ACOS Working Group Meeting

ASTHMA–COPD OVERLAP SYNDROME WORKING GROUP MEETING

CHAIR: Nicolas Roche

DATE: Saturday September 3rd

TIME: 10.30–11.45AM

VENUE: Royal College of General Practitioners; 30 Euston Square, London, UK

Agenda

•  “Proof of Concept Study” – review o Agreed methodology – UK Pilot results – Approach 1 (claims-

based approach) – Approach 2 (similarities/differences vs

Approach 1) o Phase I extension to other databases

o Phase II – clinical implications •  Other study ideas

PROOF OF CONCEPT STUDY

– AGREED METHODOLOGY – UK PILOT RESULTS

– APPROACH 2 – ROLL OUT TO OTHER DATABASES – PHASE II: CLINICAL IMPLICATIONS

Background / rationale

•  2014, GINA and GOLD published their first joint statement on Asthma-COPD Overlap Syndrome (ACOS)1

o  Current thinking now recommends reference to ACO rather than ACOS based on the clinical implications of the term “syndrome”2

•  Various criteria for diagnosis of ACO have been proposed2-4

•  The lack of a gold standard definition is a barrier to ACO research and to understanding the biology of the condition and optimum management approaches5

1. GINA-GOLD Diagnosis of disease of chronic airflow limitation: Asthma, COPD and asthma-COPD overlap syndrome (ACOS), 2014; 2. Barnes PJ. Asthma-COPD Overlap. Chest. 2016;149:7-8; 3. Miravitlles M, et al. Arch Bronconeumol 2014; 4.Koblizek V, et al. Pap Med Fac Univ Palacky Olomouc Czech Repub 2013; 5. Kankaanranta H, et al. Basic Clin Pharmacol Toxicol. 2015;6. Postma DS, Rabe KF. NEJM 2015

Definition of ACO using electronic medical records (all 5)

1.  Clinical diagnosis of COPD, asthma, or both 2.  Age at least 40 years 3.  Ever smoker

4.  Post-BD FEV1/FVC<0.7 5.  Increase in post-BD FEV1 by 12% and 200mL

Aim of the Proof of Concept Study

To inform standardised methods and tools for future ACO observational research:

•  Phase I: test various smoking-related ACO population definitions evaluating their respective prevalence and

agreement within and between a number of (initially Western) population-level databases.

•  Phase II: characterise the demographic and clinical characteristics of different ACO definitions to guide future ACO database study design

Population Definition Summary

Definition Criterion A: COPD only

B: COPD & ASTHMA

C: ASTHMA Only

D: Reference population

A A1 A2 A3 B B1 B2 B3 C C1 C2 C3 D D1 D2 D3

Diagnosis

Clinical diagnosis, billing “diagnosis”

Dx of COPD only at 2 different encounters over 2-yr

observation period; no dx of

asthma at any encounter over the 2-yr observation period

Dx of asthma and COPD in same encounter at 2 different

encounters over 2-yr

observation period; or asthma at 1 and COPD at a

2nd encounter over the same 2-yr observation period

Dx of asthma only at 2 different encounters over 2-year observation period; no

dx of COPD at any encounter over the 2-yr observation

period

No dx of asthma or COPD over 2-yr observation period;

patient has ≥2 healthcare

encounters during this 2-yr observation period

Age >40 years Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Smoking* Smoking history ever Ignore Yes Yes Yes Ignore Yes Yes Yes Ignore Yes Yes Yes Ignore Yes Yes Yes

Obstruction Post BD FEV1/FVC <70%

Ignore Ignore Yes Yes Ignore Ignore Yes Yes Ignore Ignore Yes Yes Ignore Ignore Yes Yes

Reversibility

post-BD increase in FEV1 by ≥12% and ≥200mL

Ignore

Ignore

Ignore Yes Ignore Ignore Ignore Yes Ignore Ignore Ignore Yes Ignore Ignore Ignore Yes

*Hx of past or current smoking, or smoking cessation advice

Yes = patient fulfils this criteria; Ignore = criterion not applied

Strengths of approach •  Inclusive (sensitive) approach that enables:

o  Identification of ACO in patients carrying other diagnostic labels (e.g. asthma

or COPD, both or neither)

o  Can be repeated across a wide range of databases

•  Use of electronic medical records data increases representativeness (i.e.

good external validity)

•  Diagnoses at health encounters over the most recent 2-year period: o  Allows us to start with a clinician diagnosis o  Controls for secular trends in coding o  Use of shorter observation period will pre-select for individuals with more

active disease

•  Subsequent study phases will explore the clinical impact of these

definitions (e.g. on treatment response, health outcomes)

Limitations of approach •  Some databases do not have diagnosis at each healthcare encounter, e.g. Majorica

and the Dutch Asthma & COPD database:

o  Ignores diagnosis established at a visit before the 2-year observation period

o  Subsequent study envisioned using clinical diagnosis established at any time

over a 5 or 10 year period

•  Thresholds for some criteria (e.g., age at least 40 yrs; ever smoker; 200 mL and 12%

reversibility) are arbitrary, but based on consensus and feasibility using electronic

health records

o  Alternate definitions can be explored in subsequent analyses, using clinical

sensible outcomes (e.g., treatment response) to establish appropriate criteria

o  Pack-years smoked rarely coded as discrete data in electronic medical records;

reliability also unclear

•  Does not capture second hand smoking exposure, biomass or occupational

exposures

UK Pilot Work

Database & Study Design Database •  The UK’s Optimum Patient Care Research Database

•  Fully anonymised UK primary care data

•  Historical medical records for >2.9 million patients from >576 primary care practices across the UK

•  Ethical approval for medical research & used for multiple peer-review publications

Study Design •  Historical cohort study

•  Patients with 2 years of continuous records within the observation period 1 January 2014-31 December 2015






B: COPD & ASTHMA

C: ASTHMA Only



Diagnosis


Dx of COPD only at 2 different encounters over 2-yr

observation period; no dx of

asthma at any encounter over the 2-yr observation period

Dx of asthma and COPD in same encounter at 2 different

encounters over 2-yr

observation period; or asthma at 1 and COPD at a

2nd encounter over the same 2-yr observation period

Dx of asthma only at 2 different encounters over 2-year observation period; no

dx of COPD at any encounter over the 2-yr observation

period

No dx of asthma or COPD over 2-yr observation period;

patient has ≥2 healthcare

encounters during this 2-yr observation period





Reversibility


Ignore

Ignore




A: Clinical diagnosis of COPD only

B: Clinical diagnosis of asthma and COPD

C: Clinical diagnosis of Asthma only


A3/A (A2/A defines

COPD)

B3/B B2/B

C3/C C2/C

D3/D D2/D

Proposed ACO Prevalence within the Populations A–D


B: COPD & ASTHMA

C: ASTHMA Only



Diagnosis

Clinical diagnosis, billing “diagnosis

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes





Reversibility


Ignore

Ignore

Ignore Yes Ignore Ignore Ignore Yes Ignore Ignore

Ignore Yes Ignore Ignore Ignore Yes

All patients in the Optimum Patient Care Research Database (OPCRD)

N=2,790,704

Continuous records from 1 Jan 2014-31 Dec 2015

N= 290,024

≥2 coded healthcare encounters*

N = 233,054

n= 2,500,680 ≤2 years of continuous records in the obs’n period 1 Jan 2014-31 Dec 2015

Population A: Clinical diagnosis of

COPD only N=1,017

Population B: Clinical diagnosis of Asthma and COPD

N=398

Population C: Clinical diagnosis of

Asthma only N=857

Population D: Reference

N=1,497

*A – Clinical diagnosis of COPD only: Diagnosis of COPD only at 2 different encounters over 2-year observation period; no diagnosis of asthma at any encounter over the 2-year period; B – Clinical diagnosis of Asthma and COPD: Diagnosis of asthma and COPD in same encounter at 2 different encounters over 2-year observation period; or asthma at 1 encounter and COPD at a 2nd encounter over the same 2-year obs period; C – Clinical diagnosis of Asthma only: Diagnosis of asthma only at 2 different encounters over 2-year observation period; no diagnosis of COPD at any encounter over the 2-year period; D – Reference population: No diagnosis of asthma or COPD over 2-year observation period; patient has 2 or more healthcare encounters during this 2-year period

Non-missing data to assess age, smoking history,

obstruction and reversibility N= 3,769

n= 56,970 ≤2 coded healthcare encounters for asthma and/or COPD or neither in

the period 1 Jan 2014-31 Dec 2015

n= 229,285 No data present for ≥1 of the

following: age; smoking history; airflow obstruction; airway reversibility

A: Clinical diagnosis of COPD only

B: Clinical diagnosis of asthma and COPD



A3/A = 20.5% B2/B = 61.8% B3/B = 32.1%

C2/C = 20.8% C3/C = 14.4%

D2/D = 19.7% D3/D = 8.0%

Proposed ACO Prevalence within the Populations A–D


B: COPD & ASTHMA

C: ASTHMA Only



Diagnosis

Clinical diagnosis, billing “diagnosis

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes





Reversibility


Ignore

Ignore

Ignore Yes Ignore Ignore Ignore Yes Ignore Ignore

Ignore Yes Ignore Ignore Ignore Yes

Summary: ACO prevalence using EMR

o  Approach has strengths and weaknesses

o  ACO prevalence varies depending on source population –  20%* if clinical dx COPD only –  32%* or 62% if clinical dx asthma + COPD –  14%* or 21% if clinical dx asthma only –  8%* or 20% if neither dx

*ACO definition requires airflow reversibility

o  Future studies

–  Add cross-sectional analyses to examine how patterns of comorbid conditions vary depending on the source clinical population

–  Compare results with similar cross-sectional analyses in different population-based databases

–  Cohort studies to evaluate outcomes using different ACO definitions

Phase I – Approach 2 (working with clinician diagnoses)

Population Defns Approach 1 vs 2

Claims-based Approach Clinical Database Approach

Different

No Change

Approach 2 Population Defn Summary




B: COPD & ASTHMA

C: ASTHMA Only



Diagnosis


APPROACH 2: Physician Dx of COPD within 5-years of the 2-yr observation period; no dx

of asthma over the same period

Sensitivity analysis: repeat using a 10-year Dx window

APPROACH 2: Physician Dx of COPD and Asthma (or

ACO) within 5-years of the

2-yr observation period Sensitivity analysis: repeat

using a 10-year Dx window

APPROACH 2: Physician Dx of Asthma within 5-years of the 2-yr observation period;

no dx of COPD over the same period

Sensitivity analysis: repeat using a 10-year Dx window

APPROACH 2: No physician Dx of Asthma, COPD or ACO

within 5-years of the 2-yr

observation period Sensitivity analysis: repeat

using a 10-year Dx window





Reversibility


Ignore

Ignore


Phase I – Other Eligible Databases

Database eligibility criteria Inclusion: •  To be eligible for inclusion in the study, databases must be “population-based”, requiring

them to be largely representative of the broad, heterogeneous population treated within everyday routine care in their respective country of origin. The following types of population-based studies may be eligible: o  Clinical databases (e.g. primary care databases)

o  Administrative/billing-based (e.g. insurance claims records) •  All eligible databases must also meet the following inclusion criteria:

o  Have at least two continuous years of “recent” (within the last 10 years: 2006-2015) clinical data o  Have produced at least one publication in a peer reviewed journal o  Include variables permiting:

–  Evaluation of patient age (i.e. patient age or date/year of birth) –  Evidence of current or past smoking (e.g. smoking status, pack years, prescription of

smoking cessation therapy/advice).

Exclusion: •  To maximise the external validity of the study findings and avoid biasing outcomes by

working within pre-selected populations unrepresentative of the diversity of patients managed in routine clinical practice, the following will not be eligible for inclusion in the initial phase of this study:

•  Clinical trials databases •  Case series of patients

Database information: summary (I)

DATABASE

Details Provided Country Type of Sample Source of data – Clinical Data (EMR) or

Administrative/Billing Data

To establish the "representativeness" of the population within the database

(e.g. selected for trial inclusion; unselective convenience sampling; representative of the population as a whole)

National origin of the patients within the dataset

To indicate whether the data includes direct information about a helathcare encounter (i.e. recorded in their electronic medical records) or indirect information as coded for insurance or

administrative claims purposes

Indication of the ability of each dataset to identify the 12 populations (COPD A–C; Asthma A–C; ACOS A–C and

Control A–C) proposed for revaluation

Dutch ASTHMA / COPD Service

People with respiratory symptoms treated by their GP. With or without inhalation medication. Both diagnostic

and follow up. The Netherlands

Electronic medical record, but not all visits are recorded for other encounters other than the visits to the A/C service

12 of 12

Adelphi Respiratory Disease Specific Programme

Convenience sample of consecutive outpatients visiting their physician (both primary and specialist

care settings)

France, Germany, Italy, Spain, UK, USA,

Japan, China, Canada Electronic Medical Records

9 of 12 • Unable to identify the 3x Control Populations as

survey only includes patients with a asthma or COPD diagnosis

Optimum Patient Care Research Database (OPCRD)

Patients registered at UK primary care practices that receive the Optimum Patient Care Clinical Service. Enriched sample of patients with ≥1 prescription or

diagnosis of obstructive lung disease (as initially only OLD pts received the OPC review)

UK Electronic Medical Records 12 of 12

• Only a subgroup of patients will have reversibility data (required to evaluate the 4 x C Populations)

SIDIAP

Records for patients treated by the Catalan Health Institute (CHI) – the chief provider of medical services in Catalonia. 5,8 million patients (>80% population); 274 Primary Care Centres in Catalonia; 3,400 GPs

Spain (Catalonia Region) Electronic Medical Records 12 of 12

MAJOrca Real-world Investigation in COPD and Asthma database (MAJORICA)

Combined data from the primary care system (e-SIAP), the hospital claims system (FIC), and the

pharmacy database (RELE) in the Balearics, Spain. Covers all health-care utilisation of the permanent inhabitants of the Balearics (≥1.1 million people)

Majorca Electronic medical records 12 of 12 (TBC)

PCORnet Common Data Model

Population-based (anyone with ≥1 healthcare encounter for any reason at contributing healthcare

facilities) USA Electronic Health Records 12 of 12

HealthCore

Automated computerized claims data and enrollment for approximately 51 million lives with at least medical

enrollment, and nearly 33 million lives with medical and pharmacy enrollment information from 14 Blue Cross and/or Blue Shield (BCBS) licensed plans

USA

Administrative / Billing Data +

linked medical records (from EMR review study)

12 of 12 • All A populations will be identifiable

• All B and C populations (requiring reversibility and obstruction data) will only be identifiable in those

with linked claims + chart review data

MarketScan Commercial, Medicare Supplemental, and Medicaid

contain >200 million patients since 1995. USA Administrative/Billing Data

4 of 12 • Only group A can be evaluated and only based on codes for smoking cessation (i.e. no smoking code, but inference of smoking history based on code for

smoking cessation advice)

Optum Humedica

Proprietary database containing health plan administrative and claims records. The data derive

from commercial health plans and Medicare Advantage programs.

USA Adminsitrative/Billing Data

4 of 12 • Only group A can be evaluated and only based on codes for smoking cessation (i.e. no smoking code, but inference of smoking history based on code for

smoking cessation advice)

Information has not been provided for: COBRA (France); COLIBRI (France); INITIATIVES (France); SPIROMICS (USA); CONCERT(USA); COSYCONET (Germany). These databases do not meet the eligibility criteria of “random or representative samples” so will not be eligible for inclusion in the first phase of this population characterization and agreement study

Database information: summary (II)

DATABASE

Evaluation year

Number of unique patients with ≥1 HCP contact

(for asthma, COPD, both of ACOS) in the evaluation year

Number of unique patients with ≥2 HCP contacts

(for asthma, COPD, both of ACOS) in the evaluation year


not coded for asthma, ACOS or COPD in the evaluation year


(for any reason) in evaluation year

Latest 12-month period for which data are available

This criterion is designed to capture the total number of asthma, COPD and ACOS

patients in the database within the proposed 12-month evaluation period

Patients with ACOS based co-coding of asthma and COPD within a 12-month window & presumptive diagnosis of

asthma or COPD in patients 2 consistent asthma or COPD codes in the 12-month

period

Total number of potential control patients in the database within the

proposed 12-month evaluation period

Number of potential control patients within the database – those with ≥2 encounters, neither of which have a

diagnosis of Asthma, COPD or ACOS in the 12-month period

Dutch ASTHMA / COPD Service Jan 2013–31 Dec 2014

Asthma: 1694 COPD: 946 ACOS: 324

Unnecessary as code for ACOS exists within the Netherlands Control: 3918 TBC

Adelphi Respiratory Disease Specific Programme

Dec 2014–Nov 2015 Asthma: 5,501 COPD: 5,071

ACOS: 449 (physician-confirmed)

0; database contains pt data from 1 encounter only Control: not available (n=0) Control: not available (n=0)

Optimum Patient Care Research Database (OPCRD)

March 31 2011 – April 1 2012

Asthma, COPD or Both: 119,540 Asthma: subset of above COPD: subset of above ACOS: subset of above

Asthma, COPD or Both: 40726 Asthma: subset of above COPD: subset of above ACOS: subset of above

Control: 40726 TBC

SIDIAP Jan 07 2013–Dec 31 2013



TBC TBC

MAJORICA

1 January 2014–31 December 2014

(data collection period

2011-2014)

based on ICD ever Asthma: 45,800 COPD: 27,871 ACOS: 5,093

Asthma: <45,800 COPD: <27,871 ACOS: <5100

Subset of 68,578 Subset of 68,578

PCORnet Common Data Model

1 January 2014 – 31 December 2014

All patients: 100,000,000 million records (total)

Asthma: ~6 million asthma patients (based on prevalence estimate);

COPD: ~6 million asthma patients (based on prevalence estimate);

ACOS: TBC

Asthma: TBC COPD: TBC ACOS: TBC

TBC TBC

HealthCore May 1 2014 – April 30 2015

Asthma, COPD or Both: 603,001 (ICD-9 codes 491.xx–496.xx)

Asthma: subset of above COPD: subset of above ACOS: subset of above

Asthma, COPD or Both: 312,075 (ICD-9 codes 491.xx–496.xx)


Control: not available (n=0) Control: not available (n=0)

MarketScan Jan 01 2013–Dec 31 2013

Asthma, COPD or Both: 1,998,509 Asthma: subset of above COPD: subset of above ACOS: subset of above

Asthma, COPD or Both: 1,436,631



Optum Humedica Jan 01 2013–Dec 31 2013

Asthma, COPD or Both: 1,248,091 Asthma: subset of above COPD: subset of above ACOS: subset of above



Available datasets: summary DATABASE Time for completion of Stage 1 Cost for completion of Stage 1

1. Dutch ASTHMA / COPD Service 8 weeks EUR 10,000

(~2 months post-doc salary)

2. Adelphi Respiratory Disease Specific Programme ≤ 4 weeks £0

3. Optimum Patient Care Research Database (OPCRD) 4-6 weeks £10,000

4. SIDIAP 6 weeks EUR 1,500

5. MAJORICA TBC TBC

6. PCORnet Common Data Model Data available Sept 2016;

analysis estimate ? TBC

7. HealthCore 3 weeks $4,167

(if manual programming required)

8. MarketScan "1 day" ?

9. Optum Humedica "1 day" ?

Which databases should be included in the Protocol?

?

✓

X Valuable for repeat analysis and validation when available

Phase II – Clinical Implications

Demographics A: Clinical diagnosis of

COPD only

B: Clinical diagnosis of

asthma and COPD



1,017 398 857 1,497Male 561 (55.2) 172 (43.2) 338 (39.4) 695 (46.4)Female 456 (44.8) 226 (56.8) 519 (60.6) 802 (53.6)

Age Mean (SD) 71.0 (9.7) 68.7 (10.8) 59.7 (16.6) 58.6 (17.5)Non-smoker n (%) 75 (7.37) 65 (16.3) 386 (45.0) 598 (40.0)Current smoker n (%) 297 (29.2) 110 (27.6) 130 (15.2) 331 (22.0)Ex-smoker n (%) 645 (63.4) 223 (56.0) 341 (39.8) 568 (37.9)Underweight, n (%) 48 (4.7) 13 (3.3) 14 (1.6) 36 (2.4)Healthy weight, n (%) 328 (32.3) 116 (29.2) 225 (26.3) 430 (28.7)Overweight, n (%) 342 (33.6) 123 (30.9) 276 (32.2) 467 (31.2)Obese, n (%) 296 (29.1) 145 (36.4) 340 (39.7) 541 (36.1)Missing, n (%) 3 (0.3) 1 (0.25) 2 (0.2) 23 (1.5)Cardiovascular, n (%) 458 (45.0) 148 (37.2) 240 (28.0) 441 (29.5)IHD, n (%) 235 (23.1) 82 (20.6) 107 (12.5) 201 (13.4)Heart Failure, n (%) 55 (5.4) 22 (5.5) 17 (2.0) 38 (2.5)Hypertension, n (%) 303 (29.8) 98 (24.6) 214 (25.0) 263 (17.6)Diabetes, n (%) 565 (55.6) 204 (51.3) 413 (48.2) 673 (45.0)Bronchiectasis, n (%) 51 (5.0) 27 (6.8) 25 (2.9) 27 (1.8)Rhinitis, n (%) 161 (15.8) 102 (25.6) 258 (30.1) 263 (17.6)Rhinitis (active), n (%) 77 (7.6) 58 (14.6) 156 (18.2) 126 (8.4)Eczema, n (%) 246 (24.2) 102 (25.6) 228 (26.6) 301 (20.1)Osteoporosis, n (%) 124 (12.2) 66 (16.6) 92 (10.7) 120 (8.0)GERD, n (%) 203 (20.0) 82 (20.6) 151 (17.6) 221 (14.8)GERD (active), n (%) 161 (15.8) 66 (16.6) 126 (14.7) 165 (11.0)Cerebrovascular, n (%) 114 (11.2) 24 (6.0) 48 (5.6) 108 (7.2)Chronic Kidney Disease, n (%) 124 (12.2) 52 (13.1) 71 (8.3) 122 (8.2)Myocardial Infarction, n (%) 89 (8.8) 38 (9.6) 41 (4.8) 59 (3.9)Anxiety and Depression, n (%) 111 (10.9) 45 (11.3) 99 (11.6) 150 (10.0)

Comorbidities

Total Population

Gender

Smoking History

BMI

Clinical Outcomes (per protocol) •  Presence of atopy, defined as ≥1 of the following:

o  Physician diagnosis of eczema o  Physician diagnosis of allergic rhinitis o  Eosinophilia (cut off >200/µl; REG COPD blood eosinophilia study used ≥450µl) o  Positive skin prick test o  Positive to ≥1 allergen

•  Smoking history: o  Pack years, where available o  Duration of smoking, defined as:

–  For ex-smokers: years between first current smoking / active smoking code and non-smoker or smoking cessation code

–  For current smokers: years between first current smoking record and year of study / cross sectional analysis

•  Historical “onset” of disease: o  Duration of asthma, defined as years between first recorded asthma diagnosis / encounter

and year of study / cross-sectional analysis o  Duration of COPD, defined as years between first recorded COPD diagnosis / encounter

and year of study / cross-sectional analysis o  Time between first recorded asthma diagnosis/encounter and first COPD diagnosis/

encounter

Clinical Outcomes (per protocol) •  COPD severity: in terms of GOLD status (where evaluable)

•  Comorbidities: o  Cardiovascular disease o  Other chronic respiratory conditions o  Diabetes o  Gastroesophageal reflux disease (GERD) o  Charleson Comorbidity Index o  Lung Cancer

•  Respiratory treatment: Current management (i.e. during the phase 1 24-month cross-sectional analysis period), records (prescriptions for / claims data) for the following, and combinations of the following, will be examined: SABA, SAMA, LABA, LAMA, ICS, theophylline, LTRA, Roflumilast, chronic azithromycin.

•  Exacerbations: Functional consequences of different definitions, (i) proportion of patients and (ii) annualised rate of respiratory-related exacerbations over the phase 1 24-month evaluation period, where a respiratory-related event is defined as any of the following: o  Physician diagnosis of asthma exacerbation; o  Physician diagnosis COPD exacerbation; o  Accident & Emergency / Emergency Room attendance with a lower respiratory code o  Hospital admission with a lower respiratory code o  A course of prednisolone o  A course of systemic antibiotics coded for a lower respiratory tract infection

Health & Medicine

ACOS Working Group Meeting