PREVENTION-ACHD: PRospEctiVE study on implaNTable cardioverter-defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease; Rationale and Design

We developed a risk score model with which we aim to predict the annual risk of SCD or life-threatening arrhythmias in different types of congenital heart defects (CHD). This risk score model was based on a retrospective multicentre case-controlled study that evaluated risk factors for SCD in ACHD patients. In that study SCD cases were matched to living controls by age, gender, diagnosis, type of surgical intervention, date of surgical repair and treating medical centre [1].

To identify clinical variables associated with SCD, univariable and stepwise backward multivariable conditional logistic regression models were used. A detailed description of the identification of the risk factors is described elsewhere [1], and in the online supplementary material. The stability of the variable selection procedure was evaluated with 1000 bootstrap analyses. Variables selected at least 400 times were included in the final model. For all logistic regression models, odds ratios (OR) with 95% confidence intervals were calculated. To determine the risk of SCD, we developed a point-based risk scoring system. Points were attributed to each variable in the risk score model depending on the log odds ratio or B‑coefficient, which was derived from the multivariable analysis. The resulting risk score model consists of seven risk factors for SCD, for each of which one point is attributed to the model. This model was used to assess the absolute annual risk of SCD by multiplying the hazard ratio associated with one point in the risk score by the number of points and the a-priori risk of SCD for each CHD lesion (Fig. 1). The annual incidence of SCD per congenital defect was derived from the Concor registry [16]. The lesions with the highest risk of SCD are included in the final model.

The performance of the risk score model was evaluated using the area under the receiver operating characteristics (AUROC) curve. We internally validated the performance of our model by a second bootstrapping, which included the variable selection bootstrapping procedure. In addition to the internal validation, an independent prospective registry cohort from La Paz University Hospital, Madrid, Spain was used to externally validate the risk score model. From this cohort, which includes 3311 adults with CHD from December 1989 to December 2013, all SCD cases were included [17].

In addition to validating this risk score in a prospective setting, the Consensus Statement indications will also be verified in this study for their accuracy in predicting SCD events and appropriate ICD interventions.

This is a single centre, prospective, observational study. Patients with an outpatient clinic appointment at the Academic Medical Center in Amsterdam during an enrolment period of one year will be screened at baseline using the risk score and the ICD indications according to the Consensus Statement. A flow chart of the study design is presented in Fig. 2.

Patients are deemed to be at high risk for SCD when they have at minimum a 3% annual risk of SCD according to the risk score model. ICD implantation may be considered in these patients. The control group will consist of ACHD patients with a low risk of SCD (<3% annually) according to the risk score.

The primary prevention indications from the aforementioned Consensus Statement are listed in Tab. 1.

All patients included in this registry are adults (≥18 years of age) who have been diagnosed with a structural congenital heart defect.

Exclusion criteria are the following:

Patients with congenital defects not represented in the risk score will be excluded from the analysis comparing patients with high and low risk scores, but may still be screened by applying the Consensus Statement indications.

As this is an observational study, follow-up examinations and regular treatment of patients will be performed by the patient’s own treating physician, without intervention by the investigators. The decision on whether to implant an ICD is at the treating physician’s discretion.

The initial follow-up period will be two years. After these two years the endpoint of SCD or appropriate ICD interventions in patients with an ICD will be examined. Hospital records will be inspected for SCD events, sustained ventricular arrhythmia and appropriate ICD interventions.

We obtained a waiver from the ethics committee at the Academic Medical Center—University of Amsterdam, as this observational study does not require approval from the ethics committee. The study was registered at ClinicalTrials.gov (NCT03957824).

The study is powered for the composite endpoint of SCD or sustained ventricular arrhythmia at two years of follow-up. Sustained ventricular arrhythmia is defined according to international standards as any ventricular fibrillation or ventricular tachycardia lasting longer than 30 seconds. In patients with an ICD, device programming will contain algorithms to prevent unnecessary ICD therapy for self-terminating ventricular arrhythmias [18].

The ratio of high-risk versus low-risk patients is estimated to be 1:10. We estimate that the two-year risk of SCD or sustained ventricular arrhythmia for low-risk patients is 0.4% and for high-risk patients is 6%. Considering an attrition of 10%, we calculated that with 60 high-risk patients and 600 low-risk patients a high degree of confidence (>80% power) can be provided to validate the risk score.

Secondary endpoints, in ACHD patients with an ICD, are the rates of ICD-related complications and inappropriate shocks.

By means of the presented risk score model the patient’s individual risk for SCD can be assessed. The risk score model concurs with risk factors previously reported on specific cardiac defects and adds quantitative data for other CHD lesions. Most studies seeking risk factors for SCD in CHD have involved patients with surgically repaired tetralogy of Fallot (ToF) and Mustard or Senning repair for transposition of the great arteries (TGA). However, SCD also frequently occurs in other CHD such as Eisenmenger syndrome, left-sided lesions and septal defects, which are either less prevalent or less well investigated. This risk score model includes many types of cardiac lesions and may be applied to a broad spectrum of patients.

The PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease listed ICD recommendations for ACHD patients for the first time [11]. In a retrospective analysis, the ICD recommendations in the Consensus Statement failed to identify 60% of SCD victims, ICD implantation was recommended in 17% of living controls, and the overall discriminative ability was poor [13]. However, the Consensus Statement ICD recommendations have not yet been tested in a prospective setting. PREVENTION-ACHD may therefore provide more accurate results regarding the discriminative ability of the ICD recommendations.

Patients are classified into low-risk and high-risk groups using the risk score to provide more distinctly defined ICD indications and to reduce the number of patients needed. We consider a ≥3% annual risk of SCD to be high, in part because of the young age of ACHD patients who are at risk of SCD and the cumulative rates that may be far higher than in the much older population with acquired heart disease. Moreover, according to current ESC guidelines, patients with hypertrophic cardiomyopathy are considered candidates for primary prevention ICD implantation when they have a 5-year SCD risk of 6% (class IIa). Among other reasons, the high rate of complications associated with ICD implantation in ACHD patients made us reluctant to lower the cut-off rate for high-risk patients, who may be considered for ICD implantation, to similar numbers.

Although the risk score model is derived from the largest cohort of ACHD patients who were the victim of SCD, the number of cases providing data is still limited [1]. The study was retrospective in nature, and thus the inherent limitations of such a study design apply. However, it should be noted that to date, no prospective studies on SCD in ACHD patients are available.