cme winning strategies for diagnosing and managing chronic

Fernando J. Martinez, MD, MSWeill Cornell Medical College New York-Presbyterian Hospital/Weill Cornell Medical Center New York, New York

MeiLan K. Han, MD, MSUniversity of Michigan Ann Arbor, Michigan

Chair

Faculty

Participate in interactive questions, download activity slides, and obtain your instant CME credit online.

This CME activity is jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education.

CME

Winning Strategies for Diagnosing and Managing Chronic Obstructive Pulmonary Disease

What’s Inside

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The Under-Recognition of COPD: Reviewing the Evidence to Improve Diagnosis and Monitoring

Individualizing Therapy for the COPD Patient: Current and Future Approaches

Inhaler Technique and Adherence: The Importance of Patient Education and Engagement

Audience Q&A

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Activity Information

Activity Description and Educational ObjectivesOptimal management of chronic obstructive pulmonary disease (COPD) begins with accurate diagnosis and ongoing, appropriate assessment of disease severity. The burden of COPD, and its associated morbidity and mortality, are not always recognized, and underdiagnosis remains prevalent. A personalized, evidence-based approach to the management of patients with COPD, including the selection of treatment based on various factors such as patient symptomatology, comorbidities, exacerbation risk, choice of inhalation device, and phenotypic characteristics, can help healthcare providers in guiding their patients down a path to successful treatment. Proper technique and adherence, as well as involving the patient in the creation of a COPD action plan and goal setting, so they may better manage COPD in their everyday life, are also key elements in a patient’s journey with COPD. In this activity, our expert panel explores the use of evidence-based guidelines in diagnosing patients and the therapeutic role of eosinophils. In addition, the panel discusses the creation of treatment plans, proper inhaler technique, and the importance of adherence for patients with COPD.

Upon completion of this activity, participants should be better able to:• Employ evidence-based guidelines to accurately diagnose and monitor

patients with chronic obstructive pulmonary disease (COPD)• Discuss the potential role of eosinophils in selecting maintenance therapy

for patients with COPD• Create maintenance treatment plans for patients with COPD, based on

factors including efficacy, safety, patient symptomatology, comorbidities, and exacerbation risk

• Apply strategies to ensure proper inhaler use and encourage goal setting and medication adherence for patients with COPD

Target Audience This activity has been designed to meet the educational needs of pulmonologists, primary care physicians, and other clinicians involved in the management of COPD.

Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. There are no pre-requisites and there is no fee to participate in this activity or to receive CME credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form.

Media: Enduring MaterialRelease and Expiration Dates: November 29, 2019 - November 28, 2020Time to Complete: 60 minutes

Faculty and Disclosure / Conflict of Interest Policy In accordance with ACCME requirements, Penn State College of Medicine has a conflict of interest policy that requires faculty to disclose relevant financial relationships related to the content of their presentations/materials. Any potential conflicts are resolved so that presentations are evidence-based and scientifically balanced.

ChairFernando J. Martinez, MD, MS Chief, Division of Pulmonary and Critical Care Medicine Bruce Webster Professor of Medicine Joan and Sanford I. Weill Department of Medicine Weill Cornell Medical College New York-Presbyterian Hospital/Weill Cornell Medical Center New York, New York

Fernando J. Martinez, MD, MS, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Chiesi USA, Inc.; Gala; Genentech; GlaxoSmithKline; ProterixBio, Inc.; Sunovion Pharmaceuticals Inc.; and Teva Pharmaceuticals USA. Grant/Research Support from AstraZeneca; Bayer Corporation; Biogen; GlaxoSmithKline; Nitto Denko Corporation; Merck & Co., Inc.; Promedior, Inc.; Prometic Life Sciences Inc.; Respivant; and Veracyte, Inc. Data Safety Monitoring Board for Boehringer Ingelheim Pharmaceuticals, Inc.; Genentech; and GlaxoSmithKline.

FacultyMeiLan K. Han, MD, MS Professor of Internal Medicine University of Michigan Ann Arbor, Michigan

MeiLan K. Han, MD, MS, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; GlaxoSmithKline; and Mylan Inc. Grant/Research Support from Novartis Pharmaceuticals Corporation.

Medical DirectorMary Grecco PVI, PeerView Institute for Medical Education

Mary Grecco has no financial interests/relationships or affiliations in relation to this activity.

Other PVI staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

Providership, Credit, and SupportThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Penn State College of Medicine and PVI, PeerView Institute for Medical Education. Penn State College of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Penn State College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Information about CME credit for this activity is available by contacting Penn State at 717-531-6483 or [email protected]. Reference course # G6519 – 20-T.

ProvidershipThis CME activity is jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education.

SupportThis educational activity is supported by an educational grant from GlaxoSmithKline.

Disclosure of Unlabeled UseThe faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use.

No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our reports. No responsibility is taken for errors or omissions in reports. For approved prescribing information, please consult the manufacturer’s product labeling.

The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or supporters.

About This CME ActivityPVI, PeerView Institute for Medical Education, and Penn State College of Medicine are responsible for the selection of this activity’s topics, the preparation of editorial content, and the distribution of this activity. Our activities may contain references to unapproved products or uses of these products in certain jurisdictions. The preparation of PeerView activities is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and Penn State College of Medicine.

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MeiLan K. Han, MD, MS



Pathways to the Diagnosis of COPD1

1. https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-POCKET-GUIDE-FINAL_WMS.pdf. Accessed October 15, 2019.

Symptoms • Dyspnea • Chronic cough • Sputum

Risk Factors • Host factors • Tobacco • Occupation • Indoor/outdoor

pollution

Spirometry Required to

establish diagnosis

Dr. Han: My first section here, we’re going to talk about screening for COPD. Dr. Martinez is going to talk a little bit about management, and then we’re going to wrap up with some practical advice about adherence and inhaler strategies to optimize care for patients.

So I’m guessing most of the people in the room this morning are either pulmonologists or work closely with pulmonologists. So I know I’m preaching to the choir a bit, but we do have a major problem with COPD underdiagnosis in this country. And I think it’s really several-fold with respect to both patient lack of recognition and primary care physicians,’ in some cases, lack of time.

The things that we need to be thinking about are symptoms, risk factors, and then ultimately getting spirometry. I think, as many of you know, roughly only about a third of the patients in the country that have a diagnosis of COPD have actually had confirmatory spirometry.

I actually run a transitions of care clinic to see patients after they’ve gotten out of the hospital. We all know this is very important because of CMS looking at the readmissions issue quite closely. And what’s shocking to me is that roughly 15% of patients who were discharged for a COPD exacerbation didn’t even actually have COPD when we got them into clinic and tested them. So a lot of times I know our colleagues have to make, or if you’re in the

The Under-Recognition of COPD: Reviewing the Evidence to Improve Diagnosis and Monitoring

hospital, have to make decisions on the fly. But I think for me, it really does underscore the problem that we have with even just getting the diagnosis right and obviously staging.

Development of disease-modifying

therapies Prevention

Detecting COPD

Early detection

So when I think about COPD and what we can do to ultimately, let’s say, eradicate the disease, we’ve got to prevent, we’ve got to detect early, and then we need disease-modifying therapies for patients that have established disease. So I’m going to focus a bit on early detection this morning, but I think that where the research is headed is kind of younger and younger, trying to help us understand what’s going on in 20- to 30-year-old patients. There’s a couple of cohort studies that are starting now, and even into childhood, what are the things like respiratory infections in childhood that could ultimately contribute to COPD developing as an adult?

There are undiagnosed patients that

should be treated

There are many more that may need to be treated

Detection Issues That Must Be Addressed

So as I mentioned, there are a lot of undiagnosed patients that need to be treated, so I’m going to be spending a few minutes talking about that. What I’m not going to have time to talk about today, but would be an entirely separate talk, are the people that don’t fit our current definitions for COPD, but potentially should be treated.

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So we’ve got increasing data on the fact that patients who do not meet our current criteria with respect to airflow obstruction still having symptoms, exacerbations, increased mortality. Fernando and I just got back from the European Respiratory Society meeting, where GOLD met, and this took up half a day’s worth of conversation, is what to do about all this information coming in, and do we need to actually redefine the disease? I don’t expect there to be any major changes the next year, but it’s definitely something that we’re thinking about.

COPD Is Often Missed in Primary Care1

Therapeutic nihilism

Time limitations

Failure to probe at-risk patients about symptoms and activity

levels, as well as lack of good case-finding methods

Limited spirometry availability and expertise to interpret

Under-recognition of symptoms leading to delayed presentation

Poor awareness of COPD

Lack of knowledge regarding COPD risk factors and appropriate

diagnostic testing

Care providers Patients

Barriers to Diagnosis of COPD in Primary Care

1. Han MK et al. Lancet Respir Med. 2016;4:473-526.

So I mentioned I’ve been thinking a lot about why we have so many people that are undiagnosed. I’m actually running an early COPD study right now, and so we’re running all sorts of social media advertisements, and we’re bringing people in who smoke and doing spirometry and trying to get them enrolled in this study. And to me, it’s been absolutely fascinating, the disconnect between the spirometry and what patients have been told in primary care clinic. I had one gentleman just last week, he was told, “Oh, you’re early COPD.” First spirometry ever, and his FEV1 is 35% predicted, and they still hadn’t done the spirometry in the office. This is the kind of thing that we’re seeing.

So what are the issues? How can we fix this? Well, we know providers are limited on time. Some of them may not either understand spirometry, think it’s not covered, aren’t comfortable with ordering it, and then a lot of times, you know, they’re busy and may not ask about activity limitations and things like that, particularly if patients don’t bring it to the forefront or have other things to discuss during the day. From a patient perspective, I think we need to as a community do a lot better job of educating our patients about the symptoms, things that are not normal, not just parts of normal aging, and help empower patients themselves to recognize the symptoms and actually ask their physicians about getting spirometry.

US Preventive Services Task Force

1. US Preventive Services Task Force (USPSTF). JAMA. 2016;315:1372-1377.

Now, this came out in JAMA in 2016, and technically and factually, I won’t argue with it. But unfortunately, the US Preventive Services Task Force’s continued recommendation against population-based screening in asymptomatic individuals does not really help the cause here, and I think a lot of people who maybe don’t read the document take away the message, “Oh, we shouldn’t even bother.”

So What Does the USPSTF Recommendation Mean?1

• It is worth noting the key word “asymptomatic”; many individuals at increased risk for COPD self-restrict activity to minimize symptoms

• Recommendation is based on lack of evidence, not negative evidence; report cites a lack of evidence that early detection has the ability to alter course of disease or improve patient outcomes

• Report also notes that future trials are needed to better assess the effects of screening and treatment of at-risk individuals in primary care on long-term health outcomes

• GOLD recommends case-finding in symptomatic patients but does not recommend screening in asymptomatic populations

1. US Preventive Services Task Force (USPSTF). JAMA. 2016;315:1372-1377.

And so I think it’s important to delve down into that document a little bit more and think about what they’re really saying and what evidence that’s based on. So it’s really worth noting that they mention asymptomatic individuals are not—there’s no evidence for screening asymptomatic individuals. But I think, as we know, patients, if you ask them, you know, “Are you short of breath?” and they’ll say, “Well, no.” But they maybe walked the golf course last year, and this year they’re taking a cart, so they’re self-limiting their activities to avoid dyspnea. So that may not always be the best question.

Another important thing to remember is that the recommendation is actually based on lack of evidence not negative evidence. Fernando and I are actually involved in a study to try to validate a screening tool in a large primary care–based group. So you know, these studies are hard to do, but hopefully the evidence basis is coming.

We really do need these kinds of studies to hopefully overturn the US Preventive Services Task Force recommendation. So what many of us are focusing on is not screening necessarily, but what we call case finding. So enriching the patient population for people

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likely to have COPD. And this is really the approach that GOLD recommends.

The Burden of Undiagnosed COPD1

1. Mannino DM et al. MMWR Surveill Summ. 2002;51:1-16.

050

100150200250300350400450 Diagnosed with chronic bronchitis or emphysema

Airflow limitation (GOLD 1 or higher)

Rat

e pe

r 1,0

00 o

f Pop

ulat

ion

25-44 45-54 55-64 65-74 ≥75 Age, y

7.2%

14%

20.7%

22.9%

So how big is the problem? We know the estimates vary on how many patients have COPD, but this data now— I guess it’s actually, it’s funny. I’ve been showing the slides for a long time now, and just making me realize how old I am. But anyway, these are data that Dave Mannino published when he was with the CDC. And it shows that the patients who actually had a diagnosis of COPD, in blue, there was a significant disconnect between those and those who actually had airflow limitation when you tested them, which is the orange bars. So significant increase particularly in spirometrically defined COPD as patients get older, with nearly a quarter, at least in this study, of patients over 75 actually having their full obstruction.

Undiagnosed COPD in CanCOLD Is Associated With Exacerbation-Like Events1

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50

0

10

20

30

40

50All COPD GOLD I GOLD II+

22

40

19

34 28

43

19 23

12

32

14

Exac

erba

tion-

Like

R

espi

rato

ry E

vent

s, %

Undiagnosed Diagnosed

1. Labonté LE at al. Am J Respir Crit Care Med. 2016;194:285-298.

37

Even

t bas

ed

Sym

ptom

bas

ed

So one could argue, “Well, does it really matter? Do patients who are not diagnosed?” You may be thinking, “Well, it’s probably because they’re not actually having any problems. That’s why they haven’t actually come to anyone’s attention.” And that actually simply isn’t the case.

So this is actually data from CanCOLD, which was a large population-based study in Canada designed to look at airflow obstruction. And what they demonstrated was that there actually were a significant number of respiratory events, exacerbation-like events even among patients who did not carry a diagnosis of COPD. And that was a little bit less in the diagnosed, but clearly,

still not zero. And so I think this helps us to understand that these patients who are flying under the radar are sick.

Estimated Mortality Associated With Undiagnosed COPD1

1.0

0.8

0.6

0.4

0.2

0.0 0 5 10 15 20

Surv

ival

Pro

babi

lity

Time, y

Non-OLD Undiagnosed OLD Diagnosed OLD

1. Martinez CH et al. Ann Am Thorac Soc. 2015;12:1788-1795.

Now, this is actually some data that my former mentee Carlos Martinez—

Dr. Martinez: No relation.

Dr. Han: Not to be confused with this Martinez—actually worked on, along with David Mannino. And what they demonstrated was that even undiagnosed obstructive lung disease is still associated with a pretty significant decrease in survival over time, and actually is pretty close to patients with diagnosed airflow obstruction. So I think, again, this just really underscores the problem that we’ve got really on a population level, and some of the things that we’re going to be struggling with when we see these patients come in that really haven’t been adequately evaluated on the outpatient side. I think it’s well known that sometimes patients present for the first time with a hospitalized exacerbation for COPD.

CAPTURE Instrument1 Please answer each question No Yes

1. Have you ever lived or worked in a place with dirty or polluted air, smoke, second-hand smoke, or dust?

2. Does your breathing change with seasons, weather, or air quality? 3. Does your breathing make it difficult to do things such as carry heavy loads, shovel dirt or snow,

jog, play tennis, or swim?

4. Compared with others your age, do you tire easily? 0 1 ≥2

5. In the past 12 months, how many times did you miss work, school, or other activities because of a cold, bronchitis, or pneumonia?

For Clinical Use

PEF, L/min (Recommended for scores ≥2; best of three tests) No Yes Men: ≤350 L/min Women: ≤250 L/min

1. Martinez FJ et al. Am J Respir Crit Care Med. 2017;195:748-756.

So, as I mentioned, Dr. Martinez and I are working on what we can do to improve case finding for COPD. Now, you may be aware there are a lot of screening tools that have been looked at. COPD screener is, I think, a popular one.

All of the existing screeners, except for CAPTURE, are really based on sort of expert opinion, maybe going through the literature and trying to figure out which questions from an epidemiologic

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standpoint were most predictive. And those are all good approaches. But what we did for CAPTURE was a bit different. We did those things. We held focus groups and things like that. But we kind of used multiple methods to gather a large item set of what we felt would be the best questions, and then used sort of machine learning approaches to arrive at the absolute best set of questions.

So we ended up with a subset of five questions: things like, “Have you been exposed to dirty air? Does your breathing change with the seasons? Do you have activity limitation? Do you tire easily?” And essentially trying to get at “Have you had a respiratory event or exacerbation?” We then combine those with results from peak flow to develop kind of a risk score with the suggested recommendation for whether the patient should go on for screening with spirometry.

And I’m just curious. I’ve just shown you those five questions. Does anybody notice what’s missing from this list that perhaps is on most lists? Right. We don’t have a single question on here about “Do you smoke?” So, intriguingly, we actually did look at that question. But, one thing, it actually didn’t perform any better in the test set. And I actually think this makes this questionnaire incredibly unique, because we all know that nonsmokers make up almost a quarter of the patients with COPD, right? So I think this is our first attempt to really try to capture these patients through a more formal screening questionnaire.

A New Approach to CAPTURE COPD

COPD

ASSESSMENT IN

PRIMARY CARE

TO IDENTIFY

UNDIAGNOSED

RESPIRATORY DISEASE AND

EXACERBATION RISK

1. Martinez FJ et al. Am J Respir Crit Care Med. 2017;195:748-756.

So this is what it stands for: COPD assessment in primary care to identify undiagnosed respiratory disease and exacerbation risk. One of the interesting things is that when we developed these test items, we weren’t just trying to find COPD. We’re trying to find clinically significant COPD. So patients with either high symptoms or likely to exacerbate that really would warrant therapy.

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Fernando J. Martinez, MD, MS


Featured Presentation



Refined ABCD Assessment Tool1


Spirometrically confirmed diagnosis

Assessment of airflow limitation

Assessment of symptoms/risk of

exacerbation

Post-bronchodilator FEV1/FVC <0.7

Grade FEV, % predicted

GOLD 1 ≥80

GOLD 2 50-79

GOLD 3 30-49

GOLD 4 <30

Moderate or Severe Exacerbation History

≥2 or ≥1 leading to hospital admission

0 or 1 (not leading to hospital admission)

C

B A

D

mMRC 0-1 CAT <10

mMRC ≥2 CAT ≥10

Symptoms

Dr. Martinez: All right, so what MeiLan was talking about is really a very hot area right now, this idea of identifying individuals that are undiagnosed. This CAPTURE program that we’re involved in is a study at 100 primary care centers across the United States. The goal is to be able to have those individuals in primary care identify these patients and work with you in managing them. So, you know, keep track of what occurs with that, because that’s aimed at improving identifying these individuals.

I’m going to talk about COPD assessment and management, really following what the GOLD science committee that MeiLan and I are both involved in are now advocating. So, to remind you, the current assessment is based on spirometric diagnosis. Spirometry is not out, it’s just used for diagnosis. And then therapeutic assessments are based on the construct on the right.

And so that is the concept that you are evaluating a patient’s symptoms and a patient’s risk of exacerbation principally by prior history of exacerbations. So high symptoms: B or D. Low symptoms: A, C. High risk for exacerbations: C, D. Low risk: A, B. So that’s how that whole schema came about, the idea that you’re going to ask and you’re going to continually assess these two constructs.

Individualizing Therapy for the COPD Patient: Current and Future Approaches

Goals of Management of COPD1

Airflow limitation

Symptom burden

Exacerbations

Functional limitations

Improve lung function Slow FEV1 decline

Improve symptoms

Prevent and manage exacerbations

Improve health Status and exercise tolerance

Reduce hospital admissions and mortality


So the goals of management, I think, remain the same. These are things that we’ve all accepted. We’re going to improve symptoms, minimize exacerbation, improve health status. That’s a given.

Initial Treatment Recommendations: GOLD1

Group D

LAMA or LAMA + LABAa or

ICS + LABAb

Group B

Long-acting bronchodilator (LABA or LAMA)

Group A

Bronchodilator

Group C

LAMA

mMRC 0-1, CAT <10 mMRC ≥2, CAT ≥10

≥2 moderate exacerbations or

≥1 leading to hospitalization

0 or 1 moderate exacerbations (not leading to hospital

admission)

a Consider if highly symptomatic. b Consider if eosinophil ≥300. 1. https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-POCKET-GUIDE-FINAL_WMS.pdf. Accessed October 15, 2019.

The question is how we achieve that. So in that GOLD strategy recommendation, that A, B, C, D is based, at least with this slide, on initial treatment—that’s why it says initial on top there—with a series of therapeutic options based on where the patients are. It’s not one therapeutic option in most of these, because there are potential options that you can choose from for individual patients. And I think MeiLan and I have spent a lot of time trying to figure out how to characterize individual patients to give you further guidance on how you could make decisions between those recommended options. And we’re going to give you some of that information.

LAMA/LABA Decreases AECOPD Compared With LABA and LAMA Monotherapy1

1. Oba Y et al. Cochrane Database Syst Rev. 2018;12:CD012620.

LAMA vs LABA

LABA/ICS vs LABA

LABA/LAMA vs LABA

LABA/ICS vs LAMA

LABA/LAMA v LAMA

LABA/LAMA vs LABA/ICS

Hazard Ratio

Com

paris

on

0.6 0.8 1.2 1.4 1.6 1.0


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For example, in a very recent systematic review, one of these Cochrane reviews, comparing dual bronchodilation with other comparisons, one of the things that becomes evident is that dual bronchodilation is better than single bronchodilation. Dual is better than single. So, in general, whether it’s lung function—this is exacerbation reduction potential—dual is better than single. This point down here, dual bronchodilation versus a LABA/ICS, is a very controversial topic that I will address in a follow-up question. So in general, dual tends to be better than single, okay?

LAMA/LABA vs ICS/LABA Effect Is Dependent on Patient Characteristics1

a Post hoc analysis. 1. Lipson DA et al. European Respiratory Society International Congress 2018 (ERS 2018). Poster PA4384.

Favors UMEC/VI

Favors FF/VI

0.6 0.8 1.0 1.2 1.4

Rate ratio (95% CI)

Population UMEC/VI,

N FF/VI,

N Rate ratio (95% CI)

Baseline treatment at screening

LAMA only

LAMA/LABA only

ICS/LABA only

Triple therapy

59/162 (36)

94/196 (48)

290/647 (45)

515/864 (60)

149/365 (41)

167/349 (48)

590/1340 (44)

951/1647 (58)

0.81 (0.60, 1.11)a

0.95 (0.74, 1.23)a

1.11 (0.96, 1.28)a

1.20 (1.08, 1.33)a

So then one of the areas that I think is particularly interesting is this area of when you would consider dual bronchodilation versus an ICS/LABA. And this, to me, is where you start seeing where some of the GOLD schema is actually helpful. So this is actually a subanalysis of a study that MeiLan and I were involved in, which was the IMPACT study. Severe COPD, actually a very high risk of exacerbations. Comparing triple versus each of the duals, dual bronchodilation and ICS/LABA. This is the comparison of dual bronchodilators versus ICS/LABA. So there, on top, you’ll see dual bronchodilator and ICS/LABA.

And what’s interesting is, if you have people that have less frequent exacerbations—so the A/B category in GOLD—the LABA/LAMA actually does okay in that setting. If you have people that have two or more moderate or a hospitalization, the C/D, there is where you see the steroid regimen winning. So this data set, to me, is particularly relevant, because it gives you a granular sense of an individual patient, where you’re likely going to be seeing your decision-making go.

There’s another piece of information that came out of this study, and that was in patients that came into the study that were only on the LAMA—so if you, as the clinician, only had that patient on a LAMA—the LABA/LAMA actually almost won in that comparison. So, again, less severe patients, the LABA/LAMA is not a bad option. More severe patients with exacerbation risk, that’s where inhaled steroids generally have an effect in that population.

ICS/LAMA/LABA Decreases AECOPD Compared With LABA/LAMA or LABA/ICS Therapy1

1. Li CC et al. Int J COPD. 2019;14:1539-1548.

Study or Subgroup Log (Rate ratio) SE Total Total Weight, %

Rate ratio IV, Random, 95% CI

Rate ratio IV, Random, 95% CI

Single inhaler triple therapy vs LABA/LAMA Ferguson, 2018 -0.734 0.1328 639 625 26.6 0.48 (0.37-0.62)

Lipson, 2018 -0.2877 0.0352 4,145 2,069 39.3 0.75 (0.70-0.80)

Papi, 2018 -0.1649 0.0814 764 768 34.0 0.85 (0.72-0.99)

Subtotal (95% CI) 5,548 3,462 100.0 0.69 (0.55-0.87)

Heterogeneity: Tau2 = 0.03, Chi2 = 13.52, df = 2 (P = .001), I2 = 85% Test for overall effect: Z = 3.13 (P = .002) Single inhaler triple therapy vs ICS/LABA Ferguson, 2018 -0.1985 0.7167 639 314 9.7 0.82 (0.58-1.16)

Lipson, 2017 -0.5798 0.2114 210 220 7.1 0.56 (0.37-0.85)

Lipson, 2017 -0.1625 0.0309 4,145 4,133 55.7 0.85 (0.80-0.90)

Singh, 2016 -0.2614 0.0864 687 680 27.5 0.77 (0.65-0.91)

Subtotal (95% CI) 5,681 5,347 100 0.80 (0.71-0.90)

Heterogeneity: Tau2 = 0.01, Chi2 = 4.79, df = 3 (P = .19), I2 = 37% Test for overall effect: Z = 3.74 (P = .002) Single inhaler triple therapy vs separate triple Bremner, 2018 -0.0943 0.1055 527 528 41.0 0.91 (0.74-1.12)

Vestbo, 2017 0.01 0.088 1,077 538 59.0 1.01 (0.85-1.20)

Subtotal (95% CI) 1,604 1,066 100.0 0.97 (0.85-1.10)

Heterogeneity: Tau2 = 0.00, Chi2 = 0.58, df = 1 (P = .45), I2 = 0% Test for overall effect: Z = 0.49 (P = .63) Test for subgroup differences: Chi2 = 7.71, df = 2 (P = .02), I2 = 74%

0.1 0.2 0.5 1 2 5 10Favors (triple therapy) Favors (control)

One of the big problems for us—not problems, challenges—for all of us is triples, because you now have one available triple, and you have several more that are in the pipeline. So that is a device that has a steroid, a LABA, and a LAMA all in the same device. And there have been a whole series of studies, and in general, when you compare triple versus the dual bronchodilator, you compare triple versus the ICS/LABA, the triple generally wins in that setting. So part of the question for us is at what point do you consider triple to be the principal therapy that we’re going to use? And so that’s where some of the data are evolving that give us some pieces of information.

ICS Is Associated With Improved All-Cause Mortality in IMPACT1

No. patients at risk

FF/UMEC/VI 4,151 4,150 4,142 4,137 4,131 4,119 4,113 4,107 4,097 4,092 4,082 4,073 4,062 3,919

FF/VI 4,134 4,129 4,123 4,118 4,111 4,106 4,095 4,082 4,065 4,060 4,050 4,040 4,027 3,848

UMEC/VI 2,070 2,063 2,052 2,045 2,037 2,030 2,027 2,021 2,013 2,008 2,004 1,999 1,995 1,914

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

0 28 56 84 112 140 168 196 224 252 280 308 336 364

Prob

abili

ty o

f Eve

nt, %

Time to Event, d

FF/UMEC/VI FF/VI UMEC/VI

1. Lipson DA et al. N Engl J Med. 2018;378:1671-1680.

The other piece of information that came out of the IMPACT study, which is particularly impactful—no pun intended—was that in this study, this is now the probability of dying in the trial by both steroid-containing regimens and the dual bronchodilator. I mean, you know, that is not a subtle difference in terms of all-cause mortality while you were on treatment.

Remember, this is a very sick population of individuals with COPD. So in my mind, I’ve taken this information, so the sicker the patient, the more likely I’m going to consider a steroid-based regimen. And in that case, I think that’s a useful piece of information.

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ICS Is Associated With Improved All-Cause Mortality in IMPACT1 (Cont’d)

1. Lipson DA et al. American Thoracic Society 2019 International Conference (ATS 2019). Poster A7344.

Patients with an event, n (%)

Favors FF/UMEC/VI

Favors UMEC/VI

FF/UMEC/VI (N = 4,151)

UMEC/VI (N = 2,070) HR (95% CI) P

All-cause mortality on treatment 50 (1.20) 39 (1.88) 0.58 (0.38-0.88) .011

All-cause mortality including off-treatment data 89 (2.14) 60 (2.90) 0.71 (0.51-0.99) .043

All-cause mortality including off-treatment data (with additional vital status follow-up)

98 (2.36) 66 (3.19) 0.72 (0.53-0.99) .042

0.2 0.4 0.6 0.8 1.0 1.2 HR (95% CI)

There’s a separate continual analysis of the data set with much more complete follow-up. I think it’s missing 0.4% of the entire population of 10,000 subjects, and this is an abstract that was presented at the ATS a few months ago. And in that setting, whether it’s all-cause treatment, whether it’s off-treatment data, on-/off-treatment data with all the components, all the data included, you know what? You still see a 20% to 30% reduction in mortality in this population. So this, in my mind, has been an additional piece of information that allows me to consider how I’m going to use the therapeutic options that I have available.

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has reviewed the risk of pneumonia with inhaled

corticosteroid-containing medicines when used to treat COPD.

The PRAC review confirms that COPD patients treated with

inhaled corticosteroids are at increased risk of pneumonia;

however, the Committee’s view is that the benefits of inhaled

corticosteroids continue to outweigh their risks.

Pharmacovigilance Risk Assessment Committee1

1. https://www.ema.europa.eu/en/documents/referral/inhaled-corticosteroids-article-31-referral-ema-completes-review-inhaled-corticosteroids-chronic_en.pdf. Accessed October 15, 2019.

There is risk to steroid-containing regimens. There’s benefit. I just showed you the benefits. There’s risk, and that risk includes pneumonia risk. And that’s the European Medicines Agency reviewed this a couple of years ago—this was 2016—and they concluded, yeah, you know, COPD patients on steroids have a risk of pneumonia, although they still outweigh the risk, but given the shift toward personalized therapy, the question has come, how do you tell an individual patient sitting in front of you in a clinic setting?

Risk Factors Associated With CXR-Confirmed Pneumonia in Patients With COPD Treated With ICS1,a

HR (95% CI) Age ≤64 years 1.2 (0.5-2.7)

≥65 years 3.3 (1.2-8.7) Sex Female 1.1 (0.3-4.0)

Male 2.3 (1.1-4.7) Smoking status Former smoker 1.7 (0.8-3.8)

Current smoker 2.2 (0.8-6.2) Previous pneumonia No 1.5 (0.7-3.3)

Yes 2.7 (0.9-8.1) BMI <25 kg/m2 3.4 (1.4-8.4)

≥25 kg/m2 0.9 (0.4-2.4) BMI <21 kg/m2 2.7 (0.9-7.5)

≥21 kg/m2 1.8 (0.8-3.8) GOLD stage I & II: FEV1 ≥50% predicted 1.9 (0.7-5.4)

III: FEV1 ≥30%-<50% predicted 2.9 (1.1-8.0) IV: FEV1 <30% predicted 0.8 (0.2-3.0)

Risk With FF/VI 100/25 mcg (n = 806)

Risk With VI 25 mcg (n = 818)

0.25 0.5 1 2 4 8

a Risk factors associated with pneumonia was a secondary endpoint. The primary endpoint was the annual rate of moderate (requiring treatment with SCS and/or antibiotics) and severe (necessitating hospitalization) exacerbations. 1. Crimm C et al. Ann Am Thorac Soc. 2015;12:27-34.

And for that, there are data such as these, that we generated from the fluticasone/vilanterol program, the ICS/LABA program. And for individual patients, pneumonia risk was principally seen in patients who were older, generally male, people that had a previous pneumonia that were skinny and had more severe airflow obstruction.

And so when I start now seeing patients in clinic and I’m trying to decide what I’m going to consider, if it’s an old guy who’s really skinny, who’s had a prior pneumonia, that individual has a higher risk, and you’re going to consider in that component the risk as well as the potential benefit.

IMPACT1,2

1. Lipson DA et al. Am J Respir Crit Care Med. 2018;197:A1014. 2. Lipson DA et al. N Engl J Med. 2018;378:1671-1680.

Time, wk

Cum

ulat

ive

Num

ber o

f O

n-Tr

eatm

ent E

vent

s1


0

2,500

4,000

500 1,000 1,500 2,000

3,500 3,000

52 0 24 4 8 12 16 20 28 32 36 40 44 48

Moderate/severe exacerbations

Pneumonia AESI

Moderate/Severe Exacerbations

P Pneumonia AESI

Model Estimated Annual Rate

Reduction FF/UMEC/IV vs FF/VI or UMEC/VI, %

Rate Ratio With FF/UMEC/VI (95% CI)

Model Estimated Annual Rate

FF/UMEC/VI 0.91 – – – 0.09

FF/VI 1.07 15 0.85 (0.80-0.90) <.001 0.09

UMEC/VI 1.21 25 0.75 (0.70-0.81) <.001 0.06

Clinically meaningful reduction in

moderate/severe COPD exacerbations with FF/UMEC/VI vs FF/VI and UMEC/VI,

relative to the difference in risk

of pneumonia

Now, the interesting component in IMPACT was that if you looked at the overall burden—so this is exacerbations, this is the LABA/LAMA, and this is the ICS-containing regimens—there is clearly a decrement in exacerbation rate with steroids, and the reverse is seen here. There’s a slight increase in pneumonia. But this gives you a sense of the magnitude of the difference versus exacerbation reduction versus pneumonia risk. So what we’re trying to provide you are data that allow you to make individual decisions, so then you can decide in an individual patient where’s the greatest benefit. Where’s the greatest risk? And you balance that for an individual patient. That’s where I think some of the IMPACT data are most helpful, because it really gives a lot of clarity.

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High-Dose and Long-Term ICS Use Associated With Fracture Risk1

1. Gonzalez AV et al. Chest. 2018;153:321-328.

Rat

e R

atio

of F

ract

ure

Mean Daily Dose of ICS, μg

0.90

1.00

1.10

1.20

1.30

0 500 1,000 1,500 2,000 2,500

Rat

e R

atio

of F

ract

ure

Time Since First ICS Prescription, Year

0.90

1.00

1.10

1.20

0 2 4 6 8 10

Mean Daily Dose of ICS, mcg

You also have to realize that another steroid-related effect, which is bone abnormalities, generally tends to relate to the dose and the duration, so that as you re-evaluate patients over time, this component of how long to keep a patient on an inhaled steroid is another component that we want you to understand.

Follow-Up Pharmacological Treatment1

a Consider if eos ≥300 or eos ≥2 moderate exacerbations/1 hospitalization. b Consider de-escalation of ICS or switch if pneumonia, inappropriate original indication, or lack of response to ICS. 1. https://goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-POCKET-GUIDE-FINAL_WMS.pdf. Accessed October 15, 2019.

Dyspnea

• Consider switching inhaler device or molecules

• Investigate (and treat) other causes of dyspnea

Exacerbations

b

b

In former smokers

Consider if eos <100

Consider if eos ≥100

b b

a

LABA or LAMA

LABA + LAMA LABA + ICS

LABA + LAMA + ICS

Roflumilast FEV, <50% and

chronic bronchitis Azithromycin

LABA + ICS

LABA or LAMA

LABA + LAMA

LABA + LAMA + ICS

1. If response to initial treatment is appropriate, maintain it 2. If not: consider predominant treatable trait to target (dyspnea or exacerbations); use exacerbation pathway if both exacerbations and

dyspnea need to be targeted; place patient in box corresponding to current treatment and follow indications; or assess response, adjust, and review (these recommendations do not depend on ABCD assessment at diagnosis).

And so that’s why there’s a whole component in GOLD that is the sequential evaluation so that you can make decisions regarding follow-up treatment recommendations. So that’s where these schema came. For dyspnea, that’s the x-axis of that quadrant, and for exacerbations reduction, which is the y-axis of that quadrant, all right?

© 2017 Global Initiative for Chronic Obstructive Lung Disease


Exacerbations

In former smokers



b b

a

LABA or LAMA


LABA + LAMA + ICS



Follow-Up Pharmacological Treatment: Exacerbations1

So keep that in mind, because we’re going to focus right now on exacerbation management. And so, again, you saw initial therapy in the quadrant earlier. This is now a question of what you do over

time in individual patients as you reevaluate them. And there are these little, tiny asterisks that are present in the figure, and that relates to the evolving data regarding eosinophils.

Eosinophil Count Associates in Continuous Fashion With Response to ICS/LABA Compared With LABA Alone1,2

1. Bafadhel M et al. Lancet Respir Med. 2018;6:117-126. 2. Pascoe S, et al. Lancet Respir Med. 2019;7:745-756.

0.0

0.5

1.0

1.5

2.0

2.5

0 100 200 300 400 500 6000.0

0.5

1.0

1.5

2.0

2.5

0 0.20 0.40 0.60 0.80 1.00

Annu

al E

xace

rbat

ion

Rat

es (9

5% C

I)

Baseline Blood Eosinophils Count, cells/mcL

Budesonide-formoterol 160/4.5 mcg Formoterol 4.5 mcg

Annu

al E

xace

rbat

ion

Rat

e

Eosinophil Count (x109 cells/L)


In this particular steroid, budesonide—and this is the IMPACT fluticasone data—it’s remarkably consistent. There is a relationship whereby the greater eosinophil count, the more you see separation with improvement in steroids. And the threshold seems to be at about 100. Less than 100, you don’t see a lot of steroid benefit. At about 300, you see more steroid benefit.


Dyspnea



Exacerbations

b

b

In former smokers



b b

a

LABA or LAMA


LABA + LAMA + ICS



LABA + ICS

LABA or LAMA

LABA + LAMA

LABA + LAMA + ICS


And so those thresholds have been incorporated in this schema. So if it’s greater than 300, ICS-containing regimen. So that’s where those data are coming. But you’ll see, it says, “Consider if eos.” It doesn’t say, “You must use an eos to make that decision.” And that’s in part because there are a lot of nuances to eos that are still evolving. But the data are really pretty solid, all right?

Now, in patients who continue to have events, despite being maximally treated, there are two approaches that are considered: roflumilast and azithromycin.

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Martinez FJ et al. Am J Resp Crit Car Med. 2018; 198: 1268-78 Martinez FJ et al. Am J Resp Crit Car Med. 2018; 198: 1268-78

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

n = 1,452 n = 1,436 n = 683 n = 703 n = 1,452 n = 1,436 n = 683 n = 703

No Prior Hospitalization

At Least One Prior Hospitalization

No Prior Hospitalization

At Least One Prior Hospitalization

RR = 0.95 (95% CI, 0.84-1.07)

P = .4224

RR = 0.74 (95% CI, 0.63-0.88)

P = .0005

RR = 1.02 (95% CI, 0.81-1.28)

P = .8801

RR = 0.70 (95% CI, 0.55-0.89)

P = .0035

1.03 0.98

1.43

1.06

0.17 0.17

0.60

0.42

Exacerbation Category:

Moderate or severe Severe

Roflumilast Placebo

Mea

n R

ate

of E

xace

rbat

ions

, pe

r Pat

ient

per

Yea

r Roflumilast Response Is Seen in Chronic

Bronchitis With Distinct Phenotypes1

1. Segal LN et al. J Allergy Clin Immunol. 2018;141:1961-1971.

So, roflumilast is a drug that really is sort of the epitome of personalization of therapy, because we now know that drug has an effect, but it has an effect in a very narrow population of patients—that is, patients who have chronic bronchitis by the classic criteria, and have had at least one hospitalization in the last year. So it is a very narrow group of people where you see benefit with that drug. So that’s where that drug is positioned in that GOLD schema, toward the bottom. Chronic bronchitis, prior respiratory hospitalization is the patient population.

Time to First AECOPD

360

0.2

0.4

0.6

0.8

1.0

0 135 180 225 270 315 90 45

Time, d

Prop

ortio

n Fr

ee o

f AEC

OPD

, % Azithromycin

Placebo

P < .001 Log-rank

HR = 0.73 (95% CI 0.63-0.84), P < .0001

Azithromycin Decreases AECOPD1

1. Albert RK et al. N Eng J Med. 2011;365:689-698.

0.0

Azithromycin, from a study that MeiLan and I were involved in that you guys funded in the United States—this is an NIH study—azithromycin clearly had an effect that was beneficial compared with placebo on exacerbation rates. This drug has its disadvantages: antimicrobial resistance, some hearing abnormalities, QT. You’ve got to be careful with it, but it clearly has an effect, even on top, of triple therapy. That’s in part why it’s positioned in that role in the GOLD schema.

© 2017 Global Initiative for Chronic Obstructive Lung Disease

Treatment of Stable COPD1


• Following implementation of therapy, patients should be reassessed for attainment of treatment goals and identification of any barriers for successful treatment

• Following review of the patient response treatment initiation, adjustments in pharmacologic treatment may be needed

Review • Symptoms

– Dyspnea • Exacerbations

Adjust • Escalate • Switch to inhaler or molecules • De-escalate

Assess • Inhaler technique and adherence • Nonpharmacologic approaches

(pulmonary rehab, self-management education)

Management Cycle

Remember that one of the key components of GOLD right now is this re-evaluation: risk/benefit, initial therapy, escalation, de-escalation. And so there is a positioning of de-escalation of steroid therapy in the appropriate patient based on two large studies.

Withdrawal of ICS and Exacerbations of COPD1

1. Magnussen H et al. N Engl J Med. 2014;371:1285-1294.

0.00.10.20.30.40.50.60.70.80.91.0

0 6 12 18 24 30 36 42 48 54

HR = 1.06 (95% CI, 0.94-1.19) P = .35 by Wald’s chi-square test

No. at risk IGC continuation 1,243 1,059 927 827 763 694 646 615 581 14 IGC withdrawal 1,242 1,090 965 825 740 688 646 607 570 19

Estim

ated

Pro

babi

lity

Weeks to Event

Moderate or Severe COPD Exacerbation

ICS withdrawal

ICS continuation

Primary Endpoint and Sensitivity Analyses

Hazard Ratio (95% CI)

Primary endpoint Primary endpoint including exacerbations on open-label therapy Primary endpoint excluding baseline FEV1 covariate

0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5

0.94 1.06 1.19

0.95 1.06 1.19

0.93 1.05 1.18

ICS withdrawal

better

ICS continuation better

Noninferiority margin

The WISDOM study that withdrew steroid to dual bronchodilator—no effects over a year on exacerbation rates. That’s both of those.

The SUNSET Trial1

1. Chapman KR et al. Am J Respir Crit Care Med. 2018;198:329-339.

00.10.20.30.40.50.60.7

Moderate or Severe Exacerbations

Rate ratio (95% CI): 1.08 (0.83-1.40) P = .5802

0.52 0.48

Annu

aliz

ed R

ate

(9

5% C

I)

Indacaterol/glycopyrronium (N = 527)

Tiotropium plus salmeterol/fluticasone

(N = 526)

The SUNSET trial was a 6-month study in a lower-risk population, from triple to a dual bronchodilator—no difference in exacerbation rate.

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Dyspnea



Exacerbations

b

b

In former smokers



b b

a

LABA or LAMA


LABA + LAMA + ICS



LABA + ICS

LABA or LAMA

LABA + LAMA

LABA + LAMA + ICS


And that is why in the GOLD schema, there is this recommendation that you consider stepping down in the appropriate patient, and furthermore, in both of those studies, the eosinophil level was highly predictive of a patient who would do well with steroid taper versus not.

ICS Withdrawal Effects Varies By Baseline Eosinophil Count1

Calverley PMA, et al. AJRCCM 2017; 196: 1219-21 Chapman KR et al, AJRCCM 2018; 198: 329-39

No. at risk Tiotropium plus salmeterol/fluticasone 119 117 115 109 104 99 78 Indacaterol/glycopyrronium 125 118 108 95 88 85 66

0.00.20.40.60.81.0

0 182

Calverley PMA, et al. AJRCCM 2017; 196: 1219-21

Tiotropium plus salmeterol/fluticasone Indacaterol/glycopyrronium

Exac

erba

tion-

Free

Pr

obab

ility

Time, d 15 29 57 85 141

Blood Eosinophils <300 cells/ mcL

$0.0$0.2$0.4$0.6$0.8$1.0

0 182Exac

erba

tion-

Free

Pr

obab

ility

Time, d 15 29 57 85 141

Tiotropium plus salmeterol/fluticasone Indacaterol/glycopyrronium

Blood Eosinophils ≥300 cells/ mcL

No. at risk Tiotropium plus salmeterol/fluticasone 406 392 375 355 326 305 250 Indacaterol/glycopyrronium 401 387 369 347 331 305 231

Wisdom: two or more AECOPD

Favors ICS withdrawal

Factors Number of Patients

Rate ratio

Total 841

Baseline eosinophils (<150/mcL vs ≥150/mcL) 403 421

<150/mcL ≥150/mcL

Baseline eosinophils (<300/mcL vs ≥300/mcL)

<300/mcL ≥300/mcL

669 155

Baseline eosinophils (<400/mcL vs ≥400/mcL) <400/mcL 738 ≥400/mcL 86

Baseline eosinophils (mutually exclusive subgroups) <150/mcL ≥150/mcL to <300/mcL ≥300/mcL to <400/mcL ≥400/mcL

403 266

69 86

Favors ICS

0.5 1 2 4 8

1.07

1.02 1.19

0.99 1.75

1.00 2.96

1.02 0.99 1.05 2.96

Sunset

1. Oshagbemi OA et al. COPD. 2019;16:152-159.

And look at this. Steroid, the threshold is around 300 to 400 cells/mcL, 300 cells/mcL. So in patients who are on longer-term steroids who have been relatively stable, and you’re thinking, “Eh, you know, do I want to keep this for the next 5 years in this person?” Duration and dose are related to some of the adverse events. I think eosinophils in that setting do have the advantage of giving you a little bit more granular guidance regarding when it’s safer to taper that steroid versus not. Okay? Does that make sense?

So now, the last component, which MeiLan is going to tackle principally, is something that is equally as important. It is how the patient uses their device to make sure there is maximal benefit.

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Inhaler Technique and Adherence: The Importance of Patient Education and Engagement

Consequences of Poor Adherence to Inhaled Therapy in COPD1-4

1. Calverley PM et al. N Engl J Med. 2007;356:775-789. 2. Van Boven J et al. Respir Med. 2014;108:103-113. 3. Sanduzzi A et al. Multidisc Respir Med. 2014;9:60. 4. Vestbo J et al. Thorax. 2009;64:939-943.

0

5

10

15

20

25

30

3-Ye

ar M

orta

lity,

%

Adherence >80%

Adherence ≤80%

N = 6,112

• Poor symptom control

• Worsening quality of life

• Increased relapses; need for healthcare services

• Increased mortality

• Increased healthcare expenditures

Analysis of the TORCH Study • More than half of patients with COPD will stop new prescriptions after the first month

• Sustained adherence continues to decay over time

Dr. Han: So the last section here we’re talking about inhaler technique and adherence. And I really view this as part of the management review cycle that Fernando just talked about. That’s something new that GOLD added. I think it makes sense—it’s something that we all do—but that kind of gave us a little bit more granularity on what kind of things should be included at that review visit, and certainly inhaler technique and adherence, I think, are key parts of that.

So it’s actually really interesting. When you look at adherence across all chronic diseases—that includes diabetes, heart disease, etc—adherence for respiratory medications, in particular for asthma and COPD, tends to be the worst across the board. I have to admit, I don’t fully understand that. But more than half of patients with COPD will stop new prescriptions after the first month. So that actually means, for the majority of your patients, when you send them out with that new prescription, they probably won’t be taking it—on odds they won’t be taking it the next time that you see them. And sustained adherence continues to decay over time.

Now, this really matters, because it’s associated with poorer outcomes for our patients, whether that’s poorer symptom control, worse quality of life, increased mortality, higher healthcare expenditures. You can see here—just some secondary data analysis from the TORCH study showed that for patients who were more adherent, they were much less likely to be dead at 3 years.

Several Strategies May Improve Adherence

Use of individualized action plans

Simplify treatment regimen: plans that are clinically effective and user-friendly, fewer doses per day, oral versus inhaled medications, vehicles that deliver two drugs at once

Use of home visits by healthcare staff to reinforce adherence

Use of self-monitoring, goal-setting, and other self-management techniques

So, what do we do about it? Honestly, I think one of the first things we have to do is explain to our patients why we want them on the medications. I think because of some of the short-acting bronchodilators, like albuterol, etc, patients are very much used to getting that quick hit from medications, and if they don’t get that immediate, “Oh, I feel much better,” they may not realize that it’s important to take it anyway, that there are added benefits beyond their immediate symptom relief. So I think part of it is helping patients understand that there’s some preventative and maintenance aspects to their medications. We want to try to simplify the treatment regimens as much as possible, so talking to our patients about what’s working for you, what’s not working for you, if it’s a twice daily, would we be better off with a once daily, or is there a problem with the formulation?

There certainly are other things that we can do to try to intensify the treatment regimen. One thing is to fill out and make and create an individualized action plan for patients. I think it’s really important that we inspire our patients to be advocates for their own health and to be partners with us in their journey with COPD. So I think filling out an individualized action plan together—there’s actually free ones available, for instance, from the COPD Foundation—is a good way to engage patients in partnering with you for their care.

There are other things like home visits, but I think everyone’s aware there’s monitoring devices, for instance, that can be used. Some of the electronic medical records now directly link with pharmacies, and you can actually look at fills, which can also help. So there’s a lot of things that we can do, but I think it’s really important to help patients understand why it’s important that they take their medications and give them a certain sense of ownership and responsibility and management over their own disease to partner with you.


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Poor Inhaler Technique Is Common in COPD1

1. Rau JL. Respir Care. 2006;51:158-172.

Metered Dose Inhalers Patients, % Dry Powder Inhalers Patients, %

Failure to coordinate MDI actuation with inhalation 27 Not holding device correctly 35

Too short of a breath-hold after inhalation 26 Exhaling through mouthpiece 19

Too rapid an inspiratory flow 19 Not exhaling to residual volume before inhaling 24

Inadequate shaking/mixing before use 13 Not inhaling forcefully 17

Abrupt discontinuation of inspiration as aerosol hits throat 6 Inadequate or no breath-hold 23

Actuating MDI at total lung capacity 4 Exhaling into mouthpiece after inhaling 20

Firing MDI multiple times during a single inhalation 3

• A large proportion (49% to 76%) of patients use their inhalers incorrectly • GOLD guidelines recommend rechecking inhaler technique at each patient visit

So, adherence is one issue with struggle with. The other issue is that if a patient is failing a regimen, and we’re, again, going through that management review cycle, we need to think about, is it actually the drug’s not working, or is it they actually just aren’t getting the drug to begin with? And so it doesn’t actually even matter what device type a patient is using. There is always room for error. There is always some way that it can get screwed up. So with the metered-dose inhalers, they may be inhaling too quickly for the dry powder. They might be inhaling too slowly. For each of them, there may be issues with the actuation, the coordination, the timing, etc.

So the data here suggest that, unfortunately, errors are high. And GOLD now actually recommends rechecking inhaler technique at every visit. I will be very honest with you; sometimes that’s hard to find the time. Sometimes I’ll do it myself. Sometimes I will bring one of my nurses in at the end of the visit.

I definitely try to do it at least once if there’s been an inhaler switch. I think all too often, what happens is I write one prescription, the patient leaves the office, I get a call 2 weeks later that the pharmacy won’t fill it because there is some formulary issue. The patient gets put on a completely separate drug. They come back and, well, you know, I trained them on drug A, but now they’re on drug B. So unfortunately, this is becoming an all-too-common occurrence, but does really emphasize the importance of at least thinking about that, not just at the first visit with a patient, but at subsequent visits.

Association Between Critical Inhaler Errors and Healthcare Utilization1,2,a

1.0

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

HospitalAdmissions

ED Visits AntimicrobialCourses

CorticosteroidCourses

a Data include asthma and COPD patient populations. 1. Dekhuijzen PNR et al. Patient Prefer Adherence. 2016;10:1561-1572. 2. Melani AS et al. Respir Med. 2011;105:930-938.

Odd

s R

atio

1.47

1.62

1.50 1.54

So there actually is an association, believe it or not, between critical inhaler errors and outcomes. So whether we look at hospital admissions, ED visits, or just needing to be treated with antibiotics or steroids for an exacerbation, there is a roughly 1.5-fold increase in any of these undesirable events when patients aren’t taking their medications correctly. So that’s obviously incredibly important.

Considerations When Selecting a Device1-4

1. Ouellette DR et al. Int J Chron Obstruct Pulmon Dis. 2017;12:639-650. 2. Barbara S et al. Eur Respir Rev. 2017;26:170055. 3. McDonald VM et al. Prim Care Respir J. 2011;20:389-395. 4. Jarvis S et al. Age Ageing. 2007;36:213-218.

Cost/insurance

Physical and cognitive issues: arthritis, tremors, poor strength and dexterity

Patient preference

Age

Peak inspiratory flow rate (PIFR)

So when we’re thinking about which inhaler to choose for a patient, there are obviously a lot of things that are going into that decision. I always have discussions with patients about once a day, twice a day, “Well, this particular class comes in these kinds of formulations. What do you think has worked for you? Are there kinds of medications that in the past you just didn’t tolerate or couldn’t coordinate for some reason?”

It’s becoming more and more common now to check peak respiratory flow rate. I will say that we do do this. I don’t do it at every visit, but this is something that we do for select patients in my clinic. And one thing that’s interesting is that often, most of the time I would say, when you test a patient on it, they’re not inhaling correctly for the device that they’ve been selected for. But many times the patients can be coached into getting that right. Although, of course, there’s the secondary issue of, well, I coached them right now, but is that going to be sustained over time? So it’s always definitely something to think about, and I think in an ideal setting, again, we’d be rechecking patients at every visit.

Now, ultimately, the big thousand-pound gorilla in the back of the room is that sometimes for cost or insurance reasons, the choice is sometimes taken out of our hands. And so I don’t know about your practice, but usually I’ll go ahead and let the patient try whatever has been selected, but then if it’s clear that there’s failing, then we’ll go through the trouble of pushing back on the insurance companies to get patients on what I think they would actually do better on.

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Follow-Up

• Validated teach-back methods for specific devices

• Check for inspiratory flow (eg, In-Check DIAL)

Assessments to Aid in Device Selection1

1. http://www.alliancetechmedical.com/products/check-dial-training-device/. Accessed October 15, 2019.

Cognitive

• Any test for higher level cognitive function

– Failure indicates MDI or DPI may be inappropriate

Again, some of the other patient-related factors that we need to consider when we’re trying to just select a device include things like cognitive impairment, as well as physical impairment, such as things like arthritis or inability to coordinate.

There are a couple of things that can help. There are certain validated teach-back methods for specific devices. I’m sure, like your clinics, I have a huge bucket of devices for patients. Now, ideally, they would be practicing on their own inhaler. So one thing that is nice is to try to remind your patients to actually bring in their own inhalers to every visit. I know that can be a little bit of a bag of stuff, but it’s really best if they’re actually putting their mouth on it, using their own devices to make sure that they’re using them correctly. And then, I mentioned, there are things like the In-Check DIAL that we can use to assess and train patients on, as well.

Monitoring and Follow-Up1


• Monitoring should focus on

– Dosages of prescribed medications

– Adherence to the regimen

– Inhaler technique

– Effectiveness of the current regimen

– Side effects

In order to adjust therapy appropriately as the disease progresses, each follow-up visit should include a discussion of the current therapeutic regimen

Treatment modifications should be recommended

So in order to adjust therapy appropriately—again, I’ve been harping on this for the last 5 minutes—it’s really important to just, again, reassess patients at every visit. And you’ve got to kind of think about it separately: Is it the drug? Is it the device? Or is it their technique, if there is an issue? And that’s really your opportunity to reassess.

• The burden of undiagnosed COPD increases with age – Although current recommendations do not support screening in asymptomatic patients,

many individuals at increased risk for COPD self-restrict activity to minimize symptoms

• Goals of COPD management – Improvement of lung function, symptoms, health status, and exercise tolerance – Prevention and management of exacerbations

• LAMA/LABA therapy recommended for patients still symptomatic on monotherapy

• Addition of ICS (triple therapy) may provide benefit for patients symptomatic on dual therapy and have an elevated eosinophil count

• Poor inhaler technique is common in patients with COPD and should ideally be rechecked frequently

Summary

So we’ve talked about a lot this morning. We’ve talked about screening for COPD and some of the newer approaches. We’re hoping—when is CAPTURE supposed to read out? We’re hoping that we will have data from the CAPTURE study in the next few years. We actually are working on a couple of abstracts, though, that’ll be presented at ATS.

We’ve talked about the new kind of GOLD strategy to focus on symptoms and exacerbations and follow-up with respect to treatment choices, that LAMA/LABA is great in patients, particularly who are highly symptomatic, but that ICS may make a lot of sense if patients are having frequent exacerbations, particularly with high eosinophil count. And then there’s just this concept of the management review cycle, reassessing adherence and inhaler technique, and efficacy of particular medications at every visit.

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Audience Q&A



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So I think it’s a little bit less of an issue of can the patient generate the adequate flow, and a little bit more of an issue of, are they actually doing it right for the device they’ve got? And so I think it actually can be used somewhat as a training tool to help patients understand this is how you breathe for this device.

Dr. Martinez: Yeah, there are a lot of data that are being generated now to try to address the frequency of peak inspiratory flow rate measurements, how it should be used. I’m like MeiLan. I think this is probably how I use it now, as well. I’m not exactly sure how that’s going to pan out long term.

How do you manage denial in patients who are diagnosed with COPD?

Audience Q&A: Question 2

So, MeiLan, there’s a second question that I think is quite relevant, because you’ve done this work when you did that massive project with Lancet Respiratory Medicine. How do you manage denial in patients that are diagnosed with COPD?

Dr. Han: Oh, it’s really challenging. Actually, I was at a forum with COPD patients yesterday, and actually one of them was saying he was doing a lot of advocacy work for various foundations and things like that, and was still actively smoking and kind of had to come to grips with that for himself.

It’s really hard. I think the good news is, for many of our patients, they’re going to be our patients for a long time, hopefully, with adequate treatment. And so I think developing a good relationship with patients, and over time trying to, you know, kind of help them understand this is hopefully in most cases not a death sentence, but rather a chronic disease, that we want to partner with them through and to better manage their health. Sometimes engaging caregivers and family members, I think, can help, too.

Dr. Martinez: Yeah, I agree. That’s actually in part when we generated that CAPTURE instrument for primary care. That first item that was not an accusatory smoking item was in part meant to minimize some of this potential denial issue.


What is the stance on peak inspiratory flow measurement?

Female Speaker: So for those that you can't control at the change at the pharmacy, there’s an unaffiliated website called use-inhalers.com, and it will actually give your patients feedback on how they’re using their inhalers. It has almost every brand, and it’ll walk them through. So it may be worth mentioning that resource to a patient before they even get to the pharmacy, so should it be changed after your training, they have some resource for relearning a new inhaler to at least start that journey.

Dr. Martinez: Say it again. What is it?

Female Speaker: It’s use-inhalers.com. There’s a free and a paid version of it, and it has almost everything. But it’s a really great resource.

Dr. Han: I should also mention the COPD Foundation also has a free app that has the videos, and sometimes I’ll actually run those, let the patient look at that while I’m trying to click all of the EMR things. Pharmacists are actually another untapped resource for this sort of thing, so you can tell your patients ahead of time if, for some reason, you get to the pharmacy and it’s different than what we discussed, you can ask the pharmacist to walk that inhaler through with patients, as well.

Dr. Martinez: So, MeiLan, given that this was one of the questions, and we still haven’t answered it: What is our stance on peak inspiratory flow rate measurement? I’ll let you tackle—such a simple question.

Dr. Han: I think how a patient uses an inhaler matters. I think the number of patients for whom they physically can’t generate the correct peak inspiratory flow is probably low. But I do think that patients that are inhaling at the wrong rate for the device, whether that’s high or low, is high.




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Are there any good data from a study on de-escalation of azithromycin that is longer than a year?


Dr. Martinez: Let me address a couple of these questions that we got, MeiLan. I’m giving you all of these things. So we were both involved in the azithromycin study, which was a 1-year study. And so the question is very practical, and that is, are there any good data going longer than a year?

Not that I know of. And so that study was a 1-year study because it was the practicalities of your budgeting through the NIH for that trial. It was a 1-year trial. And so it is not unreasonable to consider the potential of de-escalation at some point, as you would consider with an inhaled corticosteroid. I hate to have people on medications for life when there are potential risks of those, but there are absolutely no good data on how to address de-escalation with azithromycin. I wish I could tell you. Really good question. I don’t know any data regarding that.

Should mucolytics be part of the GOLD recommendations?


So the next question, which is a GOLD question, which is: Should mucolytics be on the GOLD recommendations? Mucolytics are actually mentioned in the GOLD statement. The challenge with mucolytics is that the most positive mucolytic data come from large studies in areas where there was generally undertreatment with inhaled medications. And so the quandary has been that there is an effect of mucolytics in people who are not on inhaled steroids, not on dual bronchodilators. That’s not the population that most of us see certainly in this country or in Europe. And so mucolytics are mentioned, but they’re mentioned with a caveat. They’re not in any of the algorithms because the data sets in comparison or in addition to the inhaled therapies just don’t exist robustly. Make sense?

Dr. Han: Yes.

Why is it difficult to treat COPD?


Dr. Martinez: Do you want to grab one of your questions there?

Dr. Han: Sure. I have kind of a fun general question here: Why is it so difficult to treat COPD? One of my favorite quotes, I think, is from Bart Celli, who said, “Think about it. We take a disease that’s defined by fixed airflow obstruction, and then we throw bronchodilators at it.” So it is one of the inherent problems.

I think the thing that I struggle with the most is just the heterogeneity of the disease. Steve Rennard a couple years ago wrote an article, and it’s called “COPD: An Orphan Disease.” And in many ways, I think it is many little orphan diseases that we are trying to treat, and each patient’s somewhat trial and error, and it does take me some time to figure out what works. In some cases, I really struggle to find an approach that keeps exacerbations at bay.

I think the good news is that we’re doing more and more research to help us individualize treatment plans, even things like eosinophils—that I was extremely skeptical about, and still have a little bit of skepticism about—but the data I think are increasing. That’s one of hopefully many other tools that we’ll have to subtype patients.

Fernando, your thoughts on why COPD is so hard?

Dr. Martinez: No, I agree completely with that. And, so I trained under Bart Celli, so I have the same positive philosophy that Celli had, and there have been a lot of advances that have occurred in COPD just in the time that I’ve been working in the COPD arena. I mean, really, there’s a lot of major advances that have been made in therapeutic approaches.

We’re now making enhancements in diagnostic approaches. Hopefully the CAPTURE program that you’re working on, MeiLan, will allow us to have early diagnosis in a legitimate fashion. But there’s a tremendous amount of work looking at potential mechanisms and how to target specific mechanisms in COPD patients, how to really refine this precision therapy. So, MeiLan, you’re involved in several of these biologic studies that are ongoing now.





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So, don’t give up on the COPD world, guys. I mean, it’s a very common and very prevalent problem. You’ve made a lot of advances already, you guys, and now you’re refining some of those advances. So I’m a fully confident person.

Why isn’t a patient with severe asthma and an FEV1/FVC <70% considered to have COPD?


So my last two questions are not easy questions. You guys asked really good questions. I wish I could tell you I had a dramatic answer for each one of these. We’ve been tap-dancing around here on some of those.

So a patient that has severe asthma and an FEV1/FVC that’s less than 70%. Why is that person not called COPD?

Dr. Han: There’s no agreed-upon definition for asthma-COPD overlap. And further, GINA and GOLD just decided to divorce on the ACO document. I think probably what we’re beginning to recognize—I mean, we ultimately want to target mechanism, right? So I think what we really need to do is to understand what the pathophysiology is of a patient who has potentially airflow obstruction that was originally driven by, say, air pollutants, and the type of inflammation, regardless of perhaps the level of airflow obstruction, versus a patient that perhaps has allergic inflammation but has similar pulmonary function tests. So, I think what we call it may end up being less important, but really trying to understand the pathophysiology behind it, so we can choose appropriate therapies.

Dr. Martinez: I think that’s absolutely correct. For some of you that are older, as I am—not these young people—you will remember that there was a Venn diagram on the original ATS statement that had asthma, COPD, chronic bronchitis, and then it had the box for airflow obstruction. We’re sort of coming back to something like that and realizing that mechanistically there were overlaps between these components. This whole ACO thing has been such a flog, such a battle.

How do you address cachexia in a COPD patient? How do you relate cachexia to roflumilast?


Dr. Martinez: The last question that I’ll address is—I’ll pose one to you, MeiLan, because I know you’ve worked in this area, and then I’ll tackle the last—there’s a two, it’s a two-parter. One of them is, how do you address cachexia in a COPD patient?

Dr. Han: Unfortunately, I don’t think we have a lot of good data. We know it’s associated with poorer outcomes. Unfortunately, I think every nutrition study, intervention nutrition study for COPD that I’m aware of has actually ended up being negative. But I do my best. We do have a nutritionist that I can have patients talk to. Sometimes they can get a little bit of support through pulmonary rehabilitation. We do try to build up their muscle as best we can through that and then advise them on caloric intake. It’s something that I track at every visit, particularly for some of my more severe patients. But I wish I had a magic bullet for that, and I don’t.

Dr. Martinez: Well, so, it is important. So this person is absolutely correct, because the second portion is that, how do you relate the cachexia to roflumilast? And so remember, roflumilast, it’s associated with a several-kilogram weight loss. And so one of the recommendations made with roflumilast is if you’re really, really skinny, you should rethink whether you’re going to use roflumilast, and you should be monitoring that patient’s weight more closely over time.

What is the role of ICS de-escalation?


And then the last question, in the last 25 seconds, is the role of ICS de-escalation. And so I’ve shown you what the GOLD statement suggested regarding de-escalation, and that it should




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be considered. Exactly when to consider it, to me, remains unclear. MeiLan published a very well-cited paper from SPIROMICS showing the tremendous variability year to year in exacerbations in patients. My sense is that if I have a patient who is at high risk, osteopenic, skinny woman or a man who I think is at risk for pneumonia, I will clearly consider de-escalation in those settings, and that is where I’ve started using eosinophils, in that setting.

What do you think, MeiLan? I’ll let you have the last word.

Dr. Han: I think it can be incredibly challenging, trying to sort some of these issues out. And obviously, talking to our individual patients, really, and bringing them into the conversation about the pros and cons, I think, of each. But I think the good news with roflumilast, at least in particular, is that the chronic bronchitis patients tend to be a little bit heavier.

Dr. Martinez: Yeah, a little chunkier.

Dr. Han: And so it’s not always an issue, but certainly can be.

Dr. Martinez: All right, we are a minute over time. So go out and enjoy the rest of the meeting, and thanks for coming so early.

Narrator: This activity has been jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education.


CME


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This CME activity is jointly provided by Penn State College of Medicine and PVI, PeerView Institute for Medical Education.

This educational activity is supported by an educational grant from GlaxoSmithKline.

Based on a panel discussion and on data from recent medical literature. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView or any of its partners, providers, and/or supporters.

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