The results of this multicenter, randomized trial showed that in infants with hypoplastic left heart syndrome or related single right ventricular anomalies, use of the Norwood procedure with an RVPA shunt, as compared with an MBT shunt, was associated with a higher rate of transplantation-free survival 12 months after randomization (the primary outcome). Secondary analyses of transplantation-free survival at 12 months, based on the shunt that was actually used rather than on the randomly assigned shunt, had similar results. With longer follow-up, however, we observed only a trend toward better outcomes with the RVPA shunt. Using a test of interaction for nonproportional hazards, we found that the nature of the treatment effect was different before and after 12 months. The reasons for the shift in the risk of death or need for transplantation between the early and intermediate periods are speculative. The MBT shunt generates continuous forward flow into the pulmonary arteries, leading to diastolic runoff, coronary steal, and an increased ratio of pulmonary blood flow to systemic blood flow. This physiological response may cause hemodynamic instability early after the Norwood procedure, as well as during the interstage period. The majority of deaths and transplantations occurred during the period from 30 days after the Norwood procedure to the time of the stage II procedure. The MBT shunt is removed at stage II, potentially allowing some of the negative factors related to use of the RVPA shunt to become evident. These factors may include damage to the right ventricle from the ventriculotomy and smaller pulmonary arteries, both of which would be potential disadvantages in infants with single-ventricle anomalies.
The secondary outcomes also differed with respect to early and late risks. Echocardiograms obtained before the stage II procedure showed that infants assigned to the RVPA shunt, as compared with those assigned to the MBT shunt, had smaller right ventricular end-systolic and end-diastolic volumes, when adjusted for body-surface area, and a higher right ventricular ejection fraction. However, by 14 months, the right ventricular end-diastolic volume was similar in the two groups, and the ejection fraction was also similar. These changes may continue over time. Tanoue and colleagues26
compared a group of subjects who underwent the Norwood procedure with an RVPA shunt with a group of historical control subjects who received an MBT shunt. The catheterization data before and after the Fontan procedure showed decreased right ventricular contractility in the RVPA shunt group, with preserved ventricular efficiency based on a lower systemic afterload. Furthermore, in our trial, the 12-month rate of unintended interventions was higher for the RVPA shunt group, in which the interventions consisted primarily of balloon dilation and stent placement. Continued follow-up of trial subjects will be needed to assess the longer-term effects of these two shunts on right ventricular function.
We explored whether the relative efficacy of the two shunts varied in subgroups of infants. The effect of shunt type on transplantation-free survival at 12 months was homogeneous across predetermined subgroups based on birth weight, the presence or absence of aortic atresia or obstructed pulmonary venous return, the degree of tricuspid-valve regurgitation before the Norwood procedure, use or nonuse of regional cerebral perfusion or deep hypothermic circulatory arrest during the Norwood procedure, and the surgeon’s experience. Only site volume showed an interaction, with higher volume negating the advantage of the RVPA shunt with respect to transplantation-free survival. This finding may reflect the expertise of individual surgeons or greater institutional experience in the perioperative care of patients with an MBT shunt. However, an analysis of multiple measures of morbidity for the Norwood hospitalization did not suggest differences in hospital course between groups, with the exception of a lower incidence of cardiopulmonary resuscitation in the RVPA shunt group after the Norwood procedure. In this regard, more extensive analyses of variations in practice patterns may be enlightening.
This trial should be viewed in light of its limitations. As with all surgical trials that compare two operations, it was not possible to keep the personnel who were caring for these infants unaware of the specific intervention. However, the components of the primary outcome (i.e., death and transplantation) were discrete, objective events. Echocardiographic and catheterization measurements were objectively defined and performed in core laboratories. The trial may not have been sufficiently powered to detect important differences in some of the secondary outcomes or interactions between shunt type and prespecified subgroup factors. The results of the intermediate follow-up represent the course of only a subgroup of all the enrolled infants, since not all of them have completed longer-term follow-up. The assessment of nonproportional hazards before and after 1 year was exploratory, and additional follow-up will be important to quantify the relative hazards associated with the two shunts. Using the number of screened infants to define center volume, we found that the category of greatest experience included infants from only two centers.
In summary, among infants with hypoplastic left heart syndrome and related single, right ventricular morphologic anomalies who underwent the Norwood procedure, 12-month transplantation-free survival was higher with the use of an RVPA shunt than with the use of an MBT shunt. However, the RVPA shunt was associated with a higher rate of unintended cardiovascular interventions and complications during the first 12 months after randomization. On the basis of available intermediate-term data, there was no significant difference between the two groups with respect to transplantation-free survival beyond 12 months. Continued surveillance of this cohort is needed to determine whether either of these shunts turns out to be superior over the long term.