Growth Differentiation Factor 15 Is Associated With Major Amputation and Mortality in Patients With Peripheral Artery Disease

Purpose: To present the 6-month results of the Stromal Cell–Derived Factor-1 Plasmid Treatment for Patients with Peripheral Artery Disease (STOP-PAD) trial. The trial was an attempt to alter the course of chronic limb-threatening ischemia (CLTI) with a biological agent vs placebo after successful arterial revascularization at or below the knee. Materials and Methods: The multicenter, randomized, double-blinded, placebo-controlled, phase 2B STOP-PAD trial ( ClinicalTrials.gov identifier NCT02544204) randomized 109 patients (mean age 71 years; 68 men) with Rutherford category 5 or 6 CLTI and evidence of persistent impaired forefoot perfusion following recent successful revascularization to 8- (n=34) or 16-mg (n=36) intramuscular injections of a non-viral DNA plasmid–based treatment vs placebo (n=34). The primary efficacy outcome was the 6-month wound healing score evaluated by an independent wound core laboratory; the primary safety endpoint was major adverse limb events (MALE), a composite of major amputation plus clinically-driven target lesion revascularization at 6 months. Results: Only one-third of the patients had complete wound healing at 6 months in the placebo (31%), 8-mg injection (33%), and 16-mg injection (33%) groups. In addition, the observed increase in the toe-brachial index from baseline to 6 months was statistically significant in each group; however, this did not result in lower rates of MALE at 6 months (24% in the placebo, 29% in the 8-mg injection, and 11% in the 16-mg injection groups). During the 6-month period, 6 patients (6%) died, and 24 patients (23%) had an amputation [only 4 (4%) major]. Conclusion: Combining revascularization and biological therapy failed to improve outcomes in CLTI at 6 months. STOP-PAD has provided insights for future trials to evaluate biological therapy.

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Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial

Vascular Medicine ◽

10.1177/1358863x19864172 ◽

2019 ◽

Vol 24 (5) ◽

pp. 422-430 ◽

Cited By ~ 1

Author(s):

Charles W Hopley ◽

Sarah Kavanagh ◽

Manesh R Patel ◽

Cara Ostrom ◽

Iris Baumgartner ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Ischemic Stroke ◽

Kidney Disease ◽

Peripheral Artery Disease ◽

Major Bleeding ◽

Cardiovascular Death ◽

Major Amputation ◽

Peripheral Artery ◽

Increased Risk ◽

Artery Disease

In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30–1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69–1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66–1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89–1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07–2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822

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Vorapaxar for Prevention of Major Adverse Cardiovascular and Limb Events in Peripheral Artery Disease

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/10742484211056115 ◽

2022 ◽

Vol 27 ◽

pp. 107424842110561

Author(s):

Justin T. Morrison ◽

Nicholas Govsyeyev ◽

Connie N. Hess ◽

Marc P. Bonaca

Keyword(s):

Peripheral Artery Disease ◽

Limb Ischemia ◽

Major Amputation ◽

Acute Limb Ischemia ◽

Peripheral Artery ◽

Cellular Effects ◽

Thrombin Inhibition ◽

Severe Manifestation ◽

Artery Disease

Peripheral artery disease (PAD) is a severe manifestation of atherosclerosis. Patients with PAD are at heightened risk for atherothrombotic complications, including myocardial infarction and stroke (MACE); however, there is also an equal or greater risk of major adverse limb events (MALE), such as acute limb ischemia (ALI) and major amputation. Therefore, there is a need for effective medical therapies to reduce the risk of both MACE and MALE. Recent trials have demonstrated the role of thrombin inhibition in reducing the risk of MACE and MALE in PAD patients. One such medical therapy, vorapaxar, is a potent inhibitor of protease activated receptor-1 which mediates the cellular effects of thrombin. Vorapaxar, used in addition to aspirin, has demonstrated robust reductions in MACE and MALE in PAD patients. In this article, we provide a contemporary review of the current state of PAD and the role of antithrombotic medications in the treatment of PAD, as well as the current clinical data on vorapaxar and strategies to integrate vorapaxar into contemporary medical management of peripheral artery disease.

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Peripheral artery disease leading to major amputation: trends in revascularisation and mortality over 18 years

Annals of Vascular Surgery ◽

10.1016/j.avsg.2021.04.037 ◽

2021 ◽

Author(s):

Lisa Abry ◽

Salome Weiss ◽

Vladimir Makaloski ◽

Alan G. Haynes ◽

Jürg Schmidli ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Major Amputation ◽

Peripheral Artery ◽

Artery Disease

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Race and Socioeconomic Status Independently Affect Risk of Major Amputation in Peripheral Artery Disease

Journal of the American Heart Association ◽

10.1161/jaha.117.007425 ◽

2018 ◽

Vol 7 (2) ◽

Cited By ~ 23

Author(s):

Shipra Arya ◽

Zachary Binney ◽

Anjali Khakharia ◽

Luke P. Brewster ◽

Phil Goodney ◽

...

Keyword(s):

Socioeconomic Status ◽

Peripheral Artery Disease ◽

Major Amputation ◽

Peripheral Artery ◽

Artery Disease

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Three-Year Outcomes From the LIBERTY 360 Study of Endovascular Interventions for Peripheral Artery Disease Stratified by Rutherford Category

Journal of Endovascular Therapy ◽

10.1177/1526602820962972 ◽

2020 ◽

pp. 152660282096297

Author(s):

Stefanos Giannopoulos ◽

Jihad Mustapha ◽

William A. Gray ◽

Gary Ansel ◽

George Adams ◽

...

Keyword(s):

Quality Of Life ◽

Peripheral Artery Disease ◽

Survival Rates ◽

Target Lesion ◽

Major Amputation ◽

Peripheral Artery ◽

Target Vessel Revascularization ◽

Endovascular Interventions ◽

Artery Disease

Purpose: To report the 3-year results of the LIBERTY 360 study, which investigated outcomes of endovascular treatment of symptomatic peripheral artery disease (PAD). Materials and Methods: The LIBERTY trial ( ClinicalTrials.gov identifier NCT01855412) was a prospective, observational, core laboratory–assessed, multicenter study of endovascular interventions enrolling >1200 participants treated at 51 sites. Data from 1189 patients were stratified according to Rutherford category (RC) and analyzed [RC 2-3 (n=500), RC 4-5 (n=589), and RC 6 (n=100)]. The primary outcomes were major amputation of the target limb and all-cause death; secondary outcomes were target vessel revascularization (TVR) or target lesion revascularization (TLR); major adverse events (MAEs; death within 30 days, TVR or TLR, and major amputation); death or major amputation combined; and change in self-reported quality of life (QoL) measures (VascuQol-25). The Kaplan-Meier (KM) method was employed to estimate the outcomes; estimates are presented with the 95% confidence intervals (CI). Predictors of 3-year MAE, death, TVR, and major amputation were analyzed using Cox proportional hazard regression modeling. Results: The 36-month KM survival rates were 86.0% in RC 2-3, 79.8% in RC 4-5, and 62.0% in RC 6 groups. The KM estimates of freedom from major amputation at 36 months were 98.5% in RC 2-3, 94.0% in RC 4-5, and 79.9% in RC 6. The 36-month KM estimates for freedom from TVR/TLR were 71.1% in RC 2-3, 64.2% in RC 4-5 and 61.9% in RC 6 groups. Patients with claudication at baseline were at lower risk for MAEs compared with RC 4-5 and RC 6 patients during the 36-month follow-up. Vascular QoL improved from baseline and persisted up to 36 months in all patients. Conclusion: Endovascular therapy is a viable treatment option for patients with symptomatic PAD, with sustained improved quality of life in both claudicants and patients with chronic limb-threatening ischemia. These results provide important point estimates for midterm outcomes after modern endovascular interventions for PAD.

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Impact of frailty on super elderly patients with peripheral artery disease from the I-PAD 3 year registry

European Heart Journal ◽

10.1093/ehjci/ehaa946.2391 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

K Nishikawa ◽

A Nagae ◽

T Miura ◽

T Katoh ◽

Y Kanzaki ◽

...

Keyword(s):

Elderly Patient ◽

Elderly Patients ◽

Peripheral Artery Disease ◽

Cardiovascular Death ◽

Major Amputation ◽

Peripheral Artery ◽

Clinical Frailty Scale ◽

Treatment Indications ◽

Artery Disease ◽

Patient Prognosis

Abstract Background Unlike age, frailty is often not taken into account in treatment indications of Endovascular treatment (EVT). One of the reason is that there was little known the relationship between frailty and the outcome of EVT for super elderly patients with peripheral artery disease (PAD). We investigate impacts of frailty on the super elderly patient prognosis who underwent EVT. Purpose To investigate impacts of frailty on the super elderly patient prognosis who underwent EVT. Methods From August 2015 to July 2016, 335 consecutive patients who underwent EVT were enrolled in the I-PAD registry from 7 institutes in Nagano prefecture. Among them, we selected and analyzed 91 super elderly PAD patients (≥80 years-old) and divided them into two groups:those with moderate or higher frailty (Clinical Frailty Scale (CFS) ≥6, n=28) and those without (CFS ≤5, n=63). The primary endpoints were cardiovascular death and major adverse cardiovascular and limb events (MACLE), defined as a composite of cardiovascular death, myocardial infarction, stroke, admission for heart failure, major amputation and revascularization. Results The median follow-up period was 2.7 years. Freedom rate from cardiovascular death and MACLE were significantly lower among patients with moderate or higher frailty than among those without (47.0% vs. 58.0%, P=0.03; 39.1% vs. 68.5%, P<0.01). Conclusion The prognosis of super elderly patients with moderate or higher frailty is worse than those without. Funding Acknowledgement Type of funding source: None

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Major Limb Outcomes Following Lower Extremity Endovascular Revascularization in Patients With and Without Diabetes Mellitus

Journal of Endovascular Therapy ◽

10.1177/1526602817705135 ◽

2017 ◽

Vol 24 (3) ◽

pp. 376-382 ◽

Cited By ~ 20

Author(s):

Andrew N. Shammas ◽

Haekyung Jeon-Slaughter ◽

Shirling Tsai ◽

Houman Khalili ◽

Mujtaba Ali ◽

...

Keyword(s):

Diabetes Mellitus ◽

Lower Extremity ◽

Peripheral Artery Disease ◽

Endovascular Procedures ◽

Major Amputation ◽

Peripheral Artery ◽

Entire Study ◽

Endovascular Revascularization ◽

Increased Risk ◽

Artery Disease

Purpose: To determine whether diabetes mellitus has an independent impact on major limb outcomes at 1 year after endovascular treatment of lower extremity peripheral artery disease (PAD). Methods: The study involved 1906 consecutive patients (mean age 66 years; 1469 men) enrolled in the observational Excellence in Peripheral Artery Disease (XLPAD) registry ( ClinicalTrials.gov identifier NCT01904851) between January 2005 and October 2015 after undergoing index endovascular procedures in 2426 limbs for arterial occlusive disease. Patient outcomes included 12-month target limb amputation (above ankle) and target limb revascularization as well as all-cause death. Kaplan-Meier analysis and adjusted Cox proportional hazard models were used for time-to-event analysis of outcomes for the entire study sample as well as for the critical limb ischemia (CLI) and claudication subgroups. Results of the Cox regression models are reported as the hazard ratio (HR) and 95% confidence interval (CI). Results: Diabetics undergoing endovascular procedures had higher rates of comorbid conditions (p<0.001), CLI (p<0.001), heavily calcified lesions (p=0.002), multivessel disease (p=0.030), and fewer infrapopliteal runoff vessels (p<0.001). Regression analysis after adjusting for confounders revealed significantly higher target limb major amputation in diabetics compared with nondiabetics (HR 5.02, 95% CI 1.44 to 17.56, p=0.011). However, repeat revascularization rates were similar. When considering CLI and claudication subgroups, diabetes was associated with a nonsignificant increased risk of 12-month major amputation only for patients presenting with CLI (HR 3.48, 95% CI 0.97 to 12.51, p=0.056). Diabetes was also associated with an increased risk of 12-month all-cause mortality in the overall study sample (HR 4.64, 95% CI 2.01 to 10.70, p<0.001) and in the CLI subgroup (HR 14.15, 95% CI 3.16 to 63.32, p<0.001) but not in the claudication subgroup (HR 1.42, 95% CI 0.45 to 4.54, p=0.552). Conclusion: Diabetes increases the risk of major amputation and all-cause death at 12 months following endovascular revascularization in patients with symptomatic PAD. These risks are especially heightened in patients presenting with CLI.

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Incidence and Factors Associated With Major Amputation in Patients With Peripheral Artery Disease

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.119.006399 ◽

2020 ◽

Vol 13 (7) ◽

Author(s):

Chandler A. Long ◽

Hillary Mulder ◽

F. Gerry R. Fowkes ◽

Iris Baumgartner ◽

Jeffrey S. Berger ◽

...

Keyword(s):

Diabetes Mellitus ◽

Mortality Rate ◽

Peripheral Artery Disease ◽

Limb Ischemia ◽

Major Amputation ◽

Peripheral Artery ◽

Factors Associated ◽

Increased Risk ◽

Baseline Group ◽

Artery Disease

Background: Peripheral artery disease (PAD) is associated with increased risk of mortality, cardiovascular morbidity, and major amputation. Data on major amputation from a large randomized trial that included a substantial cohort of patients without critical limb ischemia (CLI) have not been described. The objective was to describe the incidence and types of amputations in the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) population, subcategorize amputations in the CLI versus no CLI cohorts, and describe the events surrounding major amputation. Methods and Results: Postrandomization major amputation was analyzed in the EUCLID trial. Patients were stratified by baseline CLI status. The occurrence of major amputation was ascertained and defined as the highest level. Perioperative events surrounding major amputation were obtained including acute limb ischemia, revascularization, and all-cause mortality. All variables were assessed for significance in univariable and multivariable models. The rate of major amputation during the course of the trial was 1.6% overall, 8.4% in the CLI at baseline group, and 1.2% in the no CLI at baseline group. The annualized rate of major amputation was 0.6% in PAD overall, 3.9% in the CLI at baseline group, and 0.5% in the no CLI at baseline group. Several factors were associated with increased risk of major amputation, including history of amputation, the presence of diabetes mellitus, baseline Rutherford category 4 to 6, and an ankle-brachial index <0.8. Factors associated with a lower risk for major amputation included prior statin use. The 30-day mortality rate after major amputation was 6.5% overall, 5.6% in the CLI at baseline group, and 6.8% in the no CLI at baseline group. The annual mortality rate following major amputation was 22.8% in the CLI at baseline group and 16.0% in the no CLI at baseline group. Conclusions: The risk factors for major amputation in EUCLID patients are similar to previous large registries’ reports except for diabetes mellitus in patients with CLI. The mortality following major amputation is lower in the EUCLID trial compared with registry data. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01732822.

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P1957Impact of fraility on the super elderly patients with peripheral artery disease

European Heart Journal ◽

10.1093/eurheartj/ehz748.0704 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

K Nishigawa ◽

A Nagae ◽

T Miura ◽

T Katoh ◽

M Hirabayashi ◽

...

Keyword(s):

Overall Survival ◽

Elderly Patients ◽

Peripheral Artery Disease ◽

Major Amputation ◽

Peripheral Artery ◽

Clinical Frailty Scale ◽

Multicenter Observational Study ◽

Primary Endpoints ◽

Artery Disease

Abstract Background The current consensus is that frail patients have high risks of mortality. However, it remains unclear whether frailty is associated with mortality risks in super-elderly patients with peripheral artery disease (PAD). Methods The I-PAD registry was a prospective multicenter observational study involving 12 institutions in Nagano prefecture in Japan. From July 2015 to July 2016, the I-PAD registry enrolled 371 consecutive PAD patients who had undergone endovascular therapy (EVT). Among them, we selected and analysed 109 PAD patients who were >80 years old when they had undergone EVT and divided them into two groups: those with frailty (Clinical Frailty Scale≥5, n=47) and those without frailty (Clinical Frailty Scale≤4, n=62). The primary endpoints were overall survival and major adverse limb events (MALE), defined as a composite of all-cause death, major amputation and revascularization. Results The median follow-up period was 1.58±0.3 years. Overall, 109 patients with a mean age of 84.8±4.0 years, of whom 63.3% were men, were included. Overall survival and freedom from MALE were significantly lower among patients with frailty than among those without frailty (60.5% vs. 91.6%, P<0.001; 51.4% vs. 87.5%, P<0.001; respectively). Conclusion The prognosis of super-elderly patients with frailty is worse than that of patients without frailty.

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