Use of Protamine for Heparin Reversal After Catheter Ablation of Atrial Fibrillation

• Sponsor: University of Michigan (Other)
• Overall Status: Completed
• CT.gov ID: NCT03140631
• Collaborator: (none)
• Enrollment: 153
• Location: 1
• Arms: 2
• Actual Duration (Months): 12.4
• Patients Per Site Per Month: 12.4

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the safety, efficacy and efficiency of rapid anticoagulation reversal with protamine sulfate versus routine activated clotting time (ACT) monitoring in patients undergoing catheter based ablation of atrial fibrillation.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation; Catheter Ablation	Drug: Protamine Sulfate	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 153 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Use of Protamine for Heparin Reversal After Catheter Ablation of Atrial Fibrillation: A Randomized Trial
• Actual Study Start Date: Mar 23, 2017
• Actual Primary Completion Date: Nov 16, 2017
• Actual Study Completion Date: Apr 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Control Patients in the control arm will undergo routine post-procedure management prior to removal of vascular sheaths. This includes routine measurements of ACT beginning 90 min after the cessation of the procedure with a goal ACT of <200s or return to pre-procedural baseline prior to sheath removal.
Active Comparator: Protamine Patients in the active comparator arm will receive protamine sulfate for rapid reversal of heparin prior to sheath removal. They will first receive a small test dose with close hemodynamic monitoring followed by therapeutic dose if no reaction occurs.ACT levels will then be monitored with a goal ACT of <200s or return to preprocedural baseline prior to removal of vascular sheaths.	Drug: Protamine Sulfate; Protamine sulfate is a highly basic protein that forms stable compounds with acidic heparin to rapidly neutralize the anticoagulation effects.

Outcome Measures

Primary Outcome Measures

1. Time to Ambulation [0 to 24 hours]

   Total length of time from procedural termination to patient ambulation

Secondary Outcome Measures

1. Count of Participants Who Experienced Vascular Access Site Complications [checked at 30 and 90 days]

   Secondary endpoints will include the number of patients who experience a 90-day occurrence of vascular access site complications defined as hematoma formation, aneurysm, pseudoaneurysm, arteriovenous fistula formation, access-site related major bleeding (defined as Bleeding Academic Research Consortium (BARC) type 3a or 5), or procedural intervention for access complications (surgical repair, thrombin injection, et cetera)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient's referred for radiofrequency ablation (RFA) or cryoablation for atrial fibrillation or atrial flutter (left atrial).

• Age ≥ 18 year

• Patients who are mentally and linguistically able to understand the aim of the trial, comply with the trial protocol, verbally acknowledge the risks, benefits, and alternatives in this trial.

Exclusion Criteria:

• Previous intolerance or allergy to heparin products.

• Current or prior administration of protamine products

• History of femoral access site complications including hematoma, AV fistula, pseudoaneurysm, aneurysm.

• Known lower extremity venous thrombosis.

• Coagulopathy or blood dyscrasias.

• Active malignancy.

• Thrombocytosis (platelet count >600k/ul) or thrombocytopenia (platelet count <100k/ul)

• Planned use of vascular closure device

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Michigan Medicine	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan

Investigators

• Principal Investigator: Hakan Oral, MD, University of Michigan

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 18, 2017

More Information

Publications

None provided.

• Responsible Party: Hakan Oral, Director, Cardiac Arrhythmia Service, University of Michigan
• ClinicalTrials.gov Identifier: NCT03140631
• Other Study ID Numbers: HUM00117851
• First Posted: May 4, 2017
• Last Update Posted: Oct 23, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Hakan Oral, Director, Cardiac Arrhythmia Service, University of Michigan: atrial fibrillation; catheter ablation; protamine sulfate; anticoagulation reversal
• Additional relevant MeSH terms: Atrial Fibrillation; Protamines

Study Results

Participant Flow

Pre-assignment Detail	153 patients were enrolled in the trial; however, three patients were removed from the trial before treatment allocation due to physician discretion. These patients never received any treatments and were not included in the analysis.

Arm/Group Title	Control	Protamine
Arm/Group Description	Patients in the control arm will undergo routine post-procedure management prior to removal of vascular sheaths. This includes routine measurements of activated clotting time (ACT) beginning 90 min after the cessation of the procedure with a goal ACT of <200s or return to pre-procedural baseline prior to sheath removal.	Patients in the active comparator arm will receive protamine sulfate for rapid reversal of heparin prior to sheath removal. They will first receive a small test dose with close hemodynamic monitoring followed by therapeutic dose if no reaction occurs. Activated clotting time (ACT) levels will then be monitored with a goal ACT of <200s or return to preprocedural baseline prior to removal of vascular sheaths. Protamine Sulfate: Protamine sulfate is a highly basic protein that forms stable compounds with acidic heparin to rapidly neutralize the anticoagulation effects.
Period Title: Overall Study
STARTED	73	77
COMPLETED	73	77
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Control	Protamine	Total
Arm/Group Description	Patients in the control arm will undergo routine post-procedure management prior to removal of vascular sheaths. This includes routine measurements of ACT beginning 90 min after the cessation of the procedure with a goal ACT of <200s or return to pre-procedural baseline prior to sheath removal.	Patients in the active comparator arm will receive protamine sulfate for rapid reversal of heparin prior to sheath removal. They will first receive a small test dose with close hemodynamic monitoring followed by therapeutic dose if no reaction occurs. ACT levels will then be monitored with a goal ACT of <200s or return to preprocedural baseline prior to removal of vascular sheaths. Protamine Sulfate: Protamine sulfate is a highly basic protein that forms stable compounds with acidic heparin to rapidly neutralize the anticoagulation effects.	Total of all reporting groups
Overall Participants	73	77	150
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66 (9)	63 (12)	63 (11)
Sex: Female, Male (Count of Participants)
Female	25 34.2%	31 40.3%	56 37.3%
Male	48 65.8%	46 59.7%	94 62.7%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
BMI (kilograms/(meter squared)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms/(meter squared)]	31 (7)	32 (6)	32 (6)
CHAD2Ds2-VASc Score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	2.2 (1.2)	2.1 (1.2)	2.1 (1.2)
Warfarin use (Count of Participants)
Count of Participants [Participants]	14 19.2%	14 18.2%	28 18.7%
NOAC use (Count of Participants)
Count of Participants [Participants]	59 80.8%	63 81.8%	122 81.3%
Hemoglobin (g/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/dl]	13.7 (1.6)	14.4 (1.2)	14.1 (1.4)
Platelets (10^3 platelets/mm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [10^3 platelets/mm^3]	194 (67)	182 (72)	188 (70)
INR (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	1.4 (0.6)	1.3 (0.5)	1.4 (0.6)
Creatinine (mg/dl) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dl]	1.0 (0.8)	1.0 (0.3)	1.0 (0.6)

Outcome Measures

1. Primary Outcome

Title	Time to Ambulation
Description	Total length of time from procedural termination to patient ambulation
Time Frame	0 to 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Protamine
Arm/Group Description	Patients in the control arm will undergo routine post-procedure management prior to removal of vascular sheaths. This includes routine measurements of ACT beginning 90 min after the cessation of the procedure with a goal ACT of <200s or return to pre-procedural baseline prior to sheath removal.	Patients in the active comparator arm will receive protamine sulfate for rapid reversal of heparin prior to sheath removal. They will first receive a small test dose with close hemodynamic monitoring followed by therapeutic dose if no reaction occurs. ACT levels will then be monitored with a goal ACT of <200s or return to preprocedural baseline prior to removal of vascular sheaths. Protamine Sulfate: Protamine sulfate is a highly basic protein that forms stable compounds with acidic heparin to rapidly neutralize the anticoagulation effects.
Measure Participants	73	77
Mean (Standard Deviation) [minutes]	480 (92)	316 (80)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Protamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Count of Participants Who Experienced Vascular Access Site Complications
Description	Secondary endpoints will include the number of patients who experience a 90-day occurrence of vascular access site complications defined as hematoma formation, aneurysm, pseudoaneurysm, arteriovenous fistula formation, access-site related major bleeding (defined as Bleeding Academic Research Consortium (BARC) type 3a or 5), or procedural intervention for access complications (surgical repair, thrombin injection, et cetera)
Time Frame	checked at 30 and 90 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Protamine
Arm/Group Description	Patients in the control arm will undergo routine post-procedure management prior to removal of vascular sheaths. This includes routine measurements of ACT beginning 90 min after the cessation of the procedure with a goal ACT of <200s or return to pre-procedural baseline prior to sheath removal.	Patients in the active comparator arm will receive protamine sulfate for rapid reversal of heparin prior to sheath removal. They will first receive a small test dose with close hemodynamic monitoring followed by therapeutic dose if no reaction occurs.ACT levels will then be monitored with a goal ACT of <200s or return to preprocedural baseline prior to removal of vascular sheaths. Protamine Sulfate: Protamine sulfate is a highly basic protein that forms stable compounds with acidic heparin to rapidly neutralize the anticoagulation effects.
Measure Participants	73	77
30 days	4 5.5%	6 7.8%
90 days	4 5.5%	6 7.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Protamine
	Comments	number of participants who experienced a vascular access site complication at 90 days
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	3 months
Arm/Group Title	Control		Protamine
Arm/Group Description	Patients in the control arm will undergo routine post-procedure management prior to removal of vascular sheaths. This includes routine measurements of ACT beginning 90 min after the cessation of the procedure with a goal ACT of <200s or return to pre-procedural baseline prior to sheath removal.		Patients in the active comparator arm will receive protamine sulfate for rapid reversal of heparin prior to sheath removal. They will first receive a small test dose with close hemodynamic monitoring followed by therapeutic dose if no reaction occurs. ACT levels will then be monitored with a goal ACT of <200s or return to preprocedural baseline prior to removal of vascular sheaths. Protamine Sulfate: Protamine sulfate is a highly basic protein that forms stable compounds with acidic heparin to rapidly neutralize the anticoagulation effects.
All Cause Mortality
	Control		Protamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/73 (1.4%)		0/77 (0%)
Serious Adverse Events
	Control		Protamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/73 (1.4%)		1/77 (1.3%)
Nervous system disorders
Stroke	1/73 (1.4%)	1	0/77 (0%)	0
Vascular disorders
Major vascular complication	0/73 (0%)	0	1/77 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Control		Protamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/73 (5.5%)		5/77 (6.5%)
Vascular disorders
Minor vascular complication	4/73 (5.5%)	4	5/77 (6.5%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.