Coagulation in Acute Aortic Dissection

Study Overview
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Brief Summary
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Acute aortic dissection (AAD) involving the ascending aorta (Stanford classification type A) remains a life-threatening disease. Excessive perioperative bleeding requiring massive transfusion of allogeneic blood products, and surgical reexploration remain major challenges in these patients. Previous research has indicated that patients with AAD show pronounced haemostatic alterations prior to surgery which are aggravated during major aortic surgery with cardiopulmonary bypass and hypothermia full heparinization. Intensified anticoagulation management guided by heparin dose response (HDR) calculation, and repeated measurement of heparin concentration may be more effective than standard empiric weight-based heparin and protamine management monitored by activated clotting time (ACT) measurements to suppress thrombin generation during surgery for AAD. This randomized controlled clinical trial compares the impact of two recommended anticoagulation management strategies during surgery for AAD including deep hypothermia on activation of coagulation: Heparin/protamine-management based on HDR-titration by means of HMS Plus® versus current institutional standard (HDR- versus ACT-approach). Primary endpoint is thrombin generation as measured by early postoperative prothrombin fragment 1+2 (F1+2). Secondary endpoints are other markers of coagulation and fibrinolysis as well as clinical outcome.

Detailed Description
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Hypotheses: Primary: HDR-approach is superior to ACT-approach in terms of suppressing thrombin generation after emergent surgery for acute aortic dissection (Stanford type A). Secondary: HDR-approach is superior with regard to early postoperative haemostatic capacity requirement of blood product transfusion and haemostatic agents postoperative bleeding Design: Investigator-initiated, single-site, parallel-group (1:1), prospective, randomized, partially double-blinded trial in patients undergoing emergent surgery for acute aortic dissection comparing two heparin management strategies with superiority design. Prior to randomization, patients are stratified according to preoperative organ dysfunction and anticoagulation therapy. Acute research study design as patients with acute aortic dissection are considered incompetent according to the Danish Research Ethics Committees definition. Deferred consent by the competent patient or her/his proxy (next of kin) and an independent physician) is used. 26 consecutive patients undergoing emergent surgery for acute aortic dissection (Stanford type A) are randomized 1:1 into the following heparin management strategies with an ACT target of 480 seconds: Individualised HDR-approach Conventional ACT-approach No interim analysis. A sub-study to compare cost-benefit of both strategies is planned.

Official Title
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Impact of Anticoagulation Management on Thrombin Generation During Surgery for Acute Aortic Dissection

Conditions
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Acute Aortic Dissection, Coagulation Disorder

Intervention / Treatment
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* Procedure: Individualized HDR-approach
* Procedure: Conventional ACT-approach


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Emergent Acute Aortic Dissection with cardiopulmonary bypass Incapable of providing informed consent Exclusion Criteria: History of congenital coagulation disorder (haemophilia) Previous open cardiac surgery Death during induction of anaesthesia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Investigator-initiated single-site paralle-group (1:1) prospective, randomized, partially double-blinded trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Individualised HDR-approach<br>HMS Plus® Hemostasis Management System (Medtronic International, Tolochenaz, CH). | Procedure: Individualized HDR-approach<br>* Heparin concentration necessary to achieve target ACT > 480 sec. calculated based on individual HDR-curve. If HDR slope ˂80 s/IU/mL (reduced sensitivity to heparin), 1000 IU of AT concentrate (Antitrombin III Baxalta®, Takeda Pharma, Vallensbæk Strand, DK). Whole blood concentration of circulating heparin assessed by heparin assays. Additional heparin given as required. After weaning, protamine necessary to reverse circulating heparin calculated according to heparin-protamine titration measurement. After protamine, heparin reversal evaluated with low-range heparin-protamine titration cartridge and additional protamine given as required.<br>|
| Active Comparator: Conventional ACT-approach<br>ACT Hemostasis Management | Procedure: Conventional ACT-approach<br>* Initial Heparin 400 IU/kg (500 IU/kg if treated with heparin prior to surgery). ACT Assessment with Hemochron® Signature Elite (ITC, International Technidyne Corp., Edison, NJ, USA). Additional heparin until ACT > 480 sec. If ACT < 480 sec. after despite repeated heparin supplement with 1000 IU of AT III concentrate. Target ACT > 480 sec. during normothermic CPB, and target ACT > 700 seconds during hypothermia After weaning, protamine 10mg/mL (0.7 mg of protamine/ 100 IU total heparin administered). Heparin reversal is evaluated with an activated partial thromboplastin (APTT). If APTT > 40 seconds, additional protamine (25-50 mg i.v.).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| F1+2 | Prothrombin fragment 1+2 (pmol/L) | up to 2 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TAT | Thrombin-Antithrombin Complex (ug/L) | up to 2 days after surgery | 
| ETP | Endogenous Thrombin Potential (nmol/L x min) | up to 2 days after surgery | 
| Thrombin time | High-dose thrombin time (sec) | up to 2 days after surgery | 
| Antithrombin | (kIU/L) | up to 2 days after surgery | 
| D-dimer | D-dimer (mg/L) | up to 2 days after surgery | 
| Clot lysis | Clot lysis | up to 2 days after surgery | 
| Heparin sensitivity | Heparin sensitivity (slope) | prior to surgery | 
| Heparin (total) | Total amount of heparin | immediately after surgery | 
| Protamin (total) | Total amount of protamin | immediately after surgery | 
| Ratio | Protamin/heparin ratio | immediately after surgery | 
| Resistance | Heparin resistance | immediately after surgery | 
| Blood cell-saver | Volume of blood processed in cell-saver (mL) | immediately after surgery | 
| Blood loss sponges | Gravimetric estimation of intraoperative blood loss (calculation based on the change between dry and blood-soaked sponges, accounting for irrigation) in mL | immediately after surgery | 
| Drain output | Total mediastinal drain output (ml) | 48 hours after surgery | 
| Blood tranfusion | Tranfusion of blood products (units): Red blood cells, fresh frozen plasma, platelet concentrates | 48 hours after surgery | 
| Fibrinogen | Administration of fibrinogen concentrate (mg) | 24 hours after surgery | 
| PCC | Administration of prothrombin complex concentrate (Octaplex) (IU) | 24 hours after surgery | 
| AT concentrate | Administration of Antithrombin concentrate (IU) | 24 hours after surgery | 
| Cryoprecipitate Plasma | Administration of cryoprecipitate plasma | 24 hours after surgery | 
| Recombinant FVIIa | Administration of Recombinant FVIIa | 24 hours after surgery | 
| 2. Closure | Secondary closure | 30 days after surgery | 
| Reoperation for bleeding | Reexploration for bleeding (yes/no) | 30 days after surgery | 
| Protocol violation | Protocol violation (yes/no) | immediately after surgery | 
| Mortality | All-cause mortality | up to 90 days after surgery | 
| Stroke | Stroke (yes/no) | 30 days after surgery | 
| Myocardial infarction | Perioperative myocardial infarction (yes/no) | 30 days after surgery | 
| Renal | Requirement of continuous renal replacement therapy (yes/no) | 30 days after surgery | 
| Low cardiac output syndrome | Low cardiac output syndrome requiring inotropics or mechanical support (yes/no) | 30 days after surgery | 
| Vascular malperfusion | Visceral og peripheral vascular malperfusion requiring surgical or percutaneous intervention | 30 days after surgery | 
| Intraop. coagulation | Clinical signs of coagulation during CPB (yes/no) | Immediately after surgery | 
| Length of surgery | minutes | 30 days after surgery | 
| Length of stay ICU | days | 30 days after surgery | 
| Length of hospitalization | Hospitalization (days) | 30 days after surgery |