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

1. Koldenhof T, Wijtvliet PEPJ, Pluymaekers NAHA, Rienstra M, Folkeringa RJ, Bronzwaer P, Elvan A, Elders J, Tukkie R, Luermans JGLM, van Kuijk SMJ, Tijssen JGP, van Gelder IC, Crijns HJGM, Tieleman RG. Rate control drugs differ in the prevention of progression of atrial fibrillation. Europace. 2022 Mar 2;24(3):384-389.

2. Márquez MF, Gómez-Flores J, Aranda-Faustro A, Cazares-Campos I, Cárdenas M. Avances recientes en la fisiopatología de la fibrilación auricular [Recent advances in the pathophysiology of atrial fibrillation]. Arch Cardiol Mex. 2009 Dec;79 Suppl 2:18-25. Spanish.

3. Jost N, Kohajda Z, Kristof A, Husti Z, Juhasz V, Kiss L et al. Atrial Remodeling and Novel Pharmacological Strategies for Antiarrhythmic Therapy in Atrial Fibrillation. Current Medicinal Chemistry. 2011;18(24):3675-3694.

4. Dagres N, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on arrhythmias and cognitive function: what is the best practice?. Europace 2018;20(9):1399-1421.

5. Márquez MF (Ed.) “Fibrilación Auricular”. 2^nd Ed. Sociedad Mexicana de Cardiología, PyDESA Editorial, Mexico City, 2018.

6. Rodríguez-Diez G, Márquez MF, Iturralde-Torres P, Molina-Fernández de L LG, Pozas-Garza G, Cordero-Cabra A, Rojel-Martínez U. Joint Mexican position document on the treatment of atrial fibrillation. Arch Cardiol Mex. 2020;90(1):69-76.

7. Márquez MF, González Hermosillo JA, Cárdenas M. Guía para el diagnóstico y tratamiento de la fibrilación auricular [Guidelines for the diagnosis and treatment of atrial fibrillation]. Arch Cardiol Mex. 2006 Apr-Jun;76(2):231-6. Spanish.

8. de Vos C, Pisters R, Nieuwlaat R, et al. Progression From Paroxysmal to Persistent Atrial Fibrillation. J Am Coll Cardiol. 2010 Feb, 55 (8) 725–731.

9. https://doi.org/10.1016/j.jacc.2009.11.040Hu WS, Lin CL. Comparisons of HATCH, HAVOC and CHA2DS2-VASc scores for all-cause mortality prediction in atrial fibrillation: a real-world evidence study. Postgrad Med J. 2022 Jan 24:postgradmedj-2021-141147. doi: 10.1136/postgradmedj-2021-141147. Epub ahead of print. PMID: 35074802.

10. Luciardi H, Berman S, Santana M, Monteros L. Diltiazem por vía intravenosa en la conversión a ritmo sinusal de taquiarritmias supraventriculares [Intravenous diltiazem in the reversion to sinus rhythm in supraventricular tachyarrhythmias]. Arch Inst Cardiol Mex. 1996 Nov-Dec;66(6):505-9. Spanish.

11. De Soldati L, Stritzler G, Balassanian S, Fuksman A, Mario Krasnov C, Rosental R, Chutlian A, Fabregas R. Ensayos de desfibrilación auricular con la asociación quinidina-verapamil por vía oral [Trials of auricular defibrillation with the quinidine-verapamil combination by oral route]. Prensa Med Argent. 1972 May 26;59(17):665-70. Spanish. PMID: 5048460.

12. Shapiro M, Malo R, Férez S, Martínez-Ríos MA, Salazar E. Effectos antiarrítmicos del verapamil [Antiarrhythmic effects of verapamil]. Arch Inst Cardiol Mex. 1976 May-Jun;46(3):305-16. Spanish. PMID: 1088854.

13. Ronderos R, Escudero EM. Efectos del verapamilo en la fibrilación auricular [Effects of verapamil in atrial fibrillation]. Medicina (B Aires). 1985;45(3):247-51. Spanish. PMID: 3841935.

14. Sobrino JA, et al. Combinación de quinidina y verapamil en la fibrilación auricular. Rev Esp Cardiol 1989;42(4):262-266.

Heart attacks leave areas of scars mixed with healthy myocytes, generating areas of slow conduction within the scars, giving rise to a favorable environment for the origination of ventricular tachycardia (VT) by reentry mechanism. We all agree that in this type of scenario the implantable cardioverter-defibrillator (ICD) effectively prevents sudden death^1,2. However, ICD does not prevent TV generation. In turn, each adequate shock is not only a traumatic and painful situation for the patient, but also affects their quality of life, reduces device longevity, and is associated with reduced ventricular function and, possibly, increased mortality. Therefore, when faced with a patient with ICD and symptomatic VT, it is essential to offer something more.

SURVIVE-VT ¹ is a randomized trial, carried out in 9 centers in Spain. It compares catheter ablation (AC) versus antiarrhythmic drugs (AAD) as first-line treatment in patients with ischemic heart disease and symptomatic VT or ICD shocks. It included 145 patients (average age 70 years, 96% male, average FEY 34%) who were randomized to AC (n=71) or FAA (n=73). They all had chronic ischemic heart disease, a recent history of ICD shocks or symptomatic VT, and no antiarrhythmic pharmacological treatment. The primary endpoint was a composite of cardiovascular death, appropriate ICD shock, hospitalization for worsening heart failure, or serious treatment-related complications. Patients in the ablation group underwent substrate-guided ablation. Patients in the drug group could receive amiodarone alone, amiodarone plus beta-blockers, or sotalol. 86% received amiodarone.

After 24 months of follow-up, the primary endpoint was significantly reduced in the AC group by 28.2% vs 46.6% (Hazard Ratio [HR]: 0.52; P = 0.021). The number of patients to be treated to prevent a case with the primary endpoint was 4.6. The benefits in the AC group were mainly due to a significant reduction in treatment-related complications (9.9% vs 28.8% HR: 0.30; P = 0.006) and a non-significant trend towards fewer hospitalizations for heart failure (HR: 0.56; P = 0.198). There were no differences in mortality or ICD shocks.

The ad hoc analysis shows that in the AC group there was a significant reduction in the recurrence of slow VT not detected by the CD (1.4% vs 13.7% HR 0.18) and hospitalizations for VT. The crossover rate was higher in the FAA group (24.3% vs. 10.1%).

These results lead the authors to conclude that CA guided by substrate modification, performed in sinus rhythm and without the need for VT induction, reduces the primary point of safety and efficacy.

COMMENTS:

SURVIVE-VT tries to solve a very common clinical situation: a patient with ischemic heart disease with ICD who has VT. What do we do? Do we start pharmacological treatment and wait to see if there is a recurrence and then propose ablation? Or do we propose ablation as a first option? LAHRS Guidelines, carried out in conjunction with HRS/EHRA/APHRS, do not recommend ablation in these cases (indication IIb, level of evidence A), but in those who have recurrent VT despite treatment with amiodarone (indication I, level of evidence B-R )⁴.

The results obtained suggest that ablation, as a first line, would be better than pharmacological treatment, mainly due to the significant reduction in treatment-related complications (10% vs 29% HR 0.30 P=0.006). So, let’s focus on treatment and adverse effects.

In the FAA group, it was used mainly (86% with amiodarone), the most effective drug, but with the highest rate of adverse reactions. In the AC group, the substrate-guided ablation technique was used, which is based on the elimination of potential isolated sites to achieve scar homogenization, eliminating the transition zones between fibrosis and healthy myocytes. As there is no need to induce VT during the intervention, adverse reactions resulting from hemodynamic compromise due to repetitive VT induction are avoided. We could say that the ablation branch used the safest technique. We currently do not have solid data to support the use of one ablation technique over the other. In fact, the VISTA ⁵ study showed that substrate ablation, compared with clinical ablation, significantly reduced VT recurrence at 12 months and combined re-hospitalization and mortality.

Considering that the ablations were performed in centers with extensive experience in these procedures, 10% of complications is not a negligible number. And a separate debate requires a qualitative, not just quantitative, analysis of the complications between the two groups. In the ablation group, some of the complications were stroke and heart block. While in the pharmacological group, sinus bradycardia and hypothyroidism were quantified as serious complications.

It would have been expected that ablation would reduce the primary point by reducing VT recurrence. However, there was no reduction in ICD shocks, mortality or any type of VT (27% vs 29% P=0.42).

On a positive note, ablation significantly reduced slow TV episodes. And this is not a minor observation. Slow VT, as it is not detected and treated by the ICD, favors patient decompensation, increased hospitalizations and even requires external cardioversion. This could explain the trend towards a lower number of hospitalizations for heart failure observed in the AC group.

Finally, SURVIVE-VT highlights the high rate of adverse reactions to antiarrhythmics during follow-up and that catheter ablation “might” be considered first-line therapy in patients with ischemic heart disease and first-episode VT. We need more information to change “might” to “must”. The great advances in the field of ablation compared to the few advances in the field of antiarrhythmics make us very optimistic about the future.

Bibliografía

1. Arenal A, Ávila P, Jiménez-Candil J, et al. Substrate ablation vs antiarrhythmic drug therapy for symptomatic ventricular tachycardia. J Am Coll Cardiol. 2022;79:1441–1453.

2. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–83.

3. Poole JE, Johnson GW, Hellkamp AS, et al. Prognostic importance of defibrillator shocks in patientswith heart failure. N Engl J Med. 2008;359:1009–1017.

4. Cronin E, Bogun FM, Maury P et al. 2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias. Europace 2019; 21:1143–1144

5. Di Biase L, Burkhardt JD, Lakkireddy D, et al. Ablation of stable VTs versus substrate ablation in ischemic cardiomyopathy. The VISTA randomized multicenter trial. J Am Coll Cardiol. 2015;66:2872–2882.

Bearing in mind that:

• The most common cause of syncope is vasovagal (VVS), followed by orthostatic hypotension (OH) and cardiac causes, (1)

• The tilt test is the study used for the diagnosis of VVS and OH, being recommended (class IIa, level of evidence B) in those cases with suspected reflex cause, OH, postural orthostatic tachycardia syndrome or psychogenic syncope (PS) after “initial assessment” (interrogation, physical examination including orthostatic blood pressure test and 12-lead ECG) did not identify the cause of the syncope (“unexplained syncope”) (1)

• Epidemiological studies have shown a “bimodal” distribution of this symptom, with a peak between 15-20 years and another after 70, (2-4)

• The etiology of syncope differs with age: most young people will have VVS, while OH and cardiac causes tend to be more prevalent in older adults, (2, 5)

• Diagnosis is often challenging in older adults because prodromes tend to be short-lived or absent and possible amnesia for a loss of consciousness event, which may therefore mask your diagnosis as just a blackout. a “fall” (3, 6, 7)

• “Unexplained syncope” is associated with a poor prognosis, with increased mortality and increased cardiovascular morbidity (8),

• Torabi P. et al. (9) propose in this work the need to know the causes of “unexplained syncope” in different age groups and the factors associated with a “final diagnosis” to establish effective diagnostic approaches.

As the “age of onset” of syncope has only been investigated in certain populations (e.g. it is a bimodal pattern of “first episode” age and the influence of “early” (<30 years) vs. “late” (≥60 years) onset years of this symptom on the clinical features and the “final diagnosis”.

After ruling out cardiac causes of syncope and non-traumatic causes of loss of consciousness (eg, epilepsy), 1,972 patients with “unexplained syncope” were evaluated between 2008 and 2018 in a syncope unit of a tertiary hospital. The “final diagnoses” after the tilt test were: VVS, HO, hypersensitivity/carotid sinus disease (HSC/CAD), complex syncope (2 or more diagnoses), non-diagnostic tilt test (TTND) and SP. Patients with TTND were recommended for further evaluation to rule out cardiac and non-cardiac causes of syncope and epilepsy. Finally, 1928 patients with available data on “age at first episode” were included in the analysis, comparing clinical features and “final diagnosis” in 3 groups according to age at onset: “early” (<30 years), 30 -59 years and “late” (≥60 years).

The first finding of this study was that the “age” of the “first episode of syncope” also shows a “bimodal” distribution in this patient population, with a first peak at 15 years and the second, less pronounced, at 70. assessment” peaked at its highest at age 75, followed by a lowest at age 20.

Clinical features and “final diagnosis” were different according to “age at first episode” (early vs. late). A significantly higher frequency of prodromes (64% vs 26%), palpitations (41% vs 15%), VVS (59% vs 19%) and SP (4% vs 0.2%) were observed in those with a first ‘early’ episode compared to those who had it “delayed.” In contrast, HO (23% vs 3%), HAC/ESC (9% vs 0.6%) and complex syncope (26% vs 14%) were significantly more frequent in those with a “late” first episode, compared to those who had it “early”. No significant differences were observed in the frequency of TTND between the 2 groups (initial 19% and late 23%).

Table 1: Clinical characteristics and diagnostic result of the tilt test with “first episode of syncope” <30 (“early”) and ≥60 years (“late”).

Results are expressed as a number (percentage), except * which are expressed as a median (interquartiles). HT: high blood pressure. VSV: vasovagal syncope. OH: orthostatic hypotension. CAH/ESC: carotid sinus hypersensitivity/disease. PP: psychogenic syncope. TTND: non-diagnostic tilt test

In the subgroup of 836 patients who were evaluated for syncope after age 60 years (Table 2), only 12% reported an “early” episode. The majority (70%) had their first “delayed” episode. VVS was significantly more frequent in those with an “early” first episode (39% vs 19%), while OH was significantly more frequent in those with a “late” onset (23% vs 7%). Prodromes were significantly less frequent in those with a “late” first episode (26% vs 52%). A “late” first episode was a predictor of HO and HAC/ESC (+31% and +26%, respectively, for every 10-year difference). In contrast, an “early” first episode was the occurrence of prodromes, VLS and complex syncope (+23%, +22% and +9% respectively, for each 10-year difference). Table 3.

Table 2: Clinical features and diagnostic result of the tilt test in patients aged ≥60 years at the time of evaluation.

Results are expressed as a number (percentage), except * which are expressed as a median (interquartiles). HTA: high blood pressure. VSV: vasovagal syncope. OH: orthostatic hypotension. HSC/ESC: carotid sinus hypersensitivity/disease. PP: psychogenic syncope. TTND: non-diagnostic tilt test

Table 3: Association between “final diagnosis” of syncope according to “age at first episode”: “early” (<30) vs “late” (≥60 years)

* OR: Probability ratios presented by 10-year increments in “age at first episode” of syncope

Although the large number of patients included is highlighted as strengths of this study, the authors mention as potential limitations of being a single-center study, the potential bias of including a selected population referred to a syncope unit to perform the tilt test, and the possible error in the determination of a clinical variable, such as the one analyzed in this study, which requires patients’ memory to recall the date of an event, which sometimes occurred many years before.

In conclusion, they highlight the diagnostic value of the “age” of the “first episode” of syncope as a relevant finding, due to its association with the clinical characteristics and the “final diagnosis”:

• Shows a “bimodal” age pattern

• In those over 60 years of age, most will have their first “late” episode (≥60 years) and they will have HO and ESC more often compared to those who had “early” syncope. On the contrary, when the first episode occurred “early” (<30 years), the occurrence of prodromes, SVV and complex syncope were more frequent.

Finally, it is worth noting that, despite being evaluated in a syncope unit of a tertiary hospital, a significant proportion of patients (approximately 20%) persisted with the diagnosis of “unexplained syncope” (TTND) and the need for further evaluations or diagnoses. reevaluation.

Author:

Roberto Keegan, MD

LAHRS Co-Chair/Representative of the European Heart Rhythm Association (EHRA) Electrophysiology Certification Subcommittee 2020-2022

Former President of the Latin American Heart Rhythm Society (LAHRS) 2017-2018

Director of Electrophysiology – Hospital Privado del Sur and Hospital Español – Bahía Blanca – Argentina

References:

1. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018. http://dx.doi.org/10.1093/eurheartj/ehy037.

2. Colman N, Nahm K, Ganzeboom KS, et al. Epidemiology of reflex syncope. Clin Auton Res. 2004;14 Suppl 1:9-17. http://dx.doi.org/10.1007/s10286-004-1003-3.

3. Duncan GW, Tan MP, Newton JL, et al. Vasovagal syncope in the older person: differences in presentation between older and younger patients. Age Ageing. 2010;39(4):465-70. http://dx.doi.org/10.1093/ageing/afq039.

4. Cooke J, Carew S, Costelloe A, et al. The changing face of orthostatic and neurocardiogenic syncope with age. QJM. 2011;104(8):689-95. http://dx.doi.org/10.1093/qjmed/hcr032.

5. Ceccofiglio A, Mussi C, Rafanelli M, et al. Increasing Prevalence of Orthostatic Hypotension as a Cause of Syncope With Advancing Age and Multimorbidity. J Am Med Dir Assoc. 2019;20(5):586-8. http://dx.doi.org/10.1016/j.jamda.2019.01.149.

6. Parry SW, Kenny RA. Vasovagal syncope masquerading as unexplained falls in an elderly patient. The Canadian journal of cardiology. 2002;18(7):757-8.

7. Tan MP, Parry SW. Vasovagal syncope in the older patient. Journal of the American College of Cardiology. 2008;51(6):599-606. http://dx.doi.org/10.1016/j.jacc.2007.11.025.

8. Yasa E, Ricci F, Magnusson M, et al. Cardiovascular risk after hospitalisation for unexplained syncope and orthostatic hypotension. Heart. 2018;104(6):487-93. http://dx.doi.org/10.1136/heartjnl-2017-311857.

9. Torabi P, Rivasi G, Hamrefors V, et al. Early and late-onset syncope: insight into mechanisms. Eur Heart J. 2022. http://dx.doi.org/10.1093/eurheartj/ehac017.

10. Ganzeboom KS, Colman N, Reitsma JB, et al. Prevalence and triggers of syncope in medical students. Am J Cardiol. 2003;91(8):1006-8, A8. http://dx.doi.org/10.1016/s0002-9149(03)00127-9.

11. Sheldon RS, Sheldon AG, Connolly SJ, et al. Age of first faint in patients with vasovagal syncope. Journal of cardiovascular electrophysiology. 2006;17(1):49-54. http://dx.doi.org/10.1111/j.1540-8167.2005.00267.x.