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Additional file 1.

Supplemental material, sj-pdf-2-ctj-10.1177_17407745211038512 for Clinical trial site identification practices and the use of electronic health records in feasibility evaluations: An interview study in the Nordic countries by Niina Laaksonen, Mia Bengtström, Anna Axelin, Juuso Blomster, Mika Scheinin and Risto Huupponen in Clinical Trials

OBJECTIVE Amputation remains a frequent and feared outcome in patients with peripheral artery disease (PAD). Although typically characterized as major or minor on the extent of tissue loss, the etiologies and outcomes after amputation by extent are not well-understood. In addition, emerging data suggest that the drivers and outcomes of amputation in patients with PAD may differ in those with and without diabetes mellitus (DM). METHODS The EUCLID trial randomized 13,885 patients with symptomatic PAD, including 5345 with concomitant diabetes, to ticagrelor or clopidogrel and followed them for long-term outcomes. Amputations were prospectively reported by trial investigators. Their primary and contributing drivers were adjudicated using safety data, including infection, ischemia, or multifactorial etiologies. Outcomes following major and minor amputations were analyzed, including recurrent amputation, major adverse limb events, adverse cardiovascular events, and mortality. Multivariable logistic regression models were used to identify independent predictors of minor amputations. Analyses were performed overall and stratified by the presence or absence of DM at baseline. RESULTS Of the patients randomized, 398 (2.9%) underwent at least one lower extremity nontraumatic amputation, for a total of 511 amputations (255 major and 256 minor) over a median of 30��months. A history of minor amputation was the strongest independent predictor for a subsequent minor amputation (odds ratio, 7.29; 95% confidence interval, 5.17-10.30; P��< .001) followed by comorbid DM (odds ratio, 4.60; 95% confidence interval, 3.16-6.69; P��< .001). Compared with patients who had a major amputation, those with a minor amputation had similar rates of subsequent major amputation (12.2% vs 13.6%), major adverse limb events (15.1% vs 14.9%), and major adverse cardiovascular events (17.6% vs 16.3%). Ischemia alone was the primary driver of amputation (51%), followed by infection alone (27%), and multifactorial etiologies (22%); however, infection was the most frequent driver in those with DM (58%) but not in those without DM (15%). CONCLUSIONS Outcomes after amputation remain poor regardless of whether they are categorized as major or minor. The pattern of amputation drivers in PAD differs by history of DM, with infection being the dominant etiology in those with DM and ischemia in those without DM. Greater focus is needed on the prognostic importance of minor amputation and of the multifactorial etiologies of amputation in PAD. Nomenclature with anatomical description of amputations and eliminating terms "major" or "minor" would seem appropriate.

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X211038620 for World regional differences in outcomes for patients with peripheral artery disease: Insights from the EUCLID trial by Lars Norgren, Rebecca North, Iris Baumgartner, Jeffrey S Berger, Juuso I Blomster, William R Hiatt, W Schuyler Jones, Brian G Katona, Kenneth W Mahaffey, Hillary Mulder, Manesh R Patel, Frank W Rockhold and F Gerry R Fowkes in Vascular Medicine

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X211017641 for Impact of chronic kidney disease on hemoglobin among patients with peripheral artery disease treated with P2Y12 inhibitors: Insights from the EUCLID trial by Judith Hsia, Sarah T Kavanagh, Charles W Hopley, Iris Baumgartner, Jeffrey S Berger, Gerry R Fowkes, W Schuyler Jones, Kenneth W Mahaffey, Lars Norgren, Manesh R Patel, Frank Rockhold, Juuso Blomster, Brian G Katona, William R Hiatt and Marc P Bonaca in Vascular Medicine

Supplemental material, sj-pdf-1-ctj-10.1177_17407745211038512 for Clinical trial site identification practices and the use of electronic health records in feasibility evaluations: An interview study in the Nordic countries by Niina Laaksonen, Mia Bengtström, Anna Axelin, Juuso Blomster, Mika Scheinin and Risto Huupponen in Clinical Trials

Patients with chronic kidney disease may develop new or more severe anemia when treated with antiplatelet agents due to blood loss in conjunction with impaired erythropoiesis. Because anemia independently predicts limb amputation and mortality among patients with peripheral artery disease (PAD), we evaluated the relationship between estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) levels in the EUCLID trial in which patients with symptomatic PAD were randomized to ticagrelor or clopidogrel. At baseline, 9025, 1870, and 1000 patients had eGFR ⩾ 60, 45-59, and < 45 mL/min/1.73 m2, respectively. The mean fall in Hb during the trial was 0.46 ± 1.68 g/dL and did not differ by baseline eGFR category, although Hb fall ⩾ 10% was more frequent among patients with lower eGFR (p for trend < 0.0001). On-study treatment with iron, erythropoiesis-stimulating agents, and/or red blood cell transfusion was reported for 479 (5.3%), 165 (8.8%), and 129 (12.9%) patients in the three eGFR categories, respectively (p for trend < 0.0001). After adjustment for baseline and post-randomization effects, those not receiving anemia treatment had a smaller reduction in Hb from baseline than those receiving anemia treatment (p < 0.0001). Other determinants of Hb reduction included absence of on-study myocardial infarction, coronary or peripheral revascularization, residence outside North America, male sex, and baseline eGFR. We conclude that among patients with PAD treated with P2Y12 inhibitors, lower baseline eGFR was associated with a greater reduction in Hb. ClinicalTrials.gov Identifier: NCT01732822.

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

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