As thromboembolic events (TEE) are common in adults with congenital heart disease (ACHD), adequate oral anticoagulation for prophylaxis or treatment of TEE is important. Until now, mainly vitamin K antagonists have been used in these patients. The purpose of this study was to provide first data on the use of direct oral anticoagulants in ACHD. This prospective, observational, and longitudinal study included 102 consecutive ACHD, of whom 75 (37 women and 38 men; mean age 50 ± 13 years) could be analyzed. Most common CHD were pre-tricuspid shunts (n = 31; 41%), complex CHD (n = 16; 21%), left heart/aortic valve anomalies (n = 5; 6%), right-sided cardiac/pulmonary artery anomalies (n = 9; 13%), post-tricuspid shunts (n = 3; 4%), and others (n = 11; 15%). Five patients had cyanosis and 3 patients a Fontan circulation. Mean follow-up was 12 ± 11 months. Rivaroxaban was administered in 55 patients, apixaban in 13 and dabigatran in 7 patients for TEE prophylaxis in atrial arrhythmias (n = 57), stroke/transient ischemic attacks (n = 11), deep vein thrombosis (n = 4), pulmonary embolism (n = 1) and atrial thrombi (n = 3). Some patients had >1 indication for adequate oral anticoagulation. CHA 2 -DS 2 -VASc score was ≥2 in 23 (31%), and 9 (12%) had a HAS-BLED score ≥2. There were neither thrombotic or major bleeding events nor major side effects. In conclusion, direct oral anticoagulants appear to be safe and effective in ACHD. Long-term follow-up is needed to substantiate these findings.
Cardiovascular disorders, including thromboembolic events (TEE), are the most common causes of death. As many adults with congenital heart disease (ACHD) are prone to TEE, and morbidity and mortality from these complications are also high, adequate oral anticoagulation (OAC) for prophylaxis or treatment of TEE is of outstanding importance. To date, only data about the use of vitamin K antagonists (VKA) are available in these patients. Data on the use of novel or direct oral anticoagulants (DOAC) in ACHD are scarce. Therefore, the purpose of this analysis is to provide first real-world experience regarding the anticoagulation management of ACHD using DOACs.
Methods
A total of 102 ACHD, who attended our specialized department for ACHD, and in whom DOACs had been recommended and/or prescribed, were identified and requested to participate in a prospective observational longitudinal study. The patients were included consecutively in the order that they presented at our institution and were not selected by the physician in any particular way that might influence the results of the study. Written informed consent was obtained from all patients (age ≥18 years) who were taking, had taken, or were proposed to initiate treatment with a DOAC. Exclusion criteria were contraindication for DOACs (e.g., mechanical prosthetic heart valves), lack of cognitive competency to understand and/or fill in the questionnaire, and refusal to consent.
A detailed medical questionnaire was mailed to all patients to determine their recent clinical and treatment status and follow-up information. The patients themselves filled in the questionnaire. Patients who did not return or complete the questionnaire were sent a second questionnaire. If the second questionnaire was not returned or completed, attempts were made to contact the patient by phone. The treating physicians in our institution completed the cardiac diagnoses, medical treatment, the medical history, details of previous cardiac interventions or operations, and the clinical assessment. Medical records were obtained from all participating patients and reviewed for anatomic characteristics of respective cardiac anomalies, if applicable.
The questionnaire included questions regarding clinical aspects, including age, gender, indication, type and doses of DOAC, previous OAC, renal or liver disease, cardiovascular risk factors, alcohol intake, relevant co-medication and bleeding disorders, drug side effects ( Figure 2 ), and bleeding complications according to International Society on Thrombosis and Haemostasis, thrombotic complications, drug discontinuation, or dose reduction.
CHADS 2 score, CHA 2 -DS 2 -VASc score, and HAS-BLED score were calculated. Patients were classified according to the underlying CHD and assigned to 1 of 6 major groups, including complex CHD (group 1), obstruction of the left ventricle/anomalies of the aortic valve (group 2), obstruction of the right ventricle/anomalies of pulmonary valve or pulmonary artery (group 3), post-tricuspid shunts (group 4), pre-tricuspid shunts (group 5), and other congenital heart anomalies (group 6) ( Table 1 ). Patients with Fontan circulation and severe chronic cyanosis were analyzed separately. A total of 3 patients (1 woman) had a Fontan circulation. There were 5 patients with severe cyanosis (3 women). Diagnoses were double inlet ventricle (2), Ebstein’s anomaly (2), and atrial septal defect (1).
| Congenital Heart Diseases | N (%) |
|---|---|
| Hypoplastic left heart | 2 (3%) |
| Double inlet left ventricle | 2 (3%) |
| Double outlet right ventricle (univentricular repair) | 1 (1%) |
| Transposition of great arteries | 10 (13%) |
| Congenital corrected transposition of great arteries | 1 (1%) |
| Aortic coarctation | 1 (1%) |
| Aortic stenosis | 2 (3%) |
| Subaortic stenosis | 1 (1%) |
| Aortic regurgitation | 1 (1%) |
| Tetralogy of Fallot | 5 (7%) |
| Double outlet right ventricle/Fallot-type | 2 (3%) |
| Pulmonary atresia with ventricular septal defect | 2 (3%) |
| Ventricular septal defect | 2 (3%) |
| Patent ductus arteriosus | 1 (1%) |
| Patent foramen ovale | 9 (12%) |
| Atrial septal defect | 22 (29%) |
| Ebstein’s anomaly | 6 (8%) |
| Aneurysm of Aorta | 1 (1%) |
| Ectasia great arteries | 2 (3%) |
| Others | 2 (3%) |
The study was approved by the institutional ethics committee. Statistical analyses were made using SPSS for Windows, version 22.0 (IBM Corp, Armonk, NY). The presentation of the metric variables was performed as means and medians, and the scattering measurements expressed as standard deviations and quartiles. Categorical or nominal data were expressed as absolute and relative frequency.
Results
A total of 102 patients in whom DOACs had been recommended and/or prescribed were identified and included in the study. Sixteen patients were not considered in the analysis as follow-up data were not available yet. Another 11 patients did not receive the proposed medication: in 8 patients, the family physician did not implement the suggested treatment and 3 patients rejected the therapy ( Figure 1 ).
Ultimately, 75 patients were included in the analysis (n = 38 men; n = 37 women). Patient age was between 22 and 74 years (median 51 years; mean 50 ± 13 years). A total of 18 patients (24%) were between 20 and 40 years, and 41 patients (55%) were between 41 and 60 years. The remaining patients (16 patients, 21%) were >60 years.
Overall, complex CHD was present in 21% (n = 16) of patients, obstruction of the left ventricle/anomalies of the aortic valve in 6% (n = 5), obstruction of the right ventricle/anomalies of pulmonary valve or pulmonary artery in 13% (n = 9), post-tricuspid shunts in 4% (n = 3), pre-tricuspid shunts in 41% (n = 31), and other defects in 15% (n = 11). There were 5 patients (7%) with chronic cyanosis ( Table 1 ).
There were 17 patients (23%) with previous corrective cardiac surgery and 23 patients (31%) with palliative surgery. Re-operation was detected in 21 patients (28%). A primarily curative percutaneous interventional treatment had been performed in 30 patients (40%). Finally, 5 patients (7%) had neither a cardiac intervention nor a surgical procedure. Cardiovascular risk factors, previous disorders, and concomitant medication with known potential for interaction with DOACs are given in Table 2 .
| Epidemiological Aspects | N (%) |
|---|---|
| Cardiovascular risk factors | |
| Arterial hypertension | 7 (9%) |
| Diabetes mellitus | 7 (9%) |
| Hyperlipidemia | 12 (16%) |
| Ischemic heart disease | 8 (11%) |
| Nicotine consumption: | |
| Smoker | 20 (27%) |
| Ex-smoker | 2 (3%) |
| Alcohol consumption | 17 (23%) |
| Previous disorders | |
| TIA/Stroke | 15 (20%) |
| Thrombosis | 7 (9%) |
| Pulmonary thromboembolism | 1 (1%) |
| Bleeding | 5 (7%) |
| Chronic liver disease | 3 (4%) |
| Chronic renal disease | 1 (1%) |
| Concomitant medication | |
| Nonsteroidal anti-inflammatory drugs | 7 (9%) |
| Oral contraceptives | 5 (7%) |
| Antidepressants | 6 (8%) |
Anti-Xa antagonists were prescribed in 68 patients and thrombin antagonists in 7 patients. Rivaroxaban was the most commonly used drug (n = 55, 73%), followed by apixaban (n = 13, 17%) and dabigatran (n = 7, 9%) ( Figure 1 ).
Main indications of DOAC were TEE prophylaxis in atrial arrhythmias (n = 57 patients; 76%) and stroke/TIA (n = 15; 20%). Other indications were prophylaxis after deep vein thrombosis (n = 4, 5%), pulmonary embolism (n = 1; 1%), and atrial thrombi (n = 3; 4%) (1 patient with Fontan circulation, 1 with thrombus adhered to an ASD-Occluder, and 1 with thrombus on a pacemaker electrode). There were 10 patients with 2 indications for OAC: stroke/TIA and atrial arrhythmias ( Table 3 ).
| Indications | N (%) | Diagnoses (N) | Dabigatran N (%) | Rivaroxaban N (%) | Apixaban N (%) |
|---|---|---|---|---|---|
| Atrial arrhythmias | 57 (76%) | Hypoplastic left heart (2) Double inlet left ventricle (1) Transposition great arteries (10) Congenitally corrected TGA (1) Aortic coarctation (1) Aortic stenosis (2) Subaortic stenosis (1) Tetralogy of Fallot (2) DORV – Fallot type (3) Pulmonary atresia – VSD (2) Ventricular septal defect (2) Patent ductus arteriosus (1) Patent foramen ovale (5) Atrial septal defect (17) Ebstein’s anomaly (4) Aortic aneurysm (1) Ectasia of great arteries (1) Other (1) | 4 (7%) | 44 (77%) | 9 (16%) |
| Stroke/TIA | 15 (20%) | Hypoplastic left heart (1) Transposition great arteries (1) Tetralogy of Fallot (1) Patent foramen ovale (8) Atrial septal defect (3) Ebstein’s anomaly (1) | 3 (20%) | 10 (67%) | 2 (13%) |
| Deep vein thrombosis | 4 (5%) | Patent foramen ovale (1) Atrial septal defect (1) Ebstein’s anomaly (1) Ectasia of the great arteries (1) | 1 (25%) | 3 (75%) | – |
| Pulmonary embolism | 1 (1%) | Ebstein’s anomaly (1) | – | 1(100%) | – |
| Atrial thrombus | 3 (4%) | Atrial septal defect (1) Aortic regurgitation (1) Double outlet right ventricle (1) | – | 1 (33%) | 2 (67%) |
The CHA 2 -DS 2 -VASc score in all included patients was 0 in 40 patients (53%), 1 in 12 patients (16%), 2 in 7 patients (9%), 3 in 12 patients (16%), 4 in 1 patient (1%), 5 in 2 patients (3%) and 7 in 1 patient (1%). A CHADS 2 score ≥2 was present in 15 patients (20%). The HAS-BLED score was 0 in 54 patients (72%), 1 in 12 patients (16%), 2 in 7 patients (9%), and 3 in 2 patients (3%).
The mean follow-up period was 12 ± 11 months (range 1 to 61 months). Most patients did not report relevant side effects from DOAC ( Figure 2 ) and no major bleeding was reported. Temporary interruption of DOAC was reported in 3 patients: 2 patients because of bleeding (1 rupture of muscle fibers and another because of hematuria) and 1 because of an imminent major operation. One patient discontinued treatment because of allergic reaction. Minor bleeding events, including intermittent epistaxis, bleeding after minor injuries or dental manipulation, or predisposition to hematoma, were reported in 47%.
