DiPALS is a very impressive study. It is the first, and still only, randomized prospective trial of DPS in ALS. Although the sample size is small, this study showed a large negative effect from diaphragm pacing, with patients receiving diaphragm pacing and non-invasive ventilation living 11 months less than patients receiving non-invasive ventilation alone.
It is not yet clear why this data is so different from the results of the non-randomized studies that have been done. It is certainly not the first time that a randomized study showed something vastly different than a non-randomized one. One possible explanation is that there are biases in non-randomized studies that affect outcomes, independent of the intervention being studied. For example, in my own clinic I have found that patients who opted for diaphragm pacing were generally much more aggressive about fighting their illness than patients who opted against diaphragm pacing. That difference in attitude alone might have a significant effect on survival. Whatever the explanation, this is a great example of the importance of randomized studies.
As for the impact of DiPALS on my own practice, after years of offering this to all qualified patients and implanting approximately 60 diaphragm pacers at Duke, this study convinced me to stop. I will not be offering new diaphragm pacing implants in my clinic again unless or until an even better-designed study shows a benefit.
We are happy to see the first controlled clinical trial examining the benefit and safety of diaphragm pacing in patients with ALS.
The DiPALS study was a well-designed and -executed study, but it actually showed shorter survival in the patients receiving diaphragm pacing plus non-invasive ventilation compared with those receiving non-invasive ventilation alone. At first blush, this would appear to cast doubt on the value of pacing in ALS. However, there are some issues that mitigate the impact of the finding.
First, the study is very small for a survival study, raising the possibility that the finding was due to chance, as we have seen before with lithium and with the first riluzole study. Second, many patients in the study did not adhere to protocol and failed to utilize non-invasive ventilation. Third, all patients taken to surgery were implanted with pacing electrodes, suggesting that some patients with advanced denervation, who would not have been implanted in the United States, were implanted and unlikely to benefit.
Two registry studies of diaphragm pacing in ALS patients have demonstrated a survival advantage with pacing that led the FDA to conclude 1) the device is of probable benefit and 2) there were no safety concerns.
Two other randomized controlled trials are underway and hopefully with all of this additional data, the role of diaphragm pacing will become clearer. In particular, if there is a subset of responders to pacing, these patients might be more adequately characterized by further studies, which I believe should be done.
In this well-designed clinical trial, McDermott and colleagues found that ALS patients with respiratory insufficiency who received the diaphragm pacing simulation (DPS) system in addition to non-invasive ventilation (NIV) had a significantly shortened survival (11 months) versus the group who received NIV alone (22 months). The median survival from symptom onset was similarly shorter in the DPS+NIV group (28 months versus 45 months in the NIV-alone group). Minor differences amongst the two treatment groups (age, use of cough-assist machines, breath stacking and suction devices) are unlikely to have caused an almost doubling of the length of survival in the NIV-alone group, and the patient demographics data makes this study generalizable to ALS patients as a whole (as opposed to the previous selected DPS patient cohorts). Another clinical trial, (RepStimALS, early phrenic nerve stimulation) has suspended enrollment as of this writing.
The authors stipulate several possible mechanisms that may explain why the DPS worsened survival: Diaphragm stimulation may cause excessive muscle fatigue, may contribute to increased demise of already ill motor neurons, may cause asynchrony with the patient’s own breathing, or may accelerate neuromuscular dysfunction that has been shown in laboratory research animals.
Based on this study, DPS is not recommended for ALS patients suffering from respiratory insufficiency. NIV is a proven and beneficial treatment that can prolong survival by almost two years in ALS patients who tolerate it and by seven months in all ALS patients as a group. Together with other, safe adjunct respiratory therapies (breath stacking, mechanical and manual cough assistance, and airway clearance), NIV remains the primary treatment for respiratory insufficiency in ALS.
There is definitely no consensus on the benefit of diaphragm pacing in ALS. There is still a study ongoing in the United States run by the North East ALS consortium (NEALS). To my knowledge, they are planning to look at the data and decide if any changes need to be made or if the trial should continue.
The bottom line is the survival for the group receiving diaphragm pacing in the DiPALS study was shorter than what has been reported previously for DPS in the retrospective studies. The reason for this remains unclear.
That said, I would say no one is convinced yet whether DPS helps or hurts patients. We continue to do the procedure at our site as part of the NEALS U.S. trial, and will continue to provide that option until the trial is completed or stopped, because that is the only way to get definitive information that we can use to guide patients.
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Duke University
DiPALS is a very impressive study. It is the first, and still only, randomized prospective trial of DPS in ALS. Although the sample size is small, this study showed a large negative effect from diaphragm pacing, with patients receiving diaphragm pacing and non-invasive ventilation living 11 months less than patients receiving non-invasive ventilation alone.
It is not yet clear why this data is so different from the results of the non-randomized studies that have been done. It is certainly not the first time that a randomized study showed something vastly different than a non-randomized one. One possible explanation is that there are biases in non-randomized studies that affect outcomes, independent of the intervention being studied. For example, in my own clinic I have found that patients who opted for diaphragm pacing were generally much more aggressive about fighting their illness than patients who opted against diaphragm pacing. That difference in attitude alone might have a significant effect on survival. Whatever the explanation, this is a great example of the importance of randomized studies.
As for the impact of DiPALS on my own practice, after years of offering this to all qualified patients and implanting approximately 60 diaphragm pacers at Duke, this study convinced me to stop. I will not be offering new diaphragm pacing implants in my clinic again unless or until an even better-designed study shows a benefit.
View all comments by Richard BedlackCalifornia Pacific Medical Center
We are happy to see the first controlled clinical trial examining the benefit and safety of diaphragm pacing in patients with ALS.
The DiPALS study was a well-designed and -executed study, but it actually showed shorter survival in the patients receiving diaphragm pacing plus non-invasive ventilation compared with those receiving non-invasive ventilation alone. At first blush, this would appear to cast doubt on the value of pacing in ALS. However, there are some issues that mitigate the impact of the finding.
First, the study is very small for a survival study, raising the possibility that the finding was due to chance, as we have seen before with lithium and with the first riluzole study. Second, many patients in the study did not adhere to protocol and failed to utilize non-invasive ventilation. Third, all patients taken to surgery were implanted with pacing electrodes, suggesting that some patients with advanced denervation, who would not have been implanted in the United States, were implanted and unlikely to benefit.
Two registry studies of diaphragm pacing in ALS patients have demonstrated a survival advantage with pacing that led the FDA to conclude 1) the device is of probable benefit and 2) there were no safety concerns.
Two other randomized controlled trials are underway and hopefully with all of this additional data, the role of diaphragm pacing will become clearer. In particular, if there is a subset of responders to pacing, these patients might be more adequately characterized by further studies, which I believe should be done.
View all comments by Robert MillerIn this well-designed clinical trial, McDermott and colleagues found that ALS patients with respiratory insufficiency who received the diaphragm pacing simulation (DPS) system in addition to non-invasive ventilation (NIV) had a significantly shortened survival (11 months) versus the group who received NIV alone (22 months). The median survival from symptom onset was similarly shorter in the DPS+NIV group (28 months versus 45 months in the NIV-alone group). Minor differences amongst the two treatment groups (age, use of cough-assist machines, breath stacking and suction devices) are unlikely to have caused an almost doubling of the length of survival in the NIV-alone group, and the patient demographics data makes this study generalizable to ALS patients as a whole (as opposed to the previous selected DPS patient cohorts). Another clinical trial, (RepStimALS, early phrenic nerve stimulation) has suspended enrollment as of this writing.
The authors stipulate several possible mechanisms that may explain why the DPS worsened survival: Diaphragm stimulation may cause excessive muscle fatigue, may contribute to increased demise of already ill motor neurons, may cause asynchrony with the patient’s own breathing, or may accelerate neuromuscular dysfunction that has been shown in laboratory research animals.
Based on this study, DPS is not recommended for ALS patients suffering from respiratory insufficiency. NIV is a proven and beneficial treatment that can prolong survival by almost two years in ALS patients who tolerate it and by seven months in all ALS patients as a group. Together with other, safe adjunct respiratory therapies (breath stacking, mechanical and manual cough assistance, and airway clearance), NIV remains the primary treatment for respiratory insufficiency in ALS.
View all comments by Katalin SchererDirector of Neuromuscular Medicine, Cedars-Sinai Medical Center
There is definitely no consensus on the benefit of diaphragm pacing in ALS. There is still a study ongoing in the United States run by the North East ALS consortium (NEALS). To my knowledge, they are planning to look at the data and decide if any changes need to be made or if the trial should continue.
The bottom line is the survival for the group receiving diaphragm pacing in the DiPALS study was shorter than what has been reported previously for DPS in the retrospective studies. The reason for this remains unclear.
That said, I would say no one is convinced yet whether DPS helps or hurts patients. We continue to do the procedure at our site as part of the NEALS U.S. trial, and will continue to provide that option until the trial is completed or stopped, because that is the only way to get definitive information that we can use to guide patients.
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