Defining clinically relevant risk threshold for predicting sudden cardiac death

Background There is no consensus on a risk threshold for sudden cardiac death (SCD) that could be used in practical design and evaluation of prediction models and decisions regarding implantable cardioverter-defibrillator (ICD) therapy. Methods Baseline assumptions for a simulation framework were derived from previous randomized controlled trials (n=18) to identify minimal SCD risk threshold that would translate to mortality benefit by ICD therapy also considering the effect of competing non-sudden mortality. ICD efficacy to prevent SCDs and other data for simulations were estimated using inverse-variance weighted meta-analysis of included trials. Number needed to treat (NNT) was evaluated over a five-year horizon (≤21 defined as clinically relevant). Results Correlation analysis confirmed annual SCD incidence in trial populations as the key factor associating with ICD therapy effectiveness to reduce mortality (Pearson’s r=0.653, p<0.01). In a simulation assuming 5% annual non-sudden mortality (pooled estimate of included RCTs) and a 56% (48-62%) efficacy for ICDs to reduce SCDs or similar events, 3% annual SCD risk (≈12% over five years) emerged as the lowest practical threshold even after controlling for excess (overlapping) mortality among those saved successfully from SCD by ICD therapy. The theoretical minimum threshold for annual SCD risk is 2.0%, 2.5% and 3.5% for populations with the annual incidence of non-sudden deaths 2%, 5% and 10% (assuming no overlapping mortality). Conclusions Even under substantial competing risk, a 3% annual SCD threshold appears an optimal minimum threshold for identifying patients most likely to benefit from ICD therapy if severe mortality overlap is not observed. Key Questions What is the minimal risk threshold after which ICD therapy will likely lead to meaningful reduction in overall mortality. This information is needed in practical design of clinical trials and evaluation and development of prediction models Key Finding Analysis of the data extracted from previous randomized controlled trials revealed that annual SCD risk should be at least 3% in most scenarios (with the annual incidence of non-sudden mortality ≤5%) for ICD therapy to be effective. Take-home Message Primary prevention SCD and risk models targeted to identify high-risk individual should aim for identifying patients with 3% or higher annual risk for SCD.