Pediatric Cardiology

Higher efficacy of infliximab than immunoglobulin on Kawasaki disease, a meta-analysis

Higher efficacy of infliximab than immunoglobulin on Kawasaki disease, a meta-analysis. Li X, Tang Y, Ding Y, Chen Y, Hou M, Sun L, Qian G, Qin L, Lv H. Eur J Pharmacol. 2021 Feb 27;899:173985. doi: 10.1016/j.ejphar.2021.173985. Online ahead of print. PMID: 33652059   Take Home Points: Infliximab was more effective than the control group, with the total summary odds ratio (OR) of 0.34 (95% confidence interval (CI): 0.19–0.62). The treatment resistance of the infliximab group was lower than the IVIG group (0.36 [95% CI: 0.14–0.92]) when infliximab was combined with IVIG as the initial treatment. Infliximab treatment for IVIG resistant KD was more effective than the IVIG group (0.28 [95% CI: 0.12–0.66]). Infliximab improved clinical course in IVIG resistant KD patients. Infliximab treatment did not reduce the incidence of coronary artery lesions and did not show any significant increase in the incidence of adverse events. Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch:   Introduction Kawasaki disease (KD) is a systemic immune vasculitis disease affecting the small and medium arteries. Coronary artery lesions (CALs) are one of the most severe complications in KD patients. A high dose of intravenous immunoglobulin (IVIG) is the mainstream treatment of KD. However, about 10–20% of KD patients show resistance to IVIG treatment. A good number of studies in recent days have shown that infliximab could be an effective treatment for IVIG-resistant KD. This is a meta-analysis for the comprehensive evaluation of infliximab’s efficacy and safety as initial therapy for patients with KD and IVIG resistant KD by including both prospective and high-quality retrospective studies. Eight studies were included in this meta-analysis study. These studies covered 713 patients, with 327 cases in the infliximab treated group and 386 in the control group.     Effective of infliximab on KD The total summary OR was 0.34 (95% CI: 0.19 to 0.62) with low heterogeneity (I2 = 30.1%), which showed that infliximab was more effective than the control group. The summary OR of infliximab treatment of IVIG resistant group was 0.28 (95% CI: 0.12 to 0.66), with low heterogeneity (I2 = 0). The results revealed that infliximab treatment was as effective as the initial treatment of KD as well as for IVIG resistant KD.   Coronary artery lesions (CAL) Six studies reported the CALs complication. The summary OR of infliximab treatment on the IVIG resistant group was 0.88 (95% CI: 0.48 to 1.62), with low heterogeneity (I2 = 0). The summary OR was 0.64 (95% CI: 0.23 to 1.74) for infliximab as initial treatment group, with low heterogeneity (I2 = 0), the summary OR of infliximab as treatment of IVIG resistant group was 1.06 (95% CI: 0.49 to 2.28), with low heterogeneity (I2 = 7.9)   Adverse events (AEs) Six studies reported the AEs. Analysis revealed that the incidence of AEs between both groups was not significant. The summary OR was 0.71 (95% CI: 0.44 to 1.16), with low heterogeneity (I2 = 45.3%   Infusion reaction Infusion reaction was regarded as fever with or without chill requiring transient interruption of infusion. The results showed that the infusion reaction incidence in the infliximab group was significantly lower compared to the IVIG group. The summary OR was 0.11 (95% CI: 0.03 to 0.43), with low heterogeneity (I2 = 0).   Other adverse events Patients treated with infliximab had a prevalence of transient hepatomegaly of 19% (6/31) versus 1.5% (1/68) in patients who never received infliximab, with an odds ratio of 16.1 (95% CI, 1.8 to 140.3; P = 0 0.004).   A: Comparison of treatment effectiveness between the infliximab group and control group   B: Comparing the treatment effectiveness of infliximab between prospective and retrospective studies, in the retreatment group.     Discussion The meta-analysis demonstrated that infliximab, a TNF-α blocker is useful either as a first-line treatment in KD or as a treatment for IVIG resistant KD. This analysis has shown that infliximab is potently effective in reducing fever; however, it failed to reduce CALs. Infliximab might also increase the risk of TB and hepatitis when infection occurred. Nevertheless, physicians need to confirm the absence of TB lesions before the use of infliximab. It is highly recommended that pediatricians consider early use of infliximab in cases with refractory KD due to its safety and efficacy.   Conclusion When infliximab combined with IVIG had been used in the primal treatment of patients with KD, it could reduce the rate of resistance compared with conventional IVIG therapy. However, there was no advantage of reducing the incidence of the coronary artery lesions. Infliximab can improve treatment efficiency in treating children resistant to IVIG. There was no increase in adverse events in the treatment of infliximab. Infliximab might reduce the infusion reaction of IVIG. When patients with IVIG contraindicated or exhibited IVIG resistance, infliximab might be useful.   


The mid-term outcome of Fontan conversion compared with primary total cavopulmonary connection

The mid-term outcome of Fontan conversion compared with primary total cavopulmonary connection. Kato A, Sato J, Yoshii K, Yoshida S, Nishikawa H, Ohashi N, Sakurai T, Sakurai H, Hata T, Yoshikawa T. J Cardiol. 2021 Feb 26:S0914-5087(21)00042-3. doi: 10.1016/j.jjcc.2021.02.005. PMID: 33648806   Take Home Points: The indication of Fontan conversion (FC) from atriopulmonary connection (APC) to total cavopulmonary connection (TCPC) is unclear. Fontan conversion is a safe and feasible procedure to bring APC patients back onto the same track of primary TCPC patients in terms of hemodynamics as well as arrhythmia. The antiarrhythmic procedure should be carefully chosen because sinus node dysfunction can frequently occur and FC itself would reduce the risk of arrhythmia.     Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch:   Introduction The Fontan procedure, which is the treatment of choice for patients with functionally univentricular hearts, has been modified by the Bjork, lateral tunnel, and extracardiac total cavopulmonary connection (TCPC) procedures since the introduction of its initial version—the atriopulmonary connection (APC)—by Fontan et al. in the 1970s.   Fontan conversion, which entails connecting the inferior vena cava to the pulmonary artery using an artificial conduit, combined with arrhythmia surgery has been introduced. Possible benefits of prophylactic Fontan conversion in asymptomatic APC patients are improving cardiac output as well as preventing new onset of atrial tachyarrhythmia. On the other hand, the long-term hemodynamic outcome of patients after Fontan conversion compared with that of patients after primary TCPC is unknown. In this study, the sought to compare the midterm outcomes after prophylactic and therapeutic Fontan conversion with those after primary TCPC.   A total of 54 consecutive patients undergoing either Fontan conversion (n = 30) or primary TCPC (n = 24), followed by cardiac catheterization for postoperative hemodynamic evaluation at over 18 years of age between July 2005 and April 2019, were included in the study The included 52 patients were divided into three groups: p-FC, consisting of 15 asymptomatic APC patients who underwent prophylactic Fontan conversion; t-FC, consisting of 13 symptomatic APC patients who received therapeutic Fontan conversion [including arrhythmia (n = 11), heart failure (n = 1), and protein-losing enteropathy (n = 1)]; and p-TCPC, consisting of 24 patients who underwent primary TCPC.   Tricuspid atresia turned out to be the most frequent diagnosis in patients receiving Fontan conversion procedure and the majority of patients in the t-FC (69%) and p-FC (93%) groups were found to have a dominant left ventricle (p = 0.71).   The initial Fontan procedure was performed at the ages of 7.5 (2.3–18.7), 4.7 (1.4– 10.1), and 6.7 (2.9–26.3) years in the t-FC, p-FC, and p-TCPC groups, respectively. The patients in the t-FC and p-FC groups underwent Fontan conversion at 24.4 (14.1–37.7) and 20.3 (8.0–25.6) years of age, respectively.   Overall outcome     Arrhythmia Before Fontan conversion, nine cases of atrial tachycardia (69%), one case of ventricular tachycardia (8%), and one case of sick sinus syndrome (SSS; 8%) were found in the t-FC group, all of which were managed with concomitant antiarrhythmic surgery.   Overview of the patients who underwent therapeutic Fontan conversion (t-FC). The second row indicates pre-operative rhythm (the dotted boxes); the third row indicates anti-arrhythmic surgeries performed at the time of the Fontan conversion (the bold boxes); the fourth and fifth rows indicate cardiac rhythm and devices required post-operatively, respectively. APC, aortopulmonary connection; AT, atrial tachycardia; AVB, atrioventricular block; CRT-P, cardiac resynchronization therapy pacing; JR, junctional rhythm; RA, right atrium; SSS, sick sinus syndrome; VT, ventricular tachycardia.   Hemodynamics No difference in central venous pressure, aortic pressure, and cardiac index was observed across the three groups. Similarly, the levels of brain natriuretic protein (BNP)—which were found to be 34.3 (9.7–93.5), 10.4 (4.9–59.2), and 21.7 (4.9–365.5) in the t-FC, p-FC, and p-TCPC groups, respectively—exhibited no significant difference (p = 0.22).     Discussion Fontan conversion with the Maze procedure has emerged as a tertiary prevention strategy for those with previous APCs and tachyarrhythmia. The present study revealed that this procedure is both prophylactically and therapeutically feasible and effective and that it can yield the same outcomes in conventional APC patients as those observed with the contemporary primary extracardiac TCPC patients.   Tachyarrhythmia in patients with univentricular hearts is known to be a predictor of worse outcomes, especially in APC patients. Thus, antiarrhythmic interventions, such as the Maze procedure, combined with Fontan conversion, are likely to change the deleterious clinical course in these patients. In this cohort, arrhythmia was very well controlled following Fontan conversion that nearly half of the patients in the t-FC group experienced no recurrence without antiarrhythmic medications. Moreover, no newly developed case of tachyarrhythmia was observed in the p-FC group, suggesting the strategy, Fontan conversion +/- antiarrhythmic procedure, can exert both primary and secondary preventative effects against atrial tachyarrhythmias. Aggressive prophylactic Maze procedure appeared to be more harmful than beneficial in our study since three patients (20%) developed sinus node dysfunction postoperatively.   The strategy utilized in this study turned out to have limited efficacy in the prevention of thromboembolism, as 11% of the patients developed a thromboembolic event following Fontan conversion. Although whether antiplatelet therapy or anticoagulation is more effective has yet to be elucidated, lifelong thromboprophylaxis seems essential even after the TCPC procedure or Fontan conversion is performed —probably more in older age.   Conclusions Fontan conversion is a safe and feasible procedure that helps APC patients keep up with primary TCPC patients with respect to hemodynamics and arrhythmia. It is recommended that this procedure be performed before patients become symptomatic. However, the Maze procedure should be limited to those with a history of significant arrhythmia, as it can frequently result in sinus node dysfunction, whereas Fontan conversion itself could lower the risk of arrhythmia.   


Angiotensin-converting enzyme inhibition and pre-superior cavopulmonary connection haemodynamics in infants with single-ventricle physiology

Angiotensin-converting enzyme inhibition and pre-superior cavopulmonary connection haemodynamics in infants with single-ventricle physiology. Al Balushi A, Averin K, Hsu DT, Mackie AS. Cardiol Young. 2021 Feb 16:1-5. doi: 10.1017/S1047951121000305. PMID: 33588974   Take Home Points: ACE inhibitors did not impact mean pulmonary artery pressure or transpulmonary gradient amongst infants with single-ventricle physiology prior to Superior Cavo-pulmonary connection (Glenn) palliation. The pathophysiology of pulmonary vascular remodeling in these infants is complex, and this study suggests that enalapril plays no role in that process in this population.     Commentary from Dr. Manoj Gupta (New York, USA), section editor of Pediatric & Fetal Cardiology Journal Watch: Introduction: Angiotensin-converting enzyme inhibitors have been used in pediatric heart failure associated with left-to-right shunts or chronic valvular regurgitation because they reduce systemic vascular resistance and left-to-right shunt. Amongst single-ventricle patients, ACEi have been shown to decrease ventricular filling pressure in older children with Fontan physiology while pulmonary hypertension therapies aimed at modulating the pulmonary vascular resistance in this patient population have yielded mixed results. Adults with chronic heart failure treated with ACEi have been shown to have lower PA pressure with short term use.   Material and methods: Using the Pediatric Heart Network Infant Single Ventricle trial (ISV trial) dataset, the original ISV trial showed that enalapril in the first year of life was not associated with improved somatic growth, ventricular function, or heart failure severity, but the ISV trial did not explore the impact of ACEi on measures of pulmonary vascular health. The authors hypothesized that infants enrolled in the ISV trial who received enalapril would have lower mean PA pressure compared to those who received placebo.   The study enrolled infants at 10 centers in the United States of America and Canada from August 2003, to May 2007. Inclusion criteria were infants with single ventricle physiology between 1 week and 45 days of age with stable systemic and pulmonary blood flow in whom a superior Cavo pulmonary connection (SCPC) was planned.   The primary outcome of this analysis was: Invasively measured mean PA pressure at the time of the pre-SCPC catheterization. If the mean PA pressure was not recorded in the catheterization dataset, a pulmonary venous wedge pressure was taken as a representative of mean PA pressure if < 18 mmHg. Transpulmonary gradient and pulmonary-to-systemic blood flow ratio recorded during pre-SCPC catheterization and oxygen saturation post-SCPC (7 days after surgery) were secondary outcomes. The initial enalapril dose prescribed in the ISV trial was 0.1 mg/kg/day. The dose was up titrated as tolerated over a period of 2 weeks to the target dose of 0.4 mg/kg/day, given in two divided doses per day. Patients on enalapril were grouped into low- and high dose, based on a cut-off of 0.3 mg/kg/day.   Within the ISV trial, 179 of 230 patients underwent pre-SCPC cardiac catheterization and were included in the current analysis. There were 94 patients (53%) in the placebo group and 85 (47%) in the enalapril group. Baseline patient characteristics were similar between the two groups.  Results are provided as n (%) unless otherwise specified.DKS = Damus–Kaye–Stansel. PAB = pulmonary artery band. SD = standard deviation. *No direct measurement of pulmonary artery pressure and pulmonary vein wedge pressure > 18 mmHg   Hemodynamic outcomes The primary analysis showed no difference in the mean PA pressure between the enalapril and placebo groups (13.1 ± 2.9 versus 13.7 ± 3.4 mmHg, p = 0.31).     Secondary outcome variables also did not differ between study groups. There was no difference in the enalapril versus placebo groups for any of the outcome measures according to the morphology of the ventricle.     Pre-specified subgroup analysis was also performed according to the type of shunt. In infants who had a Sano shunt (Table 4), the mean PA pressure was 13.0 ± 2.5 in the enalapril group versus 14.0 ± 3.6 in the placebo group (p = 0.25). In the Sano shunt patients, the post-SCPC oxygen saturation was 84 ± 4% in the enalapril group versus 82 ± 5% in the placebo group (p = 0.007). In infants who received an aortopulmonary shunt, the mean PA pressure was 14.0 ± 3.2 in the enalapril group versus 14.0 ± 3.4 in the placebo group (p = 0.75), and post-SCPC oxygen saturation was similar in the enalapril and placebo groups (83 ± 6 versus 82 ± 6, respectively, p = 0.96).     Impact of high-dose enalapril: The mean PA pressure was 13.2 ± 3.6 in the high-dose enalapril group (0.3–0.4 mg/kg/day) versus 13.2 ± 3.5 in the low-dose group (0.1–0.2 mg/kg/day) (p = 0.98).   Conclusion: ACE inhibitors did not impact mean pulmonary artery pressure or transpulmonary gradient amongst infants with single-ventricle physiology prior to Glenn palliation.