Dear Editor,

We read with interest the recent paper by Sin and colleagues (1) which, we believe, raises more questions that it answers.

A major concern is the fact that ascertainment of mortality was incomplete for a significant proportion of patients (973/5086), corresponding to 19% of the total (not the reported 12%), who did withdraw prematurely from the study. This loss to follow up was more likely to occur in the placebo group. The authors use the ISOLDE study (2) to claim that patients who withdrew prematurely were more likely to die and that therefore the hazard ratio is in fact an underestimate of the benefit of inhaled corticosteroids (ICS). However, the ISOLDE data are themselves contradictory on this point. The claim is based on an abstract from the ISOLDE study that states that 29 deaths occurred before withdrawal and 74 subsequently (3). On the other hand, the original ISOLDE article reported 68 deaths before withdrawal, which would leave only 35 afterwards.(2) The claim of a higher death rate after withdrawal may therefore be incorrect.

We believe that differential identification of deaths may have occurred as suggested by Figure 1 in the paper and that this could easily have biased the hazard ratio. The figure first implies a hazard ratio of 1, with no difference in mortality between the ICS and placebo group, during the first 9 months of follow-up, the only time period where every single patient is included and loss to follow-up is of no consequence. This initial 9-month period thus involves all 5086 patients and around 50 deaths, a quarter of all deaths. The subsequent apparent benefit of ICS is exclusively the result of spurts of excess mortality in the placebo group that occurred at unusually specific time points, namely between the 9th and 12th months of follow-up, as well as just after the 24th month. In contrast, the rate of mortality in the ICS group appears to be fairly constant at roughly 1.6 deaths per 100 per year throughout the 3-year follow-up. From the natural history of COPD, however, we would also expect a constant rate of mortality in the placebo group, albeit at a higher rate, if indeed ICS are beneficial. This observation of spurts of excess mortality in the placebo group at specific time points is more suggestive of a study design effect than of a real drug effect. Indeed, if ICS were effective, their benefit would be more likely gradual throughout the follow-up, rather than kicking in to prevent short spurts in mortality precisely at 9 and 24 months after initiation. This phenomenon suggests differential misclassification of deaths or informative censoring between the placebo and ICS groups. The authors could describe the 20 or so deaths, as well as the withdrawals, occurring in the placebo group between the 9th and 12th months of follow-up, and after the 24th month.

The reduction in all-cause mortality resulted from a reduction of deaths due to cancer and to other causes, but not a reduction in cardiac deaths, and is therefore not consistent with the mechanism of benefit of inhaled corticosteroids in reducing overall mortality which is usually postulated (4). Some of the apparent beneficial effect of ICS might be the result of withdrawal of these medications (5) which will occur in the placebo arm of the trials included in the ISEEC study. Such withdrawal might result in relative adrenal insufficiency. It would therefore be useful to stratify the analysis of the possible benefit of ICS in reducing mortality by prior use of corticosteroids, both inhaled and systemic. Such a stratified analysis should also be considered in the much anticipated TORCH study.

Pierre Ernst and Samy Suissa, McGill Pharmacoepidemiology Research Unit, McGill University.

Reference List

1. Sin DD, Wu L, Anderson JA et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 2005; 60(12):992-997.

2. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br Med J 2000; 320(7245):1297-1303.

3. Waterhouse JC, Fishwick D, Burge PS. What caused death in the ISOLDE study ? European Respiratory Journal 14[Supp. 30], 387S. 1999.

4. Sin DD, Lacy P, York E, Man SF. Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170(7):760-765.

5. Wouters EF, Postma DS, Fokkens B et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax 2005; 60(6):480-487.

Dear Editor,

Inhaled corticosteroids have for some time been seeking a broader indication in COPD. The recent meta-analysis by Sin et al.[1] suggesting protection against all-cause mortality is therefore of some interest. Although not universally confirmed[2,3], this tantalising concept is being prospectively evaluated in a 3 year study of high dose inhaled corticosteroids (Flixotide 500mcg bid, alone or in combination with long acting beta-agonist) in COPD patients with FEV1 < 60%.[4]

But how might this protection be afforded? Local effects may teleologically provide organ specific protection, potentially reflected by reduced frequency or severity of pulmonary exacerbations. However, COPD is recognised as a systemic inflammatory condition associated with raised systemic inflammatory markers such as CRP, and this marker is increasingly recognised as an independent risk factor for cardiac mortality.[5]

Important questions revolving around the determinants of all cause mortality both generally and in COPD remain unresolved. How for instance should we interpret a positive trial outcome without comparative data regarding the relative impacts of the modification of such risk factors as comorbidity, smoking, diet, exercise and weight reduction? Secondly, if the benefits provided by corticosteroids could be largely attributed to systemic antiinflammatory activity then systemic corticosteroid dosing (i.e. oral prednisolone) may be more efficient and potentially cheaper. Finally, these questions will be further complicated by uncertainties regarding dosing, the need for concomitant long acting beta-agonists and adverse effect thresholds.

Currently recommended indications for inhaled corticosteroids in COPD include the prevention of exacerbations in those with FEV1 < 50% and “the prevention of decline in health status”[6,7]. Clarification and the beneficial extension of these indications will be welcomely received.

Reference

1. Sin DD, Wu L, Anderson JA et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax. 2005; 60: 992- 7.

2. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am.J.Med. 2002; 113: 59- 65.

3. Fan VS, Bryson CL, Curtis JR et al. Inhaled corticosteroids in chronic obstructive pulmonary disease and risk of death and hospitalization: time-dependent analysis. Am.J.Respir Crit Care Med. 2003; 168: 1488-94.

4. Vestbo J. The TORCH (towards a revolution in COPD health) survival study protocol. Eur.Respir J. 2004; 24: 206-10.

5. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK. C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk In Communities (ARIC) study. Am.Heart J. 2002; 144: 233-8.

6. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur.Respir J. 2004; 23: 932-46.

7. Managing stable COPD. Thorax 2004; 59: 39i-130.

Dear Editor

Chronic obstructive pulmonary disease and other disorders, associated with reduced lung function, are strong risk factors for cardiovascular events, independent of smoking. In general, for every 10% decrease in FEV1, all-cause mortality increases by 14%, cardiovascular mortality increases by 28%1. Patients with chronic obstructive pulmonary disease (COPD) are predisposed to atherosclerosis and coronary artery disease, but the underlying mechanisms are unclear. Although there is wide acceptance that atherosclerosis is related to systemic inflammation and COPD has already been accepted as a systemic inflammatory disorder "One can speculate that the increase in systemic inflammation, as seen by an elevated CRP level in patients with COPD, is a reason" for the cardiovascular diseases. When patients with chronic obstructive pulmonary disease (COPD) are treated with an inhaled corticosteroid, they are less likely to experience ischemic cardiac events. The findings are promising because of the potential for cardio-protection in a group of COPD patients. It is not yet very clear that how an inhaled corticosteroid like budesonide or fluticasone would confer such protection1-2.

One possibility is that the treatment may ameliorate the systemic inflammatory factors that patients with COPD have in anatomic sites beyond lung tissue, such as C-reactive protein (CRP) levels. It was also observed that withdrawal of inhaled corticosteroids increases serum CRP level and that reintroduction of inhaled corticosteroids would suppress CRP levels3.

It is a unique opportunity to benefit another system in the body, the cardiovascular system, with a therapy that focuses locally, on the inflammation in the airways. I strongly believe that all the patients of COPD should be treated by inhaled corticosteroids, irrespective of their severity, to protect them from cardiovascular complication of the COPD.

References

1. Don D. Sin, S.F. Paul Man. Chronic Obstructive Pulmonary Disease as a Risk Factor for Cardiovascular Morbidity and Mortality. The Proceedings of the American Thoracic Society 2:8-11(2005).

2. S.F. Paul Man, Don D. Sin. Effects of Corticosteroids on Systemic Inflammation in Chronic Obstructive Pulmonary Disease. The Proceedings of the American Thoracic Society 2:78-82(2005).

3. Paula Mayer, MA. Budesonide for COPD May Also Protect Against Heart Disease. ERS 15th Annual Meeting: Abstract 2333. Presented Sept. 19, 2005.