Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension

Abstract

Vitamin K antagonists are advised in pulmonary arterial hypertension patients despite a lack of safety data.We reviewed major bleeding in three classes of pulmonary hypertension patients, all receiving vitamin K antagonists.Bleeding event rates were 5.4 per 100 patient-years for patients with idiopathic pulmonary arterial hypertension, 19 per 100 patient-years for connective tissue disease related pulmonary arterial hypertension patients and 2.4 per 100 patient-years for chronic thromboembolic pulmonary hypertension patients. Life tables analysis showed that event-free survival was worse in patients with connective tissue disease related pulmonary hypertension than in patients with idiopathic pulmonary arterial hypertension (Wilcoxon512.8; p,0.001), and patients with chronic thromboembolic pulmonary hypertension (Wilcoxon523.2; p,0.001). Patients with idiopathic pulmonary arterial hypertension suffered more events than patients with chronic thromboembolic pulmonary hypertension (Wilcoxon57.2; p,0.01). Major bleeding was independent of age, sex, target international normalised ratio (INR) range, documented INR, vitamin K antagonist type, or right atrial pressure, but was associated with use of prostacyclin analogues.Major bleeding risk during vitamin K antagonist therapy differs among groups of patients with pulmonary hypertension. Further research regarding optimal anticoagulant therapy is needed, as well as risk-benefit analyses for pulmonary hypertension patients with a higher bleeding propensity.

Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2)

“…The potentially increased risk of pulmonary bleeding with riociguat in some patients is reflected as a warning in the local prescribing information (summary of product characteristics) and should be considered as drug-related. However, the risk of haemoptysis and pulmonary haemorrhage may be influenced by other factors, such as age, severity of disease, deterioration in pulmonary haemodynamics and concomitant treatment with anticoagulants [12,14]. The mechanism of how riociguat could cause haemoptysis and pulmonary haemorrhage is unclear.…”

Where do we go from here? Reappraising the data on anticoagulation in pulmonary arterial hypertension

“…Prostacyclin therapy not only provides vasodilation in PAH, but has also been shown to alter hemostatic and platelet pathways, possible decreasing the in situ thrombosis and hypercoagulability observed in patients with PAH (3,7,(30)(31)(32). Of note, bleeding risks are increased in patients with iPAH, CTD-PAH and chronic thromboembolic pulmonary hypertension when vitamin K antagonists (VKA) were used in conjunction with prostacyclin (33). Considering these data, increased use of prostacyclin in the REVEAL registry potentially provides enough anticoagulation or anti-platelet activity to mitigate any possible observed benefit of VKA therapy.…”

“…Alternatively, this area of clinical uncertainty would be well suited for a randomized registry study (64), an attractive, economic avenue that has not been successfully employed in PAH as of yet (65). While not without consequences (9,33), anticoagulation retains a place in treatment algorithms, prompting urgent reconciliation of this therapeutic dilemma in PAH. …”

Antithrombotics in pulmonary hypertension: more work needed before we turn to newer agents!

“…In this issue of European Respiratory Journal, HENKENS et al [13] present a retrospective single centre study providing interesting data on major bleeding in different groups of pulmonary hypertension patients undergoing VKA treatment. The authors analysed bleeding events in 99 patients with idiopathic PAH, 39 patients with PAH associated with connective tissue disease (CTD-PAH) and 60 CTEPH patients, who received VKA monitored in specialised anticoagulation clinics.…”

“…The first reason is obvious: these drugs have not been evaluated in the setting of pulmonary hypertension and the management of bleeding under these drugs has not even been resolved; in addition the effects of these agents are difficult to reverse in emergency situations. The second reason is the increase in the risk of gastrointestinal bleeding found (versus VKA) in the main phase-III atrial fibrillation trials for dabigatran and rivaroxaban (gastrointestinal bleeding was also the most frequent bleeding localisation in the study of HENKENS et al [13]). The last and maybe more important issue is related to the pharmacological properties of these new oral anticoagulants.…”