LAUSR

As treatment options for pulmonary arterial hypertension (PAH) have evolved, clinicians now face the enigma of both which medication(s) should be started and which parameters should be followed to dictate our selection of treatment. Although a number of treatment goals have been described in PAH, 6-min walk distance (6MWD) has remained one of the most widely used measures in both PAH pivotal trials as well as in clinical practice. The Phase-4 multicenter COMPASS-3 study published in this issue of Pulmonary Circulation sought to evaluate whether using a singular endpoint of 6MWD 380m produced clinically meaningful outcomes in PAH. This study was conducted during 2007–2010, i.e. before publication of recent guidelines as well as longer-term clinical trials evaluating combination therapy. Outcomes were assessed for 100 newly diagnosed PAH patients following a treat to target strategy. All patients received bosentan monotherapy for the initial 16 weeks. This was followed by combination therapy with add-on sildenafil for those who did not achieve a 6MWD 380m, while patients who reached the target walk distance continued on bosentan monotherapy. Very few patients (16/100) achieved the 6MWD target at 16 weeks. Long-term clinical worsening rates were similar between patients meeting the 380 -m distance at 16 weeks and those who did not. After the 16-week time point, the 76 patients who had not reached 380m received add-on sildenafil, and 15 out of 76 patients then reached the target 6MWD by week 28. The second part of the paper focused on prognostic measures in PAH more generally. A number of measures were predictive, particularly at 16 weeks (versus fewer at baseline), including 6MWD, NT-proBNP level, hemodynamics, and cardiac MRI measures including right ventricular end diastolic volume: left ventricular end diastolic volume (RVEDV:LVEDV) ratio, right ventricular ejection fraction, and stroke volume, among others. In the multivariate testing, NT-proBNP plus age provided a good model at both baseline and at 16 weeks, with similar predictive power to models with more variables. In the combined model that also included ‘‘change-in’’ variables, the combination of RVEDV:LVEDV ratio (baseline) and change in pulmonary vascular resistance (PVR) was felt to provide the best statistical model. The retention of change in PVR in the final model is interesting, as PVR is often excluded from multivariate models because authors either exclude it outright due to the potential for multicollinearity or it is not retained in the model after stepwise testing. However, a recent large prognostic study from the French Pulmonary Arterial Hypertension Network registry found that out of all of the hemodynamic measures tested, post-treatment RA pressure and PVR led to the most predictive model when using Akaiki Information Criteria for model selection, though stroke volume, cardiac index, and compliance were all significant predictors when added individually in place of PVR. The final section of the paper looked at correlations between hemodynamics and cardiac magnetic resonance imaging (MRI) measures. The strongest correlation was found between RVEDV:LVEDV ratio and PVR, mean pulmonary arterial pressure and PVR index. These results add to a growing literature showing that both NT-proBNP and cardiac imaging may be important prognostic measures. It is particularly valuable to see strong results for cardiac MRI from a multicenter study. Criticisms, however, include the relatively large number of measures tested and the fairly small number of outcome events for this type of analysis (i.e. 2/16 monotherapy patients [13%] and 15/76 combination therapy patients [19%, P1⁄4NS]). Returning to the walk distance analysis in the current study, the other important walk distance finding was the very modest additional improvement when sildenafil was added to bosentan – this combination yielded a median absolute 6MWD improvement of only 10m at week 28, while the group remaining on monotherapy had a median 3-m decrease between weeks 16 and 28. Although we suspect that much of this relates to limitations in the efficacy of current PAH therapy (especially given relatively modest improvements with add-on therapy in other trials), there are several other potential contributors. One concern is that this particular drug combination could be less effective, potentially due to a drug–drug interaction. Bosentan is known to decrease serum sildenafil concentrations by up