To the Editor Daniell [1] reports a case of syncope after "pill-in-the-pocket" treatment with propafenone. He mentions the CYP2D6 metabolism of propafenone and the possible interaction with CYP2D6 inhibitors. We would like to further illustrate the potential risks of propafenone in CYP2D6 poor metabolisers with the case of a 70 year-old woman who died from sudden cardiac arrest after taking 600 mg of propafenone orally for the treatment of atrial fibrillation (AF). The patient was seen on an outpatient basis following a cerebrovascular accident. An ECG showed AF with a rapid ventricular rate. The QTC interval was 430 msec. An echocardiography showed moderate left ventricular hypertrophy (LVH) with left atrial enlargement. Left and right ventricular systolic function and size were normal. She was taking gliclazide (160 mg daily) for diabetes and verapamil (240 mg daily) for hypertension. After three weeks of therapeutic anticoagulation, she received a single oral dose of 600 mg propafenone. She was in sinusal rhythm by the next day. Anticoagulation was maintained. A few months later, asymptomatic AF justified another single dose of propafenone 600 mg orally. The ECG was similar to the previous episode. She developed two hours later, a malaise with profound weakness, sweating, pallor, nausea and vomiting. On arrival, the emergency services noted cardiac arrest with asystole. Cardio- pulmonary resuscitation failed. No specific cause of death could be found. The autopsy showed moderate LVH (<14mm) but no coronary abnormalities. A small scar of myocardial infarction was noted on the lateral wall of the left ventricle. No pulmonary embolism, ischemic or hemorrhagic stroke was found. However, PCR showed homozygosity for CYP2D6*4 resulting in poor drug metabolism. In the absence of Q wave or anamnestic angina, it is unlikely that the small past infarction played a major role in sudden death. LVH is a known risk factor for ventricular arrhythmia but it is mainly reported when the septum is thicker than 14 mm. A contributory proarrhythmic adverse effect of propafenone was suggested. Dose-related proarrhythmic effects such as ventricular tachycardia, flutter, ventricular fibrillation and torsade de pointes have been described [2]. Propafenone's first-pass liver metabolism is mainly related to CYP2D6, two minor pathways being CYP1A2 and CYP3A4. CYP2D6 is subjected to polymorphism and studies in CYP2D6 intermediate and poor metabolisers (PM) have shown that Cmax is increased by nearly 50% and 150% respectively compared to extensive metabolisers after a single oral dose. Pharmacodynamics mirror pharmacokinetics with a prolongation of the PR interval in PM [3]. The PM CYP2D6 genotype and the interaction between propafenone and verapamil, a strong inhibitor of CYP3A4, may have led to increased propafenone bioavailability. This, taken together with her previous myocardial infarction and moderate LVH, might have increased the patient's susceptibility to the dose-dependant proarrhythmogenic effects of propafenone. The benefit of the "pocket pill" strategy proposed for cardiac arrhythmia [4] in vulnerable patients might well be hampered by pharmacogenetic and/or drug-drug interactions leading to unexpected and unfavourable issues. Determining the genotype or phenotype of patients treated with drugs that have narrow therapeutic margins (such as class I antiarrhythmics) may allow the prescription of an adapted dose regimen for CYP2D6 PM. References 1. Daniels HW. Syncope following "pill-in-the-pocket" treatment of atrial fibrillation with propafenone plus quinidine. Heart 2011;97:1626. 2 Capucci A, Boriani G. Propafenone in the treatment of cardiac arrhythmias. A risk-benefit appraisal. Drug Safety 1995; 12: 55-72. 3. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009;48:689-7234. 4. Alboni P, Botto GL, Baldi N, Luzi M, Russo V, Gianfranchi L et al. Outpatient treatment of recent-onset atrial fibrillation with the "pill-in -the-pocket" approach. N Engl J Med 2004; 351: 2384-91

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