Quinidine vs. ICD therapy in short-coupled ventricular fibrillation—is a randomized trial the next logical step?

This commentary refers to ‘Short-coupled ventricular fibrillation represents a distinct phenotype among latent causes of unexplained cardiac arrest: a report from the CASPER registry’, by C. Steinberg et al., doi: 10.1093/eurheartj/ehab275. and the discussion piece ‘Quinidine vs. ICD in patients with short-coupled idiopathic ventricular fibrillation: a call for a multicenter randomized trial’, by B. Belhassen, doi:10.1093/eurheartj/ehab549. The extraordinary efficacy of quinidine for the management of short-coupled ventricular fibrillation (SCVF) has been documented for >40 years and was first described by Professor Belhassen and his group in 1987.1,2 Based on these encouraging results and the well-known rates of implantable cardioverter defibrillator (ICD)-related complications (particularly in younger individuals), the author’s proposal of a multicentre, prospective randomized trial comparing quinidine vs. ICD therapy seems justified and appealing at first glance. There are however several concerns and practical obstacles that may interfere with the realization and applicability of such a trial. Given the necessity of documented ventricular fibrillation (VF) onset, the majority of SCVF patients are diagnosed during follow-up.3 Although an approach with a systematic electrophysiology study (EPS) at the time of the index hospitalization may increase the diagnostic sensitivity for SCVF, noninducibility does not exclude the diagnosis. As elegantly demonstrated by Belhassen and co-workers in a previous study,4 EPS would be required to optimize quinidine dosing. Although the feasibility and potential benefits of such a strategy are undisputed, this EPS-guided approach represents a costly and logistic hurdle that might not be sustainable in all healthcare systems beyond the context of a clinical trial with specific funding. Quinidine side effects are a well-known limitation that may interfere with drug titration and desired target doses. At present, the optimal minimally effective quinidine dose for SCVF remains unknown but will likely show marked interindividual variability due to patient-related factors and the type of administered molecule (quinidine vs. hydroquinidine). Patients in our study received quinidine sulphate at an average daily dose of 667 ± 400 mg.3 Indeed, quinidine doses in our cohort were significantly lower compared to previous studies but still showed an efficacy of 83.4% over a median follow-up duration of 65.5 months (19.5, 138). We agree with the author that the observed VF recurrence in 2/24 patients in our study was likely related to extremely low quinidine doses (<300 mg per day) which could not be further increased due to side effects. These observations also raise safety concerns regarding the potential proportion of patients who would not tolerate higher quinidine doses in the context of a randomized trial. In both patients of our study, ventricular fibrillation was successfully terminated by their ICD. The ongoing problem of limited access to quinidine in many industrialized countries should also be taken into consideration when planning an international multicenter trial for patients with SCVF.5 Finally, there will be psychological and potentially medico-legal ± ethical hurdles to face. Ethical hurdles may be related to institutional board acceptance and/or restrictions from health care authorities. Despite the downsides of long-term ICD therapy, many ICD recipients, and their families feel nevertheless reassured by the presence of the device (and probably many physicians, too). At this point, it is difficult to gauge whether SCVF patients with survived cardiac arrest and their respective treating physicians would be willing to participate in a randomized trial vs. quinidine alone. An alternative research approach could be a prospective trial randomizing SCVF patients with secondary prevention ICDs to either quinidine or placebo. This study design would be much easier to realize and could help us to identify SCVF patients who would not need an ICD. Conflict of interest: The authors had full access to the data and take full responsibility for its integrity. All authors have read and agreed to the manuscript as written. The authors have no conflicts of interest to declare.