Dr Kiran welcomes all to the new post of NH blog. As previous, we shall see a review on the current controversies, few learning scenarios and the pearls. Thanks for the feedback on the section on controversies and hope to continue. Please suggest topics of interest from your side too.

In this post, we will see the current evidence on the use of antiplatelet agents in pediatric practice with special emphasis on cardiac patients.

Q1. What are the currently available antiplatelet agents for pediatric use?

1. Aspirin: inhibits platelet function by irreversibly binding to cyclooxygenase (COX)-1
2. Dipyridamole: inhibits adenosine uptake into platelets
3. Clopidogrel: irreversibly binds to the purinergic P2Y12 receptor on platelets
4. Intravenous GP 2b/3a inhibitors abciximab, eptifibatide, and tirofiban: bind to platelet GP 2b/3a receptors, which prevents their cross-linking with fibrinogen and blocks the last common pathway of platelet aggregation

Q2: Why is antiplatelet therapy for children different from adults?

Two separate studies by Rajasekhar and collegues discussed the differences in the functional activities of platelets in newborns and that from adult population. The first was during 1994, in an article titled ‘Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood’ in the journal Thrombosis and Haemostasis. This was followed by an article in the same journal in 1997 titled ‘Platelet hyporeactivity in very-low-birth-weight neonates’. Israles and colleagues published their data in 2001 in the Journal of Pediatrics. The article was titled ‘Evaluation of primary hemostasis in neonates with a new in vitro platelet function analyzer’ which showed a decreased platelet functional response in neonates than adults. These findings suggested that neonates may require lower weight-adjusted doses of antiplatelet agents to achieve the same level of platelet inhibition as for adults and older children.
Apart from the physiological differences, some practical problems are also observed. The children are more mobile and more likely to fall and injure themselves. This is added on with their lesser degree of understanding and adherence to instructions. Reye’s syndrome is a potential complication. Also, they are less likely to understand the consequences of stopping the therapy or not adhering to the dosage.

Q3: What are the present cardiac interventional indications for antiplatelet therapy in children?

The present cardiac indications would be children who undergo implantation of cardiac devices (such as ventricular assist devices (VADs), septal defect occluders, and stents)
An expert review was published in 2008 by Fu and Hijazi under the title ‘The Amplatzer Septal Occluder, a transcatheter device for atrial septal defect closure’ where they strongly advocated the use of aspirin post-ASD device closure. They have quoted the famous study by Fischer et al published in journal Heart in 2003 with title ‘Experience with transcatheter closure of secundum atrial septal defects using the Amplatzer septal occluder: a single centre study in 236 consecutive patients’. In this study, aspirin was used in all 236 and just one patient had a neurological event after 4 years, attributable to device. The evidence is thus in favour of aspirin in this setting.
The data on aspirin with stent placement is not enough, largely due to lesser numbers done in pediatric population. In a retrospective review published by Ebeid et al in 1997, of nine patients (four were 18 years old or younger), aspirin therapy was administered for at least 1 year after implantation of balloon-expandable stents for coarctation of the aorta, and no patient showed evidence of thromboembolism after an average follow-up period of 18 months. This was published in JACC under the title ‘Use of balloon expandable stents for coarctation of the aorta: initial results and intermediate-term follow-up’. Kutty and Zahn published their data on use of aspirin after stent placement in pediatric population in 2008 in the journal Catheter and Cardiovascular Interventions under the title ‘Interventional therapy for neonates with critical congenital heart disease’. In the same year, Menon and colleagues published ‘Hybrid intraoperative pulmonary artery stent placement for congenital heart disease’ in the AJC. In this retrospective review, 24 patients (14 of whom younger than 18 years) received aspirin after undergoing hybrid pulmonary artery stent implantation secondary to congenital heart disease and did not demonstrate any episodes of stent thrombosis over a mean follow-up period of 19 months.

Q4: What are the cardiac post-surgical indications for antiplatelet therapy?

Any child who needs a systemic-to-pulmonary artery shunt is at the risk of thrombotic event. The studies quoting uselessness of therapy were very small and underpowered (Al Jubair et al in 1998 in Journal Cardiology in the Young ‘Results of 546 Blalock-Taussig shunts performed in 478 patients, Fenton et al in ATS in 2003 ‘Interim mortality in infants with systemic-to-pulmonary artery shunts’ and so on) the overall data is in favour of using aspirin (Motz et al in 1999 in journal Cardiology in the Young ‘Reduced frequency of occlusion of aortopulmonary shunts in infants receiving aspirin’, Li et al in 2007 in journal Circulation ‘Clinical outcomes of palliative surgery including a systemic-to-pulmonary artery shunt in infants with cyanotic congenital heart disease: Does aspirin make a difference? and so on).
In 2002, Monagle and Karl published their data as ‘Thromboembolic problems after the Fontan operation’ in Seminars in Thoracic and Cardiovascular Surgery. They advocated the use of aspirin, as children a with single-ventricle approach the Fontan procedure, they remain at high risk of thromboembolic complications.
The data on the use of antiplatelet agents and anticoagulation agents in post-Fontan group remains conflicting. Seipelt and co-workers wrote ‘Thromboembolic complications after Fontan procedures: comparison of different therapeutic approaches’ in ATS in 2002. This was a retrospective study investigating 87 survivors of Fontan surgery, the rates of thromboembolic complications were similar for the patients who received aspirin (1.6 events/100 patient-years) and those who received warfarin (1.1 events/100 patient-years) but much higher for those who received no antithrombotic therapy (4.2 events/100 patient-years). The journal Circulation published an abstract by Monagle et al in 2008 presented at AHA meeting. It was a multicentre randomized trial comparing heparin/warfarin versus aspirin as primary thromboprophylaxis for two years after Fontan procedure in 111 children with mean age of 3.8 years. During a 27-month follow-up period, thrombosis occurred for 24% of the heparin and warfarin recipients and 21% of the aspirin recipients (p = 0.47). The rate of major bleeding also was the same (1 event per group). These data suggest that anticoagulation and antiplatelet therapies are similarly safe and effective in preventing thrombosis after Fontan surgery. However, the favour of surgeon still remains with warfarin in large many institutes across the globe.

Q5: Role of clopidogrel

The year 2005 saw a review article by Finkelstein and colleagues on ‘Clopidogreal use in Children’ in the Journal of Pediatrics. This review served as the baseline for further research with clopidogrel. In 2008, Maltz et al published ‘Clopidogrel in a pediatric population: safety and efficacy results from a single center’ in journal Pediatric Cardiology. It was a retrospective analysis of 90 children (median age, 6.7 years) receiving various doses of clopidogrel. It had a favourable safety and tolerability profile because only two children, both of whom also received aspirin, experienced major bleeding. An additional three patients receiving aspirin plus clopidogrel experienced minor bleeding.
The only randomized control study on Clopidogrel hitherto has been published by Li et al in 2008 in journal Circulation. Popularly called the PICOLO trail, the article is titled ‘Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel trail’. In this, 92 young children aged 0 to 24 months with cardiac disease were randomized to receive placebo or clopidogrel 0.01, 0.10, 0.15, or 0.20 mg/kg/day. Via platelet aggregometry, clopidogrel 0.20 mg/kg/day was identified as the dose that provided a level of platelet inhibition similar to that achieved with 75 mg/day for adults. Notably, none of the patients experienced serious hemorrhagic events, and only four patients (2 in the placebo group and 1 each in the clopidogrel 0.01 and 0.20 mg/kg/day groups) experienced minor bleeding. The results of PICOLO underscore the importance of conducting randomized clinical trials with children, particularly dose-finding studies, because the 0.20-mg/kg/day clopidogrel dose identified in PICOLO is five times lower than the 1-mg/kg/day dose extrapolated from adult studies.
The ongoing CLARINET study may come out with the answers sought after by the pediatric cardiologists. The details of the trail can be accessed at http://clinicaltrials.gov/ct2/show/NCT00396877 The trail is by Sanofi-Aventis and Bristol-Myers Squibb and titled ‘Efficacy and safety of clopidogrel in neonates/infants with systemic to pulmonary artery shunt palliation (CLARINET)’ and is using clopidogrel at a dose of 0.20mg/kg/day.

Q6: What are the current recommendations for the use of antithrombotic therapy in children?

The current guidelines are drawn from the 2008 report by Monagle and others published in journal Chest. It is the 8th edition of American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic therapy in neonates and children. The following are excerpts from the content:
• For children with mechanical prosthetic valves who experience thrombotic events while receiving Vit K Antagonist therapy or who cannot tolerate Vit K Antagonist therapy, ASA should be used (Grade 2C)
• Antiplatelet therapy, either ASA (1–5 mg/kg/day) or Dipyridamole (3–10 mg/kg/day), should be instituted within 72 h of Ventricular Assist Device placement (Grade 2C)
• For children who have a Modified BTT shunt, postoperative ASA (1–5 mg/kg/day) or no antithrombotic therapy should be used compared with prolonged therapy using Low Molecular Wt Heparin or Vit K Antagonist (Grade 2C)
• For children who undergo the Norwood procedure, Ultra-Fractionate Heparin immediately after the procedure, with or without ongoing antiplatelet therapy, should be used (Grade 2C)
• For children who undergo Fontan surgery, ASA (1–5 mg/kg/day) or therapeutic Ultra-Fractionate Heparin followed by Vit K Antagonists should be used (Grade 1B)
• In the absence of a documented ongoing cardioembolic source, no anticoagulation or ASA therapy should be given to neonates with first AIS (Grade 1B)
• For neonates with recurrent AIS, anticoagulant or aspirin therapy may be given (Grade 2C)
• For children with AIS not secondary to sickle-cell disease, cardioembolism, or dissection, Ultra-Fractionate Heparin, Low Molecular Wt Heparin, and ASA (1–5 mg/kg/day) are all acceptable options that should be used for 2 years or longer (Grade 1B)
• Children who experience recurrent Acute Ischemic Stroke or Transient Ischemic Attack while taking ASA should be switched to either clopidogrel or anticoagulant therapy (Vit K Antagonist or Low Molecular Wt Heparin) (Grade 2C)
• For children with Kawasaki disease, high-dose ASA (80–100 mg/kg/day) should be given as an anti-inflammatory agent for up to 14 days, followed by low-dose ASA (1–5 mg/kg/day) for 6–8 weeks as prevention against Coronary Artery Aneurysm (Grade 1B)

That brings us to the end of this discussion. The evidences are still pending. However, I have tried to put available stuff for the current decision making. It can help the decision makes to avoid idiosyncrasy and to instill a uniform policy in the work-front. Also, the junior staff may find it useful to clear their own understanding of the current status. Any recommendations on this topic or any suggestions to improve this section can please be sent to drkiranvs@gmail.com The suggestions would be placed in the subsequent posts, if they come and if the posts continue!!

With this, let us get back to our regular feature: Interesting learning scenarios

FIRST OR SECOND

It is well understood that the Tricuspid atresia with NRGA outnumber the other anatomical variants. Most of the children would eventually complete their single ventricle pathways belong to Tricuspid atresia Ib. Is there any study on the number of Tri atrsia IIb having gone through the Fontan completion? Theoretically, Ib can have two sequential restrictions to Qp: one at VSD and other at pulmonary valve. Whereas, for the IIb variant, this reduces to only the latter. Can this contribute to the eventual numbers? Off late, many of the IIb variants I have come across could not make it to the operating table for having not met the criteria. It would be interesting to note the data from various other centres. If anyone have thought of this question, please let me know your observations.

BLUE IS BETTER

This was a paradoxical situation. When the ventricular EDPs are high in a congenital heart disease, the surgical and ITU teams have to exercise extra-caution. We had a 44-year-old with tetralogy-absent pulmonary valve disease with NYHA class III symptoms and baseline SO2 of 89% in room air. Her LV EDP was 22mmHg. The question was on the expectations from surgery in this scenario. The surgical team was not convinced that the surgery would relieve her symptoms, unless a pulmonary component is co-existing. However, the cardiologist was arguing that the high LV EDP is likely to be the culprit and surgery would be beneficial. Our senior surgeon brought out a point: The EDP of a cyanotic ventricle would improve with surgery and that of acyanotic would not. In other words, in adult TOF, the surgery would reduce the high EDP, but not in VSD. The argument sounded logical. Are there any studies or observations in this regard? Please let me know your take on this.

THE SEPTECTOMY SAGA

I came across a 2-month-old with large VSD with pulmonary atresia. This baby also had a hypoplastic TV, hypoplatic muscle bound RV and a stretched PFO with flap open towards LA, shunting Right to Left. The PAs were small sized and the baby saturated 70% in room air. Ideally, there is a need for increasing the Qp and advocating BTT shunt appears logical choice. However, with increase in LA return, would the PFO flap close towards RA? Once this happens, where would the RA decompress? The TV and RV appeared too small to negotiate the RA outflow. Would it not be detrimental to do the BTT shunt alone? Should we be creating a simultaneous ASD? The recommendation was to do an atrial septectomy clubbed with BTT shunt. However, for same reasons discussed in previous posts, this was not perceived as a good idea. Is there an alternate logic? Am I missing something that the surgeons are confident of? What is the experience of the readership in this issue? Please let me know. I shall try to keep the progress of this baby updated in the subsequent posts.

TYPING AND SIZE

What is the criterion for the Rastelli classification of AV canal defect? The individual opinions vary, but it remains the nature of AV valve itself. We had a newborn with complete AV canal defect. The bridging leaflet was sending its chordae onto the crest of IVS. However, the left AV valve component was hypoplastic, resulting in hypoplastic LV. This was followed by DORV and membranous pulmonary atresia. The management would be on single ventricle lines. However, there was some ambiguity on classifying this as type A Rastelli Vs type C. What is the vote of readership? Please let me know how you classify the AV canal defects in your routine practice.

EVIDENCE OF COMPROMISE

We often predict the loss of ventricular cavity in tunnel closures of VSD, especially in DORV, d-malposed setting. However, the assessment is on 2D and that too for RV, which is not a very echo-friendly structure! When we actually, predict such a scenario, are talking of the volumes or functional cavity or total area of contractile elements? Which of them would be an ideal measurement? Depending on the answer, we can actually devise our investigation in future. If anyone has data on this, please inform me.

PEDIATRIC CARDIOLOGY PEARLS

106. There are two frequent variants of the left aortic arch. One is common brachiocephalic trunk, in which the right innominate and left carotid arteries arise from a single origin. This is present in 10% of otherwise normal left arches (29) and usually is of no consequence. The other variant is separate origin of the left vertebral artery from the aortic arch proximal to the takeoff of the left subclavian artery rather than from the subclavian artery. This too is seen in 10% of normal left arches. (Edwards JE. An atlas of Acquired Diseases of the Heart and Great Vessel. Published by WB Saunders, Philadelphia in the year 1961)

107. Small VSDs, sometimes referred to as Roger's defect, are those less than one third the size of the aortic root and impose a high resistance to flow with a resultant large systolic pressure difference between the two ventricles. There is a small left-to-right shunt, normal right ventricular systolic pressure, and essentially normal work characteristics of the ventricles. The magnitude of the left-to-right shunt is related directly to the size of the defect, and there is no tendency for an increase in pulmonary vascular resistance. The pressure gradient across the defect favors the left ventricle throughout the cardiac cycle and can result in a continuous left-to-right shunt. (Levin AE, Spach MS, Canent RV Jr, et al. Ventricular pressure-flow dynamics in ventricular septal defect. In the journal Circulation in 1967 page 430)

108. The fundamental problem in AV canal defect is failure of the endocardial cushions to fuse, creating a defect in the atrioventricular septum. The primum atrial septal component of this defect is usually large. This results in downward displacement of the anterior mitral leaflet to the level of the septal tricuspid leaflet. (Gutgesell HP, Huhta JC. Cardiac septation in atrioventricular canal defect. In Journal of American College of Cardiology in the year 1986 page 1421)

109. Researchers have found a missense mutation in myosin heavy chain 6 (on chromosome 14q12) has been found to cause familial ASD. (Ching YH, Ghosh TK, Cross SJ, et al. Mutation in myosin heavy chain 6 causes atrial septal defect. In journal Nature Genetics in the year 2005 page 423)

110. The first application of a fluid dynamics principle in medicine was given by Roos. It was represented as “Increasing viscosity or decreasing vessel radius leads to an elevation of both arterial pressure and vascular resistance” (Roos A. Poiseuille's law and its limitations in vascular systems. In the journal Med Thoracics in the year 1962 page 224)

That brings us to the end of another post. Please send your responses and reactions to drkiranvs@gmail.com or use the comments box. Please keep the discussions open. I am trying for an interactive module for debating in pediatric cardiology. Please send in your suggestion on this.

Regards

Kiran