“On Trial 2009”

This year was an exciting year for a number of clinical trials. In particular, the initial results of both the SVR trial (see past content on this) and the Infant Single Ventricle Trial were presented at the AHA meeting held in Orlando, Florida. Similarly, results of the pivotal trial related to use of HeartMate II for destination therapy were presented. While the latter is primarily of relevance currently to the adult community, no doubt in the future it will bear significance for those of us in the congenital cardiac surgery community, as the HeartMate II is currently the best device/most studied for adolescent age patients.

SVR Trial Follow-up

Dr. Richard Ohye from the University of Michigan and the Pediatric Heart Network (PHN) investigators presented the results on the primary end-point of this trial, which served to compare/contrast the standard BT-shunt modified Norwood procedure versus the RV-to-PA conduit modified Norwood procedure (popularly known as the “Sano” shunt). As a reminder, the primary end-point of the study was focused on mortality or need for transplant at 1-year post-Norwood. Although the overall results were not too discrepant from perhaps what most expected (short-term the results of BT is perhaps better than the RV-to-PA variant, but longer term, there is catch-up/equivalence), there were some more subtle findings that were of great interest, at least to this individual. In particular, one of the most sobering results of the study was the relative risk of mortality or transplant at 12 months: approximately 26% to 36%. These days, one often hears the quotation of approximately 90% survival following the Norwood procedure, suggesting the “mortality barrier” related to palliation of infants with hypoplastic left heart syndrome has been overcome. These results, from some of the most active and high-volume (in terms of Norwood procedure) centers would reflect otherwise, and highlight the need for further improvement. Further, the investigators identified that ejection fraction was somewhat better preserved with the RV-to-PA conduit variants (perhaps somewhat counterintuitive in view of the ventriculotomy) at least early on (p<0.001) after the Norwood procedure. The latter would suggest that perhaps in those infants with the potential for compromised ventricular function (e.g., increased tricuspid valve regurgitation, recent history of shock or ventricular function compromise, etc.) may be better served early on with the RV-to-PA conduit variant Norwood. No doubt more exciting and interesting results will come forth from this seminal study.

Infant Single Ventricle (ISV) Trial

Although conceived and carried out at nearly the same time as the SVR trial, the ISV trial has received much less attention despite its relative importance in the context of infants with single ventricle physiology. In this study, also supported by the PHN investigators and presented at the November, 2009 AHA meeting, the investigators looked at the role of ACE-inhibition in patients with single ventricle physiology. The primary outcome of this study was to compare the effects of ACE-inhibition with placebo on somatic growth. Other significant parameters such as ventricular function, geometry, and heart failure severity were of secondary concern. This study faced many challenges, but in short, the investigators found no evidence of a beneficial effect of enalapril therapy on weight-for-age, other measures of somatic growth, ventricular structure, function or clinical heart failure. More importantly, they found a lack of effect in pre-specified subgroups, suggesting that enalapril is not beneficial even for targeted subsets of patients. This is important in view of the rather prevalent use of ACE-inhibitors in patients that have perhaps tenuous physiology related to their shunt-dependent circulation.

PITCHing after the PRIDE study

At the most recent AHA meeting, the PRIDE Study investigators on management of infants with congenital heart block (CHB) followed through with a subsequent study: Preventive IVIG Therapy for Congenital Heart Block (PITCH) Study. In this multi-center study, the lead author, Dr. Deborah M. Friedman, presented data on the clinical trial of infusion of IVIG to block CHB from occurring in affected mothers (with follow-up post-mortem examinations).  In short, the data from the combined European/US trial were without evidence that replacement doses of IVIG can prevent the development of 2nd and 3rd degree heart block. The authors, however, speculated that the results may have been negative because the chosen dose of IVIG at some centers (too low), led to insufficient effect on the harmful maternal IgG antibodies.  Thus, children were still being affected by the crossover of the maternal antibodies.  The rationale for the chosen dose was rather empiric and some data would suggest that higher doses might indeed be more efficacious. In part, the challenges in this field of study are not unlike those facing investigators interested in other congenital heart defects such as HLHS: absence of any good animal model.  Specifically, the original animal models of CHB were abandoned because they were not generating the same phenotype of disease as seen clinically, but rather produced primarily SA node disease. Future clinical trials with alternate dosing regimens may answer these questions. 

Publication Date: 29-Mar-2010
Last Modified: 26-Mar-2010