This review concluded that prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors all had benefits in people with pulmonary arterial hypertension. Only intravenous prostanoids had a proven benefit on mortality, particularly in people with severe disease. The review appeared generally well-conducted, but available data were limited and the authors agreed that the conclusions needed confirmation from longer term studies.

To assess the effects of drug therapy on pulmonary arterial hypertension.

MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to November 2009. Search terms were reported. The search was not limited by language or publication status. Bibliographies of retrieved articles and reviews were checked.

Double blind randomised controlled trials (RCTs) with a follow-up of eight weeks or longer that assessed the effect of drug therapy in adults with pulmonary arterial hypertension were eligible for inclusion. The comparator had to be placebo except for intravenous agents where the comparator could be usual therapy. Primary outcome of interest was all-cause mortality. Secondary outcomes included six-minute walk distance, Borg dyspnoea scores, functional class (New York Heart Association or World Health Organization scores), haemodynamic parameters (mean pulmonary artery pressure, mean right arterial pressure, cardiac index, pulmonary vascular resistance obtained by right heart catheterisation) and adverse events.

Drugs assessed in the included studies were prostanoids (beraprost, epoprostenol, iloprost, trepostinil), endothelin receptor antagonists (ambrisentan, bosentan, sitaxsentan), phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil) and other medications (terbogrel, rosuvastatin). Drugs were given orally except for some prostanoids (intravenous, inhaled or subcutaneous).

Mean age of participants ranged from 34 to 55 years. The proportion of women was between 60% and 88%. Aetiology of disease included idiopathic pulmonary hypertension, scleroderma, connective tissue disease and congenital heart disease. Mean pulmonary artery pressure ranged from 47 to 76mmHg. Functional class ranged from Class I to IV and the largest percentage was Class III.

Two authors independently performed the literature search. The method of selecting studies for inclusion was unclear.

Quality was assessed using the Jadad score (maximum score 5) and Cochrane Collaborations tool for assessment of risk of bias. Studies were included only if they scored 3 or more (or 2 or more for intravenous agents).

Quality was assessed by two authors independently. Discrepancies were resolved by consensus.

Where possibl, data were extracted on an intention-to-treat basis. Relative risk (RR) and 95% confidence intervals (CI) were calculated for dichotomous data and mean difference and 95% CI were calculated for continuous data. Where studies reported only the placebo-corrected mean change, this value was used for the mean change in the intervention group and zero was used for the placebo group. Where studies reported on various drug doses, data for those most commonly used, associated with fewer adverse effects and standard recommended doses were extracted.

Adverse events that were reported in three or more studies were extracted.

Where pulmonary vascular resistance was reported in Woods units, this was converted to dyn-sec/cm⁵ by multiplying by 80.

Data were extracted by two authors independently. Discrepancies were resolved by consensus.

Pooled relative risks and 95% CI and weighted mean differences (WMD) and 95% CI were calculated. A random-effects method was used where significant heterogeneity was present and otherwise a fixed-effect method was used. Heterogeneity was assessed using X² test.

In the prostanoids analyses, subgroup analyses were performed based on studies that used intravenous drugs compared to placebo. Weighted linear regression was used to investigate the relationship between mortality and functional class severity.

Twenty-four RCTs (3,758 participants) were included. Eleven trials (1,404 participants) assessed prostanoids. Eight trials (1,273 participants) assessed endothelin receptor antagonists. Three trials (950 participants) assessed PDE5 inhibitors. One trial (71 participants) assessed terbogrel. One trial (60 participants) assessed rosuvastatin. No placebo-controlled RCTs were identified for oxygen therapy, diuretics, warfarin and calcium channel blockers. Follow-up ranged from eight to 52 weeks; most reported at 12 or 16 weeks.

Prostanoids: Compared with conventional therapy or placebo, prostanoids statistically significantly reduced mortality (RR 0.49, 95% CI 0.29 to 0.82; 10 trials). The reduction was greater when comparing intravenous agents to placebo and when correlating the risk of mortality to the proportion of people with Class III or IV symptoms. Prostanoids were associated with statistically significant improvements in six-minute walk distance (29.4 metres, 95% CI 18.1 to 40.7; 10 trials), Borg dyspnoea score (seven trials), functional class (seven trials) and haemodynamic parameters (eight trials). Six studies reported adverse events. Prostanoids were associated with statistically significant increases in jaw pain, diarrhoea, peripheral oedema, headache and nausea.

Endothelin receptor antagonists: Compared with placebo, endothelin receptor antagonists had no statistically significant effect on mortality (eight trials). Endothelin receptor antagonists were associated with statistically significant improvements in six-minute walk distance (38 metres, 95% CI 27.2 to 48.7; seven trials), functional class (six trials), Borg score (five trials) and most haemodynamic changes (five trials). Abnormal liver function tests were reported in all studies (definitions varied). No effect was seen when all studies were combined. Studies that assessed bosentan had a statistically significant increase in abnormal liver function tests. No other adverse events were statistically significantly increased with treatment.

PDE5 inhibitors: Compared to placebo, PDE5 inhibitors had no statistically significant effect on mortality (three trials). PDE5 inhibitors were associated with statistically significant improvements in six-minute walk distance (33.7 metres, 95% CI 22.5 to 44.8; three trials) and all reported haemodynamic parameters (two trials). Borg score and functional class were each reported in only one study and were not analysed. Adverse events (which included visual disturbance, dyspepsia, flushing, headache and limb pain) were statistically significantly increased with treatment (three trials).

Other treatments: One study on terbogrel was terminated early because of adverse effects; terbogrel had no statistically significant effect on six-minute walk distance and haemodynamics. One study on rosuvastatin found no change in six-minute walk distance.

Data suggested that prostanoids, endothelin receptor antagonists and PDE5 inhibitors all confered therapeutic benefit. Only intravenous prostacyclin had a proven benefit on survival, particularly in people with severe disease.

The aims of the review were clearly stated in terms or participants, treatments, study designs and outcomes. The search covered several relevant sources. Studies in any language and publication status were sought, which minimised risks of publication and language biases. Methods of data extraction and quality assessment were aimed at reducing the effect of reviewer error and bias. Methods for study selection were not entirely clear. Quality was assessed; details were not presented, but studies considered of lower quality were excluded from analyses. Methods of synthesis appeared appropriate. Heterogeneity was investigated. It was unclear whether subgroup analysis was predefined. As the authors acknowledged, there were limitations to the review such as a relatively short follow-up of the included studies, pooling of data according to drug class may have concealed differences between the effects of individual drugs and statistically significant differences in six-minute walk distance and haemodynamic parameters reflected small changes of unclear clinical significance.

Overall the review appeared generally well-conducted, but some limitations need to be taken into account when interpreting the conclusions.

Practice: The authors did not state any implications for practice.

Research: The authors stated that further studies were needed to assess long-term effects of prostanoids, endothelin receptor antagonists and PDE5 inhibitors in people with pulmonary arterial hypertension. Further studies were needed to assess optimal doses and duration of therapies for people with pulmonary arterial hypertension.

None stated.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.