COPD disease severity and the risk of venous thromboembolic events: a matched case–control study

Figures & data

Figure 1 Patient flow: selection of cases and matched controls from a source population of patients contributing data to CPRD with a diagnosis of COPD.

Abbreviations: COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research Datalink; GP, general practitioner; VTE, venous thromboembolism.

Table 1 Characteristics of cases and matched controls, and ORs for first VTE (univariate analyses adjusted for age, sex, and GP practice by matching)

Characteristic	Cases	Controlsa	OR (95% CIs)
	Number (%)	Number (%)
Exacerbation frequency	3,594 (100.0)	10,782 (100.0)
Infrequent	2,547 (70.9)	7,765 (72.0)	1
Frequent	1,047 (29.1)	3,017 (28.0)	1.06 (0.97, 1.15)
Sex	3,594 (100.0)	10,782 (100.0)	Matched
Men	1,870 (52.0)	5,610 (52.0)
Women	1,724 (48.0)	5,172 (48.0)
Index age (years)	3,594 (100.0)	10,782 (100.0)	Matched
Under 60	268 (7.5)	800 (7.4)
60–69	876 (24.4)	2,643 (24.5)
70–79	1,418 (39.5)	4,280 (39.7)
80 and over	1,032 (28.7)	3,059 (28.4)
Smoking statusb	3,593 (100.0)	10,773 (100.0)
Nonsmoker	369 (10.3)	1,089 (10.1)	1.00 (0.88, 1.14)
Ex-smoker	1,634 (45.5)	4,829 (44.8)	1
Current smoker	1,590 (44.3)	4,855 (45.1)	0.96 (0.89, 1.05)
BMIb	3,494 (100.0)	10,526 (100.0)
Underweight	193 (5.5)	826 (7.9)	0.83 (0.70, 0.98)
Normal weight	1,109 (31.7)	3,910 (37.1)	1
Overweight	1,123 (32.1)	3,393 (32.2)	1.18 (1.07, 1.30)
Obese	1,069 (30.6)	2,397 (22.8)	1.61 (1.45, 1.77)
Family history	3,594 (100.0)	10,782 (100.0)
No	2,597 (72.3)	7,870 (73.0)	1
Yes	997 (27.4)	2,912 (27.0)	1.04 (0.95, 1.14)
Hypertension	3,594 (100.0)	10,782 (100.0)
No	1,764 (49.1)	5,436 (50.42)	1
Yes	1,830 (50.9)	5,346 (49.6)	1.06 (0.98, 1.14)
Dyslipidaemia	3,594 (100.0)	10,782 (100.0)
No	2,873 (79.9)	8,541 (79.2)	1
Yes	721 (20.1)	2,241 (20.8)	0.95 (0.86, 1.05)
Diabetes	3,594 (100.0)	10,782 (100.0)
No	2,998 (83.4)	8,997 (83.4)	1
Yes	596 (16.6)	1,785 (16.6)	1.00 (0.90, 1.11)
Atrial fibrillationb	3,594 (100.0)	10,781 (100.0)
No	3,129 (87.1)	9,593 (89.0)	1
Yes	465 (12.9)	1,188 (11.0)	1.21 (1.08, 1.36)
Heart failureb	3,594 (100.0)	10,780 (100.0)
No	3,059 (85.1)	9,650 (89.5)	1
Yes	535 (14.9)	1,130 (10.5)	1.52 (1.36, 1.70)
CVDs (composite)c	3,594 (100.0)	10,782 (100.0)
No CVDs	2,558 (71.2)	7,931 (73.6)	1
1 CVD	719 (20.0)	2,041 (18.9)	1.10 (1.00, 1.21)
2 or more CVDs	317 (8.8)	810 (7.5)	1.23 (1.07, 1.41)

Notes:

a Including duplicates. Since control selection was concurrent with replacement, some cases were picked as a control before they became a case and some people were selected as a control more than once. Hence among the control group there are duplicated individuals. There are 10,119 individual controls.

b Some missing data.

c Myocardial infarction, angina, peripheral arterial disease, acute coronary syndrome.

Abbreviations: BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; GP, general practitioner; OR, odds ratio; VTE, venous thromboembolism.

Table 2 Characteristics of frequent and infrequent exacerbators, separately by cases and controls

Characteristic	Cases			Controlsa			P-valueb
	Number of subjects	Infrequent	Frequent	Number of subjects	Infrequent	Frequent
		Number (%)	Number (%)		Number (%)	Number (%)
Sex	3,594	2,547 (70.9)	1,047 (29.1)	10,782	7,765 (72.0)	3,017 (28.0)
Men	1,870	1,336 (71.4)	534 (28.6)	5,610	4,105 (73.2)	1,505 (26.8)
Women	1,724	1,211 (70.2)	513 (29.8)	5,172	3,660 (70.8)	1,512 (29.2)	0.005
Index age (years)	3,594	2,547 (70.9)	1,047 (29.1)	10,782	7,765 (72.0)	3,017 (28.0)
<60	268	194 (72.4)	74 (27.6)	800	575 (71.9)	225 (28.1)
60–69	876	608 (69.4)	268 (30.6)	2,643	1,895 (71.7)	748 (28.3)
70–79	1,418	981 (69.2)	437 (30.8)	4,280	3,051 (71.3)	1,229 (28.7)
80 and over	1,032	764 (74.0)	268 (26.0)	3,059	2,244 (73.4)	815 (26.6)	0.259
Smoking statusc	3,593	2,546 (70.9)	1,047 (29.1)	10,773	7,758 (72.0)	3,015 (28.0)
Nonsmoker	369	276 (74.8)	93 (25.2)	1,089	779 (71.5)	310 (28.5)
Ex-smoker	1,634	1,150 (70.4)	484 (29.6)	4,829	3,403 (70.5)	1,426 (29.5)
Current smoker	1,590	1,120 (70.4)	470 (29.6)	4,855	3,576 (73.7)	1,279 (26.3)	0.002
BMIc	3,496	2,478 (70.9)	1,016 (29.1)	10,526	7,563 (71.9)	2,963 (28.2)
Underweight	193	143 (74.1)	50 (25.9)	826	603 (73.0)	223 (27.0)
Normal weight	1,109	783 (70.6)	326 (29.4)	3,910	2,779 (71.1)	1,131 (28.9)
Overweight	1,123	796 (70.9)	327 (29.1)	3,393	2,427 (71.5)	966 (28.5)	0.266
Obese	1,069	756 (70.7)	313 (29.3)	2,397	1,754 (73.2)	643 (26.8)
Family history	3,594	2,547 (70.9)	1,047 (29.1)	10,782	7,765 (72.0)	3,017 (28.0)
No	2,597	1,824 (70.2)	773 (29.8)	7,870	5,686 (72.3)	2,184 (27.8)
Yes	997	723 (72.5)	274 (27.5)	2,912	2,079 (71.4)	833 (28.6)	0.385
Hypertension	3,594	2,547 (70.9)	1,047 (29.1)	10,782	7,765 (72.0)	3,017 (28.0)
No	1,764	1,246 (70.6)	518 (29.4)	5,436	3,863 (71.1)	1,573 (28.9)
Yes	1,830	1,301 (71.1)	529 (28.9)	5,346	3,902 (73.0)	1,444 (27.0)	0.026
Dyslipidemia	3,594	2,547 (70.9)	1,047 (29.1)	10,782	7,765 (72.0)	3,017 (28.0)
No	2,873	2,043 (71.1)	830 (28.9)	8,541	6,177 (72.3)	2,364 (27.7)
Yes	721	504 (69.9)	217 (30.1)	2,241	1,588 (70.9)	653 (29.1)	0.172
Diabetes	3,594	2,547 (70.9)	1,047 (29.1)	10,782	7,765 (72.0)	3,017 (28.0)
No	2,998	2,125 (70.9)	873 (29.1)	8,997	6,528 (72.6)	2,469 (27.4)
Yes	596	422 (70.8)	174 (29.2)	1,785	1,237 (69.3)	548 (30.7)	0.005
Atrial fibrillationc	3,594	2,547 (70.9)	1,047 (29.1)	10,781	7,764 (72.0)	3,017 (28.0)
No	3,129	2,216 (70.8)	913 (29.2)	9,593	6,912 (72.1)	2,681 (28.0)
Yes	465	331 (71.2)	134 (28.8)	1,188	852 (71.7)	336 (28.3)	0.808
Heart failurec	3,594	2,547 (70.9)	1,047 (29.1)	10,780	7,763 (72.0)	3,017 (28.0)
No	3,059	2,178 (71.2)	881 (28.8)	9,650	6,992 (72.5)	2,658 (27.5)
Yes	535	369 (69.0)	166 (31.0)	1,130	771 (68.2)	359 (31.8)	0.003
CVDs	3,594	2,547 (70.9)	1,047 (29.1)	10,782	7,765 (72.0)	3,017 (28.0)
No CVD	2,558	1,817 (71.0)	741 (29.0)	7,931	5,770 (72.8)	2,161 (27.3)
1 CVD	719	507 (70.5)	212 (29.5)	2,041	1,450 (71.0)	591 (29.0)
2 or more CVDs	317	223 (70.4)	94 (29.7)	810	545 (67.3)	265 (32.7)	0.003

Notes:

a Including duplicates.

b The reported P-value is for the association between exacerbation frequency and the listed covariate in the control group. Values in bold indicate significantly increased odds in frequent exacerbators compared with infrequent exacerbators.

c Some missing data.

Abbreviations: BMI, body mass index; CVD, cardiovascular disease.

Table 3 Percentage of frequent exacerbators with mild, moderate, severe, and very severe disease (based on the control group only)

	GOLD stage				Medication-based staging
	1	2	3	4	1	2	3	4
Total number of subjects	1,149	4,378	2,404	614	2,691	1,908	3,898	1,614
Number of frequent exacerbators	374	1,208	753	203	594	541	1,076	604
Frequent exacerbators as % of total	28.5	27.6	31.3	33.1	22.1	28.4	27.6	37.4

Abbreviation: GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Table 4 Summary of main results

Disease measure	Crudea ORs		Adjustedb ORs		Adjustedc ORs
	OR (95% CI)	P-value	OR (95% CI)	P-value	OR (95% CI)	P-value
Exacerbation frequency
Infrequent	1		1		1
Frequent	1.06 (0.97, 1.15)	0.18	1.06 (0.97, 1.15)	0.22	1.05 (0.96, 1.14)	0.29
GOLD (FEV1) staging
Mild	1		1		1
Moderate	1.15 (1.01, 1.30)	0.031	1.17 (1.03, 1.33)	0.013	1.16 (1.03, 1.32)	0.018
Severe/very severe	1.08 (0.94, 1.23)	0.280	1.16 (1.02, 1.33)	0.030	1.14 (1.00, 1.31)	0.058
Medication-based staging
Mild/moderate	1		1		1
Severe	1.16 (1.07, 1.26)	0.001	1.16 (1.07, 1.27)	0.001	1.17 (1.06, 1.26)	0.001
Very severe	1.52 (1.37, 1.69)	0.001	1.54 (1.38, 1.72)	<0.001	1.52 (1.37, 1.69)	<0.001

Notes:

a Adjusted for age, sex, and GP practice (matching variables).

b Adjusted for age, sex, GP practice, BMI, and smoking habits.

c Adjusted for age, sex, GP practice, BMI, smoking habits, CVDs [composite measure], and heart failure. To avoid having a small number of subjects in the reference category and thus compromising the precision of the effect estimates, the normal weight category (as opposed to underweight) was selected as the baseline for BMI and ex-smokers (as opposed to never smoked) the baseline for the smoking status variable in all regression models. Having examined the distribution of subjects among the disease severity categories as part of the descriptive analysis, the “severe” and “very severe” categories (GOLD stage 3+4) were collapsed into one (when disease is staged by spirometry, less than 10% of patients are categorized as having very severe disease). Likewise, in the case of the alternative, proxy measure of disease severity based on COPD medication history, the categories “mild” and “moderate” were collapsed into a single category (this then becomes the reference category).

Abbreviations: BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; FEV₁, forced expired volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; GP, general practitioner; OR, odds ratio.