The results of this meta-analysis on RCTs performed in pulmonary arterial hypertension patients show that the mortality in the control groups is high, being approximately 3.8% in the 14.3 weeks of the mean observation period (about 1.1% per month). This confirms the severity of the condition even in the stable and selected patients population included in RCTs. A reduction in the overall mortality of 43% was observed in the patients randomized to the active treatments when compared with those randomized to the placebo control arms (21 RCTs); a reduction of 38% was also confirmed after the addition of the two remaining RCTs, which included a concurrently initiated active control arm. These results were observed even if the average duration of the RCTs was limited to 14.3 weeks and even with the inclusion of RCTs on compounds which were eventually not approved by the Regulatory Agencies because of lack of consistent efficacy such as the thromboxane synthase inhibitor, terbogrel9
and the oral available prostanoid, beraprost.22,25
Subgroups analysis according to the different classes of drugs or with baseline exercise capacity as assessed by 6MWD did not show statistically significant heterogeneity in the effects on mortality. These data suggest that the results have not been driven by one class of drugs or by a group of patients with a specific disease severity.
The reasons for these non-heterogeneous results among different classes of drugs targeting diverse pathobiological pathways are not clear and may include specific disease characteristics, such as a ceiling effect which can limit and homogenize the extent of the beneficial effects that any medical treatment can achieve. In addition, the statistical power of the meta-analysis might not be sufficient to show a difference among drug classes or disease severity groups.
The survival benefit as suggested by the NNT evaluation appears to be significant because 61.6 patients are needed to be treated for an average period of 14.3 weeks for preventing one death.
The favourable results on survival observed in the current meta-analysis when compared with a previous reported meta-analysis8
may be explained by different reasons including a more appropriate selection of the trials (excluding acute studies and studies with different pulmonary hypertension aetiologies) and a larger sample size of both, number of studies (+44%) and number of patients (+63%).
The rate of explicitly reported hospitalizations owing to pulmonary arterial hypertension observed in the control groups of eight studies of this meta-analysis appears high being approximately 8% in an average period of 14.3 weeks. The reduction by 61% in the rate of hospitalizations observed in the groups of patients randomized to the active treatments appears to support the clinical efficacy of the targeted treatments for pulmonary arterial hypertension: one hospitalization can be prevented treating 19.9 patients for the average observation period of 14.3 weeks. However, these data were reported only in 35% of the RCTs of this meta-analysis and a reporting bias based on whether results tended to be favourable cannot be excluded.
The meta-analysis has confirmed the improvement in exercise capacity as assessed by 6MWD observed in all but two of the 18 studies reporting this parameter. These results are not surprising as the 6MWD has represented the primary endpoint for the majority of the RCTs and both patients' sample size and statistical power were calculated according to the predicted change of this parameter. The weighted average improvement was about 10.8% when compared with baseline 6MWD but markedly heterogeneous results were observed among different studies ranging from −10 to +108 m.
About half of the RCTs of this meta-analysis have included WHO/NYHA functional class and cardiopulmonary haemodynamic data. The improvement of one functional class was observed more often in patients randomized to active treatments even if only about one-third of the subjects achieved this result. Also in this case a reporting bias based on whether results tended to be favourable cannot be excluded.
Statistically significant improvements in the haemodynamic data, including mean pulmonary arterial pressure, cardiac index, pulmonary vascular resistance, and right atrial pressure were observed. The weighted mean improvements of these parameters appear to be small to moderate ranging from a reduction of about −5% in pulmonary arterial pressure and an increase of 8% of the cardiac index to a reduction of about −29% of the pulmonary vascular resistance.
The limitations of this meta-analysis include the prolonged period of time between the publication of the first and the last RCT (about 18 years), the different duration of the trials (ranging from 8 to 36 weeks), the lack of blindness in some studies,17–19,30
the pooling of multiple active treatment arms (potential alteration of the trial structure), the report of secondary outcome parameters only in part of the RCTs (possible reporting bias), and potential heterogeneity in the conduct of the trials and in the definition of hospitalization for pulmonary arterial hypertension in different RCTs (no individual patients data were reviewed). On the other hand, this meta-analysis, which considered all randomized patients (intention-to-treat), also included studies with compounds which were eventually not approved because of lack of efficacy9,22,25
and doses of approved drugs which were not endorsed because less effective or for increased side effects.13,24,28,31
A publication bias, favouring the publication of positive studies, also cannot be excluded. The funnel-plot analysis (plots of effect estimates against standard error of the estimate) did not show asymmetry (see Supplementary material online, Figure S7
) and a possible publication bias should not have influenced substantially the results of this meta-analysis.
In conclusion, the results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for pulmonary arterial hypertension. A reduction in the hospitalization rate and favourable results on exercise capacity, functional capacity, and haemodynamics were also observed in the groups of RCTs reporting these data.
Despite these results, the current treatment strategy remains inadequate because the mortality rate continues to be high and the functional and haemodynamic impairments are still extensive in many patients. The non-equivocal progresses observed recently in the medical treatments of this condition are not yet sufficient. Additional efforts are required to explore new strategies including RCTs with initial combination therapy, with new classes of drugs, and with new designs including morbidity and mortality endpoints and prolonged observation periods.