Sudden cardiac death unresponsive to implantable defibrillator therapy: an urgent target for clinicians, industry and government.

A major expansion in utilization of implantable cardioverter-defibrillators (ICDs) is anticipated based on the results of randomized clinical trials (RCT) that demonstrate increased survival in a sizable population of patients with reduced left ventricular function. However, if RCT accurately reflect clinical practice, then a substantial proportion of patients will die suddenly despite ICD implantation. ICD-unresponsive sudden cardiac death (SCD) has been recognized since the initial ICD experience. Yet, despite 25 years of technical advances, the frequency of ICD-unresponsive SCD has not declined. Pooled analysis of RCT indicates a crude rate of ICD-unresponsive SCD of 5%. This may not cause alarm in an average practice, but it comprises about 30% of cardiac deaths. Meta-analyses of RCT show that ICD therapy is associated with a relative risk reduction of SCD of approximately 60%, far less than the greater than 90% efficacy that many expect. The suboptimal performance of ICD therapy accounts for the failure of some RCT to achieve statistically significant effects on survival. The number of patients with ICD-unresponsive SCD is highly correlated with the number of cardiac deaths among control patients as well as ICD recipients. Otherwise, no definite patterns have emerged that clearly distinguish this mode of demise from other modes of cardiac death. Retrospective post-hoc analyses have not revealed distinguishing characteristics of patients with ICD-unresponsive SCD with respect to clinical variables, pre-terminal symptoms or to the setting of the terminal event. Despite advanced storage capabilities of implanted devices, almost no information has become available from RCT regarding the terminal rhythm or the response of the ICD. These observations have implications for clinical management and research. Candidates for ICD implantation based on RCT should be accurately informed about the residual risk of SCD. Investigators seeking to identify populations likely to benefit from ICD therapy based on SCD incidence should recognize that a significant fraction may not respond to ICD therapy. Reducing the incidence of ICD-unresponsive SCD would substantially improve survival and cost-effectiveness related to ICD therapy. Close cooperation between clinicians, investigators and representatives of industry and government is urgently needed to develop strategies to identify patients prone to ICD-unresponsive SCD, to determine its mechanisms and to develop methods of prevention and treatment.