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Vascular disease burden after lower extremity revascularization (LER) comprises more than the first event, more vascular beds than the local arteries, and more than one clinical event type.Assess total arterial and venous thrombotic burden after LER for symptomatic peripheral artery disease (PAD) and effect of low-dose anticoagulation added to low-dose antiplatelet therapy.VOYAGER PAD randomized 6564 symptomatic PAD patients undergoing LER to rivaroxaban 2.5 mg twice-daily or placebo on aspirin background. Marginal proportional-hazards models used to generate treatment hazard ratios and associated 95% CIs for first and total events; non-thrombotic deaths treated as competing terminal events. Incidence rates calculated as number of events per 100 patient-years follow-up.Over 2.5 years (median), first and total thrombotic event rates: 7.1 and 10.3 events/100 patient-years, respectively, in placebo group. Two-thirds (925/1372) of total thrombotic events (arterial 95%, venous 5%) were nonfatal first events. Nearly one-third of patients with first event had a second arterial or venous thrombotic event. Rivaroxaban plus aspirin reduced first and total arterial and venous thrombotic events to 5.4 and 7.9 events/100 patient-years, respectively, a reduction in total thrombotic events over aspirin of 23% (HR: 0.77, 95%CI: 0.67-0.89, p = .0005), preventing 6.1 total arterial and venous thrombotic events at 3 years.Assessing total arterial and venous thrombotic events, not just first events, provides more complete information about disease burden and absolute on-treatment impact. Following LER, judicious modulation of more than one coagulation pathway can provide broader benefit than intensifying inhibition of one hemostatic system component.

Background The interaction between thrombosis and inflammation appears central to COVID-19-associated coagulopathy and likely contributes to poor outcomes. Tissue factor is a driver of disordered coagulation and inflammatory signaling in viral infections and is important for viral replication; therefore, tissue factor may be an important therapeutic target in COVID-19. Study Design ASPEN-COVID-19 (NCT04655586) is a randomized, prospective open-label blinded endpoint (PROBE), active comparator Phase 2b trial to evaluate the safety and efficacy of recombinant Nematode Anticoagulant Protein c2 (rNAPc2), a potent tissue factor inhibitor, in patients hospitalized with COVID-19 with elevated D-dimer levels. This report describes the design of the Phase 2b dose ranging and proof of concept study. Participants are randomly assigned, in a 1:1:2 ratio, to lower or higher dose rNAPc2 by subcutaneous injection on days 1, 3, and 5 or to heparin according to local standard of care; randomization is stratified by baseline D-dimer level (at 2X upper limit of normal). The primary efficacy endpoint for Phase 2b is proportional change in D-dimer concentration from baseline to Day 8 or day of discharge, whichever is earlier. The primary safety endpoint is major or non-major clinically relevant bleeding through Day 8. Phase 2b enrollment began in December 2020 and is projected to complete ∼160 participants by Q4 2021. Conclusions ASPEN-COVID-19 will provide important data on a novel therapeutic approach that may improve outcomes in hospitalized COVID-19 patients beyond available anticoagulants by targeting tissue factor, with potential effects on not only thrombosis but also inflammation and viral propagation.

Background: Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a thrombotic event associated with amputation, disability, and mortality. Previous lower extremity revascularization (LER) is associated with increased ALI risk in chronic PAD. However, the pattern of risk, clinical correlates, and outcomes after ALI early after LER are not well-studied, and effective therapies to reduce ALI post-LER are lacking. Methods: The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD; rNCT02504216) randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of low-dose aspirin. The primary outcome was a composite of ALI, major amputation of vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. ALI was prospectively ascertained and adjudicated by a blinded committee. The cumulative incidence of ALI was calculated using Kaplan-Meier estimates, and Cox proportional hazards models were used to generate hazard ratios and associated CIs. Analyses were performed as intention-to-treat. Results: Among 6564 patients followed for a median of 2.3 years, 382 (5.8%) had a total of 508 ALI events. In placebo patients, the 3-year cumulative incidence of ALI was 7.8%. After multivariable modeling, previous LER, baseline ankle-brachial index P =0.0001), with benefit starting early (HR, 0.45 [95% CI, 0.24–0.85]; P =0.0068 at 30 days). Benefit was present for severe ALI (associated with death, amputation, or prolonged hospitalization and intensive care unit stay, HR, 0.58 [95% CI, 0.40–0.83]; P =0.003) and regardless of LER type (surgical versus endovascular revascularization, P interaction=0.42) or clopidogrel use ( P interaction=0.59). Conclusions: After LER for symptomatic PAD, ALI is frequent, particularly early after LER, and is associated with poor prognosis. Low-dose rivaroxaban plus aspirin reduces ALI after LER, including ALI events associated with the most severe outcomes. The benefit of rivaroxaban for ALI appears early, continues over time, and is consistent regardless of revascularization approach or clopidogrel use.

Acute aortic syndromes, classified into aortic dissection, intramural hematoma, and penetrating aortic ulcer, are associated with high early mortality for which early diagnosis and management are crucial to optimize outcomes. Patients often present with nonspecific clinical symptoms and signs; therefore, it is important for providers to maintain a high index of suspicion for acute aortic syndromes. Electrocardiogram-gated computed tomographic angiography of the chest, abdomen, and pelvis is currently the most practical imaging modality for diagnosis and identification of complications. Evolution in surgical techniques and the development of aortic endografts have improved patient outcomes, but randomized trials are still needed.

Background Paclitaxel drug-coated devices (DCDs) were developed to improve lower extremity revascularization (LER) patency in peripheral artery disease (PAD) but have been associated with long-term mortality. Objectives This study assessed DCD safety and effectiveness in LER for PAD. Methods VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) randomized patients with PAD who underwent LER to rivaroxaban or placebo. The primary VOYAGER PAD study efficacy and safety outcomes were composite cardiovascular and limb events and Thrombolysis In Myocardial Infarction major bleeding. For prespecified DCD analyses, primary safety and effectiveness outcomes were mortality and unplanned index limb revascularization (UILR). Major adverse limb events (MALE) were a secondary outcome. Inverse probability treatment weighting was used to account for each subject's propensity for DCD treatment. Effects of rivaroxaban were assessed with Cox proportional hazards models. Results Among 4,316 patients who underwent LER, 3,478 (80.6%) were treated for claudication, and 1,342 (31.1%) received DCDs. Median follow-up was 31 months, vital status was ascertained in 99.6% of patients, and there were 394 deaths. After weighting, DCDs were not associated with mortality (HR: 0.95; 95% CI: 0.83-1.09) or MALE (HR: 1.08; 95% CI: 0.90-1.30) but were associated with reduced UILR (3-year Kaplan-Meier: 21.5% vs 24.6%; HR: 0.84; 95% CI: 0.76-0.92). Irrespective of DCD use, consistent benefit of rivaroxaban for composite cardiovascular and limb events (Pinteraction = 0.88) and safety of rivaroxaban with respect to bleeding (Pinteraction = 0.57) were observed. Conclusions In >4,000 patients with PAD who underwent LER, DCDs were not associated with mortality or MALE but were associated with persistent reduction in UILR. These findings provide insight into the safety and effectiveness of DCDs in PAD. (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD [VOYAGER PAD]; NCT02504216 )

Aims In this secondary analysis of the VOYAGER trial, rivaroxaban 2.5 mg twice/day plus aspirin 100 mg/day was assessed in older adults. Advanced age is associated with elevated bleeding risk and unfavourable net benefit for dual antiplatelet therapy in chronic coronary artery disease. The risk–benefit of low-dose rivaroxaban in patients ≥75 years with peripheral artery disease (PAD) after lower extremity revascularization (LER) has not been described. Methods and results The primary endpoint was a composite of acute limb ischaemia, major amputation, myocardial infarction, ischaemic stroke, or cardiovascular death. The principal safety outcome was thrombolysis in myocardial infarction (TIMI) major bleeding analysed by the pre-specified age cut-off of 75 years. Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute 3-year Kaplan–Meier cumulative incidence rates for primary efficacy (23.4% vs. 19.0%) and safety (3.5% vs. 1.5%) endpoints were higher in elderly vs. non-elderly patients. Efficacy of rivaroxaban (P-interaction 0.83) and safety (P-interaction 0.38) was consistent irrespective of age. The combination of intracranial and fatal bleeding was not increased in patients >75 years (2 rivaroxaban vs. 8 placebo). Overall, benefits (absolute risk reduction 3.8%, number needed to treat 26 for the primary endpoint) exceeded risks (absolute risk increase 0.81%, number needed to harm 123 for TIMI major bleeding). Conclusion Patients ≥75 years with PAD are at both heightened ischaemic and bleeding risk after LER. No excess harm with respect to major, intracranial or fatal bleeding was seen in older patients yet numerically greater absolute benefits were observed. This suggests that low-dose rivaroxaban combined with aspirin should be considered in PAD after LER regardless of age.

Background Patients with peripheral artery disease (PAD) treated with lower extremity revascularization are at increased risk of major atherothrombotic vascular events (acute limb ischemia (ALI), major non-traumatic lower-limb amputation, myocardial infarction (MI), ischemic stroke, and cardiovascular (CV)-related death). This study assessed the incidence of major atherothrombotic vascular events, venous thromboembolism (VTE) events and rates of subsequent lower extremity revascularizations in the real-world among patients with PAD after revascularization. Methods Patients aged ≥50 years with PAD who underwent peripheral revascularization were identified from Optum Clinformatics Data Mart claims database (Q1/2014-Q2/2019). The first lower extremity revascularization after PAD diagnosis was defined as index date. Incidence rates of major atherothrombotic vascular events (i.e., composite of ALI, major non-traumatic lower-limb amputation, MI, ischemic stroke, and CV-related death) and VTE were assessed during follow-up as the number of events divided by patient-years of observation (censored at the first event). Rates of subsequent revascularizations and VTE were estimated overall and compared between patients with major atherothrombotic vascular events and those without. Results Of the 38,439 patients included, 6,675 (17.4%) had a major atherothrombotic vascular event during a median follow-up of 1.0 year. The composite major atherothrombotic vascular and VTE incidence rates were 13.81/100 patient years and 1.77/100 patient years, respectively, and 40.2% of patients experienced subsequent revascularizations. Patients with a post-revascularization major atherothrombotic vascular event had significantly higher rates of subsequent revascularizations (64.6% vs. 35.1%, standardized difference [SD] ≥10%) and VTE (4.6% vs. 2.1%, SD ≥10%) versus those without. Conclusion One-in-six PAD patients aged ≥50 years who underwent peripheral revascularization experienced a major atherothrombotic vascular event within one year, and consequently, experienced higher rates of subsequent revascularizations compared with those without a major atherothrombotic vascular event post-revascularization. These findings highlight the need to improve strategies to prevent major atherothrombotic vascular events after revascularization.

Patients with peripheral artery disease (PAD) undergoing lower extremity revascularization (LER) are at high risk of major adverse limb and cardiovascular events. The VOYAGER PAD (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities) trial demonstrated that rivaroxaban 2.5 mg twice daily reduced first events by 15%. The benefit of rivaroxaban on total (first and subsequent) events in this population is unknown.This study sought to evaluate the total burden of vascular events in patients with PAD after LER and the efficacy of low-dose rivaroxaban on total events.VOYAGER PAD randomized patients with PAD undergoing LER to rivaroxaban 2.5 mg twice daily plus aspirin or aspirin alone. The primary endpoint was time to first event of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The current analysis considered all events (first and subsequent) for components of the primary endpoint as well as additional vascular events including peripheral revascularizations and venous thromboembolism. HRs were estimated by marginal proportional hazards models.Among 6,564 randomized events, there were 4,714 total first and subsequent vascular events including 1,614 primary endpoint events and 3,100 other vascular events. Rivaroxaban reduced total primary endpoint events (HR: 0.86; 95% CI: 0.75-0.98; P = 0.02) and total vascular events (HR: 0.86; 95% CI: 0.79-0.95; P = 0.003). An estimated 4.4 primary and 12.5 vascular events per 100 participants were avoided with rivaroxaban over 3 years.Patients with symptomatic PAD who are undergoing LER have a high total event burden that is significantly reduced with rivaroxaban. Total event reduction may be a useful metric to quantify the efficacy of rivaroxaban in this setting. (Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities [VOYAGER PAD]; NCT02504216).

Background: Women with coronary artery disease are shown to have worse outcomes after percutaneous coronary intervention compared with men; however, less is known about sex-based outcomes following lower extremity peripheral vascular intervention (PVI) for symptomatic peripheral artery disease. The study aims to assess whether female sex is independently associated with periprocedural complications in patients undergoing PVI. Methods: Analysis includes patients undergoing lower extremity PVI from September 2016 to March 2020 from the Vascular Quality Initiative registry. Multivariate logistic regression was used to assess the independent association of female sex with post-PVI complications. Results: Of the 119 620 patients included, 47 316 (39.6%) were women. Analysis reflected that women were at higher risk of developing access site complications, including any hematoma (odds ratio [OR], 1.45 [1.35–1.57]), hematoma requiring transfusion (OR, 2.24 [1.82–2.76]; P P P P P P P =0.003). Conclusions: In a contemporary cohort, women undergoing lower extremity PVI for symptomatic peripheral artery disease were at higher risk than men of developing periprocedural complications, including moderate or severe access site bleeding, above-knee amputation, and in-hospital mortality. This increased risk persisted despite adjustment for differences in baseline patient or procedural characteristics and warrants further investigation.

Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. VOYAGER PAD demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit in patients undergoing surgical revascularization; however, the efficacy and safety in those treated by surgical bypass including stratified by bypass conduit (venous or prosthetic) has not been described.In the VOYAGER PAD trial, patients with PAD after surgical and endovascular infrainguinal LER were randomized to rivaroxaban 2.5 mg twice daily or placebo and followed for a median of 28 months. The primary endpoint was a composite of acute limb ischemia (ALI), major amputation of vascular etiology, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Index procedure details including conduit type (venous or prosthetic) were collected at baseline.Among 6564 randomized, 2185 (33%) underwent surgical LER. Of these, surgical bypass was performed in 1448 (66%), using prosthetic conduit in 773 (53%) and venous in 646 (45%). Adjusting for baseline differences and anatomic factors, the risk for unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving prosthetic versus venous conduits (adjHR 2.53, 95% CI 1.65-3.90; p0.001) while the risk for ALI was 3 times greater (adjHR 3.07, 95% CI 1.84-5.11; p0.001). Rivaroxaban reduced the primary outcome in patients treated with bypass surgery (HR 0.78, 95% CI 0.62-0.98) with consistent benefits in those receiving venous (HR 0.66, 95% CI 0.49-0.96) and prosthetic (HR 0.87, 95% CI 0.66-1.15) conduits (pSurgical bypass with prosthetic conduit is associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjusting for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduces this risk, increases bleeding, but has a favorable benefit risk in patients treated with bypass surgery and regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.

A 69-year-old man underwent coronary angiography 7 years after coronary artery bypass. Saphenous vein graft spasm was observed during contrast injection, resulting in ventricular fibrillation. Angiography 6 years later showed graft patency. Vein graft spasm after coronary artery bypass grafting is rarely described. Further investigation is needed regarding incidence, mechanism, and clinical outcomes. (Level of Difficulty: Beginner.)

Peripheral artery disease (PAD), often treated with lower extremity revascularization, is associated with risk of major atherothrombotic vascular events (acute limb ischemia [ALI], major non-traumatic lower-limb amputation, myocardial infarction [MI], ischemic stroke, cardiovascular death). This study aims to assess healthcare resource utilization and costs of such events among patients with PAD after revascularization.Patients aged ≥50 years with PAD who were treated with lower-extremity revascularization were identified from Optum Clinformatics Data Mart claims database (01/2014-06/2019). The first lower extremity revascularization after PAD diagnosis was defined as the index date. Patients had ≥6 months of health plan enrollment before the index date. Patients were followed until the earliest of 1) end of enrollment or data; 2) diagnosis of atrial fibrillation or venous thromboembolism; or 3) oral anticoagulant use. All-cause healthcare resource use per-patient-year was compared before and after a major atherothrombotic vascular event post-revascularization among those with an event. Additionally, event-related healthcare costs per-patient-year were reported for each event type.Of the 38,439 PAD patients meeting the study criteria, 6,675 (17.4%) had a major atherothrombotic vascular event. On average, patients were observed for 7.3 months before an event and 6.2 months after an event. Patients with an event had significantly higher all-cause healthcare resource use versus similar metrics pre-event (e.g. inpatient visits among those with ALI: 3.5 ± 5.8 post-event vs. 2.0 ± 8.1 pre-event,Data do not contain clinical information. Additionally, results are limited to commercially insured and Medicare Advantage beneficiaries.Patients with PAD who experience major atherothrombotic vascular events post-revascularization have considerably higher healthcare resource use and costs compared with similar metrics pre-event. Therefore, reducing the rate of such events could reduce overall healthcare costs for this population.

Background: The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described. Methods: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization. Results: Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71–1.01) with clopidogrel and 0.86 (95% CI, 0.73–1.01) without clopidogrel without statistical heterogeneity ( P for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14–1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22–1.01] without clopidogrel; P for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( P for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44–7.13]) compared with shorter durations of clopidogrel ( P for trend=0.06). Conclusions: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02504216.

Background Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and ...

BACKGROUND: Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.OBJECTIVES: 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).

Peripheral artery disease (PAD) is a prevalent condition that confers substantial morbidity and mortality and remains underdiagnosed as well as undertreated in the overall population. Although PAD prevalence is similar or higher in women compared with men, associations of traditional and nontraditional risk factors with PAD and clinical manifestations of PAD differ by sex and may contribute to delayed or lack of diagnosis in women. Such sex-based differences in the manifestation of PAD may arise from sexual dimorphism in the vascular substrate in health as well as sex variation in the responses to vascular stressors. Despite the availability of proven therapies for improving symptoms and reducing risk of ischemic cardiovascular and limb events among patients with diagnosed PAD, important sex differences in treatment and outcomes have been observed. We provide an overview of current knowledge regarding sex differences in the epidemiology, pathophysiology, clinical presentation, and management of PAD.

BACKGROUND: Meta-analyses of randomised trials of paclitaxel-coated peripheral devices found an association with worse long-term survival. We assessed long-term mortality in patients treated with drug-coated devices insured by Medicare Advantage (MA), an alternative to traditional Medicare that represents >30% of the Medicare eligible population. METHODS: Patients treated with or without drug-coated devices for femoropopliteal artery revascularisation from 4/2015–12/2017 were studied using Optum’s De-identified Clinformatics® Datamart Database. Mortality was assessed through December 2019 using Kaplan Meier cumulative mortality curves and Cox-proportional hazard models. Inverse probability of treatment weighting was used to adjust for differences between groups. RESULTS: Of 16,796 patients revascularised, 4,427 (26.4%) were treated with drug-coated devices: 3,600 (81.3%) balloons and 827 (18.7%) stents. The median follow-up was 2.66 years (IQR 2.02–3.52). Treatment with drug-coated devices was associated with similar long-term mortality as nondrug-coated devices (adjusted HR 1.03; 95%CI=0.96–1.10; P=0.39). Results were comparable for patients treated with balloons alone (adjusted HR 1.00; 95%CI=0.92–1.08; P=0.96) or stents (adjusted HR 1.02; 95%CI=0.88–1.18; P=0.78). These findings did not differ based on treatment setting, disease severity, age, sex or comorbidity burden (interaction P>0.05 for all). CONCLUSIONS: In this large cohort, there was no evidence of increased long-term mortality following treatment with drug-coated devices. CONDENSED ABSTRACT: Meta-analyses of randomised trials of paclitaxel-coated peripheral devices found an association with worse long-term survival. To further evaluate device safety, Medicare Advantage claims data from 4/2015–12/2017 were used to identify patients treated with drug-coated and nondrug-coated devices. Inverse probability of treatment weighting was used for adjustment. Of 16,796 patients, 26.4% were treated with drug-coated devices. Median follow-up was 2.66 years (IQR 2.02 – 3.52). Treatment with drug-coated devices was associated with similar risk of long-term mortality as nondrug-coated devices (HR 1.03; 95%CI=0.96–1.10; P=0.39). In this large cohort, there was no evidence of increased long-term mortality following treatment with drug-coated devices.

Background: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. Methods: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. Results: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method ( P -interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67–0.98]; P =0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding ( P -interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding ( P -interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39–1.95]; P =0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage ( P =0.95) and postprocedural bleeding requiring intervention ( P =0.93) was not significantly increased. Conclusions: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov ; Unique Identifier: NCT02504216.

Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other cardiovascular diseases such as coronary heart disease and stroke and leg outcomes such as amputation). Despite its prevalence and clinical importance, PAD has been historically underappreciated by health care professionals and patients. This underappreciation seems multifactorial (eg, limited availability of the first-line diagnostic test, the ankle-brachial index, in clinics; incorrect perceptions that a leg vascular disease is not fatal and that the diagnosis of PAD would not necessarily change clinical practice). In the past several years, a body of evidence has indicated that these perceptions are incorrect. Several studies have consistently demonstrated that many patients with PAD are not receiving evidence-based therapies. Thus, this scientific statement provides an update for health care professionals regarding contemporary epidemiology (eg, prevalence, temporal trends, risk factors, and complications) of PAD, the present status of diagnosis (physiological tests and imaging modalities), and the major gaps in the management of PAD (eg, medications, exercise therapy, and revascularization). The statement also lists key gaps in research, clinical practice, and implementation related to PAD. Orchestrated efforts among different parties (eg, health care providers, researchers, expert organizations, and health care organizations) will be needed to increase the awareness and understanding of PAD and improve the diagnostic approaches, management, and prognosis of PAD.

Paclitaxel drug-coated devices (DCDs) were developed to improve lower extremity revascularization (LER) patency in peripheral artery disease (PAD) but have been associated with long-term mortality.This study assessed DCD safety and effectiveness in LER for PAD.VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) randomized patients with PAD who underwent LER to rivaroxaban or placebo. The primary VOYAGER PAD study efficacy and safety outcomes were composite cardiovascular and limb events and Thrombolysis In Myocardial Infarction major bleeding. For prespecified DCD analyses, primary safety and effectiveness outcomes were mortality and unplanned index limb revascularization (UILR). Major adverse limb events (MALE) were a secondary outcome. Inverse probability treatment weighting was used to account for each subject's propensity for DCD treatment. Effects of rivaroxaban were assessed with Cox proportional hazards models.Among 4,316 patients who underwent LER, 3,478 (80.6%) were treated for claudication, and 1,342 (31.1%) received DCDs. Median follow-up was 31 months, vital status was ascertained in 99.6% of patients, and there were 394 deaths. After weighting, DCDs were not associated with mortality (HR: 0.95; 95% CI: 0.83-1.09) or MALE (HR: 1.08; 95% CI: 0.90-1.30) but were associated with reduced UILR (3-year Kaplan-Meier: 21.5% vs 24.6%; HR: 0.84; 95% CI: 0.76-0.92). Irrespective of DCD use, consistent benefit of rivaroxaban for composite cardiovascular and limb events (PIn4,000 patients with PAD who underwent LER, DCDs were not associated with mortality or MALE but were associated with persistent reduction in UILR. These findings provide insight into the safety and effectiveness of DCDs in PAD. (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD [VOYAGER PAD]; NCT02504216).

Background: A reduced ankle-brachial index (ABI) is a measure of atherosclerosis and is associated with ischemic risk in the general population. Whether this relationship is maintained in peripheral artery disease after lower extremity revascularization (LER), which can modify ABI, is unknown. Methods: The EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) enrolled 13 885 patients with symptomatic peripheral artery disease; 57% with prior LER, and 43% with ABI ≤0.80. The primary major adverse cardiovascular events (MACE) outcome was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Major adverse limb events (MALE) included acute limb ischemia and major amputation. An adjusted Cox proportional hazards model demonstrated a nonlinear relationship between ABI and outcomes. A restricted cubic spline model with 4 knots was developed to identify the best fitting model to describe the relationship between ABI and MACE and MALE risk. Results: Baseline ABI (mean±SD) was 0.77±0.21 in participants with prior LER and 0.63±0.14 in those without prior LER ( P P P P =0.0004) and MALE (hazard ratio, 1.27 [95% CI, 1.08–1.49]; P =0.003). Conclusions: Patients with established peripheral artery disease, particularly those with prior LER, have an increased risk of MACE and MALE. The ABI remains a strong predictor of MACE and MALE ischemic events with an inverse relationship below an ABI threshold for patients with and without prior LER. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01732822.

Background: Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated. Methods: EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized patients with peripheral artery disease to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index ≤0.80 or previous lower extremity revascularization. Patients were grouped according to the primary outcome, postrandomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were developed for secondary outcomes of major adverse cardiovascular events (myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation. Results: Among 13 885 patients, 1.7% (n=232) had 293 ALI hospitalizations (0.8 per 100 patient-years). Patients with versus without ALI were younger and more often had previous peripheral revascularization and lower baseline ankle-brachial index. Treatment during ALI hospitalization included endovascular revascularization (39.2%, n=115), surgical bypass (24.6%, n=72), and major amputation (13.0%, n=38). After multivariable adjustment, any previous peripheral revascularization (Hazard Ratio [HR] 4.7, 95% CI 3.3–6.8, P P =0.03), and baseline ankle-brachial index ≤0.60 (HR 1.3 per 0.10 decrease, 95% CI 1.1–1.5, P P =0.02) and baseline statin use (HR 0.7, 95% CI 0.5–0.9, P P =0.04), all-cause mortality (adjusted HR 3.3, 95% CI 2.4–4.6, P P Conclusions: Previous peripheral revascularization, baseline atrial fibrillation, and lower ankle-brachial index identify peripheral artery disease patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.

Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in peripheral artery disease (PAD). Lipid-lowering therapies (LLT) that reduce LDL-C decrease this risk.The authors examined LLT use and actual achieved LDL-C in PAD.PAD patients in MarketScan from 2014 to 2018 were identified. Outcomes included LLT use, defined as high-intensity (HI) (high-intensity statin, statin plus ezetimibe, or PCSK9 inhibitor), low-intensity (any other lipid regimen), or no therapy, and follow-up LDL-C. Factors associated with LDL-C70 mg/dl were identified with multivariable logistic regression.Among 250,103 PAD patients, 20.5% and 39.5% were treated at baseline with HI and low-intensity LLT, respectively; 40.0% were on no LLT. Over a 15-month median follow-up period, HI LLT use increased by 1.5%. Among 18,747 patients with LDL-C data, at baseline, 25.1% were on HI LLT, median LDL-C was 91 mg/dl, and 24.5% had LDL-C 70 mg/dl. Within the HI LLT subgroup, median LDL-C was 81 mg/dl, and 64% had LDL-C ≥70 mg/dl. At follow-up, HI LLT use increased by 3.7%, median LDL-C decreased by 4.0 mg/dl, and an additional 4.1% of patients had LDL-C 70 mg/dl. HI LLT use was greater after follow-up MACE (55.0%) or MALE (41.0%) versus no ischemic event (26.1%). After MACE or MALE, LDL-C was 70 mg/dl in 41.5% and 36.1% of patients, respectively, versus 27.1% in those without an event. Factors associated with follow-up LDL-C 70 mg/dl included smoking, hypertension, diabetes, prior lower extremity revascularization, and prior myocardial infarction but not prior acute or critical limb ischemia.In PAD, LLT use is suboptimal, LDL-C remains elevated, and LLT intensity is a poor surrogate for achieved LDL-C. Less aggressive lipid management was observed in PAD versus cardiovascular disease, highlighting missed opportunities for implementation of proven therapies in PAD.

Prior studies have observed an association between the burden of atherosclerotic vascular disease and the risk of venous thromboembolism (VTE). The association is not well described in peripheral artery disease (PAD) after lower extremity revascularization (LER).To describe the risk of, factors associated with, and outcomes after VTE, as well as the association of low-dose rivaroxaban plus antiplatelet therapy with VTE after LER.This global, multicenter cohort study used data from the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) randomized clinical trial, which enrolled patients from 2015 to 2018 with median follow-up of 28 months. Participants included patients with PAD undergoing LER. Patients with an indication for therapeutic anticoagulation were excluded. Data were analyzed from September 2020 to September 2021.Randomization to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily; short-term clopidogrel was used at the discretion of the treating physician.Symptomatic VTE was a prespecified secondary outcome and prospectively collected.Among 6564 patients (median [IQR] age, 67 [61-73] years; 4860 [74.0%] men), 66 patients had at least 1 VTE. The 3-year rate of VTE in patients receiving placebo was 1.7%, and the pattern of risk was linear (year 1: 0.5%; year 2: 1.1%). After multivariable modeling, weight (hazard ratio [HR], 3.04; 95% CI, 1.09-8.43), hypertension (HR, 2.11; 95% CI, 0.91-4.89), prior amputation (HR, 2.07; 95% CI, 0.95-4.53), and older age (HR, 1.81; 95% CI, 1.06-3.11) were associated with increased risk of VTE. VTE was associated with risk of subsequent mortality (HR, 7.22; 95% CI, 4.66-11.19). Compared with aspirin alone, rivaroxaban plus aspirin was associated with lower VTE risk (HR, 0.61; 95% CI, 0.37-0.998; P = .047), with benefit apparent early and sustained over time. This association was not modified by use of clopidogrel at randomization (without clopidogrel: HR, 0.55; 95% CI, 0.29-1.07; with clopidogrel: HR, 0.69; 95% CI, 0.32-1.48; P for interaction = .67).In this cohort study, there was continuous risk for VTE after LER in patients with PAD, with greater risk in patients who were older and had obesity and those with more severe PAD, as reflected by prior amputation. Low-dose rivaroxaban plus aspirin was associated with lower VTE risk compared with aspirin alone, with benefits apparent early and continued over time. The spectrum of venous and arterial thrombotic events and overall benefits of more potent antithrombotic strategies for prevention should be considered after LER for PAD.

Introduction: Chronic kidney disease (CKD) is common among patients undergoing lower extremity revascularization (LER) for peripheral artery disease (PAD) and identifies a population at high risk for adverse outcomes. The VOYAGER PAD trial demonstrated the efficacy of rivaroxaban in PAD patients after LER on a composite of cardiovascular (CV) and limb ischemic events (HR 0.85 vs placebo, 95% CI 0.76-0.96; p=0.009); this analysis examines the prespecified subgroup of patients with CKD. Methods: VOYAGER PAD (NCT02504216) was a double-blind, placebo-controlled trial which randomized PAD patients with recent LER to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily. The primary endpoint was a composite of acute limb ischemia, major amputation for vascular cause, myocardial infarction, ischemic stroke or CV death. The primary safety endpoint was TIMI major bleeding. Analysis of the intention-to-treat population utilized Kaplan Meier estimates and Cox proportional-hazards models. Results: Among 6319 VOYAGER patients with baseline estimated glomerular filtration rate (eGFR), 21% were 2 . During 28-month (median) follow up, patients with CKD had a higher rate of major CV and limb events: placebo group 10.0 events/100 patient-years (95% CI 8.5, 11.8) for eGFR Conclusions: Rivaroxaban reduced major CV and limb events in patients with PAD undergoing LER, including those with CKD, a particularly high-risk population.

Introduction: Peripheral artery disease (PAD), frequently requiring lower-extremity revascularization (LER), is associated with risk of major atherothrombotic vascular events (acute limb ischemia [ALI], major amputation of vascular etiology, myocardial infarction [MI], ischemic stroke [IS], cardiovascular [CV] death). Understanding the incidence and healthcare costs of such events in PAD patients post-revascularization may be important in translation. Methods: Patients with PAD who underwent LER were identified from Optum Clinformatics Data Mart claims database (Q1 2014 - Q2 2019). The first LER was considered index. Patients were required to be ≥50 years old at index with ≥6 months of prior health plan enrollment. Patients with IS, atrial fibrillation (AF), venous thromboembolism (VTE), intracranial hemorrhage, ESRD, or oral anticoagulant (OAC) use pre-index; or diagnoses of MI 30 days or ALI 14 days pre-index were excluded. Patients were followed until the earliest of 1) end of enrollment/data; 2) diagnosis of AF or VTE; or 3) OAC use. For each major vascular event, the incidence rate was assessed as the number of first events divided by patient-years of observation. Event-related healthcare costs per-patient-year (PPY) were also reported. Results: Of the 38,439 PAD patients meeting the study criteria, 6,675 (17.4%) had a major atherothrombotic vascular event over a median follow-up of 1.0 years (IQR: 0.4-2.1). The composite event incidence rate was 13.81 per 100 patient years [ALI: 5.51; lower-limb amputation: 5.15; MI: 3.19; IS: 2.06; CV-related death: 0.88]. PPY event-related costs ranged from $57,825 for IS to $108,302 for lower-limb amputation (Figure). Conclusions: One in six PAD patients have a major atherothrombotic vascular event within one year post-LER. Costs of these events are high, particularly for limb complications. Therefore, reducing the rate of such events could reduce the overall healthcare costs for this population.

Introduction: Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with peripheral artery disease (PAD). Strategies that lower LDL-C levels reduce this risk. Hypothesis: We hypothesized that real-world PAD patients are overall undertreated with lipid lowering therapies (LLT) but that LLT use and achieved LDL-C are improved in high risk patients with ischemic events. Methods: Patients with PAD in the MarketScan database linked to PROGNOS lab data from January 1, 2014 through December 31, 2018 were examined. Outcomes included use of LLT, defined as high intensity (HI) (high intensity statin, any statin plus ezetimibe, or any use of a PCSK9 inhibitor), low intensity (LI) (any other lipid regimen), or no therapy, and follow up LDL-C level. Goal LDL-C was defined as Results: Among 18,747 PAD patients, 25% were on HI LLT, 43% were on LI LLT, and 32% were on no therapy at baseline (Figure A). The median LDL-C was 91 mg/dl (IQR 70, 118), and 25% of patients were at goal (Figure B). After a median follow up of 18 months, use of HI LLT increased by 4%, the median LDL-C decreased by 5 mg/dl, and an additional 3% of patients were at goal LDL-C. Greater use of HI LLT was observed among patients with a MACE (55%) or MALE (41%) event during follow up compared with patients without an ischemic event (26%) during follow up (Figure C). Follow up LDL-C levels remained above goal for most patients (post-MACE: median LDL-C 77 mg/dl, 42% patients at goal; post-MALE: median LDL-C 80 mg/dl, 36% patients at goal). Conclusions: In PAD patients, use of LLT is suboptimal, and LDL-C levels remain elevated. After an ischemic event, LLT use is intensified, with greater use of HI LLT observed after MACE than MALE. Despite this, LLT remains underutilized, with >50% of patients not at goal LDL-C. Strategies to better implement proven therapies to reduce risk in this high risk population are needed.

Background: Prior studies suggest that atherosclerotic vascular disease may be associated with risk of venous thromboembolism (VTE), though the relationship remains uncertain and has not been well-studied in peripheral artery disease (PAD) after lower extremity revascularization (LER). Hypothesis: We hypothesized that patients with PAD undergoing LER are at risk for VTE and that this risk may be reduced by low-dose rivaroxaban plus aspirin versus aspirin alone. Methods: VOYAGER PAD randomized 6,564 PAD patients undergoing LER to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily. Clopidogrel was allowed for up to 6 months. Patients could not be enrolled if they had an indication for therapeutic anticoagulation, including secondary prevention of VTE. Symptomatic VTE was a prespecified secondary endpoint. Results: Over a median of 28 months, there were 66 patients with VTE. In patients randomized to placebo, risk for VTE accrued steadily after randomization at a rate of ~0.5% per year resulting in a 3-year rate of 1.66%. Compared with placebo, rivaroxaban reduced the risk of VTE by 39% (HR 0.61, 95% CI 0.37-1.00, p=0.047), with benefit apparent early and sustained over time (Figure). The efficacy of rivaroxaban was not modified by use of clopidogrel at randomization (without clopidogrel HR 0.55, 95% CI 0.29, 1.07; with clopidogrel HR 0.69, 95% CI 0.32, 1.48; p-interaction = 0.67). Conclusions: PAD is associated with continuous and linearly increasing risk for VTE after LER. A strategy of low-dose rivaroxaban plus aspirin versus aspirin alone reduced this risk by 39% with benefits apparent early and continued over time. The addition of clopidogrel does not modify this benefit. VTE, along with arterial thrombotic events, is part of the adverse thrombotic risk profile in PAD patients, and low-dose rivaroxaban plus aspirin provides protection against venous and arterial thrombosis.

Patients with peripheral artery disease (PAD) are at heightened risk for ischemic events related to atherothrombosis. Antithrombotic therapies can reduce the risk of atherothrombotic events but increase bleeding. Importantly, there is growing appreciation of the heterogeneity in risk profile and effect of antithrombotic therapies in different populations, including those with PAD. Further, patients with PAD are at risk for not only major adverse cardiovascular events but also major adverse limb events, and the drivers of risk for each are different. Within PAD populations, data from trials may be difficult to interpret due to differences among the studies with regards to patient population, clinical settings, and outcomes examined. The acute setting of peripheral revascularization which involves plaque rupture and endothelial disruption confers very high risk of major adverse limb events early postprocedure. Among patients with chronic PAD for whom the goal of antithrombotic therapy is secondary prevention, concomitant coronary artery disease, particularly with prior myocardial infarction, is associated with greatest risk for major adverse cardiovascular events, while prior peripheral revascularization or amputation is associated with greatest risk for major adverse limb events. Understanding of the potential impact of clinical setting and patient risk profile is important to guide evidence-based decisions regarding antithrombotic therapy in patients with PAD. In this article, we provide a contemporary review of data supporting the use of antithrombotic therapy in PAD, as well as a clinical framework for analysis and translation of these data into practice, highlighting areas in need of further investigation.

Atherosclerotic cardiovascular disease (ASCVD) is associated with significant morbidity and mortality worldwide. Increased serum levels of low-density lipoprotein cholesterol (LDL-C) are an independent risk factor for ASCVD, and clinical trial data have shown that lowering LDL-C generally reduces cardiovascular risk. Until recently, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been the main therapy for lowering LDL-C. However, some statin-treated patients have persistently elevated residual cardiovascular risk due to inadequate lowering of LDL-C levels or non-LDL-related dyslipidemia. In addition, adverse effects of statins may limit their tolerability and therefore the ability to attain effective doses in some patients. A new class of drugs that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed to treat hyperlipidemia. This review discusses the history and mechanism of action of PCSK9 inhibitors, their metabolic effects, and clinical outcomes associated with these medications, highlighting recent large cardiovascular outcome trials investigating these therapies.