Figures
- Fig. 1—
Search strategy. COPD: chronic obstructive pulmonary disease.
Tables
- Table 1—
Asthma-related deaths
First author [ref.] Daily dose of randomised treatment Concomitant LABA therapy ICS-exposed patient Cause of death Pauwels 26 Formoterol 4.5 μg p.r.n. Salmeterol Yes Asthma Pauwels 26 Formoterol 4.5 μg p.r.n. Yes Asthma Pauwels 26 Formoterol 4.5 μg p.r.n. No Asthma O'Byrne 28 Formoterol/budesonide 9/160 μg plus terbutaline 400 μg p.r.n. Yes Asthma O'Byrne 29 Formoterol 9 μg plus budesonide 160 μg Yes Status asthmaticus Pleskow 32 Formoterol 48 μg No Asthma von Berg 33 Formoterol 18 μg Yes Respiratory failure Pauwels 26 Salbutamol 200 μg p.r.n. No Asthma Pauwels 26 Salbutamol 200 μg p.r.n. Yes Asthma LABA: long-acting β-agonist; ICS: inhaled corticosteroids.
- Table 2—
Other causes of death
First author [ref.] Daily dose of randomised treatment Concomitant LABA therapy ICS-exposed patient Cause of death Pauwels 26 Formoterol 4.5 μg p.r.n. Salmeterol Yes Cardiac failure, myocardial infarction Pauwels 26 Formoterol 4.5 μg p.r.n. Formoterol Yes Cardiopulmonary failure Pauwels 26 Formoterol 4.5 μg p.r.n. No Myocardial infarction Pauwels 26 Formoterol 4.5 μg p.r.n. Yes Myocardial ischaemia Pauwels 26 Formoterol 4.5 μg p.r.n. Salmeterol Yes Myocardial infarction, cardiac failure, intestinal ischaemia Pauwels 26 Formoterol 4.5 μg p.r.n. Salmeterol Yes Myocardial infarction Pauwels 26 Formoterol 4.5 μg p.r.n. Unknown Ovarian cancer Pauwels 26 Formoterol 4.5 μg p.r.n. Unknown Brain neoplasm Pauwels 26 Formoterol 4.5 μg p.r.n. Unknown Cerebrovascular accident Pauwels 26 Formoterol 4.5 μg p.r.n. Unknown Carbon monoxide poisoning O'Byrne 28 Formoterol/budesonide 9/160 μg Yes Sudden death Pauwels 30 Formoterol 18 μg plus budesonide 640 μg Yes Suicide Brambilla 35 Formoterol 24 μg plus salbutamol 100 μg p.r.n. Yes Cerebrovascular accident Brambilla 35 Formoterol 24 μg plus salbutamol 100 μg p.r.n. Yes Brain metastasis secondary to lung carcinoma Buhl 36 Formoterol/budesonide 9/320 μg Yes Cardiac arrest Jenkins 37 Formoterol/budesonide 36/1280 μg Yes Pulmonary embolism Scicchitano 38 Formoterol/budesonide 9/320 μg plus formoterol/budesonide 4.5/160 μg p.r.n. Yes Metastases to peritoneum Zetterström 39 Formoterol/budesonide 18/640 μg Yes Suicide Pauwels 26 Salbutamol 200 μg p.r.n. No Aortic stenosis, tracheobronchitis Pauwels 26 Salbutamol 200 μg p.r.n. No Sudden cardiac death Pauwels 26 Salbutamol 200 μg p.r.n. Formoterol Yes Cardiac arrest Pauwels 26 Salbutamol 200 μg p.r.n. Yes Cardiac failure, ovarian cancer Pauwels 26 Salbutamol 200 μg p.r.n. No Myocardial infarction Pauwels 26 Salbutamol 200 μg p.r.n. Salmeterol Yes Myocardial infarction Pauwels 26 Salbutamol 200 μg p.r.n. Salmeterol Yes Myocardial infarction Pauwels 26 Salbutamol 200 μg p.r.n. Unknown Hepatorenal syndrome, hepatic cirrhosis Pauwels 26 Salbutamol 200 μg p.r.n. Unknown Cerebrovascular accident O'Byrne 28 Budesonide 640 μg plus terbutaline 400 μg p.r.n. Yes Unknown Price 31 Budesonide 800 μg Yes Cerebral haemorrhage Pleskow 32 Salbutamol 720 μg Unknown Acute pancreatitis Brambilla 35 Salbutamol 100 μg p.r.n. Yes Cardio-respiratory deficiency Scicchitano 38 Budesonide 640 μg plus terbutaline 400 μg p.r.n. Yes Myocardial infarction Scicchitano 38 Budesonide 640 μg plus terbutaline 400 μg p.r.n. Yes Hypertrophic cardiomyopathy LABA: long-acting β-agonist; ICS: inhaled corticosteroids.
- Table 3—
Odds ratios for risk of death associated with formoterol treatment at randomisation
All deaths Asthma deaths Simple contingency two-by-two table method Formoterol deaths# 25/27821 (0.09) 7/27821 (0.03) Comparator deaths# 17/21506 (0.08) 2/21506 (0.01) OR (95% CI) 1.1 (0.6–2.2) 2.7 (0.5–26.7) Peto’s method Studies with data n 12 5 OR (95% CI) Fixed effects 1.2 (0.6–2.2) 2.8 (0.7–10.4) Random effects 1.2 (0.6–2.2) 2.8 (0.7–10.4) Bayesian method Relative risk (95% credible interval) Vague prior 1.1 (0.5–2.5) 2.0 (0.4–10.1) Informative prior¶ 1.3 (0.8–1.9) 3.2 (1.3–8.7) #: presented as deaths/total subjects (%). ¶: the prior used for total deaths was the confidence interval for the odds ratio for all deaths of 0.8–2.1 from SMART (Salmeterol Multicentre Asthma Research Trial); for asthma deaths the confidence interval 1.2–15.3 was used.
- Table 4—
Sensitivity analyses based on exposure to formoterol, and exclusion of subjects taking maintenance salmeterol treatment
All deaths Asthma deaths Simple contingency two-by-two table method Formoterol deaths# 24/27,363 (0.09) 6/27,363 (0.02) Comparator deaths# 12/19,045 (0.06) 2/19,045 (0.01) OR (95% CI) 1.4 (0.7–3.1) 2.1 (0.4–21.2) Peto’s method Studies with data n 12 5 OR (95% CI) Fixed effects 1.4 (0.7–2.7) 2.2 (0.5–8.8) Random effects 1.4 (0.7–2.7) 2.2 (0.5–8.8) Bayesian method Relative risk (95% credible interval) Vague prior 1.2 (0.6–2.9) 1.8 (0.3–12.3) Informative prior¶ 1.3 (0.9–1.9) 3.1 (1.2–8.8) #: presented as deaths/total subjects (%). ¶: the prior used for total deaths was the confidence interval for the odds ratio for all deaths of 0.8–2.1 from SMART (Salmeterol Multicentre Asthma Research Trial); for asthma deaths the confidence interval 1.2–15.3 was used.
Supplementary information
Files in this Data Supplement:
- Supplementary information
-
Reference list
Table E1: The number of subjects in formoterol and comparator arms, trial length and observation times in the 62 studies included in the meta-analysis
Figure E1: Calculation of number of subjects exposed to formoterol and salbutamol, but not salmeterol in the RELIEF study E39
- Supplementary information
-
Vol 34 Issue 4
Table of Contents
Risk of mortality associated with formoterol: a systematic review and meta-analysis
