Sequential combination therapy reduces clinical worsening and improves functional status and exercise capacity in patients with pulmonary arterial hypertension (PAH) World Health Organization (WHO) functional classification II and III, confirmed a meta-analysis of randomized, controlled trials.

It should therefore be recommended for patients with PAH who have established background therapy even though the incidence of side effects and withdrawal is higher, researchers said.

Previous meta-analyses of combination therapies to treat PAH pooled together sequential therapy and initial combination therapy. This could “threaten the authenticity and clinical significance” of the 2 approaches, according to the authors of the study, which is published in the journal Pulmonary Pharmacology & Therapeutics

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Here, a team from the Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, in Changsha, Hunan, China searched the literature for randomized controlled trials comparing sequential combination therapy and background therapy in patients with PAH.

This way, they identified 17 studies comprising 4343 patients of whom 97.2% had WHO functional class II or III disease. 

The researchers found that sequential combination therapy decreased clinical worsening and functional class, and increased the 6-minute walk distance. However, it did not reduce mortality, and the rate of lung transplantation or admission to hospital and treatment escalation compared to background therapy. 

The incidences of adverse events and serious adverse events were similar between the 2 treatment approaches. However, sequential combination therapy increased all-cause and drug-related treatment discontinuation. The incidences of headache, flushing, nausea, diarrhea, and jaw pain were also higher with sequential combination therapy.

Despite these, the authors of the study concluded that PAH-specific agents should be added to the treatment schedule of patients with PAH WHO functional class II or III who are being treated with established stable doses of PAH-specific background therapy to improve clinical worsening, functional status, and exercise capacity.


Tan Z, Wu PY, Zhu TT, Su W, Fang ZF. Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: a meta-analysis of randomized-controlled trials. Pulm Pharmacol Ther. 2022;30:102144. doi:10.1016/j.pupt.2022.102144