COPD Study Finds Benefits, Risks in Triple Therapy

[gerald]

We have been hearing about the great benefits of the new Triple inhalers and all that they will do for us!  

It almost sounded too good to be true and this study is showing that that is the case.   There appears to be an almost 50% increase in cases of Pneumonia attributed to use of the triple therapy.

What is even more concerning is that they, rather that increase the testing, are trying to explain away the results.


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COPD Study Finds Benefits, Risks in Comparison of Triple, Dual Therapy
By Allison Inserro

A new study comparing triple therapy for chronic obstructive pulmonary disease (COPD) against dual therapy resulted in a lower rate of moderate or severe COPD exacerbations and a lower rate of hospitalizations. However, triple therapy had a much higher incidence of pneumonia, which the researchers said was to be expected.

Triple inhaled therapy for COPD consists of a combined inhaled corticosteroid (ICS), a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA). Triple therapy is recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator or LABA/ICS combination. The GOLD guidelines do not recommend ICS as a monotherapy given the pneumonia risks.

Results of the study—The Informing the Pathway of COPD Treatment (IMPACT) trial—were published in The New England Journal of Medicine Wednesday.1 The 1-year randomized trial involved 10,355 patients with COPD.

It compared a once-daily combination of fluticasone furoate, an ICS, at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate–vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium–vilanterol (at doses of 62.5 μg and 25 μg, respectively).

Each regimen was administered in a single Ellipta inhaler. Ellipta is sold by GlaxoSmithKline, which also sponsored the study. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment.

The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate–vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P <.001) and 1.21 per year in the umeclidinium–vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P <.001).

The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium–vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P <.001).

The incidence of pneumonia in the ICS groups were higher than in the umeclidinium–vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium–vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P <.001).

The rate of pneumonia was more than 50% higher with triple therapy than with the umeclidinium–vilanterol combination (9.6 vs 6.1 per 100 patient-years).

In an accompanying editorial, the authors recommended that the GOLD guidelines stay unchanged for now and that triple therapy be reserved only for patients with severe loss of lung function and frequent exacerbations (called “group D” in the guidelines).2

“Although single-inhaler triple therapy offers simplicity in treating COPD, any potential benefit could be lost and potential undue harm induced if triple therapy is expanded to patients with GOLD groups A, B, and C,” the authors wrote.

The editorial said the trial has several strengths. It addressed the key question posed by GOLD guidelines, about when to move from a dual bronchodilator regimen to triple therapy. The trial used the same agents and doses of LAMA and LABA in the triple-therapy and comparison groups. Moreover, data on exacerbations in many of the patients who discontinued trial treatment during follow-up were included in the data analysis, which helped to lessen bias.

However, they called the results challenging to interpret. The authors wrote that the results may have been affected by who was included in the study. Since many of the trial patients were already treated with ICS and may have also had asthma, they were not the natural population to study in order to answer the question as to whether or not patients should step up from dual therapy to triple therapy. That may have inflated the final results of the study, the editorial's authors wrote. They recommended that until more evidence is available, clinicians should rely on the updated GOLD 2017 guidelines.

www.ajmc.com/newsroom/copd-study-finds-benefits-risks-in-comparison-of-triple-dual-therapies

[skate4life]

The authors wrote that the results may have been affected by who was included in the study. Since many of the trial patients were already treated with ICS and may have also had asthma, they were not the natural population to study in order to answer the question as to whether or not patients should step up from dual therapy to triple therapy. That may have inflated the final results of the study, the editorial's authors wrote. They recommended that until more evidence is available, clinicians should rely on the updated GOLD 2017.

Having used separate LABA, LAMA, ICS, and now am using a LABA/LAMA, ICS + daily oral steroids, I want to add my own thoughts. I have never had pneumonia nor do I have any asthma or overlap symptoms. The only advantage to Stiolto (LABA/LAMA combo) is that the respimat produces a finer mist to get further into lung parts. I am very sensitive to the LAMA (tiotropium) and when I was taking the LABA (Striverdi) separately, I split the LAMA into one inhalation in am, one in pm. This worked well for 1-1/2 years until adding Daliresp put a strain on my budget, even with using ADC for the tiotropium. So doc just gave me samples of Stiolto. After 5 days, I switched back to the separate components and did notice a difference right away but stayed with it for 4 days. I went back to the sample of Stiolto. Through it all, I maintained my ICS and oral prednisone. Ironically, the LAMA portion in Stiolto side effect is not as troublesome now, so am taking Stiolto + ICS, oral pred in am, ICS in evening and that's it.

What I do not like about the triple therapy, is that it becomes difficult to distinguish which drug is causing the person's distress. Is it really the steroid causing the pneumonia or does the patient have silent GERD? Is the pneumonia bacterial and confirmed by the lab or is it viral? Does the patient properly use the inhaler, do they have enough power to truly inhale from the device? This study used only one type of steroid in their Ellipta. Perhaps a different steroid would have a different result. Nor did the study say if the Ellipta is powder based versus a respimat/mist version. The drugs with a powder based have proven to be a big problem for many people, myself included.

Anyway, I just see this whole study flawed in a lot of ways.

[jarca]

did i read that correctly?---to me it sounded like the triple therapy had more cases of pneumonia not less?
I also thought that they are now starting to show that inhaled steroids have adverse affects & aren't that great to use.

[gerald]

That is corret, the combined inhaler shows a 50% increase in cases of Pneumonia.   

As for the inhaled steriods, there have been studies for the last 2-3 years that have indicated that the steriods may not be benefiting the patients.  However, they have not been able to identify or reproduce where/when steriods are not useful. 

We are getting into the realms of 3/4/5 medications, their interactions, their side effects, their cancelling each other out!  That is an area that is just starting to be studied and I suspect where the biggest surprises will come from.

[skate4life]

Here is another review of this study:

"It is a challenge to provide simple comments about the IMPACT study. Why? It is complicated because 70% of all subjects were taking an inhaled corticosteroid before starting the study, and then the Group 2 subjects had the inhaled corticosteroid stopped because they were assigned to receive two bronchodilators (Anoro). With this withdrawal of the inhaled corticosteroid, there was a rapid surge of flare-ups in the first month in this group. Groups 1 and 3 continued to take an inhaled corticosteroid.

Another concern described in an editorial written by Drs. Suissa and Drazen was that the rate of pneumonia was more than 50% higher with triple therapy (Trelegy) compared with the combination of two long-acting bronchodilators (Anoro). These authors recommended that health care professionals continue to follow the GOLD 2017 recommendations that triple therapy be added only if patients have a flare-up while taking one of the four available dual bronchodilators (Anoro, Bevespi, Stiolto, and Utibron)."

www.donaldmahler.com/copd-news/
Pulmonologist