Brian Katona - Academia.edu (original) (raw)

Papers by Brian Katona

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy

A prospective surveillance program was initiated to determine the relative role of antibiotics co... more A prospective surveillance program was initiated to determine the relative role of antibiotics containing N‐methylthiotetrazole (NMTT) versus patient risk factors in producing antibiotic‐associated bleeding. Five hundred forty‐six critically ill patients with serum albumin 30 g/L or below were evaluated for evidence of a bleeding event as documented by clinical observation, hemoglobin changes, and transfusions. Bleeding events occurred in 16% of patients receiving an aminoglycoside combination, 10% receiving antibiotics with the NMTT side chain, and 14.5% receiving antibiotics not containing NMTT (p>0.05). The bleeding rate was highest in febrile patients with cancer (14.5%) and lowest in those with a suspected or documented abdominal infection (10%) (p=0.04), but within each patient group there was no difference among the antibiotics. We conclude that the use of NMTT‐containing antibiotics is not an independent risk factor for bleeding, but the role of severity of illness may be...

Journal of the American College of Cardiology

Journal of the American Heart Association

Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse c... more Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories. Methods and Results In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle‐brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revasculariz...

Circulation: Cardiovascular Interventions, 2021

Background: A reduced ankle-brachial index (ABI) is a measure of atherosclerosis and is associate... more 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: Base...

Diabetologia, 2018

Cardiovascular safety and efficacy of exenatide once-weekly in patients with moderate renal dysfu... more Cardiovascular safety and efficacy of exenatide once-weekly in patients with moderate renal dysfunction in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) A.F. Hernandez1, M.A. Bethel2, G.L. Bakris3, P. Merrill1, S.M. Gustavson4, B.G. Katona4, P. Ohman4, Y. Lokhnygina1, R.J. Mentz1, R.R. Holman2, for the EXSCEL Study Group; 1Duke Clinical Research Institute, Durham, USA, 2Diabetes Trials Unit, Oxford, UK, 3University of Chicago Medicine, Chicago, USA, 4AstraZeneca, Gaithersburg, USA.

Circulation, 2020

Background/Introduction: Amputation is a major morbidity of peripheral artery disease (PAD). Alth... more Background/Introduction: Amputation is a major morbidity of peripheral artery disease (PAD). Although traditionally attributed to ischemia, the multifactorial nature is increasingly recognized, particularly in those with concomitant diabetes mellitus (DM). Elucidating the drivers of amputation in PAD with and without DM may be important in developing strategies for prevention. Purpose: To elucidate the primary drivers of amputations in patients with PAD with and without DM. Methods: EUCLID randomized 13,885 patients with PAD. Investigators prospectively reported all amputations. In this post-hoc analysis, amputations (major – ankle and above, minor – distal to ankle) were retrospectively adjudicated using safety data when available to characterize the drivers including infection, ischemia, or multifactorial. Etiologies were evaluated by DM status at baseline. Results: A total of 415 patients (3% of total) underwent 533 (260 major and 263 minor) amputations over a median of 30 months...

Diabetes Care, 2019

OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascul... more OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI −0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70–1.07]). N...

Diabetic Medicine, 2021

Although models exist to predict amputation among people with type 2 diabetes with foot ulceratio... more Although models exist to predict amputation among people with type 2 diabetes with foot ulceration or infection, we aimed to develop a prediction model for a broader range of major adverse limb events (MALE)—including gangrene, revascularization and amputation—among individuals with type 2 diabetes.

European Journal of Vascular and Endovascular Surgery, 2019

Introduction-Vein is regarded superior to artificial graft in peripheral arterial bypass surgery.... more Introduction-Vein is regarded superior to artificial graft in peripheral arterial bypass surgery. However, often this option is limited due to previous bypass, stripping, or poor quality of the ipsilateral greater saphenous vein (GSV). In this case the contralateral GSV or arm veins are preferred alternative vein grafts. The lesser saphenous vein (LSV) is a forgotten, but attractive alternative. There are only limited reports on the use of LSV as a bypass conduit available. We report our experience using LSV as part of an all autologous vein bypass policy. Methods-Retrospective analysis of a consecutive patient series treated at an academic tertiary referral center from 1/98 e 2/17. Results-120 operations in 118 patients using LSV were performed. Indications were peripheral arterial occlusive disease (n¼91; Rutherford classification 3: n¼11; 4: n¼21; 5,6: n¼59), acute ischemia (n¼14), popliteal artery aneurysm (n¼12), and bypass revisions (n¼3). Risk factors for vascular disease included hypertension (71%), hyperlipidemia (50%), diabetes (38%), coronary heart disease (37%), current smoking (20%). Preoperative vein mapping was performed in all patients. The vein was harvested via a dorsolateral approach with a continuous incision. In 97 patients the LSV was used as the entire conduit whereas in the remaining 23 patients it was spliced either to another vein (GSV n ¼ 14, arm vein n ¼5) or prosthetic grafts (n ¼ 4). Distal target artery was popliteal (n¼49), tibial (n¼36) or inframalleolar (n¼35). Median Follow-up was 19.3 months (2 mos-13,6 yrs). Patients receiving a primary bypass (n ¼ 59) versus patients receiving redo bypass (n ¼ 61) showed significantly better patency. Primary patency rates after 1, 3, and 5 years were 70%, 63% and 55% in the primary bypass group and respectively 50%, 41% and 31% in the redo bypass group. Secondary patency rates in the primary bypass group after 1, 3, and 5 years were 84%, 77%, and 72% respectively and 56%, 42%, and 38% in the redo group. Difference: primary patency (p ¼ 0,026), secondary patency (p ¼ 0,001). Limb salvage (p ¼ 0,005) was also significantly better in primary bypass patients, whereas survival (p ¼ 0,7) did not differ significantly. No independent risk factor could be identified for graft failure, limb salvage and survival in univariate analysis. Conclusion-The LSV is a valuable and versatile alternative vein graft in peripheral bypass surgery, especially for shorter grafts. Preoperative vein mapping is mandatory to rule out unsuitable veins before surgery and to avoid extensive dissection in the calf. The LSV vein should not be underestimated as a valuable option in bypass surgery as it has a high utilization rate, is relatively easy to harvest in regional anesthesia and achieves excellent long-term results in selected patients.

Journal of the American College of Cardiology, 2020

Background: Polyvascular disease (PVD) and diabetes mellitus (DM) are additive for the risk of ma... more Background: Polyvascular disease (PVD) and diabetes mellitus (DM) are additive for the risk of major adverse cardiovascular events (MACE) in patients with coronary disease. Whether this risk relationship for MACE as well as for amputation is also true in symptomatic peripheral artery disease (PAD) is not well defined. Methods: Patients with PAD in EUCLID were evaluated for the risk of MACE (CV death, myocardial infarction, or stroke) and major amputation according to baseline PVD, DM, or both. Associations between PVD, DM and outcomes were adjusted using Cox PH models.

Circulation: Cardiovascular Interventions, 2019

Background: The relationship between invasive vascular procedures and bleeding in patients with p... more Background: The relationship between invasive vascular procedures and bleeding in patients with peripheral artery disease has not been well described in the literature. This post hoc analysis from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) aimed to describe the incidence of major and minor postprocedural bleeding and characterize the timing and severity of bleeding events relative to the procedure. Methods: EUCLID was a multicenter, randomized controlled trial of 13 885 patients with symptomatic peripheral artery disease that tested the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events. A total of 2661 patients underwent 3062 coronary revascularization, peripheral revascularization, and amputation during the study. The primary safety end point was Thrombolysis in Myocardial Infarction major or minor bleeding. All bleeding events were formally adjudicated by a clinical end point class...

Journal of the American College of Cardiology, 2019

Circulation, 2019

Background: Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascul... more 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)...

Journal of the American College of Cardiology, 2018

Background Rates and predictors of major bleeding in patients with peripheral artery disease (PAD... more Background Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events. Methods EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined. Results TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and β-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P b .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event. Conclusions In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and β-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

Journal of the American College of Cardiology, 2018

Background: Cytochrome P450 2C19 (CYP2C19) is a hepatic enzyme involved in metabolism of clopidog... more Background: Cytochrome P450 2C19 (CYP2C19) is a hepatic enzyme involved in metabolism of clopidogrel to its active metabolite. Polymorphisms with 2 loss-of-function (LOF) alleles lead to poor metabolism of clopidogrel, but little is known about the effects of both heterozygous state for LOF and gain-of-function (GOF) mutations in peripheral artery disease (PAD). Methods: We examined the genetic status of 13,885 randomized EUCLID patients. Those with homozygous LOF CYP2C19 were excluded prior to randomization (n=616). Patients with normal alleles, heterozygous for LOF and GOF, and homozygous for GOF were compared for baseline characteristics and clinical outcomes: adjudicated cardiovascular death, MI, and ischemic stroke. The primary safety endpoint was major bleeding. Results: Patients excluded with homozygous LOF were most frequently from the US (16%), Japan (12.5%), and China (10.9%). Median age was 66 years; and patients with LOF/GOF or LOF/normal alleles more often had prior stroke, were from Asia, and less often diabetic compared with normal allele patients. The primary efficacy and safety endpoints occurred at the same frequency in clopidogrel-treated patients with heterozygous LOF/GOF alleles, and homozygous GOF alleles compared with normal CYP2C19 patients (Table). Conclusion: In patients with symptomatic PAD on clopidogrel, heterozygous LOF, and GOF CYP2C19 mutations were associated with similar long-term cardiovascular outcomes compared with normal patients.

Journal of the American College of Cardiology, 2019

Background: Large studies in patients with diabetes mellitus (DM) have identified agents that low... more Background: Large studies in patients with diabetes mellitus (DM) have identified agents that lower major adverse cardiovascular (CV) event (MACE) rates, but certain agents increase rates of lower extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of DM and risk for LEA, thus prompting this subgroup analysis of EXSCEL. Methods: EXSCEL tested the effects of the GLP-1 agonist exenatide vs. placebo on the rates of the primary composite MACE endpoint (CV death, myocardial infarction, or stroke). In this post hoc analysis, we assessed the association of PAD with rates of MACE, LEA, and the effects of exenatide vs. placebo in patients with and without PAD. Results: EXSCEL included 2,800 patients with PAD. Patients with PAD had higher unadjusted rates of MACE compared with patients without PAD (uHR 1.36, 95% CI 1.21-1.52; P <0.001); there was no statistically significant difference after adjusting for baseline characteristics (aHR 1.07, 95% CI 0.95-1.20; P=0.29). PAD patients had higher all-cause mortality (aHR 1.39, 95% CI 1.21-1.61; P <0.001), and more LEA (aHR 5.02, 95% CI 3.83-6.57; P<0.001). Exenatide treatment effects vs. placebo for the primary composite, key secondary, and limb-specific endpoints (Figure) did not differ based on PAD status. Conclusion: EXSCEL participants with PAD had higher crude rates of MACE, all-cause mortality and LEA compared with those without PAD. There were no differential rates of MACE or LEA comparing exenatide with placebo.

JAMA Network Open, 2018

IMPORTANCE The effect of polyvascular disease on cardiovascular outcomes in the background of per... more IMPORTANCE The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear. OBJECTIVE To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease. DESIGN, SETTING, AND PARTICIPANTS In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31,

Journal of the American College of Cardiology, 2017

Circulation, Jan 13, 2016

On behalf of the International Steering Committee and Investigators of the EUCLID Trial ORIGINAL ... more On behalf of the International Steering Committee and Investigators of the EUCLID Trial ORIGINAL RESEARCH ARTICLE BACKGROUND: In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for longterm management is unknown. METHODS: The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. RESULTS: Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor-versus clopidogrel-treated patients were found for the primary efficacy end point (11.

The New England journal of medicine, Jan 5, 2017

Background Peripheral artery disease is considered to be a manifestation of systemic atherosclero... more Background Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. Methods In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median ...

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy

A prospective surveillance program was initiated to determine the relative role of antibiotics co... more A prospective surveillance program was initiated to determine the relative role of antibiotics containing N‐methylthiotetrazole (NMTT) versus patient risk factors in producing antibiotic‐associated bleeding. Five hundred forty‐six critically ill patients with serum albumin 30 g/L or below were evaluated for evidence of a bleeding event as documented by clinical observation, hemoglobin changes, and transfusions. Bleeding events occurred in 16% of patients receiving an aminoglycoside combination, 10% receiving antibiotics with the NMTT side chain, and 14.5% receiving antibiotics not containing NMTT (p>0.05). The bleeding rate was highest in febrile patients with cancer (14.5%) and lowest in those with a suspected or documented abdominal infection (10%) (p=0.04), but within each patient group there was no difference among the antibiotics. We conclude that the use of NMTT‐containing antibiotics is not an independent risk factor for bleeding, but the role of severity of illness may be...

Journal of the American College of Cardiology

Journal of the American Heart Association

Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse c... more Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories. Methods and Results In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle‐brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revasculariz...

Circulation: Cardiovascular Interventions, 2021

Background: A reduced ankle-brachial index (ABI) is a measure of atherosclerosis and is associate... more 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: Base...

Diabetologia, 2018

Cardiovascular safety and efficacy of exenatide once-weekly in patients with moderate renal dysfu... more Cardiovascular safety and efficacy of exenatide once-weekly in patients with moderate renal dysfunction in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) A.F. Hernandez1, M.A. Bethel2, G.L. Bakris3, P. Merrill1, S.M. Gustavson4, B.G. Katona4, P. Ohman4, Y. Lokhnygina1, R.J. Mentz1, R.R. Holman2, for the EXSCEL Study Group; 1Duke Clinical Research Institute, Durham, USA, 2Diabetes Trials Unit, Oxford, UK, 3University of Chicago Medicine, Chicago, USA, 4AstraZeneca, Gaithersburg, USA.

Circulation, 2020

Background/Introduction: Amputation is a major morbidity of peripheral artery disease (PAD). Alth... more Background/Introduction: Amputation is a major morbidity of peripheral artery disease (PAD). Although traditionally attributed to ischemia, the multifactorial nature is increasingly recognized, particularly in those with concomitant diabetes mellitus (DM). Elucidating the drivers of amputation in PAD with and without DM may be important in developing strategies for prevention. Purpose: To elucidate the primary drivers of amputations in patients with PAD with and without DM. Methods: EUCLID randomized 13,885 patients with PAD. Investigators prospectively reported all amputations. In this post-hoc analysis, amputations (major – ankle and above, minor – distal to ankle) were retrospectively adjudicated using safety data when available to characterize the drivers including infection, ischemia, or multifactorial. Etiologies were evaluated by DM status at baseline. Results: A total of 415 patients (3% of total) underwent 533 (260 major and 263 minor) amputations over a median of 30 months...

Diabetes Care, 2019

OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascul... more OBJECTIVE To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). RESEARCH DESIGN AND METHODS Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). RESULTS EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI −0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70–1.07]). N...

Diabetic Medicine, 2021

Although models exist to predict amputation among people with type 2 diabetes with foot ulceratio... more Although models exist to predict amputation among people with type 2 diabetes with foot ulceration or infection, we aimed to develop a prediction model for a broader range of major adverse limb events (MALE)—including gangrene, revascularization and amputation—among individuals with type 2 diabetes.

European Journal of Vascular and Endovascular Surgery, 2019

Introduction-Vein is regarded superior to artificial graft in peripheral arterial bypass surgery.... more Introduction-Vein is regarded superior to artificial graft in peripheral arterial bypass surgery. However, often this option is limited due to previous bypass, stripping, or poor quality of the ipsilateral greater saphenous vein (GSV). In this case the contralateral GSV or arm veins are preferred alternative vein grafts. The lesser saphenous vein (LSV) is a forgotten, but attractive alternative. There are only limited reports on the use of LSV as a bypass conduit available. We report our experience using LSV as part of an all autologous vein bypass policy. Methods-Retrospective analysis of a consecutive patient series treated at an academic tertiary referral center from 1/98 e 2/17. Results-120 operations in 118 patients using LSV were performed. Indications were peripheral arterial occlusive disease (n¼91; Rutherford classification 3: n¼11; 4: n¼21; 5,6: n¼59), acute ischemia (n¼14), popliteal artery aneurysm (n¼12), and bypass revisions (n¼3). Risk factors for vascular disease included hypertension (71%), hyperlipidemia (50%), diabetes (38%), coronary heart disease (37%), current smoking (20%). Preoperative vein mapping was performed in all patients. The vein was harvested via a dorsolateral approach with a continuous incision. In 97 patients the LSV was used as the entire conduit whereas in the remaining 23 patients it was spliced either to another vein (GSV n ¼ 14, arm vein n ¼5) or prosthetic grafts (n ¼ 4). Distal target artery was popliteal (n¼49), tibial (n¼36) or inframalleolar (n¼35). Median Follow-up was 19.3 months (2 mos-13,6 yrs). Patients receiving a primary bypass (n ¼ 59) versus patients receiving redo bypass (n ¼ 61) showed significantly better patency. Primary patency rates after 1, 3, and 5 years were 70%, 63% and 55% in the primary bypass group and respectively 50%, 41% and 31% in the redo bypass group. Secondary patency rates in the primary bypass group after 1, 3, and 5 years were 84%, 77%, and 72% respectively and 56%, 42%, and 38% in the redo group. Difference: primary patency (p ¼ 0,026), secondary patency (p ¼ 0,001). Limb salvage (p ¼ 0,005) was also significantly better in primary bypass patients, whereas survival (p ¼ 0,7) did not differ significantly. No independent risk factor could be identified for graft failure, limb salvage and survival in univariate analysis. Conclusion-The LSV is a valuable and versatile alternative vein graft in peripheral bypass surgery, especially for shorter grafts. Preoperative vein mapping is mandatory to rule out unsuitable veins before surgery and to avoid extensive dissection in the calf. The LSV vein should not be underestimated as a valuable option in bypass surgery as it has a high utilization rate, is relatively easy to harvest in regional anesthesia and achieves excellent long-term results in selected patients.

Journal of the American College of Cardiology, 2020

Background: Polyvascular disease (PVD) and diabetes mellitus (DM) are additive for the risk of ma... more Background: Polyvascular disease (PVD) and diabetes mellitus (DM) are additive for the risk of major adverse cardiovascular events (MACE) in patients with coronary disease. Whether this risk relationship for MACE as well as for amputation is also true in symptomatic peripheral artery disease (PAD) is not well defined. Methods: Patients with PAD in EUCLID were evaluated for the risk of MACE (CV death, myocardial infarction, or stroke) and major amputation according to baseline PVD, DM, or both. Associations between PVD, DM and outcomes were adjusted using Cox PH models.

Circulation: Cardiovascular Interventions, 2019

Background: The relationship between invasive vascular procedures and bleeding in patients with p... more Background: The relationship between invasive vascular procedures and bleeding in patients with peripheral artery disease has not been well described in the literature. This post hoc analysis from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) aimed to describe the incidence of major and minor postprocedural bleeding and characterize the timing and severity of bleeding events relative to the procedure. Methods: EUCLID was a multicenter, randomized controlled trial of 13 885 patients with symptomatic peripheral artery disease that tested the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events. A total of 2661 patients underwent 3062 coronary revascularization, peripheral revascularization, and amputation during the study. The primary safety end point was Thrombolysis in Myocardial Infarction major or minor bleeding. All bleeding events were formally adjudicated by a clinical end point class...

Journal of the American College of Cardiology, 2019

Circulation, 2019

Background: Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascul... more 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)...

Journal of the American College of Cardiology, 2018

Background Rates and predictors of major bleeding in patients with peripheral artery disease (PAD... more Background Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events. Methods EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined. Results TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and β-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P b .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event. Conclusions In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and β-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

Journal of the American College of Cardiology, 2018

Background: Cytochrome P450 2C19 (CYP2C19) is a hepatic enzyme involved in metabolism of clopidog... more Background: Cytochrome P450 2C19 (CYP2C19) is a hepatic enzyme involved in metabolism of clopidogrel to its active metabolite. Polymorphisms with 2 loss-of-function (LOF) alleles lead to poor metabolism of clopidogrel, but little is known about the effects of both heterozygous state for LOF and gain-of-function (GOF) mutations in peripheral artery disease (PAD). Methods: We examined the genetic status of 13,885 randomized EUCLID patients. Those with homozygous LOF CYP2C19 were excluded prior to randomization (n=616). Patients with normal alleles, heterozygous for LOF and GOF, and homozygous for GOF were compared for baseline characteristics and clinical outcomes: adjudicated cardiovascular death, MI, and ischemic stroke. The primary safety endpoint was major bleeding. Results: Patients excluded with homozygous LOF were most frequently from the US (16%), Japan (12.5%), and China (10.9%). Median age was 66 years; and patients with LOF/GOF or LOF/normal alleles more often had prior stroke, were from Asia, and less often diabetic compared with normal allele patients. The primary efficacy and safety endpoints occurred at the same frequency in clopidogrel-treated patients with heterozygous LOF/GOF alleles, and homozygous GOF alleles compared with normal CYP2C19 patients (Table). Conclusion: In patients with symptomatic PAD on clopidogrel, heterozygous LOF, and GOF CYP2C19 mutations were associated with similar long-term cardiovascular outcomes compared with normal patients.

Journal of the American College of Cardiology, 2019

Background: Large studies in patients with diabetes mellitus (DM) have identified agents that low... more Background: Large studies in patients with diabetes mellitus (DM) have identified agents that lower major adverse cardiovascular (CV) event (MACE) rates, but certain agents increase rates of lower extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of DM and risk for LEA, thus prompting this subgroup analysis of EXSCEL. Methods: EXSCEL tested the effects of the GLP-1 agonist exenatide vs. placebo on the rates of the primary composite MACE endpoint (CV death, myocardial infarction, or stroke). In this post hoc analysis, we assessed the association of PAD with rates of MACE, LEA, and the effects of exenatide vs. placebo in patients with and without PAD. Results: EXSCEL included 2,800 patients with PAD. Patients with PAD had higher unadjusted rates of MACE compared with patients without PAD (uHR 1.36, 95% CI 1.21-1.52; P <0.001); there was no statistically significant difference after adjusting for baseline characteristics (aHR 1.07, 95% CI 0.95-1.20; P=0.29). PAD patients had higher all-cause mortality (aHR 1.39, 95% CI 1.21-1.61; P <0.001), and more LEA (aHR 5.02, 95% CI 3.83-6.57; P<0.001). Exenatide treatment effects vs. placebo for the primary composite, key secondary, and limb-specific endpoints (Figure) did not differ based on PAD status. Conclusion: EXSCEL participants with PAD had higher crude rates of MACE, all-cause mortality and LEA compared with those without PAD. There were no differential rates of MACE or LEA comparing exenatide with placebo.

JAMA Network Open, 2018

IMPORTANCE The effect of polyvascular disease on cardiovascular outcomes in the background of per... more IMPORTANCE The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear. OBJECTIVE To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease. DESIGN, SETTING, AND PARTICIPANTS In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31,

Journal of the American College of Cardiology, 2017

Circulation, Jan 13, 2016

On behalf of the International Steering Committee and Investigators of the EUCLID Trial ORIGINAL ... more On behalf of the International Steering Committee and Investigators of the EUCLID Trial ORIGINAL RESEARCH ARTICLE BACKGROUND: In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for longterm management is unknown. METHODS: The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. RESULTS: Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor-versus clopidogrel-treated patients were found for the primary efficacy end point (11.

The New England journal of medicine, Jan 5, 2017

Background Peripheral artery disease is considered to be a manifestation of systemic atherosclero... more Background Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. Methods In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median ...