Capturing Exacerbations of Chronic Obstructive Pulmonary Disease with EXACT. A Subanalysis of FLAME

Abstract

Rationale: Chronic obstructive pulmonary disease exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n = 457) from the FLAME (Effect of Indacaterol Glycopyrronium vs. Fluticasone Salmeterol on COPD Exacerbations) study used the Exacerbations of COPD Tool (EXACT) to capture symptom-defined exacerbations.

Objectives: To evaluate the effect of indacaterol/glycopyrronium versus salmeterol/fluticasone on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU).

Methods: All patients in FLAME used an electronic diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery, and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time to first symptom-defined (EXACT) exacerbation and assessed differences between symptom-defined and HCRU events in terms of number, severity, and concordance.

Measurements and main results: A nonsignificant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio, 0.83; 95% confidence interval [CI], 0.60-1.14; P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with indacaterol/glycopyrronium versus salmeterol/fluticasone (hazard ratio, 0.76; 95% CI, 0.56-1.03; P = 0.075). These results were consistent with data from the overall FLAME population. Of the symptom-defined (EXACT) events, 23.5% corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (κ index, 0.24; 95% CI, 0.15-0.33).

Conclusions: Regardless of the exacerbation definition used, our findings support the use of long-acting β₂ agonists/long-acting muscarinic receptor antagonists as the preferred treatment option for patients at risk of future exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT01782326).

Keywords: concordance; defined symptom; exacerbation; treatment.

Figure 1.

The effect of indacaterol/glycopyrronium versus salmeterol/fluticasone propionate on the rate and time to first symptom-defined (EXACT) exacerbation in the EXACT subset. CI = confidence interval; COPD = chronic obstructive pulmonary disease; EXACT = Exacerbations of COPD Tool; IND/GLY = indacaterol/glycopyrronium; NS = not significant; SFC = salmeterol/fluticasone propionate.

Figure 2.

(A and B) Series plots of mean EXACT total scores of (A) first reported (open squares) and unreported (open circles) symptom-defined (EXACT) exacerbations and of (B) first healthcare resource use exacerbations (solid squares). In A, the analysis is based on patients with at least one symptom-defined (EXACT) chronic obstructive pulmonary disease (COPD) exacerbation. Symptom-defined (EXACT) COPD exacerbations starting between first dose and 1 day after the date of last treatment are included. A symptom-defined (EXACT) COPD exacerbation is considered reported when at least 1 day of the event is in between the time window of start date ± 7 days of a moderate or severe COPD exacerbation as reported on the electronic case report form. In B, the analysis is based on patients with at least one moderate or severe COPD exacerbation (with a non-missing EXACT total score) between first dose and 1 day after the date of last treatment. COPD exacerbations that occurred within 7 days of each other are collapsed as one event. EXACT = Exacerbations of COPD Tool; HCRU = healthcare resource use.