Sleep medicine pioneer David Rapoport, MD, had his doubts when he first saw the nasal EPAP (expiratory positive airway pressure) device, but first impressions can be deceiving.
When David Rapoport, MD, director of the Sleep Medicine Program at the New York University (NYU) School of Medicine, first heard about Ventus Medical’s Provent expiratory positive airway pressure (EPAP) device, he could not hide his skepticism. As one of the early users and developers of nasal CPAP, and a holder of multiple U.S. and European patents for CPAP improvements, Rapoport knew that bringing a new device to the rigorous world of medicine was no easy task.
The founder of Ventus Medical first shared preliminary evidence with Rapoport, prior to any formal publication of the data. “When I first looked at it, I made the mistake of believing it was just another form of CPAP, and not a very good one at that,” says Rapoport, who also holds a degree in physics from the Massachusetts Institute of Technology. “The more I looked and wore it myself, the more I realized that there was more to it than met the eye. It harkened back to the concept of pulling on the upper airway through expanding the lung, which you become aware of when you wear it. You feel your lungs inflating. That fascinated me as a possible mechanism.”
To date, there have been seven published studies attesting to the clinical efficacy of Provent Therapy’s EPAP device, and Rapoport is now a member of the Scientific Advisory Board of the Belmont, Calif-based company. Ventus continues the deliberate process of building evidence and educating sleep physicians, with the most influential study to date involving 19 centers, 250 subjects, a placebo control, and a 3-month follow-up, with results appearing in a 2011 issue of the journal Sleep1.
“In the Sleep study, roughly half the people were in a sham arm and the other half in the active Provent arm,” explains Rajiv Doshi, a consulting assistant professor of Medicine at Stanford University, Palo Alto, and founder of Ventus Medical. “The study showed dramatic and statistically significant improvements in AHI for the active arm, but not in the sham arm. This benefit was maintained for the full 3 months of the study. At the same time, the Provent arm showed significant improvement in sleepiness, as measured by the Epworth Sleepiness Scale, and high compliance rates.”
We interviewed Dr. Rapoport to discuss the concept of nasal EPAP and its place in the clinical arena. Is the sleep world ready for a new class of therapy? Is there a clinical need for nasal EPAP? How does this counter intuitive device actually work?
You have been involved with clinical research in sleep medicine since 1979, and co-founded the NYU Sleep Disorders Center in 1989. As someone who has witnessed the evolution of sleep medicine for more than 30 years, what should sleep physicians know about EPAP and Ventus Medical’s Provent Therapy device in particular?
David Rapoport MD, director of the Sleep Medicine Program at the New York University (NYU) School of Medicine states; Provent Therapy is not another way to deliver CPAP. It quite clearly does not do that at all. We used to think that sleep apnea was a disorder primarily treated during inspiration, and that pressure during inspiration served to hold the airway open. That was the original idea proposed by Colin Sullivan, MD, in the description of CPAP when he called it a pneumatic splint. That is not how Provent works.
Provent works almost entirely during expiration. When you breathe out, it builds up a pressure by resisting your breathing. It is similar to something that patients with COPD do when they do pursed-lip breathing. They pucker up their lips and use their mouth to create a resistance. They blow out almost as if they are puffing. That creates a back pressure, and that is exactly what Provent does, except it does it through the nose, and through a valve. It does almost nothing during inspiration. It opens up wide and lets you breathe in during inspiration.
Why does that have any effect on OSA, and what are the possible mechanisms?
It does several things, all of which are good for sleep apnea. But we don’t know which one is the most important. It could be more than one, and it could depend on the patient. It may be that it works through different combinations of three mechanisms.
When you blow out against a resistance [wearing Provent], your lungs reach an end position at the end of exhalation known as functional residual capacity, which is larger with Provent. Your lungs stay expanded more than they would normally be at the beginning of the next breath. Why should that have an effect? The theory is that when you inflate the lungs, you are actually pulling on the structures they are attached to at the center of the chest, which are attached to the upper airway. When you pull down on the upper airway, it behaves the way any collapsible tube does—it becomes stiffer.
If you take a rubber hose, or any kind of collapsible tube, you see it’s quite floppy, but if you pull it, it becomes more rigid and collapses less. That is called tracheal traction, and it is a mechanism which we were aware of but not paying much attention to. Provent has drawn our attention to the importance of this mechanism.
With your background in physics, was this mechanism something you expected would play a role?
We thought this mechanism would turn out to be the major phenomenon, and it does happen, and it does play a role, but it’s not clear that is the only thing that these Provent valves do.
What other mechanisms were you able to identify?
If you impede breathing and don’t allow free exhalation, we generally do not think that has much of an effect on the total amount you breathe, but it turns out it can, especially with Provent—which has a fairly high resistance. While you’re asleep, some of your reflexes to control the level of breathing don’t function as well as they do while you’re awake. The level of CO2 in the blood rises slightly, and we were able to confirm that increased CO2 was present in patients who were breathing on Provent—both awake and asleep.
What happens when you raise CO2?
If you raise CO2 slightly, you increase the drive to breathe, and that normally compensates and produces a reflex increase in breathing. However, it also produces an increase in the amount of tone that is driven in the muscles that control the stiffness of the upper airway—and we think that might play a role.
It has been shown in other studies that giving CO2 externally does increase the stiffness of the upper airway, and the tone in the muscles, and may have a small effect on sleep apnea by itself. So this is creating the patient’s own CO2 and using that to raise the level in the blood—increasing the level of drive—and therefore the amount of stiffness in the upper airway.
What is the final mechanism?
The final mechanism that we were not able to measure, but we suspect from our data, occurs when you dilate the airway during expiration. At the very beginning of the next breath, the airway itself is larger, and so it has further to collapse during inspiraton. Because it is larger, there is less total resistance in the system. Therefore, when you start breathing in, there is less collapsing pressure because you are sucking against a tube, which has less resistance, and so it collapses less.
Those three mechanisms show potentially why this device works. The bottom line in all these studies is that a good reason is fine, but you have to show that something actually does work. Both of our own studies, which were small, and other larger clinical trials that were published, show that Provent works in a substantial number of patients. About half of the patients succeeded in getting a dramatic improvement in their apnea.
Have sleep physician colleagues been receptive to the device and its technology?
I’m not in a very good position to judge the overall reaction, but I can tell you physicians are looking for other solutions besides CPAP. CPAP works incredibly well, but it is not tolerated by patients as much as we would like. So there are many patients who refuse to use it, or stop using it.
Is Provent easier to try?
The nice thing about Provent is that all you have to do to try it is put it on. It costs almost nothing except for the cost of the sleep study to evaluate it, so it’s easy to try it and see what works.
Is there a way to effectively predict success yet?
In the first paper in the Journal of Clinical Sleep Medicine2, we had hoped to identify some factors to help us predict that, and we were not successful in finding these factors. Fortunately, it’s very easy to just put it on and see if it works, provided you actually do some monitoring and don’t just ask patients to tell you. The ease of trying it is a big plus over other therapies.
Why aren’t more people trying it at this point?
It is mostly not reimbursed yet. However, it is now broadly available throughout the Veterans Administration System, and that will allow a larger number of people to try it. There are some private health care reinsurers who are reimbursing, and in those markets people are using it.
Are doctors expressing interest?
Doctors are very interested, but patients probably will not be able to do this in large numbers until broad reimbursement for this device is approved. I understand that is a long process, and I’m not in a position to say if or when, but it seems that with the papers that have been published that is where we are headed.
What about Medicare reimbursement?
Certainly many therapies are kind of marginal until they are included in Medicare. If you look at kidney dialysis, that was once very rarely used and it was a difficult thing to get patients on it in the early days. Once that became approved by Medicare, it exploded and is now a major form of therapy. Kidney dialysis would be too expensive for people to afford without reimbursement.
What are other patient populations that may be ideal for EPAP?
The primary need is for those patients who have rejected or are non-compliant on CPAP. There are also those who have mild sleep apnea, and those who may have reversible conditions, and only wear CPAP for 3 to 6 months. These people may want to use Provent. Others with allergies might benefit from transient use of Provent.
In these cases, CPAP is difficult to use as an intervention. Provent could help us with this. If it turns out that Provent helps, and these people are benefitting, it will then become the ideal therapy for these types of people.
What was your conclusion from the paper that appeared in the Journal of Clinical Sleep Medicine?3
The major question posed was whether we could predict ahead of time, from the patients’ physical characteristics, who would be a responder to Provent. That paper was not a success in that we were not able to predict.
It was not the heaviest patients. It was not the most severe patients, and it was not the patients who had certain lung function patterns which we had thought might be important.
That paper was more useful in that it showed us what was not the case, and it opened up this idea of the change inlung volume being important. The second paper was all about trying to nail that down and show what actually happened through MRI imaging. That data is limited by the fact that it was mostly done while the patients were awake (Journal of Applied Physiology3) for that particular test. It was a bit of a side effect that we were able to show that other mechanisms played a role.
We really are not good at predicting who it is going to work in at this point. That has been a pattern in all sleep apnea work. Whenever we have a treatment that does not work in everyone, which almost all fall under that category, we are not good at telling who it is going to work in.
What is the typical patient reaction to Provent?
When they first see the device, patients are less negative than they might be with CPAP. That helps a bit in getting started. However, when you first put this device on and actually try to breathe through it, it is a little uncomfortable—perhaps more so than the CPAP.
Most people find that CPAP is not terribly bad in terms of how it affects breathing when they first wear it. They don’t like the mask and the strap, and some of the cumbersome aspects of it, whereas the Provent is relatively uncomfortable when you try to breathe through it.
What kind of pattern do patients typically fall into?
The nice thing is that people adapt to it after they use it for a few days. It’s actually not very important to breathe through it—while you’re awake at least. We generally recommend that people breathe through their mouth while awake, and of course when you do that, it is as if you are not wearing the device. It is completely taken out of the circuit and you feel no effects.
We recommend people breathe through their mouth while awake, and that makes it comfortable and easy to use. The reason that works is that when the majority of people go to sleep, they spontaneously revert to breathing through their nose. The device effectively turns itself on only when you are asleep, and that makes it very attractive. If it is not waking you up, it is helping you. That seems to be the pattern most patients fall into.
And you believe the discomfort is something that patients can deal with relatively quickly?
The discomfort is something manageable. But it is true that if you are trying to breathe through it, it is a bit uncomfortable until you get used to it. Once you are used to it, it is not troublesome. People who have been using the device for a week or so don’t seem to have a problem.
How long have you known about Provent?
I was not involved in the development of the device. I was approached during their clinical trials to help them understand how it worked. That is what I am interested in doing. My interest has been more mechanistic than anything else.
Is it difficult to get noticed among the large competitors in the sleep apnea arena?
I don’t think so. And I doubt very much that Provent will replace CPAP. I think CPAP manufacturers are quite aware of the fact that there is a large group of patients who are not enthusiastic about CPAP.
There are clearly those who don’t use CPAP and would benefit from Provent. But the real impact of this treatment is the much larger number of patients—perhaps two to three times that number—who have relatively mild disease. In many countries, and under many insurance systems, those people are not even covered for CPAP, and generally are not treated.
Is combination therapy being seriously considered?
We are starting to see people think about combination therapy. If Provent works for 50% of people and oral appliances works for 50%, what happens if you combine them? Similarly, if a bit of weight loss improves things but does not cure it, and you combine with Provent, does that work?
I believe combination therapy is where not only Provent, but other new and clever devices/therapies—perhaps drugs—will ultimately have an impact. I don’t think that competes with CPAP. I think it supplements.
What are your hopes for the future of EPAP?
Although I am now a member of the Scientific Advisory Board of the company, I don’t have any particular vested interest. My hope for the field is that we will continue to have alternative therapies to CPAP.
CPAP has had a long and successful run, and is likely to remain a form of treatment for a very long time, but it is quite clear we are not addressing the entire spectrum of disease. It is very important to have alternative therapies.
Provent is one of the ones that is most attractive, especially if it continues to show the kind of success rate that it has, and I believe it will. Provent, when a patient accepts it, is almost invariably worn for the entire night. Even if Provent only works in a certain percentage of people, it works completely for those people.
David Rapoport, MD, is Director of the Sleep Medicine Program at the New York University (NYU) School of Medicine
1. A Novel Nasal Expiratory Positive Airway Pressure (EPAP) Device for the Treatment of Obstructive Sleep Apnea: A Randomized Controlled Trial Berry, RB, Kryger, MH, Massie, CA [Sleep 2011;34 (4):479-485]
2. Long term use of a nasal expiratory positive airway pressure (EPAP) device as a treatment for obstructive sleep apnea Kryger MH, Berry RB, Massie CA. [Journal of Clinical Sleep Medicine 2011; 7:5:449-453]
3. Changes in lung volume and upper airway using MRI during application of nasal expiratory positive airway pressure in patients with sleep disordered breathing. Braga CW, Chen Q, Burschtin O, et al. [Journal of Applied Physiology 2011;111:1400-1409]