Major hemorrhage on anticoagulants is a dramatic presentation that creates a bias against restarting the anticoagulant for fear of precipitating another hemorrhage. What often gets lost in this one-sided assessment of risk is the underlying threat of thromboembolic disease, for which the patient was anticoagulated to begin with. A more balanced approach between the risk of hemorrhage and stroke and prospective randomized data on which to base it is direly needed. This proposal is relevant to the mission of NHLBI as it deals with heart disease, since the most common indication for oral anticoagulation is atrial fibrillation. It deals with blood disease, albeit an iatrogenic coagulopathy caused by anticoagulation therapy. It deals with the clinical setting of bleeding, both in gastrointestinal bleeding and intracranial hemorrhage.
It aims to enhance the health of patients with these diseases by studying the risk/benefit of restarting anticoagulation after major hemorrhage. Its goals are immediately translational into clinical practice. It fosters training and mentoring of an emerging scientist and physician, and it creates and supports a robust, collaborative research infrastructure in partnership with the private non-profit Seton Healthcare Family and the new University of Texas Dell Medical School in Austin. There are no evidence-based guidelines on when to restart warfarin after major hemorrhage, much less the Novel Oral Anticoagulants (NOACs) increasingly being used. The overall goal of this application is to elucidate a research plan to inform the clinical decision to restart anticoagulation after major hemorrhage that will establish Dr. Milling as an independent impactful researcher in this field. Dr. Milling will enrollin a formal master's degree program: Masters of Science in Clinical Investigations at the University of Texas Health Science Center - San Antonio. He will also undergo extensive and immersive training in hemostasis and coagulation, the design and conduct of multicenter clinical trials, conceptual training in the field of adaptive trial design, and health economics. Dr. Milling will receive careful mentorship from Drs. Steven Warach, Scott Berry Todd Olmstead and Jerrold Levy utilizing both formal training curriculum and informal meeting frameworks to draw from their extensive and diverse experience and guidance. Dr. Milling will conduct a three-phased research design, including the development of a National Practice Survey Tool for Clinical Trials (survey of patients, PCPs, and Cardiologists), laying the ground work for a larger multicenter, adaptive, time dose clinical trial and a future R01 submission, to find the ideal time to restart oral anticoagulants after a major hemorrhage that balances the risk of recurrent hemorrhage with the risk of thromboembolic disease.

Public Health Relevance

This project will study various early to late anticoagulation restart intervals in order to establish an evidence based guideline and risk/benefit patient centered tool to evaluate restarting anticoagulation after major hemorrhage. The study plan will cover a single indication for anticoagulation (atrial fibrillation), four drugs (warfarin, apixaban rivaroxaban and dabigatran), and two bleeding presentations (ICH and GIB). It aims to enhance the health of patients and populations with these diseases, by optimizing the risk/benefit of restarting anticoagulation after major hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL127227-02
Application #
9339720
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Werner, Ellen
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Seton Healthcare
Department
Type
DUNS #
078495868
City
Austin
State
TX
Country
United States
Zip Code
78723
Milling Jr, Truman J; Clark, Carol L; Feronti, Charles et al. (2018) Management of Factor Xa inhibitor-associated life-threatening major hemorrhage: A retrospective multi-center analysis. Am J Emerg Med 36:396-402
Waring, Elizabeth D; Milling, Truman J; Warach, Steven (2018) Intravenous Thrombolysis at 3.5 Hours From Onset of Pediatric Acute Ischemic Stroke. Pediatr Emerg Care :
Levy, Jerrold H; Douketis, James; Steiner, Thorsten et al. (2018) Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non-vitamin K Anticoagulant Reversal. Anesthesiology 129:1171-1184
Levy, Jerrold H; Koster, Andreas; Quinones, Quintin J et al. (2018) Antifibrinolytic Therapy and Perioperative Considerations. Anesthesiology 128:657-670
Milling, Truman J; Fromm, Christian; Ganetsky, Michael et al. (2017) Management of Major Bleeding Events in Patients Treated With Dabigatran for Nonvalvular Atrial Fibrillation: A Retrospective, Multicenter Review. Ann Emerg Med 69:531-540
Refaai, Majed A; Kothari, Truptesh H; Straub, Shana et al. (2017) Four-Factor Prothrombin Complex Concentrate Reduces Time to Procedure in Vitamin K Antagonist-Treated Patients Experiencing Gastrointestinal Bleeding: A Post Hoc Analysis of Two Randomized Controlled Trials. Emerg Med Int 2017:8024356
Milling Jr, Truman J; Frontera, Jennifer (2017) Exploring indications for the Use of direct oral anticoagulants and the associated risks of major bleeding. Am J Manag Care 23:S67-S80
Milling Jr, Truman J; Spyropoulos, Alex C (2016) Re-initiation of dabigatran and direct factor Xa antagonists after a major bleed. Am J Emerg Med 34:19-25
Milling Jr, Truman J; Kaatz, Scott (2016) Preclinical and Clinical Data for Factor Xa and ""Universal"" Reversal Agents. Am J Med 129:S80-S88
Connolly, Stuart J; Milling Jr, Truman J; Eikelboom, John W et al. (2016) Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 375:1131-41

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