Longitudinal change in lung function

5.6.5.1. Change in FEV1 between BOLD and Follow-up study

The post-bronchodilator FEV1 values (in litres) and changes between studies were not parametrically distributed. Results are presented in Table 24, Figure 14 and Figure 15. There was a significant decline in FEV1 (litres) between the BOLD and Follow-up studies (Wilcoxon p<0.0001), with a median decline of 0.155L.

Table 24: Comparison of FEV1 (litres) between BOLD and Follow-up studies (all subjects).

n Mean Median sd Min Max (IQR)

BOLD FEV1 106 1.78 1.64 0.655 0.65 4.01 (1.28 - 2.27) Wilcoxon

p<0.0001

Follow-up FEV1 106 1.63 1.51 0.662 0.61 3.57 (1.12 - 2.13)

1 2 3 4 Litres Wilcoxon p=0.0000 (FEV1 in litres)

FEV1 at BOLD & TOPD Studies

BOLD 2005 TOPD (2010)

Figure 14: Comparison of FEV1 (litres) between BOLD and Follow- up studies (all subjects).

1 2 5 19 36 13 2 1 0 10 20 30 40 Number -2 -1 0 1 2

Change in FEV1 (litres) (n =106)

Between BOLD (2005) and TOPD (2010)

Change in FEV1

Figure 15: Change in FEV1 (litres) between BOLD and Follow-up studies (all subjects).

Comparison of the changes in FEV1 (as percentage predicted) using the Student’s t-test for parametrically distributed variables [Table 25, Figure 16 and Figure 17], showed no difference in the FEV1 (% predicted) between the studies (t-test for paired samples: p=0.316).

Table 25: Comparison of FEV1 (% predicted) between BOLD and Follow-up studies.

n Mean Sd Min Max

BOLD FEV1 106 0.638 0.169 0.278 1.058 t-test for paired

samples; p=0.316 Follow-up FEV1 106 0.627 0.189 0.231 1.019 Change in FEV1 (% predicted) 106 -0.011 0.110 -0.334 0.476 .2 .4 .6 .8 1 Proportion of predicted

t test paired samples: p=0.316

(FEV1 as percentage predicted)

FEV1 at BOLD & TOPD Studies

BOLD 2005 TOPD 2005

Figure 16: Comparison of FEV1 (% predicted) between BOLD and

Follow-up studies. (n=106) 0 5 10 15 20 25 Frequency -40 -20 0 20 40 Change in FEV1 (% predicted)

Between BOLD (2005) and TOPD (2010)

Change in FEV1 (% predicted)

Figure 17: Change in FEV1 (% predicted) between BOLD and

The decline in FEV1 (L) was assessed according to GOLD stage at the BOLD 2005 study – a non-parametric variable. Although the mean decline in FEV1 appeared to be larger in the higher GOLD staging groups, when the appropriate non-parametric tests (i.e. Kruskal-Wallis test) were used to compare median values, no significant difference was found (Kruskal-Wallis; p=0.479). As GOLD stage 4 only comprised of one subject at follow-up, this stage was omitted from the analysis [see Table 26, Figure 18 and Figure 19].

Table 26: Change in FEV1 (mL) between the studies, grouped according to GOLD stage at BOLD study (2005).

n Mean Median sd Min Max IQR

GOLD 1 17 -202 -210 191 -440 140 -378: -60 GOLD 2 65 -177 -120 282 -1 370 470 -300: -40 GOLD 3 23 55 -170 464 -700 1 800 -250: 50 GOLD 4 1 370 370 - - - - Overall 106 -149 -155 324 -1 370 1 800 -300: -000 1 2 3 4 FEV1 in Litres

Stage 1 Stage 2 Stage 3 Stage 4

(grouped by GOLD Status at BOLD 2005)

FEV1 (in litres) at BOLD & TOPD Studies

BOLD 2005 TOPD 2010

GOLD Staging

Figure 18: FEV1 (litres) at BOLD and Follow-up studies, grouped according to GOLD stage in 2005.

-2,000 -1,000 0 1,000 2,000 Change in FEV1 (ml)

Stage 1 Stage 2 Stage 3 Stage 4

Kruskal Wallis p=0.4790

n=106

Between BOLD & TOPD Studies

Change in FEV1

Figure 19: Change in FEV1 (mL) between studies, grouped according to GOLD stage in 2005.

The median rate of change in FEV1 (mL per year), a non-parametrically distributed variable, was 28.93 mL/yr [see Table 27 and Figure 20]. No significance difference in rate of decline was found between subjects in the different GOLD stages assessed at the BOLD 2005 study (Kruskal-Wallis; p=0.247).

Table 27: Rate of change in FEV1 (mL per year) between BOLD and Follow-up studies.

(n=106) Mean Median sd IQR Min Max

Rate of FEV1 Change (mL/yr) -28.29 -28.93 59.71 (-54.76 – 0.00) -246.26 317.15 1 2 4 20 36 14 1 1 0 10 20 30 40 Number -300 -200 -100 0 100 200 300

Rate of Change in FEV1 (ml/year)

Between BOLD (2005) and TOPD (2010)

Rate of Change in FEV1

Figure 20: Rate of change in FEV1 (mL/ yr) between BOLD and Follow-up studies.

To examine the potential effect of treatment of airflow limitation on the results of spirometry in the Follow-up study, the association between rate of change in FEV1 and use of respiratory medication was assessed. No association between the use of any respiratory medication, LABA or ICS use alone; and rate of change of FEV1 was found (Wilcoxon p=0.168, p=0.868 and p=0.614, respectively). However, subjects who used SABAs showed a greater rate of decline in FEV1 (Wilcoxon p=0.0467) [see Table 28]. However, this is likely to be reverse causation, with SABAs being dispensed for subjects with

worsening lung function.

Table 28: Rate of change of FEV1 according to use of short-acting beta2- agonist (SABA).

n Mean Median IQR Min Max

No SABA use 74 -21.33 -21.21 -49.41: 5.65 -246.26 317.15

5.6.5.2. Change in FVC between the BOLD and Follow-up study

Between the BOLD and Follow-up studies, there was a significant decline in FVC (in litres) (Wilcoxon p=0.0419), but not FVC (% predicted) (Wilcoxon p=0.773) [see Table 29, Figure 21 and Figure 22].

Table 29: Comparison of FVC between BOLD and Follow-up studies.

(n=106) Mean Median sd Min Max IQR FVC (litres) At BOLD 2005 2.97 2.77 0.943 1.2 5.75 2.22: 3.54 Wilcoxon p=0.0419 At TOPD 2010 2.86 2.66 0.983 1.21 5.7 2.09: 3.45 Change in FVC -92.45 -75.00 564.04 1820 2730 -420.00: 200.00 FVC (% Predicted) At BOLD 2005 82.54 82.29 17.29 42.86 147.40 69.08: 92.08 Wilcoxon p=0.773 At TOPD 2010 82.64 82.64 15.36 48.17 128.86 71.82: 94.21 Change in FVC (%) 0.104 2.478 16.287 -61.263 52.352 -9.384: 10.423 1 2 3 4 5 6 FVC (in litres)

Wilcoxon Rank Sum: p=0.0419

(FVC in litres)

FVC at BOLD & TOPD Studies

BOLD 2005 TOPD 2010

Figure 21: Comparison of FVC (in litres) between BOLD and Follow-up

studies. 40 60 80 100 120 140 FVC (% Predicted)

*NHANES III Prediction Equations used

(FVC as percentage predicted)

FVC at BOLD & TOPD Studies

BOLD 2005 TOPD 2010

Figure 22: Comparison of FVC (% predicted) between BOLD and

Follow-up studies.

A significant difference in the change in FVC, in both millilitres (Kruskal-Wallis p=0.0073) and % predicted (Kruskal-Wallis p=0.0101), was observed when analysing according to GOLD stage at the BOLD 2005 study [see Table 30, Figure 23 and Figure 24].

Subjects in GOLD stage 1 at BOLD 2005 had a significantly greater decline in FVC compared to subjects in both GOLD stages 2 and 3 (p=0.0171

and p=0.0025, respectively). However, there was no significant difference in the change in FVC between subjects in GOLD stages 2 and 3 (p=0.136). GOLD stage 4 comprised of only one subject, and was therefore excluded from the analysis.

Table 30: Change in FVC between studies, grouped according to GOLD stage at BOLD 2005 study.

n Mean Median sd Min Max IQR

Change in FVC (in mL) GOLD 1 17 -386 -350 406.9 -1160 500 -520: -190 GOLD 2 65 -99 -80 510.1 -1820 1540 390: 190 Kruskal- Wallis GOLD 3 23 119 140 714.9 -1050 2730 -160: 270 p=0.0073 GOLD 4 1 510 510 - - - - - Total 106 -92 -75 564 -1820 2730 -420: 200 Change in FVC (% predicted) GOLD 1 17 10.09 -8.49 17.159 -61.26 16.00 -16.98: 1.43 GOLD 2 65 0.39 2.12 14.746 -33.45 52.35 -8.47: 10.42 GOLD 3 23 6.16 8.02 17.02 -23.89 52.14 -3.31: 15.50 Kruskal- Wallis GOLD 4 1 15.45 15.45 - - - p=0.0101 Total 106 0.10 2.48 16.29 -61.26 52.35 -9.38: 10.42 -2,000 -1,000 0 1,000 2,000 3,000 Change in FVC (ml)

Stage 1 Stage 2 Stage 3 Stage 4

n=106

Between BOLD & TOPD Studies

Change in FVC (millilitres)

Figure 23: Change in FVC (mL) between studies, grouped according to GOLD stage in 2005.

-50

0

50

Change in FVC (% Predicted)

Stage 1 Stage 2 Stage 3 Stage 4

Between BOLD & TOPD Studies

Change in FVC (% Predicted)

Figure 24: Change in FVC (% predicted) between studies, grouped according to GOLD stage

5.6.5.3. Change in FEV1:FVC between BOLD and Follow-up study

The absolute FEV1:FVC, a non-parametric variable, was found to be significantly lower in the Follow-up study compared with the BOLD study (Wilcoxon p=0.0047). The mean change in FEV1:FVC, a parametric variable, decreased by 2.5% (mean) [see Table 31].

When comparing the change in FEV1:FVC between GOLD stage groups in BOLD 2005, only a trend to significance was observed, with GOLD stages 2 and 3 demonstrating a greater decline (ANOVA; p=0.091). GOLD stage 4 (n=1) was excluded from this analysis.

Table 31: Comparison of FEV1:FVC between BOLD & TOPD studies.

n Mean sd IQR Min Max

BOLD 2005 106 60.0 9.00 (55.86 - 67.22) 35.44 70.21 Wilcoxon

TOPD 2010 106 57.5 13.96 (46.13 - 66.20) 27.01 89.60 p=0.0047

n Mean sd Min Max

Change in FEV1:FVC Overall 106 -2.50 9.76 -25.45 22.33 By GOLD stage (2005) GOLD 1 17 1.98 8.871 -9.52 19.23 GOLD 2 65 -3.08 9.659 -25.45 22.33 ANOVA GOLD 3 23 -4.52 10.116 -21.17 19.18 p=0.091 GOLD 4 1 5.20 - - - 20 40 60 80 100 FEV1:FVC Ratio n=106 at BOLD & TOPD Studies

FEV1:FVC Ratio

BOLD 2005 TOPD 2010

Figure 25: Comparison of FEV1:FVC between BOLD and TOPD studies.

20 40 60 80 100 FEV1:FVC Ratio

Stage 1 Stage 2 Stage 3 Stage 4

FEV1:FVC Ratio by GOLD Status in 2005

BOLD 2005 TOPD 2010

Figure 26: Comparison of FEV1:FVC between studies, grouped according to GOLD stage in 2005.