In PAH trials, clinical worsening risk rose with time

 

Current clinical trials evaluating combination therapy for pulmonary artery hypertension (PAH) may be longer than what is needed to demonstrate treatment benefit, results of a recent meta-analysis suggest.

In PAH trials of combination therapy, the absolute risk reduction of clinical worsening beyond 6-12 months was relatively constant, according to results of the study published in the May issue of the journal Chest^®.

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That finding “questions the requirement for longer-term event-driven trials beyond that duration in an orphan disease such as PAH,” wrote investigator Annie C. Lajoie, MD, of the Pulmonary Hypertension Research Group, Quebec City, and her coauthors.

The meta-analysis by Dr. Lajoie and her colleagues included 3,801 patients enrolled in one of 15 previously published randomized clinical trials. Of those trials, four were long-term, event driven studies, with a mean duration of 87 weeks, while the remainder were shorter studies with a mean duration of 15 weeks.

For the long-term, event-driven trials, the mean number needed to treat (NNT) was 17.4 at week 16, gradually decreasing to 8.8 at 52 weeks of follow-up, remaining stable after that, according to investigators.

Consistent with that finding, the mean relative risk of clinical worsening was 0.38 at 16 weeks, and similarly, 0.41 at 26 weeks, investigators reported. After that, the relative risk progressively increased to 0.54 at 52 weeks and 0.68 at 104 weeks.

Looking at all trials combined, Dr. Lajoie and her colleagues observed that longer trial duration had a positive correlation with relative risk of clinical worsening (P = .0002).

 

Pragmatically, these results raise the possibility that PAH combination therapy trials could be shorter in duration. Some recent event-driven studies have lasted up to 6 years, with patients on treatment for about 2 of those years, investigators noted.

“In the context of an orphan disease with limited and competing recruitment for trials and the rapidly changing treatment paradigm in PAH, the optimal duration of future trials should be revisited,” Dr. Lajoie and her colleagues wrote in a discussion of their findings.

They also cautioned that NNT, a measure of how many patient treatments are needed to prevent one additional adverse event, could be “misleading” despite its value as a simple measure of treatment impact.

Likewise, relative risk can be misleading; for example, a treatment reducing event risk from 30% to 20% represents a relative risk reduction of approximately 35%, but so does a treatment reducing event risk from 3% to 2%, the researchers noted.

 

“Multiple factors, in addition to the efficacy of the therapy and the comparator, may directly influence the NNT and relative risk and should be taken into account in their interpretation,” they said in their report.

Dr. Lajoie had no disclosures related to the study. Her coauthors had disclosures related to Actelion Pharmaceuticals, Bayer, and GlaxoSmithKline, among others.

SOURCE: Lajoie AC et al. Chest. 2017 May;153(5):1142-52.

 

Current clinical trials evaluating combination therapy for pulmonary artery hypertension (PAH) may be longer than what is needed to demonstrate treatment benefit, results of a recent meta-analysis suggest.

In PAH trials of combination therapy, the absolute risk reduction of clinical worsening beyond 6-12 months was relatively constant, according to results of the study published in the May issue of the journal Chest^®.

Rawpixel/iStock/Getty Images

That finding “questions the requirement for longer-term event-driven trials beyond that duration in an orphan disease such as PAH,” wrote investigator Annie C. Lajoie, MD, of the Pulmonary Hypertension Research Group, Quebec City, and her coauthors.

The meta-analysis by Dr. Lajoie and her colleagues included 3,801 patients enrolled in one of 15 previously published randomized clinical trials. Of those trials, four were long-term, event driven studies, with a mean duration of 87 weeks, while the remainder were shorter studies with a mean duration of 15 weeks.

For the long-term, event-driven trials, the mean number needed to treat (NNT) was 17.4 at week 16, gradually decreasing to 8.8 at 52 weeks of follow-up, remaining stable after that, according to investigators.

Consistent with that finding, the mean relative risk of clinical worsening was 0.38 at 16 weeks, and similarly, 0.41 at 26 weeks, investigators reported. After that, the relative risk progressively increased to 0.54 at 52 weeks and 0.68 at 104 weeks.

Looking at all trials combined, Dr. Lajoie and her colleagues observed that longer trial duration had a positive correlation with relative risk of clinical worsening (P = .0002).

 

Pragmatically, these results raise the possibility that PAH combination therapy trials could be shorter in duration. Some recent event-driven studies have lasted up to 6 years, with patients on treatment for about 2 of those years, investigators noted.

“In the context of an orphan disease with limited and competing recruitment for trials and the rapidly changing treatment paradigm in PAH, the optimal duration of future trials should be revisited,” Dr. Lajoie and her colleagues wrote in a discussion of their findings.

They also cautioned that NNT, a measure of how many patient treatments are needed to prevent one additional adverse event, could be “misleading” despite its value as a simple measure of treatment impact.

Likewise, relative risk can be misleading; for example, a treatment reducing event risk from 30% to 20% represents a relative risk reduction of approximately 35%, but so does a treatment reducing event risk from 3% to 2%, the researchers noted.

 

“Multiple factors, in addition to the efficacy of the therapy and the comparator, may directly influence the NNT and relative risk and should be taken into account in their interpretation,” they said in their report.

Dr. Lajoie had no disclosures related to the study. Her coauthors had disclosures related to Actelion Pharmaceuticals, Bayer, and GlaxoSmithKline, among others.

SOURCE: Lajoie AC et al. Chest. 2017 May;153(5):1142-52.

 

Current clinical trials evaluating combination therapy for pulmonary artery hypertension (PAH) may be longer than what is needed to demonstrate treatment benefit, results of a recent meta-analysis suggest.

In PAH trials of combination therapy, the absolute risk reduction of clinical worsening beyond 6-12 months was relatively constant, according to results of the study published in the May issue of the journal Chest^®.

Rawpixel/iStock/Getty Images

That finding “questions the requirement for longer-term event-driven trials beyond that duration in an orphan disease such as PAH,” wrote investigator Annie C. Lajoie, MD, of the Pulmonary Hypertension Research Group, Quebec City, and her coauthors.

The meta-analysis by Dr. Lajoie and her colleagues included 3,801 patients enrolled in one of 15 previously published randomized clinical trials. Of those trials, four were long-term, event driven studies, with a mean duration of 87 weeks, while the remainder were shorter studies with a mean duration of 15 weeks.

For the long-term, event-driven trials, the mean number needed to treat (NNT) was 17.4 at week 16, gradually decreasing to 8.8 at 52 weeks of follow-up, remaining stable after that, according to investigators.

Consistent with that finding, the mean relative risk of clinical worsening was 0.38 at 16 weeks, and similarly, 0.41 at 26 weeks, investigators reported. After that, the relative risk progressively increased to 0.54 at 52 weeks and 0.68 at 104 weeks.

Looking at all trials combined, Dr. Lajoie and her colleagues observed that longer trial duration had a positive correlation with relative risk of clinical worsening (P = .0002).

 

Pragmatically, these results raise the possibility that PAH combination therapy trials could be shorter in duration. Some recent event-driven studies have lasted up to 6 years, with patients on treatment for about 2 of those years, investigators noted.

“In the context of an orphan disease with limited and competing recruitment for trials and the rapidly changing treatment paradigm in PAH, the optimal duration of future trials should be revisited,” Dr. Lajoie and her colleagues wrote in a discussion of their findings.

They also cautioned that NNT, a measure of how many patient treatments are needed to prevent one additional adverse event, could be “misleading” despite its value as a simple measure of treatment impact.

Likewise, relative risk can be misleading; for example, a treatment reducing event risk from 30% to 20% represents a relative risk reduction of approximately 35%, but so does a treatment reducing event risk from 3% to 2%, the researchers noted.

 

“Multiple factors, in addition to the efficacy of the therapy and the comparator, may directly influence the NNT and relative risk and should be taken into account in their interpretation,” they said in their report.

Dr. Lajoie had no disclosures related to the study. Her coauthors had disclosures related to Actelion Pharmaceuticals, Bayer, and GlaxoSmithKline, among others.

SOURCE: Lajoie AC et al. Chest. 2017 May;153(5):1142-52.