Skip main navigation

Impact of Procedural Bleeding in Peripheral Artery Disease

An Analysis From EUCLID Trial
Originally publishedhttps://doi.org/10.1161/CIRCINTERVENTIONS.119.008069Circulation: Cardiovascular Interventions. 2019;12:e008069

    Abstract

    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 classification group.

    Results:

    Major bleeding events most often occurred ≤7 days following the procedure. The incidence of Thrombolysis in Myocardial Infarction major or minor bleeding ≤7 days following peripheral revascularization (3.3%; 95% CI, 2.5%–4.1%) was similar to rates after coronary revascularization (4.0%; 95% CI, 2.6%–5.4%) and lower extremity amputation (2.3%; 95% CI, 0.8%–3.8%). The severity of bleeding events (as graded by drop in hemoglobin, need for transfusion, bleeding in a critical location, and fatal bleeding) was also similar following peripheral, coronary revascularization, and lower extremity amputation.

    Conclusions:

    The incidence of Thrombolysis in Myocardial Infarction major/minor bleeding following peripheral revascularization is comparable to rates after coronary revascularization and lower extremity amputation, and the majority of bleeding events occur within 7 days following the procedure. The severity of periprocedural bleeding is also similar after procedures, with the most frequently adjudicated reason being a drop in hemoglobin ≥2 g/dL. Future studies should be performed to enhance our understanding of bleeding risk related to revascularization and amputation procedures in peripheral artery disease patients.

    WHAT IS KNOWN

    • Peripheral revascularization is a class I recommendation for patients with critical limb ischemia and for those with intermittent claudication who have failed medical therapy and exercise training and performance continues to increase.

    • Although risk of bleeding has been studied extensively in coronary revascularization, there have been limited studies evaluating the occurrence, severity, and impact of periprocedural bleeding in patients with peripheral artery disease.

    WHAT THE STUDY ADDS

    • This is the largest peripheral artery disease cohort study analyzing procedural bleeding that has been performed; there were 3 main findings.

    • The majority of periprocedural bleeding occurred within 7 days and was similar between peripheral revascularization, coronary revascularization, and amputation.

    • The severity of bleeding events (as graded by drop in hemoglobin, need for transfusion, bleeding in a critical location, and fatal bleeding) was also similar following peripheral, coronary revascularization, and lower extremity amputation.

    Introduction

    Peripheral artery disease (PAD) is a manifestation of atherosclerosis that affects the lower extremities. It is a major health concern affecting >200 million people worldwide.1 Many patients with PAD have functional limitations and are at high risk of poor cardiovascular outcomes, including myocardial infarction, ischemic stroke, amputation, and death.2 Peripheral revascularization is a class I recommendation for patients with critical limb ischemia and for those with intermittent claudication who have failed medical therapy and exercise training.1 While the performance of peripheral revascularization continues to increase, the occurrence, severity, and impact of periprocedural bleeding has not been well studied in patients with PAD.

    In contrast, the risk of bleeding has been studied extensively in patients with coronary artery disease undergoing coronary artery bypass graft surgery and percutaneous coronary intervention. Major bleeding postpercutaneous coronary intervention has been shown to be independently associated with increases in both short- and long-term risk of mortality and major adverse cardiovascular events.3–5 Previous studies have also demonstrated the association of antiplatelet and antithrombotic medications with an increased risk of bleeding in patients with PAD.6–8 Although some patients in these studies did undergo endovascular revascularization, the relationship between procedure and bleeding has not been prospectively assessed. A retrospective analysis from the Society of Vascular Surgery Vascular Quality Initiative evaluated the incidence and risk factors for access site hematomas and pseudoaneurysms after peripheral vascular interventions, reporting that access site complications occurred in 3.5% of procedures and of those, 9.7% were moderate requiring transfusion, 5.4% were moderate requiring thrombin injection, and 10.5% were severe requiring surgery.9 Importantly, these events were not adjudicated and the timing of events was not reported.

    The EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) was a large, multicenter, multinational study of patients with symptomatic PAD.10 A number of revascularization procedures and associated bleeding events occurred during study conduct. The ascertainment process for bleeding events was broad, and all bleeding events were adjudicated by a clinical end point classification group. The first aim of this report is to describe the incidence of both major and minor periprocedural bleeding events in patients with PAD undergoing peripheral revascularization, coronary revascularization, and lower extremity amputation. The second aim is to characterize the timing of bleeding events relative to the procedure. The third aim is to characterize the severity of bleeding events using formal adjudicated results.

    Methods

    The data that support the findings of this study are available from the corresponding author on reasonable request.

    Study Design and Population

    EUCLID was a double-blind, active-comparator, randomized controlled trial to test the hypothesis that monotherapy with ticagrelor would be superior to clopidogrel in preventing major adverse cardiovascular events (myocardial infarction, ischemic stroke, cardiovascular death) in patients with symptomatic PAD. Details from the EUCLID study have been previously published. From December 2012 through March 2014, a total of 16 237 patients were enrolled and screened for randomization at 811 clinical centers in 28 countries. A total of 13 855 patients underwent randomization and were followed for the occurrence of composite primary events through May 9, 2016.10

    Patients were randomized in a 1:1 fashion to receive either ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Randomization was performed via interactive voice-response or Web-response system. As the treatment effect on the primary end point was nearly identical between randomized groups, all participants were pooled for these analyses. The study protocol was approved by appropriate ethics committees at participating sites, and all patients provided written informed consent.

    End Points

    The end points for this analysis include (1) major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) criteria and (2) TIMI major/minor bleeding. The definition of procedural bleeding is a TIMI major/minor bleeding at the time of or following coronary revascularization (percutaneous coronary intervention and coronary artery bypass graft surgery), peripheral revascularization (lower extremity endovascular and surgical procedures), and lower extremity amputation. The performance of these procedures was allowed during the course of the study and was at the discretion of local clinical experts. All procedures and bleeding events were site-reported in an electronic Web-based capture system with submission of supporting source documentation where applicable. Automatic triggers were additionally used to identify potential bleeding events with a drop in hemoglobin. Adjudication of bleeding events was performed according to definitions in the EUCLID Clinical End points Classification Charter with board certification in cardiology as a prerequisite.

    Statistical Analysis

    The analysis population included randomized participants in the EUCLID trial. We analyzed all events that occurred during the study and used P to report intergroup comparisons. Baseline characteristics were summarized by mean and SD, median and 25th, 75th percentiles for continuous variables, and counts and percentages for categorical variables. Timing of TIMI major and minor bleeding events following procedures was analyzed for participants who had peripheral revascularization, coronary revascularization (coronary artery bypass graft or percutaneous coronary intervention), and lower extremity amputation. Bleeding event rates and 95% CIs at 7, 30, 180 days, 1-year post-procedure, and up to 900 days were estimated using the Kaplan-Meier method. Cumulative event rates for bleeding were also compared using the log-rank test. For participants with multiple events or multiple procedures, only the first event following the first procedure of interest was analyzed. Further analyses using the International Society on Thrombosis and Haemostasis (ISTH) classification were carried out to investigate the severity of bleeding events within 30 days of a procedure because TIMI subcategories did not require grading the severity of bleeding events (eg, decrease in hemoglobin ≥2 g/dL, transfusion of ≥2 units of packed red blood cells, symptomatic bleed in a critical location, and fatal bleeding). Kaplan-Meier estimated event rates of ISTH major bleeding are reported for participants with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of whole blood or red cells, symptomatic bleed in a critical location, and fatal bleeding.

    All analyses were conducted with the use of SAS software version 9.0 or higher (SAS Institute).

    Results

    Of the 2661 patients undergoing peripheral/coronary revascularization or lower extremity amputation (a total of 3062 procedures were performed), 218 patients experienced TIMI major or minor bleeding periprocedurally. If the patient had both procedures, the bleeding associated with each individual procedure is reported and then analyzed separately. A diagram showing the patient flow from the overall EUCLID trial is shown in Figure 1. Demographic and clinical characteristics of patients according to whether or not they had TIMI major or minor bleeding are shown in Table 1. Patients with major or minor periprocedural bleeding events were more commonly older, female, enrolled in North America, and were more likely to have a history of smoking, coronary or carotid revascularization, coronary artery disease, or dyslipidemia. These patients were also more commonly on antiplatelet, statin, or β-blocker therapy at baseline. In addition, bleeding events were more common in patients randomized to ticagrelor over clopidogrel; however, the increase was not statistically significant (8.1% versus 7.6%; P=0.62). Finally, these patients more commonly had disease in > 1 vascular bed (coronary, cerebrovascular, lower extremity).

    Table 1. Baseline Characteristics of Patients With and Without TIMI Major or Minor Bleeding Events Post-Procedure (Coronary and/or Peripheral Revascularization and Lower Extremity Amputation)

    CharacteristicPatients With TIMI Major or Minor Bleeding Event(s) (N=218)Patients Without TIMI Major or Minor Bleeding Event(s) (N=2452)P Value of Association of Baseline Characteristics to TIMI Major or Minor Bleeding
    Age, median (25th, 75th), y67.0 (61.0, 73.0)66.0 (60.0, 72.0)0.3530
    Female sex76 (36.4%)660 (26.9%)0.0035
    Geographic region<0.0001
     Europe75 (35.9%)1216 (49.6%)
     Asia14 (6.7%)220 (9.0%)
     North America110 (52.6%)814 (33.2%)
     Central/South America10 (4.8%)202 (8.2%)
    History of coronary or carotid revascularization86 (41.1%)907 (37.0%)0.1871
    History of coronary stent implantation43 (20.6%)491 (20.0%)0.8369
    Prior CABG41 (19.6%)387 (15.8%)0.1407
    Prior TIA21 (10.0%)110 (4.5%)0.0004
    Dyslipidemia169 (80.9%)1978 (80.7%)0.8938
    Medications
     Prior antiplatelet therapy191 (91.4%)2197 (89.6%)0.3781
     Statins163 (78.0%)1871 (76.3%)0.5945
     Beta-blockers107 (51.2%)1140 (46.5%)0.1426
     Clopidogrel95 (45.5%)985 (40.2%)0.1572
     PPIs62 (29.7%)563 (23.0%)0.0244
    Limb symptoms0.5952
     Asymptomatic45 (21.5%)473 (19.3%)
     Mild/moderate claudication99 (47.4%)1201 (49.0%)
     Severe claudication47 (22.5%)626 (25.5%)
     CLI18 (8.6%)151 (6.2%)
    Inclusion criteria for randomization0.3213
     ABI/TBI criterion51 (24.4%)687 (28.0%)
     Prior revascularization158 (75.6%)1765 (72.0%)
    History of diabetes mellitus889 (42.1%)1080 (44.0%)0.7545
    Prior CAD84 (40.2%)905 (36.9%)0.2940
    Number of affected vascular beds at enrollment0.3210
     188 (42.1%)1176 (48.0%)
     280 (38.3%)918 (37.4%)
     341 (19.6%)358 (14.6%)
    Smoking status at baseline0.5562
     Current smoker74 (35.7%)834 (34.3%)
     Former smoker95 (45.9%)1202 (49.4%)
     Never smoked38 (18.4%)398 (16.4%)

    ABI indicates ankle-brachial index; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CLI, critical limb ischemia; PPI, proton pump inhibitor; TBI, toe-brachial index; TIA, transient ischemic attack; and TIMI, Thrombolysis in Myocardial Infarction.

    Figure 1.

    Figure 1. Flow diagram of patients in EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) who experienced procedural bleeding.

    Procedures Performed

    In EUCLID, 770 patients underwent coronary revascularization (626 percutaneous coronary intervention, 176 coronary artery bypass graft). A total of 1738 patients underwent lower extremity revascularization (1347 endovascular, 688 surgical), 203 carotid revascularization procedures, and 38 other revascularization procedures including mesenteric and renal arteries. A total of 387 underwent any amputation during the course of the study (148 above knee, 69 below knee, 170 minor). These numbers are reported in Tables 2, 3, and 4; Table I in the Data Supplement.

    Table 2. Severity of Bleeds Within 30 Days of Procedure

    ISTH Bleeding CategoriesPeripheral RevascularizationCoronary RevascularizationAmputationP Value (Log-Rank Test Comparing 3 Procedures)
    Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)
    ISTH major and minor bleeding post-procedure330/1905 (17.3%)132/770 (17.1%)58/387 (15.0%)0.5448
     ISTH major bleeding post-procedure187/1905 (9.8%)76/770 (9.9%)38/387 (9.8%)0.8837
     ISTH minor bleeding post-procedure175/1905 (9.2%)71/770 (9.2%)26/387 (6.7%)0.2584
    ISTH major and minor bleeding within 30 days of procedure130/1905 (6.8%)6.9 (5.8–8.0)61/770 (7.9%)8.0 (6.1–9.9)27/387 (7.0%)7.1 (4.5–9.7)
    Major bleeding ISTH major
     Any89 (4.6%)4.7 (3.7–5.7)40 (5.1%)5.2 (3.6–6.8)20 (5.2%)5.3 (3.0–7.6)0.8837
     Decrease in hemoglobin ≥2 g/dL75 (3.9%)4.0 (3.1–4.9)32 (4.2%)4.2 (2.8–5.6)16 (4.1%)4.2 (2.2–6.2)0.7758
     Transfusion of ≥2 units of PRBCs8 (0.4%)0.4 (0.1–0.7)4 (0.5%)0.5 (0.0–1.0)3 (0.8%)0.8 (0.0–1.7)0.5946
     Symptomatic bleed in a critical location3 (0.2%)0.2 (0.0–0.4)4 (0.5%)0.5 (0.0–1.0)00.5283
     Fatal bleeding3 (0.2%)0.3 (0.0–0.8)010.3 (0.0–0.8)0.2306
     Access site bleeding6 (0.3%)0.3 (0.0–0.6)3 (0.4%)0.4 (0.0–0.8)0
    Bleeding associated with cardiac surgery28 (3.6%)3.6 (2.3–4.9)
    Bleeding associated with noncardiac surgery63 (3.3%)3.3 (2.5–4.1)17 (4.4%)4.5 (2.4–6.6)
    Minor bleeding ISTH minor42 (2.2%)2.2 (1.5–2.9)21 (2.7%)2.8 (1.6–4.0)9 (2.3%)2.4 (0.9–3.9)
     Access site bleeding80.4 (0.1–0.7)70.9 (0.2–1.6)0

    ISTH indicates International Society on Thrombosis and Haemostasis; KM, Kaplan Meier; and PRBCs, packed red blood cells.

    Table 3. Severity of Bleeds Within 30 Days of Procedure: Further Breakdown of Peripheral Revascularization

    ISTH Bleeding CategoriesPeripheral Revascularization (N=1905)
    Endovascular (N=1347)Surgical (N=688)Carotid (N=203)Other (MESENTERIC”, “RENAL; N=38)
    Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)
    ISTH major and minor bleeding post-procedure211/1347159/68827/2038/38
    ISTH major bleeding post-procedure105/1347121/68811/2035/38
    ISTH minor bleeding post-procedure127/134756/68821/2034/38
    ISTH major and minor bleeding within 30 days of procedure664.9 (3.7–6.1)274.4 (2.8, 6.0)136.4 (3.0–9.8)25.3 (0–12.5)
    Major bleeding ISTH major
     Any362.7 (1.8–3.6)8412.3 (9.8–14.8)63.0 (0.7–5.3)25.3 (0–12.5)
     Decrease in hemoglobin ≥2 g/dl302.2 (1.4–3.0)7410.8 (8.5–13.1)21.0 (0–2.4)25.3 (0–12.5)
     Transfusion of ≥2 units of PRBCs20.1 (0–0.3)81.2 (0.4–2.0)10.5 (0–1.5)0
     Symptomatic bleed in a critical location10.1 (0–0.2)031.5 (0–3.2)0
     Fatal bleeding30.2 (0–0.5)20.3 (0–0.7)00
     Access site bleeding60.4 (0–0.8)10.1 (0–0.4)00
    Bleeding associated with noncardiac surgery141.0 (0.5–1.5)7511.0 (8.7–13.3)21.0 (0–2.4)12.6 (0–7.7)
    Minor bleeding ISTH minor322.4 (1.6–3.2)131.9 (0.9–2.9)73.5 (1.0–6.0)0

    ISTH indicates International Society on Thrombosis and Haemostasis; KM, Kaplan Meier; and PRBCs, packed red blood cells.

    Table 4. Severity of Bleeds Within 30 Days of Procedure: Further Breakdown of Coronary Revascularization

    ISTH Bleeding CategoriesCoronary Revascularization (N=770)
    CABG (N=176)PCI (N=626)
    Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)Patients With Events no. (%)KM Estimated Rate% at 30 D (95% CI)
    ISTH major and minor bleeding post-procedure51/17690/626
     ISTH major bleeding post-procedure38/17646/626
     ISTH minor bleeding post-procedure19/17654 /626
    ISTH major and minor bleeding within 30 d of procedure4123.5 (17.2–29.8)274.4 (2.8–6.0)
    Major bleeding ISTH major
     Any3218.3 (12.6–24.0)142.3 (1.1–3.5)
     Decrease in hemoglobin ≥2 g/dL2614.9 (9.6–20.2)121.9 (0.8–3.0)
     Transfusion of ≥2 units of PRBCs31.7 (0–3.6)10.2 (0–0.5)
     Symptomatic bleed in a critical location31.7 (0–3.6)10.2 (0–0.5)
     Fatal bleeding00
     Access site bleeding030.5 (0–1.0)
    Bleeding associated with cardiac surgery3117.7 (12.1–23.3)20.3 (0–0.7)
    Minor bleeding ISTH minor95.2 (1.9–8.5)132.1 (1.0–3.2)

    CABG indicates coronary artery bypass grafting; ISTH, International Society on Thrombosis and Haemostasis; KM, Kaplan Meier; PCI, percutaneous coronary intervention; and PRBCs, packed red blood cells.

    Incidence of Bleeding

    The overall incidence of TIMI major or minor bleeding following procedures is shown in Table 5. The incidence of bleeding ≤7 days following peripheral revascularization (3.3%; CI, 2.5%–4.1%) was similar to the rates following coronary revascularization (4.0%; CI, 2.6%–5.4%) and lower extremity amputation (2.3%; CI, 0.8%–3.8%). The cumulative incidence of major/minor bleeding within 30 days following peripheral revascularization increased (4.0%; CI, 3.1%–4.9%) but remained similar to rates after coronary revascularization (4.4%; CI, 2.9%–5.9%) and lower extremity amputation (4.0%; CI, 2.0%–6.0%).

    Table 5. Kaplan-Meier Estimated Cumulative Event Rate of TIMI Major or Minor Bleeding at Different Time Points Post-Procedure

    No. of Events
    KM Event Rate (95% CI)
    ≤7 D≤30 D≤180 D≤365 DAll
    Peripheral revascularization6275107124147
    3.3% (2.5%–4.1%)4.0% (3.1%–4.9%)5.8% (4.7%–6.9%)7.0% (5.8%–8.2%)
    Coronary revascularization3134485566
    4.0% (2.6%–5.4%)4.4% (2.9%–5.9%)6.5% (4.7%–8.3%)7.8% (5.8%–9.8%)
    Amputation915222531
    2.3% (0.8%–3.8%)4.0% (2.0%–6.0%)6.0% (3.6%–8.4%)7.0% (4.3%–9.7%)

    KM indicates Kaplan-Meier; and TIMI, Thrombolysis in Myocardial Infarction.

    Timing of Bleeding

    TIMI major or minor bleeding events following peripheral revascularization most often occurred periprocedurally (Table 5). Among patients who experienced any bleeding events post-procedure, nearly half of them occurred within the first 7 days (62 versus 147). The cumulative event rate within the first 7 days was 3.3%, CI, 2.5%–4.1% compared with those at 30 days (4.0%; CI, 3.1%–4.9%), 180 days (5.8%; CI, 4.7%–6.9%), and 365 days (7.0%; CI, 5.8%–8.2%; Figure 2 and 3). The largest rise in the cumulative event rate occurred almost immediately following revascularization and increased more slowly throughout the study period.

    Figure 2.

    Figure 2. Estimated cumulative event rate of Thrombolysis in Myocardial Infarction major or minor bleeding post-procedure. CABG indicates coronary artery bypass grafting; and PCI, percutaneous coronary intervention.

    Severity of Bleeding

    The ISTH bleeding definition was used to analyze severity of bleeding because we were unable to subcategorize major and minor bleeds using the TIMI definition. Important differences in the ISTH and TIMI definitions for major bleeding include drop in hemoglobin (≥2 versus ≥5 g/dL) and the transfusion criteria included in the ISTH definition. Minor bleeding according to the TIMI definition includes a hemoglobin drop of 3 to 5 g/dL while the definition for ISTH includes hospital or surgical intervention, or change in antithrombotic therapy. Major and minor bleeding events according to ISTH definitions occurred in 130 patients in the peripheral revascularization group (6.8%; 95% CI, 5.8%–8.0%) within 30 days of the procedure, 61 patients in the coronary revascularization group (8.0%; 95% CI, 6.1%–9.9%), and 27 patients in the amputation group (7.1%; 95% CI, 4.5%–9.7%; Table 2). A drop in hemoglobin levels ≥2 g/dL was the most frequently adjudicated reason for major bleeding and was similar across all procedural groups. The rates of blood transfusion (≥2 units), symptomatic bleeding in a critical location, and fatal bleeding after procedure were similar between peripheral revascularization, coronary revascularization, and lower extremity amputation.

    Source of Bleeding

    The source of bleeding is reported in Table 2. Access site bleeding occurred in 24 patients (14 peripheral revascularization, 10 coronary revascularization, 0 amputation).

    Discussion

    This post hoc analysis from the EUCLID trial provides important insights into postprocedural bleeding in patients with PAD. The incidence of major or minor bleeding after peripheral revascularization was 3.3% within 7 days following the procedure and was comparable with bleeding rates after coronary revascularization and lower extremity amputation. The severity of major and minor bleeding events within 30 days post-procedure was comparable in patients undergoing peripheral revascularization, coronary revascularization, and lower extremity amputation. Finally, bleeding events occurred more commonly in patients randomized to ticagrelor compared with clopidogrel, but the increase was not statistically significant.

    The literature assessing the relationship between bleeding and peripheral revascularization and lower extremity amputation is sparse. We present findings that differ from a few prior studies of bleeding following peripheral revascularization; however, we recognize that it is difficult to compare these studies because of important issues including differences in bleeding definitions and the role of antiplatelet agents. A single-center randomized controlled trial reported an incidence of hematoma following endovascular revascularization of 7.9% (6/76),11 while an observational single-center study reported an incidence of bleeding within 30 days following endovascular revascularization of 0.2%.12 Both values are outside the cumulative event rate CIs reported in this study (4.0%; 95% CI, 3.1%–4.9%). A more recent retrospective multicenter analysis also reports similar results. They found that access site complications, including hematomas and pseudoaneurysms, occurred in 3.5% of revascularization procedures and of those, 9.7% required transfusion.9

    These results build on existing knowledge in a few ways. First, this study is contemporary, as patients were enrolled from 2012 to 2014. Second, a consistent trigger process was used to identify all bleeding events, and all identified events were formally adjudicated using standard bleeding definitions. Strict adjudication processes in this study ensure that (1) events are not overreported, (2) interpretation of events is not biased by clinician interpretation, and (3) influence of external factors (such as reimbursement incentives and quality measures) are minimized.13 Furthermore, standardized definitions are consistently applied allowing for legitimate comparisons between past and future research using the same definitions.13 Finally, in addition to describing the incidence of bleeding events, the timing and severity of bleeding events were adjudicated and reported. This is unique and critical because clinicians can use this information to improve management plans by more accurately risk-stratifying patients before procedures and more precisely calibrating risk post-procedure. Future studies should continue to focus on the factors impacting major and minor bleeding in peripheral revascularization and lower extremity amputation, and the vascular community should make a push to minimize the occurrence and impact of bleeding events in patients with PAD.

    There were a few limitations to this study. Every attempt was made to ascertain the occurrence of both invasive procedures and bleeding events; however, it is possible that some patients had procedures and bleeding events not captured in this analysis. Furthermore, the management of medications (including the study medications) surrounding invasive vascular procedures was left to the discretion of the operators, and the impact of these decisions was not accounted for in this analysis. In addition, these were not randomized comparisons, thus limiting the ability to establish any causal relationship. Finally, the patients in this study were highly selected (ie, symptomatic PAD, 50% had prior peripheral revascularization, 30% had concomitant coronary artery disease), and may not reflect a general population of patients with PAD.

    Conclusions

    In conclusion, the incidence of major and minor bleeding following peripheral revascularization is comparable with bleeding rates after coronary revascularization and lower extremity amputation. In addition, bleeding events most often occur within 7 days following the procedure. Finally, the severity of periprocedural bleeding events was comparable across procedures, with the most frequently adjudicated reason being a drop in hemoglobin ≥2 g/dL. Future studies should be performed to enhance our understanding of bleeding risk related to peripheral revascularization and lower extremity amputation in patients with PAD.

    Figure 3.

    Figure 3. Estimated cumulative event rate of Thrombolysis in Myocardial Infarction major bleeding post-procedure: log-rank test. CABG indicates coronary artery bypass grafting; and PCI, percutaneous coronary intervention.

    Acknowledgments

    We thank Elizabeth E.S. Cook, of the Duke Clinical Research Institute, for editorial assistance.

    Footnotes

    Guest Editor for this article was Gjin Ndrepepa, MD.

    The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCINTERVENTIONS.119.008069.

    W. Schuyler Jones, MD, Duke University Medical Center, Box 3330, Durham, NC 27710. Email

    References

    • 1. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease.Circ Res. 2015; 116:1509–1526. doi: 10.1161/CIRCRESAHA.116.303849LinkGoogle Scholar
    • 2. Sigvant B, Hasvold P, Kragsterman B, Falkenberg M, Johansson S, Thuresson M, Nordanstig J. Cardiovascular outcomes in patients with peripheral arterial disease as an initial or subsequent manifestation of atherosclerotic disease: results from a Swedish Nationwide Study.J Vasc Surg. 2017; 66:507–514.e1. doi: 10.1016/j.jvs.2017.01.067CrossrefMedlineGoogle Scholar
    • 3. Rao SV, McCoy LA, Spertus JA, Krone RJ, Singh M, Fitzgerald S, Peterson ED. An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the national cardiovascular data registry cathPCI registry.JACC Cardiovasc Interv. 2013; 6:897–904. doi: 10.1016/j.jcin.2013.04.016CrossrefMedlineGoogle Scholar
    • 4. Kwok CS, Rao SV, Myint PK, Keavney B, Nolan J, Ludman PF, de Belder MA, Loke YK, Mamas MA. Major bleeding after percutaneous coronary intervention and risk of subsequent mortality: a systematic review and meta-analysis.Open Heart. 2014; 1:e000021. doi: 10.1136/openhrt-2013-000021CrossrefMedlineGoogle Scholar
    • 5. Chhatriwalla AK, Amin AP, Kennedy KF, House JA, Cohen DJ, Rao SV, Messenger JC, Marso SP; National Cardiovascular Data Registry. Association between bleeding events and in-hospital mortality after percutaneous coronary intervention.JAMA. 2013; 309:1022–1029. doi: 10.1001/jama.2013.1556CrossrefMedlineGoogle Scholar
    • 6. Cacoub PP, Bhatt DL, Steg PG, Topol EJ, Creager MA; CHARISMA Investigators. Patients with peripheral arterial disease in the CHARISMA trial.Eur Heart J. 2009; 30:192–201. doi: 10.1093/eurheartj/ehn534CrossrefMedlineGoogle Scholar
    • 7. Bonaca MP, Scirica BM, Creager MA, Olin J, Bounameaux H, Dellborg M, Lamp JM, Murphy SA, Braunwald E, Morrow DA. Vorapaxar in patients with peripheral artery disease: results from TRA2{degrees}P-TIMI 50.Circulation. 2013; 127:1522–9, 1529e1. doi: 10.1161/CIRCULATIONAHA.112.000679LinkGoogle Scholar
    • 8. Jones DW, Schermerhorn ML, Brooke BS, Conrad MF, Goodney PP, Wyers MC, Stone DH; Vascular Quality Initiative. Perioperative clopidogrel is associated with increased bleeding and blood transfusion at the time of lower extremity bypass.J Vasc Surg. 2017; 65:1719–1728.e1. doi: 10.1016/j.jvs.2016.12.102CrossrefMedlineGoogle Scholar
    • 9. Ortiz D, Jahangir A, Singh M, Allaqaband S, Bajwa TK, Mewissen MW. Access site complications after peripheral vascular interventions: incidence, predictors, and outcomes.Circ Cardiovasc Interv. 2014; 7:821–828. doi: 10.1161/CIRCINTERVENTIONS.114.001306LinkGoogle Scholar
    • 10. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, Katona BG, Mahaffey KW, Norgren L, Jones WS, Blomster J, Millegård M, Reist C, Patel MR; EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease.N Engl J Med. 2017; 376:32–40. doi: 10.1056/NEJMoa1611688CrossrefMedlineGoogle Scholar
    • 11. Spronk S, Bosch JL, den Hoed PT, Veen HF, Pattynama PM, Hunink MG. Intermittent claudication: clinical effectiveness of endovascular revascularization versus supervised hospital-based exercise training–randomized controlled trial.Radiology. 2009; 250:586–595. doi: 10.1148/radiol.2501080607CrossrefMedlineGoogle Scholar
    • 12. Dosluoglu HH, Lall P, Cherr GS, Harris LM, Dryjski ML. Role of simple and complex hybrid revascularization procedures for symptomatic lower extremity occlusive disease.J Vasc Surg. 2010; 51:1425–1435.e1. doi: 10.1016/j.jvs.2010.01.092CrossrefMedlineGoogle Scholar
    • 13. Seltzer JH, Heise T, Carson P, Canos D, Hiatt JC, Vranckx P, Christen T, Cutlip DE. Use of endpoint adjudication to improve the quality and validity of endpoint assessment for medical device development and post marketing evaluation: rationale and best practices. a report from the cardiac safety research consortium.Am Heart J. 2017; 190:76–85. doi: 10.1016/j.ahj.2017.05.009CrossrefMedlineGoogle Scholar