Pediatric Thromboprophylaxis of Large Coronary Artery Aneurysm Using Rivaroxaban.

Giant or large coronary artery aneurysms (CAA) are rare in children, most often secondary to Kawasaki disease, and anticoagulation is recommended to prevent thromboembolism. There are no published pediatric reports on the use of a direct oral anticoagulant for this indication. We describe the anticoagulation management of an 8-year-old boy with a dilated right CAA secondary to Kawasaki disease that has remained stable on rivaroxaban and aspirin, following bleeding complications on enoxaparin and challenges on warfarin. The use of rivaroxaban appears to be safe and effective in the prevention of thrombosis in a pediatric patient with CAA.

Etanercept with IVIg for acute Kawasaki disease: a long-term follow-up on the EATAK trial.

BACKGROUND: The Etanercept as Adjunctive Treatment for Acute Kawasaki Disease, a phase-3 clinical trial, showed that etanercept reduced the prevalence of IVIg resistance in acute Kawasaki disease. In patients who presented with coronary artery involvement, it reduced the maximal size and short-term progression of coronary artery dilation. Following up with this patient group, we evaluated the potential long-term benefit of etanercept for coronary disease. METHODS: Patients were followed for at least 1 year after the trial. The size of dilated arteries (z-score ≥ 2.5) was measured at each follow-up visit. The z-score and size change from baseline were evaluated at each visit and compared between patients who received etanercept versus placebo at the initial trial. RESULTS: Forty patients who received etanercept (22) or placebo (18) in the Etanercept as Adjunctive Treatment for Acute Kawasaki Disease trial were included. All patients showed a persistent decrease in coronary artery size measurement: 23.3 versus 5.9% at the 6-month visit, 24 versus 13.1% at the 1-year visit, and 20.8 versus 19.3% at the ≥ 2-year visit for etanercept or placebo, respectively, with similar results for decrease in coronary artery z-scores. In a multivariate analysis, correcting for patients' growth, a greater size reduction for patients on the etanercept arm versus placebo was proved significant for the 6-month (p = 0.005) and the 1-year visits (p = 0.019) with a similar end outcome at the ≥ 2-year visit. DISCUSSION: Primary adjunctive therapy with etanercept for children with acute Kawasaki disease does not change the end outcome of coronary artery disease but may promote earlier resolution of artery dilation.

Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial.

OBJECTIVES: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA). STUDY DESIGN: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy. RESULTS: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. CONCLUSIONS: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.

Low-Molecular-Weight Heparin vs Warfarin for Thromboprophylaxis in Children With Coronary Artery Aneurysms After Kawasaki Disease: A Pragmatic Registry Trial.

BACKGROUND: The substantial risk of thrombosis in large coronary artery aneurysms (CAAs) (maximum z-score ≥ 10) after Kawasaki disease (KD) mandates effective thromboprophylaxis. We sought to determine the effectiveness of anticoagulation (low-molecular-weight heparin [LMWH] or warfarin) for thromboprophylaxis in large CAAs. METHODS: Data from 383 patients enrolled in the International KD Registry (IKDR) were used. Time-to-event analysis was used to account for differences in treatment duration and follow-up. RESULTS: From diagnosis onward (96% received acetylsalicylic acid concomitantly), 114 patients received LMWH (median duration 6.2 months, interquartile range [IQR] 2.5-12.7), 80 warfarin (median duration 2.2 years, IQR 0.9-7.1), and 189 no anticoagulation. Cumulative incidence of coronary artery thrombosis with LMWH was 5.7 ± 3.0%, with warfarin 6.7 ± 3.7%, and with no anticoagulation 20.6 ± 3.0% (P < 0.001) at 2.5 years after the start of thromboprophylaxis (LMWH vs warfarin HR 1.5, 95% confidence interval [CI] 0.4-5.1; P = 0.56). A total of 51/63 patients with coronary artery thrombosis received secondary thromboprophylaxis (ie, thromboprophylaxis after a previous thrombus): 27 LMWH, 24 warfarin. There were no differences in incidence of further coronary artery thrombosis between strategies (HR 2.9, 95% CI 0.6-13.5; P = 0.19). Severe bleeding complications were generally rare (1.6 events per 100 patient-years) and were noted equally for patients on LMWH and warfarin (HR 2.3, 95% CI 0.6-8.9; P = 0.25). CONCLUSIONS: LMWH and warfarin appear to have equivalent effectiveness for preventing thrombosis in large CAAs after KD, although event rates for secondary thromboprophylaxis and safety outcomes were low. Based on our findings, all patients with CAA z-score ≥ 10 should receive anticoagulation, but the choice of agent might be informed by secondary risk factors and patient preferences.

Coronary Drug-Eluting Stent Infection Complicated by Coronary Artery Aneurysm and Purulent Pericarditis: Complete Resolution Without Surgery.

Coronary stent infection is considered to be a rare but catastrophic complication of percutaneous coronary intervention. In this report, we present a 72-year-old man who developed a coronary stent infection complicated by coronary aneurysm and purulent pericarditis. Coronary artery aneurysm resolved over a period of 8 months following the successful management of infection with intensive antibiotic therapy alone. This case suggests that conservative therapy can be a therapeutic option in patients with high operative risks.

Variation in the management of Kawasaki disease.

Intravenous immunoglobulin (IVIG) reduces coronary aneurysms in patients with Kawasaki disease (KD), but additional management options remain challenging, with no generalisable evidence-based recommendations. We performed a survey of 724 physicians from 73 countries to assess variation in practice. IVIG was the preferred initial treatment by 659 (91%) of respondents. Criteria for adjunctive primary treatment varied considerably and definitions of IVIG resistance varied markedly by geographical continent, Human Development Index tiers and medical specialty. A second dose of IVIG was used most often for patients with coronary aneurysm non-responsive to initial treatment (572, 79%), but corticosteroids (379, 52%) and tumour necrosis factor alpha inhibitors (208, 29%) were also frequently used. Our findings highlight the need for international collaborative efforts to optimise management of patients with KD worldwide.

Resection of a large mycotic aneurysm of the left anterior descending coronary artery.

A 50-year-old Indigenous woman, on home haemodialysis, was found to have a large mycotic aneurysm of the proximal left anterior descending coronary artery at the site of a previous drug-eluting stent. Blood cultures grew methicillin-sensitive S taphylococcus aureus bacteraemia. She underwent a complex operation involving resection of the mycotic aneurysm, removal of the stent and a coronary artery bypass graft to the distal left anterior descending (LAD) coronary artery using the left internal mammary artery. She had a complicated intensive care unit admission with pericardial tamponade on day 1 postoperatively requiring reopening and removal of clot and type 1 respiratory failure requiring reintubation on day 10 postoperatively. Once extubated, she developed prolonged hyperactive delirium and a significant decline in mobility. Over the course of a 6-week hospital admission, she received extensive multidisciplinary care and was discharged for rehabilitation to a peripheral hospital. She was discharged home after rehabilitation with ongoing follow-up with infectious diseases.

The peculiarities of Kawasaki disease at the extremes of age: Two case reports.

RATIONALE: Extremes of age is an important risk factor for the development of coronary arteries aneurysms (CAAs) associated to Kawasaki disease (KD) along with male gender, prolonged fever and a delay in diagnosis or treatment. PATIENT CONCERNS: We report two cases of KD in the extremes of age, a 5-month-old male infant and a 9-year-old child in order to underline the features of this disorder outside the typical age range of 1 to 4 years. The 5-month-old male was admitted in our clinic for generalized polymorphous exanthema and fever for approximately 7 days. The laboratory test pointed out leukocytosis and increased inflammatory biomarkers. The 9-year-old male child was admitted in our clinic for fever and submandibular adenopathy. The onset was approximately 5 days before the admission with a sudden development of unilateral, painless, submandibular lymphadenopathy for which the ENT specialist recommended antibiotics and nonsteroid anti-inflammatory drugs. In the 2nd day of admission, he presented severe desquamation of hands and soles. DIAGNOSIS: Both cases were diagnosed with KD. The echocardiography showed no cardiac impairment in the infant, while in the older patient it revealed mild dilation of the left coronary artery. INTERVENTIONS: Both patients received intravenously immunoglobulin and pulsed methylprednisolone. OUTCOMES: The evolution was favorable in both cases, but in the infant, the C-reactive protein levels persisted mildly elevated for approximately 2 months after the diagnosis. LESSONS: The peculiarities of KD in the extremes of age are related to a higher frequency of incomplete features and an increased incidence of coronary artery lesions resulting in a delay of the diagnosis, and subsequent poorer outcomes.

Kawasaki disease triggered by parvovirus infection: an atypical case report of two siblings.

BACKGROUND: There are reports of the familial occurrence of Kawasaki disease but only a few reports described Kawasaki disease in siblings. However, the familial cases were not simultaneous. In these patients the idea of infective agents as trigger must be considered. CASE PRESENTATION: We describe two siblings with atypical presentations of Kawasaki disease; the sister was first diagnosed as having parvovirus infection with anemia and the brother was diagnosed as having myocarditis. The first patient was a 9-month-old Caucasian girl with fever, conjunctivitis, rash, and pharyngitis, and later she had cervical adenopathy, diarrhea and vomiting, leukocytosis, and anemia, which were explained by positive immunoglobulin M against parvovirus. However, coronary artery lesions with aneurysms were documented at day 26 after fever onset. An infusion of intravenous immunoglobulin and high doses of steroids were not efficacious to resolve the coronary lesions. She was treated with anakinra, despite a laboratory test not showing inflammation, with prompt and progressive improvement of coronary lesions. Her 7-year-old Caucasian brother presented vomiting and fever at the same time as she was unwell, which spontaneously resolved after 4 days. Four days later, he again presented with fever with abdominal pain, associated with tachypnea, stasis at the pulmonary bases, tachycardia, gallop rhythm, hypotension, secondary anuria, and hepatomegaly. An echocardiogram revealed a severe hypokinesia, with a severe reduction of the ejection fraction (20%). He had an increase of immunoglobulin M anti-parvovirus, tested for the index case of his sister, confirming the suspicion of viral myocarditis. He received dopamine, dobutamine, furosemide plus steroids, with a progressive increase of the ejection fraction to 50%. However, evaluating his sister's history, the brother showed a myocardial dysfunction secondary to Kawasaki shock syndrome. CONCLUSIONS: We report on familial Kawasaki disease in two siblings which had the same infectious trigger (a documented parvovirus infection). The brother was diagnosed as having post-viral myocarditis. However, in view of the two different and simultaneous evolutions, the girl showed Kawasaki disease with late coronary artery lesions and aneurysms, whereas the brother showed Kawasaki shock syndrome with myocardial dysfunction. We stress the effectiveness of anakinra in non-responder Kawasaki disease and the efficacy on coronary aneurysms.

Effective infliximab therapy for the early regression of coronary artery aneurysm in Kawasaki disease.

BACKGROUND: There is limited information available regarding the role of infliximab (IFX) following the acute phase of Kawasaki disease (KD). We aimed to evaluate whether IFX is associated with coronary artery aneurysm (CAA) regression. METHODS: Between 2005 and 2016, we identified 971 consecutive patients with KD from 3 tertiary institutions, and 49 (5%) with CAAs were enrolled in our study. Patients were divided into 2 groups: 27 who received IFX and 22 who did not. The persistence rate of CAAs was compared between the groups. RESULTS: Age, sex, and duration of the febrile period did not significantly differ between the groups. The maximum value of C-reactive protein was higher in the IFX- than in the non-IFX group. The maximum z-score of CAAs did not differ between the groups. The 2-, 4- and 6-year cumulative persistence rate of CAA was 24%, 24% and 24% in IFX-group, whereas 67%, 52% and 33% in non-IFX group, respectively (P = 0.03). The median duration of CAA regression was 1.1 vs. 4.6 years. Among those who developed medium- or large-sized CAAs, the 2-, 4- and 6-year cumulative persistence rate of CAA was 33%, 33% and 33% in IFX group, whereas 77%, 51% and 48% in non-IFX group, respectively (P = 0.047). Multivariate logistic regression analysis indicated that the maximum z-score (hazard ratio 0.72, p < 0.001) and response to IFX (hazard ratio 4.56, p = 0.017) were independently related to regression. CONCLUSION: IFX therapy was observed to be effective for the early improvement of CAAs in patients with intravenous immunoglobulin-resistant KD.

Immunoglobulin G4-related multiple cardiovascular lesions successfully treated with a combination of open surgery and corticosteroid therapy.

Immunoglobulin G4-related disease, a newly emerging systemic autoimmune disorder, can potentially involve the cardiovascular system. The standard treatment for immunoglobulin G4-related cardiovascular disease has not been established. We encountered a very rare case of an immunoglobulin G4-related inflammatory abdominal aortic aneurysm coexisting with a coronary artery aneurysm and periarteritis. The patient underwent surgical resection for the abdominal aortic aneurysm, followed by successful corticosteroid therapy for the coronary artery lesions. This is the first report of steroid-sensitive immunoglobulin G4-related coronary artery disease. A carefully planned treatment strategy for the multiple cardiovascular lesions was invaluable in the present case.

Thrombolytic therapy in Kawasaki disease: a report of four cases.

Four patients with a thrombus in a coronary artery aneurysm due to Kawasaki disease (KD) were treated at our hospital between 1994 and 2009. All the cases were treated with intravenous coronary thrombolysis (IVCT) therapy and the cases with acute myocardial infarction were treated with additional intracoronary thrombolysis therapy. Although both thrombolytic therapies were effective, IVCT required more time than intracoronary thrombolysis to resolve the thrombus. We concluded that IVCT can be used as the first-line thrombolytic therapy for KD, except in cases with acute myocardial infarction.

[The role of immunosuppressive agents in Kawasaki disease: a discussion of two cases]. / Place des immunosuppresseurs dans les formes évoluées de maladie de Kawasaki : à propos de deux cas avec atteinte cardiaque sévère.

INTRODUCTION: Kawasaki disease (KD) is the most common cause of acquired heart disease in developed countries. Ten percent of patients with KD develop coronary aneurism. Ten percent of patients treated with intravenous immunoglobulin (IgIV) have persistent coronary dilatations, which sustains the search for new therapies. We describe 2 cases of refractory KD and discuss the therapeutic options. CLINICAL REPORT: A 3-year-old child and a 3-month-old infant had refractory KD. Both were treated with IgIV and corticosteroids. They both had persistent fever and major coronary artery dilatation. The first patient received a treatment with acetyl-salicylic-acid (ACA) only. The second received an immuno-therapy with an anti-TNF-α agent. Fever and inflammatory symptoms disappeared within 12h in the second case. Coronary artery aneurisms worsened during the first month and then stabilized. The first child had fever and inflammatory symptoms for a longer duration, but coronary artery dilatations stabilized and disappeared with no additional treatment than ACA. DISCUSSION AND CONCLUSION: TNF-α is known to be one of the inflammatory factors involved in KD disease. Anti-TNF-α agents have been tested in treatment of refractory KD. In one of the cases reported herein, this therapy was not effective on coronary artery aneurism. More studies are needed to define the optimal treatment of refractory KD.

Extensive coronary aneurysms with thrombosis in resistant Kawasaki disease.

Giant coronary artery aneurysms that occur in 0.5 to 1% of patients with Kawasaki disease can be fatal if associated with thrombosis. Some patients may show persistent inflammation and fever despite treatment with repeated doses of intravenous immunoglobulin (IVIG), steroids, and aspirin. This report describes an infant boy with resistant Kawasaki disease who presented with extensive coronary artery involvement and coronary thrombosis. His inflammation was not controlled with multiple doses of IVIG, parenteral and oral steroids, or high-dose aspirin, and he finally needed infliximab, a monoclonal antibody against tumor necrosis factor alpha. The progression of coronary thrombosis was arrested by the platelet glycoprotein 2b/3a receptor blocker, abciximab, during the acute phase of the disease.

Spontaneous coronary artery dissection: long-term follow-up of a large series of patients prospectively managed with a "conservative" therapeutic strategy.

OBJECTIVES: This study sought to assess the long-term clinical outcome of patients with spontaneous coronary artery dissection (SCD) managed with a conservative strategy. BACKGROUND: SCD is a rare, but challenging, clinical entity. METHODS: A prospective protocol, including a conservative management strategy, was followed. Revascularization was only considered in cases with ongoing/recurrent ischemia. Inflammatory/immunologic markers were systematically obtained. RESULTS: Forty-five consecutive patients (incidence 0.27%) were studied during a 6-year period. Of these, 27 patients (60%) had "isolated" SCD (I-SCD), and 18 had SCD associated with coronary artery disease (A-SCD). Age was 53 ± 11 years, and 26 patients were female. Most patients presented with an acute myocardial infarction. SCD had a diffuse angiographic pattern (length: 31 ± 23 mm). In 11 patients, the diagnosis was confirmed by intracoronary imaging techniques. Sixteen patients (35%) required revascularization during initial admission. One patient died after surgery, but no additional patient experienced recurrent myocardial infarction. No significant inflammatory/immunologic abnormalities were detected. At follow-up (median 730 days), only 3 patients presented with adverse events (1 died of congestive heart failure, and 2 required revascularization). No patient experienced a myocardial infarction or died suddenly. Event-free survival was similar (94% and 88%, respectively) in patients with I-SCD and A-SCD. Notably, at angiographic follow-up, spontaneous "disappearance" of the SCD image was found in 7 of 13 (54%) patients. CONCLUSIONS: In this large prospective series of consecutive patients with SCD, a "conservative" therapeutic strategy provided excellent long-term prognosis. Clinical outcome was similar in patients with I-SCD and A-SCD. The natural history of SCD includes spontaneous healing with complete resolution.

Spontaneous coronary artery dissection during cabergoline therapy.

Although spontaneous coronary artery dissection is a rare cause of acute coronary syndrome, it should be considered during the evaluation of patients who have chest pain. Coronary vasospasm can lead to spontaneous dissection. The dopamine agonist cabergoline is known to cause digital vasospasm. Herein, we report a case of spontaneous right coronary artery dissection in a 43-year-old woman who was taking cabergoline as therapy for prolactinoma. To our knowledge, this is the first report of an apparent relationship between cabergoline therapy and spontaneous coronary artery dissection. The possible association of cabergoline with coronary artery spasm and dissection should be considered in patients who present with chest pain while taking this medication.

Rapid progression of coronary aneurysm to stenosis in a patient with Kawasaki disease.

In Kawasaki disease, coronary aneurysms typically regress slowly, although some may develop stenosis 1-2 decades after the acute illness. This is the first case report describing rapid progression of coronary aneurysm to stenosis within 14 weeks.