Adamek, L

Agusti, A

Decramer, M

Jones, PW

Mullerova, H

Raillard, A

Wedzicha, JA

Zhu, C-Q

American Journal of Respiratory and Critical Care Medicine

English

St George's Online Research Archive

CARDIOVASCULAR DISEASE DOES NOT PREDICT EXACERBATION RATE OR MORTALITY IN COPD  Paul W Jones1,2, Hana Mullerova3, Alvar Agusti4, Marc Decramer5, Lukasz Adamek6, Alice Raillard7, Chang-Qing Zhu8, Jadwiga A Wedzicha9  1Institute of Infection and Immunity, St. George’s University of London, London, United Kingdom 2 Respiratory Medical Franchise, GSK, Brentford, United Kingdom 3 Respiratory Epidemiology, GSK R&D, Uxbridge, United Kingdom 4Respiratory Institute, Hospital Clinic, IDIBAPS, Universitat de Barcelona and CIBER Enfermedades Respiratorias (CIBERES), Spain 5Respiratory Division, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium 6 Formerly employed by Respiratory Medical Franchise, GSK, Brentford, United Kingdom  7 Formerly employed by Direction Excellence Medicale Opérationnelle, GSK France, Paris, France 8 Clinical Statistics, GSK R&D, Uxbridge, United Kingdom 9National Heart and Lung Institute, Imperial College London, London, UK  Correspondence: PW Jones. Institute of Infection and Immunity, St. George’s University of London, London, United Kingdom. Email: pjones@sgul.ac.uk  Funding: This study was funded by GSK. Page 1 of 121  Author contributions:  All authors contributed to the study design and conduct, interpreted the results, and participated in the manuscript writing. HM, LA, AR and CCZ also contributed to the study data analysis plan.     Page 2 of 122  To the Editor Cardiovascular disease (CVD) is common in patients with chronic obstructive pulmonary disease (COPD) (1-4), yet it is unclear whether its presence increases the incidence of acute exacerbations (AECOPD) or the risk of death. Observational studies have shown that COPD is associated with a 2-5 times higher risk of ischaemic heart disease (IHD), cardiac dysrhythmia, heart failure, diseases of the pulmonary circulation, and diseases of the arteries, compared with non-COPD populations (4,5). A prospective evaluation of COPD exacerbations in patients with comorbid IHD from the London COPD Cohort reported longer duration but not an increased frequency of AECOPD in patients with IHD (6). This prospective study was designed to test the hypothesis that the presence of CVD increases the risk of AECOPD and/or death in COPD patients recruited in a primary care setting. Methods The ACCESS study (Assessment of Comorbidities in COPD in European Symptomatic Subjects; NCT01516528; 115058 study) was a prospective, longitudinal, observational, non-drug interventional, two-year study in COPD patients enrolled from primary care in Belgium, France, Germany, the Netherlands, Poland, and Spain.  Patients, visiting their general practitioner (GP) for any reason, were invited to participate if they were ≥40 years old, current or ex-smoker (smoking history of ≥10 pack-years), a minimum of 12 months of prior history of COPD, and a forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) post-bronchodilator ratio <0.70. Patients with a primary diagnosis of asthma, pulmonary fibrosis, asbestosis, any cancer or clinically significant bronchiectasis were excluded. Page 3 of 123  Patients were followed up for 27 months through clinic visits at screening (-3 months), baseline (0 months), 12 months and 24 months, and by phone at 3, 6, 9, 15, 18 and 21 months. Written informed consent was obtained from all subjects and the study was approved by independent ethics committees as per the requirements in each country.   The prevalence of CVD at baseline was defined using a composite measure with previously published criteria (7). The primary outcome was the annual rate of moderate-severe AECOPD during the 24-month follow-up period. Moderate AECOPD was defined as a worsening of symptoms that required oral corticosteroids and/or antibiotics, whilst severe exacerbations were defined as those that included hospitalization. Mortality was a secondary outcome; details of patient deaths were obtained from the GP. To derive event rates and test associations, we applied multivariable negative binomial regression and Cox proportional hazards regression models, respectively. All analysis was pre-specified except hospitalizations and mortality outcome modeling which were post-hoc.  Results 2,887 evaluable patients were included in this analysis. Their mean age was 66 years, 70% were male, and 47% were current smokers with a mean post-bronchodilator FEV1% predicted of approximately 60% (Table 1). The mean number of moderate-severe AECOPD episodes in the previous year was 0.61 (95% CI: 0.57, 0.64); for severe AECOPD: 0.08 (95% CI:  0.07, 0.09). At baseline, COPD patients with CVD (1375, 48%) were older and more likely to be ex-smokers, but had similar airflow limitation and history of exacerbations to those without CVD.  Page 4 of 124  Over 24 months, there was no difference in the annualized rate of AECOPD between those with or without CVD (adjusted rate per patient: 0.63 (95% CI: 0.57, 0.69) vs. 0.63 (95% CI: 0.58, 0.69); the Rate Ratio was 0.99 (95% CI: 0.88,1.11) (Table 2). Male sex, lower post-bronchodilator FEV1 % predicted, and higher CAT score, but not older age, were significantly independently associated with a higher overall rate of exacerbations. Addition of history of AECOPD events in the 12 months prior to study baseline into models was significantly associated with the rate during the study, but it didn’t change the effect of CVD on this outcome (Rate Ratio: 1.01 [95% CI: 0.90,1.12]). Additionally, a sensitivity analysis for each CVD diagnosis from the composite CVD definition, did not show any relationship between individual CV diseases and the incidence of AECOPD. The unadjusted annual rate of severe exacerbations (requiring hospitalization) was 51% higher in patients with CVD than those with no CVD (Rate Ratio 1.51 [95% CI: 1.16; 1.97], p=0.003)). In the adjusted multivariable model, this trend was not statistical significant (Rate Ratio 1.14 (95% CI: 0.87; 1.50) (Table 2). The crude mortality rate was greater in patients with CVD compared with no CVD (3.0 events per 100 patient years [95% CI: 2.3, 3.6] vs. 1.5 [95% CI: 1.1, 2.0]), however, this association was attenuated in the multivariable model (Hazard Ratio in patients with/without CVD: 1.26 (95% CI: 0.85, 1.87) due to statistically significant effects of age, gender and COPD clinical characteristics. Discussion:  This is the first large scale study to prospectively evaluate the relationship between CVD and exacerbation rates and mortality in a well characterized cohort of COPD patients. Although, on average, the patients were relatively mild in terms of lung function, CAT score and exacerbation rate, the cohort did contain the whole range of Page 5 of 125  disease severity. We found that the presence of CVD was not independently associated with an increased risk of exacerbations or death. This finding was not expected in view of prior evidence that there was a link (8-10). There are at least two reasons to explain this difference. Some earlier studies had methodological limitations, for example, two were retrospective and used data extracted from routine electronic medical records. Furthermore, it is also important to understand temporal associations and mechanisms of causality. For example, patients hospitalized for AECOPD are at increased risk of myocardial infarction following admission (11,12), and case series data provide evidence of a link through viral infections, which may trigger both AECOPD and vascular events (13,14). It is conceivable that within this primary care population, there was an insufficient number of patients of a particular phenotype in whom a link does exist, or patients did not have sufficiently severe COPD to demonstrate the link, but the sample was large and the rate ratio was very close to 1.0, so the likelihood of this being a factor is low. We conclude that there is little or no evidence that the presence of CVD in COPD patients increases the risk of exacerbations or death, but it may increase the risk of hospitalization.   Page 6 of 126  Acknowledgements The authors thank all participants for their willingness to contribute to medical research and all field investigators for their high-quality daily work. We acknowledge editorial support in the form of draft manuscript development, collating of author comments and copyediting which was provided by Kate Hollingworth of Continuous Improvement Ltd. This support was funded by GSK. We also thank Paola Rabier (GSK) who performed the coordination of the Data Management activities between countries, Mathieu Vasselle (GSK) who managed the statistical activities at the start of the studies, Celine Fragneaud (Lincoln) who provided the statistical results and Camille Martinet (GSK) for reviewing the paper.  Disclosure statement This study was funded by GSK (study HZC115058, NCT01516528). PWJ, HM and C-QZ are employees of GSK and hold GSK shares. LA and AR were employees of GSK during the study conduct and analysis.  AA has received funds for speaking at meetings, participating in advisory boards and/or research from Almirall, Astra-Zeneca, Boheringer-Ingelheim. GSK, MSD, Menarini, Novartis, Teva, Takeda and Kyorin. JAW reports, during the conduct of the study, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from GlaxoSmithKline, personal fees from Pfizer, grants, personal fees and non-financial support from Takeda, personal fees and non-financial support from Astra Zeneca, personal fees and non-financial support from Boehringer Ingelheim, grants and personal fees from Johnson and Johnson, grants and personal fees from Vifor Pharma, personal fees from Bayer, personal fees from Chiesi, personal fees from Napp. MD has received a grant from Astra Zeneca, and Page 7 of 127  has received funds for consultancy work, giving lectures and/or partciapting in advisory boards from Boehringer-Pfizer, GSK, Nycomed, Dompé, Novartis, and Altana.     Page 8 of 128  REFERENCES 1. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Available from: http://www.goldcopd.org/. 2. Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest 2005;128:2640–2646.  3. Agarwal S, Rokadia H, Senn T, Menon V. Burden of cardiovascular disease in chronic obstructive pulmonary disease. Am J Prev Med 2014;47(2):105–114. 4. Müllerova H, Agusti A, Erqou S, Mapel DW. Cardiovascular comorbidity in COPD. Systematic literature review. Chest 2013;144(4):1163–1178. 5. Chen W, Thomas J, Sadatsafavi M, FitzGerald JM. Risk of cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Lancet Respir Med 2015;3:631–39. 6. Patel ARC, Donaldson GC, Mackay AJ, Wedzicha JA, Hurst JR. The impact of ischemic heart disease on symptoms, health status, and exacerbations in patients with COPD. Chest 2012;141:851–857. 7. Vestbo J, Anderson J, Brook RD, Calverley PMA, Celli BR, Crim C,  Martinez FJ, Yates J, Newby DE, on behalf of the SUMMIT Investigators. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. The Lancet 2016;387:1817-1826. 8. Dalal AA, Shah M, Lunacsek  O, Hanania NA. Clinical and economic burden of patients diagnosed with COPD with comorbid cardiovascular disease. Respir Med 2011;105:1516-1522. 9. McGarvey L, Lee AJ, Roberts J, Gruffydd-Jones K, McKnight E, Haughney J. Page 9 of 129  Characterisation of the frequent exacerbator phenotype in COPD patients in a large UK primary care population. Respir Med 2015;109:228-237. 10. Niewoehner DE, Lokhnygina Y, Rice K, Kuschner WG, Sharafkhaneh A, Sarosi GA, Krumpe P, Pieper K, Kesten S. Risk Indexes for Exacerbations and Hospitalizations Due to COPD. Chest 2007;131:20–28. 11. McAllister DA, Maclay JD, Mills NL, Leitch A, Reid P, Carrutherse R, O’Connore J, McAlpine L, Chalmers G, Newby DE, Clark E, Macfarlane PW, MacNee W. Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD. Eur Respir J 2012;39:1097–1103. 12. Donaldson GC, Hurst JR, Smith CJ, Hubbard RB, Wedzicha JA. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010;137(5):1091–1097. 13. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004;351:2611-8. 14. Clayton TC, Capps NE, Stephens NG, Wedzicha JA, Meade TW. Recent respiratory infection and the risk of myocardial infarction. Heart 2005;91:1601–1602.    Page 10 of 1210  Table 1: Baseline characteristics at the screening visit  Patients with CVD (N=1375) Patients without CVD (N=1512)  Total (N=2887) Age (years), mean (SD)  69.7 (8.7) 62.9 (9.9) 66.1 (10.0) Male, n (%)  1050 (76) 964 (64) 2014 (70) Body mass index, mean kg/m2   (SD)  27.9 (5.1) 26.5 (5.3) 27.2 (5.2) Current smoker, n (%)  534 (39) 820 (54) 1354 (47) CAT score*, mean (SD)   15.6 (7.7) 14.5 (7.7) 15.0 (7.7) Mean post-bronchodilator FEV1 % predicted (SD)  58.8 (19.1) 60.0 (19.8) 59.4 (19.5) GOLD grade airflow limitation 1 - mild 2 - moderate 3 - severe 4 - very severe  183 (13.3) 736 (53.5) 376 (27.3) 80 (5.8)  238 (15.7) 779 (51.5) 393 (26.0) 102 (6.7)  421 (14.6) 1515 (52.5) 769 (26.6) 182 (6.3) GOLD 2016 group†, n (%) A – low symptom/low risk B – high symptom/low risk C – low symtoms/high risk D – high symptom/high risk  228 (17) 548 (40) 91 (7) 505 (37)  337 (22) 549 (37) 119 (8) 497 (33)  565 (20) 1097 (38) 210 (7) 1002 (35) COPD exacerbations in12 months prior to baseline Moderate-severe  N (%) patients with ≥1 event Mean (95% CI) Events requiring hospitalization N (%) patients with ≥1 event Mean (95% CI)    516 (38) 0.60 (0.54;0.65)  113 (8) 0.11 (0.09;0.14)    570 (38) 0.61 (0.56;0.66)  68 (4) 0.05 (0.04;0.07)    1086 (38) 0.61 (0.57;0.64)  181 (6) 0.08(0.07;0.09) *CAT was assessed at the baseline visit; †Combined assessment based on CAT as a symptom measure according to GOLD 2016. CVD: cardiovascular disease; CAT: COPD Assessment Test; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 sec; GOLD: Global Initiative for Chronic Obstructive Lung Disease; SD: standard deviation; CI: confidence interval Page 11 of 1211  Table 2:  Adjusted annual rate of moderate-severe COPD exacerbations and hospitalizations due to COPD after 24 months of follow-up - Negative binomial regression analysis including covariates  CVD (N=1375) No CVD (N=1512) Adjusted annual rate per patient of moderate-severe exacerbations (95% CI)  0.63 (0.57;0.69)  0.63 (0.58;0.69) Rate Ratio in patients with CVD / without CVD (95% CI) Effect of covariates; parameter estimate (p-value):  Age  Gender (female)  Smoking status (current smoker)  Post-bronchodilator FEV1 % predicted  CAT score 0.99 (0.88;1.11)    0.0057 (0.074) 0.1788 (0.004) - 0.0997 (0.093) - 0.0142 (<0.001)  0.0368 (<0.001) Adjusted annual rate per patient of hospitalizations due to COPD (95% CI)  0.05 (0.04;0.06)  0.04 (0.04;0.06) Rate Ratio in patients with CVD / without CVD (95% CI) Effect of covariates (p-value)  Age  Gender (female)  Smoking status (current smoker)  Post-bronchodilator FEV1 %  predicted  CAT score 1.14 (0.87;1.50)   0.0395 (<0.001) 0.2738 (0.059) 0.0416 (0.767) -0.0381 (<0.001)  0.0725 (<0.001) Models were also adjusted for the country effect. CVD: cardiovascular disease; CAT: COPD Assessment Test; FEV1: forced expiratory volume in 1 sec; CI: confidence interval    Page 12 of 12

Cardiovascular Disease Does Not Predict Exacerbation Rate or Mortality in Chronic Obstructive Pulmonary Disease.

Paul W. Jones

Hana Mullerova

Alvar Agusti

Marc Decramer

Lukasz Adamek

Alice Raillard

Chang-Qing Zhu

Jadwiga A Wedzicha

Crossref

Cardiovascular Disease Does Not Predict Exacerbation Rate or Mortality in Chronic Obstructive Pulmonary Disease

Spiral - Imperial College Digital Repository

Cardiovascular disease does not predict exacerbation rate or mortality in COPD

http://openaccess.sgul.ac.uk/109160/7/Jones%20et%20al.pdf

Cardiovascular Disease Does Not Predict Exacerbation Rate or Mortality in Chronic Obstructive Pulmonary Disease.

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Spiral - Imperial College Digital Repository