Safety of long acting muscarinic antagonists: are all these drugs always and equally safe?

Abstract

Inhaled bronchodilators – such as long-acting muscarinic receptor antagonists (LAMAs) – are central to the pharmacological management of symptomatic chronic obstructive pulmonary disease. LAMAs are considered to be safe drugs at recommended dosages. In the present issue of the Journal safety of umeclidinium, a recently marketed LAMA, at twice the recommended dosage, has been evaluated with good results in a Japanese, COPD population. However, because muscarinic receptors are expressed not only in the lungs but also at the level of heart, digestive and urinary apparatus, the potential exists for LAMAs to cause adverse events related to stimulation of receptors in these organs. Head-to-head and post-marketing vigilance studies are required to determine the profile risk of these drugs, ultimately, and whether differences exist between currently available LAMAs.

Keywords:

• Chronic obstructive pulmonary disease
• COPD
• LAMAs
• Long-acting muscarinic receptor antagonists
• Potential adverse events

Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Smoking cessation is the only treatment able to delay the progress of disease, but inhaled bronchodilators are also central to the pharmacological management of symptomatic COPD subjects. Long-acting muscarinic receptor antagonists (LAMAs) are a major class of inhaled bronchodilators. Until recently tiotropium was the only marketed LAMA, but other LAMAs are currently available, such as aclidinium and glycopyrronium. Umeclidinium bromide (UMEC) is also a newer LAMA, being a potent antagonist of M3 muscarinic receptors with long-term duration of bronchodilation¹. Several controlled trials have suggested that the optimal dosing of UMEC is 62.5 µg once daily (OD).

Most randomized controlled trials of LAMAs have focused on efficacy parameters as primary outcomes. They have shown that the long-term regular treatment of stable COPD subjects with LAMAs reduces symptoms, frequency and severity of exacerbations, and improves health status and exercise tolerance; no serious adverse events were reported. Few head-to-head studies between LAMAs have been performed, but the current idea is that they are equivalent in efficacy. However, as more LAMAs are available, clinicians shall decide the first choice among LAMAs and possibly safety may have a key-role¹.

Even if inhaled LAMAs are generally considered to be safe, muscarinic receptors are expressed not only in the lungs, but also at the level of heart, digestive and urinary apparatus. Because LAMAs are not fully selective for lung receptors, their use may be associated with adverse events related tostimulation of receptors in these organs.

By far, tiotropium has been the most used LAMA. The most common adverse events of subjects receiving tiotropium compared to placebo were dry mouth, constipation and urinary retention, usually mild and seldom causing the stopping of treatment. Meta-analyses and some observational studies have shown that tiotropium, mainly when delivered via the Soft Mist Inhaler Respimat, increased the risk of non-fatal and fatal cardiovascular events^1,2. Although this point is debated, it is important to add information from studies to establish the safety of newer agents^1,3. Overall, the risk of serious adverse events is increased at higher than recommended dosages. UMEC is not the exception and the incidence of cardiovascular adverse events has been shown to be dose-related in COPD subjects with significant increases in heart rate at a dose of 1000 µg OD⁴. While UMEC is generally well tolerated at the recommended dose of 62 µg OD¹, it is, therefore, of great interest to know the risk associated with possible inadvertent over-dosage of the drug, as it may occur in clinical practice.

Most studies have investigated UMEC in Caucasian subjects¹. It is known that the toxicological profile of drugs may change in populations with different genetic backgrounds⁵. The study by Yamagata et al.⁶, published in this issue of the journal, is worthy of consideration, showing the toxicological profile of UMEC administered at twice the recommended dose in a population of Japanese patients with COPD. This interesting 52 week, multicenter, open study evaluated the safety of UMEC at the unapproved dose of 125 µg OD as primary endpoint in 131 Japanese patients with COPD⁶. The authors observed that some subjects have suffered from constipation (N = 11, 8%), thirst (2%), dry eye (<1%) and urinary retention (<1%). Investigators attributed to UMEC constipation in two cases (2%) and blurred vision in two cases (2%). Severe adverse events during the treatment period were reported in nine patients (7%) but none were considered to be drug-related. Increased blood bilirubin was recognized in one patient due to UMEC⁶. UMEC is a substrate of cytochrome P450 2D6 and it is mainly metabolized in the liver. It is important to remember that there are relevant differences in pharmacokinetics between LAMAs. Tiotropium and, in a lesser degree, glycopyrronium are cleared in the urine. As a consequence, tiotropium is not indicated in moderate-to-severe renal failure (creatinine clearance <50 ml/min) and glycopyrronium is not recommended in severe renal failure¹. Renal failure is a common co-morbidity in COPD⁷. By contrast, aclidinium is metabolized by esterases without involvement of cytochrome P450. UMEC is primarily metabolized into inactive derivatives by CYP2D6 in the liver. Both aclidinium and umeclidinium can be used in renal impairment¹. Yamagata et al.⁶ reported a drop-out rate of 15%, an expected percentage in a fragile population for a trial of 52 weeks’ duration. The main causes of withdrawal were exacerbations and pneumonia, consistent with previous studies¹. Pneumonia was observed in 12 cases; 11 out of 12 were taking either ICS/LABA or ICS alone⁶. The use of ICS is associated with the risk of pneumonia in COPD subjects, mainly in the emphysematous type⁸, prevalent in the enrolled population from Yamagata (88% of total)⁶. Nevertheless, only in three cases was pneumonia considered a severe adverse event. All considered, despite the relatively small number of subjects and the lack of a control group, the study convincingly shows a good tolerance profile in this population. UMEC at 125 µg OD was well tolerated, with frequency and type of adverse effects not different from those expected in other parts of the world¹, and it could be reassuring for Japanese doctors to know that the treatment could be relatively safe in their patients, even if users were taking double the recommended dose of the drug either in error or hoping for a greater bronchodilator effect.

The study has two main limitations. The first one is that the subject population was composed almost completely of males (98%), thus it cannot apply to female subjects. The sex distribution is indeed representative of the distribution of the disease in Japan, where tobacco smoking is relatively rare in females. However, studies in other populations do not indicate gender-related differences in the occurrence of side effects¹. Nevertheless, Japanese doctors should be conscious that there is limited information on the tolerability of higher than optimal doses of the drug in Japanese COPD females. The second problem is that, like many other trials with similar numbers of subjects, the study was not powered to detect effects on uncommon possible side effects. One aspect that has recently drawn much attention is the possibility of cardiovascular toxicity by LAMAs. Although the available data are relative to tiotropium^1,2 and do not necessarily apply to UMEC and newer LAMAs, the risk of cardiovascular effects may be a class effect common to all anticholinergic agents and some potential of cardiovascular events cannot be ruled out, particularly at higher doses. In this regard, it is worth noticing that in the study presented by Yamagata et al.⁶ one case of angina and one of supraventricular tachycardia proved to be drug-related, along with an additional episode of supraventricular tachycardia which was considered unrelated to the drug. All the episodes were transient and non-fatal and the limited number of cases does not allow us to draw firm conclusions regarding the cardiovascular safety of the treatment at these higher doses. However, while waiting for more data from post-marketing studies, which are more likely to provide useful data on this kind of events, we recommend for the moment a cautious approach to subjects with COPD associated with cardiovascular disease.

LAMAs are administered either alone or in combination with long-acting beta2-agonists (LABAs), the other major class of inhaled bronchodilators. A risk of cardiovascular adverse events is traditionally attributed to the use of LABAs even if, when LABAs were compared to tiotropium alone, the frequency of cardiovascular side effects was not greater⁹. To date, randomized controlled trials have shown that the risk of cardiovascular events using LABA/LAMA fixed dose combinations was uncommon, if there was any¹. However, population-based studies have shown an increased risk of cardiovascular events in COPD subjects using LABA/LAMA combinations^10,11. We also recommend caution using LABA/LAMA in COPD subjects with cardiovascular diseases.

A last remark on Ellipta, the newer multidose dry powder inhaler used to deliver UMEC: Yamagata et al. did not describe problems of poor inhaler use among enrolled subjects⁶ that, by contrast, are commonly observed in real life¹. Komase et al. have recently observed that, in 150 Japanese subjects, Ellipta appears easy to load and patients like it¹². Ellipta has a lower number of steps required for proper usage with respect to other devices, but whether in real life it could be translated into a reduced risk of inhaler mishandling or overdosing remains to be proven. Further studies are required to focus on patients’ use of and satisfaction with this device in clinical practice. We support some extra effort in patient education, particularly in the instructions on correct dose and proper use of the inhaler.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

A.S.M. has disclosed the following relationships: advisory board member, recipient of speaker honoraria and consultancy fees for AstraZeneca/Almirall, Chiesi, Guidotti/Malesci, Novartis, Mundipharma, GSK, Sole24 Ore, Teva and Artsana. P.S. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.