Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator

Abstract

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus.

Methods and results: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%.

Conclusion: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.

Keywords: Arrhythmogenic right ventricular cardiomyopathy; Genetic cardiomyopathies; Implantable cardioverter-defibrillator; Risk stratification; Sudden cardiac death; Ventricular arrhythmias.

Structured Graphical Abstract

Validation of the arrhythmogenic right ventricular cardiomyopathy (ARVC) risk calculator in a distinct cohort. AHA, American Heart Association; ECG, electrocardiogram; HRS, Heart Rhythm Society; ICD, implantable cardioverter-defibrillator; ITFC, International Task Force Criteria; NSVT, non-sustained ventricular tachycardia; PVC, premature ventricular complex; VA, ventricular arrhythmia.

Figure 1

Survival free from sustained ventricular arrhythmia at follow-up. The cumulative event-free survival for any ventricular arrhythmia with 95% confidence intervals (shaded area) is plotted.

Figure 2

Calibration plots presenting the agreement between predicted (x-axis) and observed (y-axis) 1-year (Panel A) and 5-year (Panel B) risk of ventricular arrhythmia. Triangles represent binned Kaplan–Meier estimates with 95% confidence intervals for quintiles of predicted risk. The straight line is the continuous calibration hazard regression with the dotted line represents optimal calibration (i.e. perfect correspondence between predictions and observations across the risk spectrum). The calibration is shown to be acceptable across the risk spectrum with no significant under or over prediction in any risk category. VA, ventricular arrhythmia.

Figure 3

Assessment of the model fit. Assessment of the individual predictors (A) show an absence of diversion from the initial model as all coefficients are non-significantly different from 0. Compared survival probability of the derivation and validation cohorts (B) and baseline survival hazard (i.e. predictors-adjusted survival) presented as survival curves (C) both show similar expected survival. NSVT, non-sustained ventricular tachycardia; PVC, premature ventricular complex; TWI, T-wave inversion; RVEF, right ventricular ejection fraction.

Figure 4

Decision curve analysis comparing the clinical utility of our model (dashed thick black line) with the 2015 International Task Force Consensus Statement algorithm for the treatment of arrhythmogenic right ventricular cardiomyopathy (dashed red line), the 2017 American Heart Association algorithm for the management of ventricular arrhythmia and prevention of sudden cardiac death (dashed green line) and the 2019 Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy with exclusion of the Programmed ventricular stimulation (dashed blue line). The clinical utility of each treatment strategy is compared by plotting the net benefit (y-axis) for a range of possible implantable cardioverter-defibrillator placement thresholds based on the 5-year risk of ventricular arrhythmia (x-axis). Higher net benefit values indicate greater benefit while a value of 0 indicates no benefit. The published risk calculator depicted a better net benefit than the other published algorithms for implantable cardioverter-defibrillator implantation thresholds below a 35%. Above this threshold its performance was similar to the Heart Rhythm Society consensus algorithm. ICD, implantable cardioverter-defibrillator; ARVC, arrhythmogenic right ventricular cardiomyopathy, VA ventricular arrhythmia, SCD sudden cardiac death.

Figure 5

Impact of implantable cardioverter-defibrillator use threshold on clinical outcomes. The potential impact of different thresholds for implantable cardioverter-defibrillator use according to the model is presented on the left side and the proportion of patients who would get an implantable cardioverter-defibrillator according to the different consensus statements is presented on the right side. For each threshold (x-axis) the proportion of patients (y-axis) who have events (red) who do not have events (blue), who would receive an implantable cardioverter-defibrillator (solid colours) or not receive one (hashed colours) are presented. The triangles represent the number of implantable cardioverter-defibrillator needed per event prevented for each threshold (right-sided y-axis). The numerical values are presented in the table below. Implantable cardioverter-defibrillator:ventricular arrhythmia, ratio of implantable cardioverter-defibrillator placements required to protect one patient developing ventricular arrhythmia; other abbreviations as in figure 4.