Atrioventricular block (AVB) frequently develops in patients taking bradycardic drugs (BDs)1 such as beta-blockers, nondihydropyridine calcium antagonists, and digoxin.

BDs have classically been considered a reversible cause of AVB2–4 but it is difficult to determine if a patient's AVB is connected to these drugs per se or if there is an underlying conduction disorder. Moreover, few studies have analyzed the clinical course and prognosis of patients who develop AVB while taking BDs.1,5–8 According to European clinical practice guidelines,2 patients with reversible AVB, such as that caused by BDs, are not indicated for permanent pacemaker implantation (class III recommendation, level of evidence C). However, the new 2018 guidelines of the American College of Cardiology/American Heart Association (ACC/AHA)3 consider permanent pacemaker implantation to be “reasonable” in selected patients who have symptomatic second- or third-degree AVB and are undergoing medically necessary and stable antiarrhythmic or beta-blocker therapy, without the need for a washout period (class IIa recommendation, level of evidence B). Based on recent work,1,6,7 the guidelines additionally assert in the section on specific related recommendations that, although a BD overdose can cause reversible AVB, the therapeutic doses of these drugs do not generally cause AVB. Thus, controversy surrounds the management of high-grade AVB in patients receiving BD therapy.

The objective of this study was to analyze the need for pacemaker implantation in the short- and mid-term after BD discontinuation in a consecutive series of patients attending either of 2 emergency departments with symptomatic high-grade AVB in the presence of BDs. An additional aim was to identify the variables predicting pacemaker requirement in the short-term due to AVB persistence or during follow-up due to recurrence.

The patient flow diagram of the study can be seen in figure 1. Of the 152 patients who attended the emergency department with high-grade AVB while taking BDs, we studied 127 patients meeting the inclusion criteria. Thus, 25 patients were excluded (due to acute coronary syndrome [n=12], clinical impossibility of drug discontinuation [n=7], digoxinemia> 2 ng/mL [n=4], and hyperkalemia ≥ 6.5 mEq/L [n=2]).

Of the 127 patients finally included (age, 79 [71-83] years; 50.4% men), 52.8% (n=67) still had AVB after BD discontinuation (group 1); the remainder (n=60) recovered atrioventricular conduction and were discharged without pacemaker implantation (group 2). The mean follow-up duration was 24 months and 2 patients (1.5%) were lost to follow-up. During this period, 40 patients in group 2 (66.6%) had AVB recurrence and underwent pacemaker implantation; in 37 of these, the block recurred in the 3 years after emergency department discharge (group 2 A).

In the overall sample, 107 patients (84.36%) required acute pacemaker implantation or implantation during follow-up despite drug discontinuation; 104 required the pacemaker implantation at the 3-year follow-up (groups 1 and 2 A), whereas the AVB resolved and did not recur after drug discontinuation in only 23 (18.1%; group 2 B) (figure 1). The median time to AVB recurrence was 65 [12-201] days.

Acute or 3-year need for pacemaker implantation

Multivariable analysis with multiple logistic regression (table 3) showed that pacemaker need due to irreversible AVB or AVB recurrence at the 3-year follow-up was significantly associated with the following: heart rate <35 bpm (odds ratio [OR]=8.12; 95% confidence interval [95%CI], 1.82-36.17; P=.006), wide QRS on ECG (OR=5.65; 95%CI, 1.77-18.04; P=.003), and a clinical presentation other than syncope or presyncope (OR=4.09; 95%CI, 1.18-14.13; P=.026). Concomitant antiarrhythmic treatment was a protective factor (OR=0.12; 95%CI, 0.02-0.66; P=.014). This model had an area under the ROC curve discrimination of 0.82 (0.71-0.94) (figure 2) to identify patients requiring a pacemaker at 3 years of follow-up despite BD discontinuation. A probability value of 0.85 with 75% sensitivity and 87% sensitivity was chosen because it provided the best discriminatory power.

Table 3.

Factors associated with AVB persistence or recurrence at 3 years

Variable	Crude OR	P	Adjusted OR	P
Heart rate <35 bpm	4.69 [1.31-16.81]	.017	8.12 [1.82-36.17]	.006
Wide QRS	3.51 [1.33-9.28]	.011	5.65 [1.77-18.04]	.003
Without syncope*	3.09 [0.98-9.74]	.054	4.09 [1.18-14.13]	.026
Antiarrhythmic agents	0.34 [0.11-1.29]	.113	0.12 [0.02-0.66]	.014
Diabetes mellitus	1.77 [0.71-4.41]	.204		.246
Digoxin	77.91 [0.01-5.13 × 105]	.071		.998

AVB, atrioventricular block; OR, odds ratio.

*

Mode of presentation other than syncope or presyncope.

Figure 2.

Area under the receiver operating characteristic (ROC) curve of the logistic regression model for the need for pacemaker implantation at 3 years of follow-up.

(0.05MB).

Our results show that almost 85% of patients who attend an emergency department with AVB while taking BDs ultimately require permanent pacemaker implantation. These data are in line with those published previously,1,5–8 but our work involves a series of patients from 2 centers and a larger sample size, enabling more robust analysis. In addition, 4 independent variables were identified that could help to predict patients who will eventually require a permanent pacemaker or, in contrast, to identify patients, fewer than 20%, who will not require a pacemaker in the mid-term.

The ramifications of these results are substantial because they indicate the need to consider a change to the clinical practice. First, according to our findings and those of other studies,1,5–8 AVB is rarely attributable to BDs alone. Rather, the results seem to indicate that these drugs reveal a latent conduction disorder. In addition, the delay to pacemaker implantation, imposed to determine whether the block resolves with drug discontinuation, can have deleterious consequences for patients due to reduced cardiac output or the need for a temporary pacemaker, with the associated comorbidities,6 as well as for the health care system due to a prolonged hospital stay, particularly that in the emergency department or coronary care unit.

In the mid-term, the clinical recurrence of AVB can have severe repercussions for patients, such as syncope, trauma, and fractures. These are particularly impactful in vulnerable elderly patients,10 who are more susceptible to developing bradycardia secondary to BD therapy.11

Although BD use is a relatively frequent finding in the presence of symptomatic AVB, few studies have analyzed its clinical course.1,6 Those results, similar to those published by other authors, such as Zeltser et al.,1 indicate a recurrence rate close to 50%. In an interesting study, Knudsen et al.6 analyzed patients under treatment with BDs who required temporary pacemaker implantation due to AVB: about 90% ultimately required a permanent pacemaker, with a nonnegligible complication rate. In this context, some authors have proposed pacemaker implantation independently of BD use.12 Notable considerations include the waste of resources due to the need for patient monitoring while the BD is eliminated, as well as the risk of a clinical deterioration in these patients while they await definitive treatment. In addition, the risk of syncope or sudden cardiac death is negligible in patients who have been discharged after restoration of atrioventricular conduction. In contrast, it should not be forgotten that pacemaker implantation is still an invasive procedure, one that is not complication-free. Accordingly, it is essential to identify those patients who will benefit from the device. A specially designed comparative study is required to investigate the prognosis of early pacemaker implantation in patients who recover from pharmacological AVB vs a conservative strategy.

The innovative aspect of the present work is that it identifies variables that help to predict those patients attending an emergency department with BD-associated AVB who will eventually require a definitive pacemaker. These variables, which can be obtained in the first bedside evaluation, predict the clinical course and reduce possible complications due to a delay to the permanent treatment. They also indicate patient groups with different behaviors who should be the focus of future studies for further knowledge advances. Notably, although the need for pacemaker implantation (acute or during follow-up) was high in all groups, a pacemaker was ultimately required by 90% of patients with wide QRS and a very low heart rate (< 35 bpm) or with a clinical presentation other than syncope. In addition, patients under treatment with groups Ic and II antiarrhythmic agents13 (flecainide, propafenone, and amiodarone) in combination with BDs appear to have fewer intrinsic conduction disorders and to recover normal conduction without the need for pacemakers. This could be explained by the effect of these drugs on the His-Purkinje system and on cell refractoriness.14–17 For their part, beta-blockers, nondihydropyridine calcium antagonists, and digoxin are characterized by their stronger negative chronotropic effects due to their direct action on the sinoatrial and atrioventricular nodes and lack of action on intra-Hisian and infra-Hisian conduction.18–22 This finding reinforces the belief that His-Purkinje involvement and its correct identification are crucial for clinical decision making. Indeed, the electrocardiographic variables independently associated with the eventual need for pacemaker implantation (wide QRS and heart rate <35 bpm) indicate an infra-Hisian location of the AVB. This location should not be affected by beta-blockers, calcium antagonists, or digoxin, which would reinforce the hypothesis of an underlying conduction disorder with a high risk of recurrence even without BDs. Although few patients were being treated with digoxin (n=15), their recurrence rate was very high, which is why it should be taken into account, despite not being included in the logistic regression model.

Another interesting finding is that patients with more latent symptoms, such as asthenia and heart failure, seem to more frequently have a more permanent conduction system disorder than those who initially have syncope or presyncope, whose bradyarrhythmia is more likely to resolve without recurrence. A possible explanation for this finding could be that, while a sudden clinical presentation such as syncope may be related to paroxysmal AVB, heart failure or asthenia could be related to persistent AVB that has become established during a sufficiently prolonged period to lead to more durable symptoms. Regarding the literature, our data fail to confirm the findings of Osmonov et al.,7 which indicated that a history of heart failure could protect against pacemaker need.

In most patients with AVB taking BDs, the bradyarrhythmia persists or recurs after drug discontinuation, indicating the presence of an intrinsic conduction disorder. In the mid-term, more than 80% of such patients require pacemaker implantation. Predictive variables can help to identify patients who will require a pacemaker, without the need to wait for new recurrences and avoiding the associated complications.

No funding has been received to support this study.

None to declare.