OR 1.5 [1.4-1.7], and OR 1.2 [1.2-1.3] at 0-30 days, 4-6 months, and 7-9 months, respectively). Over 26-month follow-up, patients with HF were at two-fold higher risk of VTE than patients without HF (adjusted HR 2.31 [2.18-2.45]). VTE during follow-up was associated with long-term mortality (adjusted HR 1.60, 95% CI 1.56-1.64). In conclusion, patients with HF are at increased risk of VTE early after a new HF diagnosis. VTE in patients with HF is associated with long-term mortality.