Understanding "Heparin Resistance" in Cardiac Surgery
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| ClinicalTrials.gov Identifier: NCT01598883 |
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Recruitment Status :
Completed
First Posted : May 15, 2012
Last Update Posted : December 14, 2016
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Cardiopulmonary Bypass Altered Heparin Response | Drug: Heparin Drug: ATryn | Phase 1 |
This study uses a prospective, randomized, open-label cross-over design to evaluate the responses to recombinant human AT (rhAT) and/or supplemental heparin for restoration of heparin-responsiveness in the presence of biomarkers of acute inflammation, so called acute phase reactants. Our ultimate goal is, of course, to apply this knowledge to optimize perioperative management of anticoagulation in patients undergoing cardiopulmonary bypass.
We will first identify enrolled patients with altered heparin responsiveness (AHR) as defined by an ACT < 450 seconds (the MGH standard target ACT after the initial dose of heparin for CPB). Patients who achieve an ACT > 450 sec will not enter the randomization phase of the study, their participation in the study will be complete and their routine clinical care will continue unaltered. Those with AHR (post-heparin ACT < 450 sec) will be randomized to receive either supplemental heparin or supplemental AT. Those that fail to achieve an adequate ACT after the first supplementation will cross-over to receive the alternate supplement. Blood samples (totaling at most 20 ml) will be taken at each step to measure heparin level, AT level, AT activity. Once a patient is placed onto cardiopulmonary bypass their participation in the study will be complete.
By design, this study replicates routine clinical management of heparin anticoagulation for cardiopulmonary bypass at the MGH. Most patients (80%) coming to cardiac surgery who will undergo CPB respond adequately to a routine initial bolus dose of heparin (ACT > 450 after 350 U/kg); as noted, subjects in this study that achieve the target ACT will be managed according to routine clinical practice without further testing or intervention.
Under routine care, patients with an inadequate initial response to heparin receive either supplemental heparin (150 U/kg) or pooled human antithrombin (1000 Units), or both. In this study, subjects with inadequate heparin response (ACT < 450) after the initial heparin bolus, will be randomly assigned to two comparison groups; half will receive supplemental heparin (150 U/kg) and half will receive AT (1000 IU). Subjects who fail to respond to their assigned first intervention will cross-over to receive the alternate intervention.
Some subjects may not achieve the target ACT despite receiving both supplemental heparin and AT comprising a group of patients with "true heparin resistance" whose coagulation profiles can be further characterized to better understand the mechanisms of the resistance. These subjects will be considered to have completed the study even though they are not yet on cardiopulmonary bypass and will be managed according to the best clinical judgment of their physicians. They may receive additional heparin, additional AT, fresh-frozen plasma, or any combination of these. These patients may be at risk for thrombotic complications during the post-operative period. Accordingly, when clinically appropriate, these individuals may be referred for further evaluation of their coagulation status, but these evaluations will not be done as part of this study.
This is a pathophysiological risk-factor association study that seeks to better understand the phenomenon of altered heparin responsiveness. Accordingly, there is no specific study endpoint apart from achieving an ACT of > 450 sec. In all enrolled subjects we will measure the levels of three acute phase reactants, Factor VIII, fibrinogen and CRP, heparin levels (anti Xa), AT level (immunofixation) and AT activity after the initial heparin dose. For all subjects who do not achieve and ACT of > 450 we will also measure additional heparin levels (anti Xa), AT level (immunofixation), and AT activity after each intervention in the randomization/crossover phase. The total amount of blood taken for the research-specific laboratory test is less than 20 ml.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 504 participants |
| Allocation: | Randomized |
| Intervention Model: | Crossover Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Basic Science |
| Official Title: | Understanding "Heparin Resistance" in Cardiac Surgery: Altered Heparin Responsiveness and Its Association With Acute Inflammatory Reactions |
| Study Start Date : | June 2012 |
| Actual Primary Completion Date : | December 2014 |
| Actual Study Completion Date : | December 2014 |
| Arm | Intervention/treatment |
|---|---|
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ACT after initial heparin bolus less than 450
If a patients activated clotting time (ACT) is less than 450 after the bolus dose of heparin (350U/kg) they will be randomized to one of two interventions.
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Drug: Heparin
150 U/kg
Other Name: Heparin Sodium Drug: ATryn 1000 IU
Other Name: Antithrombin (recombinant) |
| Active Comparator: ACT after first intervention less than 450 |
Drug: Heparin
150 U/kg
Other Name: Heparin Sodium Drug: ATryn 1000 IU
Other Name: Antithrombin (recombinant) |
- Altered Heparin Responsivness (AHR) [ Time Frame: Participants will be followed from the administration of the initial heparin bolus to being placed on CPB, an average of 15 minutes. ]We will first identify patients with AHR as defined by an ACT <450 seconds (the MGH standard target ACT after the initial dose of heparin for CPB). We will evaluate the hypothesis that AHR may be directly related to, modulated or mediated by interactions between heparin, antithrombin (AT), the heparin-AT complex, and one or more acute phase proteins.
- "True Heparin Resistance" [ Time Frame: Patients will be followed from the administration of the initial heparin bolus to being placed on CPB, an average of 15 minutes. ]Those with AHR (post-heparin ACT < 450 sec) will be randomized to receive either supplemental heparin or supplemental AT. Those that fail to achieve an adequate ACT after the first supplementation will cross-over to receive the alternate supplement. If patient still fails to achieve an adequate ACT after both supplementations they will be classified as having "True Heparin Resistance".
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
- Patients scheduled for elective cardiac or aortic surgery requiring CPB for which heparin will be used for systemic anticoagulation
- Patients scheduled for urgent surgery who are hemodynamically stable and capable of giving voluntary consent
- Patients with platelet factor 4 antibody positivity (antiPF4+) for whom heparin anticoagulation will be used
Exclusion Criteria:
- Patients for whom heparin will not be used for anticoagulation
- Patients with known congenital AT-deficiency
- Patients with known goat milk allergy
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01598883
| United States, Massachusetts | |
| Massachusetts General Hospital | |
| Boston, Massachusetts, United States, 02114 | |
| Principal Investigator: | Greg Koski, MD, PhD | Massachusetts General Hospital |
| Responsible Party: | Greg Koski, Greg Koski, PhD, MD, CPI (Honorary), Massachusetts General Hospital |
| ClinicalTrials.gov Identifier: | NCT01598883 History of Changes |
| Other Study ID Numbers: |
Altered Heparin Responsiveness |
| First Posted: | May 15, 2012 Key Record Dates |
| Last Update Posted: | December 14, 2016 |
| Last Verified: | December 2016 |
Additional relevant MeSH terms:
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Calcium heparin Heparin Antithrombins Anticoagulants Fibrinolytic Agents |
Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Serine Proteinase Inhibitors Protease Inhibitors Enzyme Inhibitors |