BPCO: evidenze in tema di

broncodilatazione

Claudio Norbiato AO Ordine Mauriziano

Torino

Il sottoscritto Claudio Norbiato ai sensi dell’art. 3.3 sul Conflitto di Interessi, pag. 18,19 dell’Accordo Stato-Regione del 19 aprile 2012, per conto di Planning Congressi srl, dichiara che negli ultimi due anni NON ha avuto rapporti diretti di finanziamento con soggetti portatori di interessi commerciali in campo sanitario

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

- AO Ordine Mauriziano Medicina Interna -

BPCO…

M E D I C I N A I N T E R N A

2019

Approccio al problema

- AO Ordine Mauriziano Medicina Interna -

NEJM 2019

M E D I C I N A I N T E R N A

2019

Approccio al problema

N Engl J Med 2019; 381:1257-66.

- AO Ordine Mauriziano Medicina Interna -

A livello mondiale si stima che la BPCO sia responsabile di 4 morti al minuto e l’Organizzazione Mondiale della Sanità (OMS) prevede che sarà la terza causa di morte entro il 2030, dopo le malattie cardiovascolari e i tumori. In Italia si stima che esistano circa 6 milioni di soggetti affetti da BPCO, che costituisce una delle prime cause di ricovero in ospedale e causa circa 20.000 morti l’anno, con costi sociali e umani enormi

Approccio al problema

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

Nuova era nella terapia broncodilatatrice

- AO Ordine Mauriziano Medicina Interna -

LAMA/LABA

● LAMA/LABA migliorano FEV1 e riducono il numero di riacutizzazioni (Int J COPD 2015) (NEJM 2016)

● Nello studio FLAME (NEJM 2016: indacaterolo/glicopirronio vs

fluticasone/salmeterolo) si è ottenuto miglioramento del SGRQ ● Aumentata incidenza di polmoniti nei pazienti in terapia

con fluticasone/salmeterolo (Eur Resp J 2016)

In summary, comparative data on trials of the new LAMA/LABA FDC inhalers against one of the ICS/LABA combination inhalers (fluticasone plus salmeterol) are now available, and the results significantly favor the LAMA/LABA inhalers in terms of efficacy (improvements in FEV1), patient-reported outcomes (TDI, mMRC), and quality of life measures (SGRQ)

1. Umeclidinium 62.5 μg + vilanterol 25 μg (GlaxoSmithKlein) 2. Indacaterol 85 μg + glycopyrronium 43 μg (Pfizer) 3. Tiotropium 2.5 μg + olodaterol 2.5 μg (Boehringer Ingelheim) 4. Aclidinium 340 μg + formoterol 12 μg (AstraZeneca)

M E D I C I N A I N T E R N A

2019

Nuova era nella terapia broncodilatatrice

- AO Ordine Mauriziano Medicina Interna -

Cochrane Database of Systematic Reviews 2017

M E D I C I N A I N T E R N A

2019

We included 11 studies comprising 9839 participants Most studies included people with moderate to severe COPD, without recent exacerbations

- AO Ordine Mauriziano Medicina Interna -

“Although risk of serious side effects and death were not affected by the choice of treatment, compared to LABA + ICS, LAMA + LABA was associated with a lower risk of flare-ups, fewer episodes of pneumonia, larger improvement in how well the lungs work, and improved quality of life”.

Cochrane Database of Systematic Reviews 2017

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2017

LAMA + LABA

LAMA + LABA

Sintomi persistenti

Ulteriori riacutizzazioni

GRUPPO C: pazienti poco sintomatici (CAT <10; mMRC 0-1)ma con storia di riacutizzazioni

GRUPPO B: pazienti sintomatici (CAT >10; mMRC >2) ma senza storia di riacutizzazioni

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2017

Pazienti sintomatici (CAT > 10; mMRC > 2) e con storia di riacutizzazioni

Gruppo D

LAMA + LABA

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna - - AO Ordine Mauriziano Medicina Interna -

GOLD 2017

The Global Initiative for Obstructive Lung Disease (GOLD) recommendations suggest triple inhaled therapy with a LAMA plus a LABA plus an ICS as a step-up pharmacotherapeutic approach in COPD patients with symptoms and history of frequent exacerbations who continue to experience exacerbations notwithstanding dual LABA/LAMA therapy.

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna - - AO Ordine Mauriziano Medicina Interna -

GOLD – Mondo reale

Int Journal of COPD 2015 10 2207-2217

Eur Clin Resp Journal 2017 4: 1-10

M E D I C I N A I N T E R N A

2019

Results During the study period, 32% of patients received TT. Of these, 19%, 28%, 37%, and 46% of patients classified as GOLD A, B, C, and D, respectively, progressed to TT after diagnosis (P< 0.001). Of all patients prescribed TT, 25% were prescribed TT within 1 year of diagnosis, irrespective of GOLD classification

- AO Ordine Mauriziano Medicina Interna -

GOLD – Mondo reale

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD – Mondo reale

Between 2005 and 2014, there was a statistically significant decrease in the proportions of patients treated with only ICS (from 5% to 2%), with only LABA + ICS (from 16% to 12%) and a statistically significant increase in the proportion of patients using triple inhaled therapy (from 29% to 40%)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD – Mondo reale

We speculate that the widespread use of triple inhaled therapy is due to the chronic characteristic of the disease, with a documented high proportion of persistent breathlessness in spite of maximum optimized treatment

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Most studies evaluating the efficacy of “open triple” therapy, either adding a LAMA to a fixed ICS/LABA or vice versa, not only showed improvement in lung function compared with ICS/LABA or single LAMA therapy, but also improvements in health status, rescue medication use, and the risk of exacerbations, while maintaining a good safety profile

In contrast, in the 1-year WISDOM trial, which was designed to test ICS withdrawal from triple therapy, dual bronchodilation was as effective as triple therapy in terms of exacerbation prevention; in the patients randomized to withdraw ICS, there was a decrease of 38 mL of FEV1 at the end of WISDOM, although this stabilized over the subsequent year

However, all these open triple studies were short in duration, underpowered or retrospective, and required the use of at least two devices, sometimes of different handling characteristics. Nonetheless, triple therapy has become increasingly popular in clinical practice worldwide suggesting a continuing need to improve symptom control and reduce risk of exacerbations and hospitalization, particularly in patients with symptomatic COPD (Int J Chron Obstr Pulm Dis 2015)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

■ BDP/FF/G has been developed as an extrafine formulation (aerosol particles with mass median aerodynamic diameter ,2 μm) in a pressurized metered-dose inhaler; two inhalations twice daily.

■ FLF/VI/UMEC has been developed as a multidose dry-powder inhaler (MDDPI) formulation to be delivered through the ELLIPTA device. Each single inhalation provides a recommended dose of one inhalation per day

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

■ FLF/VI/UMEC In the EU, is indicated as a maintenance treatment in adult patients with moderate-to-severe COPD who are not adequately treated by a combination of an ICS and a LABA or a LABA and a LAMA.

■ BDP/FF/G is indicated in the European Union (EU) for maintenance treatment in adult patients with moderate-to-severe COPD who are not adequately treated by a combination of an ICS and a LABA.

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Am J Respir Crit Care Med Vol 196, Iss 4, pp 438–446, 2017

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

2016 - 2018

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

The extrafine BDP/FF/G Phase III program included three 12-month studies (TRILOGY, TRINITY, and TRIBUTE), with a total of 2,529 patients with severe-to-very severe airflow limitation (FEV1 <50% predicted) randomized to BDP/FF/G. All patients included had: • high symptom burden (COPD Assessment Test [CAT] >10) • exacerbation history (>1 exacerbation in the previous year). • excluded pts who had received triple therapy in the previous year. Overall, the studies demonstrated improvements in FEV1, health status (St George’s Respiratory Questionnaire) and reduction in the rate of moderate/severe exacerbations compared with ICS/LABA, LAMA monotherapy, and LAMA/LABA.

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Interestingly, a pooled post hoc analysis of the three studies showed that BDP/FF/G reduced the number of fatal events by 32% compared to the non-ICS-containing reference arms (IND/GLY or tiotropium), although statistical significance was missed (P=0.096) due to the overall relatively small number of events.

Eur Resp J 2018; 1801230

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

The studies FULFIL and IMPACT provided consistent evidence of improvements in FEV1 and health status, and a reduction in annual exacerbation rate compared to the reference comparators

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

The large sample size of IMPACT (more than 10,000 patients randomized overall) meant that the study could demonstrate that all-cause mortality was lower with the regimens containing the ICS FLF (triple therapy and FLF/VI) than with the LAMA/LABA UMEC/VI. This result is consistent with the trend observed with the pooled post hoc analysis of the BDP/FF/G studies, suggesting that triple ICS-containing regimens do have an impact on mortality in patients with symptomatic COPD and an exacerbation history.

Am J Resp Crit Care Med 2018; 197;A1015

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

One of the criticisms of the TRIBUTE and IMPACT studies was the recruitment of patients with a history of asthma (although not current asthma) and the consequent potential influence on the overall results of the studies. Suissa and Drazen suggest that the inclusion of patients with a history of asthma, and more specifically the potential abrupt withdrawal of ICS in case of randomization to the LAMA/LABA arm, might have triggered exacerbations, hence exaggerating the benefit in favor of triple therapy (NEJM 2018; 378, 1723-24)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

The difference in the rate of exacerbation between LAMA/LABA/ICS and LAMA/LABA over follow-up is due to the first-month’s surge, with practically no differences in the subsequent rates between the two groups.

Eur Respir J 2018; 52:1801848

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Eur Respir J 2018; 52:1801848

The rate of death per month over time for the IMPACT trial: the difference in mortality between LAMA/LABA/ICS and LAMA/LABA is localised in the first 4 months of follow-up.

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Eur Respir J 2019; 53:1900147

In a post-hoc analysis triple therapy noy only prolonged the combined estimate to exacerbations versus LAMA/LABA but the effect size increased for multiple events (for time to first, second and thid exacerbations) The subgroup that gained most benefit fron triple therapy over the duration of the study was the group in which patients were not receiving ICS prior to study entry

Triple therapy had a significant benefit on health-related quality of life and, more importantly, showed a signal toward improved survival

Papi A, Petruzzelli S, Vezzoli S, et al.

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

In the TRIBUTE study the pneumonia incidence was not different in patients treated with either BDP/FF/G or IND/GLY (4% for both). This result contrasts with FLAME, in which 1 year treatment with FLP/SAL was associated with a greater incidence of pneumonia (4.8%) than IND/GLY (3.2%; P=0.02).

In FULFIL trial the risk of pneumonia was higher in patients treated with FLF/UMEC/VI than BUD/FF (2.2% vs 0.8%, respectively). Similarly, in IMPACT study patients treated with FLF/VI/UMEC had a higher incidence of pneumonia (8%) compared to UMEC/VI (5%; P<0.001) and similar incidence to that treated with FLF/ VI (7%; P=0.85)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

This might suggest that the dose, pharmacological characteristics, such as the size or extent of the immunosuppressive effect, or particle size of different ICS molecules, may influence the risk of ICS-associated pneumonia events; indeed, in a cohort database study, patients with obstructive lung disease who received extrafine ICS had a lower risk of pneumonia than those who received fine-particle ICS.

PLoS One 2017; :12(6):e0178112

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Even though the studies were not designed to evaluate the effect of triple therapy on survival, in IMPACT study there was a significant survival difference in favor of the triple combination compared with the dual bronchodilator therapy and a smaller, but still important difference compared with the ICS/LABA combination. (Eur Respir J 2018; 1801230)

It is important to note that proper management of frequently presenting concomitant chronic diseases like chronic heart failure, ischemic heart disease, stroke, diabetes, and hypertension is needed to improve overall patient outcomes. (Eur Respir J 2018; 51(1):1702569)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2019

Grouping applied to an individual may change over time

GOLD 2019 retains the ABCD grouping to decide on appropriate initial pharmacological treatment.

However, GOLD 2019 states that the ABCD grouping should not be used for patients who are already on maintenance treatment

Symptoms and exacerbations are still the focus of treatment and there are separate algorithms for each

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Dopo l’avvio della terapia, i pazienti devono essere rivalutati per quanto riguarda il raggiungimento degli obiettivi terapeutici e l’identificazione di eventuali ostacoli al successo del trattamento e può essere necessario adeguare la terapia farmacologica.

GOLD 2019

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2019

The dyspnoea pathway closely follows the GOLD 2017 recommendations for groups B and D, using additional long acting bronchodilator treatment to manage symptoms.

The follow up exacerbation pathway is very different, as the integration of exacerbation risk and blood eosinophil counts influences the recommendations regarding the use of combination inhalers.

- AO Ordine Mauriziano Medicina Interna -

GOLD 2019

- AO Ordine Mauriziano Medicina Interna -

The exception is GOLD D, with two key changes. 1. Eosinophils ≥ 300 cells/μl is suggested as an indicator to

consider ICS/LABA treatment, as this threshold identifies patients with a higher likelihood of benefit from ICS treatment. A retrospective analysis of real world clinical practice data supports this recommendation; the effects of ICS/LABA as an initial treatment on exacerbation prevention were greater than LAMA treatment in patients with eosinophils ≥ 300 cells / μl, but not below this threshold.

2. Box stating that LAMA/LABA is a preferred treatment in GOLD 2017 has been removed due to the new evidence on exacerbation prevention showing that the magnitude of effect of LAMA/LABA over LAMA was smaller than expected (DYNAGITO), and that ICS/LABA is a better treatment than LAMA/LABA in some patients (IMPACT)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2019

Variability of blood eosinophils Factors that can influence blood eosinophil counts include sepsis and oral corticosteroids, which reduce counts . ● The intra-class correlation coefficient (ICC) of repeat blood

eosinophil counts are reported as 0.64 at 1 year, increasing to 0.70 when excluding patients where oral corticosteroid use

● ICC values can be interpreted as excellent (>0.75), fair to good

(0.40–0.75), or poor (<0.40). These ICC values for repeated blood eosinophil counts in COPD patients, therefore, lie in the fair to good or excellent categories and are similar to reported values for cholesterol (ICC= 0.70–0.72) and glycated haemoglobin (HbA1C; ICC = 0.59)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2019

Blood eosinophils and ICS response ● Three post-hoc analyses of RCTs that compared ICS/LABA versus

LABA all showed a similar pattern of results; there was a continuous relationship between blood eosinophil counts and the effect of ICS on exacerbation prevention, with higher eosinophil counts predicting a greater drug response (no benefit of ICS below 100 eosinophils and higher effect at > 300)

● In TRIBUTE and IMPACT there was a greater effect of triple therapy on exacerbation rate reduction in patients with blood eosinophils >200 (-20%) and > 150 (-32%)

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2019

Blood eosinophils and ICS response

100 300

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

GOLD 2019

Current evidence indicates that the individual assessment of exacerbation risk and blood eosinophil count can be combined to help predict the likelihood of clinical benefit with ICS containing combinations.

This should be coupled with an individualized assessment of the risk of side effects, notably pneumonia, mycobacterial infection, osteoporosis, diabetes and cataracts.

Data do not support the use of blood eosinophils as a biomarker to predict exacerbation risk or other clinical outcomes in the general COPD population.

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

Several reviews and editorials have been already published on triple therapy in COPD , but none of them address the issues related to the possible use of triple therapy in real life, possibly outside of the strict indications reported by the registration agencies, or when triple therapy should not be considered at all even when recommended.

ERJ Open Res 2019; 5: 00185-2018

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

While the strongest part of the evidence for triple therapy is based on results on exacerbations, in individual patients the change of treatment is most frequently based on symptoms.

Patients with a rapid decline in lung function; there is increasing amount of more recent literature that supports a role for ICS combined with bronchodilators suggesting an effect on lung function decline.

All symptomatic COPD patients with a history of asthma and/or current asthma, or concomitant traits characteristic for the presence of asthma, should be considered for triple therapy if not adequately controlled by LABA/ICS

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

Even without any evidence, we believe that there are two other conditions where triple therapy may be considered as first choice and not as a step-up:

● First, in the patient discharged from the hospital after an acute exacerbation of COPD, and in whom COPD is diagnosed for the first time because of the severe exacerbation.

● Second, in patients who present for the first time, and are

diagnosed with severe airway obstruction FEV1 <50%), are symptomatic, had frequent moderate (⩾2) or severe exacerbations (⩾1 hospitalisation) in the previous year, and have peripheral eosinophilia (>300 cells·μL−1),

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

Triple therapy should not be considered to improve survival in COPD patients

Triple therapy should not be recommended as regular treatment for patients without a history of exacerbations in the previous year.

Unless strictly necessary because either bronchodilators are not sufficient, or there is a history of active severe uncontrolled asthma, we would not recommend the use of ICS, including triple therapy, in patients with <100 eosinophils.

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

Patients with COPD at risk of recurrent pneumonias with or without bronchiectasis, patients with bronchiectasis and recurrent respiratory infections, and patients with active tuberculosis should be not be treated with ICS, including triple therapy, and if ICS are strictly required, they should be carefully monitored for the risk of infection.

Patients with HIV treated with antiretroviral therapy often present with COPD; ICS should not be co-administered in HIV patients on an ARV-boosted regimen due to the strong inhibition of their metabolism, which increases the risk of Cushing’s syndrome, particularly fluticasone and budesonide. Only beclomethasone dipropionate may be considered, if strictly needed, but with careful monitoring.

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

The majority of patients will not receive triple therapy at first presentation, but depending their natural history might end up escalating to triple therapy.

Patients who present persistent accelerated decline in

lung function or those having a previous diagnosis of asthma or overlapping characteristics might be candidates for at least a trial with triple therapy

Patients who present for the first time with hospitalisation or high symptoms and high exacerbation risk could be considered for triple therapy, which is then re-evaluated during follow up.

Grazie

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

- AO Ordine Mauriziano Medicina Interna -

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Pharmacotherapy in Patients with a Confirmed Diagnosis

of COPD

NEJM 2019 381;13 september 26

Triple therapy of LAMA+LABA+IGC

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Who should be treated with triple therapy? BDP/FF/G and FLF/VI/UMEC are both approved in the EU as maintenance treatments in adult patients with moderate-to-severe COPD who are not adequately treated by a combination of an ICS and a LABA (with FLF/VI/UMEC also approved for patients inadequately treated with a LABA and a LAMA)

International Journal of COPD 2018 :13 3971–3981

M E D I C I N A I N T E R N A

2019

L. Vanfleteren, LM Fabbri, A. Papi, S.Petruzzelli, B. Celli

- AO Ordine Mauriziano Medicina Interna -

Concluding remarks The most recent studies of ICS combined with LABA and

LAMA in a single inhaler showed that triple therapy represents the most potent pharmacological treatment available for patients with COPD with moderate-to-very severe airflow limitation, particularly those with an exacerbation history.

Compared to LAMA, ICS/LABA, or LAMA/LABA, triple therapy

not only has been shown to improve lung function, health status, rescue medication use, and risk of exacerbations, but also for the first time shows a promising signal on improved survival.

International Journal of COPD 2018 :13 3971–3981

L. Vanfleteren, LM Fabbri, A. Papi, S.Petruzzelli, B. Celli M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Is there a way to usher in the era of “precision medicine” for our patients with COPD: targeting of ICS to the “right” patients at the “right” time. ICS should be provided for COPD patients who also have

asthma (i.e. asthma–COPD overlap) ICS can increase the risk of pneumonia There are significant risk factors associated with ICS-related

pneumonia. These include advanced age, reduced body mass index, severe airflow limitation (GOLD grades 3 and 4), low blood eosinophil count or a prior history of mycobacterial disease Eur Respir J 2018; 52:1801940

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Eur Respir J 2018; 52:1801940

Asthma-COPD overlap or

Blood eosinophils >300/ul

No asthma and

Blood eosinophils <300/ul

M E D I C I N A I N T E R N A

2019

- AO Ordine Mauriziano Medicina Interna -

Advice is provided regarding the discontinuation of ICS, either by the de-escalation from triple therapy to LAMA/LABA or switching from ICS/LABA to LAMA/LABA. The common clinical scenarios when this may be considered are: (1) concerns about side effects, such as likelihood and impact of pneumonia (2) inappropriate original indication (e.g. the patient had no history of exacerbations and ICS had been prescribed to manage symptoms) (3) lack of response to ICS. The withdrawal of ICS should be closely monitored, with evidence indicating that the greatest probability of a deleterious effect is in patients with ≥300 eosinophils / μl.

M E D I C I N A I N T E R N A

2019