medwireNews: The initiation of triple therapy with a long-acting muscarinic antagonist (LAMA), a long-acting beta-2 agonist (LABA), and an inhaled corticosteroid (ICS) via a single inhaler for chronic obstructive pulmonary disease (COPD) is associated with a slightly higher cardiovascular risk than being treated with a single-inhaler LABA–ICS combination, the results of a real-world study suggest.
The risk for a major adverse cardiovascular event (MACE), defined as hospitalization for myocardial infarction or stroke, or all cause-mortality, occurring over the course of 1 year of treatment was a significant 28% higher for patients newly starting the triple therapy than those receiving the dual combination.
This “small increase” was “driven mainly by all-cause mortality,” which “accounts for over 80% of the MACE events,” Samy Suissa (Jewish General Hospital, Montreal, Quebec, Canada) and co-authors write in Chest. They report that the hazard ratio (HR) for all-cause death in their analysis was a significant 1.31.
The excess risk for MACE was mainly within the first 4 months of treatment initiation, with a HR of 1.41 for triple versus dual treatment. The HR for acute myocardial infarction was 1.00 and for stroke hospitalization was 1.06, although the team notes that the confidence intervals were wide, and the number of events available for analysis was small.
“Our observational study was motivated by signals from the large IMPACT and ETHOS randomized trials that found a numerically higher incidence of cardiovascular adverse events compared with those receiving LABA-ICS,” the researchers explain.
These trials are important as they provided support for a recent change in COPD recommendations from treating with LABA–ICS to initiating triple therapy for people with a history of exacerbations and high blood eosinophil counts.
To examine the risk for cardiovascular events in the real-world practice setting, the team used data from the Clinical Practice Research Datalink (CPRD), which contains the primary care medical records of more than 50 million people enrolled in more than 1800 general practices in the UK.
To emulate a clinical trial, they obtained CPRD data on new users of a LAMA–LABA–ICS combination who were aged 40 years or older and had been treated with the combination within a 5-year period, starting from 15 September 2017. This was the date that the first triple agent single inhaler COPD therapy became available in the UK.
Overall, a total of 10,255 new users of triple therapy were identified, and using time-conditional propensity scores, they were matched based on lifestyle, clinical diagnoses, and prescription drug use with 10,255 users of LABA–ICS.
The matching process used meant that the 24% of the study cohort who were new users of triple therapy with no prior use of LABA–ICS were matched to new users of LABA–ICS, while 76% of the study cohort with prior history of LABA–ICS use were matched to those who had also already been using LABA–ICS.
With regards to baseline characteristics, the mean age at study start was 70.5 years in the single-inhaler triple therapy and 70.6 years in the single-inhaler dual therapy group, with just under half (47.8% and 47.1%, respectively) in each group being men. Approximately half of participants were current smokers (49.3% and 49.1%, respectively).
“It is notable that 65% of the subjects who initiated single-inhaler triple therapy had less than two exacerbations in the year prior to initiating this treatment, including 42% who had none,” say the researchers. “Moreover, among those who did not switch from a LABA-ICS inhaler, 50% had no exacerbation in the year prior to initiating triple therapy,” they add, despite the recommendation to use triple therapy being based on data only for the presence of exacerbation.
Concluding, the researchers recommend reappraisal of the IMPACT and ETHOS data on cardiovascular safety stratified by prior LAMA use.
“In the meantime, cautious use of single-inhaler triple therapy in the real-world clinical practice setting of COPD treatment could first involve restricting it to the patient profile studied in the trials of these inhalers,” they suggest.
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