Antiplatelet Activity of Aspirin in Infants After Aortopulmonary and Cavopulmonary Shunts
Condition: Congenital Heart Disease
MeSH terms: Heart Diseases; Heart Defects, Congenital
Study type: Observational

Summary: 
      Background: Blood clots cause poor outcomes, including death, in babies with heart defects
      that require a surgical connection ("shunt") to provide blood flow to their lungs. Aspirin
      (ASA) blocks the part of the blood that helps clots form (platelets). Aspirin is used in
      babies with shunts to prevent blood clots. The dose of aspirin given to babies is based on
      adult research. Because babies are different from adults, the investigators do not know if
      the dose is enough to block platelets, or if it is too much and may cause bleeding. The
      investigators can test the platelets using a blood test called Thromboelastography with
      Platelet Mapping (TEG-PM). This test needs a small amount of blood so it can be used in
      babies.

      Hypothesis and Specific Aims: The investigators suspect the aspirin doses typically given
      babies are not enough to block platelets and prevent blood clots in their shunts. The
      investigators want to determine the percentage of babies whose platelets are not blocked
      enough (< 70% inhibition), by using TEG-PM. The investigators also want to determine how
      often bleeding or clots occur in babies receiving aspirin.
    

Detailed description: 
      Background: Aortopulmonary and cavopulmonary shunts ("shunts") are surgically placed to
      provide pulmonary blood flow in infants with congenital heart disease who require the shunt
      for survival. Thrombosis occurs in about 17% of these shunted infants (Li et al, 2007;
      Monagle et al, 2012) with an associated morbidity of 23% and mortality of 7%.(Li et al, 2007)
      One study reported a third of all deaths were from shunt thrombosis.(Fenton, 2003) Despite
      insufficient evidence to guide appropriate dosing, current thromboprophylaxis guidelines
      recommend aspirin (ASA) for thrombus prevention in these high-risk infants. No therapeutic
      monitoring exists to ensure consistent and effective anticoagulation and prevent
      over-anticoagulation to minimize bleeding complications. Previous studies examining the
      effectiveness of ASA in shunt thrombosis prevention have conflicting results. The most recent
      large, prospective observational study showed a significant association between ASA use and
      lower risk of thrombosis and death (Li et al, 2007), but the study was limited by lack of
      standardized ASA dosing and failure to include adverse events. To further complicate the
      picture, adult studies have described a phenomenon termed "ASA resistance," where thrombosis
      occurs despite ASA therapy.(Frelinger et al, 2008; Heistein et al, 2008; Szczeklik et al,
      2005; Frelinger et al, 2006) ASA resistance has not been adequately studied in the pediatric
      population leading to a knowledge gap between therapeutic dosing and the adequate prevention
      of thrombosis combined with minimization of bleeding complications. Thromboelastography with
      Platelet Mapping (TEG-PM) is a blood test that specifically evaluates the percentage of
      inhibition of the arachidonic acid pathway targeted by ASA. It can be used for serial
      monitoring of the adequacy of anticoagulation with ASA in shunted infants and to provide
      evidence of safe and effective dosages for its use in other pediatric populations.

      Hypothesis and Specific Aims:

      Hypothesis: The investigators hypothesize that ASA dosing by current guidelines (1-5
      mg/kg/day) favors protection from bleeding complications and fails to achieve adequate
      inhibition of the arachidonic acid pathway to prevent thrombosis.

      Specific Aim 1: The primary aim is to determine the percentage of infants treated with ASA
      after shunt surgery who have adequate (> 70%) inhibition of the arachidonic acid pathway as
      measured by TEG-PM.

      Outcome: The percentage of arachidonic inhibition, as measured by TEG-PM, at 3 designated
      time points after starting ASA postoperatively. Therefore, TEG-PM will be measured at these
      designated time points:

        1. After the third dose of ASA

        2. At the first post-operative cardiology clinic visit (between 2 and 4 weeks after
           hospital discharge)

        3. At a follow-up cardiology clinic visit 3-6 months after the initiation of ASA

      Specific Aim 2: The secondary aim is to describe the frequency of bleeding and thrombotic
      events while on ASA.

      Outcome: The number of bleeding and thrombotic events from initiation of ASA therapy to end
      of study will be documented.

      ASA administration: ASA will be initiated by the cardiac intensive care unit attending
      physician postoperatively, at a dose of 1-5 mg/kg/day, but no less than 20 mg per day; the
      initiation of ASA at 1-5 mg/kg/day is standard of care and recommended by the College of
      Chest Physicians (Monagle et al, 2012), albeit with limited evidence for its use. TEG-PM
      results obtained for research purposes will be available only to the research team. The dose
      of ASA will not be adjusted by results from the research TEG-PM. However, if bleeding or
      thrombosis occurs, TEG-PM is obtained by local practice and ASA dosing adjusted by the
      treating physician. If the dose of ASA is changed while the patient is hospitalized, TEG-PM
      will be obtained 2 hours after the third (adjusted or restarted) dose.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Infants undergoing cardiac surgery involving aortopulmonary and/or cavopulmonary shunts
        with planned aspirin treatment
      
Keywords: Aspirin; ASA; aortopulmonary shunt; cavopulmonary shunt; shunt; TEG; Antiplatelet