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and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.
To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female
At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).
In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.
“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.
Next steps: Assess clinical outcomes after inhaled treprostinil
Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”
While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.
He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”
Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.
“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”
The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.
As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”
The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.
and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.
To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female
At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).
In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.
“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.
Next steps: Assess clinical outcomes after inhaled treprostinil
Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”
While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.
He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”
Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.
“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”
The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.
As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”
The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.
and was associated with some additional clinical benefits, according to a new study published in the New England Journal of Medicine.
To investigate treprostinil therapy for pulmonary hypertension in this subset of patients with lung disease, Aaron Waxman, MD, PhD, of Brigham and Women’s Hospital in Boston, and his fellow researchers launched the multicenter, randomized, double-blind, placebo-controlled INCREASE trial. They assigned 163 patients to the inhaled treprostinil group – administered via an ultrasonic, pulsed-delivery nebulizer over 16 weeks – and 163 patients to the placebo group. Their average age was 66.5 years, 73% were white, and 47% were female
At baseline, the mean 6-minute walk distance (6MWD) for all patients was 259.6 m. After 16 weeks, the treprostinil group gained a mean of 21.08 m in 6MWD, and the placebo group lost 10.04 m. The least-squares mean difference between the groups from baseline in the 6MWD was 31.12 m (95% confidence interval, 16.85-45.39; P < .001). After sensitivity analysis with multiple imputation, the difference remained significant at 30.97 m (95% CI, 16.53-45.41; P < .001).
In a comparison of N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels from baseline to 16 weeks, the treprostinil group saw a decrease of 15% while the placebo group’s levels increased by 46% (treatment ratio 0.58; 95% CI, 0.47-0.72; P < .001). Clinical worsening occurred in 37 patients (23%) in the treprostinil group and 54 patients (33%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40-0.92; P = .04), while serious adverse events occurred in 23.3% of the patients on treprostinil and 25.8% of the patients on placebo. There was no significant difference between groups in patient-reported quality of life, as assessed via the St. George’s Respiratory Questionnaire.
“There was no guarantee that this was going to work in this condition,” said Adriano Tonelli, MD, of the department of pulmonary medicine at the Cleveland Clinic, in an interview. “Several small studies have tried different medications, for pulmonary hypertension or otherwise, in patients with interstitial lung disease with minimal effect, if any. Given that all the prior studies were not categorically positive, the expectation, at least on my end, was that we needed to wait and see.” Dr. Tonelli and coauthors published a post hoc analysis of inhaled treprostinil studied in the TRIUMPH and BEAT trials.
Next steps: Assess clinical outcomes after inhaled treprostinil
Although the results of this study by Waxman et al, are encouraging, and the need for a treatment in this type of pulmonary hypertension is very real, more narrowing down will be needed to confirm the benefits of inhaled treprostinil, wrote Darren B. Taichman, MD, PhD, of the University of Pennsylvania in an accompanying editorial. He wrote, “After all, patients and physicians may reason, ‘It can’t hurt.’ Unfortunately, however, it could. Therapies approved for pulmonary arterial hypertension have been studied in patients with [ILD]-associated pulmonary hypertension and have shown inconsistent results, with some studies showing no benefit or suggesting harm.”
While the 6MWD has been used as an end point in previous drug trials for pulmonary arterial hypertension, Dr. Taichman wrote that improvements in such a variable were “probably too modest to be unequivocally consequential for many patients.” To confirm the benefits – and detriments – of treatments like inhaled treprostinil, it’s time for studies to focus on clinical end points, he stated, including hospitalizations, disease progression, and death.
He also highlighted the disparity between a treatment that led to increased walk distance and decreased clinical worsening yet did not register an improvement in health-related quality of life. He noted that the oft-cited minimal clinically important difference for 6MWD is approximately 30 m – similar to the difference recorded here. That said, he wrote, “prevention of deterioration is not to be ignored, even if it does not make a patient feel better.”
Regarding quality of life, Dr. Tonelli observed that this questionnaire, standard fare in respiratory research, may not have been perfectly suited for this particular study.
“You have to put it in the context of, ‘How good is the questionnaire to capture a difference in this particular disease over a 16-week period?’ ” he said. “It might not be sensitive enough to capture a significant change. The questionnaire was not developed for pulmonary hypertension in interstitial lung disease, of course. It was developed more generically. It may not capture all that you need to show significance.”
The investigators acknowledged the study’s other potential limitations, including a short duration, a notable percentage of patients who discontinued the trial early, and the fact that clinical worsening and exacerbation of disease were investigator reported and not confirmed by an independent committee.
As for next steps in assessing pulmonary hypertension treatments, Dr. Tonelli pointed to the direction of future research. “The other big study that needs to come out in our field, and I believe it’s being worked on, is inhaled treprostinil in pulmonary hypertension due to chronic obstructive pulmonary disease [COPD],” he said. “That’s a major unmet need; the COPD population is larger than the population for interstitial lung disease, and one would wonder whether inhaled treprostinil would benefit those patients as well. At the moment, we have no treatments for that condition. In the future, a COPD study will be needed.”
The study was supported by United Therapeutics. Author disclosures are listed on the New England Journal of Medicine website.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE