Safety of intravenous β-adrenoceptor blockers for computed tomographic coronary angiography

Abstract

Aims

To assess the safety of our clinical practice using off-label intravenous metoprolol to facilitate computed tomographic (CT) coronary angiography.

Methods

A retrospective analysis of scan reports and hospital admissions data was conducted to identify adverse events occurring following CT coronary angiography in patients who had received intravenous metoprolol prior to the scan.

Results

A total of 3098 patients were included, of whom 1871 received intravenous metoprolol. Nine hundred and one patients received more than 15 mg and 129 patients received metoprolol despite a resting heart rate <65 beats min⁻¹. There was a single adverse incident, comprising transient loss of consciousness.

Conclusions

The use of intravenous metoprolol to facilitate cardiac CT scanning appears safe. Dose limits recommended for other indications, generally in acutely unwell patients, may not need to be as stringent in this population.

What is already known about this subject

• Heart rate control is essential for high quality cardiac computed tomographic (CT) imaging with low radiation exposure.

• β-adrenoceptor blocker therapy is widely used, but the safety of this practice has not been explicitly demonstrated.

What this study adds

• This study suggests that our current clinical practice using intravenous β-adrenoceptor blockers prior to cardiac CT is safe.

• Doses of β-adrenoceptor blocker considered maximal for other indications may not be relevant to this patient group.

Introduction

Rapid development of computed tomography (CT) scanning techniques and technology have resulted in the mainstream use of CT coronary angiography for the investigation of coronary artery disease, with increasing utilization 1. To ensure diagnostic images of any obstruction to these vessels, a few millimetres in diameter, heart rate control is essential. Image acquisition usually occurs during cardiac diastole, when cardiac motion is minimized or briefly ceased, and lower heart rates prolong this phase, which reduces image artefacts. Slower heart rates also facilitate the use of optimal radiation-reducing techniques 2. For example at higher heart rates, the scanning time is increased to include more of the cardiac cycle in order to identify an optimally motion-free phase, or to allow the analysis of multiple phases to overcome the otherwise limited image quality.

The use of β-adrenoceptor blockers to achieve heart rate control is well established, most commonly with metoprolol 3, although centres vary widely in their choice of agent, administration route and dose. Although recent European data suggest a trend towards increasingly aggressive use of β-adrenoceptor blockade 3, there is little literature documenting the safety of this approach, and guidelines for practitioners have recommended conservative dosing regimens 4,5. While defensively safe, such protocols result in a substantial proportion of patients failing to meet the target heart rate 5,6, with the potential implications of poorer image quality and greater radiation exposure.

We pursue aggressive heart rate control with intravenous metoprolol tartrate (Betaloc®, AstraZenica UK Ltd, Luton, UK), in an off-label fashion, due to its favourable pharmacological characteristics, including rapid onset, predictability and short half-life (average 3.5 h, range 1–9 h) 7 compared with alternative agents. To evaluate the safety of our practice, a retrospective data analysis was performed.

Methods

Study methods

The study was reviewed by the Research & Development department at our institution and registered locally as a clinical audit. Further review and the need for informed consent were waived.

The records of all patients undergoing CT coronary angiography on clinical grounds over a 3 year period (July 2010–June 2013) at our tertiary cardiothoracic centre were examined to establish β-adrenoceptor blocker usage and the occurrence of immediate complications. Patients undergoing non-coronary assessment, and those referred from outside the hospital catchment area, were excluded. All adverse incidents where treatment or monitoring was required (such as contrast allergy) were recorded in the clinical report, produced contemporaneously to the scan. We reviewed all clinical reports and the hospital admissions database was interrogated for readmissions within 48 h.

β-adrenoceptor blocker administration

The decision to administer intravenous metoprolol was taken by the supervising physician at the time of the scan, and administered by them. Advanced life support facilities were immediately available. The target heart rate was <65 beats min⁻¹, and ideally <60 beats min⁻¹ 2, during a breath-hold (which provides physiological augmentation to bradycardia in most patients) with no pre-defined, maximum dose. Metoprolol was administered in 5 mg boluses at 1 min intervals and titration was continued provided an observable impact on heart rate was being achieved. While the patient's three-lead electrocardiogram was continuously monitored throughout administration we did not routinely record or monitor the patient's blood pressure.

Most standard contraindications were observed 7, including allergy to the drug or its excipients, high grade atrioventricular block (first degree block with a PR interval >260 ms, any second or third degree block), severe or decompensated heart failure or severe peripheral vascular disease. We also excluded patients with severe aortic stenosis. We treated the concomitant use of verapamil as an absolute contraindication to intravenous metoprolol, but not diltiazem, and we will administer a modest dose of metoprolol (up to 10–20 mg), cautiously with the latter. The use of oral β-adrenoceptor blockers was not considered when deciding to use intravenous β-adrenoceptor blockers, other than as reassurance of the patient's likely tolerance.

Patients with asthma were counselled about the potential risk, but were offered β-adrenoceptor blockers if they were not using high dose inhaled β₂-adrenoceptor agonists, had not required corticosteroid therapy within the last year and had no other indications of poor control or risk factors for severe exacerbation (e.g. previous critical care admission). Chronic obstructive pulmonary disease was not a contraindication to the use of β-adrenoceptor blockade, although we avoided intravenous administration where patients had a significant bronchospastic component, requiring regular, high dose bronchodilator therapy. Patients with such a relative contraindication or caution were offered an informed choice, comprising careful use of metoprolol, scanning with increased radiation dose or an alternative imaging modality. Inpatients with acute illness, such as sepsis or potential pulmonary embolus, did not undergo rate control, nor did patients with unexplained syncope as the index presentation.

Following the scan patients are observed for at least 20 min prior to discharge (i.e. beyond the time to peak onset). Vital signs are not routinely monitored.

Results

We identified 3098 consecutive patients meeting the inclusion criteria. In 68 cases the use or dosage of β-adrenoceptor blockers could not be verified. One thousand one hundred and fifty-nine patients (37%) did not receive β-adrenoceptor blockers due to satisfactory baseline heart rate or contraindication. One thousand eight hundred and seventy-one patients received intravenous metoprolol with a dose range of 2.5–70 mg (median dose 15 mg, interquartile range 10–25) (Figure 1). Nine hundred and one (29%) patients received more than the licensed dose of 15 mg (noting that there is no formal licence for the use of metoprolol for cardiac CT). One hundred and twenty-nine patients received intravenous metoprolol despite a resting heart rate ≤65 beats min⁻¹, with a median dose of 6 mg (interquartile range 5–10). No complications or adverse incidents were reported in this cohort. There were no unplanned hospital admissions within 48 h of the CT.

Figure 1.

Number of patients receiving β-adrenoceptor blockers in 10 mg strata

Out of all 1871 patients there was one adverse incident. Brief loss of consciousness occurred, without sequelae, in an outpatient under investigation for atypical chest pain and syncope, who had received 15 mg metoprolol prior to CT. The patient fully recovered and was discharged from hospital following a short period of cardiac monitoring, ultimately being diagnosed with reflex syncope. No other complications or adverse incidents occurred and no other patients required any medical treatment.

Discussion

Our data, comprising the largest analysis of real-world practice in this setting, suggest that the off-label use of intravenous β-adrenoceptor blockers to facilitate cardiac CT is safe. Complications are rare, provided that due consideration and appropriate patient assessment is undertaken, on an individual basis. We have also demonstrated, in a small subset, that β-adrenoceptor blockers can be used at doses above that currently recommended for other indications 7 in selected patients. As cardiac CT becomes increasingly widespread, the ability to achieve safe heart rate control has important implications for both image quality, and potentially therefore for the need for additional downstream testing, and for radiation exposure.

The low rate of complications and side effects compared with the expected frequencies seen in clinical trials and surveillance needs careful consideration. This is a retrospective analysis and therefore there is an inherent risk of reporting bias, although the data have been collected prospectively for clinical purposes and so recall bias has been reduced. Most of the common side effects of metoprolol are minor, such as dizziness, headache or nausea, which patients may not report or may attribute to the iodinated contrast media administered during the final phase of imaging. The use of a single dose of metoprolol is also likely to be relevant, with side effect profiles being generated from patients taking longer term, generally oral, therapy and side effects such as weight gain and fatigue are much less relevant. While bradycardia will be reported as an adverse incident in the context of arrhythmia or myocardial infarction (and occurs commonly), relative bradycardia is of course the objective when using metoprolol for cardiac CT. Perhaps the significance in this analysis is the absence of any patients requiring intervention for profound, symptomatic or compromising bradycardia.

Our judicious use of β-adrenoceptor blockers in patients with bronchospastic disease, and avoidance in acutely unwell patients also avoids many of the other side effects we would expect to see in such cohorts, whereas intravenous metoprolol is generally used for patients suffering acute myocardial infarction or arrhythmia, both of which can cause significant clinical instability and even death. We experienced no complications in any of these groups. Finally, postural disorders are also considered to be a common side effect of intravenous metoprolol, although with syncope occurring rarely 7. Even with our single adverse event, the rate of postural symptoms is low. This is likely to be due to a combination of mild or self-limiting symptoms not being reported by patients and not requiring medical intervention, the use of a one-off dose, and mitigation by the use of intravenous contrast which provides a 100–125 ml fluid bolus and may contribute to intravascular volume expansion.

The majority of other side effects are considered to be uncommon (incidence 0.1–0.9%) rare (incidence 0.01–0.09%) or very rare (incidence <0.01%) 7, and may not occur in a sample size such as ours. That said, our service has over 10 years of experience of cardiac CT and now scans around 2000 patients per year, with similarly low rates of complication reported anecdotally.

Competing Interests

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

Contributors

BC designed the project, undertook data collection and analysis, wrote and revised the manuscript and approved the final version.

VR assisted with project design, undertook data collection, critically revised the manuscript and approved the final version.

CR and GM-H contributed to project design and provided supervision, critically revised the manuscript and approved the final version.