[6] Drug-drug interaction: caution should also be exercised with the concomitant use of PAH-target therapies and warfarin. Bosentan partially induces the cytochrome P450 system, thereby increasing warfarin metabolism and the required dose. The platelet-inhibiting effect of prostacyclin analogues and sildenafil is widely acknowledged, yet its clinical relevance is still Everolimus RAD001 unclear, with respect to concomitant use of warfarin. [7] Age: elderly patients are at increased bleeding risk while on anticoagulant. At the same time increased age is associated

with increased mortality risk in PAH patients. In the COMPERA, 8 age was an independent predictor of mortality among patients with idiopathic PAH (HR: 1.35; 95% CI: 1.14 to 1.61). Similarly, in the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL), male patients >60 year was an independent predictor of increased mortality (HR, 2.2; 95% CI, 1.6 to

3.0). 14 Data on the risk-benefit ratio of anticoagulant therapy in pediatric PAH population is lacking. Unfortunately, the COMPERA database was not designed to systematically capture all bleeding events. All the study could state was that bleeding complications were responsible for ∼2% of the deaths in all cohorts, and that serious bleedings occurred predominantly in the anticoagulation group. No data were available regarding less severe bleeding or the development of iron deficiency anemia. Risk factors for increased bleeding were not systematically assessed in COMPERA; the presence of these risk factors might have affected the decision to use (or not to use) anticoagulants, as well as survival. Target INR Generally, the target INR in PAH patients varies, from 1.5–2.5 in most centers of North America, to 2.0–3.0 in European centers. 6 Unfortunately, data regarding INR in the COPMERA study were deficient; it was mentioned that the INR was 2–3 in all but one center

and that about 58% of patients in the anticoagulation group had received anticoagulants for the entire observation period. Furthermore, COMPERA did not provide data regarding the frequency and duration of INR values inside and outside the target range, or reasons for anticoagulant discontinuation. New oral anticoagulants In COMPERA, 6% of patients in the anticoagulant group were receiving new oral anticoagulants. In atrial fibrillation Dacomitinib and venous thromboembolism studies, new oral anticoagulants were, on the whole, non-inferior for efficacy and, to different degrees, superior for some bleeding endpoints compared with vitamin K antagonist. However, the use of new oral anticoagulants in PAH patients cannot be recommended because of the lack of evidence on efficacy and safety in addition to the difficulty to reverse the anticoagulant effect in emergency situations and the potential vulnerability to drug-drug interactions with PAH-targeted therapies.