Inhaled corticosteroids (ICS) have had a wild and controversial rollercoaster ride in chronic obstructive pulmonary disease (COPD). With the success of ICS in asthma and with the advent of the Dutch Hypothesis, suggesting that asthma and COPD had a similar pathogenic origin, there was great hope that ICS would be the saviour for millions of patients suffering from COPD, by palliating symptoms and changing its natural history. Based on this promise, by the mid 1980s, clinicians were routinely recommending ICS therapy to their patients, even though there was an absence of compelling grade A evidence from large randomised controlled trials (RCTs) demonstrating efficacy 1.
By the late 1990s, the promise was shattered by the publication of several seminal RCTs that clearly showed that ICS did not modify the rate of decline in forced expiratory volume in 1 s (FEV1) and had only a modest effect on symptoms 2–4. These data re-inforced the notion that COPD was a steroid-resistant state and many leading experts in the field concluded that ICS had no role in COPD, except during exacerbations 5. Ostensibly, ICS were dead and buried.
However, the new millennium brought new hope for ICS. Proponents argued that while ICS may not alter the rate of decline in FEV1, it improved patient based outcomes including survival. This optimism was fuelled by several large observational studies and meta-analyses 6–9 that demonstrated a distinct survival benefit for patients who were prescribed ICS. This enthusiasm, however, was dashed in 2007 by the publication of the long-awaited TORCH (TOwards a Revolution in COPD Health) Study, which failed to show an unequivocal survival advantage for patients assigned to a steroid-containing treatment strategy over a 3-yr period 10. ICS were dead and buried for the second time.
Yet almost immediately, ICS was resurrected from the dead, this time on the notion that COPD is an inflammatory disorder with multiple extrapulmonary manifestations, driven largely by a persistent systemic inflammatory process, which worsens during periods of exacerbation 11. Although COPD is associated with many different comorbidities, cardiovascular disorders (CVDs) are of particular importance, as they are the leading causes of hospitalisation and a major contributor of total mortality, accounting for a quarter to a third of all deaths in COPD patients 12. Since systemic inflammation is an important co-factor in the genesis of CVD, it was reasoned that ICS could mitigate the risk of CVD and, thus, reduce the overall health burden of COPD patients by attenuating the inflammatory load. Additional support for this theory came from large epidemiological studies and post hoc analyses of RCTs, showing the possible benefits of ICS in reducing the rate of myocardial infarctions, angina, stroke and heart failure morbidity and mortality in COPD patients 13–16.
In this issue of the European Respiratory Journal, Loke et al. 17 provide fresh data that challenge the notion that ICS reduce the risk of myocardial infarction and cardiovascular deaths in COPD. In this carefully conducted systematic review and meta-analysis, they used data from 23 high-quality RCTs to demonstrate that ICS did not affect the risk of myocardial infarction (relative risk (RR) 0.95; p = 0.68), or cardiovascular death (RR 1.02; p = 0.89). This was a carefully conducted systematic review, performed in accordance with established guidelines 18. The outcome was clearly defined and the studies were rigorously and comprehensively selected. Methodologically, the review was sound. So based on these findings, is this the final chapter in the story of ICS in COPD?
The answer is an emphatic “no”. First, readers should be mindful that none of the trials included in the present meta-analysis was powered specifically on CVD end-points. In most cases, CVDs were captured as safety events. Because these events in general are not collected with the same rigor or comprehensiveness as those related to the primary outcome, subtle (but clinically relevant) differences between treatment and comparator groups may have been missed. Secondly, although there were nearly 20,000 patients in this meta-analysis, only 212 of them (representing 1.1% of the cohort) experienced myocardial infarction. Since this is a far lower rate than what would be expected for a group of ex- and current smokers in their 60s and 70s 19, certain confounding factors such as selection bias (against subjects with significant cardiovascular comorbidity) and case ascertainment bias (i.e. a large number of myocardial infarction events being missed in the trials) may also explain the null findings in the present meta-analysis.
Finally, despite the “negative” opinions of ICS proffered by academics, it is hard to ignore the fact ICS-based therapies are widely used in clinical practice. Indeed, the worldwide sales of fluticasone/salmeterol combination alone topped more than US$7 billion in 2007, making it the third best selling pharmaceutical product in the world, trailing only behind Lipitor® (atorvastatin), which grossed US$12.7 billion and Plavix® (clopidogrel), which grossed US$7.9 billion 20. The worldwide sale of the other commonly used steroid-containing COPD drug, budesonide/formoterol, was US$1.6 billion in 2007. In 2010, the sales of fluticasone/salmeterol combination are expected to exceed US$9 billion 21, likely putting this product at the top of the best seller's list. This begs the obvious question: why are clinicians using ICS for patients with COPD? The sceptics would argue that these data are driven by clever marketing. However, clinicians are not so easily misled. In reality, marketing has only a modest effect on demand for pharmaceutical products 22. A more plausible (and simple) explanation is that clinicians (and patients) use ICS-based therapy for COPD because they work.
Clinicians use pharmaceutical products in COPD for three primary reasons: 1) to provide symptom relief; 2) to reduce the risk of exacerbations; and 3) to increase survival without incurring significant side-effects. In the case of ICS, although their effect on mortality is still disputed, there is unequivocal evidence that they (in combination with a long-acting β2-agonist) reduce symptoms, improve quality of life, reduce exacerbations and increase lung function above and beyond that which can be achieved by long-acting bronchodilators alone 23, 24. At the grass roots level, clinicians have “known” about these effects based on empirical data and clinical experience long before they were validated by large RCTs.
So where does this leave the field? Although ICS-based therapies represent a significant innovation in COPD management, they are far from ideal. Despite “optimal” COPD management, most patients with COPD experience at least one or two exacerbations per year and many go on to have severe exacerbations requiring hospitalisation 25. Globally, COPD mortality continues to climb at an alarming rate, such that by 2030, nearly 9 million people will die annually from COPD (currently 3 million per year) 26. The pipeline for new drugs for COPD is relatively dry compared to those for other major causes of mortality, such as HIV/AIDS, cancer and diabetes (fig. 1⇓). Additionally, in COPD, the only “biomarker” that is widely accepted by regulatory agencies for new drug approval is FEV1. Unfortunately, it is a near impossible hurdle to overcome as COPD by definition is “irreversible” in terms of lung function. Notwithstanding this and other obstacles, ICS-based therapies have been successful in obtaining regulatory approval and, most importantly, reducing the disease burden of patients suffering from COPD. The mechanisms by which ICS enhance patient-based outcomes in COPD are largely unknown and remain “up in the air”. In the past, we have spent an enormous amount of time, money and energy trying to ascertain reasons why ICS should not work in COPD. We propose that it might be more productive to focus on possible mechanisms by which they might work in COPD. This may enable us to identify novel molecules and pathways for new drug and biomarker discoveries. Although there were some limitations, as noted previously, the work by Loke et al. 17 suggests that ICS do not change CVD outcomes in COPD and encourages us to look elsewhere for clues to the ongoing mystery of how steroids work in COPD.
New pharmaceutical compounds in current development for select conditions. Only includes compounds in clinical trial or under review by the US Federal Drug and Food Administration. Data obtained from the Pharmaceutical Research and Manufacturers of America 27. COPD: chronic obstructive pulmonary disease; depres.: depression.
Support statement
D.D. Sin is a senior scholar with the Michael Smith Foundation for Health Research, and is a Canada Research Chair in COPD.
Statement of interest
Statements of interest for both authors can be found at www.erj.ersjournals.com/misc/statements
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