This is story of how a company called Asthmatx introduced a new surgery. The promoters call this surgery Bronchial Thermoplasty. However “plasty” is a misnomer for this surgery since there is no repair, molding or reshaping involved. A more accurate term is Bronchial Thermal Cautery (BTC) since the bronchial walls are cauterized using a heat probe. The heat probe called Alair® has been approved by the FDA. The probe is introduced in the lungs using bronchoscopy. Then the Alair® Thermoplasty System uses radio frequency waves to heat the probe. The end result is that the interior of the bronchial walls is cauterized by heat. There is heat damage to bronchial lining, muscles and cartilage. Then the healing occurs. There is some evidence that the muscle wall thickness is reduced, based upon studies in dogs. There are no studies in asthmatic patients as bronchial biopsies were not done.
It is not often that an entirely new surgery appears in the medical field. This is especially true if the surgery is for a medical condition like asthma, and there is no similar surgery for any other disease or any other part of the human body.
Theory of Surgery: Asthma is a chronic disease without a clear cut explanation of its cause in most patients. There is narrowing of airway passages, bronchi, causing the patient to gasp for breath. The narrowing is caused by inflammation inside bronchi and constriction of muscles in the bronchial wall. The muscles of bronchial wall are called Airway Smooth Muscle (ASM). There is increase in size of ASM in asthmatics as compared to non-asthmatics. No one knows for sure if the increase in ASM is the result or the cause of asthma. It is theorized that reduction of ASM may benefit asthmatics.
Procedure: A heat cautery probe in inserted in bronchi using a bronchoscope. Then the probe is heated using radio frequency energy. Then the probe is moved to a different bronchus and the procedure is repeated. The whole lung is treated in three different sessions.
Animal Experiments: Investigators carried out heat cautery on bronchial walls of dogs. After cautery the dogs were subject to a test, called Methacholine Challenge Test (MCT). A similar test, also called Methacholine Challenge Test in humans, tests for a person’s tendency to have bronchial asthma. The company implied that since MCT in dogs showed improvement and therefore the surgery might be beneficial to asthmatic patients. The FDA asked for more studies in dogs and then approved studies in human beings.
Human Experiments: The company with the FDA approval, first tested the surgery in patients of lung cancer who were scheduled to have their diseased lungs removed. The surgery was tolerated by these non-asthmatic patients.
Clinical Trials: Three clinical trials were conducted on asthmatic patients. The first trial was called AIR trial and conducted on mild and moderate asthmatics. The trial compared surgery with regular medical care. The second trial was called RISA trial and was conducted on severe asthmatics. It compared surgery with medical treatment. The third trial called AIR-2 was conducted in moderate asthmatics. It compared surgery with sham surgery. Sham surgery was carried out by performing bronchoscopy but not cauterizing the bronchial walls.
AIR trial: The study involved about 115 moderately severe asthmatics who were divided into two groups. One group received surgery and the other regular medical care. The severe asthmatics were excluded from this study. When the study was first registered at the web site, the primary end point was “symptom free days.” Later on it was changed to “Asthma Quality of Life Questionnaire (AQLQ) score.” After the study was completed the primary end point was again changed to “mild exacerbations of asthma.”
The investigators claimed that the rate of mild exacerbation was reduced by surgery. There was no change in severe exacerbations, symptom free days or FEV1. There were more hospitalizations in the surgery group.
Five Year Follow-up: The surgery patients were followed for five years. The medical patients were followed for three years. There was no difference in control of asthma in the two groups, except that the surgery patients required more hospital admissions than patients on medical treatment.
RISA trial: This is the only clinical study of this surgery on severe asthmatic patients. Fifteen patients were subjected to surgery and seventeen patients on medical treatment served as controls. Almost 25% of the patients developed complications from surgery, severe enough to need hospitalization. The study was designed to evaluate the safety of surgery in severe asthmatics. The investigators concluded that the study showed that surgery was safe in severe asthmatics. This conclusion drawn by the company investigators does not make any sense. When 25% of the patients develop severe asthma, lung collapse, etc, severe enough to need hospitalization, than that surgery is not safe. The company realized this and excluded all severe asthmatics from their next study, the AIR-2 trial.
AIR-2 trial: This study was mandated by the FDA for approval of this surgery. The company set the selection criteria in such a way that the most severe of the severe asthmatics were excluded. The FDA overlooked such obvious flaw in the study design.
The study divided patients in two groups, surgery group and sham group. The surgery group patients had bronchoscopy and cauterization of bronchial walls. The sham group had bronchoscopies without cautery.
The study lasted one year. The surgery group had more severe asthma episodes than the sham group. However if you removed the episodes in the first two months the sham group had more asthma episodes. The company seized upon this very selected data and made it the most prominent finding in their article. They claimed that surgery reduced the number of severe asthma episodes.
One single patient in the sham group developed severe asthma after bronchoscopy. He/she needed nine hospital admissions in the study period. If we exclude this one outlier from the study the sham group had a better outcome than the surgery group.
Overall there was no clinical benefit of surgery over sham treatment. All of the parameters of asthma were equal in surgery and sham group. The company claimed that the surgery patients had statistically significant improvement in AQLQ score. However the difference between the surgery and the sham group was very small and of no clinical significance.
The FDA convened an advisory panel. The minutes of the panel meeting, presentation and discussion revealed that the panel members did not ask any important questions about measurements of asthma, like FEV1, symptom score, rescue inhaler use etc. There were more questions about why the results were different in USA compared to overseas, then about asthma control.
First there was presentation by the FDA staff. Then the company staff presented the data. Then there was one hour for public to make comments. The whole hour was packed by Alair® supporters. Doctors and patients gave glaring testimony as how their asthma had improved dramatically after treatment with Alair®. No one from the sham group came to tell how they had improved just as much as the surgery group.
The advisory panel recommended approval of surgical device for this new surgery for asthma. The FDA approved the Alair® device.
A new surgery, that was unknown to doctors a few years ago, was born.