HEALTH-RELATED QUALITY OF LIFE ASSESSMENT USING SINGLE-INHALER DUAL VERSUS TRIPLE THERAPY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS

Objectives: The study compared triple therapy (inhaled corticosteroids/long-acting beta2-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) versus dual therapy [LABA/LAMA] in improving lung function and health-related quality of life (HRQoL) of patients with chronic obstructive pulmonary disease (COPD). Methods: This prospective and observational study compared 12 weeks of triple therapy (Formoterol – 6 mcg/Ciclesonide – 200 mcg/Tiotropium – 9 mcg) versus dual therapy (Formoterol – 6 mcg/Tiotropium – 9 mcg) in COPD patients. The primary objective included HRQoL as measured by improvement (decrease) from baseline in St. George respiratory questionnaire (SGRQ) score and COPD assessment test (CAT) scores. Coprimary endpoint included the change from baseline in forced expiratory volume in 1 second (FEV1). Results: After 12 weeks of treatment, triple therapy (n=30) and dual therapy (30), mean improvement (decrease) from baseline in SGRQ scores was −21.06 (95% CI, −24.92–−17.20) and −5.89571 (95% CI, −7.71–−4.07), respectively, and mean improvement (decrease) from baseline in CAT scores was −2.83 (95% CI, −3.73–−1.94] and −1.8 (95% CI, −2.25–−1.35), respectively. The mean change from baseline in FEV1% predicted was 3.09 (95% CI, 2.18–4.00) and 1.69 (95% CI, 1.43–1.97) for triple and dual therapy, respectively. For all the endpoints, the between-group mean differences were statistically significant (p<0.001). Conclusion: Triple therapy (Formoterol – 6 mcg/Ciclesonide – 200 mcg/Tiotropium – 9 mcg) can provide improvements in lung function and quality of life over dual therapy (Formoterol – 6 mcg/Tiotropium – 9 mcg) in patients with moderate to severe COPD. Future studies should focus on which drug combination of triple therapy is more effective and cost-effective than other possible triple therapy drug combinations.


INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a disorder of gradual lung function loss developing due to increasing breathing restrictions. Beta-agonists, corticosteroids, and muscarinic antagonists are a mainstay in the management of COPD. Based on the disease severity, recent GOLD guidelines recommend step-up therapy in the management of COPD [1,2]. To reap greater benefits, different combinations of long-acting beta2-agonists (LABA), inhaled corticosteroids (ICS), and long-acting muscarinic antagonists (LAMA) have been compared. These explorations proved triple therapy to be beneficial than dual therapy in terms of improvements in lung function, but variable results were obtained when the health-related quality of life (HRQoL) was concerned [3,4].
Research has shown that COPD patients had deteriorated HRQoL [5,6]. In this regard, St. George respiratory questionnaire (SGRQ) and COPD assessment test (CAT) have been validated and used extensively in clinical trials [7][8][9][10]. The various patient-reported outcomes such as shortness of breath, inability to perform daily chores, mental stress, and enhanced hospitalizations can be better measured using HRQoL [11][12][13][14]. HRQoL measures such as SGRQ and CAT scores along with objective parameters like spirometry can provide exhaustive coverage of treatment response following drug therapy [15].
Thus, the objective of the present study was to evaluate the effectiveness of triple therapy (Formoterol -6 mcg/Ciclesonide -200 mcg/Tiotropium -9 mcg) versus dual therapy (Formoterol -6 mcg/Tiotropium -9 mcg) in terms of lung function (forced expiratory volume in 1 s [FEV1] and forced vital capacity) and HRQoL (SGRQ and CAT scores).

Study site
This prospective, non-interventional, open-labeled, and comparison study was performed in the outpatient and inpatient Pulmonology Department of Owaisi Hospital and Research Centre, a tertiary care hospital of South India, during the period of September 2018-February 2019. Due to a small number of patients, the study was designed to be conducted as a pilot study. A total of 60 moderate (50%≤ FEV1 <80% predicted) and severe (30≤ FEV1 <50% predicted) COPD patients who were already on dual and triple therapy for the past 3 months were recruited and divided into two groups of 30 each. The recruitment was done based on convenience sampling. As this is a non-interventional study, specific visits are not mandated by the protocol. The following are the inclusion and exclusion criteria.

Inclusion criteria
The following criteria were included in the study.
• Patients of both genders, above 18 years and below 65 years • Those patients who are prescribed with any one of the following drug therapies, i.e., either dual therapy or triple therapy • Patients who are willing to give their informed consent to participate in the study • Patients diagnosed with moderate or severe COPD.

Exclusion criteria
The following criteria were excluded from the study. • Patients who are not willing to participate in the study • Pregnant woman are excluded • Pediatrics patients are excluded • Patients without moderate to severe COPD • Patients with COPD but with a history of pleural effusion, congestive heart failure, coronary artery disease, malignancies, tuberculosis, and bronchiectasis.

Ethical approval
The study was approved by the Institutional Ethics Committee of Owaisi Hospital and Research Centre. All subjects gave informed consent to participate in the study and allowed the use of their personal data for research purposes.

Data collection
This study collected demographic, clinical, and HRQoL data of COPD patients. The study required a minimum of two visits during the 6-month survey. The data were collected from patients, patients treatment chart/ case sheets, lab reports, and from patient's attendees. Spirometry was performed at baseline and every month until 6 month period. Similarly, SGRQ and CAT forms were explained and completed from patients at baseline and every month until 6-month duration. For baseline and final values, a minimum of 3 months difference was considered. The patients were subdivided into responders and non-responders based on the minimal clinically important difference (MCID). MCID for SGRQ was >4 units improvement (decrease) from baseline for total score [16] and for CAT scores, MCID was >2 unit improvement (decrease) from baseline for total score [8,9].

Statistical analysis
Continuous variables were presented as mean and standard deviation. Categorical variables were presented as numbers and percentages. Risk ratios and their associated 95% confidence intervals were used as effect measures for responders versus non-responders between triple and dual therapies. Similarly, mean difference and their associated 95% confidence intervals were used as effect measures for presenting improvement from baseline values in FEV1, SGRQ, and CAT scores between triple and dual therapies. p<0.05 was deemed statistically significant. All statistical analysis was performed using Epi Info Software version 7.0 (CDC, Atlanta, Georgia, USA).

RESULTS
The present study divided 60 patients into triple therapy and dual therapy containing 30 patients each. Treatment groups were well balanced in terms of patient characteristics and baseline parameters ( Table 1). The study subjects were divided into subgroups of age, gender, family history, and smoking history to find out in which subgroup the benefit was significant.

SGRQ scores
The mean change from baseline in SGRQ scores was −21.06 (95% CI, −24.92-−17.20) and −5.89571 (95% CI, −7.71-−4.07) for triple therapy and dual therapy, respectively. Significant differences were observed between initial and final symptoms, activity and impact, and total SGRQ scores of triple therapy patients (Fig. 1). On the other hand, except for symptom component of SGRQ scores, significant differences were observed between initial and final activity, impact, and total SGRQ scores of dual therapy patients (Fig. 2). Mean difference between triple and dual therapy SGRQ scores was −15.13 (95% CI, −17.15-−13.11) which was statistically significant (p<0.01) (Fig. 3). Based on the MCID of >4 units improvement (decrease) from baseline in SGRQ total scores, the number of responders in triple and dual therapies was 29 (97%) and 17 (57%), respectively. The percentage benefit of triple therapy over dual therapy was 97-57%=40% and the number needed to treat to benefit (NNTB) was 1/0.4=2.5. The overall benefit of response versus non-response was statistically significant in favor of triple therapy (risk ratio = 1.69, 95% CI: 1.44-1.99) (Fig. 4).

Lung function
The mean change from baseline in FEV1% predicted was 3.09 (95% CI, 2.18-4.00) and 1.69 (95% CI, 1.43-1.97) for triple and dual therapy, respectively. The mean difference between triple and dual therapy FEV1% predicted values was found to be 1.30 (95% CI, 0.94-1.67) which was highly significant. Age >40 years, male patients, patients with a negative history of COPD and past smokers significantly benefitted from triple therapy. Contrastingly, no significant difference between triple and dual therapies was found in female patients, patients with positive COPD history, age <40 years patients, current smokers, and nonsmokers (Fig. 5).

DISCUSSION
The present study proved that triple therapy was better than dual therapy in terms of lung function and quality of life. This is one of the very few studies where quality of life has been used as a primary outcome parameter for comparing treatment interventions. It is well established that the effectiveness of COPD pharmacological interventions should not be limited to lung function alone [17,18]. Except for in the subgroup analysis, triple therapy achieved statistically significant improvements in lung function and quality of life compared to the dual therapy. The statistically nonsignificant results in subgroup analysis may be attributed to the smaller sample size of the study.
Both the therapies showed improvements in lung function and quality of life, but the improvement was more with the triple therapy. This was true with SGRQ mean difference scores where all the subgroups showed statistically significant improvements in favor of triple therapy.
Triple therapy achieved 97% response rates, whereas dual therapy achieved 57% response rates in terms of SGRQ scores. Patients with age >40 years, males, current smokers, and negative family history patients appeared to respond more with triple therapy when SGRQ scores were concerned. Conversely, between-treatment mean difference SGRQ scores showed statistically significant improvements in favor of triple therapy with all the subgroups. On the other hand, FEV1% predicted between-treatment mean difference values present a different picture, where female patients, patients with positive COPD family history and nonsmokers did not seem to benefit much from the triple therapy. These discrepancies in FEV1 and SGRQ scores are also replicated by another study [19], where comparison results of the change in FEV1 and other patient-reported outcomes do not correlate well with each other [19,20]. To the best of our knowledge, this is the first study to perform subgroup analysis to compare the effectiveness of triple therapy versus dual therapy.
Both therapies showed improvements from baseline in CAT scores.
Triple therapy excelled in all the CAT scores, SGRQ scores, and FEV1% predicted values in terms of between-treatment mean difference and number of responders, but the association between CAT scores, FEV1, and SGRQ scores do not align in the subgroup analysis. Whereas only females had statistically significant mean difference in CAT scores favoring triple therapy, all the subgroups had statistically significant mean difference in SGRQ scores favoring triple therapy. Multiple reasons can be attributed to the discrepancy in SGRQ and CAT score results. First, the SGRQ scale includes a variety of COPD specific health status factors which contribute to the SGRQ scores. CAT scores exclude many of these factors due to item reduction compared to SGRQ scores influencing the output of CAT scores [21]. Likewise, SGRQ has been shown to be more responsive in the case of patients with deteriorated lung function [22] as is the case with the present study patients.
Triple therapy proved to be efficacious than dual therapy in many of the clinical trials, but the magnitude of the effect varies with our study and other studies [23][24][25][26][27]. A recent meta-analysis has shown a betweentreatment mean difference of 0.09 (95% CI, 0.07-0.12) in absolute FEV1 change from baseline and a between-treatment mean difference −1.67 (95% CI, −2.02-−1.31) in SGRQ score from baseline smaller than what has been reported by our study. Various reasons may be responsible for these differences. First, these trials were longer in duration, have used different doses of drugs, have used different drug combinations of ICS, LABA, and LAMA were majorly conducted as randomized controlled trials, etc. [28].
There are various limitations to this study. The sample size used was very small. The study was conducted as an observational study. An equal number of male and female patients must have been recruited.
The study was conducted in Hyderabad only. We did not check the medication adherence of the patients at home and were checked only at follow-ups. We did not account for changes in dosing regimens, different devices used, and different drugs in the LABA, LAMA, and corticosteroid classes. The study does not account for the cost of the therapy which is the major driver for drug use by the patients. Nevertheless, our study was conducted in a real-world setting and thus was able to capture the effectiveness of the drug therapies in the subgroups.

CONCLUSION
Triple therapy (Formoterol -6 mcg/Ciclesonide -200 mcg/Tiotropium -9 mcg) can provide improvements in lung function and quality of life over dual therapy (Formoterol -6 mcg/Tiotropium -9 mcg) in patients with moderate to severe COPD. Future studies should focus on which drug combination of triple therapy is more effective and cost-effective than other possible triple therapy drug combinations.

AUTHORS' CONTRIBUTIONS
Syed Aamir Ali: Concept, statistical analysis, manuscript preparation, manuscript editing, and manuscript review. Remaining authors: Design, literature search, data acquisition, and data analysis.