Dr. Kirsten Patrick, deputy editor, interviews both Dr. Ronald Labonté, Canada Research Chair in Globalization and Health Equity at the Institute of Population Health and Professor at the University of Ottawa, and Dr. Raphael Lencucha, Assistant Professor in the School of Physical and Occupational Therapy at McGill University. In their commentary, published in CMAJ, Labonté and Lencucha propose a pragmatic approach to regulating electronic nicotine delivery systems in Canada: cautious measures similar to tobacco control, while using price incentives to shift tobacco users to electronic devices as a harm reduction mechanism until useful data accumulate on relative health outcomes. ...continue reading
by Matthew Stanbrook, Deputy Editor, CMAJ, in San Diego, U.S.A.
Idiopathic pulmonary fibrosis is a chronic progressive disease in which the normal connective tissue of the lungs (the interstitium) is replaced by scar tissue through mechanisms we are rapidly understanding much better. The disease causes the lungs to become stiff (decreased lung compliance), small (lung restriction) and impaired in their primary function of gas exchange (impaired diffusion capacity). It affects an estimated 20,000-30,000 Canadians and has a median survival of 2-4 years from diagnosis, although some patients live much longer. While its onset is typically late in life, the disease can rarely occur much earlier, as attested by my hospital’s lung transplantation program, whose graduates include triumphs like social media superstar and Ellen DeGeneres guest Hélène Campbell, as well as tragedies like Cambridge, Ontario’s organ donation advocate Kayla Baker, who despite getting a new lung died earlier this year at the tender age of 15. I have had the privilege of crossing paths with both of these young women, whose stories are inspiring, yet serve as a stark reminder of the desperate need for effective treatments for this disease.
Patients with idiopathic pulmonary fibrosis, and those of us who care for them, have long been frustrated by the lack of such treatments, and more so by the fact that most innovative therapies tested to date have failed to show benefit and have often increased rather than decreased mortality. All this has suddenly changed with new research presented last week at the 2014 American Thoracic Society Annual Conference. These studies have now documented clear and compelling benefits of two medications, one of which is already in clinical use in Canada. Another equally important study has shown the lack of benefit of an older but widely used treatment.
Let’s start with the bad news. For decades, we had been treating idiopathic pulmonary fibrosis with potent systemic anti-inflammatory medications such as prednisone, azathioprine, and cyclophosphamide, based on the observation that chronic inflammation is a consistent feature of the disease, but likely the wrong mechanism on which to focus, as it turns out. We did so well in advance of obtaining any good evidence of benefit with this approach, which as usual turns out to have been a bad idea. In 2011, the large PANTHER IPF trial, evaluating combination therapy with prednisone, azathioprine and acetylcysteine, was stopped early by its data safety monitoring board due to findings of increased mortality with this regimen. In addition to a placebo arm, this trial had a 3rd arm that was randomized to acetylcysteine alone. After a brief hiatus of 3 months, the PANTHER IPF trial was allowed to continue with these latter 2 arms.
Acetylcysteine (also referred to as N-acetylcysteine or NAC) was thought to be possibly beneficial in idiopathic pulmonary fibrosis based mainly on the IFIGENIA study, which in 2005 showed that patients randomized to acetylcysteine, prednisone and azathioprine had less of a decline in vital capacity (a validated surrogate outcome measure in idiopathic pulmonary fibrosis) than those randomized to prednisone and azathioprine alone. Tellingly, IFINGENIA did not have an arm that was untreated, and in retrospect it seems more likely that acetylcysteine may have decreased the tendency for prednisone and azathioprine to kill patients, although given PANTHER IPF’s initial findings, clearly not well enough. Acetylcysteine’s purported beneficial mechanism lay in its property as the biological precursor of glutathione, which functions in the lung as a major antioxidant. That should have been a red flag right there—more often than not, “antioxidant properties” seems to be scientific code for “we really have no idea how this treatment would actually work” and denotes a treatment that turns out not to once proper studies are done. The final results of the PANTHER IPF trial, presented at the conference by Ganesh Raghu, Professor and Director of the Interstitial Lung Disease/Sarcoid/Pulmonary Fibrosis Program at the University of Washington, proves that acetylcysteine doesn’t work, either: there was no difference between patients receiving acetylcysteine or placebo in vital capacity (the primary outcome), death, or other clinical or surrogate endpoints that might denote benefit. There was an excess of non-fatal cardiac events in the acetycysteine group—of unclear meaning given the large number of outcomes evaluated, but certainly not encouraging.
As respirologist and New England Journal of Medicine Editor-in-Chief Jeffrey Drazen stated at the conference, there was never a good scientific reason to think that acetylcysteine alone would work in idiopathic pulmonary fibrosis; instead, “this was a straw at which people grasped”. Unfortunately, it seems a few are still grasping: while most of the IPFnet investigators were balanced and appropriate in describing the trial results, PANTHER IPF investigator and Executive Vice Chair of Medicine at Weill Cornell University Fernando Martinez devoted much of a separate session at the conference to highlighting observed differences in “trends” between patients enrolled before and after the 2011 alert that temporarily halted the trial—notwithstanding that none of the differences reached statistical significance. This is specious and unscientific. As PANTHER IPF investigator and Chair of Medicine at the University of California, San Francisco, Talmadge King—arguably the world’s leading authority on interstitial lung diseases—stated, “I don’t know how you make a big deal over something meaning nothing”. Right you are, Dr. King. Acetylcysteine has fallen into common use, in part because it can be widely obtained without prescription as a supplement, and perhaps because it is thought at least to be harmless (which, as it turns out, may not be the case). We all need to move on and to encourage our patients to move on as well, not to waste their money and their hope on a treatment that doesn’t work.
And we finally have an effective therapy towards which to move: pirfenidone. Pirfenidone was previously tested in the 2 large CAPACITY randomized trials. Unfortunately, only 1 of the 2 trials showed a significant difference in the primary outcome, vital capacity. This was good enough to get the drug approved for clinical use in Canada and Europe, but not good enough for the U.S. Food and Drug Administration, which refused to approve the drug and mandated a new study. The results of this study, the ASCEND trial, were present at the conference by Dr. King. Unlike its predecessors, the ASCEND trial featured greater attention to quality control, with centralized adjudication of pulmonary function measurements and clinical events. I have been skeptical of pirfenidone to date, given the past track record of treatment for idiopathic pulmonary fibrosis that I described above, and also because we still don’t know the mechanisms by which this treatment acts in IPF (remembering the example of acetylcysteine). However, the results of ASCEND seem quite convincing: the proportion of patients who died or experienced a significant decline in vital capacity after 1 year was lower in the pirfenidone group by an absolute difference of 15% (equivalent to a number needed to treat of 7). When the results of ASCEND were pooled with those of the two CAPACITY trials, the findings were homogeneous and revealed a statistically significant 48% reduction in the hazard of all-cause mortality and a two-thirds reduction in mortality attributed specifically to pulmonary fibrosis.
In addition to pirfenidone, we will soon have a second therapy with demonstrated efficacy in idiopathic pulmonary fibrosis: nintedanib. Unlike pirfenidone, we actually know how this one works: it’s a tyrosine kinase inhibitor, a class of medications that has spawned several new anti-cancer drugs recently. Its mechanism, as helpfully explained at the conference by Martin Kolb, Associate Professor of Respirology, Pathology and Molecular Medicine at McMaster University, is that, as with all tyrosine kinase inhibitors, it mimics ATP and thereby prevents cellular signaling from the cell membrane to the nucleus. Of specific relevance here, nintedanib does so in fibroblasts, inhibiting their migration, proliferation and transformation to myofibroblasts—all key steps in the pathogenesis of idiopathic pulmonary fibrosis, which best resembles a misdirected process of wound healing and repair. Nintedanib has now been evaluated in the paired INPULSIS-1 and INPULSIS-2 trials, presented at the conference by Luca Richeldi, Professor of Respiratory Medicine and Chair of Interstitial Lung Disease at the University of Southhampton, UK. As with pirfendione, nintedanib showed a clinically and statistically significant different in vital capacity at 1 year. Deaths were also fewer with nintedanib, although differences did not reach statistical significance (the trials were not powered to evaluated mortality).
These new findings have immediately sparked much well-justified optimism within the respiratory community. For the first time, we can now confidently regard idiopathic pulmonary fibrosis as a treatable disease. There remain many substantial hurdles to overcome for our patients: as Dr. Drazen pointed out, these drugs have shown they can slow the progression of disease, but in most cases haven’t stopped it. There is thus immediate interest in studying these drugs in combination with each other and with other promising agents in development that have been derived from an improved understanding of disease mechanisms (such as simtuzumab, an inhibitor of lysyl oxidase like-2, an enzyme whose activity has been implicated in the formation of fibroblast foci, which are a pathologic hallmark of idiopathic pulmonary fibrosis). Both drugs have common side effects, particularly involving the GI tract, although these seem tolerable in severity. And both, of course, will be expensive. However, with clear benefits and a mortality reduction now documented for a frequently fatal disease that has previously had no clearly effective treatments, regulatory authorities, insurance companies and government third-party payers will have a hard time saying no.
Of course, there was more than idiopathic pulmonary fibrosis on display at the conference. Other research highlights included:
- Among women who continued to smoke during pregnancy, infants of mothers who were randomized to Vitamin C 500 mg per day had better lung function at birth and fewer episodes of wheeze at 1 year than those whose mothers were randomized to placebo and similar in both respects to infants of non-smoking mothers. Benefits were seen predominantly with mothers who carried a known nicotinic receptor polymorphism previously shown to be associated with smoking-related lung diseases. Noteworthy for being one of the few randomized trials to show that Vitamin C does anything worthwhile in anyone, but the biological rationale appears to have been much better worked out in this case and lends plausibility to the findings. Of course, the most important and effective treatment in this context is smoking cessation, but the evidence that the mechanism of neonatal lung impairment may be based on effects of nicotine would imply that pregnant women using nicotine replacement therapy for this purpose should perhaps also receive Vitamin C.
- E-cigarette vapour increased the virulence of methicillin-resistant Staphylococcus aureus (MRSA) in a mouse model. This was similar to the effect of cigarette smoke, although the mechanisms were different. The results provide more evidence suggesting that e-cigarettes are not a harmless substitute for cigarette smoking.
- Statins do not reduce COPD exacerbations, it seems. In the STATCOPE trial, a unique collaboration funded by both the Canadian Institutes of Health Research and the U.S. National Heart, Lung and Blood Institute, simvastatin 40 mg daily, given for 1-3 years to COPD patients who did not otherwise have an indication for a statin, showed no obvious benefits or harms. Similarly, in the RODEO trial, rosuvastatin 10 mg daily for 12 weeks did not improve pulmonary or peripheral artery endothelial function. These studies thus fail to confirm prior observational data suggesting that statins might be beneficial in COPD. Oh, and it seems that statins are of no benefit in ARDS associated with sepsis, either.
- Lung volume reduction for COPD, attempted endoscopically with a gelfoam sealant, more than doubled the risk of respiratory adverse events, including 2 deaths, leading to the premature termination of the ASPIRE trial. Conventional lung volume reduction performed surgically has been shown previously to be of potential benefit, but only in a small proportion of highly selected COPD patients. Hopes that this therapy might be expanded to more patients with less invasive approaches continue to meet with frustration—even if the idea is sound, the right technique just isn’t there yet, it seems.
- Vitamin D supplementation in asthma patients who were Vitamin D deficient did not reduce asthma treatment failure or facilitate dose reduction of inhaled steroids, even though it did usually raise Vitamin D levels above the threshold for sufficiency. The hypothesis was based on prior studies suggesting that Vitamin D deficiency is associated with worse asthma outcomes. Vitamin D deficiency has been implicated in the pathogenesis of several diseases in which Vitamin D supplementation has subsequently failed to demonstrated benefit. Perhaps asthma should now be counted among these, although in fairness, the VIDA trial really shows only that Vitamin D cannot replace an effective dose of inhaled steroids, rather than ruling out any potential benefit of Vitamin D in asthma.