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Clinical Research| Volume 71, P280-287, February 2021

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

  • Orkun Doganer
    Correspondence
    Correspondence to: Orkun Doganer, Department of Vascular Surgery, Dijklander Ziekenhuis, Maelsonstraat 3, 1624 NP Hoorn, the Netherlands
    Affiliations
    Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands

    Department of Vascular Surgery, Amsterdam University Medical Centers location VU Medical Center, Amsterdam, the Netherlands
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  • Vincent Jongkind
    Affiliations
    Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands

    Department of Vascular Surgery, Amsterdam University Medical Centers location VU Medical Center, Amsterdam, the Netherlands
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  • Jan D. Blankensteijn
    Affiliations
    Department of Vascular Surgery, Amsterdam University Medical Centers location VU Medical Center, Amsterdam, the Netherlands
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  • Kak Khee Yeung
    Affiliations
    Department of Vascular Surgery, Amsterdam University Medical Centers location VU Medical Center, Amsterdam, the Netherlands
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  • Arno M. Wiersema
    Affiliations
    Department of Vascular Surgery, Dijklander Ziekenhuis, Hoorn, the Netherlands

    Department of Vascular Surgery, Amsterdam University Medical Centers location VU Medical Center, Amsterdam, the Netherlands
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Published:August 05, 2020DOI:https://doi.org/10.1016/j.avsg.2020.07.035

      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.

      Introduction

      Unfractionated heparin (in short: heparin), a sulfated glycosaminoglycan, is administered during non-cardiac arterial procedures (NCAP) to prevent arterial thromboembolic complications (ATEC). Heparin has a well-established anticoagulatory effect and has been used for more than 70 years.
      • Murray G.
      Heparin in surgical treatment of blood vessels.
      Despite its widespread application, many pharmacodynamic specifics of heparin are still not widely recognized.
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      Most importantly, heparin has a nonlinear dose-response curve and a nonlinear elimination curve in the individual patient.
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      Furthermore, the effect of heparin varies between different brands of heparin and even between batches of the same brand.
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      • et al.
      Subtle differences in commercial heparins can have serious consequences for cardiopulmonary bypass patients: a randomized controlled trial.
      During cardiac interventions, the anticoagulant effect of heparin is therefore routinely monitored using the activated clotting time (ACT).
      • Hattersley P.G.
      Activated coagulation time of whole blood.
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      Target ACT values have been incorporated in guidelines, but the range of these target ACT levels in cardiac interventions is quite broad and varies between guidelines (200 to 375 s., depending on the procedure, even higher for cardiopulmonary bypass).
      • Bull B.S.
      • Huse W.M.
      • Brauer F.S.
      • et al.
      Heparin therapy during extracorporeal circulation. II. The use of a dose-response curve to individualize heparin and protamine dosage.
      • Tolleson T.R.
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      • et al.
      Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial.
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      • et al.
      Revisiting optimal anticoagulation with unfractionated heparin during coronary stent implantation.
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      • et al.
      Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention.
      In contrast, in a systematic review of the literature on the optimal ACT during NCAP, a lack of data and absence of consensus was found.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      Current guidelines on the treatment of patients during NCAP do not offer evidence based recommendations for heparin dose or target ACT values.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • et al.
      Inter-society consensus for the management of peripheral arterial disease (TASC II).
      • Chaikof E.L.
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      • et al.
      The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm.
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • et al.
      (ESVS) 2019 clinical practice guidelines on the management of abdominal aorto-iliac artery aneurysms.
      Accordingly, there is a wide variety in heparin dose protocols. A fixed dose of heparin (5 000 international units (IU)) is most widely used but various body weight-dependent doses (60–100 IU/kg) are also often used.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      ,
      • Wakefield T.W.
      • Lindblad B.
      • Stanley T.J.
      • et al.
      Heparin and protamine use in peripheral vascular surgery: a comparison between surgeons of the Society for Vascular Surgery and the European Society for Vascular Surgery.
      • Wiersema A.M.
      • Vos J.A.
      • Bruijninckx C.M.A.
      • et al.
      Periprocedural prophylactic antithrombotic strategies in interventional radiology: current practice in The Netherlands and comparison with the United Kingdom.
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      • et al.
      Perioperative prophylactic antithrombotic strategies in vascular surgery: current practice in The Netherlands.
      • Poisik A.
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      • et al.
      Safety and efficacy of fixed-dose heparin in carotid endarterectomy.
      • Veerhoek D.
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      • van der Sluijs M.G.J.M.
      • et al.
      Individual differences in heparin sensitivity and their effect on heparin anticoagulation during arterial vascular surgery.
      • Lensvelt M.M.A.
      • Holewijn S.
      • Fritschy W.M.
      • et al.
      SUrgical versus PERcutaneous Bypass: SUPERB-trial; Heparin-bonded endoluminal versus surgical femoro-popliteal bypass: study protocol for a randomized controlled trial.
      • Roy M.
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      • Ruel M.
      • et al.
      Anticoagulation obtained below the arterial Clamp using a single fixed bolus of heparin in vascular surgery: a Pilot study.
      • Nissborg E.
      • Wahlgren C.M.
      Anticoagulant effect of standard dose heparin during peripheral endovascular intervention.
      To date, no comparative studies have been performed investigating different heparin dose protocols in relation to clinical outcome parameters in NCAP.
      During NCAP, the anticoagulant effect of heparin in the individual patient is not monitored as standard operating procedure by measuring the ACT. Previous studies report conflicting results and currently, there is a lack of a proven compelling clinical advantage of standard ACT measurements during NCAP. In absence of this evidence, measuring the ACT represents adjunctive procedures with concomitant costs and is therefore not common practice.
      However, the incidence of ATEC and bleeding complications in NCAP is still substantial. The success of arterial procedures depends largely on the delicate balance between coagulation and anticoagulation, and an optimal heparin dose could play a major role in this balance. The measuring the ACT during non-cardiac arterial procedures (MANCO) consortium was created to investigate optimal heparin dosing during NCAP.
      Measuring the ACT During Non-cardiac Arterial Procedures. (MANCO); ClinicalTrials.gov Identifier: NCT03426293.
      The first step toward better patients’ safety in NCAP is measuring ACT in current practice.
      The purpose of the present study was to investigate the feasibility of routine ACT measurements during NCAP, to measure the ACT after a standardized heparin bolus of 5 000 IU and to investigate the occurrence of ATEC and hemorrhagic complications in a large prospective cohort series.

      Materials and Methods

      Design and Patients

      The MANCO registry is an ongoing, prospective, multicenter registry for patients undergoing NCAP at the participating hospitals. The MANCO registry is registered at clinicaltrials.gov (NCT number: NCT03426293; NTR ID: NL6788).
      Measuring the ACT During Non-cardiac Arterial Procedures. (MANCO); ClinicalTrials.gov Identifier: NCT03426293.
      In the MANCO registry, ACT measurements are used for the evaluation of different local heparin protocols. In the present study, patients were evaluated when undergoing NCAP with a specific heparinization protocol. All included patients received a standardized bolus of 5 000 IU of unfractionated heparin. Patients were enrolled in this study from December 2016 to September 2018. All included patients who received a standardized bolus of 5 000 IU heparin were from a single, high-volume hospital. Local ethics committee approval was obtained. Patients with chronic renal failure (creatinine clearance below 30 ml/min.) and protocol violation (initial heparin dose unequal to 5 000 IU) were excluded. No patient had a thrombophilia at baseline. Data record included, among others, age, gender, body weight, height, preprocedural and postprocedural antithrombotic therapy, and variables related to the surgical procedure. The patients were divided into three groups based on the type of procedure: open, endo, and hybrid (combining open and endovascular techniques, most commonly common femoral artery endarterectomy and percutaneous transluminal angioplasty with or without stenting of iliac or femoral arteries). Patient data were checked by two authors (O.D. and A.W.).

      Heparin Dosing

      All included patients received a fixed single bolus of 5 000 IU heparin intravenously before cross-clamping or after insertion of the sheath in case of endovascular procedures. No additional dosages of heparin were administered. Administration of heparin was performed by the anesthesiology assistant on request of the surgeon. Local flushing of arteries with heparin solution was routinely performed, using a solution of 10,000 IU heparin in 1 000 mL 0.9% sodium chloride (10 IU heparin/mL). The total amount used for flushing per procedure was estimated 20 mL, equaling 200 IU of heparin.

      Anticoagulation Monitoring

      ACT measurements were performed as a bedside point-of-care test with the Hemostasis Management System Plus (HMS Plus, Medtronic Inc.®, Minneapolis, MN, USA). The high range-activated clotting time cartridges (HR-ACT, Medtronic Inc.®, Minneapolis, MN, USA) were used to measure the ACT. Blood samples for ACT measurements were collected from a radial artery catheter into 3 ml tubes. The first 5 ml of blood was discarded to avoid contamination of the sample with heparin used for flushing. The ACT was measured at the following times: after anesthetic induction (T0), 5 minutes after the administration of heparin (T1), and at 30 minute intervals thereafter (T2 and so on). In addition, an ACT increase of 50 and 100% from the baseline ACT was analyzed. Feasibility of implementation of the ACT measurement procedure was tested by analyzing the success rate of the actual tests performed in relation to the maximum possible tests to perform.

      Preprocedural and Postprocedural Antithrombotic Therapy

      Preprocedural monotherapy with acetylsalicylic acid or clopidogrel was continued during the procedure. In case of preprocedural dual antiplatelet therapy, one of both was discontinued, except during carotid endarterectomy. During carotid endarterectomy, dual antiplatelet use was continued. Preprocedural vitamin K antagonists and direct oral anticoagulation drugs were discontinued as per the National Guideline on Antithrombotic Therapy 2 to 5 days preprocedurally.
      Federation of medical specialists in The Netherlands, guideline database, antithrombotic policy, perioperative anticoagulation policy.
      If required (mostly CHA2DS2-Vasc for atrial fibrillation stroke risk > 8) bridging was instituted using low-molecular weight heparin.
      • Camm A.J.
      • Lip G.Y.H.
      • De Caterina R.
      • et al.
      2012 Focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
      If urgent procedures had to be undertaken in < 4–5 days and reversal was required, 1–2 mg vitamin K orally was prescribed to expedite the reversal process. Postprocedural anticoagulation was restarted if hemostasis was secured; postprocedural bridging was applied on indication.

      Protamine

      Protamine could be used at the completion of a procedure to neutralize any residual heparin effect by using a dose of 12.5 to 50 mg per patient. The decision to administer protamine was not protocolized but left to the discretion of the attending vascular surgeon. The decision was mainly based on personal experience or the perceived prolonged coagulation at the operative site.

      Outcome Measurements

      The primary study end point was the level of periprocedural anticoagulation as measured by the ACT. Secondary outcomes were: I) ATEC: graft thrombosis, embolism, myocardial infarction, transient ischemic attack, minor and major stroke, pulmonary embolism, bowel ischemia, unexpected tissue loss/amputation, peripheral emboli or redo surgery of an anastomosis because of clot formation, II) bleeding complications as per European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG) classification grade one or more (grade 0, no need of blood products with the exception of 1 unit of red blood cells (RBCs); grade 1, transfusion of platelets, plasma, or 2 to 4 units of RBCs, or both; grade 2, transfusion of 5 to 10 units of RBCs or reoperation for bleeding, or both; grade 3, transfusion of more than 10 units of RBCs),
      • Mariscalco G.
      • Gherli R.
      • Ahmed A.B.
      • et al.
      Validation of the European multicenter study on coronary artery bypass grafting (E-CABG) bleeding severity definition.
      III) all other complications. All end points were registered during the same admission of the primary procedure or during 30 days follow-up. To explore an optimal ACT value, patients were divided in three groups for all end points: ACT <200 s., ACT between 200 and 250 s., and ACT >250 s.

      Statistical Analysis

      Statistical analysis was performed using the SPSS® statistical software package 22.0 (IBM, New York, NY, USA). Normality test was performed to the set of multiple ACT measurements at T0 and T1. The null hypothesis was that the data were normally distributed, and the alternative hypothesis was that the data were not normally distributed. Based on the number of patients, the Shapiro-Wilk test was used and the data was normal distributed. Continuous, normally distributed variables were expressed as mean ± standard deviation or percentage. Descriptive statistics were used to report and determine the distribution of the ACT. The paired t-test was used to test normal distributed data. The Mann-Whitney U test was used to test skewed and ordinal data. The test results were reported as t-statistics (degrees of freedom), followed by the P-value. A P-value less than 0.05 was considered as statistically significant.

      Results

      Patients

      During the study period, ACT measurements were performed during elective NCAP in 200 patients. Seven patients were excluded from the study because of a renal clearance below 30 ml./min.⁻1. Three other patients were excluded because of protocol deviations. Two patients received 2 500 IU because of an anticipated increased bleeding risk, and one patient mistakenly received 25,000 IU. The ACT measurements of the ten excluded patients were not analyzed. In total, 190 patients were evaluated. The patient characteristics and procedure details are depicted in Table I. The preprocedural and postprocedural antithrombotic therapy is depicted in Table II. All patients received a standardized dose of 5 000 IU heparin, equivalent to a mean dose of 66 ± 14 IU/kg which varied from 37 to 109 IU/kg.
      Table IPatient demographics and procedure details
      Demographics and procedure detailsn = 190
      Age (y)72 ± 10 (39–93)
      Gender
       Male137 (72%)
       Female53 (28%)
      BMI (kg/m2)26 ± 5 (16–41)
      Type of procedure
       Open104 (55%)
       EVAR55 (29%)
       Hybrid31 (16%)
      Type of intervention anatomically
       CEA39 (21%)
       Open AAA21 (11%)
       EVAR55 (29%)
       Open occlusive aortailiac8 (4%)
       Hybrid occlusive aortailiac6 (3%)
       Open peripheral arterial36 (19%)
       Hybrid peripheral arterial25 (13%)
      Mean ± S.E.M. (range).
      BMI, body mass index; CEA, carotid endarterectomy; AAA, abdominal aortic aneurysm repair; EVAR, endovascular aortic aneurysm repair.
      Table IIPreprocedural and postprocedural antithrombotic therapy.
      Type of antithromboticsn = 190
      Preprocedural anticoagulants
       Acetylsalicylic acid42 (22%)
       Clopidogrel70 (37%)
       Dual antiplatelet23 (12%)
       VKA27 (14%)
       DOAC3 (2%)
       Combination12 (6%)
       Other9 (5%)
       None4 (2%)
      Postprocedural anticoagulants
       Acetylsalicylic acid16 (8%)
       Clopidogrel95 (50%)
       Dual antiplatelet22 (12%)
       VKA34 (18%)
       DOAC4 (2%)
       Combination14 (7%)
       Other3 (2%)
       Missing data2 (1%)
      VKA, vitamin K antagonists; DOAC, direct oral anticoagulants.
      During the study period, 190 patients underwent elective NCAP. ACT measurements were performed in 188 (99%) for T0 and 180 (95%) for T1. No periprocedural errors that could have been attributed to performing the ACT measurements were recorded. Missing values were because of timing of the measurements, where the anesthesia assistant who should perform the measurement was busy or distracted because of the situation on the OR.

      Act

      The mean ACT values are depicted in Table III. The mean ACT at T0 was 129 ± 18 s. (n = 188, two missing measurements, range 61–185 s.) (Fig. 1A) and at T1 191 ± 36 s. (n = 180, ten missing measurements, range 103–341 s.) (Fig. 1B). The ACT values at T1 were peak ACT values. However, in 30 of 148 patients (20%), the ACT at T2 was higher than at T1. In 42 patients, the ACT measurement at T1 or T2 was missing and therefore, these were not included in this specific analysis. At T1, 60 patients (33%) reached an ACT of 200 s. and at T2 and T3 (30 minutes and one hour after the initial heparin bolus), this gradually declined to 29 patients (19%) and 11 patients (12%), respectively. At T1, 10 patients (6%) reached an ACT of 250 s. Taking the periprocedural peak ACT into account, 67 patients (35%) reached an ACT of 200 s. and 10 patients (5%) reached an ACT of 250 s. In 123 patients, (65%) the ACT remained < 200 s. The mean procedure time was 133 ± 55 min.
      Table IIIComparison of ACT values between: I) all patients; II) patients with no complications; III) patients with ATEC (arterial occlusions based on graft thrombosis); IV) patients with bleeding complications based on the E-CABG bleeding severity classification; V) patients with bleeding complications based on incidence of local hematoma during 30 day follow-up
      Time of ACT measurement (min.)Mean ACT (s.)

      (n = 190)
      ACT (s.)

      No complications
      No complications including the groups ATEC and bleeding complications based on the E-CABG.
      (n = 155)
      ACT (s.) ATEC (only graft thrombosis)

      (n = 13)
      ACT (s.)

      Bleeding complications
      Bleeding complication based on the E-CABG bleeding severity classification.
      (n = 22)
      ACT (s.)

      Bleeding complications
      Bleeding complications for patients developing wound hematoma during 30 day follow-up.
      (n = 22)
      T0 (0)129 ± 18 (n = 188)128 ± 18 (n = 154)127 ± 17 (n = 12)129 ± 19 (n = 22)139 ± 18 (n = 22)
      T1 (5)192 ± 34 (n = 180)190 ± 32 (n = 146)187 ± 39 (n = 13)207 ± 43 (n = 21)197 ± 30 (n = 21)
      T2 (30)178 ± 26 (n = 153)177 ± 26 (n = 123)172 ± 32 (n = 11)172 ± 44 (n = 20)185 ± 25 (n = 15)
      T3 (60)168 ± 26 (n = 94)170 ± 27 (n = 70)156 ± 16 (n = 8)169 ± 23 (n = 16)177 ± 40 (n = 12)
      T4 (90)161 ± 24 (n = 45)161 ± 22 (n = 32)162 ± 25 (n = 4)164 ± 32 (n = 9)166 ± 40 (n = 6)
      T5 (120)148 ± 25 (n = 13)143 ± 24 (n = 9)-158 ± 27 (n = 4)-
      T6 (150)151 ± 9 (n = 5)150 ± 13 (n = 3)-154 ± 5 (n = 2)-
      Procedure time (min.)-133 ± 55 (n = 187)124 ± 45 (n = 153)160 ± 72 (n = 13)184 75 (n = 21)131 ± 43 (n = 22)
      a No complications including the groups ATEC and bleeding complications based on the E-CABG.
      b Bleeding complication based on the E-CABG bleeding severity classification.
      c Bleeding complications for patients developing wound hematoma during 30 day follow-up.
      Figure thumbnail gr1
      Fig. 1(A) Distribution of the baseline ACT (T0). (B) Distribution of the ACT 5 min. after the initial bolus of 5 000 IU heparin (T1).
      After the initial heparin bolus at T1, 74 patients (42%) had a 50% increase of the baseline ACT. This declined to 44 patients (29%) at T2 and 14 patients (15%) at T3. In addition, after the initial heparin bolus at T1, 9 patients (5%) had a 100% increase of the baseline ACT.
      A 50% increase of the baseline ACT was equal to a mean ACT of 194 ± 28 s. (range 92–278 s.), and a 100% increase of the baseline ACT was equal to a mean ACT of 259 ± 37 s. (range 122–370 s.). With an ACT of 238 s., 94.45% (2 standard deviation) of patients had a 50% increase of the baseline ACT, and with an ACT of 318 s., 94.45% of patients had a 100% increase of the baseline ACT.
      The patients with a body weight of 65–75 kilograms were selected. In these 46 patients, the ACT values at T0 ranged from 84 to 176 s., the ACT at T1 ranged from 137 to 256 s., the ACT at T2 ranged from 142 to 201 s., and the ACT at T3 ranged from 140 to 282 s.

      Protamine

      Ten of the 190 patients (5%) received protamine, of which eight open and two endo procedures. One patient (10%) received a dose of 50 mg, seven patients (70%) received 25 mg, and two patients (20%) received 12.5 mg of protamine. In these ten patients, the ACT at T1 was 224 ± 51 s., which decreased to 138 ± 27 s. at the end of the procedure after protamine administration. In two of these ten patients (20%), a bleeding complication occurred, both grade 1 based on the E-CABG bleeding severity classification, and no patient (0%) developed an ATEC. No relationship was found between the administration of protamine and the number of complications.

      Complications

      Complications are depicted in Table IV: In 17 of 190 patients (9%), ATEC occurred. In 13 patients (7%) (nine open surgery, four hybrid), graft thrombosis occurred. In 10 of these 13 patients (77%), embolectomy or thrombectomy was necessary, nine patients underwent reoperation, and one patient underwent embolectomy during the index procedure. In none of the patients (0%), major cardiac events occurred. Postprocedurally, one patient (1%) developed a pulmonary embolism which was treated with an antithrombotic. One patient (1%) who underwent open repair of an infrarenal abdominal aortic aneurysm developed postprocedural bowel ischemia of the sigmoid and underwent surgical resection. Two patients (1%) underwent unplanned amputation, one patient underwent minor amputation of the hallux, and one patient underwent major amputation of one limb. Two patients (1%) required reoperation because of wound hematoma. One patient (1%) died of colorectal cancer during 30 day follow-up, and there was no other mortality.
      Table IVIncidence of clinical complications during 30 day follow-up
      Complicationn = 190
      ATEC17 (9%)
      Graft thrombosis13 (7%)
      Cardiac events-
      Pulmonary embolism1 (0.5%)
      Renal insufficiency (temporary)5 (3%)
      Bowel ischemia1 (0.5%)
      Unexpected tissue loss/amputation2 (1%)
      Wound infection9 (5%)
      E-CABG bleeding severity classification22 (12%)
       Grade 117 (9%)
       Grade 25 (3%)
      Total periprocedural blood loss (ml)
       Open567 ± 720
       Hybrid224 ± 265
      Noninfectious fluid collection24 (13%)
       Wound hematoma22
       Seroma1
       Lymphocele1
      Death1 (0.5%)
      ATEC, arterial thromboembolic complications; E-CABG, coronary artery bypass grafting bleeding severity classification.
      In patients with an ACT of <200 s. (n = 124), 8.9% ATEC and 9.7% hemorrhagic complications occurred versus 7.3% ATEC and 12.7% hemorrhagic complications in patients with an ACT between 200 and 250 s. (n = 55). In patients with an ACT >250 s. (n = 11), 18.2% ATEC and 27.3% hemorrhagic complications occurred.

      Discussion

      The present study demonstrates that standard ACT measurements are feasible and can safely be implemented during NCAP. A wide variation exists in individual sensitivity to heparin in patients undergoing NCAP measured by the ACT. Despite a standardized bolus of 5 000 IU heparin, ATEC occurred in 17 patients (9%) and hemorrhagic complications in 22 patients (12%). In the heterogeneous patient group of the present study, the lowest number of ATEC occurred in the group of patients with an ACT between 200 and 250 s. as measured by the Hemostasis Management System Plus (HMS Plus, Medtronic Inc.®, Minneapolis, MN, USA).
      Despite being in use for more than 70 years, the optimal dose of heparin during NCAP is unknown. Surveys have shown that a fixed dose of 5 000 IU is most often used, whereas body weight-based dosing is also often applied. Body weight-based dosages vary from 60 to 100 IU/kg.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      No studies have been performed investigating optimal heparin dose based on clinical outcome and practice can vary from country to country or even from surgeon to surgeon. Because of the difficulty to predict the anticoagulatory effect of heparin, measuring the effect of heparin is of potential value to reduce ATEC and hemorrhagic complications in NCAP. The ACT point-of-care test has been the preferred test to monitor the anticoagulant effect of heparin because it has a number of advantages over other laboratory tests (including the APTT and anti-Xa): short time between sampling and results, small blood sample size needed, low errors associated with sample mislabeling or mishandling, and low risk of sample degradation over time.
      • Spinler S.A.
      • Wittkowsky A.K.
      • Nutescu E.A.
      • et al.
      Anticoagulation monitoring part 2: unfractionated heparin and low-molecular-weight heparin.
      Furthermore, the ACT test can be performed by attending and already present personnel during NCAP, such as anesthetic nurses. Plasma anti-Xa is considered the gold standard for measuring plasma heparin concentrations. However, the plasma anti-Xa is not a point-of-care test, can only be measured in few centers, is time-consuming and thus, not applicable in the operating room. A significant variability in ACT values between different brands of ACT devices has been reported.
      • Doherty T.M.
      • Shavelle R.M.
      • French W.J.
      Reproducibility and variability of activated clotting time measurements in the cardiac catheterization laboratory.
      • Chia S.
      • Van Cott E.M.
      • Raffel O.C.
      • et al.
      Comparison of activated clotting times obtained using Hemochron and Medtronic analysers in patients receiving anti-thrombin therapy during cardiac catheterisation.
      • Lee J.M.
      • Park E.Y.
      • Kim K.M.
      • et al.
      Comparison of activated clotting times measured using the Hemochron Jr. Signature and Medtronic ACT Plus during cardiopulmonary bypass with acute normovolemic haemodilution.
      Therefore, findings from the present study cannot be extrapolated on a 1:1 basis to institutions using different brands of ACT devices or different type of cartridges to perform the measurements. The optimal ACT during NCAP is unknown, as was demonstrated in a recently published systematic review.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      Therefore, every institution has to create its own heparin dose protocol and set its own ACT goals.
      Based on the results in this prospective cohort, the definition of the optimal ACT could be 200–250 s., as the number of ATEC and severe bleeding was lowest in the patients with these ACT values. This corresponds well with a 50 to 100% increase compared with the baseline ACT. The variance of ACT values was high in the present study. Interestingly, even in patients with the same body weight. As mentioned in the results in 46 patients with a body weight of 65–75 kilograms, the ACT values at T0 and T1 ranged from 84 to 176 s. and from 137 to 256 s., the ACT at T2 ranged from 142 to 201 s., and the ACT at T3 ranged from 140 to 282 s. This suggests that body weight-based heparin dosing would not result in predictable ACT values either. Body weight-based dosing therefore does not seem to exclude the need to determine the value of the actual ACT during NCAP.
      No robust evidence exists on the subject of heparin reversal by using protamine. Routine use of protamine during elective peripheral vascular surgical reconstruction does not appear to provide any clinical benefit.
      • Coyne T.J.
      • Wallace M.C.
      • Benedict C.
      Peri-operative anticoagulant effects of heparinization for carotid endarterectomy.
      • Szalados J.E.
      • Ouriel K.
      • Shapiro J.R.
      Use of the activated coagulation time and heparin dose-response curve for the determination of protamine dosage in vascular surgery.
      • Dorman B.H.
      • Elliott B.M.
      • Spinale F.G.
      • et al.
      Protamine use during peripheral vascular surgery: a prospective randomized trial.
      Reversing heparin with protamine reduces postprocedural wound drainage after carotid surgery but may predispose to internal carotid artery thrombosis and stroke.
      • Fearn S.J.
      • Parry A.D.
      • Picton A.J.
      • et al.
      Should heparin be reversed after carotid endarterectomy? A randomised prospective trial.
      Furthermore, elevated protamine concentrations are associated with progressive dose-dependent reduction in thrombin generation resulting in an increased risk of hemorrhagic complications.
      • Ni Ainle F.
      • Preston R.J.S.
      • Jenkins P.V.
      • et al.
      Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation.
      Further research is needed to address the dosing and beneficiary effect of protamine during NCAP. However, it seems self-evident that administering protamine without knowing the actual (anti)coagulation status of the patient seems not logical and not safe.
      The costs for the ACT measurements with the HMS Plus were: I) heparin (∼five Euro per procedure), II) ACT cartridges (∼3 Euro per cartridge, on average five cartridges were necessary per procedure, totaling 15 Euro per procedure), and the costs of III) the HMS plus device (∼25,000 Euro).
      The main strengths of this study are that all patients received heparin using a standardized dose protocol, patients were enrolled prospectively, and the present study is the largest one in which a standardized heparin dose protocol was analyzed using the ACT in patients undergoing NCAP. Primary and secondary end points were clearly defined. In the present study, the E-CABG bleeding severity classification was used instead of Clavien-Dindo classification for bleeding.
      • Clavien P.A.
      • Sanabria J.R.
      • Strasberg S.M.
      Proposed classification of complications of surgery with examples of utility in cholecystectomy.
      The E-CABG is specifically developed to grade periprocedural and postprocedural bleeding complications and is validated to predict mortality in patients undergoing cardiac bypass grafting. The E-CABG classification has some overlap with the Clavien-Dindo and takes interventions into account but also increased perioperative blood loss requiring blood transfusion.
      • Mariscalco G.
      • Gherli R.
      • Ahmed A.B.
      • et al.
      Validation of the European multicenter study on coronary artery bypass grafting (E-CABG) bleeding severity definition.
      Patients with a renal clearance <30 ml. min.⁻1 were excluded for this study because dose adjustments of heparin may be indicated when the creatinine clearance falls below 30 ml. min.⁻1. Close monitoring of anticoagulation is recommended when doses of heparin are administered in patients with severe chronic renal impairment.
      Main limitations of this study are that the group of patients was heterogeneous and different type of procedures was studied. This study was not powered to correlate ATEC and hemorrhagic complications with the periprocedural ACT. From the sparse data in literature, suggested goal values in guidelines and results from the presented study, it can be deducted that a goal ACT of 200–250 s. could potentially provide the individual patient with adequate and safe anticoagulation during NCAP.
      • Doganer O.
      • Wiersema A.M.
      • Scholtes V.
      • et al.
      No concluding evidence on optimal activated clotting time for non-cardiac arterial procedures.
      • Norgren L.
      • Hiatt W.R.
      • Dormandy J.A.
      • et al.
      Inter-society consensus for the management of peripheral arterial disease (TASC II).
      • Chaikof E.L.
      • Dalman R.L.
      • Eskandari M.K.
      • et al.
      The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm.
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • et al.
      (ESVS) 2019 clinical practice guidelines on the management of abdominal aorto-iliac artery aneurysms.

      Conclusion

      This study showed that measuring the ACT in the OR during non-cardiac arterial procedures is feasible, safe, and could fluently be implemented in daily routine. A single bolus of 5 000 IU heparin does not provide adequate, safe, and tailor-made anticoagulation in most patients. Further research should provide evidence if ACT-guided heparinization leads to a safe balance in preventing arterial thromboembolic complications without increasing hemorrhagic complications. A challenging task for further research is to individualize the heparin dose protocol and to establish the optimal ACT value during non-cardiac arterial procedures. Trials on these topics are currently performed by our study group.

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