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Pulmonary arterial hypertension associated with connective tissue disease: meta-analysis of clinical trials
  1. Masataka Kuwana1,
  2. Hiroshi Watanabe2,
  3. Nobushige Matsuoka3,
  4. Naonobu Sugiyama4
  1. 1Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  2. 2Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Shizuoka, Japan
  3. 3Division of Clinical Statistics, Pfizer Japan Inc., Tokyo, Japan
  4. 4Division of Medical Affairs, Pfizer Japan Inc., Tokyo, Japan
  1. Correspondence to Dr Masataka Kuwana;kuwanam{at}


Objectives Few studies have focused on pulmonary arterial hypertension (PAH) associated with connective tissue diseases (CTDs). The optimal treatment for CTD-PAH has yet to be established.

Design Meta-analysis of the data from evaluations of treatment for PAH generally (19 studies) and CTD-PAH specifically (nine studies) to compare the effects of pulmonary vasodilative PAH agents. MEDLINE, EMBASE and BIOSIS were searched. English-language full-text articles published between January 1990 and August 2012 were eligible.

Setting International.

Participants Patients with PAH generally (n=3073) and CTD-PAH specifically (n=678).

Primary outcome measure Exercise capacity (6 min walk distance, 6 MWD).

Results Patients with PAH (all forms) had mean age 32–55 years (women, 61–87%); CTD-PAH patients had mean age 45–55 years (women, 74–95%). Overall estimate of mean change in 6 MWD from baseline (95% CI) for the active treatment group versus the control group in all patients with PAH was 34.6 m (27.4–41.9 m). Pooled mean differences from the results for patients receiving placebo by subgroup of patients receiving phosphodiesterase (PDE)-5 inhibitors, endothelin receptor antagonists (ERAs) and prostacyclin (PGI2) analogues were 22.4–45.5, 39.5–44.2 and 12.4–64.9 m, respectively. Overall estimate of mean difference between changes in 6 MWD in patients with CTD-PAH was 34.2 m (23.3–45.0 m). Pooled mean differences by subgroup of patients receiving PDE-5 inhibitors, ERAs and PGI2 analogues in patients with CTD-PAH were 37.0–47.1, 14.1–21.7 and 21.0–108.0 m, respectively. ERAs were less effective in patients with CTD-PAH than all-form patients with PAH: 14.1 m (−4.4–32.6 m) vs 39.5 m (19.5–59.6 m) for bosentan and 21.7 m (2.2–41.3 m) vs 44.2 m (30.2–58.2 m) for ambrisentan.

Conclusions All three types of PAH agent are effective. However, ERAs may be a less effective choice against CTD-PAH; further studies are needed. Limitations include the limited number of studies for some agents and for patients with CTD-PAH.


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