Discussion
IPF, pulmonary hypertension, pulmonary arterial hypertension
EVENT, DISEASE, PULMONARY ARTERIAL HYPERTENSION, ADVERSE EVENT, SECONDARY, EVENTS, PULMONARY HYPERTENSION
This post hoc analysis of the INCREASE trial provides evidence of a higher likelihood for clinical benefit using iTre, especially at higher dosages, when compared with placebo in patients with PH resulting from ILD. Our analysis evaluated clinical change 4 weeks after study entry to allow sufficient time for drug uptitration. The benefit was seen on both ends of the clinical outcome spectrum, with both lower rates of clinical worsening and higher rates of clinical improvement experienced in the iTre group compared with the placebo arm during the 16-week study. These benefits also appeared most apparent with higher dosages of iTre. Approximately three-quarters of patients were able to achieve a dosage of ≥ 9 bps four times daily, suggesting that titrating to higher dosages of iTre is feasible in most patients over a relatively short period with appropriate adverse event management.This analysis further reinforces that iTre prevents clinical worsening and in addition demonstrates that iTre is associated with significantly more patients experiencing clinical improvement when compared with those receiving placebo. Furthermore, our analysis suggests that higher-dosage iTre is more effective than lower-dosage in achieving these outcomes. The results from this analysis in patients with PH resulting from ILD are consistent with previous reports in World Health Organization group 1 pulmonary arterial hypertension (PAH), which suggest that higher doses of iTre have beneficial effects on survival and delayed time to parenteral therapy.To our knowledge, clinical improvement has not been evaluated previously in any ILD study and is rarely sought in PAH clinical trials. The REPLACE study evaluated the switching of phosphodiesterase 5 inhibitor therapy to riociguat with clinical improvement as the primary end point.Because the concept of clinical improvement in PH resulting from ILD largely is unexplored, what should be regarded as constituting improvement is open to debate. We chose a 15% increase in the 6MWD, which for most patients would be in the range of the minimally important difference that has been estimated to be anywhere from 22 to 50 m in patients with IPF, the most common of the ILDs.The decision to analyze patients for clinical events only after week 4 was to avoid any biases imposed by the early uptitration period. Specifically, if we had analyzed patients for events in the first 4 weeks, then the bias would have been toward more clinical worsening events in the low-dosage group, because all the patients were in the uptitration phase during this period. However, the fact that a sizable group of patients did show clinical worsening during this early phase of the study does underscore the need for the early implementation of therapy. During the 4- to 16-week period, 29.5% of patients (44 of 149) switched groups. However, which group should their clinical worsening be attributed to if they switched over and then experienced an event shortly thereafter? For this reason, we believe that the best analysis was to adopt the equivalent of an intention-to-treat approach based on the groupings at week 4. Given this limitation to our analysis, we performed a sensitivity analysis of clinical events of the same four groupings based on the last dosage received. This analysis demonstrated very similar results and reinforces the robustness of our primary analysis. Another option would have been to perform an analysis based on the total exposure to iTre by using the cumulative dose of iTre for each patient through the 16-week trial and then to determine the median cumulative dose to define the cutoff for the high- and low-dosage subgroups. However, in a dose-response analysis using cumulative dose, any patient who discontinued the study early or died during the study invariably would be assigned to the low-dose group. This would skew the results favorably to the high-dose group, and therefore, we do not believe it would paint an accurate picture of the true dose-response relationship for iTre.Limitations of this analysis include the unavoidable issue of patients crossing groups between 4 and 16 weeks and the inherent difficulty in clinical event attribution. However, we believe that we adequately addressed this between the primary and secondary analyses, both of which showed very similar results. The relatively short duration of the study is another limitation; it is certainly likely that we would have observed more events with a longer duration of follow-up. We chose to start the analysis at 4 weeks because this allowed adequate time for most patients to uptitrate and also coincided with a mandated study visit. As discussed, any clinical worsening events during this initial period would have been ascribed to the lower dosage group, which would have introduced an inherent bias favoring the higher-dosage group. The fact that a number of clinical worsening events occurred during this early period of dose optimization supports the concept of high vigilance and screening for interceding pulmonary hypertension in patients with ILD with the goal of early drug implementation. We also cannot rule out that tolerability of higher dosages could be a surrogate for disease severity. For instance, patients who are unable to titrate up may have clinical features putting them at higher risk of poor outcomes. Specifically, the iTre < 9 bps group showed a lower baseline 6MWD compared with the iTre ≥ 9 bps group. This provides further support for the earlier initiation of therapy. Finally, clinical worsening events were not adjudicated centrally, but the components of this composite end point are mostly objective.