Treatment and prognosis of patients with Kawasaki disease and giant coronary artery aneurysm: a retrospective observational study
Naoki Saito1
, Ryota Ebata1,2, Kentaro Okunushi1, Kumi Yasukawa3, Hiromichi Hamada1
Contributions: (I) Conception and design: H Hamada, R Ebata; (II) Administrative support: H Hamada; (III) Provision of study materials or patients: H Hamada, N Saito; (IV) Collection and assembly of data: N Saito, K Okunushi; (V) Data analysis and interpretation: N Saito, H Hamada; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Background: There is no established regimen for antithrombotic therapy in patients with Kawasaki disease (KD) who develop giant coronary artery aneurysm (GA). This single-center retrospective study evaluated the outcome of a unified antithrombotic regimen in these patients.
Methods: Sixteen KD patients with GA onset between 1999 and 2013 were included. The patients were started on intravenous heparin and then switched to warfarin in addition to low-dose aspirin when blood tests indicated that the inflammatory response had subsided and the aneurysm had ceased dilating. The target prothrombin time-international normalized ratio (PT-INR) was 2.0–2.5. Patients with no cardiac events or thrombus formation within 2–3 years of onset were considered for discontinuation of anticoagulation and continuation on antiplatelet treatment alone.
Results: The median follow-up duration was 5.8 years (range, 0.25–9.9 years). There were 7 cases of myocardial infarction, including 1 that was fatal and 1 that were asymptomatic. There was no significant difference in the day of KD treatment initiation, onset of GA, or follow-up duration between patients with cardiovascular events (CEs; n=7) and those without CEs (n=9). CEs were significantly more common in patients with larger maximum Z-score (P=0.044) and multiple GAs than in those with a single GA (P=0.007). The prothrombin time at the time of events was below the management target in 3 of the 7 patients with CEs.
Conclusions: The prognosis of KD patients with GA was unsatisfactory in this study, especially in those with large and multiple GAs. In addition to antiplatelet therapy, we recommend continuation of strict anticoagulation therapy in these patients.
Keywords: Kawasaki disease; coronary artery disease; myocardial infarction; major adverse cardiovascular events
Submitted Jul 01, 2024. Accepted for publication Dec 16, 2024. Published online Feb 25, 2025.
doi: 10.21037/cdt-24-289
Highlight box
Key findings
• Cardiac events were significantly more common in Kawasaki disease patients with large giant aneurysms and aneurysms in multiple branches than in those with giant aneurysm in a single branch.
What is known and what is new?
• Patients with giant coronary artery aneurysm are at high risk of cardiovascular events.
• Patients with Kawasaki disease and giant aneurysms in multiple branches experienced significantly more cardiac events.
What is the implication, and what should change now?
• Continuation of strict anticoagulation therapy in addition to antiplatelet therapy is recommended in Kawasaki disease patients with multiple giant aneurysms.
Introduction
Kawasaki disease (KD) is an acute systemic vasculitis of unknown cause that mainly occurs in childhood and was first reported in Japan by Tomisaku Kawasaki in 1967 (1). It is a syndrome caused by inflammation mainly in the medium-sized arteries with characteristic clinical symptoms, including fever, rash, eye redness, lip and tongue redness, swelling of the hands and feet, and cervical lymphadenitis (2,3). Treatment consists of intravenous immunoglobulin (IVIG) and oral aspirin, which has an 80% efficacy rate. However, a serious complication of KD is coronary artery aneurysm (CAA), which occurs in 7–8% of patients and persists for more than 1 month after onset in 2–3% of cases (3,4). Patients with giant coronary artery aneurysms (GAs; i.e., aneurysms ≥8 mm in diameter or coronary artery Z-score ≥10) are at high risk of cardiovascular events (CEs), particularly myocardial infarction and heart failure, and require lifelong treatment (5).
In Japan, where KD was first recognized and treated, at least 272,000 people were estimated to have KD by the end of 2010, 117,000 of whom had reached adulthood (6). Nationwide surveys in Japan have investigated deaths from coronary sequelae of KD in young adults in detail (7,8). A questionnaire-based survey of 644 hospitals across Japan in 2010–2011 identified 67 deaths in patients who were judged to have had KD in childhood. In these patients, death occurred at a median interval of 16 years after the acute phase and the culprit lesion was characterized by aneurysm ≥6 mm in the acute KD and giant aneurysm in the long-term (8). KD patients with GA have the highest risk of CEs (5,8-10). Antiplatelet and anticoagulation therapies are used in these patients, but there is insufficient evidence to guide their dosage and duration (3,4,11).
Since 1998, we have been treating KD patients with GAs using a uniform antithrombotic protocol at our facility in Chiba Prefecture, Japan. In this retrospective study, we examined the status of GAs and their treatment and outcomes in order to evaluate our antithrombotic treatment protocol and add some evidence regarding the long-term management for KD with GA, and it is hoped that this work will provide insights for the management of adult KD patients with GA. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-289/rc).
Methods
The medical records at Chiba University Hospital were retrospectively searched to identify patients with a diagnosis of KD and GA who were treated in the acute phase of KD between 1999 and 2013. GA was defined as a coronary artery diameter of ≥8 mm (3,11,12). Moderate CAA was defined as a coronary artery diameter of ≥4 and <8 mm, and small CAA was defined as a coronary artery diameter of ≥3 and <4 mm. The maximum diameter in the acute phase was recorded by echocardiography and coronary angiography. Coronary artery Z-scores were computed using a calculator based on data for Japanese children (13). Patients who declined to participate in this research in writing and those deemed unsuitable for inclusion in the opinion of the principal investigator were excluded.
The following data were obtained from the medical records: age at onset of KD, date of treatment initiation for KD, results of laboratory tests, details of treatment, details of antithrombotic therapy, date of resolution of fever, date of CAA development, site(s) of GA, CEs, and death. CEs were defined as myocardial infarction, angina pectoris, and asymptomatic myocardial infarction. Asymptomatic myocardial infarction was diagnosed by electrocardiographic evidence of ischemic change at the time of routine evaluation in the outpatient department. Seven patients had CEs (event group) and 9 did not (non-event group).
Our antithrombotic protocol for patients with KD and CAA is as follows. We consider pyrexia to have resolved when the patient’s temperature remained below 37.5 ℃ for 48 h. We then reduce the aspirin dose from 30–50 to 3–5 mg/kg/day. Continuous intravenous heparin is started when the diameter of a CAA is ≥6 mm and then switched to oral warfarin when laboratory tests confirm that the inflammatory response has resolved and the aneurysm has stopped dilating (phase 1). The warfarin dose is determined by a target prothrombin time-international normalized ratio (PT-INR) of 2.0–2.5 on coagulation tests. Patients with no CEs or findings of thrombosis in the first 2–3 years of the illness (phase 2) are considered for discontinuation of warfarin and continuation on aspirin alone (phase 3).
Initial coronary angiography is performed when coronary arteritis is judged to have subsided, which is typically around 3 months after onset of KD. A second coronary angiogram is performed 1 year after onset of KD. If there are no significant morphological changes on echocardiography, additional angiography or contrast computed tomography/magnetic resonance imaging is performed 1–3 years later. If there are symptoms of suspected myocardial infarction or thrombus on echocardiography, an imaging study is performed on an ad-hoc basis.
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Graduate School of Medicine, Chiba University (No. HK202406-11). Informed consent was obtained from all eligible patients.
Statistical analysis
The data are shown as the median (range). Differences in continuous variables were compared between groups using the Student’s t-test or Wilcoxon’s test. Differences in incidence between groups were compared using the Chi-squared test. The statistical analysis was performed using JMP14 software (SAS Institute Inc., Cary, NC, USA). A P value <0.05 was considered statistically significant.
Results
A total of 342 patients with KD were treated at Chiba University Hospital between 1999 and 2013. GAs were detected in 16 of these patients (4.7%). Moderate CAAs were detected in 12 (3.5%), and small CAAs in 1 (0.3%). The study included the 16 patients (11 male, 5 female) with GA onset during the study period.
In the 16 patients with GA onset, the median age at onset of KD was 3.9 years (range, 0.25–8.0 years), the median follow-up duration was 5.8 years (range, 0.25–9.9 years), and the median age at the time of the study was 8.4 years (range, 2.5–14.8 years). The median interval between presentation and diagnosis of CAA was 8 days (range, 3–37 days), and the median duration of illness at maximum GA diameter was 22 days (range, 7–37 days). All patients were initially treated with IVIG and oral aspirin in the acute phase of KD. Of the 16 patients, 12 received additional IVIG and 11 received steroids (Table 1).
Table 1
| Items | Total | Group E | Group N | P |
|---|---|---|---|---|
| N | 16 | 7 | 9 | NA |
| Age at onset of KD (years) | 3.9 (0.25–8.0) | 0.83 (0.25–6.7) | 4.7 (0.33–8.0) | 0.14 |
| M/F | 11/5 | 4/3 | 7/2 | 0.60 |
| Acute treatment | ||||
| Duration of illness at start of treatment (days) | 5 (2–22) | 4 (3–5) | 6 (2–22) | 0.07† |
| Treatment | ||||
| IVIG and aspirin | 16 | 7 | 9 | >0.99 |
| Additional IVIG | 12 | 7 | 5 | 0.02 |
| Steroids added | 11 | 7 | 4 | 0.006 |
| Onset of CAA (days) | 8 (3–18) | 8 (7–17) | 7 (3–18) | 0.95 |
| Follow-up duration, years | 5.8 (0.25–9.9) | 5.8 (2.0–8.9) | 2.0 (0.25–9.9) | 0.29 |
| Giant aneurysms | ||||
| Maximum Z-score | 16.0 (9.3–45.7) | 18.8 (14.0–45.7) | 12.4 (9.3–19.7) | 0.044† |
| Location of giant aneurysms | 0.02 | |||
| RCA only | 2 | 0 | 2 | |
| LCA only | 4 | 0 | 4 | |
| RCA and LCA | 10 | 7 | 3 | |
| Cardiac events | ||||
| Death | 1 | 1 | 0 | NA |
| MI | ||||
| 1 event | 3 | 3 | 0 | NA |
| 2 events | 1 | 1 | 0 | NA |
| Asymptomatic MI | 3 | 3 | 0 | NA |
| CABG | 3 | 3 | 0 | NA |
Data are presented as n or median (range). †, Wilcoxon’s test. Group E: with cardiovascular events. Group N: without cardiovascular events. NA, not applicable; KD, Kawasaki disease; M, male; F, female; IVIG, intravenous immunoglobulin; CAA, coronary artery aneurysm; RCA, right coronary artery; LCA, left coronary artery; MI, myocardial infarction; CABG, coronary artery bypass grafting.
Table 1 summarizes the patient characteristics and treatment according to CE status. There was no significant difference in the date of treatment initiation for KD, date of detection of CAA, or follow-up duration between the groups. There was a significant difference in maximum Z-scores during follow-up between patients in the event group and those in the non-event group. KD was treated by additional IVIG in all 7 patients in the event group and in 5 of the 9 in the non-event group. Steroids were administered to all 7 patients in the event group and in 4 of the 9 patients in the non-event group.
Eight CEs occurred in 7 of the 16 patients (44%, all in the event group) (Table 1) and included 5 cases of myocardial infarction and 3 of asymptomatic myocardial infarction. The coronary vessels involved in the 8 CEs were the right coronary artery (n=4) and the left anterior descending artery (n=4). All culprit lesions were completely occluded at the time of the CEs. In the event group, 1 patient experienced fatal myocardial infarction and 3 underwent coronary artery bypass grafting. Three patients had CEs in phase 1, 2 had CEs in phase 2, and 2 had CEs in phase 3 (Table 2). Four events occurred when the prothrombin time was poorly controlled. Case 7 had a myocardial infarction 3 months after discontinuation of warfarin (Table 2).
Table 2
| Case | CE | Culprit branch for CE | Culprit branch Z-score | Treatment phase† | Period from KD onset to CE | Antithrombotic therapy at time of CE | Coagulation status at time of CE |
|---|---|---|---|---|---|---|---|
| 1 | MI | RCA | 16.5 | 1 | 1 month | Heparin | APTT X1‡ |
| 2 | MI | LAD | 15.4 | 1 | 1.5 months | Heparin, Wa, ASA | APTT X2‡, PT-INR 1.3 |
| 3 | SMI | RCA | 15.5 | 1 | 5 months | Wa, ASA | APTT X1.5‡, PT-INR 2.0 |
| 4 | MI, death | LAD | 14.6 | 2 | 2.0 years | Wa, ASA | PT-INR 1.3 |
| 5 | MI | RCA | 16.5 | 2 | 2.0 years | Wa, ASA | PT-INR 1.8 |
| 6 | MI | LAD | 18.7 | 3 | 9.3 years | ASA | NA |
| SMI | LAD | 18.7 | 12.3 years | Wa, ASA | PT-INR 1.1 | ||
| 7 | MI | RCA | 14.0 | 3 | 3.2 years | DAPT | NA |
†, each phase is explained in Methods section of the main text; ‡, APTT is expressed as a multiple of the control value. Group E: with cardiovascular events. CE, cardiovascular event; KD, Kawasaki disease; MI, myocardial infarction; RCA, right coronary artery; APTT, activated partial thromboplastin time; LAD, left anterior descending artery; Wa, warfarin; ASA, aspirin; PT-INR, prothrombin time-international normalized ratio; SMI, silent myocardial infarction; DAPT, dual antiplatelet therapy; NA, not applicable.
The distribution of patients in each group by number of GAs is shown in Table 3. All patients in the event group had multivessel lesions (2 GAs, 4/7 cases; 3 or 4 GAs, 3/7 cases). In contrast, 5 patients with a single GA in the non-event group did not have any CEs and were switched to antiplatelet therapy alone. Patients with GAs in multiple branches had significantly more CEs than those with GA in a single branch (P=0.007).
Table 3
| Number of GAs | Group E | Group N | P value |
|---|---|---|---|
| Single | 0 | 5 | 0.007 |
| Double | 4 | 4 | |
| Triple | 3 | 0 |
Group E: with cardiovascular events. Group N: without cardiovascular events. GAs, giant coronary artery aneurysms.
Discussion
In this study, the incidence of CEs was 44% in 16 KD patients with GA on antithrombotic therapy over a median of 5.8 years. A recent systematic review of studies that have investigated the prognosis of CAA in KD reported that 10-year survival ranged from 92% to 99% and 10-year major adverse CE-free survival ranged from 66% to 91% (14). That report included all sizes of CAA. The 10-year survival rate for patients with GA was reported to be 94–99% and 10-year CE-free survival to be 58–71% at 10 years (9). In terms of the prognosis, our results are comparable with those previously reported. However, the incidence of 44% for CEs is still very high, and we believe our treatment protocol is unsatisfactory and needs to be improved. In our antithrombotic protocol, anticoagulation was discontinued after 2 or 4 years if a patient had no CEs, regardless of the morphology or number of CAAs. By evaluating this protocol, this work provides evidence that can contribute to establishing discontinuation criteria.
The first step needed to improve management of patients with GA is strict control of prothrombin time. Three of our patients who experienced CEs had a low prothrombin time of 1.0–1.5 at the time of the event. It is important to counsel patients and families about the high risk of CEs, increase patient adherence, and adjust the dosage of medication appropriately. The second step is the therapeutic option of adding another antiplatelet agent. Dual antiplatelet therapy has been recommended for adults with coronary vascular disease (15-17). However, the risk of bleeding is expected to be increased, and large-scale trials are difficult to conduct in KD patients with CAA, making it difficult to draw firm conclusions.
The maximum Z-score during follow-up was significantly larger in the group with CE. A prognostic study of 209 Japanese patients with KD and GA reported a significantly greater maximum Z-score in the group with CE (10). In the present study, all patients with CEs had a maximum Z-score of ≥14 and those without CEs had a wide distribution of maximum Z-scores ranging from 9.3 to 19.7.
Our results suggest that the presence of GAs in multiple branches is associated with a high risk of CEs, which is in line with the findings of a study by Tsuda et al. (9). They reported that CEs were significantly more common in patients with GAs in multiple branches than in those with GA in a single branch. Furthermore, potentially good collateral arteries may develop more easily in patients with unilateral GA than in those with bilateral GA (9,18). This finding is important in terms of treatment decision-making in both the early and late stages. Optimal treatment by coronary artery bypass grafting could be considered, especially in patients with bilateral GA.
This study has several limitations. First, the sample size was small, and the follow-up duration was relatively short. However, our findings are consistent with those of previous studies that included larger numbers of patients with longer follow-up. Second, the study was conducted in 2013–2014. The treatment guidelines were revised in the US in 2017 and in Japan in 2020 (3,4). The latest guidelines for KD recommend continued anticoagulation for the most severe cases of CAA, including GA, which is supported by our results.
Conclusions
In this case series, the prognosis of KD with GA was unsatisfactory in patients treated using our protocol of anticoagulation and antiplatelet therapy, especially in those with large and multiple GAs. We recommend continuation of strict anticoagulation therapy in addition to antiplatelet therapy in these patients.
Acknowledgments
None.
Footnote
Provenance and Peer Review: This article was commissioned by the Guest Editor (Harald Kaemmerer) for the series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part VI” published in Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-289/rc
Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-289/dss
Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-289/prf
Funding: This work was supported by
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-289/coif). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Graduate School of Medicine, Chiba University (No. HK202406-11). Informed consent was obtained from all eligible patients.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Kawasaki T. Acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children. Arerugi 1967;16:178-222. [PubMed]
- Kobayashi T, Ayusawa M, Suzuki H, et al. Revision of diagnostic guidelines for Kawasaki disease (6th revised edition). Pediatr Int 2020;62:1135-8.
- McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation 2017;135:e927-99. [Crossref] [PubMed]
- Miura M, Ayusawa M, Fukawaza R, et al. Guidelines for Medical Treatment of Acute Kawasaki Disease (2020 Revised Version). Journal of Pediatric Cardiology and Cardiac Surgery 2021;5:41-73.
- Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 1996;94:1379-85. [Crossref] [PubMed]
- Nakamura Y, Yashiro M, Uehara R, et al. Epidemiologic features of Kawasaki disease in Japan: results of the 2007-2008 nationwide survey. J Epidemiol 2010;20:302-7. [Crossref] [PubMed]
- Nakamura Y, Matsubara Y, Kosami K, et al. Follow up of Kawasaki disease based on nationwide survey data in Japan: Mortality among those with a history of Kawasaki disease in Japan: Results of a 30-year follow up: Mortality among those with a history of Kawasaki disease in Japan: Results of a 30-year follow up. Pediatr Int 2022;64:e15268. [Crossref] [PubMed]
- Mitani Y, Tsuda E, Kato H, et al. Emergence and Characterization of Acute Coronary Syndrome in Adults After Confirmed or Missed History of Kawasaki Disease in Japan: A Japanese Nationwide Survey. Front Pediatr 2019;7:275. [Crossref] [PubMed]
- Tsuda E, Hamaoka K, Suzuki H, et al. A survey of the 3-decade outcome for patients with giant aneurysms caused by Kawasaki disease. Am Heart J 2014;167:249-58. [Crossref] [PubMed]
- Fukazawa R, Kobayashi T, Mikami M, et al. Nationwide Survey of Patients With Giant Coronary Aneurysm Secondary to Kawasaki Disease 1999-2010 in Japan. Circ J 2017;82:239-46. [Crossref] [PubMed]
- Fukazawa R, Kobayashi J, Ayusawa M, et al. JCS/JSCS 2020 Guideline on Diagnosis and Management of Cardiovascular Sequelae in Kawasaki Disease. Circ J 2020;84:1348-407. [Crossref] [PubMed]
- Research Committee on Kawasaki Disease. Report of subcommittee on standardization of diagnostic criteria and reporting of coronary artery lesions in Kawasaki disease. Tokyo: Ministry of Health and Welfare; 1984.
- Kobayashi T, Fuse S, Sakamoto N, et al. A New Z Score Curve of the Coronary Arterial Internal Diameter Using the Lambda-Mu-Sigma Method in a Pediatric Population. J Am Soc Echocardiogr 2016;29:794-801.e29. [Crossref] [PubMed]
- Lee JJY, Lin E, Widdifield J, et al. The Long-term Cardiac and Noncardiac Prognosis of Kawasaki Disease: A Systematic Review. Pediatrics 2022;149:e2021052567. [Crossref] [PubMed]
- Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665-71. [Crossref] [PubMed]
- Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66. [Crossref] [PubMed]
- Toyota T, Shiomi H, Morimoto T, et al. Short versus prolonged dual antiplatelet therapy (DAPT) duration after coronary stent implantation: A comparison between the DAPT study and 9 other trials evaluating DAPT duration. PLoS One 2017;12:e0174502. [Crossref] [PubMed]
- Tateno S, Terai M, Niwa K, et al. Alleviation of myocardial ischemia after Kawasaki disease by heparin and exercise therapy. Circulation 2001;103:2591-7. [Crossref] [PubMed]
