National Heart, Lung, and Blood Institute Working Group on Guided Antithrombotic Therapy: Current Status and Future Research Directions

Executive Summary

The NHLBI convened a Working Group (WG) Meeting on Guided Antithrombotic Therapy on June 30 and July 1, 2011, at the National Institutes of Health in Bethesda, MD. The WG included cardiologists, hematologists, interventionalists, clinical trialists, genetic epidemiologists, basic scientists, and other stakeholders to address 1) the development and clinical use of anticoagulant and antiplatelet medications and 2) to provide recommendations and develop a research agenda for the NHLBI to enhance understanding and effectiveness of antithrombotic therapy, and to advance guided antithrombotic therapy.

The specific goals of the WG were:

• to define the state-of-the-science and research frontier in antithrombotic therapy;
  
  
• to assess the need for functional testing to effectively guide antithrombotic therapy;
  
  
• to assess the current state-of-the-science of pharmacogenetics studies of anticoagulant and antiplatelet medications to guide antithrombotic therapy; and
  
  
• to define the roles of stakeholders in the identification of gaps, areas where new agents could be useful, and to help plan appropriately sized clinical trials, and overall to improve antithrombotic therapy.
  
  

Discussion:

The agenda covered by the WG included a) coagulation, platelet activation and aggregation, and antithrombotic therapy; b) issues surrounding antithrombotic therapy failure – how to define it, how to predict and diagnose it, available tests and how to optimize them; c) the factors that affect the efficacy, safety, and predictability of antithrombotic therapies; d) how to optimize antithrombotic therapy, improve upon present interventions, and individually tailor therapy to increase efficacy and safety and to avoid failure; and e) the clinical applicability and cost-effectiveness of individually tailored antithrombotic therapy based on functional and genetic testing. The WG characterized and discussed challenges for guided antithrombotic therapy in four domains: therapeutic strategies, antithrombotic metrics, pharmacology and pharmacogenetics, and stakeholders’ roles. Overall, the WG sought to identify and prioritize the most pressing clinical needs to focus future research and translational efforts.

Recommendations:

The WG identified a set of research and policy priorities related to guided antithrombotic therapy.

1. Clinical trials were recommended to:
   
   
   • Compare factor IIa inhibition vs. factor Xa inhibition in atrial fibrillation
     
     
   • Compare mechanical vs. pharmacological interventions for atrial fibrillation
     
     
   • Compare mechanical vs. pharmacological interventions for asymptomatic carotid stenosis
     
     
   • Compare catheter-directed thrombolytic therapy vs. standard therapy in acute stroke
     
     
   • Compare periprocedural bridging anticoagulant therapies in patients with prosthetic heart valves
     
     
   • Compare factor IIa inhibitor vs. factor Xa inhibitor in valvular heart disease
     
     
   • Compare various drug monitoring strategies to assess their influence on the safety and efficacy of newer anticoagulant and antiplatelet medications
     
     
   • Assess whether tailoring antiplatelet therapy by genetic and/or functional assays improve clinical outcomes
     
     
2. Other high-priority research identified included:
   
   
   • Cost-effectiveness studies of various strategies for the use of antithrombotic therapy (e.g., unguided use of clopidogrel vs. functional test and/or genetic test-guided choice of clopidogrel or an alternative thienopyridine)
     
     
   • Genetic epidemiological studies and genome-wide studies to define heritability of and genetic loci associated with various aspects of platelet biology, hemostasis and thrombosis phenotypes, and response to newer antithrombotic medications (with respect to pharmacokinetics and pharmacodynamics, clinical response, and adverse events)
     
     
   • Genome-wide studies to define second-order interactions, e.g., gene-gene interactions, gene-environment interactions, and drug-drug interactions modified by genotype
     
     
   • Basic science studies for the functional validation and characterization of discovered genetic loci in cell-based models, animal models, and humans
     
     
   • Basic science studies to identify potential antithrombotic targets that lead to new drugs that inhibit thrombosis, preferably without inhibiting hemostasis
     
     
   • Development of a platform for inexpensive, accurate, rapid POC testing for genetic data and integration of this data with other clinical information
     
     
   • Development and validation of algorithms that combine clinical, procedural, and demographic data with or without genetic and functional data to optimize risk stratification of patients who are candidates for antithrombotic therapy
     
     
   • Behavioral studies of prescribers to assess adoption of new drugs and monitoring strategies
     
     
   • Behavioral studies of patients to assess drug adherence, with or without targeted interventions to enhance adherence
     
     
3. DNA and body fluid samples should be collected in all clinical trials for genetic and functional studies.
   
   
4. Other stakeholders should be engaged through:
   
   
   • Acting as a convener for professional organizations to collaboratively identify and publicize gaps in knowledge
     
     
   • Working with patient advocacy groups to increase awareness of antithrombotic therapy and to increase participation in clinical research studies
     
     
   • Supporting the development of a centralized data repository and informatics-based modeling “think tank” that could be accessed by academia, industry, regulatory agencies, and patient advocacy groups
     
     
   • Partnering with other national/international funding bodies to support large, international, definitive clinical studies

Publication Plans:

The Working Group plans to write a detailed summary of the meeting for publication in an appropriate peer-reviewed journal.

Participating Division and Institute:

Division of Cardiovascular Sciences, Division of Blood Diseases and Resources, NHLBI

Chair:

Valentin Fuster, MD, PhD, Mount Sinai School of Medicine

Subgroup Chairs:

• Deepak L. Bhatt, MD, MPH, VA Boston and Brigham and Women’s Hospital
  
  
• Robert M. Califf, MD, Duke University Medical Center
  
  
• Barry S. Coller, MD, The Rockefeller University
  
  
• Marc S. Sabatine, MD, MPH, Brigham and Women’s Hospital

Working Group Members:

• Dominick J. Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville
  
  
• Eric R. Bates, MD, University of Michigan Health System
  
  
• David J. Cohen, MD, MSc, Saint Luke’s Mid America Heart Institute
  
  
• Bruce Furie, MD, Beth Israel Deaconess Medical Center
  
  
• Jean-Sebastien Hulot, MD, PhD, Mount Sinai School of Medicine
  
  
• Kenneth G. Mann, PhD, University of Vermont
  
  
• Jessica L. Mega, MD, MPH, Brigham and Women’s Hospital
  
  
• Alan D. Michelson, Children’s Hospital Boston
  
  
• Kiran Musunuru, MD, PhD, MPH, Harvard University
  
  
• Christopher J. O’Donnell, MD, MPH, NHLBI’s Framingham Heart Study
  
  
• Matthew J. Price, MD, Scripps Translational Science Institute
  
  
• David J. Schneider, MD, University of Vermont
  
  
• Daniel I. Simon, MD, Case Western Reserve University School of Medicine
  
  
• Jeffrey I. Weitz, MD, McMaster University
  
  
• Marlene S. Williams, MD, Johns Hopkins Bayview Medical Center

NHLBI Staff:

• Ahmed A.K. Hasan, MD, PhD
  
  
• W. Keith Hoots, MD
  
  
• Yves D. Rosenberg, MD, MPH

Staff Contact:

• Ahmed A.K. Hasan, MD, PhD
  hasana@nhlbi.nih.gov Tel: 301-435-0064
  
  

Last Updated September 2011