Clinical Trials in PAH: Interpreting Risk Reduction With Caution

Doctors, researchers meeting, discussing
Doctors, researchers meeting, discussing
Researchers raise issues regarding interpretation of clinical trial results in the field of pulmonary arterial hypertension.

In the ever-evolving landscape of clinical trials conducted in patients with pulmonary arterial hypertension (PAH), the calculation and interpretation of risk reduction and the number needed to treat (NNT) must be considered to account for the progressive shift in study design and duration.

The investigators of an analysis published in the European Respiratory Review sought to expand on some issues recently raised with respect to interpretation of meta-analyses on combination therapies in PAH.

In trials of patients with PAH, clinical worsening is generally a composite end point that is defined as a combination of death, hospitalization, lung transplantation, treatment escalation, and symptomatic progression. Comparison of the cumulative incidence of the outcome between 2 groups at a specific time of follow-up might result in aberrant estimation of the NNT.

The effect of time dependency on risk ratio (RR, or the odds) and NNT is even more of an issue when trials of various durations are compared. RR and NNT are inherently time-dependent measures, such that when the RR reduction is constant over time, increasing duration of follow-up will cause a progressive decline in the NNT as the absolute event rate rises, whereas the RR will increase progressively (and thus decrease the RR reduction).

Recent event-driven clinical trials in patients with PAH have compared combination therapy with monotherapy. Among these trials are SERAPHIN ( Identifier: NCT00660179), AMBITION ( Identifier: NCT01178073), and GRIPHON ( Identifier: NCT01106014).

The investigators concluded that in the field of PAH, the comparison of NNT and RR between treatments is often misleading unless the treatments were tested in similar study populations with the same severity of disease, the same outcomes, against the same comparator, and during the same period of time. These comparisons must be interpreted with caution in the absence of head-to-head clinical trials.

Related Articles


Lajoie AC, Bonnet S, Lacasse Y, Lega JC, Provencher S. Interpreting risk reduction in clinical trials for pulmonary arterial hypertension. Eur Respir Rev. 2018;27(148). pii:180020.