FAERS Database Insights: Revisiting the β-Blocker and Asthma Association

While β-blockers remain highly effective for CVD management, they have been associated with respiratory adverse events (AEs), such as bronchospasm and worsening respiratory symptoms. Additionally, they can diminish the effectiveness of β2-agonists, which are commonly used to manage asthma and chronic obstructive pulmonary disease (COPD) [1,2]. In some cases, β-blockers may trigger moderate to severe asthma exacerbations and increase mortality risk among patients with advanced COPD [1,5]

Cardioselective β1-blockers are generally safe and effective for patients with cardiovascular diseases (CVDs), even in those with respiratory conditions like COPD and asthma. While β-blockers can occasionally impair pulmonary function, they are not contraindicated in these conditions. The European Society of Cardiology (ESC) guidelines recommend initiating cardioselective β1-blockers at low doses with careful monitoring for airway obstruction symptoms, such as wheezing and shortness of breath [6].

Studies indicate that β-blockers, including both β1-selective and nonselective agents, not only reduce all-cause and in-hospital mortality in COPD patients but also offer cardiovascular benefits without significant respiratory compromise [7]. However, nonselective β-blockers or those with low β1-selectivity can exacerbate asthma symptoms in patients with classical pulmonary asthma [7]. The ESC guidelines further highlight that low-dose cardioselective β1-blockers may be cautiously used in patients with chronic asthma [8].

Although both cardioselective and non-cardioselective β-blockers can lead to slight reductions in FEV1 and FVC values, only non-cardioselective β-blockers significantly lower the FEV1/FVC ratio, indicating notable airflow obstruction [9]. Importantly, any initial decline in lung function with β-blockers tends to be temporary, even in patients with reactive airway disorders [10].

To further evaluate respiratory risks, the World Health Organization’s VigiBase database was analyzed for reports of fatal asthma or bronchospasm associated with cardioselective β1-blockers. Out of 583 asthma cases and 1,015 bronchospasm cases, only 6 and 12 deaths were reported, respectively, often involving pre-existing lung disease and concomitant conditions like sepsis, pneumonia, or cancer [11]. The data suggested that bronchospasm was rarely the primary cause of death, and the β-blockers themselves were not directly implicated [12,13].

While asthma is not an absolute contraindication for cardioselective β1-blockers, careful prescribing and patient monitoring remain essential [7,8]. The choice of β1-blocker should prioritize safety, considering the minimal but present risk of bronchoconstriction in asthmatic patients [15]. To further refine this approach, the study assessed data from the FDA's Adverse Event Reporting System (FAERS) to identify β-blockers with the least risk of asthma-related adverse events.

The FAERS database contains anonymized data; therefore, ethics committee approval was not required for this analysis.

A total of 251,145 adverse events (AEs) related to β-blockers were reported to FAERS by March 31, 2024. Among these, 4,104 cases were identified as asthma-related events. The analysis categorized β-blockers based on two major classifications: the European Society of Cardiology (ESC) classification and the Vashistha and Kumar classification to assess the asthma-related risks associated with each category.(Table 2)

The ESC classification divides β-blockers into three major categories:

1. Selective β1-blockers

2. Non-selective β-blockers

3. Dual α- and β-blockers

Low-Risk Groups:

1. Dual α- and β-blockers

2. Hydrophilic β-blockers

3. Lipophilic β-blockers

Discussion

The use of β-blockers, a cornerstone in the management of several CVDs including hypertension, angina, heart failure, and arrhythmias, requires careful consideration in patients with asthma or other reactive airway diseases due to the potential risk of bronchoconstriction and exacerbation of respiratory symptoms. As the safety margin of these drugs is narrower than in COPD, the latest European Society of Hypertension guidelines recommend against using β-blockers to treat hypertension in patients with asthma [27].

Our analysis suggests that selective β1-blockers without ISA should be avoided in asthma patients due to an appreciably elevated risk, whereas selective β1-blockers with ISA should be used with caution due to a moderately elevated risk. However, this finding contrasts with the evidence from a meta-analysis of patients treated with long-term cardioselective β1-blockers, which indicated no increased risk of exacerbation, death, or asthma [28]. Analysis of pharmacovigilance databases was also very reassuring regarding the tolerability of selective β1-blockers in asthmatics [28].

Moreover, findings from the 2014 systematic review and meta-analysis by Morales et al. further support this conclusion. Their study highlighted that while selective β-blockers are generally better tolerated, they are not completely risk-free. The risk from acute exposure can be minimized by using the smallest effective dose and β-blockers with greater β1-selectivity. Importantly, β-blocker-induced bronchospasm responded partially to β2-agonists, with nonselective β-blockers blunting the response more than selective ones. This underscores the need for individualized risk assessment when prescribing β-blockers to asthma patients. [59].

Additionally, Bennett et al. conducted a comprehensive literature review and global pharmacovigilance search, revealing no published reports of severe or fatal asthma exacerbations associated with cardioselective β1-blockers. Supporting this, three large observational studies found no increase in asthma exacerbations among patients treated with these β1-blockers, reinforcing their potential safety profile in asthma management. [60].

Similarly, the meta-analysis by Huang et al. identified increased asthma risk with oral timolol and intravenous propranolol compared to placebo, while β1-selective agents like celiprolol, bisoprolol, and atenolol were associated with a lower incidence of asthma attacks. These findings emphasize the importance of selecting appropriate β-blockers for asthma patients to minimize respiratory risks[61].

Nevertheless, one of the more intriguing aspects of our analysis was the emergence of a number of differences between the individual drugs in the two classes. To explain these differences, it could be argued that the pharmacology of cardioselective β1-blockers suggests that none of the currently available β-blockers exhibit absolute selectivity for β1-ARs [2]. While cardioselective β1-blockers tend to demonstrate less pronounced β2-AR antagonism compared to non-selective β-blockers, several of them show minimal preference for β1-ARs over β2-ARs [29].

The aforementioned hypothesis does not, however, account for the AEs observed with bisoprolol and acebutolol, which have been demonstrated to possess high affinity for β1-ARs [2]. It is possible that additional pharmacological properties are involved [30]. Nebivolol is a highly selective β1-AR blocker that also activates endothelial nitric oxide synthase. The potential role of nitric oxide in airway control is well established [31]. Celiprolol is a β1-AR blocker with partial β2-agonist activity, weak blockade of postjunctional α1-ARs, and prejunctional α2-AR effects.

Non-selective β-AR blockers without ISA also demonstrated considerable variability. They are typically avoided in asthma patients due to the inherent risk of β2-AR blockade in the airways, which may result in bronchoconstriction [2]. However, while timolol exhibited a markedly elevated risk of asthma-related events, nadolol showed a significantly reduced risk. Timolol is the most prescribed non-selective β-AR blocker eye drop [32]. It has greater selectivity for the β2-AR than other commonly used non-selective β-AR blockers [32]. Nadolol is also an inverse agonist [33]. This implies that when it binds to β-ARs, it not only blocks the effects of adrenaline and noradrenaline, but also induces a reduction in basal receptor activity below the level observed in the absence of any ligand (agonist or antagonist), thereby shifting the balance of spontaneously active receptors towards the inactive state [34]. By attenuating basal receptor activity, inverse agonists may potentially elicit bronchodilation in the absence of external agonists [35]. There is evidence that nadolol has beneficial effects on airway hyperresponsiveness [36].

Although there is evidence that the infusion of propranolol is associated with a significantly higher risk of developing an asthma attack, predominantly in patients with a pre-existing history of asthma [37], our data indicate that this β-blocker, when considered within the broader category of non-selective β-AR blockers without ISA, exhibits a neutral to slightly increased risk of asthma-related events. It is noteworthy that the administration of propranolol in patients with hypertension and anxiety was associated with increased β2-AR bronchodilating function, which is contrary to the anticipated outcome [38]. It can be reasonably deduced that propranolol may not fully block the activity of β2-ARs, as it has the potential to induce inverse agonism [2]. In a rat model of passive cigarette smoking, Guo and colleagues observed that one-month course of propranolol treatment enhanced β2-AR-mediated relaxation [39]. Concurrently, it attenuated the contractile response to acetylcholine by reducing noradrenaline. In contrast, metoprolol, which is a selective β1-AR blocker with ISA, reduced blood catecholamine levels but did not increase airway smooth muscle responsiveness to β2-AR agonists. A single-center, randomized, double-blind, placebo-controlled trial conducted in the United Kingdom revealed that patients with chronic asthma who received 80 mg/d of propranolol did not experience any AE [40,41]. However, propranolol is associated with a higher risk of asthma-related problems if it is classified as a lipophilic β-blocker. Being lipophilic, propranolol is capable of crossing cell membranes and affecting lung tissue, which may result in a worsening of asthma symptoms. Conversely, β-blockers with a hydrophilic profile, such as sotalol and nadolol, demonstrated a lower risk, potentially due to their limited penetration into lung tissue, which in turn leads to a diminished likelihood of bronchoconstriction.

There was little data on non-selective β-AR blockers with ISA in the FAERS database, but these drugs should generally be avoided in asthma patients as they can worsen respiratory symptoms.

The dual α- and β-AR blockers demonstrated a significantly lower risk of AEs, which may be attributed to their ability to cause vasodilation and reduce airway resistance. However, carvedilol exhibited a higher risk, whereas labetalol demonstrated a comparatively lower risk. The differential risk profiles of carvedilol and labetalol for asthma-related AEs can be ascribed to their distinct pharmacological properties. The higher risk of carvedilol can be attributed to its significant β2-AR antagonism [25], which can lead to bronchoconstriction. Conversely, the lower risk of labetalol may be due to its balanced adrenergic blockade. It exhibits a higher affinity for α1-ARs compared to β1- or β2-ARs and a lower affinity for β2-ARs than carvedilol [29,42]. This difference should be carefully considered when selecting a dual α- and β-AR blocker for patients with asthma or those at risk of respiratory complications.

In any case, when interpreting the results of our analysis, it is important to recognize the limitations associated with the FAERS data. Thus, although the results of this study are compelling, they do not provide conclusive evidence that β-blockers lead to asthma-related AEs.

The FDA itself has highlighted that relying on FAERS data alone is an inadequate approach for determining the safety profile of a drug [16,43]. Indeed, there is currently no definitive evidence linking the reported event, whether an AE or a medication error, to the drug in question. This is because the FDA does not require definitive evidence establishing a causal link between a product and an event. AE reports are voluntarily submitted by healthcare providers, consumers, and manufacturers, which may result in false, exaggerated, inaccurate, incomplete, or delayed information. The information provided in these reports is limited to the observations and perspectives of the reporters. Although it is recommended that both consumers and healthcare professionals report any AEs, it is essential to recognize that such reactions may be linked to the underlying disease being addressed, may result from other medications taken simultaneously, or may occur due to various other reasons. In any case, reports are often not sufficiently detailed for accurate evaluation, nor are they subject to medical review, which increases the risk of misclassification.

FAERS data cannot establish a definitive causal link between a drug and an adverse event (AE) due to limited patient population data, underreporting, duplicate reports, and inherent biases in spontaneous reporting. Reporting is influenced by factors like time on the market and media coverage, known as the Weber effect and notoriety effect, respectively. AE signals may rise after a drug’s launch and fluctuate over time, while widespread reporting can mask signals, known as the cloaking effect. Despite these limitations, the FAERS analysis highlights variability in asthma-related AE risk across β-blocker classes, emphasizing the need for careful β-blocker selection, especially in patients with respiratory conditions.(44-50) Table 3

The Global Initiative for Asthma underscores the potential risks of β-blockers in asthma patients, including bronchospasm and, in rare cases, asthma-related mortality. Despite these concerns, β-blockers offer significant cardiovascular benefits, such as reducing mortality in asthmatics hospitalized for acute coronary events. This duality has led to inconsistent guidelines: Japanese recommendations advocate cautious use of β1-selective blockers in patients with comorbid cardiovascular disease (CVD), while the British Thoracic Society and NHLBI advise complete avoidance, including ophthalmic formulations.

These conflicting guidelines often result in the underuse of β-blockers, depriving patients with both CVD and respiratory conditions of potentially life-saving treatment. Given that up to one-third of patients with heart failure and reduced ejection fraction also have respiratory comorbidities, asthma or COPD should not automatically contraindicate β-blocker use. Instead, prescribing should be guided by thorough clinical evaluation, including spirometry, bronchodilator reversibility testing, and assessment of airway hyperresponsiveness.

Our real-world data highlight that esmolol, metoprolol, nebivolol, and nadolol are associated with a lower risk of asthma-related adverse events and should be preferred in patients with respiratory conditions. In contrast, betaxolol, bisoprolol, acebutolol, propranolol, and timolol carry a higher risk and should be avoided. Atenolol and bisoprolol warrant cautious use, particularly in patients with a history of reactive airway disease. (Table 4)

Recent network meta-analyses further suggest that while oral timolol and intravenous propranolol increase asthma risk, celiprolol, bisoprolol, practolol, and sotalol may reduce it. However, the identification of bisoprolol as the third most prevalent β1-blocker associated with asthma episodes in the VigiBase analysis warrants further investigation, given conflicting evidence regarding its safety in mild-to-moderate asthma.

In conclusion, β-blocker use in asthma patients should be individualized, considering the specific drug’s safety profile, patient characteristics, and asthma severity. Our findings, combined with existing evidence, provide critical insights to inform clinical decision-making in this complex therapeutic landscape.

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