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The rise and fall of treatment trials in group 3 pulmonary hypertension: Where do we go from here?
Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).
Group 3 PH – The rationale to treat
Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.
Previous studies of pulmonary vasodilator therapy for group 3 PH
Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).
The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
Hot off the presses – RISE-IIP
The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.
To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.
The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
RISE’ing from the ashes – Where do we go from here?
So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.
The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.
Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).
Group 3 PH – The rationale to treat
Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.
Previous studies of pulmonary vasodilator therapy for group 3 PH
Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).
The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
Hot off the presses – RISE-IIP
The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.
To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.
The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
RISE’ing from the ashes – Where do we go from here?
So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.
The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.
Treatment of fibrotic interstitial lung disease (ILD) is often dissatisfying to clinicians and patients. Despite significant advances in the field, particularly the validation of the efficacy of the antifibrotic drugs nintedanib (Richeldi L, et al. N Engl J Med. 2014;370[22]:2071) and pirfenidone (King TE Jr, et al. N Engl J Med. 2014;370[(22]:2083) in slowing the progression of idiopathic pulmonary fibrosis (IPF), we are still left with a paucity of therapeutic options to modulate the course of disease and improve functional outcomes. Given the difficulties in addressing the progression of parenchymal fibrosis, the pulmonary community has looked for alternative ways to approach treatment of ILD. One potential therapeutic inroad that has garnered substantial interest is the treatment of concurrent pulmonary hypertension (PH) or group 3 PH (Seeger W, et al. J Am Coll Cardiol. 2013;62 (25 Suppl):D109).
Group 3 PH – The rationale to treat
Group 3 PH has an indisputable association with adverse outcomes, including decreased functional status, increased need for supplemental oxygen, and decreased survival (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4.2017;67-84). In fact, PH is such a powerful predictor of survival in fibrotic ILD, the International Society of Heart and Lung Transplant (ISHLT) guidelines on candidate selection for lung transplantation cite development of PH as an indication for transplant listing (Weill D, et al. J Heart Lung Transplant. 2015;34:1). When one considers the strong association between group 3 PH and adverse outcomes, the numerous pulmonary vasodilator agents available to treat pulmonary arterial hypertension (PAH), and the success achieved in treating PAH, it is easy to see why group 3 PH is such a tempting therapeutic target.
Previous studies of pulmonary vasodilator therapy for group 3 PH
Over 20 studies assessing the effectiveness of pulmonary vasodilator therapy in ILD have been published (King CS, Nathan SD. Pulmonary Hypertension and Interstitial Lung Disease. Ed 2. Ch 4. 2017;67) The majority was small and unblinded with inherent limitations. To date, no randomized controlled trial (RCT) of therapy for group 3 PH has demonstrated efficacy. Several studies amongst the RCTs deserve highlighting. The most encouraging RCT of therapy for group 3 PH was STEP-IPF. This study compared sildenafil with placebo in 180 patients with advanced IPF. Though the study failed to demonstrate a difference in the primary endpoint of ≥ 20% increase in 6-minute walk test (6MWT) distance, it did show improvement in several secondary endpoints, including arterial oxygen saturation and quality of life measures (Zisman DA, et al. N Engl J Med. 2010;363[7]:620).
The BUILD-3 study compared bosentan with placebo in 617 patients with IPF. Enrolled patients were not required to have PH. While bosentan was well tolerated, it failed to improve the primary endpoint of time to disease progression or death or secondary endpoints regarding quality of life or dyspnea (King TE Jr, et al. Am J Respir Crit Care Med. 2011; 184[1]:92). A smaller study comparing bosentan with placebo in 60 patients with fibrotic ILD with right-sided heart catheterization (RHC) confirmed PH failed to demonstrate any difference in pulmonary vascular hemodynamics, functional status, or symptoms (Corte TJ, et al. Am J Respir Crit Care Med. 2014;190[2]:208). Studies of the newer endothelin receptor antagonists, macitentan (Raghu, et al. Eur Respir J. 2013;42[6]:1622) and ambrisentan (Raghu, et al. Ann Int Med. 2013;158[9]:641), were conducted and failed to demonstrate improvements in outcomes, as well. Overall, the results of the available RCTs of pulmonary vasodilator therapy in group 3 PH have been disappointing, failing to conclusively improve the primary outcome in any of the studies performed.
Hot off the presses – RISE-IIP
The latest letdown in group 3 PH is “Riociguat for the Treatment of Pulmonary Hypertension in Idiopathic Interstitial Pneumonia (RISE-IIP). The results of the study were recently presented at the European Respiratory Society meeting in Milan, Italy, by my colleague from Inova Fairfax Hospital (Falls Church, VA), Dr. Steven Nathan. Riociguat is a soluble guanylate cyclase stimulator approved for use in PAH and chronic thromboembolic pulmonary hypertension. The rationale for the study was that riociguat would improve pulmonary hemodynamics leading to improved functional status. Additionally, several preclinical models have demonstrated antifibrotic effects of the drug (Geschka S, et al. PLoS One. 2011;6:e21853). Justification for the study was also bolstered by promising results from a pilot study conducted in 22 patients with RHC-confirmed PH with a mean pulmonary artery pressure (mPAP) > 30 and fibrotic lung disease. In this study, patients treated with riociguat had improved pulmonary vascular resistance, cardiac output, and 6MWT distance.
To be included in RISE-IIP, patients were required to have an idiopathic interstitial pneumonia, PH confirmed by RHC with a mPAP ≥ 25 mm Hg, World Health Organization Functional Class 2-4 symptoms, and a forced vital capacity (FVC) ≥ 45% predicted. Pertinent exclusion criteria included significant left-sided heart disease and extent of emphysema greater than fibrosis on HRCT. Patients with connective tissue disease, chronic hypersensitivity pneumonitis, occupational lung disease, and sarcoidosis were ineligible to participate. The placebo-controlled portion of the study lasted 26 weeks then crossed into an open label extension trial.
The study enrolled 147 total patients, with 73 receiving riociguat and 74 in the placebo arm. There was no significant improvement in the primary outcome of change in 6MWT distance or the secondary combined endpoint assessing clinical worsening. The study was terminated early for safety due to an increased number of deaths and adverse events in the treatment group. During the blinded phase of the study, eight deaths (11%) occurred in the riociguat arm as compared with three deaths (4%) in the placebo arm. Seventy patients entered the open label extension phase of the trial, and 9 of these patients died. Eight of these deaths occurred in the patients previously receiving placebo who were switched to riociguat. The authors of the study found no conclusive potential etiology to explain the increased mortality seen.
RISE’ing from the ashes – Where do we go from here?
So, what should we take away from the negative results of the RISE-IIP trial? Some may argue that treatment of group 3 PH is a flawed premise and should be abandoned. Perhaps development of group 3 PH is an adaptive response to worsening fibrotic lung disease, and treatment of the PH is unlikely to alter outcomes and introduces the possibility of harm through worsening hypoxemia due to increased ventilation/perfusion mismatch with nonselective pulmonary vasodilation. I suspect the truth is somewhat more nuanced. I believe there is a select population with severe or “out-of-proportion” PH that may still benefit from vasodilator therapy. Trials targeting patients with a higher mPAP or low cardiac index could test this hypothesis but will be difficult to enroll. Another possibility is that our mechanism of drug delivery in prior trials has been suboptimal. Inhaled pulmonary vasodilator therapy should minimize the risk of worsening ventilation/perfusion mismatch. An RCT assessing the response to inhaled treprostinil in group 3 PH (NCT02630316) is currently enrolling at 96 centers across the United States. Until data supporting positive effects from treating group 3 PH emerge, I would recommend against off-label treatment and encourage referral to clinical trials. Given the potential for harm, riociguat should be avoided in group 3 PH. If off-label therapy is being entertained in a patient with severe PH that is out of proportion to the extent of fibrotic lung disease, it should be initiated cautiously at a center experienced in treating PH. Finally, clinicians should refer appropriate candidates with ILD and group 3 PH for lung transplantation evaluation.
The great inventor Thomas Edison is credited with saying “I have not failed. I’ve just found 10,000 ways that won’t work.” While disappointing, negative studies are to be expected as we search for improved therapies for our patients. It’s essential that we reflect upon these studies, so we can improve future trial design.
Lessons Learned From SERVE-HF
Great attention has been paid to the SERVE-HF trial (“Treatment of Sleep-disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure”), which showed increased all-cause mortality and cardiovascular mortality in the Adaptive Servo-ventilation (ASV) group compared with the control group of conventional heart failure management alone. The results of this trial led to the recommendation by multiple ASV manufacturers and medical societies to withdraw clinical use of ASV from patients with heart failure and a reduced ejection fraction (HFrEF) less than 45%.
Sleep-disordered breathing is common in patients with HFrEF with prevalence rates of 50% to 75%. Central sleep apnea (CSA) is associated with increased mortality in heart failure (HF) and is found in 25% to 40% of this subpopulation. It is estimated that the severity of CSA increases in parallel with the severity of the HF. For several years, treatment of CSA with positive pressure ventilation was believed to favor outcomes in HFrEF with a protective effect.
In the Canadian Positive Airway Pressure for Patients with CSA and HF (CANPAP) trial, subjects were randomized to treatment with CPAP or no CPAP. This trial was terminated early; it did not show an advantage of CPAP in morbidity or mortality. A post-hoc analysis suggested that mortality might be reduced if the frequency of respiratory events per hour or apnea hypopnea index (AHI) is reduced to 15/hour or less while using CPAP.
Hoping to improve the outcomes of HF, SERVE-HF was the first randomized, large scale, multinational trial directed to treat CSA in patients with HFrEF < 45% and concomitant clinically significant sleep apnea with AHI > 15/hour of central predominance (CSA index >10/hour). Treatment arms compared the addition the ASV, one of the most effective noninvasive positive pressure ventilation technologies for central apneas that offers automated inspiratory pressure support in addition to expiratory positive pressure vs conventional medical treatment alone in the control group.
The study published in the New England Journal of Medicine in September 2015 was designed in an intention-to-treat basis with the primary end point of time to first event, a composite of death from any cause, lifesaving cardiovascular intervention (heart transplant, implantation of LVAD, resuscitation after sudden cardiac arrest, or defibrillation for ventricular arrhythmia), or unplanned hospitalization for heart failure. The study did not show significant differences in the primary end point between the ASV and control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval, 0.97 to 1.31; P=.10).1
The most interesting and unexpected outcome was an increase in the all cause mortality and cardiovascular mortality in the ASV group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=.01; and hazard ratio from cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=.006).1 These findings led to the above recommendations from manufacturers, as well as a position statement from the American Academy of Sleep Medicine. These findings cannot be extrapolated to the obstructive sleep apnea population with concomitant HFrEF or to patients with HF with preserved ejection fraction, where positive pressure ventilation has offered an advantage1 likely by a different physiologic mechanism not fully uncovered at this time, believed to be an overall effect of afterload reduction.
Selection and self-selection bias in this study was addressed in a new analysis by the same SERVE-HF investigator group published August 2017, where a time-dependent model of on-treatment analysis (done to tease out if the original results were related to the treatment assignment or to poor adherence) was conducted to understand potential causes of the initial findings in the original study. It showed patients randomized to ASV who crossed over to the control group were at higher risk of cardiovascular death than control subjects; also the control patients with crossover to ASV had a signal of lower risk of cardiovascular death risk compared with patients assigned to ASV.2 Reduced adherence to ASV treatment during SERVE-HF was a concern, since it resulted in a reduced exposure to the treatment. The on-treatment analysis showed again an increase of cardiovascular death in HFrEF patients with predominant CSA treated with ASV in addition to conventional heart failure treatment compared with the control group.2 There was no increase in cardiovascular death risk associated with ASV use intervals (dose effect). This effect is not related to the amount of hours used per night.
The effect of the recommended withdrawal of treatment in HFrEF patients with EF<45% and moderate to severe central predominant sleep apnea is being addressed in smaller studies. A single center retrospective analysis observed the effects after ASV discontinuation in this population. Thirteen out of 126 patients treated with ASV who met SERVE-HF criteria were followed for at least a year; 93% of the subjects who met criteria had ASV removed; immediate recurrence of the central apnea was observed in most (except two patients), while adverse events were not identified (defined as need for emergency hospitalization). Day and nighttime symptoms were reported by 61% of the group, and they were started on alternative treatments.3 At 1 year after ASV removal, 88% of patients were still alive, overall cardiac function did not change in 1 year (P=0.17), and seven patients required adjustment of medications for heart failure. Symptomatic patients were treated with oxygen supplementation for nocturnal symptoms or CPAP if they had daytime sleepiness. None was treated with bi-level PAP, acetazolamide, or phrenic nerve stimulation. Four patients insisted on continuation of ASV despite understanding physician concerns. 3 This study helps to demonstrate that ASV discontinuation is feasible but requires close follow-up. However, larger, long-term prospective reviews are required to draw statistically meaningful conclusions about the consequences and safety of ASV removal; these studies will be difficult to conduct under the current indications for ASV in the interest group.
At this time, investigators have shifted to further understand the causes of the increase in cardiovascular mortality, overall mortality, and the understanding of the pathophysiologic processes associated with ASV use in HFrEF. It is not known whether the effect in mortality is related to the specific ASV device/algorithm used to suppress CSA or is related to the ASV principle itself. Upcoming studies will assist in clarifying these details. Currently, there is an ongoing trial looking at the effect of ASV on survival and hospital admissions in heart failure (ADVENT–HF) using a different ASV device; this study will hopefully elucidate the impact of class effect vs device effect. It may also provide better insight of the etiology of mortality and the impact of improved ASV compliance, first addressed by the on-treatment analysis of the SERVE-HF.4
Although the reasons for increased mortality related to ASV are unclear, proposed hypotheses include: central apnea is an adaptive mechanism to HFrEF and the reversal of central apneas might adversely affect the underlying disease process,1 low adherence to ASV may impact outcomes, and specific devices may induce hyper-/hypoventilation generated by the algorithm designs of the specific ASV device and this may result in electrolyte abnormalities that generate arrhythmias.
The ADVENT-HF trial, although similar in design, has significant differences from SERVE-HF: different ASV devices may have a different impact on cardiac output and ventilation, recruited patients included those with less daytime sleepiness, and the potential to assess the effect of ASV in patients with OSA and low daytime sleepiness in patients with reduced EF.5,6 This ongoing study may help us to further understand why there is increased mortality and what effect ASV has on the treatment of sleep apnea in patients with HFrEF.
References
1. Cowie MR, et al. N Engl J Med. 2015;373(12):1095-1105.
2. Woehrle H, et al. Eur Respir J. 2017; 50:1601.
3. Brill AK, et al. Sleep Med. 2017;37:201-207.
4. Bradley TD, et al. Can Respir. 2015;22(6):313.
5. Lyons OD, et al. Eur J Heart Fail. 2017;19(4):579-587.
6. Haruki N, et al. Can J Cardiol. 2016;32(12):1402-1410.
Dr. Barrantes is an assistant professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas.
Great attention has been paid to the SERVE-HF trial (“Treatment of Sleep-disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure”), which showed increased all-cause mortality and cardiovascular mortality in the Adaptive Servo-ventilation (ASV) group compared with the control group of conventional heart failure management alone. The results of this trial led to the recommendation by multiple ASV manufacturers and medical societies to withdraw clinical use of ASV from patients with heart failure and a reduced ejection fraction (HFrEF) less than 45%.
Sleep-disordered breathing is common in patients with HFrEF with prevalence rates of 50% to 75%. Central sleep apnea (CSA) is associated with increased mortality in heart failure (HF) and is found in 25% to 40% of this subpopulation. It is estimated that the severity of CSA increases in parallel with the severity of the HF. For several years, treatment of CSA with positive pressure ventilation was believed to favor outcomes in HFrEF with a protective effect.
In the Canadian Positive Airway Pressure for Patients with CSA and HF (CANPAP) trial, subjects were randomized to treatment with CPAP or no CPAP. This trial was terminated early; it did not show an advantage of CPAP in morbidity or mortality. A post-hoc analysis suggested that mortality might be reduced if the frequency of respiratory events per hour or apnea hypopnea index (AHI) is reduced to 15/hour or less while using CPAP.
Hoping to improve the outcomes of HF, SERVE-HF was the first randomized, large scale, multinational trial directed to treat CSA in patients with HFrEF < 45% and concomitant clinically significant sleep apnea with AHI > 15/hour of central predominance (CSA index >10/hour). Treatment arms compared the addition the ASV, one of the most effective noninvasive positive pressure ventilation technologies for central apneas that offers automated inspiratory pressure support in addition to expiratory positive pressure vs conventional medical treatment alone in the control group.
The study published in the New England Journal of Medicine in September 2015 was designed in an intention-to-treat basis with the primary end point of time to first event, a composite of death from any cause, lifesaving cardiovascular intervention (heart transplant, implantation of LVAD, resuscitation after sudden cardiac arrest, or defibrillation for ventricular arrhythmia), or unplanned hospitalization for heart failure. The study did not show significant differences in the primary end point between the ASV and control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval, 0.97 to 1.31; P=.10).1
The most interesting and unexpected outcome was an increase in the all cause mortality and cardiovascular mortality in the ASV group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=.01; and hazard ratio from cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=.006).1 These findings led to the above recommendations from manufacturers, as well as a position statement from the American Academy of Sleep Medicine. These findings cannot be extrapolated to the obstructive sleep apnea population with concomitant HFrEF or to patients with HF with preserved ejection fraction, where positive pressure ventilation has offered an advantage1 likely by a different physiologic mechanism not fully uncovered at this time, believed to be an overall effect of afterload reduction.
Selection and self-selection bias in this study was addressed in a new analysis by the same SERVE-HF investigator group published August 2017, where a time-dependent model of on-treatment analysis (done to tease out if the original results were related to the treatment assignment or to poor adherence) was conducted to understand potential causes of the initial findings in the original study. It showed patients randomized to ASV who crossed over to the control group were at higher risk of cardiovascular death than control subjects; also the control patients with crossover to ASV had a signal of lower risk of cardiovascular death risk compared with patients assigned to ASV.2 Reduced adherence to ASV treatment during SERVE-HF was a concern, since it resulted in a reduced exposure to the treatment. The on-treatment analysis showed again an increase of cardiovascular death in HFrEF patients with predominant CSA treated with ASV in addition to conventional heart failure treatment compared with the control group.2 There was no increase in cardiovascular death risk associated with ASV use intervals (dose effect). This effect is not related to the amount of hours used per night.
The effect of the recommended withdrawal of treatment in HFrEF patients with EF<45% and moderate to severe central predominant sleep apnea is being addressed in smaller studies. A single center retrospective analysis observed the effects after ASV discontinuation in this population. Thirteen out of 126 patients treated with ASV who met SERVE-HF criteria were followed for at least a year; 93% of the subjects who met criteria had ASV removed; immediate recurrence of the central apnea was observed in most (except two patients), while adverse events were not identified (defined as need for emergency hospitalization). Day and nighttime symptoms were reported by 61% of the group, and they were started on alternative treatments.3 At 1 year after ASV removal, 88% of patients were still alive, overall cardiac function did not change in 1 year (P=0.17), and seven patients required adjustment of medications for heart failure. Symptomatic patients were treated with oxygen supplementation for nocturnal symptoms or CPAP if they had daytime sleepiness. None was treated with bi-level PAP, acetazolamide, or phrenic nerve stimulation. Four patients insisted on continuation of ASV despite understanding physician concerns. 3 This study helps to demonstrate that ASV discontinuation is feasible but requires close follow-up. However, larger, long-term prospective reviews are required to draw statistically meaningful conclusions about the consequences and safety of ASV removal; these studies will be difficult to conduct under the current indications for ASV in the interest group.
At this time, investigators have shifted to further understand the causes of the increase in cardiovascular mortality, overall mortality, and the understanding of the pathophysiologic processes associated with ASV use in HFrEF. It is not known whether the effect in mortality is related to the specific ASV device/algorithm used to suppress CSA or is related to the ASV principle itself. Upcoming studies will assist in clarifying these details. Currently, there is an ongoing trial looking at the effect of ASV on survival and hospital admissions in heart failure (ADVENT–HF) using a different ASV device; this study will hopefully elucidate the impact of class effect vs device effect. It may also provide better insight of the etiology of mortality and the impact of improved ASV compliance, first addressed by the on-treatment analysis of the SERVE-HF.4
Although the reasons for increased mortality related to ASV are unclear, proposed hypotheses include: central apnea is an adaptive mechanism to HFrEF and the reversal of central apneas might adversely affect the underlying disease process,1 low adherence to ASV may impact outcomes, and specific devices may induce hyper-/hypoventilation generated by the algorithm designs of the specific ASV device and this may result in electrolyte abnormalities that generate arrhythmias.
The ADVENT-HF trial, although similar in design, has significant differences from SERVE-HF: different ASV devices may have a different impact on cardiac output and ventilation, recruited patients included those with less daytime sleepiness, and the potential to assess the effect of ASV in patients with OSA and low daytime sleepiness in patients with reduced EF.5,6 This ongoing study may help us to further understand why there is increased mortality and what effect ASV has on the treatment of sleep apnea in patients with HFrEF.
References
1. Cowie MR, et al. N Engl J Med. 2015;373(12):1095-1105.
2. Woehrle H, et al. Eur Respir J. 2017; 50:1601.
3. Brill AK, et al. Sleep Med. 2017;37:201-207.
4. Bradley TD, et al. Can Respir. 2015;22(6):313.
5. Lyons OD, et al. Eur J Heart Fail. 2017;19(4):579-587.
6. Haruki N, et al. Can J Cardiol. 2016;32(12):1402-1410.
Dr. Barrantes is an assistant professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas.
Great attention has been paid to the SERVE-HF trial (“Treatment of Sleep-disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure”), which showed increased all-cause mortality and cardiovascular mortality in the Adaptive Servo-ventilation (ASV) group compared with the control group of conventional heart failure management alone. The results of this trial led to the recommendation by multiple ASV manufacturers and medical societies to withdraw clinical use of ASV from patients with heart failure and a reduced ejection fraction (HFrEF) less than 45%.
Sleep-disordered breathing is common in patients with HFrEF with prevalence rates of 50% to 75%. Central sleep apnea (CSA) is associated with increased mortality in heart failure (HF) and is found in 25% to 40% of this subpopulation. It is estimated that the severity of CSA increases in parallel with the severity of the HF. For several years, treatment of CSA with positive pressure ventilation was believed to favor outcomes in HFrEF with a protective effect.
In the Canadian Positive Airway Pressure for Patients with CSA and HF (CANPAP) trial, subjects were randomized to treatment with CPAP or no CPAP. This trial was terminated early; it did not show an advantage of CPAP in morbidity or mortality. A post-hoc analysis suggested that mortality might be reduced if the frequency of respiratory events per hour or apnea hypopnea index (AHI) is reduced to 15/hour or less while using CPAP.
Hoping to improve the outcomes of HF, SERVE-HF was the first randomized, large scale, multinational trial directed to treat CSA in patients with HFrEF < 45% and concomitant clinically significant sleep apnea with AHI > 15/hour of central predominance (CSA index >10/hour). Treatment arms compared the addition the ASV, one of the most effective noninvasive positive pressure ventilation technologies for central apneas that offers automated inspiratory pressure support in addition to expiratory positive pressure vs conventional medical treatment alone in the control group.
The study published in the New England Journal of Medicine in September 2015 was designed in an intention-to-treat basis with the primary end point of time to first event, a composite of death from any cause, lifesaving cardiovascular intervention (heart transplant, implantation of LVAD, resuscitation after sudden cardiac arrest, or defibrillation for ventricular arrhythmia), or unplanned hospitalization for heart failure. The study did not show significant differences in the primary end point between the ASV and control group (54.1% and 50.8%, respectively; hazard ratio, 1.13; 95% confidence interval, 0.97 to 1.31; P=.10).1
The most interesting and unexpected outcome was an increase in the all cause mortality and cardiovascular mortality in the ASV group (hazard ratio for death from any cause, 1.28; 95% CI, 1.06 to 1.55; P=.01; and hazard ratio from cardiovascular death, 1.34; 95% CI, 1.09 to 1.65; P=.006).1 These findings led to the above recommendations from manufacturers, as well as a position statement from the American Academy of Sleep Medicine. These findings cannot be extrapolated to the obstructive sleep apnea population with concomitant HFrEF or to patients with HF with preserved ejection fraction, where positive pressure ventilation has offered an advantage1 likely by a different physiologic mechanism not fully uncovered at this time, believed to be an overall effect of afterload reduction.
Selection and self-selection bias in this study was addressed in a new analysis by the same SERVE-HF investigator group published August 2017, where a time-dependent model of on-treatment analysis (done to tease out if the original results were related to the treatment assignment or to poor adherence) was conducted to understand potential causes of the initial findings in the original study. It showed patients randomized to ASV who crossed over to the control group were at higher risk of cardiovascular death than control subjects; also the control patients with crossover to ASV had a signal of lower risk of cardiovascular death risk compared with patients assigned to ASV.2 Reduced adherence to ASV treatment during SERVE-HF was a concern, since it resulted in a reduced exposure to the treatment. The on-treatment analysis showed again an increase of cardiovascular death in HFrEF patients with predominant CSA treated with ASV in addition to conventional heart failure treatment compared with the control group.2 There was no increase in cardiovascular death risk associated with ASV use intervals (dose effect). This effect is not related to the amount of hours used per night.
The effect of the recommended withdrawal of treatment in HFrEF patients with EF<45% and moderate to severe central predominant sleep apnea is being addressed in smaller studies. A single center retrospective analysis observed the effects after ASV discontinuation in this population. Thirteen out of 126 patients treated with ASV who met SERVE-HF criteria were followed for at least a year; 93% of the subjects who met criteria had ASV removed; immediate recurrence of the central apnea was observed in most (except two patients), while adverse events were not identified (defined as need for emergency hospitalization). Day and nighttime symptoms were reported by 61% of the group, and they were started on alternative treatments.3 At 1 year after ASV removal, 88% of patients were still alive, overall cardiac function did not change in 1 year (P=0.17), and seven patients required adjustment of medications for heart failure. Symptomatic patients were treated with oxygen supplementation for nocturnal symptoms or CPAP if they had daytime sleepiness. None was treated with bi-level PAP, acetazolamide, or phrenic nerve stimulation. Four patients insisted on continuation of ASV despite understanding physician concerns. 3 This study helps to demonstrate that ASV discontinuation is feasible but requires close follow-up. However, larger, long-term prospective reviews are required to draw statistically meaningful conclusions about the consequences and safety of ASV removal; these studies will be difficult to conduct under the current indications for ASV in the interest group.
At this time, investigators have shifted to further understand the causes of the increase in cardiovascular mortality, overall mortality, and the understanding of the pathophysiologic processes associated with ASV use in HFrEF. It is not known whether the effect in mortality is related to the specific ASV device/algorithm used to suppress CSA or is related to the ASV principle itself. Upcoming studies will assist in clarifying these details. Currently, there is an ongoing trial looking at the effect of ASV on survival and hospital admissions in heart failure (ADVENT–HF) using a different ASV device; this study will hopefully elucidate the impact of class effect vs device effect. It may also provide better insight of the etiology of mortality and the impact of improved ASV compliance, first addressed by the on-treatment analysis of the SERVE-HF.4
Although the reasons for increased mortality related to ASV are unclear, proposed hypotheses include: central apnea is an adaptive mechanism to HFrEF and the reversal of central apneas might adversely affect the underlying disease process,1 low adherence to ASV may impact outcomes, and specific devices may induce hyper-/hypoventilation generated by the algorithm designs of the specific ASV device and this may result in electrolyte abnormalities that generate arrhythmias.
The ADVENT-HF trial, although similar in design, has significant differences from SERVE-HF: different ASV devices may have a different impact on cardiac output and ventilation, recruited patients included those with less daytime sleepiness, and the potential to assess the effect of ASV in patients with OSA and low daytime sleepiness in patients with reduced EF.5,6 This ongoing study may help us to further understand why there is increased mortality and what effect ASV has on the treatment of sleep apnea in patients with HFrEF.
References
1. Cowie MR, et al. N Engl J Med. 2015;373(12):1095-1105.
2. Woehrle H, et al. Eur Respir J. 2017; 50:1601.
3. Brill AK, et al. Sleep Med. 2017;37:201-207.
4. Bradley TD, et al. Can Respir. 2015;22(6):313.
5. Lyons OD, et al. Eur J Heart Fail. 2017;19(4):579-587.
6. Haruki N, et al. Can J Cardiol. 2016;32(12):1402-1410.
Dr. Barrantes is an assistant professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas.