The revival of verapamil in atrial fibrillation

Summary of the study:

Koldenkof et al published in Europace the work entitled “Rate control differs in the prevention of progression in atrial fibrillation” ¹. It is a sub-analysis of the RACE 4 study. Only patients without using antiarrhythmics were included. Investigators included 666 patients over 18 years of age with a diagnosis of paroxysmal atrial fibrillation (AF) of recent diagnosis. They classified subjects into three groups, those who used heart rate (HR) control with verapamil, those who used beta-blockers (BB) and one group who did not use any drug for rate modulation. It is important to note that those patients who presented symptoms of heart failure decompensation and patients with acute coronary syndrome within 3 months prior to screening were excluded. Of 666 study participants, 47 (7%) used verapamil, 383 (57.5%) used BB, and 236 (35.4%) received no treatment for HR control. The primary endpoint was a combined of need for first electrical cardioversion, pharmacological cardioversion and pulmonary vein isolation due to AF, while the secondary points included major cardiovascular events such as decompensated heart failure, acute coronary syndrome, hospitalization for arrhythmias, major bleeding, thrombotic events embolic or adverse effects of the drugs administered. After a 37-month follow-up, the analysis showed that the primary composite endpoint occurred in 17% of the subjects in the group that used verapamil compared to 33% in the groups that used BB or those that did not use HR control, with a statistically significant P value of 0.038. Authors concluded that the use of verapamil, a non-dihydropyridine calcium antagonist, was associated with a lower probability of progression of AF, in patients recently diagnosed with this condition¹.

Editorial comment:

The published results of this substudy are really interesting. They show the advantages of the initial use of calcium antagonists not only as a HR control strategy but also as a preventive therapy to avoid progression of the disease in patients with newly diagnosed AF compared to other pharmacological drugs such as the most commonly used BB. From a pathophysiological point of view, this benefit is easily understandable since it is well known that the release of significant amounts of calcium from the sarcoplasmic reticulum is fundamental for the perpetuation and, therefore, the progression of the substrate responsible for the onset of atrial fibrillation^2,3,4. It is known that calcium overload participates in signaling silencing and the progression of more calcium leak during diastole causing afterdepolarizations and therefore, helping to the development of an electrical substrate that perpetuates atrial fibrillation^{5, 6}.If we take into consideration electrophysiological factors such as heterogeneous refractory periods favor the start of fibrillatory conduction waves and abnormal electrical activity that leads to the progression of atrial fibrillation because the calcium reduces the atrial refractory periods⁵.Therefore, the early implementation of a non-dihydropyridine calcium antagonist therapy, such as verapamil, would be justified, as it not only is associated with a lower need for pharmacological or electrical cardioversion, but it also reduces the need for invasive procedures such as pulmonary veins isolation⁷. On the other hand, it would be interesting to define the exact role of the autonomic nervous system and what is its participation in the pathophysiology of this condition, especially the role of the adrenergic pathways in the perpetuation and sustaining of AF⁸. BB therapy may be limited in many patients because it is associated with lower HR in those with concomitant sinus node disease.

What are the limitations of this publication?

We must keep in mind that these benefits are the result of an early diagnosis and a timely establishment treatment. Once AF has progressed to its persistent or permanent presentations, maybe it would not be possible to obtain these advantages. On the other hand, we must highlight that the number of patients who were in the verapamil group (n=47, only 17% of the study sample) was much lower compared to the other groups (i.e., BB were used in 383 patients [57.5%])¹.Therefore, a prospective and controlled study is needed to confirm these results. Such study could provide with a more balanced groups, with the same clinical and demographic characteristics, including the HATCH score that was lower in the verapamil group than in the beta-blocker group⁹.In such prospective study, emphasis in contraindications for the use of verapamil should be taken into account as it may result in a lower number of candidates for such therapy. Adverse events must be clear registered. A sufficient sample size should be calculated to detect significant differences in mortality. Another consideration to be made is that other non-dihydropyridine calcium antagonists should probably also be studied, like diltiazem¹⁰.

Final remarks:

Verapamil has been studied in Ibero-America since many years ago^11-14. With this new information presented by Koldenhof et al, the early use of non-dihydropyridine calcium antagonists such as verapamil, in patients with newly diagnosed atrial fibrillation, can be beneficial in those who do not have contraindications. Its use could be associated with less progression of this condition. We must keep in mind that these benefits may be restricted by the exclusion criteria mentioned above, so the selection of patients according to their comorbidities is of vital importance prior to the initiation of this pharmacological agent. The study of Koldenhof et al could represent the “revival” of an old drug, verapamil, in AF.

Autores:

Dr. Manlio F. Márquez Murillo

Médico Adscrito al Servicio de Electrocardiología del Instituto Nacional de Cardiología Ignacio Chávez.

Académico Titular de la Academia Nacional de Medicina de México.

Vocal del Comité de Investigación del Instituto Nacional de Cardiología Ignacio Chávez

Secretario del Consejo Mexicano de Cardiología

Coordinador de la Alianza contra la Muerte Súbita, una Iniciativa de la Sociedad Interamericana de Cardiología

Sistema Nacional de Investigadores SNI II

References

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