Combination Therapy Improves Pulmonary Hypertension Outcomes

Damian McNamara

May 20, 2016

SAN FRANCISCO — For patients with pulmonary arterial hypertension, combination therapy reduces the risk of clinical worsening better than monotherapy, a new meta-analysis indicates.

In addition, combination therapy cut the risks for hospitalization, treatment escalation, symptomatic progression, and other clinical outcomes.

"The thing that surprised me is that our subgroup analysis showed that these therapies are equally effective in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease," said Steve Provencher, MD, from Laval University in Quebec City, Canada.

"Normally, pulmonary arterial hypertension associated with connective tissue disease has a worse prognosis, but combination therapy delayed worsening in both groups," he told Medscape Medical News.

"I'm also surprised that the combination therapy was equally effective, even when baseline severity or functional class was different," Dr Provencher said.

Results were presented during a poster session here at the American Thoracic Society 2016 International Conference.

A previous meta-analysis showed a minimum benefit of combination therapy (Am J Cardiol. 2011;108:1177-1182). However, few randomized controlled trials comparing combination therapy with monotherapy were published at that time, Dr Provencher explained.

Since then, more data and more meta-analyses have emerged that suggest greater benefits with combination therapy (such as Chest. 2014;145:1055-1063 and J Cardiovasc Pharmacol. 2012;60:342-346).

So Dr Provencher and his colleagues conducted their own meta-analysis. They searched Medline, Embase, and the Cochrane Library from January 1990 to May 2015. They identified 17 randomized controlled trials that met their criteria, with 4095 patients.

"When we looked at the primary end point — clinical worsening — there was no heterogeneity between drug classes, suggesting the efficacy of each drug is similar," Dr Provencher reported. However, combination therapy was significantly better at reducing risk of clinical worsening than monotherapy (risk ratio [RR], 0.65; P < .00001).

Table. Risk Reduction Associated With Combination Therapy Over Monotherapy

Outcome Risk Ratio
Clinical worsening 0.65
Hospitalization 0.72
Treatment escalation 0.46
Symptomatic progression 0.52
WHO functional class improvement 1.19


Combination therapy was not significantly better than monotherapy for reductions in all-cause mortality (RR, 0.86; P = .09) or mortality related to pulmonary arterial hypertension (RR, 0.77, P = .06). However, there was a significant 22.1 m increase in 6-minute walking distance with the combination (P < .00001).

The meta-analysis included trials in which patients on monotherapy were randomized to an additional agent or placebo. Adjunctive treatments came from five drug classes: prostacyclins, guanylate cyclase stimulators, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, and specific prostacyclin IP receptor agonists.

The meta-analysis might not have been sensitive to all the differences between drug classes, cautioned Dr Provencher. And he noted that some studies in the meta-analysis looked at different populations.

"Still, this meta-analysis gives us an idea that this treatment strategy is effective," he said.

This latest meta-analysis provides "new evidence for combination therapy in clinical practice," said Zhi-Cheng Jing, MD, from FuWai Hospital and the National Center for Cardiovascular Disease in Beijing.

"We can conclude that hospitalization, treatment escalation, and symptomatic progression were reduced, and WHO functional class and 6-minute walk distance were improved in the combination treatment arms, indicating a better exercise capacity and quality of life," he told Medscape Medical News. "However, the combination therapy was still not good enough and couldn't prevent patients from dying in short- to medium-term trials."

We still don't know which patients benefit more from combination therapy, when to initiate combination therapy, or what is the best drug combination for certain patients with pulmonary arterial hypertension, Dr Jing pointed out.

"In the future, perhaps some kind of precision medicine should be introduced into patient evaluation before we consider the individualized treatment strategy," he added.

This study was not funded by industry. Dr Provencher is a consultant for Actelion, Bayer, and GlaxoSmithKline. Dr Jing has disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2016 International Conference: Abstract 7920. Presented May 18, 2016.

Follow Damian McNamara on Twitter: @MedReporter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.