Clinical Outcomes of 5000 IU Heparin Versus Activated Clotting Time-Guided Heparinization During Noncardiac Arterial Procedures: A Propensity Score Matched Analysis.

PURPOSE: Previous studies have shown that activated clotting time (ACT)-guided heparinization leads to better anticoagulation levels during noncardiac arterial procedures (NCAP) than a standardized bolus of 5000 IU. Better anticoagulation should potentially result in lower incidence of thrombo-embolic complications (TEC). Comparative investigations on clinical outcomes of these heparinization strategies are scarce. This study investigated clinical outcomes of ACT-guided heparinization with a starting dose of 100 IU/kg in comparison with a single standardized bolus of 5000 IU heparin during NCAP. MATERIALS AND METHODS: Analysis from a prospectively collected database of patients undergoing NCAP in 2 vascular centers was performed. Patients receiving ACT-guided heparinization were matched 1:1 with patients receiving 5000 IU heparin using propensity score matching (PSM). Primary outcomes were TEC, bleeding complications, and mortality within 30 days of procedure or during the same admission. RESULTS: A total of 759 patients (5000 IU heparin: 213 patients, ACT-guided heparinization: 546 patients) were included. Propensity score matching resulted in 209 patients in each treatment group. After PSM, the groups were comparable, with the exception of a higher prevalence of peripheral arterial disease in the ACT-guided heparinization group (103 patients, 49% vs 82 patients, 39%, p=0.039). The target ACT (>200 seconds) was reached in 198 patients (95%) of the ACT-guided group versus 71 patients (34%) of the 5000 IU group (p<0.001), indicating successful execution of the ACT-guided protocol. Incidence of TEC (13 patients, 6.2% vs 10 patients, 4.8%, p=0.52), mortality (3 patients, 1.4% vs 0 patients, p=0.25), and bleeding complications (32 patients, 15% vs 25 patients, 12%, p=0.32) did not differ between patients receiving ACT-guided heparinization and 5000 IU heparin. Protamine was administered in 118 patients (57%) in the ACT group versus 11 patients (5.3%) in the 5000 IU group (p<0.001), but did not influence incidence of TEC (17 patients, 5.9% vs 6 patients, 4.7%, p=0.61) or bleeding complications (34 patients, 12% vs 22 patients, 17%, p=0.14). CONCLUSION: No difference in TEC, bleeding complications, or mortality was found between ACT-guided heparinization and a single bolus of 5000 IU heparin during NCAP. CLINICAL IMPACT: Previous studies have shown that activated clotting time (ACT)-guided heparinization leads to better anticoagulation levels during non-cardiac arterial procedures (NCAP) then a standardized bolus of 5000 IU. Comparative investigations on clinical outcomes are scarce. This study focussed on clinical outcomes of both protocols in NCAP in a propensity score matched cohort. Thrombo-embolic complications (TEC), bleeding complications and mortality within 30 days after NCAP or during the same admission were comparable between groups. Future studies should focus on optimizing ACT-guided protocols, specifically in patients with a high risk of TEC and bleeding complications.

Systematic review of clinical guidelines and consensus statements concerning heparin and protamine dosing and monitoring of anticoagulation levels for non-cardiac arterial procedures.

OBJECTIVES: This systematic review was performed to examine all published practice Guidelines and Consensus Statements (together: GCS) on heparin dosing and monitoring during non-cardiac arterial procedures (NCAP). The objective was to scrutinize the recommendations and advice outlined within these GCS documents and to evaluate the supporting evidence for these recommendations. Additionally, the use of the activated clotting time (ACT) and target ACT values were explored. METHODS: This systematic review was performed in accordance with the PRISMA Guidelines. Medline and Embase databases were searched to identify all GCSs in the English language on NCAP. The final literature search was performed in January 2023. This search was supplemented by searching websites of relevant professional vascular surgical organizations for GCSs. Titles and abstracts were assessed by two independent reviewers. RESULTS: Of 9716 titles identified, 27 GCSs met the predefined inclusion criteria: six GCSs regarding carotid intervention, seven regarding procedures for aneurysmal disease of the abdominal aorta and iliac arteries, 12 regarding interventions for acute and chronic peripheral arterial occlusive disease and two regarding open and endovascular interventions of thoraco-abdominal aortic aneurysms. Administration of heparin is advised for al NCAP. There was high variability concerning heparin dose: both standard dose as weight based dosing (30-150 IU/kg) was advised. Recommendations on repeated doses, ACT monitoring and heparin reversal using protamine also varied widely. In none of the GCSs, the type of the ACT measuring device or used cartridges were specified. CONCLUSIONS: Large variability was found between the included GCSs with regard to the recommendations on heparin dose and target ACT values during NCAP. Advice and recommendations in GCSs were based on low-quality studies or without providing any reference at all. The described variability in recommendations emphasizes the need for large prospective (randomized) studies or the incorporation of data on heparin and the use of ACT monitoring into verified vascular surgery registries, to develop evidence-based, practical and uniform applicable recommendations.

Activated clotting time-guided heparinization during open AAA surgery: a pilot study.

BACKGROUND: Arterial thrombo-embolic complications (TEC) are still common during and after non-cardiac arterial procedures (NCAP). While unfractionated heparin has been used during NCAP for more than 70 years to prevent TEC, there is no consensus regarding the optimal dosing strategy. The aim of this pilot study was to test the effectiveness and feasibility of an activated clotting time (ACT)-guided heparinization protocol during open abdominal aortic aneurysm (AAA) surgery, in anticipation of a randomized controlled trial (RCT) investigating if ACT-guided heparinization leads to better clinical outcomes compared to a single bolus of 5000 IU of heparin. METHODS: A prospective multicentre pilot study was performed. All patients undergoing elective open repair for an AAA (distal of the superior mesenteric artery) between March 2017 and January 2020 were included. Two heparin dosage protocols were compared: ACT-guided heparinization with an initial dose of 100 IU/kg versus a bolus of 5000 IU. The primary outcome was the effectiveness and feasibility of an ACT-guided heparinization protocol with an initial heparin dose of 100 IU/kg during open AAA surgery. Bleeding complications, TEC, and mortality were investigated for safety purposes. RESULTS: A total of 50 patients were included in the current study. Eighteen patients received a single dose of 5000 IU of heparin and 32 patients received 100 IU/kg of heparin with additional doses based on the ACT. All patients who received the 100 IU/kg dosing protocol reached the target ACT of > 200 s. In the 5000 IU group, TEC occurred in three patients (17%), versus three patients (9.4%) in the 100 IU/kg group. Bleeding complications were found in six patients (33%) in the 5000 IU group and in 9 patients (28%) in the 100 IU/kg group. No mortality occurred in either group. CONCLUSIONS: This pilot study demonstrated that ACT-guided heparinization with an initial dose of 100 IU/kg appears to be feasible and leads to adequate anticoagulation levels. Further randomized studies seem feasible and warranted to determine whether ACT-guided heparinization results in better outcomes after open AAA repair.

One-year follow-up after active aortic aneurysm sac treatment with shape memory polymer devices during endovascular aneurysm repair.

OBJECTIVE: To determine the safety and efficacy of treating abdominal aortic aneurysm (AAA) sacs with polyurethane shape memory polymer (SMP) devices during endovascular aneurysm repair (EVAR), using a technique to fully treat the target lumen after endograft placement (aortic flow volume minus the endograft volume). SMP devices self-expand in the sac to form a porous scaffold that supports thrombosis throughout its structure. METHODS: Two identical prospective, multicenter, single-arm studies were conducted in New Zealand and the Netherlands. The study population was adult candidates for elective EVAR of an infrarenal AAA (diameter of ≥55 mm in men and ≥50 mm in women). Key exclusion criteria were an inability to adequately seal a common iliac artery aneurysm, patent sac feeding vessels of >4 mm, and a target lumen volume of <20 mL or >135 mL. Target lumen volumes were estimated by subtracting endograft volumes from preprocedural imaging-based flow lumen volumes. SMP devices were delivered immediately after endograft deployment via a 6F sheath jailed in a bowed position in the sac. The primary efficacy end point was technical success, defined as filling the actual target lumen volume with fully expanded SMP at the completion of the procedure. Secondary efficacy outcome measures during follow-up were the change in sac volume and diameter, rate of type II endoleak and type I or III endoleaks, and the rate of open repair and related reinterventions, with data collection at 30 days, 6 months, and 1 year (to date). Baseline sac volumes and diameters for change in sac size analyses were determined from 30-day imaging studies. Baseline and follow-up volumes were normalized by subtraction of the endograft volume. RESULTS: Of 34 patients treated with SMP devices and followed per protocol, 33 patients were evaluable at 1 year. Preprocedural aneurysm volume was 181.4 mL (95% confidence interval [CI], 150.7-212.1 mL) and preprocedural aneurysm diameter was 60.8 mm (95% CI, 57.8-63.9 mm). The target lumen volume was 56.3 mL (95% CI, 46.9-65.8 mL). Technical success was 100% and the ratio of SMP fully expanded volume to estimated target lumen volume was 1.4 ± 0.3. Baseline normalized sac volume and diameter were 140.7 mL (95% CI, 126.6-154.9 mL) and 61.0 mm (95% CI, 59.7-62.3 mm). The adjusted mean percentage change in normalized volume at 1 year was -28.8% (95% CI, -35.3 to -22.3%; P < .001). The adjusted mean change in sac diameter at 1 year was -5.9 mm (95% CI, -7.5 to -4.4 mm; P < .001). At 1 year, 81.8% of patients (95% CI, 64.5%-93.0%) achieved a ≥10% decrease in normalized volume and 57.6% of patients (95% CI, 39.2%-74.5%) achieved a ≥5 mm decrease in diameter. No device- or study procedure-related major adverse events occurred through 1 year after the procedure. CONCLUSIONS: Treatment of AAA sacs with SMP devices during EVAR resulted in significant sac volume and diameter regression at 1 year with an acceptable safety profile in this prospective study.

The Additional Value of Activated Clotting Time-Guided Heparinization During Interventions for Peripheral Arterial Disease.

PURPOSE: Unfractionated heparin is widely used to lower the risk of arterial thromboembolic complications (ATECs) during interventions for peripheral arterial disease (PAD), but it is still unknown which heparin dose is the safest in terms of preventing ATECs and bleeding complications. This study aims to evaluate the incidence of complications during interventions for PAD and the relation between this incidence and different heparinization protocols. MATERIALS AND METHODS: A retrospective analysis of a prospective multicenter cohort study was performed. Between June 2015 and September 2022, 355 patients who underwent peripheral interventions for PAD were included. All patients who were included before July 2018 received 5000 international units (IU) of heparin (group 1). Starting from July 2018, all included patients received an initial dose of 100 IU/kg, with potential additional heparin doses based on activated clotting time (ACT) values (group 2). Data on ACT values and complications within 30 days post-procedurally were collected. RESULTS: In total, 24 ATECs and 48 bleeding complications occurred. In group 1, 8.7% (n=11) of patients suffered from ATEC, compared with 5.7% (n=13) in group 2. Thirteen percent of patients (n=17) in group 1 had a bleeding complication, compared with 14% (n=31) in group 2. Arterial thromboembolic complications were more often found in patients with peak ACT values of <200 seconds, compared with ACT values between 200 and 250 seconds, 15% (n=6) versus 5.9% (n=9), respectively, p=0.048. Patients with peak ACT values >250 seconds had a higher incidence of bleeding complications compared with an ACT between 200 and 250 seconds, 24% (n=21) versus 9.8% (n=15), respectively, p=0.003. Forty-four percent of patients (n=23) in group 1 reached a peak ACT of >200 seconds, compared with 95% (n=218) of patients in group 2 (p=0.001). CONCLUSION: ATEC was found in 6.8% (n=24) and bleeding complications in 14% (n=48) of patients who underwent a procedure for PAD. There was a significantly higher incidence of ATECs in patients with a peak ACT value <200 seconds, and a higher incidence of bleeding complications in patients with a peak ACT value >250 seconds. The findings obtained from this study may serve as a basis for conducting future research on heparinization during procedures for PAD, with a larger sample size. CLINICAL IMPACT: Heparin is administered during arterial interventions for peripheral arterial disease (PAD) to decrease the risk of arterial (thrombo)embolic complications (ATEC) during or shortly following surgery. The effect of heparin is unpredictable in the individual patient, and the optimal dosage of this anticoagulant has not yet been established. Using the activated clotting time (ACT), the anticoagulatory effect of heparin can be monitored periprocedurally. Previous research on the incidence of both ATEC and bleeding complications, or on the optimal dosage of heparin administration, is scarce. This study aims to investigate the incidence of ATEC and bleeding complications between 2 different dosage protocols of heparin-a standard bolus of 5000 IU or ACT-guided heparinization-and thereby provide clarity on the optimal dose of heparin during peripheral arterial interventions for PAD.

The Effect of Smoking on the Activated Clotting Time and the Incidence of Complications in Noncardiac Arterial Procedures.

PURPOSE: Smoking is a well-known risk factor for developing arterial diseases and for an increase of complications during and after vascular procedures. Although smoking has a proven effect on hemostasis, no literature is available on the effect of smoking on the activated clotting time (ACT), which is used to monitor the effect of heparin during noncardiac arterial procedures (NCAP). The aim of this study was to examine the effect of smoking on ACT values and the incidence of complications during the same admission or 30 day follow-up of NCAP. MATERIALS AND METHODS: A post hoc analysis of a prospective multicenter cohort study was performed. Patients older than 18 years, who underwent NCAP between December 2016 and April 2021, were enrolled. Patients were divided into 2 groups based on smoking status: never/former smokers and current smokers. Two heparin dosing protocols were used: an initial bolus of 5000 IU or 100 IU/kg bodyweight. RESULTS: In total, 773 patients met the inclusion criteria. Five minutes after administration of 5000 IU of heparin, mean ACT values were 190 and 196 seconds for nonsmokers and smokers, respectively (p=0.078). After 100 IU/kg of heparin, mean ACT values were 229 and 226 seconds for nonsmokers and smokers, respectively (p=0.37). Incidence of complications in the whole study cohort was not significantly different for nonsmokers compared with smokers (arterial thrombo-embolic complication [ATEC] 4.7% vs 5.7% p=0.55; hemorrhagic complications 15% vs 18% p=0.29). In subgroup-analysis, a significant difference between smoking groups was found for hemorrhagic complications after open aneurysm repair (p=0.024). However, after adjusting for confounders, the difference between the smoking groups annulled. CONCLUSION: The results of this study suggest that smoking does not have a significant effect on ACT values or on the incidence of complications in NCAP. Large-scale studies are required to further analyze potential factors having an effect on the ACT and perioperative and postoperative complications, which could help individualize heparinization strategy. CLINICAL IMPACT: There is high variance between patients in their response on administration of heparin, this is not yet fully understood. This study investigated the effect of smoking in a large prospective multicentre cohort. The results suggests that active smoking does not have an effect on the activated clotting time after administration of heparin. Also no significant effect of smoking could be found on the incidence of all registered complications. Monitoring of the effect of heparin remains important to provide patients with safe anticoagulation during vascular procedures.

Perprocedural Heparinization in Non-cardiac Arterial Procedures: The Current Practice in the Netherlands.

PURPOSE: Heparin is the most widely-used anticoagulant to prevent thrombo-embolic complications during non-cardiac arterial procedures (NCAP). Unfortunately, there is a lack of evidence and consequently non-uniformity in guidelines on perprocedural heparin management. Detailed insight into the current practice of antithrombotic strategies during NCAP in the Netherlands is important, aiming to identify potential optimal protocols and local differences concerning perprocedural heparinization. MATERIALS AND METHODS: A comprehensive online survey was distributed electronically to vascular surgeons of every hospital in the Netherlands in which NCAP were performed. Data were collected from September 2020 to October 2021. RESULTS: The response rate was 90% (53/59 hospitals). During NCAP, all surgeons generally administered heparin before arterial clamping. In 74% (39/54) of hospitals, a single heparin dosing protocol was used for all types of patients and vascular procedures. In 40%, there was no uniformity in heparin dosing between vascular surgeons. Depending on the procedure, a fixed bolus heparin, predominantly 5000 IU, was administered in 73% to 93%. In the remaining hospitals (7%-27%), a bodyweight-based heparin protocol was used, with an initial dose of 70 or 100 IU/kg. A minority (28%) monitored the effect of heparin in patients using the activated clotting time add (ACT) after activated clotting time. Target values varied between 180 and 250 seconds or 2 times the baseline ACT. CONCLUSION: This survey demonstrates considerable variability in perprocedural heparinization during NCAP in the Netherlands. Future research on heparin dosing is needed to harmonize and optimize heparin dosage protocols and contemporary guidelines during NCAP, and thereby improve vascular surgical care and patient safety. CLINICAL IMPACT: This survey demonstrated persisting intra- and inter-hospital variability in perprocedural heparinization during non-cardiac arterial procedures (NCAP) in the Netherlands. The observed variability in heparinization strategies highlights the need for high quality evidence on perprocedural anticoagulation strategies. This is needed in order to harmonize and optimize heparin dosage protocols and contemporary guidelines and thereby improve vascular surgical patient care. Based on the current results, an international survey will be conducted by the authors to gain additional insight into the antithrombotic strategies used during NCAP, aiming to harmonize anticoagulation protocols worldwide.

Active aortic aneurysm sac treatment with shape memory polymer during endovascular aneurysm repair.

Preprocedural image analysis and intraprocedural techniques to fully treat infrarenal abdominal aortic aneurysm sacs outside of the endograft with shape memory polymer (SMP) devices during endovascular aneurysm repair were developed. Prospective, multicenter, single-arm studies were performed. SMP is a porous, self-expanding polyurethane polymer material. Target lumen volumes (aortic flow lumen volume minus endograft volume) were estimated from the preprocedural imaging studies and endograft dimensions. SMP was delivered immediately after endograft deployment via a 6F sheath jailed in a bowed position in the sac. Technical success was achieved in all cases, defined as implanting enough fully expanded SMP volume to treat the actual target lumen volume.

Unfractionated heparin and the activated clotting time in non-cardiac arterial procedures.

INTRODUCTION: Unfractionated heparin is administered during non-cardiac arterial procedures (NCAP) to prevent thromboembolic complications. In order to achieve a safe level of anticoagulation, the effect of heparin can be measured. The aim of this review was to provide an overview on what is known about heparin, suggested tests to monitor the effect of heparin, including the activated clotting time (ACT), and the factors that could influence that ACT. EVIDENCE ACQUISITION: A literature search in PubMed was performed. Articles reporting on heparin, clotting time tests (including thrombin time, activated partial thromboplastin time, anti-activated factor X and ACT), and ACT measurement devices were selected. EVIDENCE SYNTHESIS: Heparin has a non-predictable effect in the individual patient, which could be measured using the ACT. However, ACT values can be influenced by many factors, such as hemodilution, hypothermia and thrombocytopenia. In addition, a high variation in ACT outcomes is found between measurement devices of different brands. In the sparse literature on the role of ACT during NCAP, no consensus has been reached on optimal target ACT values. An ACT >250 seconds leads to more bleeding complications. Females have a longer ACT after heparin administration, with a higher risk of bleeding complications. CONCLUSIONS: The effect of heparin is unpredictable. ACT can be used to monitor the effect of heparin and achieve individualized anticoagulation, tailored to the patient and the specifics of the operative procedure. However, the ACT itself can be affected by several factors and caution must be present, as measured ACT values differ between measurement devices.

Major Bleeding During Thrombolytic Therapy for Acute Lower Limb Ischaemia: Value of Laboratory Tests for Clinical Decision Making, 17 Years of Experience.

OBJECTIVE: Regular measurement of fibrinogen as dose guidance in catheter directed thrombolysis (CDT) for acute limb ischaemia (ALI) has recently been dropped from European guidelines based on inconsistent literature. This study aimed to determine whether low fibrinogen levels and high activated partial thromboplastin time (APTT) are associated with an increased major bleeding risk during CDT. METHODS: All consecutive patients treated with CDT for ALI in two Dutch hospitals between January 2004 and April 2021 were analysed retrospectively. Patients were treated with two dosing regimens (low dose: 50 000 IU/hour; high dose: 100 000 IU/hour) of urokinase and, after 2018, with a single low dose regimen of alteplase (rtPA) due to urokinase manufacturing problems. The incidence of major bleeding and associated APTT and fibrinogen levels were reviewed from patient charts. RESULTS: Of the 443 included cases, 277 underwent CDT with urokinase and 166 with rtPA. The incidence of major bleeding in the whole cohort was 7%. Patients with a fibrinogen levels < 1.0 g/L developed more major bleeding than those in whom the fibrinogen level did not drop below 1.0 g/L (15% vs. 6%; p = .041). Systemic heparinisation during CDT or high (> 80 seconds) APTT were not significantly associated with major bleeding. Angiographic success (47% vs. 72%; p = .003) and 30 day amputation free survival (53% vs. 82%; p < .001) were lower for cases with major bleeding. Older age (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.02 - 1.11), cardiac history (OR 3.35, 95% CI 1.39 - 8.06), high dose regimens (≥ 75 000 IU/hour urokinase; OR 2.67, 95% CI 1.18 - 6.04), and fibrinogen values < 1.0 g/L (OR 5.59, 95% CI 1.98 - 15.77) were independent predictors for major bleeding during CDT. CONCLUSION: High dose thrombolytic regimens and fibrinogen levels of ≤ 1.0 g/L are associated with more major bleeding during thrombolytic therapy. Major bleeding significantly worsened the clinical outcome. A prospective comparative study is needed to assess the benefit of monitoring fibrinogen levels.

Editor's Choice - Sex Differences in Response to Administration of Heparin During Non-Cardiac Arterial Procedures.

OBJECTIVE: Females are more prone to complications during non-cardiac arterial procedures (NCAPs) than males. The current study investigated the difference in the effect of peri-procedural prophylactic heparin in males and females, using the activated clotting time (ACT). This was a retrospective analysis of a prospective multicentre cohort study. METHODS: All patients undergoing elective NCAP using heparin and ACT measurements between January 2016 and March 2020 were included. Two heparin dosage protocols were used: weight based dosing of 100 IU/kg (international units per kilogram) or a bolus of 5 000 IU. The primary outcome was the anticoagulatory effect of heparin after five minutes, measured by ACT. Secondary outcomes were the effect of heparin after 30 minutes, bleeding complications, and arterial thromboembolic complications (ATECs). RESULTS: A total of 778 patients were included; 26% were female. After 100 IU/kg (n = 300), females more often reached longer ACT (< 200 seconds: 22% vs. 25%, p = .62; 200 - 250 seconds: 41% vs. 53%, p = .058; 251 - 280 seconds, 26% vs. 15%, p = .030). The mean ACT after 100 IU/kg heparin was 233 seconds (95% confidence interval [CI] 224 - 243) for females and 226 seconds (95% CI 221 - 231) for males (p = .057). After a bolus of 5 000 IU of heparin (n = 411), females reached significantly higher levels of anticoagulation than males (mean ACT 204 seconds vs. 190 seconds: p ≤ .001; ACT < 200 seconds: 44% vs. 66%; p < .001; ACT 200 - 250 seconds: 47% vs. 30%, p = .001; ACT 251 - 280 seconds: 7.8% vs. 2.3%, p = .009). Thirty minutes after heparin administration, 58% of all patients had an ACT < 200 seconds. ATECs did not differ between females and males (6.9% vs. 5.1%, p = .33) but bleeding complications were higher in females (27% vs. 16%, p = .001). CONCLUSION: Heparin leads to significantly longer ACT in females during NCAP. Further research is needed to investigate whether individually based heparin protocols lead to fewer bleeding complications and lower incidence of ATECs.

Weight Based Heparin Dosage with Activated Clotting Time Monitoring Leads to Adequate and Safe Anticoagulation in Non-Cardiac Arterial Procedures.

BACKGROUND: Unfractionated heparin has an unpredictable effect in an individual patient. The activated clotting time (ACT) can be used to measure the effect of heparin in the individual patient and guide additional heparin dosages. Previous cohort studies showed that a standardized bolus of 5,000 IU during noncardiac arterial procedures (NCAP) does not lead to an adequate ACT in the vast majority of patients. The aim of this study was to investigate whether an initial heparin dose of 100 IU/kg leads to an adequate but safe ACT, from 200 to 300 s. METHODS: In this multicenter prospective study, 186 patients undergoing NCAP were enrolled and received an initial heparin dose of 100 IU/kg. Target ACT was set at ≥250 s initially; during the course of the study the target ACT was lowered to ≥200 s. After the initial heparin dose, additional heparin dosages were administered depending on the ACT values following a heparin dose protocol. ACT measurements and complications were monitored. RESULTS: The mean baseline ACT was 134 ± 17 s. The mean ACT 5 minutes after the initial heparin dose was 227 ± 37 s. After the initial dose of heparin, 78 and 46% of patients reached an ACT of 200 and 250 s, respectively. Seven patients (4%) reached an ACT of 300 s or more. Ninety-four patients (51%) received at least one additional dose of heparin. After one additional dose of heparin, 91% of patients reached an ACT of 200 s and 13 patients (7%) reached an ACT of 300 s or more. Arterial thromboembolic complications occurred in 4.3% and bleeding complications occurred in 9.7%. CONCLUSIONS: A bolus of 100 IU/kg of heparin during NCAP results in adequate coagulation in most patients. ACT measurements enable accurate additional dosing, ensuring the individual patient tailored and safe coagulation. KEY WORDS: anticoagulants; heparin; blood coagulation tests; vascular surgical procedures; peripheral vascular disease.

Nationwide Experience with EVAS Relining of Previous Open or Endovascular AAA Treatment in The Netherlands.

OBJECTIVE: Relining of a previously placed surgical graft or endograft for an abdominal aortic aneurysm (AAA) is a reintervention to treat progression of disease or failure of the primary (endo)graft. Endovascular Aneurysm Sealing (EVAS) relining is a technique with potential advantages due to the absence of a bifurcation, the possibility for a unilateral approach, and sealing concept of the endobags. The purpose of this study was to describe the nationwide experience with EVAS relining of previous AAA repair in the Netherlands. METHODS: A retrospective analysis of all patients who underwent EVAS relining in 7 high volume vascular centres in the Netherlands between 2014 and 2019 was performed. Primary outcomes were technical and clinical success. Secondary outcomes were perioperative outcomes, complications and survival. RESULTS: Thirty-three patients underwent EVAS relining of open (n = 10) or endovascular (n = 23) repair. 26 were elective cases, 5 were urgent and 2 were acute (ruptured). Mean time between primary treatment and EVAS relining was 99 ± 74 months. Indications after open repair were proximal progression of disease (n = 7) and graft defect (n = 3). Indications after EVAR were type IA (n = 10), type IB (n = 3), type IIIA (n = 4), type IIIB (n = 3) endoleak, and endotension (n = 3). 18 patients underwent regular EVAS, 4 unilateral EVAS and 11 chimney-EVAS. In-hospital mortality was 6% (both patients with rAAA). Technical success was achieved in 97%. Median follow-up after EVAS relining was 20 months (range 0-43). Freedom from reintervention at 1-year and 2-year were 83% and 61% and the estimated survival 79% and 71%, respectively. EVAS relining after open repair had a clinical success of 90% at 1-year and of 70% at latest follow-up, while after EVAR clinical success rates were 70% and 52%, respectively. CONCLUSION: EVAS relining of previous AAA repair is associated with high technical success, however with limited clinical success at median follow-up of 20 months. Clinical success was higher in patients with EVAS relining after open repair than after EVAR. In patients with failed AAA repair, EVAS relining should only be considered, when established techniques such as fenestrated repair or open conversion are not available or indicated.

ACTION-1: study protocol for a randomised controlled trial on ACT-guided heparinization during open abdominal aortic aneurysm repair.

BACKGROUND: Heparin is used worldwide for 70 years during all non-cardiac arterial procedures (NCAP) to reduce thrombo-embolic complications (TEC). But heparin also increases blood loss causing possible harm for the patient. Heparin has an unpredictable effect in the individual patient. The activated clotting time (ACT) can measure the effect of heparin. Currently, this ACT is not measured during NCAP as the standard of care, contrary to during cardiac interventions, open and endovascular. A RCT will evaluate if ACT-guided heparinization results in less TEC than the current standard: a single bolus of 5000 IU of heparin and no measurements at all. A goal ACT of 200-220 s should be reached during ACT-guided heparinization and this should decrease (mortality caused by) TEC, while not increasing major bleeding complications. This RCT will be executed during open abdominal aortic aneurysm (AAA) surgery, as this is a standardized procedure throughout Europe. METHODS: Seven hundred fifty patients, who will undergo open AAA repair of an aneurysm originating below the superior mesenteric artery, will be randomised in 2 treatment arms: 5000 IU of heparin and no ACT measurements and no additional doses of heparin, or a protocol of 100 IU/kg bolus of heparin and ACT measurements after 5 min, and then every 30 min. The goal ACT is 200-220 s. If the ACT after 5 min is < 180 s, 60 IU/kg will be administered; if the ACT is between 180 and 200 s, 30 IU/kg. If the ACT is > 220 s, no extra heparin is given, and the ACT is measured after 30 min and then the same protocol is applied. The expected incidence for the combined endpoint of TEC and mortality is 19% for the 5000 IU group and 11% for the ACT-guided group. DISCUSSION: The ACTION-1 trial is an international RCT during open AAA surgery, designed to show superiority of ACT-guided heparinization compared to the current standard of a single bolus of 5000 IU of heparin. A significant reduction in TEC and mortality, without more major bleeding complications, must be proven with a relevant economic benefit. TRIAL REGISTRATION {2A}: NTR NL8421 ClinicalTrials.gov NCT04061798 . Registered on 20 August 2019 EudraCT 2018-003393-27 TRIAL REGISTRATION: DATA SET {2B}: Data category Information Primary registry and trial identifying number ClinicalTrials.gov : NCT04061798 Date of registration in primary registry 20-08-2019 Secondary identifying numbers NTR: NL8421 EudraCT: 2018-003393-27 Source(s) of monetary or material support ZonMw: The Netherlands Organisation for Health Research and Development Dijklander Ziekenhuis Amsterdam UMC Primary sponsor Dijklander Ziekenhuis Secondary sponsor(s) N/A Contact for public queries A.M. Wiersema, MD, PhD Arno@wiersema.nu 0031-229 208 206 Contact for scientific queries A.M. Wiersema, MD, PhD Arno@wiersema.nu 0031-229 208 206 Public title ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair (ACTION-1) Scientific title ACTION-1: ACT Guided Heparinization During Open Abdominal Aortic Aneurysm Repair, a Randomised Trial Countries of recruitment The Netherlands. Soon the recruitment will start in Germany Health condition(s) or problem(s) studied Abdominal aortic aneurysm, arterial disease, surgery Intervention(s) ACT-guided heparinization 5000 IU of heparin Key inclusion and exclusion criteria Ages eligible for the study: ≥18 years Sexes eligible for the study: both Accepts healthy volunteers: no Inclusion criteria: Study type Interventional Allocation: randomized Intervention model: parallel assignment Masking: single blind (patient) Primary purpose: treatment Phase IV Date of first enrolment March 2020 Target sample size 750 Recruitment status Recruiting Primary outcome(s) The primary efficacy endpoint is 30-day mortality and in-hospital mortality during the same admission. The primary safety endpoint is the incidence of bleeding complications according to E-CABG classification, grade 1 and higher. Key secondary outcomes Serious complications as depicted in the Suggested Standards for Reports on Aneurysmal disease: all complications requiring re-operation, longer hospital stay, all complications.

More Effective Anticoagulation During Non-Cardiac Arterial Procedures Using Activated Clotting Time Guided Heparin Administration.

OBJECTIVES: Arterial thrombo-embolic complications (ATEC) are still common during and after non-cardiac arterial procedures (NCAP) despite the administration of (a fixed bolus of) heparin. These ATEC could be due to existing individual differences in heparin sensitivity. The purpose of this study was to evaluate the feasibility and safety of an ACT guided heparin dose protocol and to evaluate if a more effective target ACT can be achieved during NCAP. METHODS: In this multi-center prospective study, 194 patients undergoing elective and non-elective NCAP were enrolled and received heparin according to a heparin dose protocol which aimed to obtain a target ACT of 250 seconds (s.), measured by the Medtronic HMS Plus. Patients received a standardized bolus of 5 000 IU followed by additional boluses depending on the actual ACT. Primary outcome was the ACT value reached. Secondary outcomes were incidence of all ATEC and haemorrhagic complications. RESULTS: The mean baseline ACT was 138 ± 17 s. The mean ACT five minutes after the initial heparin bolus of 5 000 IU was 197 ± 31 s. 48% of patients reached an ACT of 200 s. and six per cent of patients reached an ACT of 250 s. Additional dosages of heparin were administered in 72% of patients. With this ACT guided heparin protocol 86% of patients reached an ACT of 200 s. and 26% of patients reached an ACT of 250 s. A negative correlation was found between body weight and the ACT at T1 (P ˂ 0.001). ATEC and haemorrhagic complications occurred in 11.3% and 16.5% of patients. The lowest incidence of ATEC was found in patients with peak ACT between 200 and 250 s, namely 6.3%. CONCLUSION: This ACT guided heparin protocol proved to be feasible, safe and more patients reached an ACT > of 200 s. compared to a standardized heparin bolus of 5 000 IU. Further research is needed to investigate if ACT guided heparin administration could be preferable over not monitoring the anticoagulant effect of peri-procedural heparin and results in a lower incidence of ATEC, without an increase in haemorrhagic complications.

Survival and Living Situation After Ruptured Abdominal Aneurysm Repair in Octogenarians.

OBJECTIVE: To determine the 30 day and one year mortality and post-operative living situation in octogenarians treated for ruptured abdominal aortic aneurysm (rAAA). METHODS: A retrospective study was performed at four centres in the Netherlands. All consecutive patients aged ≥80 years, presenting with a rAAA between January 2013 and October 2018, were included. The primary outcomes were post-operative living situation and one year mortality. RESULTS: In total, 157 patients were included. Forty-seven received palliative care and 110 patients had surgery. After endovascular or open repair, the one year mortality rate was 50.0%. The 30 day mortality rate was 40.8% (95% confidence interval [CI] 27-55) and 31.7% (95% CI 20-44), for endovascular and open repair, respectively (p = .32). Sixty-five per cent of survivors were discharged home, while 34.8% went to a nursing home for rehabilitation. Of the surviving patients, 82.6% went back to living in their pre-rupture home situation. Of the investigated variables, only a high body mass index proved a significant predictor of death at 30 days and one year. Compared with operated patients, patients turned down for surgery were older (mean age 87.5 ± 3.8 vs. 84.0 ± 3.5; p < .001), lived significantly more often in a nursing home (odds ratio 1.02, 95% CI 1.00-1.03; p < .001), were more often dependent (odds ratio 3.69, 95% CI 2.31-5.88; p < .001) and had a lower Glasgow Coma Scale score on arrival (odds ratio 0.42, 95% CI 0.25-0.69; p = .002). All palliative patients died within three days. CONCLUSION: Overall treatment outcomes showed that octogenarians should not be denied surgery based on age alone, as half of the octogenarians that undergo surgical treatment are still alive one year after rAAA repair. In addition, > 80% returned to their own home after rehabilitation.

A Standardized Bolus of 5 000 IU of Heparin Does not Lead to Adequate Heparinization during Non-cardiac Arterial Procedures.

BACKGROUND: In non-cardiac arterial procedures (NCAP), heparin is administered to prevent arterial thromboembolic complications (ATEC). Heparin has a nonpredictable effect in the individual patient, also known as variation in heparin sensitivity. Various dosing protocols are in use, but the optimal dose is currently still unknown. A standardized bolus of 5 000 IU heparin is most frequently used by vascular surgeons and interventional radiologists. The activated clotting time (ACT) is an established method to measure the level of anticoagulation, but has, until now, not gained widespread use in NCAP. The purpose of this study was to evaluate the anticoagulant effect during NCAP of a standardized bolus of 5 000 IU heparin by measuring the ACT. METHODS: In this prospective study, 190 patients undergoing NCAP were enrolled between December 2016 and September 2018. The ACT was measured during open and endovascular/hybrid procedures. All patients received a standardized bolus of 5 000 IU heparin. The ACT was measured by the Hemostasis Management System Plus (HMS Plus, Medtronic®), before, 5 minutes after administration of heparin, and every 30 minutes thereafter. The primary outcome was periprocedural ACT values measured. Secondary outcomes were ATEC and hemorrhagic complications. RESULTS: A large individual patient variability in the response to heparin was found. The mean baseline ACT in all patients was 129 ± 18 s., and the mean ACT 5 minutes after the initial bolus of heparin was 191 ± 36 s. After the initial dose of 5 000 IU heparin 60 (33%) and 10 (6%) patients reached an ACT of 200 and 250 s., respectively. Despite the use of heparin, ATEC occurred in 17 patients (9%). The lowest number of ATEC occurred in the group of patients with an ACT between 200 and 250 s. CONCLUSIONS: A standardized bolus of 5 000 IU heparin does not lead to adequate and safe heparinization in non-cardiac arterial procedures. Patient response to heparin shows a large individual variability. Therefore, routine ACT measurements are necessary to ascertain adequate anticoagulation. Further research is needed to investigate if heparin dosing based on the ACT could result in less arterial thromboembolic complications, without increasing hemorrhagic complications.

Outcome of Ruptured Abdominal Aortic Aneurysm Repair in Octogenarians: A Systematic Review and Meta-Analysis.

OBJECTIVE: This meta-analysis sought to identify the mortality and ambulatory state 30 days and one year post-operatively in octogenarians treated for ruptured abdominal aortic aneurysm (rAAA) by endovascular aneurysm repair (EVAR) or open repair (OR). rAAA is a life threatening emergency occurring increasingly in octogenarians. Surgical treatment, open or endovascular, offers the only chance of survival albeit with significant mortality and morbidity rates and a high burden to society. In order to make an informed decision on management, contemporary treatment outcomes should be known. The aim of this study was to perform a systematic review and meta-analysis on rAAA repair in octogenarians. METHODS: The Pubmed, Embase and Cochrane databases were searched for articles published between 2013 and October 2018 on octogenarians treated for a rAAA. Meta-analysis was performed using the random effects model to calculate the 30 day and one year mortality. RESULTS: The search resulted in a total of 1569 articles, of which eight retrospective studies could be included, reporting on 7526 patients. All studies reported 30 day mortality in octogenarians, and the one year mortality was addressed in four studies. Ambulatory state was not reported. Meta-analysis showed a 30 day mortality of 43% (95% confidence interval (CI) 33-53) and a one year mortality of 47% (95% CI 32-62). Patients after EVAR had a significant lower mortality at 30 days (risk ratio (RR) 0.50, 95% CI 0.38-0.67) and at one year (RR 0.65, 95% CI 0.44-0.96). CONCLUSION: The 30 day and one year mortality rates for rAAA repair in octogenarians are similar to the outcome at all ages, with a significant survival advantage of EVAR over OR. Patients should therefore not be denied treatment of a rAAA based on age alone.

No Concluding Evidence on Optimal Activated Clotting Time for Non-cardiac Arterial Procedures.

OBJECTIVES: Heparin has a non-predictable effect in the individual patient. The activated clotting time (ACT) is used to measure the level of anticoagulation after administration of heparin. To date, appropriate heparin dose protocols and corresponding therapeutic ACT values have not been established in non-cardiac arterial procedures (NCAP). The aim of this review was to study the use of ACT monitoring during NCAP, and whether an optimal ACT could be determined based on the fewest arterial thrombo-embolic complications (ATEC) and bleeding complications. METHODS: This systematic review was performed in accordance with the PRISMA Guidelines. A systematic search was conducted in MEDLINE, EMBASE, and the Cochrane database. Any associations were evaluated between peri-procedural ACT levels and ATEC and bleeding complications detected during the same admission as the primary procedure or during 30 day follow up. Also, heparin dose protocols, peri-procedural target ACTs, different ACT devices, protamine use and pre-, peri-, and post-procedural anticoagulation therapy were evaluated. RESULTS: In total, 21 studies with 3982 patients were included, on both open and endovascular NCAP. Four studies were primarily designed to correlate peak peri-procedural ACT with clinical outcomes; however, the definitions of the results and the clinical outcomes were too heterogeneous for analysis. There was major variability in all studied aspects of ACT measurement, heparin and protamine use, and in the type of procedures in the included studies. Overall methodological quality of the included studies was poor. No randomised controlled trials were found. Studies were at a high risk of bias. CONCLUSIONS: This systematic review demonstrates a lack of data and no consensus in the literature concerning the optimal ACT, and the possible association with haemorrhagic complications and ATEC during NCAP.