Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review

BackgroundSafety of long-acting beta agonists (LABA) has been questioned and recent evidence suggested a detrimental effect on asthma control as well as an increased risk of death.ObjectiveTo evaluate the safety of regular use of LABA compared with placebo or LABA added to inhaled corticosteroids (ICS) compared with ICS in persistent asthma.MethodsRandomized studies from MEDLINE, EMBASE, and Cochrane Controlled Trials Register were identified. Additionally, AstraZeneca, GlaxoSmithKline, Novartis and FDA clinical trials databases were searched. Primary outcomes were asthma exacerbations (AE) requiring systemic corticosteroids or hospitalization, life-threatening exacerbations and asthma-related deaths.ResultsWe identified 92 randomized clinical trials with 74,092 subjects. LABA (as monotherapy) reduced exacerbations requiring corticosteroids (Relative Risk [RR] = 0.80; 95% CI, 0.73–0.88), without detrimental effects on hospitalizations or life-threatening episodes. Contrarily, LABA showed a significant increase in asthma-related deaths (Relative Risk = 3.83; 95% CI, 1.21–12.14). Subgroup analysis suggests that children, patients receiving salmeterol, and a duration of treatment >12 weeks are associated with a higher risk of serious adverse effects; also there was a protective effect of concomitant use of ICS. On the other hand, combination of LABA/ICS reduced exacerbations (RR = 0.73; 95% CI, 0.67–0.79), and hospitalizations (RR = 0.58, 95% CI, 0.45–0.74). Combined therapy was also equivalent to ICS in terms of life-threatening episodes and asthma-related deaths. Again, children and use of salmeterol were associated with an increased risk of some severe outcomes as compared with adults and formoterol users, respectively.ConclusionsThis review reinforced the international recommendations in terms of the use of LABA remains the preferred add-on therapy to ICS for patients whose disease cannot adequately controlled with ICS, and that LABA cannot be prescribed as a monotherapy. Nevertheless, in spite of the protective effect of the ICS, children and salmeterol use still show an increased risk of non-fatal serious adverse events.     

Effectiveness of Treatment With Dual Bronchodilation (LABA/LAMA) Compared With Combination Therapy (LABA/ICS) for Patients With COPD: A Population-Based Study

BackgroundInitiation of treatment of COPD with a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) is frequent irrespective of the risk of exacerbations.MethodWe performed a retrospective, population-based, observational study aimed at comparing the effectiveness of a LABA/long-acting antimuscarinic agent (LAMA) and LABA/ICS in patients with COPD over a one-year follow-up. Data were obtained from an administrative healthcare claims database. The primary outcome was the risk of first exacerbation. A sensitivity analysis was conducted in a propensity-score matched population.ResultsThe population consisted of 14,046 COPD patients; 11,329 (80.6%) initiated LABA/ICS and 2717 (19.4%) LABA/LAMA. The matched population included 1650 patients in each arm. During follow-up, 69.6% patients in the LABA/ICS group and 64.4% in the LABA/LAMA group presented an exacerbation. The mean time to the first exacerbation was 6.03 months (95% confidence interval (CI): 5.94–6.12) for LABA/ICS and 6.4 months (95%CI: 6.21–6.59) for LABA/LAMA; p < 0.001. The time to scalation to triple therapy was also significantly prolonged in LABA/LAMA. Similar results were obtained in the matched population. LABA/LAMA was associated with a significantly lower risk of exacerbations and escalation to triple therapy compared to LABA/ICS, except in patients with frequent exacerbations and high blood eosinophils in which no differences were observed in the time to first exacerbation.ConclusionInitiation of treatment with LABA/LAMA was associated with a lower risk of exacerbation and escalation to triple therapy compared to LABA/ICS in the majority of patients with COPD in primary care.     

Adherence to Long-Acting Inhaled Therapies among Patients with Chronic Obstructive Pulmonary Disease (COPD)

Abstract

Background: Long-acting inhaled medications are an important component of the treatment of patients with chronic obstructive pulmonary disease (COPD), yet few studies have examined the determinants of medication adherence among this patient population. Objective: We sought to identify factors associated with adherence to long-acting beta-agonists (LABA) and inhaled corticosteroids (ICS) among patients with COPD. Methods: We performed secondary analysis of baseline data collected in a randomized trial of 376 Veterans with spirometrically confirmed COPD. We used electronic pharmacy records to assess adherence, defined as a medication possession ratio of ≥0.80. We investigated the following exposures: patient characteristics, disease severity, medication regimen complexity, health behaviors, confidence in self-management, and perceptions of provider skill. We performed multivariable logistic regression, clustered by provider, to estimate associations. Results: Of the 167 patients prescribed LABA, 54% (n = 90) were adherent to therapy while only 40% (n = 74) of 184 the patients prescribed ICS were adherent. Higher adherence to LABA and ICS was associated with patient perception of their provider as being an “expert” in diagnosing and managing lung disease [For LABA: OR = 21.70 (95% CI 6.79, 69.37); For ICS OR = 7.93 (95% CI 1.71, 36.67)]. Factors associated with adherence to LABA, but not ICS, included: age, education, race, COPD severity, smoking status, and confidence in self-management. Conclusions: Adherence to long-acting inhaled medications among patients with COPD is poor, and determinants of adherence likely differ by medication class. Patient perception of clinician expertise in lung disease was the factor most highly associated with adherence to long-acting therapies.     

Real-world evaluation of asthma reliever therapy among continuous users of asthma maintenance medication in Japan: A retrospective cohort study using a claims database

BackgroundThe decrease in mortality rate owing to asthma has slowed in recent years. A large proportion of patients with asthma remain uncontrolled in Japan. This study aimed to determine the prevalence of short-acting beta 2 agonists (SABA) overuse and its associated factors.MethodsThis large-scale retrospective cohort study analyzed continuously treated patients with asthma aged 15–74 years between January 2017 and December 2017 using a Japanese insurance claims database. Characteristics, disease information, and prescribed drugs were extracted from the database, and treatment steps were defined according to drug combinations based on the criteria of the Japanese asthma guidelines. SABA overuse was defined as ≥3 canisters per year. Factors associated with SABA overuse were estimated using multivariable logistic regression.ResultsAmong 7,483 patients with mild-to-moderate asthma, 7,001 (93.6%) and 482 (6.4%) had low and high SABA use, respectively. Inhaled corticosteroids (ICS)/long-acting β-agonists (LABA) were the main asthma control treatments. The proportions of patients who overused SABA were 347 (9.9%) and 1,201 (5.6%) in the ICS and ICS/LABA groups, respectively. The factors associated with SABA overuse were male sex, ICS monotherapy, higher treatment steps, no history of allergic rhinitis, no history of chronic sinusitis, and no asthma management.ConclusionsThere is a relatively low prevalence of SABA overuse among asthmatic patients in Japan. ICS/LABA therapy, treatment steps, allergic rhinitis, chronic sinusitis, and asthma management are associated with a decreased risk of SABA overuse. Further studies are needed to investigate the association between SABA overuse and asthma exacerbation and mortality.     

Identifying patient-specific beliefs and behaviours for conversations about adherence in asthma

Background: Asthma guidelines advise addressing adherence at every visit, but no simple tools exist to assist clinicians in identifying key adherence‐related beliefs or behaviours for individual patients. Aims: To identify potentially modifiable beliefs and behaviours that predict electronically recorded adherence with controller therapy. Methods: Patients aged ≥14 years with doctor‐diagnosed asthma who were prescribed inhaled corticosteroid/long‐acting β₂‐agonist (ICS/LABA) completed questionnaires on medication beliefs/behaviours, side‐effects, Morisky adherence behaviour score and Asthma Control Test (ACT), and recorded spirometry. Adherence with ICS/LABA was measured electronically over 8 weeks. Predictors of adherence were identified by univariate and multivariate analyses. Results: 99/100 patients completed the study (57 female; forced expiratory volume in 1 s mean ± standard deviation 83 ± 23% predicted; ACT 19.9 ± 3.8). Mean electronically recorded adherence (n= 85) was 75% ± 25, and mean self‐reported adherence was 85% ± 26%. Factor analysis of questionnaire items significantly associated with poor adherence identified seven themes: perceived necessity, safety concerns, acceptance of asthma chronicity/medication effectiveness, advice from friends/family, motivation/routine, ease of use and satisfaction with asthma management. Morisky score was moderately associated with actual adherence (r=?0.45, P < 0.0001). In regression analysis, 10 items independently predicted adherence (adjusted R²= 0.67; P < 0.001). Opinions of friends/family about the patient's medication use were strongly associated with poor adherence. Global concerns about ICS/LABA therapy were more predictive of poor adherence than were specific side‐effects; the one‐third of patients who reported experiencing side‐effects from their steroid inhaler had lower adherence than others (mean 62% vs 81%; P= 0.015). Conclusions: This study identified several specific beliefs and behaviours which clinicians could use for initiating patient‐centred conversations about medication adherence in asthma.     

Triple versus LAMA/LABA combination therapy for Japanese patients with COPD: A systematic review and meta-analysis

BackgroundIn symptomatic COPD patients with a history of exacerbations, additional treatment with inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy is recommended based on the evidence of low incidence of exacerbations but with a caution for pneumonia. However, ethnic differences may affect the response to drugs. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this treatment in the Japanese population (PROSPERO: CRD42020191978).MethodsWe searched relevant randomized control trials and analyzed the exacerbations, quality of life, lung function, and adverse events including pneumonia and mortality as the outcomes of interest.ResultsWe identified a total of three RCTs (N = 632). Treatment with ICS/LAMA/LABA triple therapy significantly decreased the exacerbations (rate ratio, 0.56; 95% CI, 0.38 to 0.85) and improved the trough FEV₁ (mean difference, 0.04; 95% CI, 0.01 to 0.07) compared to LAMA/LABA therapy. However, triple therapy showed a significantly higher incidence of pneumonia compared to LAMA/LABA (odds ratio, 3.38; 95% CI, 1.58 to 7.22). Concerning other adverse events including mortality, there were no significant difference between these therapies.ConclusionsIn the current meta-analysis of the Japanese population, we confirmed that triple therapy causes a higher incidence of pneumonia than LAMA/LABA treatment but is a more preferable treatment since it showed a lower incidence of exacerbations and higher trough FEV₁ in patients with symptomatic moderate to severe COPD. However, since the sample sizes were not statistically large enough, further trials involving Japanese patients are needed.     

Inhaled corticosteroids are more effective in COPD patients when used with LABA than with SABA

Adding long-acting beta agonists (LABA) to inhaled corticosteroids (ICS) has been associated with beneficial effects in COPD patients in randomized controlled trials and observational studies. However, it is not known whether adding short-acting beta agonists (SABA) to ICS instead of LABA will be similarly effective in COPD. We compared the effectiveness of combination therapies involving ICS with LABA versus ICS with SABA in reducing risk of re-hospitalization or death among COPD patients within a year of discharge from a first COPD hospitalization. Using the UK General Practice Research Database, we obtained 437 pairs of patients who either used ICS plus LABA or ICS plus SABA, each pair having been matched on disease severity. We found that 12.1% of patients prescribed ICS with LABA experienced re-hospitalization or death within 12 months compared with 18.1% among those given ICS with SABA. In multivariate analyses, we found a 38% risk reduction (P<0.007) among patients given ICS with LABA relative to those given ICS with SABA. Models stratified by SABA use generated a risk reduction of 35% (P=0.02) among those given ICS and LABA with SABA in the 90-day period, and of 49% (P<0.05) among those given ICS and LABA without any SABA compared with the combination users of ICS and SABA. We conclude that in moderate to severe COPD patients, the combined use of ICS with LABA is more effective in reducing the risk of re-hospitalization or death than the combined use of ICS with SABA.     

The efficacy and safety of different long-acting β2-agonists combined with inhaled glucocorticoid regimens in patients with asthma: a network meta-analysis

Objective: To determine the efficacy and safety of current maintenance therapies consisting of different regimens of long-acting β2-agonists (LABA) with inhaled corticosteroids (ICS) in patients with asthma. Methods: A network meta-analysis (NMA) was conducted after a comprehensive search for relevant studies in the PubMed, Cochrane Library, and Embase databases up to January 1, 2017. Randomized clinical trials comparing LABA combined with ICS in patients with asthma were selected. Results: Seventeen trials were included in the analysis, comprising 10,961 patients and seven treatment regimens. Our NMA revealed that there were no statistically significant differences between agents regarding the frequency of moderate or severe exacerbations. For adverse effects, there were no significant differences between the included studies. Moreover, six of the results showed no statistically significant differences between agents regarding symptom-free days. The heterogeneity and inconsistency analysis of the outcomes showed that there were no differences between the regimens. Conclusions: Our findings have shown that there were no statistically significant differences between the different regimens of LABA?+?ICS regarding the frequency of moderate or severe exacerbations, adverse events, and symptom-free days.     

Long-acting Muscarinic Antagonist Versus Inhaled Corticosteroid when Added to Long-acting β-agonist for COPD: A Meta-analysis

The purpose of this study was to systematically review the efficacy and safety of long-acting β-agonist/long-acting muscarinic antagonist (LABA/LAMA) and LABA/inhaled corticosteroid (ICS) combinations in patients with advanced chronic obstructive pulmonary disease (COPD). Randomized clinical trials of at least 12 weeks of duration comparing LABA/LAMA and LABA/ICS combinations were included. We chose forced expiratory volume in 1 second (FEV¹), St. George's Respiratory Questionnaire (SGRQ) score, Transitional Dyspnea Index (TDI), COPD Assessment Test (CAT) score, COPD exacerbations, mortality, and other safety parameters as outcome assessment criteria. We included six randomized controlled trials with a total of 4,319 patients. Most patients did not have a history of exacerbation. LABA/LAMA was associated with greater improvement in FEV¹ than LABA/ICS (mean difference (MD) 0.09L, 95%confidence interval (CI) 0.07 to 0.11L; high certainty). Two treatments appeared clinically equivalent in improving SGRQ (MD ?0.12, 95%CI ?1.16 to 0.92; high certainty), TDI (MD 0.15, 95%CI ?0.05 to 0.35; high certainty), and CAT scores (MD 0.28 95%CI ?0.29 to 0.85; moderate certainty). LABA/LAMA was associated with an absolute reduction of approximately 8% in the incidence of pneumonia compared with LABA/ICS (risk ratio 0.41, 95%CI 0.18 to 0.94; moderate certainty). There was no significant difference in safety and exacerbation outcomes. However, equivalence of two treatments could not be concluded due to imprecision especially for mortality, cardiac serious adverse events, and severe exacerbations. Our findings support the use of dual long-acting bronchodilators for patients with advanced COPD but without frequent exacerbations given the excess risk of pneumonia with LABA/ICS.     

Comparison of three combined pharmacological approaches with tiotropium monotherapy in stable moderate to severe COPD: a systematic review

BackgroundGuidelines recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids (ICS) and their combinations for maintenance treatment of moderate to severe COPD. However, there are limited data supporting combination therapy.MethodsThis systematic review assessed the efficacy of three therapeutic approaches: tiotropium plus long-acting beta2-agonist (LABA) (“dual” therapy), LABA/ICS (“combined” therapy), and tiotropium plus LABA/ICS (“triple” therapy), all compared with tiotropium monotherapy. Randomized controlled trials were identified after a search of different databases of published and unpublished trials.ResultsTwenty trials (6803 participants) were included. “Dual” therapy showed significant improvements in forced volume in the first second (FEV₁), health-related quality of life (HRQoL), and dyspnea. However, it failed to reduce the risk of COPD exacerbations. Compared with tiotropium, “combined” therapy presented modest but significant effects on FEV₁, HRQoL, and dyspnea. Again, there was no significant difference in exacerbations, but it was associated with a significant increase of serious adverse effects (SAE) (number need to treat for harm [NNTH] = 20; 95% CI: 11–119). Finally, “triple therapy” increased FEV₁, improved HRQoL (both benefits exceeded minimal important differences) and decrease COPD exacerbations in anon-significant way. (Odds ratio [OR] = 0.57; 95% CI: 0.24 to 1.37, p = 0.21).Conclusions“Dual” and “triple” therapy seem like the most promising for patients with moderate to very severe COPD. However, data are still scarce and studies too short to generate a strong recommendation. Future studies should examine long-term efficacy and safety.     

Long‐acting muscarinic antagonist + long‐acting beta agonist versus long‐acting beta agonist + inhaled corticosteroid for COPD: A systematic review and meta‐analysis

Some trials have been conducted to compare long‐acting muscarinic antagonist (LAMA) + long‐acting beta agonist (LABA) versus LABA + inhaled corticosteroids (ICS) for chronic obstructive pulmonary disease (COPD), but no meta‐analysis were reported. Two investigators independently searched for eligible articles using the PubMed, Web of Science and Cochrane databases. Articles in authors' reference files were also regarded as candidates. The eligibility criteria for the current meta‐analysis were original trials written in English comparing the impact of LAMA + LABA and LABA + ICS for COPD patients. A pooled value for the continuous value was calculated using the genetic inverse variance method for mean difference. Incidence of events was evaluated using the odds ratio (OR). Minimal clinically important difference were 50 mL for forced expiratory volume in 1 s (FEV₁), four points for St George Respiratory Questionnaire (SGRQ) and one point for transition dyspnoea index (TDI). We included seven randomized controlled trials and one cross‐over trial with follow‐up period of 6–26 weeks. Compared with LABA + ICS, LAMA + LABA led to significantly greater improvements of trough FEV₁ by 71 (95% CI: 48–95) mL, TDI by 0.38 points (95% CI: 0.17–0.58), less exacerbations with an OR of 0.77 (95% CI: 0.62–0.96) and less pneumonia with an OR of 0.28 (95% CI: 0.12–0.68). Frequencies of any adverse event, serious adverse event, adverse event leading to discontinuation, all‐cause death and change of total score of SGRQ were not different in both arms. LAMA + LABA might be a better option for treating COPD than LABA + ICS.     

Tolerability of Bisoprolol on Domiciliary Spirometry in COPD

We investigated if serial domiciliary measures of spirometry were sensitive at detecting subtle effects of beta-2 blockade associated with bisoprolol in (n = 17) patients with COPD. After a two-week run in on inhaled corticosteroid (ICS) and long acting beta-2 agonist (LABA): beclometasone/formoterol 100/6 µg, patients’ started additional a long acting muscarinic receptor antagonist: (LAMA) Tiotropium 18 µg, with concomitant weekly dose titration of bisoprolol: 1.25–2.5–5 mg. After a further week of bisoprolol 5 mg, they were stepped back down to (ICS/LABA) for one week. Mean age was 64 years, mean FEV₁ 52% predicted, and mean FEV₁/FVC ratio of 0.46. Compared to baseline am FEV₁ of 1.38 L (95% CI 1.14–1.61 L), both ICS/LABA/LAMA and ICS/LABA in conjunction with bisoprolol showed statistically significant mean falls of 100 ml (1.28 L, 95% CI 1.03–1.53 L), and 120 ml, respectively (1.26 L, 95% CI 1.01–1.51 L); equalling and exceeding the MCID of 100 ml, respectively. These changes were disconnected from symptoms, reliever use and oxygen saturation.     

Comparison and optimal use of fixed combinations in the management of COPD

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Indications for the use of long-acting β₂-agonists (LABAs) and inhaled corticosteroids (ICS) in patients with COPD are described in the various international guidelines, but no special recommendations are made concerning the use of combination inhalers containing a LABA as well as an ICS. To determine the place of combination inhalers in the treatment of COPD we reviewed recent literature concerning this subject. On molecular level ICS/LABA combination therapy has anti-inflammatory properties which cannot be attributed to ICS alone. All clinical studies indicate that the two available combinations (salmeterol/fluticasone and formoterol/budesonide) significantly reduce exacerbation rate of moderate/severe exacerbations when compared with placebo. Some studies also showed a significant reduction in exacerbation rate compared with LABA monotherapy, but not compared with ICS monotherapy. From the patient’s perspective, ICS/LABA combination inhalers are the first choice when both need to be prescribed, possibly improving patient compliance for ICS. Currently little evidence is available to predict if flexible treatment with LABA/ICS combination inhalers will improve disease control in COPD. Further studies are needed to elucidate the clinical benefit of combination inhalers versus the individual components in different inhalers, and to investigate the clinical benefit of flexible dosing of combination inhalers in patients with COPD.     

Addition of Leukotriene Receptor Antagonists to Inhaled Corticosteroids Improved QOL of Patients with Bronchial Asthma Surveyed in Suburban Tokyo,Japan

BackgroundBronchial asthma is a chronic inflammatory disease that has a severe impact on health worldwide.MethodsA survey of 10,771 patients with bronchial asthma in the Tama region, Tokyo was conducted for 5 years to examine treatment and quality of life (QOL). Subjects were patients aged ≥ 16 years and their physicians who replied to a questionnaire sent in November from 2002 to 2006. Symptoms of bronchial asthma, visits to an emergency room, use of drugs, and severity of asthma were investigated.ResultsAsthmatic symptoms improved over the 5 years, with a reduction in the number of emergency room visits. Since inhaled corticosteroids (ICS) were used by > 80% of patients in 2002, we suspected that increased use of concomitant leukotriene receptor antagonists (LTRA) and long-acting β₂ agonists (LABA) might have contributed to these findings. The effects of these drugs were compared between ICS + LTRA (n = 45) and ICS + LABA (n = 54) groups of patients. There was no significant difference in the ICS dose between these groups. In the ICS + LABA group, 18.5% and 22.2% of patients visited an emergency room before and after initiation of combination therapy, respectively, with no statistically significant difference. In contrast, the rate of emergency room visits in the ICS + LTRA group decreased from 24.4% to 6.6% after addition of LTRA.ConclusionsThese results suggest that the frequency of visits to an emergency room was decreased by complementing the anti-inflammatory effect of ICS with further treatment of inflammation, particularly with LTRA.     

Long-Acting Beta-Agonists and the Risk of Intensive Care Unit Admission in Children

Objective. A possible association between long-acting beta-agonists (LABA) and severe asthma exacerbations including death remains controversial. We examined whether LABA in the setting of combination therapy with inhaled corticosteroids (ICS) increase the risk of near-fatal asthma in children using a case–control study design. Methods. Medical records from admissions for asthma exacerbations in children 4–18 years of age during the 2005 calendar year at Children’s Hospital of Pittsburgh of UPMC were reviewed. Cases and controls were determined by pediatric intensive care unit (PICU) and floor admission, respectively. Exposure was defined by LABA use in combination with ICS versus ICS alone. Results. Records from 85 PICU and 96 pediatric floor admissions were reviewed. LABA use in combination with ICS did not increase the risk of PICU admission (odds ratio 1.07, 95% CI 0.46–2.52) compared to ICS only without LABA. After adjusting for demographics, asthma severity, history of PICU admissions, and concurrent infection, LABA/ICS use still did not increase the risk of PICU admission (adjusted odds ratio 0.84, 95% CI 0.26–2.76) compared to ICS alone. There were no deaths and five intubations within the study period. Conclusions. The combination of LABA and ICS did not appear to increase the risk of near-fatal asthma in children.     

Clinical safety of long-acting beta2-agonist and inhaled corticosteroid combination therapy in COPD

Long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combination therapy is recommended by international treatment guidelines for COPD. The current literature concerning the safety of LABAs and ICS, both as monotherapies and in combination, in patients with COPD is reviewed. Bronchodilators such as LABAs are key treatments for COPD due to their effects on bronchial smooth muscle and airflow limitation. LABAs are well-tolerated in patients with COPD, with a low incidence of reported adverse events (AEs). Most AEs associated with LABA use are due to systemic exposure and include muscle tremor and cardiac effects. Placebo-controlled studies in patients with COPD demonstrate that there is no increase in risk of cardiac AEs with LABA therapy. ICS therapy targets airway inflammation in COPD, and is associated with a reduction in the frequency of COPD exacerbations, and improvements in symptoms, lung function and health status. Localized effects such as oropharyngeal irritation are common with ICS, but are not considered to be serious. Potential ocular effects with ICS therapy in patients with COPD have been identified and require further investigation. Rare, but more serious AEs related to ICS use are the effects on bone and the suppression of endogenous cortisol production; however, the clinical relevance of these effects is unclear. Clinical data indicate that LABA/ICS combination therapy is more effective in COPD than either agent used alone and is not associated with any additional AEs.