Antiarrhythmic Drug Prescription in Patients After Myocardial Infarction in the Last Decade

Avanzini, Fausto; Latini, Roberto; Maggioni, Aldo P.; Colombo, F.; Santoro, Eugenio; Franzosi, Maria Grazia; Tognoni, Gianni

doi:10.1001/archinte.1995.00430100065007

Cited by 6 publications

(1 citation statement)

References 32 publications

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“…The clinical therapeutic window is thus concerningly narrow. Unsurprisingly therefore, although initial clinical trials reported positive findings [31][32][33][34][35]37,39,59 mexiletine has not emerged as a drug for primary prevention of SCD 12 ; as with all antiarrhythmics its ADRs are perceived to outweigh benefit in this context 5,16 . Consequently, since this, the most useful drug has limited utility, there remains an important unmet clinical need for primary prevention.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart

Hesketh

Wilder

Ranadive

et al. 2020

Sci Rep

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the 'translational therapeutic index' (tti) is a drug's ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. In early nonclinical research, discovery and safety studies are normally undertaken separately. our aim was to evaluate a novel integrated approach for generating a tti for drugs intended for prevention of ischaemia-induced ventricular fibrillation (VF). We templated the current best available class 1b antiarrhythmic, mexiletine, using the rat Langendorff preparation. Mexiletine's beneficial effects on the incidence of VF caused by 120 min regional ischaemia were contrasted with its concurrent adverse effects (on several variables) in the same hearts, to generate a TTI. Mexiletine 0.1 and 0.5 µM had no adverse effects, but did not reduce VF incidence. Mexiletine 1 µM reduced VF incidence to 0% but had adverse effects on atrioventricular conduction and ventricular repolarization. Separate studies undertaken using an intraventricular balloon revealed no detrimental effects of mexiletine (1 and 5 µM) on mechanical function, or any benefit against reperfusion-related dysfunction. Mexiletine's TTI was found to be less than two, which accords with its clinical therapeutic index. Although non-cardiac adversity, identifiable from additional in vivo studies, may reduce the tti further, it cannot increase it. our experimental approach represents a useful early-stage integrated risk/benefit method that, when TTI is found to be low, would eliminate unsuitable class 1b drugs prior to next stage in vivo work, with mexiletine's tti defining the gold standard that would need to be bettered. Coronary heart disease and acute myocardial infarction (AMI) constitute the largest cause of death worldwide 1 with sudden cardiac death (SCD) responsible for approximately 50% of lethality 2,3. Most SCD is due to ischaemia-induced arrhythmias, particularly ventricular fibrillation (VF) and ventricular tachycardia 4. Currently available antiarrhythmic drugs have failed against SCD 5. The reason for this is that the benefit afforded by those drugs found to suppress SCD is offset by adverse drug reactions (ADRs); in some trials, mortality was actually increased 6-8 while in other trials attempts to minimise ADR risk by use of lower drug doses resulted in loss of effectiveness 9,10. Presently the class 1b antiarrhythmic, mexiletine, and the non-selective class III drug, amiodarone 11 , are the only antiarrhythmics prescribed for SCD outside the hospital setting, but even these drugs are not considered sufficiently efficacious for use in the larger lower-risk populations 5,12 leaving a huge and longstanding unmet therapeutic need 4. Since amiodarone is an anomalous example of a class (III) that is otherwise discounted as a solution to SCD owing to proarrhythmia 5,12 , this leaves only class 1b agents as an avenue for new drug development. An essential part of the process of any new drug development is to mitigate against ADRs during the nonclinical phase. In view of this, we and oth...

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