Background Cardiovascular comorbidity is common among patients with chronic obstructive pulmonary disease (COPD) and there is concern that long-acting bronchodilators (long-acting muscarinic antagonists (LAMAs) and long-acting beta2 agonists (LABAs)) may further increase the risk of acute coronary events. Information about the impact of treatment intensification on acute coronary syndrome (ACS) risk in real-world settings is limited. We undertook a nationwide nested case–control study to estimate the risk of ACS in users of both a LAMA and a LABA relative to users of a LAMA.
Methods We used routinely collected national health and pharmaceutical dispensing data to establish a cohort of patients aged >45 years who initiated long-acting bronchodilator therapy for COPD between 1 February 2006 and 30 December 2013. Fatal and non-fatal ACS events during follow-up were identified using hospital discharge and mortality records. For each case we used risk set sampling to randomly select up to 10 controls, matched by date of birth, sex, date of cohort entry (first LAMA and/or LABA dispensing), and COPD severity.
Results From the cohort (n=83 417), we identified 5399 ACS cases during 281 292 person-years of follow-up. Compared with current use of LAMA therapy, current use of LAMA and LABA dual therapy was associated with a higher risk of ACS (OR 1.28 (95% CI 1.13 to 1.44)). The OR in an analysis restricted to fatal cases was 1.46 (95% CI 1.12 to 1.91).
Conclusion In real-world clinical practice, use of two versus one long-acting bronchodilator by people with COPD is associated with a higher risk of ACS.
- clinical epidemiology
- COPD epidemiology
- COPD pharmacology
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In patients with chronic obstructive pulmonary disease (COPD), is concomitant use of a long-acting muscarinic antagonist (LAMA) and a long-acting beta2 agonist (LABA) associated with a higher risk of acute coronary syndrome in the real-world setting of clinical practice than use of a LAMA alone?
The combined use of a LAMA and a LABA, rather than a LAMA alone, could increase the risk of acute coronary syndrome by about 30% in patients with COPD, a population already at high risk of acute coronary events.
The research has important implications for healthcare providers and patients who are considering the potential benefits and harms of using two versus one long-acting bronchodilator.
Coronary heart disease and chronic obstructive pulmonary disease (COPD) are leading causes of health loss and death worldwide1 and in New Zealand.2–4 Cardiovascular comorbidity is common among patients with COPD.5 This can partially be explained by shared risk factors such as smoking and age, however COPD also appears to be an independent risk factor for coronary heart disease.5
Successive editions of the Global Initiative for Chronic Obstructive Lung Disease Guidelines have recommended concomitant use of a long-acting muscarinic antagonist (LAMA) and long-acting beta2 agonist (LABA) if COPD symptoms are not well controlled on one long-acting bronchodilator6; and a recent American Thoracic Society clinical practice guideline strongly recommended the combined use of a LAMA and LABA, rather than monotherapy, in patients with dyspnoea or exercise intolerance.7 However, there is concern that long-acting bronchodilators might further increase the risk of acute coronary events in patients with COPD.8 This is important, given that the impact of these drugs (singly or in combination) on clinically important outcomes is relatively modest7 9–15 and patients with COPD are more likely to die from coronary events than from respiratory failure.16
Although the findings from randomised controlled trials (RCTs) appear to be reassuring about the cardiovascular safety of long-acting bronchodilators, the trials were usually underpowered for safety endpoints, and patients with pre-existing cardiovascular disease and other comorbidities were frequently excluded.17 Meta-analyses of those RCTs have also had limited power to examine cardiovascular risk9–15 and the authors of one review9 reported they were unable to undertake a meta-analysis of serious cardiovascular events because of a lack of consistency in reporting those outcomes. These limitations have prompted calls for more inclusive RCTs, as well as large observational studies, in real-world settings of clinical care.17
We undertook a national study to estimate the risk of acute coronary syndrome (ACS) in users of both a LAMA and a LABA relative to users of a LAMA. We also sought to explore the risk of ACS according to history of ischaemic cardiovascular disease, ethnicity, and concomitant use of an inhaled corticosteroid (ICS).
Case–control study, nested within a national cohort of patients who initiated long-acting bronchodilator therapy for COPD.
Data sources and derivation of study cohort
The study was based on linked data from the Ministry of Health’s National Collections,18 including the Pharmaceutical Collection (records of all claims by community-based pharmacists for the dispensing of prescription drugs which are publicly funded—most medicines prescribed in New Zealand), the National Health Index Collection (demographic data), the National Minimum Dataset (public hospital and publicly funded private hospital discharges), the Mortality Collection (inpatient and community-based deaths), and the New Zealand Cancer Registry (all cancers, except non-melanoma skin cancers).
We took several steps to derive the study cohort (figure 1). First, the Ministry identified all patients who were dispensed a LAMA, LABA, or LABA/ICS product in New Zealand at least once between 1 February 2005 and 31 December 2013 (end of follow-up) and provided us with linked demographic, health and pharmaceutical dispensing data for these patients. The date of the first dispensing of a long-acting bronchodilator was taken as the cohort entry date. We then excluded patients with incorrectly linked records (0.4%), those aged <45 years at cohort entry and those with a history of at least one hospital discharge diagnosis of asthma and no COPD diagnoses (to minimise the inadvertent inclusion of patients prescribed a LABA or LABA/ICS inhaler solely for asthma), those who entered the cohort between 1 February 2005 and 31 January 2006 (to avoid the bias that can arise from the inclusion of patients already using the drugs of interest at the start of follow-up), and those who entered the cohort on 31 December 2013 (to ensure that we identified ACS events that occurred after the first dispensing of a long-acting bronchodilator).
Summarising LAMA and LABA exposure in the study cohort
Nested case–control analyses
Identification of cases
Cohort members were classified as a case if there was a record between cohort entry and 31 December 2013, of (1) a hospital admission in which there was a principal or additional discharge diagnosis coded to any of the following International Statistical Classification of Diseases and Related Health Problems, Australian Modification, (ICD-10-AM) rubrics: I200 (unstable angina), I21 (acute myocardial infarction), or I22 (subsequent myocardial infarction, <28 days after a previous myocardial infarction); or (2) death and any of the above ICD-10-AM rubrics were coded as the underlying cause of death. We took the date of the first ACS event during follow-up as the index date for each case and their matched controls.
Selection of controls
For each case, we used risk set sampling to randomly select up to 10 controls, matched by date of birth (±365 days), sex, date of cohort entry (±183 days), and COPD severity (online supplemental table 2).
Ascertainment of user status on the index date
We classified individuals as current users of LAMA and LABA dual therapy, LAMA therapy, or LABA therapy if use occurred in the 30-day period before the index date (online supplemental figure 3). Conversely, those whose most recent therapy ended >30 days before the index date were classified as unexposed, as were patients whose only therapy in the 30 days before the index date was an ICS. Similarly, for the analyses exploring the impact of concomitant ICS use, we classified individuals as current users if the relevant exposure occurred in the 30 days before the index date. Individuals exposed to more than one LAMA-containing or LABA-containing therapy in the 30 days before the index date were classified according to the therapy they used closest to that date.
We ascertained user status without knowledge of whether an individual was a case or a control.
We used data from the National Collections to derive covariates for descriptive purposes and multivariate analyses. Covariates chosen a priori for inclusion in the adjusted models were demographic characteristics (self-identified ethnicity categorised according to the Ministry of Health Ethnicity Data Protocols19 and an area-based measure of deprivation, NZDep0620), Charlson comorbidity score (based on hospital admissions in the preceding 5 years), a history of conditions associated with an increased risk of subsequent cardiovascular events (ACS, other ischaemic heart disease, raised blood pressure, dyslipidaemia, heart failure, ischaemic stroke, transient ischaemic attack, diabetes), a history of conditions that might have influenced prescribing decisions about LAMA, LABA, and ICS products (life-threatening arrhythmia, benign prostatic hypertrophy/bladder outflow obstruction, hyperthyroidism, closed-angle glaucoma, osteoporotic fracture), and the use of medications which increase or decrease the risk of ACS (non-steroidal anti-inflammatories, oral theophylline, lipid-lowering agents, antiplatelets, anticoagulants, blood pressure-lowering medications).
The primary analysis explored the risk of ACS in users of LAMA and LABA dual therapy (LAMA and LABA with or without ICS), and of LABA therapy (LABA with or without ICS), relative to LAMA therapy (LAMA with or without ICS). Secondary analyses were undertaken based on cases for whom ACS was the principal diagnosis and for those whose ACS event was fatal. We also undertook secondary analyses stratified by history of ischaemic cardiovascular disease (history/no history of ACS, other ischaemic heart disease, ischaemic stroke, and/or transient ischaemic attack at any time before the index date), ethnicity (Māori, the indigenous people/non-Māori), and ICS exposure in the 30 days before the index date (exposed/not exposed).
Conditional logistic regression was used in the primary analysis to estimate unadjusted and adjusted ORs and 95% CIs. For the secondary analyses stratified by history of ischaemic cardiovascular disease, ethnicity, and ICS exposure, we used logistic regression and adjusted for the matching factors in addition to the other covariates. Chained equations,21 using all the data included in the analysis, were used to estimate the missing ethnicity and deprivation data (which were assumed to be missing at random). Fifty sets of data were imputed using a run-in of 150.
Analyses were carried out in Stata V.15.0.
Estimation of incidence rates
Crude incidence rates of ACS in users of LAMA and LABA dual therapy, LAMA therapy, and LABA therapy were estimated by dividing the number of cases which occurred during an episode of use of the relevant therapy by the total person-years of exposure for that therapy (censored at the index date for cases); 95% CIs were calculated using the mid-P exact method.22 We also calculated age-adjusted and sex-adjusted rates with 95% CIs,23 as well as crude and age-adjusted and sex-adjusted rates for Māori and non-Māori, with the age distribution of the total New Zealand population as the standard.
Patient and public involvement
Patients were not involved in the design, or conduct, or reporting, or dissemination plans of our research.
Overall, we identified 83 417 patients who initiated use of a LAMA, LABA, or LAMA/ICS inhaler between 1 February 2006 and 30 December 2013. A total of 5422 patients had an ACS event during 281 292 person-years of follow-up, however controls could not be found for 23 of these cases and they were excluded from the case–control analyses.
Table 2 and online supplemental table 3 show the characteristics of the 5399 cases and 51 563 controls included in the case–control analyses. Similar patterns of hospital discharge diagnoses and medication use were seen relative to the index date (online supplemental table 4).
The results of the primary analysis are shown in table 3. In the adjusted matched analysis, current users of LAMA and LABA dual therapy were 1.3 times as likely as current users of LAMA therapy to have an ACS event (OR 1.28 (95% CI 1.13 to 1.44)). Relative to current users of LAMA therapy, patients who were not currently using a long-acting bronchodilator were less likely to have an ACS event (OR 0.84 (95% CI 0.76 to 0.92)), while there was no difference in risk between current users of LABA therapy and current users of LAMA therapy (OR 1.0 (95% CI 0.91 to 1.10)). An unmatched analysis, adjusted for the matching factors, as well as the other covariates, yielded very similar estimates. Analyses confined to cases with a principal diagnosis of ACS (online supplemental table 5) and fatal ACS events (online supplemental table 6) also produced similar findings; the matched adjusted ORs for LAMA and LABA dual therapy versus LAMA therapy were 1.22 (95% CI 1.05 to 1.41) and 1.46 (95% CI 1.12 to 1.91), respectively. There was no evidence of a different pattern of results for the comparisons between LAMA and LABA dual therapy, LABA therapy, and LAMA therapy over time (p=0.06, online supplemental table 7).
The results of the analyses stratified by a history of ischaemic cardiovascular disease (online supplemental table 8) and by ethnicity (online supplemental table 9) were consistent with those of the primary analysis and there was no evidence of effect modification (p=0.3 and p=0.4, respectively). The findings for the analysis stratified by current use of an ICS differed somewhat (online supplemental table 10); while the unmatched adjusted OR for LAMA and LABA dual therapy versus LAMA therapy in the ICS-exposed stratum was similar to that found in the primary analysis, the corresponding OR in the stratum with no ICS exposure was consistent with no effect although the numbers were small and the 95% CI was correspondingly wide. The interaction effect was not significant (p=0.7).
Overall, the age-adjusted and sex-adjusted incidence rates for LAMA and LABA dual therapy and LAMA therapy were 25.1 (95% CI 20.5 to 29.6) and 22.4 (95% CI 18.3 to 26.4) per 1000 person-years, respectively, giving an absolute excess risk of 2.7 per 1000 person-years (online supplemental table 11). Among Māori, users of LAMA therapy had a higher rate than users of LAMA and LABA dual therapy, although the numbers of cases were small and the estimates less precise.
In this large national study of patients with COPD who commenced treatment with long-acting bronchodilators, current users of LAMA and LABA dual therapy were about 1.3 times as likely to be admitted to hospital with, and/or die from, ACS as current users of LAMA therapy. Very similar estimates were found in secondary analyses based on cases for whom ACS was the principal diagnosis, those with fatal ACS, and in analyses stratified by history of ischaemic cardiovascular disease and ethnicity.
Findings in relation to previous studies
Most RCTs that compared the use of two versus one long-acting bronchodilator and had at least 12 months’ follow-up were too small to provide meaningful estimates of ACS risk.24–26 Meta-analyses that included such RCTs, as well as those with shorter follow-up time, also had limited power.13–15 Two of those meta-analyses examined the risk of a composite outcome of all-cause non-fatal serious adverse events and did not report on the risk of cardiac events,13 14 while a network meta-analysis based on just 322 severe cardiac adverse events among 20 736 patients in 22 RCTs reported an OR of 0.98 (95% CI 0.78 to 1.25) for the LAMA and LABA versus LAMA comparison.15
Our findings are consistent with a safety analysis in an RCT that was unpublished at the time the data were extracted for the network meta-analysis. In the IMPACT trial, a multicentre RCT that compared the rate of moderate or severe COPD exacerbations during a 12-month follow-up period in 10 355 patients allocated to one of three combination inhalers, ischaemic coronary events occurred more frequently in the LAMA/LABA and LAMA/LABA/ICS arms than in the LABA/ICS arm; the rates per 1000 person-years were 30.6, 26.1 and 18.5, respectively.27
A few observational studies have compared the risk of cardiovascular events in patients concurrently using a LAMA and a LABA relative to users of one long-acting bronchodilator,28–32 however the primary analyses in four investigations28–30 32 focused on various composite outcomes (which collectively included coronary heart disease, arrhythmia, heart failure, ischaemic and haemorrhagic stroke, and transient ischaemic attack) rather than acute coronary events. In the fifth study, which explored the risk of four cardiovascular outcomes in the primary analysis, the acute myocardial infarction estimate was based on a relatively small number of cases (n=415) and a 37% increase in risk could not be ruled out (HR 1.12 (95% CI 0.92 to 1.37)).31 The sole observational study to have reported estimates for concomitant LAMA and LABA use relative to LAMA found a weak association for a composite cardiovascular outcome in the primary analysis, although this could have been a chance finding (HR 1.13 (95% CI 0.60 to 2.13)).28 Importantly, the first exposure was carried forward in the analysis and that could have led to an underestimation of the association because of misclassification of exposure status. In a secondary analysis that considered changes in treatment over time, the association was stronger although the CI was still wide (HR 1.26 (95% CI 0.74 to 2.15)).
In line with other observational studies that examined the risk of composite cardiovascular outcomes or ACS, we also observed a lower risk of ACS in patients who were not currently using a long-acting bronchodilator33 34 and comparable ACS risk between users of LAMA therapy and users of LABA therapy.33–38
Strengths and limitations
This study has several strengths. First, New Zealand has a universal healthcare system, and information about the dispensing of publicly funded medicines (which included all LABA, LABA/ICS, and LAMA products that were available in New Zealand during the study period) from community pharmacies, hospital discharge diagnoses, and causes of death are all recorded in the Ministry of Health’s National Collections and can be linked across the collections using a unique patient identifier (the National Health Index). This allowed us to identify a national cohort of new users of long-acting bronchodilators and to obtain information about individuals’ medication use and medical history both before cohort entry and during follow-up. Second, we are confident that the primary comparison (LAMA and LABA dual therapy versus LAMA therapy) was based on patients with COPD, because funded access to LAMA products during the study period was restricted to those with a spirometry-confirmed diagnosis of COPD. Third, our study included substantially more ACS cases than previous investigations and this allowed more precise estimates of risk. Fourth, to minimise potential confounding by indication, cases and controls were matched on severity of COPD and we addressed the primary aim in a matched analysis and adjusted for severity of COPD in the secondary unmatched analyses. In addition, we explored the degree to which worsening of COPD during follow-up (which, independently of medication, might have been associated with a higher risk of ACS) was associated with escalation to LAMA and LABA dual therapy. Among patients with mild/moderate COPD at cohort entry who were initially treated with LAMA therapy, only 19% escalated to LAMA and LABA dual therapy within 90 days following the first indication of increasing COPD severity; the majority remained on LAMA therapy for at least 9 months. The corresponding proportion for those initially on LABA therapy was only 6%. Given this prescribing behaviour, confounding by indication is unlikely to explain much of the observed increased risk of ACS.
The study also has several limitations. First, medicines dispensed in hospitals are not recorded in the Pharmaceutical Collection; however, the absence of this information is unlikely to have had a substantive impact on our study because inpatient stays for COPD are generally of short duration3 and patients collect medicines prescribed at discharge from community pharmacies. Second, we did not have access to the results of investigations to validate the diagnosis of ACS; however, there is good agreement between ACS diagnoses recorded in the national hospital discharge database and those documented by clinicians in the All New Zealand Acute Coronary Syndrome Quality Improvement registry.39 Third, we could not find controls for 23 older cases; however, the exclusion of this small number of cases should not have distorted our findings. Fourth, our definition of exposure to long-acting bronchodilators was based on dispensed inhalers and, as with all studies that do not involve direct observation of medicine consumption, it is impossible to know whether patients actually used these as directed. It is possible that cohort members who were dispensed LAMA and LABA dual therapy were less likely to have adhered to their prescribed regimen than users of LAMA therapy as this would have involved the use of two inhalers (combined LAMA/LABA products were not available during the study period); the impact of this would be to have been to underestimate risk. Fifth, while we adjusted for hospital discharge diagnoses of diabetes, hyperlipidaemia, and raised blood pressure, as well as the use of lipid and blood pressure-lowering medication, we did not have access to the results of glycated haemoglobin or total cholesterol/high-density lipoprotein ratio tests, or to blood pressure measurements, so we cannot rule out residual confounding by these factors. Nor did we have information on some well-established risk factors such as smoking, obesity, and family history of premature cardiovascular disease. However, our inability to adjust for smoking status is unlikely to be an important source of confounding in this study of patients with COPD, as a very high proportion of cohort members are likely to have been current or former smokers. Finally, the analysis stratified by current ICS use had limited power.
Given that the use of two versus one long-acting bronchodilator is associated with relatively modest improvements in patient-relevant health outcomes, our finding that LAMA and LABA dual therapy was associated with a higher risk of ACS than use of LAMA therapy has important implications for clinical decisions about the potential benefits and harms of treatment intensification.
We thank Analytical Services at the New Zealand Ministry of Health for providing the necessary data.
Contributors All authors contributed to the study conception and design, and to the interpretation of the findings. LP, SW, DB, and KS contributed to the acquisition and analysis of data. LP drafted the manuscript. SW, DB, KS, SH, RJ, and JD critically revised the manuscript.
Funding The research was funded by a Strategic Research Grant from the Department of Preventive and Social Medicine, Otago Medical School–Dunedin Campus, University of Otago.
Disclaimer The funder had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study was approved by the Southern Health and Disability Ethics Committee (reference: 15/STH/66).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available. The authors are not permitted to share the data directly with third parties. Enquiries about access to data from the National Collections may be sent to firstname.lastname@example.org.
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