Introduction

Pulmonary hyperinflation and cardiovascular disease are significant contributors of COPD disease burden and mortality. There exists a correlation between hyperinflation and impairment of cardiac function with reduced biventricular end-diastolic volumes. Dual bronchodilator therapy with long-acting β-agonist (LABA) and long-acting muscarinic antagonist (LAMA) reduces hyperinflation but its effect on cardiac function are not very well known. Indacaterol-Glycopyrronium is an inhaled, once-daily dual bronchodilator containing LABA indacaterol and LAMA glycopyrronium indicated for maintenance therapy in COPD.

Aim

To assess whether intervention with LABA/LAMA would reduce pulmonary hyperinflation and cause an increase in preload and cardiac filling.

Method

Study Design

• Double-blind, randomized, two-period crossover, placebo-controlled, single-center study

  Inclusion Criteria

• COPD patients aged at least 40 years with a smoking history of at least ten pack-years, baseline pulmonary hyperinflation with a residual volume >135% of predicted, and airflow limitation indicated by post-bronchodilator forced expiratory volume in 1 sec (FEV₁) of less than 80% predicted and forced vital capacity (FVC) ratio <0·7
• Patients with stable cardiovascular disease were included except patients with arrhythmias, heart failure, unstable ischaemic heart disease or uncontrolled hypertension

Treatment Strategy

• Cohort was randomized to receive either a combined inhaled dual bronchodilator containing the indacaterol 110 μg plus glycopyrronium 50 μg once daily for 14 days, followed by a 14-day washout, then a matched placebo for 14 days, or to receive the same treatments in reverse order
• Any ongoing hypertensive therapies were kept stable throughout the study
• Salbutamol was given as rescue medication
• Cardiac parameters were evaluated using MRI
• Lung function was assessed using constant-volume body plethysmography and spirometry
• Patient-reported outcomes were also analyzed
• Efficacy measurements were done at visit 5 on day 15 and visit 7 on day 43

  Endpoints

  Primary Endpoint

• Left-ventricular end-diastolic volume

  Secondary Endpoints

• Right-ventricular end-diastolic volume
• Left and right ventricular end-systolic volumes
• Left and right ventricular ejection fractions
• Left-ventricular cardiac index
• Left and right ventricular stroke volume
• Left and right ventricular cardiac mass
• Heart rate
• Systolic and diastolic blood pressure
• Residual volume
• Total lung capacity
• Inspiratory capacity
• Functional residual capacity
• Slow vital capacity
• Effective resistance
• Forced expiratory volume in 1 sec (FEV₁)
• Forced vital capacity (FVC)
• COPD assessment test score (CAT)
• Transition dyspnea index (TDI)

  Safety Endpoint

  Results

• A total of 30 patients were assigned to indacaterol-glycopyrronium followed by placebo and 32 to placebo followed by indacaterol-glycopyrronium
• These 62 patients were included in the intent-to-treat analysis and 60 were included in the per-protocol analysis
• The treatment periods were completed by 57 patients
• Most patients were males, current smokers with moderate-to-severe COPD
• After 14 days of indacaterol-glycopyrronium treatment, there was a notable difference in left-ventricular end-diastolic volume with a treatment difference of 5.23 (p<0·0001) as seen in Figure 1.

  Figure 1. Analysis of left-ventricular end-diastolic volume indexed to body surface area (ml/m²)

  

• The improvement in cardiac index was accompanied by a significant increase in left ventricular stroke volume indexed to body surface area and right ventricular stroke volume index as seen in Table 1.

  Table 1. Cardiac outcomes

  	Baseline mean	Treatment least squares means (95% CI)	Treatment difference	P value
  Left ventricular stroke volume (ml/m2)
  Indacaterol-glycopyrronium	33.89	39.11 (36.49-41.73)	4.04	<0.0001
  Placebo	34.46	35.07 (32.43-37.70)
  Right ventricular stroke volume (ml/m2)
  Indacaterol-glycopyrronium	33.63	38.92 (36.37-41.46)	3.63	<0.0001
  Placebo	34.59	35.28 (32.72-37.84)

• Improvements were noted in all body plethysmography measurements with indacaterol-glycopyrronium
• Clinically significant improvements were noted in CAT; LS mean difference (95% CI) -3.6, p<0.0001 and TDI; LS mean difference (95% CI) -3.6, p<0.0001 with dual bronchodilation
• AEs were reported in 54% and 43% of the patients who received dual bronchodilation and placebo respectively
• The most common AEs reported with indacaterol-glycopyrronium were cough (15%) and throat irritation (12%)
• Headache (8%) and upper respiratory tract infection (7%) were common in placebo group
• Serious AEs occurred in 2% in both groups; endometrial cancer in the indacaterol-glycopyrronium group and myocardial infarction in placebo group; however these were not related to treatment related
• There were no deaths reported

• Incidence of adverse events (AEs)

 Conclusion

• Treatment with once daily indacaterol and glycopyrronium for 14 days resulted in a significant reduction in hyperinflation and improved the cardiac function in patients with COPD and pulmonary hyperinflation.
• This treatment also demonstrated reduction in symptoms, supporting the early use of dual bronchodilation in COPD patients, showing signs of hyperinflation.

Lancet Respir Med. 2018 May;6(5):368-378.