Prevalence of undiagnosed COPD in male patients with coronary artery disease: a cross-sectional study in Jordan

Abstract

Purpose

COPD and coronary artery disease (CAD) are common chronic diseases with shared risk factors. COPD continues to be largely underdiagnosed and undertreated. We aimed to describe the prevalence and predictors of undiagnosed COPD in Jordanian men with CAD.

Patients and methods

In a cross-sectional study conducted at a referral center in Jordan, male patients who underwent coronary angiography for suspected CAD and reported $10 pack-year of cigarette smoking were recruited. Pre- and post-bronchodilator spirometry was undertaken for all participants, and COPD was defined as post-bronchodilator FEV₁/FVC <70%. The finding of ≥50% coronary luminal narrowing confirmed the presence of CAD.

Results

Spirometry was undertaken for 376 men with mean age of 56.02±10.55 years, and 72.6% were active cigarettes smokers with a mean pack-year of 55.89±34.25. A CAD diagnosis was confirmed in 300 (79.8%) men. Spirometric criteria for COPD were met in 76 (15.7%) patients, of whom 91.5% were not previously diagnosed. COPD-related symptoms were common: chronic cough (44.4%), dyspnea (66.2%), and wheezes (27.9%). COPD was more common in patients with (18.0%) compared to patients without (6.6%) CAD (P=0.014). Multivariate logistic regression showed that the risk of COPD was higher in patients with CAD (OR 3.16, 95% CI, 1.10–9.09, P=0.033) and in those with chronic bronchitis (OR 13.07, 95% CI, 6.69–25.52, P<0.001).

Conclusion

There was a high prevalence of COPD among male patients with CAD and most were underdiagnosed despite having respiratory symptoms. Male smokers with CAD and respiratory symptoms should be evaluated for airflow limitation and the presence of COPD.

Keywords:

• COPD
• cardiovascular disease
• coronary catheterization
• airflow limitation
• spirometry

Introduction

COPD is a common and preventable respiratory disease characterized by persistent symptoms and airflow limitation, caused mainly by exposure to tobacco smoking.¹ COPD is the fourth leading cause of death in the world and is projected to be the third leading cause of death by 2020;² it continues to be an important health burden.¹

Patients with COPD commonly have comorbidities, including coronary artery disease (CAD), which may complicate treatment and increases the morbidity and mortality of the affected individuals. Furthermore, CAD continues to be the leading cause of disability and death in subjects older than 35 years^3,4 and accounts for half of all cardiovascular deaths in the United States.³ The coexistence of COPD and CAD is expected, given the shared common risk factor of cigarette smoking and the increased prevalence of both diseases with advancing age. Moreover, systematic inflammation in COPD,⁵ increased arterial stiffness, and endothelial dysfunction are potential modifiable mechanisms of cardiovascular morbidity and mortality in patients with COPD.⁶

The reported prevalence of CAD in patients with COPD can be up to 60%, with a relative risk of CAD as high as seven-fold.⁷ Furthermore, risk factors for CAD are common in individuals with COPD.⁸ Although the prevalence of COPD in patients with CAD is not widely reported, available reports show that it ranges from 10.5% to 33.6% and most cases of COPD were not previously diagnosed.^9–12 Lastly, patients with CAD who have coexisting COPD have increased morbidity and mortality,^12,13 whereas cardiovascular disease comorbidity is an important cause of mortality in patients with COPD.¹⁴

Prevalence and impact of both CAD and COPD is projected to increase in developing countries due to growing exposure to risk factors and an expected increase in the rate of tobacco consumption.¹⁵ Despite the relatively young population, the prevalence of COPD across the Middle East region is 3.6%¹⁶ and COPD is still largely underdiagnosed and undertreated.¹⁷ Given the scarcity of evidence on the association between COPD and CAD in developing countries and in the Middle East region in particular,^18,19 this study was conducted to describe the prevalence and predictors of COPD among male Jordanian smokers with angiographically proven CAD.

Material and methods

A cross-sectional study was conducted at the Prince Muna Cardiac Center, King Abdullah University Hospital in the northern part of Jordan. The hospital is a 600-bed referral center for a population of 2.8 million (one third of the Jordanian population). This study was approved by the Institutional Review Board of Jordan University of Science and Technology, and participants provided written informed consent. All adult male patients who underwent coronary angiography (CATH) for suspected CAD and had a history of cigarette smoking (≥10 pack-year) were recruited for the study. We excluded patients who were 1) unable to undertake spirometry testing (intubated, in shock, acute pulmonary edema, and patient with active angina pain) and 2) patients with a history of bronchial asthma or bronchiectasis.

During a single face-to-face encounter, sociodemographic data, smoking history, previous diagnosis of COPD, and risk factors for CAD were obtained. COPD-related symptoms were derived from the Arabic version of the Clinical COPD Questionnaire.²⁰ Pre- and post-bronchodilator spirometry using a portable spirometer (FlowScreen^® CT; eResearch Technology GmbH, Höchberg, Germany) was conducted during the same session. Spirometry was undertaken by trained study coordinators and the results were interpreted by a staff pulmonologist according to standard guidelines.^21,22 The device was calibrated on each testing day, according to the manufacturers’ instructions. The test was clearly explained and demonstrated to each participant. Forced expiratory maneuvers were repeated until three reproducible acceptable readings were obtained and the best FEV₁, FVC, and FEV₁/FVC ratios were used. The post-bronchodilator test was conducted during the same session for patients with a pre-bronchodilator FEV₁/FVC ratio of less than 70% and 15 minutes after the inhalation of 400 µg salbutamol from a metered-dose inhaler (Ventolin^®; GlaxoSmithKline plc, London, UK). COPD was defined as the presence of post-bronchodilator FEV₁/FVC of less than 70%. Airflow limitation was graded according to the Global Initiative for Obstructive pulmonary Disease (GOLD) classification into GOLD 1 (FEV₁≥80%), GOLD 2 (80%. FEV₁≥50%), GOLD 3 (50%. FEV₁≥30%), and GOLD 4 (FEV₁<30%) stages. Chronic bronchitis was defined as having cough and sputum production for at least 3 months in each of two consecutive years. CATH procedures were carried out and reported by a staff cardiologist using a Philips coronary angiography device (Allura Xper FD10\10 Clarity, Phillips, Amsterdam, the Netherlands). Patients with luminal coronary vessel narrowing ≥50% were considered to have CAD.

Statistical analysis

The IBM Statistical Package for Social Sciences software (SPSS) for Windows, Version 24.0 (IBM Corp, Armonk, NY, USA) was used for data processing and analysis. Characteristics of the subjects’ variables were described using frequency distribution for categorical variables and mean and SD for continuous variables. Tests of significance between groups were carried out using the chi-squared test or Fisher’s exact test for categorical variables, whereas continuous variables were first examined for deviation from normality at P<0.01 (Levene’s test) and, after demonstrating a normal distribution, the Student’s t-test or ANOVA were conducted. Post hoc comparative analysis was conducted between different treatment groups of CAD and in those without CAD using Tukey’s HSD test. Multivariate logistic regression analysis with backward elimination was conducted (OR, elimination threshold P>0.1) to determine the predictors of COPD, including age, active smoking vs ex-smoking, presence of CAD, chronic bronchitis, and symptoms of chough, dyspnea, and wheezes. The results of the logistic regression analysis were presented as ORs and their 95% CIs. A P-value of <0.05 was considered statistically significant for all analyses conducted.

Results

Participants

Between July and December 2017, a total of 785 patients underwent CATH, 427 (54.4%) met our cigarette-smoking criteria, and 413 (96.7%) were males. Thirty-seven patients were excluded for being unable/unwilling to complete spirometry (n=29) or for having bronchial asthma (n=8). Clinical data and spirometry were completed for 376 participants (91.0%) and were included in the analysis (Figure 1).

Figure 1 Flow chart of study participants showing excluded patients at different stages of the study.

Abbreviation: CAD, coronary artery disease.

Mean age of all participants was 56.02±10.55 years (range 21–85 years) and most were active cigarette smokers (273; 72.6%) with a mean pack-year of 55.89±34.25 (range 10–240). Symptoms of COPD were common; 167 (44.4%) patients with chronic cough, 249 (66.2%) with dyspnea, 105 (27.9%) with wheezing, and 89 (23.7%) met the clinical criteria of chronic bronchitis. CATH results showed that 300 (79.8%) had coronary angiographic evidence of CAD – 249 (83.0%) were treated with percutaneous coronary angioplasty (PCI), 33 (11.0%) were referred for coronary artery bypass surgery (CABG), and 18 (6.0%) received medical therapy. Patients with CAD were older (P=0.008), had more diabetes mellitus (P=0.037) and hypertension (P=0.028), and had greater airflow limitation with lower FEV₁ (P=0.034) and lower FEV₁/FVC ratio (P=0.038). There was no difference in smoking habits, presence of hyperlipidemia, frequency of respiratory symptoms, or body mass index (BMI) between those with and without CAD (Table 1).

Table 1 Characteristics of the participants according to the coronary artery disease status

Characteristic	All n=376	CAD n=300	No CAD n=76	P-value
Age, years mean ± SD	56.02±10.55	56.75±10.14	53.16±11.65	0.008
Diabetes mellitus, n (%)	148 (39.4)	126 (42.0)	22 (28.9)	0.037
Hypertension, n (%)	257 (68.4)	213 (71.0)	44 (57.9)	0.028
Hyperlipidemia, n (%)	100 (26.6)	79 (26.3)	21 (27.6)	0.819
Current smoker, n (%)	273 (72.6)	216 (72.0)	57 (75.0)	0.600
Pack-year, mean ± SD	55.89±34.25	56.81±35.47	52.22±28.88	0.297
Body mass index, mean ± SD	28.90±4.95	28.78±4.75	29.42±5.68	0.321
Chronic cough, n (%)	167 (44.4)	139 (46.3)	28 (36.8)	0.137
Dyspnea, n (%)	249 (66.2)	198 (66.0)	51 (67.1)	0.856
Wheezes, n (%)	105 (27.9)	83 (27.7)	22 (28.9)	0.824
Chronic bronchitis, n (%)	89 (23.7)	73 (24.3)	16 (21.1)	0.548
Previous COPD diagnosis, n (%)	9 (2.4)	8 (2.7)	1 (1.3)	0.693a
COPD (GOLD criteria)	59 (15.7)	54 (18.0)	5 (6.6)	0.014
Pre-bronchodilator
FEV1, L	2.61±0.72	2.57±0.71	2.77±0.74	0.034
FEV1, % predicted	79.68±16.57	78.943±16.44	82.57±16.88	0.089
FVC, L	3.22±0.89	3.20±0.90	3.31±0.88	0.367
FVC, % predicted	78.52±15.83	78.04±15.71	80.42±16.25	0.241
FEV1/FVC ratio	81.01±9.54	80.50±9.95	83.04±7.46	0.038

Note:

a Fisher’s exact test.

Abbreviations: CAD, coronary artery disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Chronic obstructive lung disease

Table 2 describe the demographics, symptoms, and spirometry findings in patients with and without COPD. Fifty-nine patients (15.7%) met the GOLD criteria of COPD and 12 (20.3%) had GOLD 1, 40 (67.8%) had GOLD 2, and 7 (11.9%) had GOLD 3. The majority of patients with COPD (54; 91.5%) were not previously diagnosed. Patient with COPD were older (P<0.001), had higher smoking intensity (P=0.009), had lower BMI (P=0.001), and had more COPD-related symptoms (P<0.001) than those who did not have COPD. The prevalence of COPD increased with age from 6.5% in patients <50 years old to 37.5% in those ≥70 years, P<0.001. The pre-bronchodilator mean FEV₁, % predicted was 65.64±15.61 (range 31%–118%) and the mean FEV₁/FVC ratio was 63.46±6.98 (range 39.0%–76.0%) whereas the post-bronchodilator mean FEV₁, % predicted was 68.25±15.82 (range 45%–102%) and the mean post-bronchodilator FEV₁/FVC ratio was 63.98±6.58 (range 37.0%–69.7%).

Table 2 Characteristics and spirometry findings of participants with chronic obstructive lung disease

Characteristic	No COPD n=317	COPD n=59	P-value
Age, years mean ± SD	54.93±10.25	61.92±10.28	<0.001
Current smoker, n (%)	228 (71.9)	45 (76.3)	0.492
Pack-year, mean ± SD	53.61±33.10	66.49±38.46	0.009
Body mass index, mean ± SD	29.28±5.00	26.87±4.13	0.001
Chronic cough, n (%)	115 (36.3)	52 (88.1)	<0.001
Dyspnea, n (%)	194 (61.2)	55 (93.2)	<0.001
Wheezes, n (%)	73 (23.0)	32 (54.2)	<0.001
Chronic bronchitis, n (%)	48 (15.1)	41 (69.5)	<0.001
Previous COPD diagnosis, n (%)	4 (1.3)	5 (8.5)	0.006a
Diabetes mellitus, n (%)	126 (39.7)	22 (37.3)	0.723
Hypertension, n (%)	220 (69.4)	37 (62.7)	0.310
Hyperlipidemia, n (%)	88 (27.8)	12 (20.3)	0.236
Pre-bronchodilator
FEV1, L	2.71±0.68	2.06±0.71	<0.001
FEV1, % predicted	82.29±15.41	65.64±15.61	<0.001
FEV1/FVC ratio	84.28±5.55	63.46±6.98	<0.001
Post-bronchodilator
FEV1, L	2.80±0.79	2.15±0.71	0.008
FEV1, % predicted	81.36±20.28	68.25±15.82	0.019
FEV1/FVC ratio	79.73±5.68	63.98±6.58	<0.001
CAD	246 (77.6)	54 (91.5)	0.014
Therapeutic strategy (CAD), n (%)
Percutaneous angioplasty	207 (65.3)	42 (71.2)	0.340a
Coronary artery bypass surgery	24 (7.6)	9 (15.3)
Medical therapy	15 (4.7)	3 (5.1)

Note:

a Fisher’s exact test.

Abbreviation: CAD, coronary artery disease.

Multivariate logistic regression with backward elimination was conducted to identify independent predictors of COPD among patients who underwent CATH (Table 3). In addition to coexisting CAD (OR=3.16, 95% CI 1.10–9.09, P=0.033), increasing age (OR=1.07, 95% CI 1.03–1.10, P<0.001) and having chronic bronchitis (OR=13.07, 95% CI 6.691–25.52, P<0.001) were independent predictors of COPD.

Table 3 Multivariate logistic regression model for the predictors of COPD

Variables	Univariate logistic regression		Backward stepwise model
	OR (95% CI)	P-value	OR (95% CI)	P-value
COPD (n=376)
Coronary artery disease	3.12 (1.20–8.09)	0.019	3.16 (1.10–9.09)	0.033
Age (years)	1.07 (1.04–1.10)	<0.001	1.07 (1.03–1.10)	<0.001
Chronic bronchitis	12.77 (6.77–24.05)	<0.001	13.07 (6.69–25.52)	<0.001
Pack-year	1.01 (1.00–1.02)	0.011	–	–
Active vs ex-smoker	1.26 (0.66–2.40)	0.492	–	–

COPD and CAD

COPD was more common in patients with CAD (54/300; 18.0%) compared to those without CAD (5/76; 6.6%) (P=0.014). The prevalence of COPD was 16.1% in the medical therapy group, 16.9% in the PCI group, and 27.3% in the CABG group (P=0.340). Similarly, the prevalence of COPD was not different between those who had single-vessel (17.1%), two-vessel (17.1%), or ≥3-vessel (19.1%) disease (P=0.191). ANOVA combined with post hoc analysis (Table 4) showed that airflow limitation (FEV₁ and FEV₁, %) was more prominent in patients who required CABG compared with patients without CAD (P=0.006 and P=0.018), respectively. However, there was no difference in airflow limitation among different groups of CAD treatment (P>0.05).

Table 4 Spirometry findings according to therapeutic strategy of patients with coronary artery disease compared to patients without coronary artery disease

Parameters	No CAD	Medical therapy	PCI	CABG	ANOVA (F)	P-value
FEV1, L	2.77±0.74a	2.59±0.73	2.61±0.71	2.28±0.67a	3.66	0.013
FEV1, % predicted	82.57±16.88b	76.78±18.85	79.96±16.43	72.49±13.78b	3.10	0.027
FVC, L	3.31±0.88	3.20±0.88	3.24±0.89	2.90±0.93	1.65	0.177
FVC, % predicted	80.42±16.25	78.17±16.37	78.80±15.50	72.24±16.20	2.14	0.094
FEV1/FVC ratio	83.04±7.46	79.28±11.27	80.75±9.52	79.27±12.31	1.78	0.150

Note:

a,b Indicates significant (P<0.05) difference between the groups using Tukey’s HSD post hoc analysis.

Abbreviations: CAD, coronary artery disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass surgery.

Discussion

This study described the prevalence of COPD in a population of male smokers with angiographically proven CAD in a developing country. Our main findings showed high prevalence of undiagnosed COPD in patients with CAD, and that the risk of COPD was higher in older patients with respiratory symptoms.

Our results were consistent with previous reports on the increased prevalence of COPD in patients with CAD.^9–12 A large multicenter study in Europe examined the prevalence of airflow limitation consistent with COPD in current and ex-smokers with ischemic heart disease. The prevalence of COPD ranged from 18.3% to 41.3%, whereas 70.6% of all patients and one third of those with severe airflow limitation were underdiagnosed. In a study from Spain, 33.6% of patients with CAD had air flow limitation consistent with COPD. Although they reported higher prevalence than this study, their patients were mostly older males, and those without CAD had a high prevalence of COPD (17.5%).⁹ In Japan, the prevalence of COPD in patients with CAD ranged from 10.5% to 25.9%.^10,11 Most recently, a study from Spain used methodology and definitions similar to those in our study and showed that one fourth of patients who underwent PCI for CAD had COPD.¹² Despite these consistent reports on the association between CAD and COPD, the latter is still largely underdiagnosed^{9,11,12,18,19} and carries higher mortality and morbidity.¹² In this study, the findings are in agreement with the inference in these reports: most patients with COPD who had CAD were not previously diagnosed. The low rate of diagnosis of COPD among our symptomatic heavy smokers is puzzling but in agreement with a previous study in primary care in Jordan.¹⁷ This may be partly explained by the lack of spirometry service in most primary-care centers in Jordan, by the notion that patients may be diagnosed with chronic bronchitis but not made aware of the diagnosis, or patients may simply deny having a disease that is strongly linked to their smoking habit.

Using a different methodology, epidemiological and hospital-based studies addressed the prevalence and risk of cardiovascular diseases including CAD in patients with an established diagnosis of COPD.^7,23 Results of a meta-analysis showed a consistent increased risk (two- to five-fold) of CAD in patients with COPD relative to those without COPD.²³ However, the risk appears to vary with the studied population, methodology of the study, and case definition. In the US population, 16.1% of patients with physician-diagnosed COPD had CAD, whereas 6.1% of patients without COPD had CAD. Patients with COPD were twice as likely to have CAD,²⁴ and this risk appears to be two times higher in those >60 years of age.²⁵ In a UK primary-care setting, the risk of acute myocardial infarction in patients with established diagnosis of COPD can be as high as ten-fold.²⁶ Finally, in various European populations, the prevalence of CAD in patients with COPD ranged from 14% to 30%.²³

Reports from developing countries on the association between COPD and CAD are scarce. In a small study from Sudan, 28% of patients with angiographically conformed CAD had FEV₁ <80% and were considered to have COPD. Another study from Pakistan found that one third of patients with CAD (based on ECG criteria) had COPD (FEV₁/FVC ratio <70%). Lastly, a large regional epidemiological study on the prevalence and impact of COPD in the Middle East and North Africa (BREATHE study) showed that the overall prevalence of COPD was 3.6% (ranging from 1.9% to 6.1%),¹⁶ and one fourth of all subjects with COPD reported having coexisting cardiovascular disease.²⁷ Our results are comparable to these regional studies, with almost one-in-five men with CAD having COPD. The prevalence of COPD in subjects without CAD (6.6%) is comparable to what has been reported in the general population in Jordan (5.4%–8.2%).^16,17

This significant association may be explained by the shared enhanced systemic inflammatory biomarkers including interleukin 6, C-reactive protein, and fibrinogen in patients with COPD and CAD,^5,6 which is more prominent during COPD exacerbations.²⁸ Moreover, hypoxic stress and the impaired arterial flow-mediated dilation in COPD²⁹ may result in vascular dysfunction that is noted in patients with COPD. The prevalence of both COPD and CAD increases with advancing age. In this study, the prevalence of COPD increased from 6.5% in younger patients to 37.5% in the older ones. Lastly, our patient population showed a high smoking intensity – a shared risk factor for both diseases.

The coexistence of COPD and CAD is detrimental and associated with a negative impact on the outcome of the affected individuals. Patients with undiagnosed COPD who undergo PCI have higher morbidity and mortality,^12,13 and cardiovascular comorbidity increases the burden of patients with COPD as more than a quarter of patients with COPD die of cardiovascular disease.^14,30 Moreover, patients admitted for COPD exacerbation were found to have a high troponin level in the absence of acute coronary symptoms and a subsequent coronary angiography showed significant coronary stenosis.³¹ A recent extended follow-up study on patients with CAD showed persistent increase of cardiovascular mortality in patients with coexisting COPD.³² Additionally, when treating patients who are diagnosed with both COPD and CAD, the long-term use of beta-2 agonists is considered a safe practice,³³ and the use of cardio-selective beta-blockers in CAD may even lower the mortality of patients with COPD. Lastly, statins – commonly used in patients with CAD – may be helpful in treating coexisting COPD.³⁴

In this study, there was a trend toward increased prevalence of COPD in patients who were referred for CABG compared with those who had PCI or medical therapy, but the difference was not statistically significant. Similarly, there was no increase in prevalence with increasing number of diseased coronary vessels. These findings may be partially explained by the lack of power in this study to detect the differences as well as by the notion that choice of therapy may be influenced by other factors beside the severity and complexity of the coronary disease. Moreover, the sole use of the number of vessels to stratify the severity of CAD has limitations,³⁵ and a more comprehensive angiographic scoring system has been developed to better define the severity and prognosis of coronary atherosclerosis.^36,37

This study had number of limitations that merit consideration. The study sample was recruited from a single referral center in Jordan, and women were not included in the analysis. Women represented <5% of smokers who had coronary angiography, and national data in Jordan showed that whereas one in two adult men smoke cigarettes, only 5% of women were regular smokers. This may limit the generalization of the results to the general population in Jordan and to other countries in the region. Furthermore, the study excluded patients with CAD and a smoking history of less than 10 pack-years and this may have resulted in an overestimation of the prevalence of COPD. In contrast, the study did not include patients with acute myocardial infarction and patients who were too ill to carry out spirometry, which may have resulted in a lower prevalence of COPD. Finally, the study was cross-sectional in nature and, therefore, was not intended to identify the impact of this strong association on short- and long-term morbidity and mortality of patients with CAD. Further multicenter and longitudinal studies using a robust scoring system of the severity of CAD are needed to address the impact of airflow limitation and COPD on the outcomes of patients with CAD in developing countries.

Conclusion

There was a high prevalence of COPD among male patients with CAD and most were underdiagnosed despite having respiratory symptoms. Smoking men with CAD and respiratory symptoms should be evaluated for airflow limitation and the presence of COPD.

Acknowledgments

The authors thank Mr Bryan Simmons for proofreading the manuscript.

Disclosure

The authors report no conflicts of interest in this work.