Impact of Procedural Bleeding in Peripheral Artery Disease: An Analysis From EUCLID Trial
Circulation: Cardiovascular Interventions
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.
Graphical Abstract
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).
| Characteristic | Patients 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), y | 67.0 (61.0, 73.0) | 66.0 (60.0, 72.0) | 0.3530 |
| Female sex | 76 (36.4%) | 660 (26.9%) | 0.0035 |
| Geographic region | <0.0001 | ||
| Europe | 75 (35.9%) | 1216 (49.6%) | |
| Asia | 14 (6.7%) | 220 (9.0%) | |
| North America | 110 (52.6%) | 814 (33.2%) | |
| Central/South America | 10 (4.8%) | 202 (8.2%) | |
| History of coronary or carotid revascularization | 86 (41.1%) | 907 (37.0%) | 0.1871 |
| History of coronary stent implantation | 43 (20.6%) | 491 (20.0%) | 0.8369 |
| Prior CABG | 41 (19.6%) | 387 (15.8%) | 0.1407 |
| Prior TIA | 21 (10.0%) | 110 (4.5%) | 0.0004 |
| Dyslipidemia | 169 (80.9%) | 1978 (80.7%) | 0.8938 |
| Medications | |||
| Prior antiplatelet therapy | 191 (91.4%) | 2197 (89.6%) | 0.3781 |
| Statins | 163 (78.0%) | 1871 (76.3%) | 0.5945 |
| Beta-blockers | 107 (51.2%) | 1140 (46.5%) | 0.1426 |
| Clopidogrel | 95 (45.5%) | 985 (40.2%) | 0.1572 |
| PPIs | 62 (29.7%) | 563 (23.0%) | 0.0244 |
| Limb symptoms | 0.5952 | ||
| Asymptomatic | 45 (21.5%) | 473 (19.3%) | |
| Mild/moderate claudication | 99 (47.4%) | 1201 (49.0%) | |
| Severe claudication | 47 (22.5%) | 626 (25.5%) | |
| CLI | 18 (8.6%) | 151 (6.2%) | |
| Inclusion criteria for randomization | 0.3213 | ||
| ABI/TBI criterion | 51 (24.4%) | 687 (28.0%) | |
| Prior revascularization | 158 (75.6%) | 1765 (72.0%) | |
| History of diabetes mellitus | 889 (42.1%) | 1080 (44.0%) | 0.7545 |
| Prior CAD | 84 (40.2%) | 905 (36.9%) | 0.2940 |
| Number of affected vascular beds at enrollment | 0.3210 | ||
| 1 | 88 (42.1%) | 1176 (48.0%) | |
| 2 | 80 (38.3%) | 918 (37.4%) | |
| 3 | 41 (19.6%) | 358 (14.6%) | |
| Smoking status at baseline | 0.5562 | ||
| Current smoker | 74 (35.7%) | 834 (34.3%) | |
| Former smoker | 95 (45.9%) | 1202 (49.4%) | |
| Never smoked | 38 (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.
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.
| ISTH Bleeding Categories | Peripheral Revascularization | Coronary Revascularization | Amputation | P 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-procedure | 330/1905 (17.3%) | 132/770 (17.1%) | 58/387 (15.0%) | 0.5448 | |||
| ISTH major bleeding post-procedure | 187/1905 (9.8%) | 76/770 (9.9%) | 38/387 (9.8%) | 0.8837 | |||
| ISTH minor bleeding post-procedure | 175/1905 (9.2%) | 71/770 (9.2%) | 26/387 (6.7%) | 0.2584 | |||
| ISTH major and minor bleeding within 30 days of procedure | 130/1905 (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 | |||||||
| Any | 89 (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/dL | 75 (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 PRBCs | 8 (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 location | 3 (0.2%) | 0.2 (0.0–0.4) | 4 (0.5%) | 0.5 (0.0–1.0) | 0 | 0.5283 | |
| Fatal bleeding | 3 (0.2%) | 0.3 (0.0–0.8) | 0 | 1 | 0.3 (0.0–0.8) | 0.2306 | |
| Access site bleeding | 6 (0.3%) | 0.3 (0.0–0.6) | 3 (0.4%) | 0.4 (0.0–0.8) | 0 | ||
| Bleeding associated with cardiac surgery | 28 (3.6%) | 3.6 (2.3–4.9) | |||||
| Bleeding associated with noncardiac surgery | 63 (3.3%) | 3.3 (2.5–4.1) | 17 (4.4%) | 4.5 (2.4–6.6) | |||
| Minor bleeding ISTH minor | 42 (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 bleeding | 8 | 0.4 (0.1–0.7) | 7 | 0.9 (0.2–1.6) | 0 | ||
ISTH indicates International Society on Thrombosis and Haemostasis; KM, Kaplan Meier; and PRBCs, packed red blood cells.
| ISTH Bleeding Categories | Peripheral 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-procedure | 211/1347 | 159/688 | 27/203 | 8/38 | ||||
| ISTH major bleeding post-procedure | 105/1347 | 121/688 | 11/203 | 5/38 | ||||
| ISTH minor bleeding post-procedure | 127/1347 | 56/688 | 21/203 | 4/38 | ||||
| ISTH major and minor bleeding within 30 days of procedure | 66 | 4.9 (3.7–6.1) | 27 | 4.4 (2.8, 6.0) | 13 | 6.4 (3.0–9.8) | 2 | 5.3 (0–12.5) |
| Major bleeding ISTH major | ||||||||
| Any | 36 | 2.7 (1.8–3.6) | 84 | 12.3 (9.8–14.8) | 6 | 3.0 (0.7–5.3) | 2 | 5.3 (0–12.5) |
| Decrease in hemoglobin ≥2 g/dl | 30 | 2.2 (1.4–3.0) | 74 | 10.8 (8.5–13.1) | 2 | 1.0 (0–2.4) | 2 | 5.3 (0–12.5) |
| Transfusion of ≥2 units of PRBCs | 2 | 0.1 (0–0.3) | 8 | 1.2 (0.4–2.0) | 1 | 0.5 (0–1.5) | 0 | |
| Symptomatic bleed in a critical location | 1 | 0.1 (0–0.2) | 0 | 3 | 1.5 (0–3.2) | 0 | ||
| Fatal bleeding | 3 | 0.2 (0–0.5) | 2 | 0.3 (0–0.7) | 0 | 0 | ||
| Access site bleeding | 6 | 0.4 (0–0.8) | 1 | 0.1 (0–0.4) | 0 | 0 | ||
| Bleeding associated with noncardiac surgery | 14 | 1.0 (0.5–1.5) | 75 | 11.0 (8.7–13.3) | 2 | 1.0 (0–2.4) | 1 | 2.6 (0–7.7) |
| Minor bleeding ISTH minor | 32 | 2.4 (1.6–3.2) | 13 | 1.9 (0.9–2.9) | 7 | 3.5 (1.0–6.0) | 0 | |
ISTH indicates International Society on Thrombosis and Haemostasis; KM, Kaplan Meier; and PRBCs, packed red blood cells.
| ISTH Bleeding Categories | Coronary 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-procedure | 51/176 | 90/626 | ||
| ISTH major bleeding post-procedure | 38/176 | 46/626 | ||
| ISTH minor bleeding post-procedure | 19/176 | 54 /626 | ||
| ISTH major and minor bleeding within 30 d of procedure | 41 | 23.5 (17.2–29.8) | 27 | 4.4 (2.8–6.0) |
| Major bleeding ISTH major | ||||
| Any | 32 | 18.3 (12.6–24.0) | 14 | 2.3 (1.1–3.5) |
| Decrease in hemoglobin ≥2 g/dL | 26 | 14.9 (9.6–20.2) | 12 | 1.9 (0.8–3.0) |
| Transfusion of ≥2 units of PRBCs | 3 | 1.7 (0–3.6) | 1 | 0.2 (0–0.5) |
| Symptomatic bleed in a critical location | 3 | 1.7 (0–3.6) | 1 | 0.2 (0–0.5) |
| Fatal bleeding | 0 | 0 | ||
| Access site bleeding | 0 | 3 | 0.5 (0–1.0) | |
| Bleeding associated with cardiac surgery | 31 | 17.7 (12.1–23.3) | 2 | 0.3 (0–0.7) |
| Minor bleeding ISTH minor | 9 | 5.2 (1.9–8.5) | 13 | 2.1 (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%).
| No. of Events | |||||
|---|---|---|---|---|---|
| KM Event Rate (95% CI) | |||||
| ≤7 D | ≤30 D | ≤180 D | ≤365 D | All | |
| Peripheral revascularization | 62 | 75 | 107 | 124 | 147 |
| 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 revascularization | 31 | 34 | 48 | 55 | 66 |
| 4.0% (2.6%–5.4%) | 4.4% (2.9%–5.9%) | 6.5% (4.7%–8.3%) | 7.8% (5.8%–9.8%) | ||
| Amputation | 9 | 15 | 22 | 25 | 31 |
| 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.
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.
Acknowledgments
We thank Elizabeth E.S. Cook, of the Duke Clinical Research Institute, for editorial assistance.
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© 2019 American Heart Association, Inc.
History
Received: 5 April 2019
Accepted: 15 July 2019
Published in print: October 2019
Published online: 4 October 2019
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Disclosures
Kansal, Huang: Nothing to report. Dr Rockhold participated in research funding at NIH, PCORI, Duke Clinical Research Institute, Alzheimer’s Drug Discovery Foundation, AstraZeneca, ReNeuron, Luitpold, BMS, Janssen; Consulting/Honoraria: California Institute for Regenerative Medicine, PCORI, BARDA, Merck Serono, Janssen, resTORbio, Eidos Therapeutics, FuturaMedical, AbbVie, Amgen, Complexa, Adverum Biotechnologies, AstraZeneca, Aldeyra, KLSMC, Merck Research Laboratories, Chimerix; Equity interest: GlaxoSmithKline, DataVant, M3 Biotechnology. Dr Baumgartner took part in research grants from Abbott Vascular, Cook, Terumo, Amgen, and Boston Scientific; Consulting fees from Amgen. Dr Berger collected advisory board fees from Janssen, Merck, and Takeda. Dr Blomster is an Employee of AstraZeneca at the time of the trial. F.G. Fowkes is a participant in advisory boards: AstraZeneca, Merck, Bayer. B. Katona is an employee of AstraZeneca. Full disclosure information of Dr Mahaffey is available at https://profiles.stanford.edu/kenneth-mahaffey?tab=research-and-scholarship. Dr Norgren provided research grants from AnGes, Mitsubishi; Steering committee honoraria: AnGes, AstraZeneca, Bayer, Cesca, Mitsubishi, Pluristem. Dr Hiatt provided research grants from NIH, Bayer, Janssen, AstraZeneca. Dr Patel provided research grants from HeartFlow, Bayer, Janssen, NHLBI; Advisory board: HeartFlow, Bayer, Janssen. Dr Jones provided research grants from Agency for Healthcare Research and Quality, AstraZeneca, American Heart Association, Bristol-Myers Squibb, Doris Duke Charitable Foundation, Patient-Centered Outcomes Research Institute; Honoraria/other: American College of Radiology, Daiichi Sankyo. The other authors report no conflicts.
Sources of Funding
The EUCLID trial was funded by AstraZeneca.
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- Effect of Peripheral Interventions in Patients with Peripheral Artery Disease Receiving Rivaroxaban and Aspirin: Analyses from the XATOA Registry, European Journal of Vascular and Endovascular Surgery, 68, 6, (784-795), (2024).https://doi.org/10.1016/j.ejvs.2024.07.017
- Antithrombotic Therapy in High Bleeding Risk, Part II, JACC: Cardiovascular Interventions, 17, 20, (2325-2336), (2024).https://doi.org/10.1016/j.jcin.2024.09.011
- The effects of CYP2C19 genotype polymorphism and clopidogrel resistance on ischemic event occurrence in patients with peripheral arterial disease undergoing revascularization: A prospective cohort study, Thrombosis Research, 236, (37-50), (2024).https://doi.org/10.1016/j.thromres.2024.02.010
- Antithrombotic Therapy in Peripheral Artery Disease: Current Evidence and Future Directions, Journal of Cardiovascular Development and Disease, 10, 4, (164), (2023).https://doi.org/10.3390/jcdd10040164
- Bleeding Risk in Patients with Peripheral Arterial Disease, Life, 13, 1, (47), (2022).https://doi.org/10.3390/life13010047
- Az alsó végtagi endovascularis verőér-beavatkozások során alkalmazott antithromboticus, antikoaguláns terápia szempontjai, Orvosi Hetilap, 163, 3, (98-108), (2022).https://doi.org/10.1556/650.2022.32336
- World regional differences in outcomes for patients with peripheral artery disease: Insights from the EUCLID trial, Vascular Medicine, 27, 1, (21-29), (2021).https://doi.org/10.1177/1358863X211038620
- Impact of chronic kidney disease on hemoglobin among patients with peripheral artery disease treated with P2Y 12 inhibitors: Insights from the EUCLID trial , Vascular Medicine, 26, 6, (608-612), (2021).https://doi.org/10.1177/1358863X211017641
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