1. Asthma-COPD Overlap (ACO) Working Group Meeting
CHAIR: Marc Miravitlles
DATE: Saturday 9th September 2017
TIME: 12.30–13.10
VENUE: Melia Milano Hotel, Via Masaccio 19, Milan, Italy

2. Agenda 1) Update on current projects:
a) ACOS proof of concept study- Comparability of different population-definitions of ACOS within a UK database.
2) Current ideas for future projects:
Phase 1 Repetition of the analyses in other national databases to evaluate the ACO definitions.
Phase 2 Implications of a mixed asthma-COPD phenotype vs COPD alone on patient outcomes.
Prioritisation of projects and next steps to move one of these projects forward.
3) Any new project ideas? And how these ideas should be prioritised.

3. Agenda
1) Update on current project ‘ACOS proof of concept study- Comparability of different population-definitions of ACOS within a UK database’. 2) Ideas for future projects. 3) Any new project ideas? 4) Prioritisation of projects and work plan to move projects forward.

4. ACOS proof of concept study
Update on current projects
ACOS proof of concept study

5. Background / rationale
2014, GINA and GOLD published their first joint statement on Asthma-COPD Overlap Syndrome (ACOS)1
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

6. Proof of Concept Study Aim:
Explore the influence of the definition on the prevalence and clinical presentation of ACO in databases used for observational research, in order to inform (a) standard definition(s) for future studies and clinical trials.
Study design:
Historical cohort study using the UK’s Optimum Patient Care Research Database which contains >2.9 million patients from >576 primary care practices across the UK
Patients with 2 years of continuous records within the observation period 1 January December 2015

7. Population Definition Summary

8. Population Definition Summary

9. ACO prevalence in the clinical populations
Population A
Clinical diagnosis of COPD only
Population B
Clinical diagnosis of Asthma & COPD
Population C
Clinical diagnosis of Asthma only
ACO prevalence
20.5%
(208/1,015)
32.1%
(127/395)
14.4%
(109/755)
p-value compared to asthma and COPD*
p<0.001
Reference
*Chi-squared test

11. Summary: ACO prevalence using EMR
Approach has strengths and weaknesses
ACO prevalence varies depending on source population
20%* if clinical dx COPD only
32%* if clinical dx asthma + COPD
20%* if clinical dx asthma + COPD AND Asthma diagnosed when patients ≤40 years of age
14%* if clinical dx asthma only
8%* if neither dx
*ACO definition requires airflow reversibility
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

12. (Prioritisation and work plan)
2) Current ideas for future projects
(Prioritisation and work plan)
Phase 1 Repetition of the analyses in other national databases to evaluate the ACO definitions.
Phase 2 Implications of a mixed asthma-COPD phenotype vs COPD alone on patient outcomes.

13. Phase I
Repetition of the analyses in other national databases to evaluate the ACO definitions.

14. Database eligibility criteria
Inclusion:
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 databases may be eligible:
Clinical databases (e.g. primary care databases)
Administrative/billing-based (e.g. insurance claims records)
Have at least two continuous years of “recent” (within the last 10 years: ) clinical data
Have produced at least one publication in a peer reviewed journal
Include variables permitting:
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

15. Database information: summary (I)
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 healthcare 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
• 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)
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
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
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.
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.
Adminsitrative/Billing Data
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

16. Database information: summary (II)
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
Number of unique patients with ≥1 HCP contact not coded for asthma, ACOS or COPD in the evaluation year
Number of unique patients with ≥2 HCP contact not coded for asthma, ACOS or COPD in the 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
Number of potential control patients in the database within the proposed 12-month evaluation period
Dutch ASTHMA / COPD Service
Jan 2013–31 Dec 2014
Asthma: 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)
Optimum Patient Care Research Database (OPCRD)
March – April
Asthma, COPD or Both: 119,540 Asthma: subset of above COPD: subset of above ACOS: subset of above
Asthma, COPD or Both: Asthma: subset of above COPD: subset of above ACOS: subset of above
Control: 40726
SIDIAP
Jan –Dec
Asthma, COPD or Both: 275,615 Asthma: subset of above COPD: subset of above ACOS: subset of above
Asthma, COPD or Both: 174,180 Asthma: subset of above COPD: subset of above ACOS: subset of above
MAJORICA
1 January 2014–31 December 2014  (data collection period )
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
PCORnet Common Data Model
1 January 2014 – 31 December 2014
All patients: 100,000,000 records Based on prevalence estimate-
Asthma: ~6 million asthma patients COPD: ~6 million asthma patients ACOS: TBC
Asthma: TBC COPD: TBC ACOS: TBC
HealthCore
May – April
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) Asthma: subset of above COPD: subset of above ACOS: subset of above
MarketScan
Jan –Dec
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 Asthma: subset of above COPD: subset of above ACOS: subset of above
Optum Humedica
Asthma, COPD or Both: 1,248,091 Asthma: subset of above COPD: subset of above ACOS: subset of above
Asthma, COPD or Both: 883,404 Asthma: subset of above COPD: subset of above ACOS: subset of above

17. Which databases should be included in the protocol?
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 ?
7. HealthCore
3 weeks
$4,167 (if manual programming required)
8. MarketScan
"1 day" ?
9. Optum Humedica ✓ X
Valuable for repeat analysis and validation when available ?

18. Phase II
Implications of a mixed asthma-COPD phenotype vs COPD alone on patient outcomes

19. Implications of a mixed asthma-COPD phenotype vs COPD alone on patient outcomes
Aims:
To identify the prevalence and incidence of patients diagnosed as having ACO
To identify the burden and cost of ACO compared with COPD and asthma populations
To assess respiratory and cardiovascular outcomes in ACO, COPD, asthma treated with ICS, ICS/LABA and LABA.
Characterising ACO patients to develop a diagnostic tool

20. Clinical Outcomes Presence of atopy, defined as ≥1 of the following:
Physician diagnosis of eczema
Physician diagnosis of allergic rhinitis
Eosinophilia (cut off >200/μl; REG COPD blood eosinophilia study used ≥450μl)
Positive skin prick test
Positive to ≥1 allergen
Smoking history:
Pack years, where available
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:
Duration of asthma, defined as years between first recorded asthma diagnosis / encounter and year of study / cross-sectional analysis
Duration of COPD, defined as years between first recorded COPD diagnosis / encounter and year of study / cross-sectional analysis
Time between first recorded asthma diagnosis/encounter and first COPD diagnosis/encounter

21. Clinical Outcomes
COPD severity: in terms of GOLD status (where evaluable)
Comorbidities:
Cardiovascular disease
Other chronic respiratory conditions
Diabetes
Gastroesophageal reflux disease (GERD)
Charleson Comorbidity Index
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:
Physician diagnosis of asthma exacerbation;
Physician diagnosis COPD exacerbation;
Accident & Emergency / Emergency Room attendance with a lower respiratory code
Hospital admission with a lower respiratory code
A course of prednisolone
A course of systemic antibiotics coded for a lower respiratory tract infection

22. REG projects with an ACO component
Clinical and Cost implications of OLDOSA
The term “OLDOSA syndrome” has been proposed1, which refers to the coexistence of OLD (obstructive lung disease: COPD and asthma) and OSA
AIMS:
Evaluate the impact of (i) continuous positive airway pressure (CPAP) therapy
(ii) a sleep breathing disorder diagnosis (as a proxy for CPAP treatment)
(iii) an OSA diagnosis
on clinical outcomes and healthcare resource utilisation in UK patients with comorbid OLD
Obstructive sleep apnoea WG are looking for anyone interested in being involved
1. Ioachimescu OC, et al. Respirology. 2013;18:421-31

23. 3) Any new ideas for projects

24. Prioritisation Are these projects still: Relevant? Feasible? Valid?
A priority?
How do we set priorities in ACO research?
How to we ensure these priorities are pursued?
What are the two most important projects to push forwards?

25. Next steps for Phase I study-
Evaluation of ACO definition in other national databases
Develop a work plan-
Will it be possible to share the data? So one person can do all the analysis
Or will different people need to analyse the different databases?
Should be possible to share analysis scripts to minimize analysis time.
Need to secure - funding
- database access
- analytical support