Coagulation in Acute Aortic Dissection

Coagulation Disorder Clinical Trial

— CAAD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05484830
• Other study ID #: 1-10-72-30-22
• Status: Recruiting
• Phase: N/A
• Start date: November 1, 2022
• Est. completion date: November 30, 2024

Study information

• Verified date: November 2022
• Source: Aarhus University Hospital Skejby
• Contact: Ivy Modrau, MD, dr.med.
• Phone: +45 24778856
• Email: ivymod[@]clin.au.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 26
• Est. completion date: November 30, 2024
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Aortic Dissection
• Aneurysm, Dissecting
• Blood Coagulation Disorders
• Coagulation Disorder
• Hemostatic Disorders

Intervention

Procedure:
• Individualized HDR-approach
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.
• Conventional ACT-approach
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.).

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital Skejby	Aarhus

Sponsors (1)

Lead Sponsor	Collaborator
Ivy susanne Modrau, MD

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	F1+2	Prothrombin fragment 1+2 (pmol/L)	up to 2 days after surgery
Secondary	TAT	Thrombin-Antithrombin Complex (ug/L)	up to 2 days after surgery
Secondary	ETP	Endogenous Thrombin Potential (nmol/L x min)	up to 2 days after surgery
Secondary	Thrombin time	High-dose thrombin time (sec)	up to 2 days after surgery
Secondary	Antithrombin	(kIU/L)	up to 2 days after surgery
Secondary	D-dimer	D-dimer (mg/L)	up to 2 days after surgery
Secondary	Clot lysis	Clot lysis	up to 2 days after surgery
Secondary	Heparin sensitivity	Heparin sensitivity (slope)	prior to surgery
Secondary	Heparin (total)	Total amount of heparin	immediately after surgery
Secondary	Protamin (total)	Total amount of protamin	immediately after surgery
Secondary	Ratio	Protamin/heparin ratio	immediately after surgery
Secondary	Resistance	Heparin resistance	immediately after surgery
Secondary	Blood cell-saver	Volume of blood processed in cell-saver (mL)	immediately after surgery
Secondary	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
Secondary	Drain output	Total mediastinal drain output (ml)	48 hours after surgery
Secondary	Blood tranfusion	Tranfusion of blood products (units): Red blood cells, fresh frozen plasma, platelet concentrates	48 hours after surgery
Secondary	Fibrinogen	Administration of fibrinogen concentrate (mg)	24 hours after surgery
Secondary	PCC	Administration of prothrombin complex concentrate (Octaplex) (IU)	24 hours after surgery
Secondary	AT concentrate	Administration of Antithrombin concentrate (IU)	24 hours after surgery
Secondary	Cryoprecipitate Plasma	Administration of cryoprecipitate plasma	24 hours after surgery
Secondary	Recombinant FVIIa	Administration of Recombinant FVIIa	24 hours after surgery
Secondary	2. Closure	Secondary closure	30 days after surgery
Secondary	Reoperation for bleeding	Reexploration for bleeding (yes/no)	30 days after surgery
Secondary	Protocol violation	Protocol violation (yes/no)	immediately after surgery
Secondary	Mortality	All-cause mortality	up to 90 days after surgery
Secondary	Stroke	Stroke (yes/no)	30 days after surgery
Secondary	Myocardial infarction	Perioperative myocardial infarction (yes/no)	30 days after surgery
Secondary	Renal	Requirement of continuous renal replacement therapy (yes/no)	30 days after surgery
Secondary	Low cardiac output syndrome	Low cardiac output syndrome requiring inotropics or mechanical support (yes/no)	30 days after surgery
Secondary	Vascular malperfusion	Visceral og peripheral vascular malperfusion requiring surgical or percutaneous intervention	30 days after surgery
Secondary	Intraop. coagulation	Clinical signs of coagulation during CPB (yes/no)	Immediately after surgery
Secondary	Length of surgery	minutes	30 days after surgery
Secondary	Length of stay ICU	days	30 days after surgery
Secondary	Length of hospitalization	Hospitalization (days)	30 days after surgery