IMPACT in COPD

It seems that the role of steroid therapy for COPD is back in the debate again.  Recently, the results of IMPACT were published in New England Journal of Medicine, demonstrating the benefits of triple therapy in patients with COPD. Triple therapy involves the use of an inhaled glucocorticoid (ICS), a long-acting muscarinic antagonist (LAMA) and a long-acting beta 2 agonist (LABA).

It wasn’t too long ago that dual therapy with inhaled glucocorticoid (ICS) and LABA (long acting beta2 agonist) was found to increase the risk of pneumonia and related mortality.  As such, the management of COPD has been shifted to avoid the use of ICS, focusing on treatment with dual therapy with a long acting muscarinic antagonist (LAMA) with a long acting beta2 agonist (LABA).  But dual therapy with LAMA and LABA isn’t without safety concerns either. There seems to be mounting cardiovascular concerns with this combination as well.

However, the controversy continues with whether inhaled glucocorticoid is beneficial for patients with COPD, particularly with those who have frequent recurrent COPD exacerbations.  In the Informing the Pathway of COPD Treatment (IMPACT) trial, its objectives were to evaluate the relative benefits and risks of the following three regimens in patients with symptomatic COPD and a history fo exacerbation:

  • Triple Therapy: ICS+LABA+LAMA
  • Dual Therapy: ICS + LABA
  • Dual Therapy: LAMA + LABA

Here are some highlights of the study:

IMPACT was a randomized, double-blind, parallel-group, multicenter trial with the primary objective to evaluate the effects of the following three regimens:

  • Triple therapy (FF-UMEC-VI)
    • Fluticasone furcate (ICS) 100 mcg
    • Umeclidinium (LAMA) 62.5mcg
    • Vilanterol (LABA) 25 mcg
  • Dual ICS + LABA (FF-VI)
    • Fluticasone Furcate (ICS) 100 mcg
    • Vilanterol (LABA) 25 mcg
  • Dual LAMA + LABA (UMEC-VI)
    • Umeclidinium (LAMA) 62.5mcg
    • Vilanterol (LABA) 25 mcg

Patient Characteristics:

  • 40 years of age or older
  • symptomatic COPD (COPD Assessment TEst Score ≥ 10; range 0-40, with higher scores indicating more symptoms; minimal clinically important difference, 2 units)
  • FEV1 less than 50% of the predicted normal value and history of at least one moderate or severe exacerbation in the previous year  OR
  • FEV1 of 50-80% of the predicted normal value and at least two moderate exacerbations or one severe exacerbation in the previous year.

Trial Period: Jun 2014-Jul 2017 in 37 countries

Primary outcomes – to evaluate the rate of moderate or severe COPD exacerbation, specifically the annual rate of moderate or severe exacerbations during treatment (including 1 day after the last dose was administered)

Results

Slide1

The rate of moderate or severe exacerbations during treatment among patients assigned to Triple Therapy was 0.91 per year, as compared with 1.07 per year among those assigned to Dual ICS+LAMA (rate ratio with triple therapy, 0.85; 95% confidence interval, 0.80 to 0.90; 15% difference; p < 0.001) and 1.21 per year among those assigned to Dual LABA+LAMA (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; p< 0.001).

The annual rate of severe exacerbations during treatment was:

  • 0.13 among patients assigned to triple therapy
    • 0.15 among patients assigned to dual ICS+LAMA (rate ratio with triple therapy, 0.87; 95% CI, 0.76 to 1.01; 13% difference; p=0.06)
    • 0.19 among patients assigned to dual LABA+LAMA (rate ratio with triple therapy, 0.66; 95% CI, 0.56 to 0.78; 34% difference; p < 0.001)

Adjudicated cause-specific death:

Cardiovasular Deaths Respiratory Causes Death Associated with Patient’s Underlying COPD
Triple Therapy Group 16

(4.2 per 1000 pt-yr)

15

(4.0 per 1000 pt-yr)

18

(4.8 per 1000 pt-yr)

Dual ICS + LAMA 21

(6.0 per 1000 pt-yr)

12

(3.4 per 1000 pt-yr)

14

(4.0 per 1000 pt-yr)

Dual LABA + LAMA 15

(8.7 per 1000 pt-yr)

9

(5.2 per 1000 pt-yr)

15

(8.8 per 1000 pt-yr)

Safety and Adverse-Event Profile

Slide1

My thoughts about IMPACT:

This is a pharmaceutical (GSK) sponsor trial. There is definitely bias to promote the new product – Trelegy Ellipta.  The results also demonstrate the benefits of triple therapy in COPD patients with a history of exacerbation. On a preliminary review, it also suggests the safety profile may be better with the triple therapy group or is equivalent to the dual therapy groups.

However, this study has also confirmed the increased risk of pneumonia with steroid exposure. What is unclear (and the study did not attempt to reveal) is whether there is an association between the pneumonia and the mortality result, making to difficult to draw any conclusion about the impact of pneumonia on meaningful clinical outcomes.

On a practical level, it would be helpful to assess whether triple therapy improves quality of life for patients with COPD.  One cannot ignore the cost – in Canada, Trelegy Ellipta costs about $170 for one-month supply of Trelegy. It is currently not covered by Ontario Drug Benefits but its status may change as it is still being reviewed by Common Drug Review CADTH.

Another question to consider is whether these results can be extrapolated to other inhalation devices such as ADVAIR  or Symbicort containing ICS and LABA with a LAMA inhaler such as Tiotropium?

The treatment of COPD continues to evolve. But it remains to be a progressive condition that is costly to manage. Prevention with smoking cessation is indeed the most cost effective strategy.

Below is a video that demonstrate how to use Ellipta.  Note that Ellipta is available as:

  • Trelegy Ellipta (ICS with fluticasone furoate +LAMA with umeclidinum +LABA with vilanterol)
  • Incruse Ellipta (LAMA containing umeclidinium)
  • Anora Ellipta (LAMA with umeclidinium and LABA with vilanterol)
  • Arnuity Ellipta (ICS with fluticasone furoate)
  • Breo Ellipta (ICS with fluticasone furoate and LABA with vilanterol)

Thanks for reading my post.

Advertisements

Published by

drugopinions

My name is Cynthia Leung and I am a practicing pharmacist in Kingston Ontario, Canada. This blog is for me to share my ideas, opinions and perspectives on how medications are used in our health care system. Note that these posts are my own opinions and do not represent the opinions of my current or former employers and / or organizations that I may belong to. Any possible case scenarios described in my posts would be modified to maintain patient confidentiality. This blog is not a platform for professional advise for patients or health care providers and the content is not meant to support any clinical decisions or replace professional opinions. Also the images are either taken or created by the author, or adapted with permission. I hope you will enjoy reading my posts!

2 thoughts on “IMPACT in COPD”

  1. Biggest issue for me as a family MD is keeping up with all the different agents newly available.
    Of course these patients sound more severe. For those with not so bad FEV1/FEV6 wouldnt start with triple therapy. A SABA prn with a LAMA would be my choice and increase as symptoms and V1/V6 dictate.

    Like

    1. I agree. Triple therapy is reserved for severe cases. This study is designed to “reassure “ clinicians the safety of triple therapy. But in my opinion it’s hard to say if the risks have been accurately portrayed.

      Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.