Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis

Data analysis

Group comparisons were made using unpaired t-tests or Chi-squared statistics. PFT trends were evaluated against mortality using proportional hazards analysis 17, with findings re-examined in multivariate models, including adjustment for age, sex, smoking status and baseline disease severity (CPI and D_L,CO levels in separate models) as follows.

1) Outcome was evaluated from the date of the 6-month follow-up PFTs. Mortality was compared between patient subgroups (significant decline; marginal decline; stable disease) in IPF and NSIP. Progression-free survival (i.e. duration of follow-up to a significant decline in FVC or death) was compared between patient subgroups in IPF.

2) Alternative threshold values for PFT decline were examined against mortality in IPF, comparing patients with marginal decline and those with stable disease. In post hoc analysis, the FVC threshold of 5% in IPF, corresponding to marginal decline, was compared with alternative thresholds (3, 4, 6 and 7%) using proportional hazards analysis. This analysis was performed to identify the optimal FVC trend threshold for possible use in pharmaceutical studies with regard to recruitment of patients with more progressive disease and end-point definition.

3) Survival analyses were repeated in the entire cohort of both IPF and NSIP patients (n = 156), with baseline D_L,CO <40% pred (n = 71) and, separately, with D_L,CO >40% pred (n = 85). This subanalysis was performed to explore the hypothesis that the prognostic value of PFT trends is influenced by the severity of baseline functional impairment.

Baseline demographics and determinants of outcome

Patients with IPF were older, more often male and more often current or ex-smokers, as shown in table 1⇓. Mortality was higher in IPF (5-yr survival 19%) than in NSIP (5-yr survival 65%).

Prevalence of serial decline in D_L,CO and FVC

As shown in table 2⇓, declines in D_L,CO and FVC at 6 months were more prevalent in IPF than in NSIP. In IPF, a high proportion of patients had either a significant or marginal decline (D_L,CO 55%; FVC 49%). In NSIP, fewer patients showed a marginal decline, such that the overall proportion with a significant or marginal decline was only 24% for D_L,CO and 28% for FVC.

In IPF patients a marginal decline in FVC was confirmed when PFTs were next measured in 16 of 18 cases (88.9%). One patient died without repeat PFTs.

Mortality in relation to PFT trends

Mortality was compared between patient subgroups with a significant decline, marginal decline and stable disease. Median survival was 29 months in patients with stable or improved serial FVC trends at 6 months (n = 38), 14 months in patients with a marginal decline in FVC at 6 months (n = 23), and 7 months in patients with a significant decline in FVC at 6 months (n = 23). In patients with IPF, mortality was higher with a marginal FVC decline (hazard ratio (HR) 2.31, 95% CI 1.19–4.50; p = 0.01) and with a significant FVC decline (HR 2.80, 95% CI 1.54–5.06; p<0.001) than in stable disease (fig. 1⇓). As shown in table 3⇓, this finding was robust with adjustment for disease severity (marginal decline versus stable disease; p<0.005). Mortality did not differ between patients with a marginal FVC decline and patients with a significant FVC decline.

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Fig. 1—

4-yr survival in relation to the magnitude of serial change in forced vital capacity at 6 months in patients with idiopathic pulmonary fibrosis (n = 84). Declines of 5–10% (marginal; ▾) and >10% (significant; ▪) were both associated with a worse prognosis than stable disease (•) (p<0.005).

By contrast, a marginal decline in D_L,CO was not associated with increased mortality in IPF (fig. 2⇓). Similarly, a marginal PFT decline (both in FVC and in D_L,CO) was not associated with increased mortality in NSIP. A significant decline in D_L,CO and FVC in both disease cohorts was predictive of increased mortality.

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Fig. 2—

4-yr survival in relation to the magnitude of serial change in diffusing capacity of the lung for carbon monoxide at 6 months in patients with idiopathic pulmonary fibrosis (n = 84). Survival did not differ between those with stable disease (•) or a 7.5–15% (marginal; ▾) decline. Patients with a >15% (significant; ▪) decline had a worse prognosis than those with stable disease or a marginal decline (p<0.0005).

In the combined cohort (n = 156), a marginal decline in FVC was associated with a poor outcome, both in 71 patients with severe disease (baseline D_L,CO <40%: HR 2.27, 95% CI 1.28–4.02; p<0.005) and in 85 patients with less severe disease (baseline D_L,CO >40%: HR 2.98, 95% CI 1.08–3.60; p = 0.03).

Progression-free survival in IPF

As shown in figure 3⇓, progression-free survival was highest in patients with stable disease, and higher in patients with a 5–10% decline in FVC than in those with a significant FVC decline (HR 2.24, 95% CI 1.63–3.08; p<0.001). When compared with stable disease, patients with a 5–10% decline in FVC had a marginal reduction in progression-free survival (HR 1.82, 95% CI 0.97–3.40; p = 0.06), which became statistically significant with adjustment for baseline D_L,CO (HR 2.56, 95% CI 1.17–4.38; p = 0.02) and CPI levels (HR 2.34, 95% CI 1.19–4.60; p = 0.01).

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Fig. 3—

2-yr progression-free survival in relation to the magnitude of forced vital capacity (FVC) serial change at 6 months in idiopathic pulmonary fibrosis (n = 84). A decline of 5–10% (marginal; ▾) or >10% (significant; ▪) is associated with worse prognosis than stable disease (•) (p<0.005). Patients with marginal decline had an intermediate progression-free survival compared with those with stable disease or a significant decline in FVC.

Parallel analyses of D_L,CO trends in IPF revealed that progression-free survival did not differ between patients with stable disease and those with a marginal decline in D_L,CO (p = 0.88).

Threshold values

Alternative threshold values for marginal change of between 3% and 7% were evaluated for FVC decline in IPF, with the exclusion of patients with a significant decline in FVC. The prognostic significance of thresholds of 4, 5 or 6% were broadly similar (table 4⇓). By contrast, a 3 or 7% threshold was non-discriminatory.

The sensitivity and specificity of a marginal and a significant decline in identifying mortality within 1 yr and within 2 yrs is shown in table 5⇓. Marginal change offered advantages over significant change in predicting death within 2 yrs, although the rise in sensitivity from 37 to 65% was partially offset by a smaller fall in specificity from 85 to 72%.

Relevance to clinical practice

It should be stressed that, in isolation, marginal FVC trends are not sufficiently prognostically accurate to determine management. However, our findings suggest that marginal reductions in serial FVC provide important ancillary support for true disease progression in the context of symptomatic deterioration or equivocal change on chest radiography. In other cases, marginal FVC trends provide a logical indication for more intense evaluation, including the performance of HRCT or repetition of PFTs. In that regard, marginal trends were reproduced in the great majority of patients when PFTs were next performed.

There are also possible implications for routine prognostic evaluation. The use of marginal trend thresholds may identify patients with real disease progression at higher risk of mortality who are not captured by traditional thresholds based on significant decline 1, 2, 4, 5. Clinicians are often confronted with diagnostic ambiguity between fibrotic NSIP and IPF, in the absence of surgical lung biopsy. Serial PFT trends at 6–12 months provide useful prognostic information, with stability indicative of a better outcome 2, 3, 5, 12. However, our results indicate that patients with IPF should be regarded as stable only if the FVC has declined by <5% at 6 months, although it should also be stressed that the long-term outcome remains poor, even in stable IPF, and that a single study is an insufficient basis on which to change routine clinical recommendations 19.

Relevance to clinical trials

The criteria used to define marginal decline in the present study were based on the principle that selected cut-off values should facilitate rapid computation in clinical practice. The current ATS criteria for significant change do not exactly capture the reproducibility of individual indices but are a close and user-friendly approximation. However, in pharmaceutical studies in which average population effects are defined rather than change in individual patients, clinical convenience is a lesser consideration and this prompted us to explore lower threshold values for marginal decline in the hope of amplifying the outcome signal. We demonstrated that threshold values of 4, 5 and 6% provided equivalent predictive power, whereas threshold values of 3 and 7% were non-discriminatory.

These findings have implications for the selection of end-points. In therapeutic trials of pirfenidone 8 and N-acetylcysteine 7 in IPF, average treatment effects were not definitive. With pirfenidone treatment, the relative FVC benefit was only 0.13 L at 9 months 8. N-acetylcysteine therapy was associated with a relative improvement of 8% in FVC and 14% in D_L,CO 7. These average effects are deceptive because they are not uniform but represent a clear benefit in some but not all cases. Our findings underline the possibility that even marginal FVC benefits in individuals may represent a worthwhile therapeutic effect (although the degree to which the 6-month trends in our study can be equated to 12-month trends in clinical trials is unclear). However, surrogate end-points are not fully validated by a single study 19, and independent verification of disease progression may be required. Serial HRCT, which has yet to be validated as an independent outcome variable in IPF, may have a valuable role in providing collateral morphological evidence of disease progression. A combined end-point of marginal FVC decline and progression of disease on HRCT (or, alternatively, declining exercise tolerance) merits further study.

More importantly, our findings have implications for the selection of patients for enrolment in clinical trials. Current end-points in therapeutic studies may not be sufficiently sensitive. In a retrospective analysis of a placebo-controlled trial of interferon-γ, the primary end-point (change in FVC, change in alveolar–arterial oxygen tension gradient or death) was met in <30% of cases 20. By implication, a prohibitively large number of patients would be required to demonstrate a worthwhile partial treatment effect. It can be argued that patients with more indolent disease tend to be selectively enrolled in placebo-controlled studies in diffuse lung disease 21–23. Our results indicate that an enrolment criterion of marginal or significant decline in FVC during the 6 months before entry into a clinical trial, selects patients more likely to meet a progression-free survival end-point during a treatment period of 1–2 yrs. However, as in the detection of disease progression in clinical practice, it appears likely that the optimal algorithm for patient selection, when refined in future studies, will consist of a combination of marginal FVC trends and other ancillary evidence of disease progression, including symptomatic decline and/or evidence of disease progression on HRCT.

Limitations of the study

Selection bias is an important consideration because of possible over-representation of NSIP in this and other studies, due to the exclusion of IPF patients in whom typical HRCT appearances obviated biopsy. Furthermore, although histological evaluation provided diagnostic security and allowed a comparison between IPF and fibrotic NSIP, biopsied patient cohorts are known to be younger and to have less severe functional impairment 24. However, serial FVC trends are known to have a greater prognostic value in less severe disease (as judged by lack of desaturation on a baseline walk test) 3. Thus, marginal trends in FVC may be less prognostically useful in IPF patients with advanced disease.

The recent widespread introduction of N-acetylcysteine therapy as part of standard treatment for IPF and severe fibrotic NSIP had the potential to confound our results, based upon findings in the IFIGENIA study 7. This consideration prompted us to limit the date of presentation to June 2005. In a small percentage of patients, N-acetylcysteine was introduced during follow-up in the last year of the follow-up period to October 2006. However, it is unlikely that this had a major effect on our findings as it is known that mortality is not significantly influenced by anti-oxidant therapy during the first year of treatment 7.

It should also be stressed that the results of this study are more directly applicable to clinical practice than to therapeutic trials, which generally last for 12 months in IPF. Although 6-month follow-up was almost always possible in surviving patients in our cohort, follow-up at 12 months was highly variable (especially in the last 5 years of the study, with the advent of a “shared care” algorithm with local chest physicians). Thus, an evaluation of the prognostic significance of a 12-month functional trend (as in an earlier study containing some patients in the current study 2) was no longer practicable in this extended population. Our findings need to be reproduced in another cohort, with follow-up extended to 12 months, to validate marginal change in FVC as a primary end-point in pharmaceutical studies.

Progression-free survival provides an additional outcome variable but represents a blunt end-point when compared with mortality as it depends upon the timing of routine monitoring and opportune lung function testing. By contrast, vital status is generally collated monthly. This factor is unlikely to have materially influenced our results in IPF patients as follow-up PFTs were performed 3–6-monthly in almost all cases.

In conclusion, short-term marginal changes in FVC predict a poor outcome in patients with IPF. Our results have important implications for clinical decision-making and recruitment into clinical therapeutic trials.