How Not to Treat Idiopathic Pulmonary Fibrosis.
One of the first things I wrote about on these pages was the importance of having good evidence backing up what we doctors do to people, and how commercial editorial policies of medical journals have at least the potential of denying doctors and their patients timely knowledge of information that might inform their medical choices. I thought of that article again when I looked at one of the several email news summaries I get from various organizations.
One of the highlighted items that caught my eye was a report that “Combination therapy for pulmonary fibrosis appears to increase risk of death [and] hospitalization.” Several of the diseases I used to treat included pulmonary fibrosis and were notoriously difficult to manage. I clicked the “More…” button and was led to this week’s New England Journal of Medicine. The article provides a stunning example of how we physicians still allow ourselves to be led down the garden path of ineffective medical care.
The study was limited to well documented idiopathic pulmonary fibrosis (IPF). To simplify, pulmonary fibrosis is a process where the substance of the lung turns into scar tissue. This blocks the ability of the lung to get oxygen and expel carbon dioxide. The “idiopathic” form is so named because its cause is not known. People with this disease have symptoms much like people with emphysema, but do not live as long. People live an average of 2 to 5 years after diagnosis. It’s not very nice and not very common. There is no “approved” treatment, but that does not keep doctors and their patients from trying. Unfortunately and as happens all to frequently in medicine, we feel compelled (doctors and patients alike) to try something– anything. One “standard” therapy for IPF has emerged that has never been convincingly shown to actually work. There is a real cost to such hopeful practice, in dollars and in blood.
In brief, 236 patients with well documented IPF and who had mild to moderate disease (and therefore something to gain if worsening can be prevented) were studied. The study was sponsored by a branch of the National Institutes of Health (NIH) and conducted in 25 clinical centers around the country. The medicines tested were: N-acetylcysteine (NAC), an antioxidant commonly used to loosen secretions in bronchitis but also having chemical properties useful for detoxifying metabolic poisons; and both azathioprine (Imuran) and prednisone, two powerful immuno-suppressives and anti-inflammatory agents with broad effects on the body. The patients were randomly assigned to one of three groups. One received only NAC. A second group received “Triple Therapy” consisting of NAC, prednisone, and azathioprine. The third group received sugar pills– Placebo. Many patients and doctors object to participating in a study where an”inactive” therapy might be received but this study shows why for an ethical study such thinking is misinformed, even dangerous.
As now occurs in modern studies where the stakes are high, the study was monitored by an independent group to make sure that a potential miracle-treatment, or for that matter a disaster was not permitted to go unrecognized for an inappropriate length of time. In fact, the group of patients taking the triple therapy had to be dropped from the study because patients receiving this widely accepted treatment were dropping like flies compared to those taking the inactive sugar pills. Not only were the side effects awful, but of the 77 and 78 patients in the Triple Therapy and Placebo groups respectively, 15 vs. 2 died, 23 vs. 7 had to be hospitalized, and 24 vs. 8 had a serious adverse event. Many more of the Triple Therapy patients were unable to continue their pills anyway because of unacceptable side effects. (They may have been the lucky ones.) To make matters worse, there did not even seem to be any benefit to the underlying disease. You don’t have to be a rocket statistician to recognize that something bad was happening to the patients who were receiving what had come to be a standard treatment! It was not even clear why the study patients died. Therefore in “standard” practice, it is likely that treating physicians are attributing patient deaths to the disease itself rather than the treatment. New drugs get added or compared to the ineffective old ones,and so the cycle of transforming a harmful treatment into a standard one continues. We do a lot of this.
We could write more about the course and findings of this nice study. Points I would like to make and discuss include the following:
- Idiopathic Pulmonary Fibrosis is an uncommon but bad disease. Many treatments have been offered, but they have had little impact. It is clear however, that the cure can sometimes kill more people than the disease, and more quickly.
- We physicians can easily, and frequently do great harm. Sometimes we can do great good.
- Many of our treatments given with the best intentions have no real evidence for effectiveness.
- A theoretical basis for effectiveness is only that. Theories kill people too.
- Remember, the only difference between a drug and a poison is the dose and the circumstance. Azathioprine and prednisone are powerful drugs. Essentially everyone who takes them gets predictable and serious side effects. You have to be very sure drugs like these suppress disease, prolong life, or at the very least, improve the quality of life enough to offset their inevitable side effects. This study confirms my belief, that we physicians are very poor in making this medical calculus.
- The imperative to “do something– anything” can be overwhelming. The hardest thing to do in medicine is to do the least. Medical care is more than just giving medicine.
- How can it come to pass that the medical profession does so much with so little proof of effectiveness? Good question.
- Patients and doctors often refuse to participate in effectiveness studies because they do not want to take the placebo for fear of missing the best thing. Guess what? You might do a lot better with the sugar pill!
- Why was this study funded by the NIH and not one of the rolling-in-cash drug companies? Guess!
- This is the kind of study that will be funded by Obamacare. Quick, lets overturn the legislation before someone gets helped!
- We need to be doing more of these studies, not less. The time do do a placebo controlled study is first thing, before some ineffective (or worse) therapy becomes the standard of care. Once proven effective, the better treatment becomes the new standard of care against which potentially better treatments can be tested.
- The article was published at least 7 months and probably a good bit longer after the safety surveillance committee determined that the treatment was worse than the disease. Is that too long? Were doctors and patients still using the old protocols? As it happens, the NIH announced the termination of the study and the reasons for it almost immediately. Was that enough notice? Do you think that big-name drug companies inform the public of their bad results in such a timely way, if at all?
- Only the Triple Therapy arm of the study was terminated. That part comparing NAC to placebo is ongoing. In fact, the University of Louisville is a participating center for this arm and I recommend your support. Wouldn’t it be nice to know that even this purportedly benign drug is actually doing some good?
- Reducing ineffective care and improving health– isn’t that what we call a “win-win?”
Peter Hasselbacher, MD
May 22, 2012