Pulmonary arterial hypertension (PAH) is a pathophysiological disorder defined as an increase in mean pulmonary artery pressure ≥25mmHg, a raised pulmonary vascular resistance ≥3 Wood units and a precapillary wedge pressure ≤15mmHg, as assessed by right heart catheterisation1. The aetiology of the condition is still undergoing characterisation but dysregulation of endothelial growth factors and angiogenesis in the small arterial vessels of the lung, lead to vasoconstriction and flow restriction through the development of obliterative plexiform lesions2.

Whilst standardised anticoagulation for all patients with idiopathic PAH, heritable PAH and PAH due to anorexigens is only to be “considered” with a low-level recommendation in the 2015 ESC/ERS guidelines (IIb, C), vitamin K antagonists (VKAs) are used as standard therapy in some centres. In the PAH French registry more than 90% of patients receive anticoagulant therapy3. The historical rationale for this is a suggested procoagulant state and anatomo-pathological findings of undiagnosed pulmonary embolus in patients with idiopathic pulmonary arterial hypertension (IPAH).  Data from 187 matched patients with IPAH, however, failed to demonstrate a beneficial effect of warfarin on patient survival4,5. Patients with IPAH receiving therapy with long-term intravenous prostaglandins should be anticoagulated as they carry the additional risk of catheter-associated thrombosis3.

Chronic thromboembolic pulmonary hypertension (CTEPH) belongs to the clinical category of pulmonary hypertension Class 4 – CTEPH and pulmonary artery obstructions, result from non-resolved fibrothrombotic obstructions of the large pulmonary arteries and combined small vessel arteriopathy. The Spanish pulmonary hypertension registry data has reported a modest incidence of CTEPH ie. 3.2 cases per million. Crucially, this cohort can be effectively treated with licenced vasodilator therapies3. Life-long anticoagulation is mandatory in patients with CTEPH with a high-level recommendation in the 2015 ESC/ERS guidelines (I,C)3,6. VKAs are used as standard and should be continued lifelong post endarterectomy3.

Direct oral anticoagulants (DOACs) inhibit either factor Xa – rivaroxaban, apixaban and edoxaban or factor IIa – dabigatran. Formally described as novel oral anticoagulants (NOACs) these agents have now been licensed for up to 9 years, mainly for the treatment of atrial fibrillation and venous thromboembolism. DOACs are often selected in preference to VKAs due to similar efficacy, reduced bleeding profiles and the lack of a need for regular laboratory monitoring. Furthermore, VKAs have a narrow therapeutic window and are prone to high pharmacological variability4.

The increasing use of DOACs in the clinical world –particularly in relation to stroke prevention in atrial fibrillation-  raises the question as to whether there is a role for these agents in PAH.  They are not currently recommended in CTEPH as there are no data regarding safety or efficacy3. In addition to the established difficulties around reversal, there are specific pharmacological considerations that would suggest a cautious approach should be taken regarding the potential introduction of these medications in the treatment of PAH.

Whilst universal reversal agents for DOACs are under development, currently only the dabigatran targeted idarucizumab is available at a cost of £2400 per treatment7. Cessation of bleeding is a pertinent issue in patients with PAH as the risk of significant haemorrhage is higher than in the general population and has been demonstrated to be 2.4 per 100 patient-years in patients with CTEPH and 5.4 per 100 patient-years in patients with IPAH8.

DOAC absorption and metabolism is highly modified by transporters and hepatic cytochrome which may lead to drug-drug interactions with targeted PAH therapies. The endothelin receptor antagonist Bosentan, widely used for treatment of PAH, is a particular concern in this regard, as it induces cytochrome P450 3A4 which is involved in the metabolism of rivaroxaban (30%) and apixaban (50%), with concomitant use likely to reduce their biological efficiency. Phosphodiesterase-5 inhibitors, conversely, act as slight inhibitors of cytochrome P450 3A4 further complicating the potential effects in patients receiving combination therapy9.

DOAC elimination occurs in the kidneys, leaving CKD patients and those with other forms of kidney dysfunction susceptible to bioaccumulation and increased risk of bleeding. Whilst patients included in initial DOAC trials may have been selected to avoid such risk, edoxaban phase III trials included a 50% dose reduction which was shown to negate additional bleeding in patients with a major risk factor of bioaccumulation ie. body weight <60kg, creatinine clearance <50ml/min, concomitant treatment with a strong inhibitor4.

Given the increasingly widespread usage of DOACs and the fact that patients do not need laboratory monitoring, the question emerges as to the safe use of these medications in PAH. Whilst the use of DOACs in PAH is not currently recommended, further prospective work elucidating the pharmacodynamics of currently available NOACs should aid to determine whether there is a role for NOACs in PH. Further evaluation of the bleeding profiles of these medications would additionally be necessary, along with the development of reliable and affordable reversal agents.

References

  1. Hoeper M, Bogaard H, Condliffe R et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013; vol no. 25 supplement:D42–D50.
  2. Jeffery T, Morrell N. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis. 2002; 45: 173–202.
  3. Galiè N, Humbert M, Vachiery J et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European 2016.
  4. Gabriel L, Delacenne X, Bedouch P et al. Risk of Direct Oral Anticoagulant Bioaccumulation in Patients with Pulmonary Hypertension. Respiration 2016; 91:307-315.
  5. Preston I, Roberts K, Miller D et al. Effect of Warfarin Treatment on Survival of Patients With Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation 2015; Dec 22;132(25): 2403–2411.
  6. Kim N, Delcroix M, Jenkins D et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol 2015;62:D92–D99.
  7. National Institute for Health and Care Excellence (2015) Reversal of the anticoagulant effect of dabigatran: idarucizumab. NICE guideline (ESNM73).
  8. Henkens I, Hazenoot T, Boonstra A, Huisman M, Vonk-Noordegraaf A. Major bleeding with vitamin K antagonist anticoagulants in pulmonary hypertension Eur Respir J 2013; 41: 872–878.
  9. Bertoletti L, Delavenne X, Montani D, Mismetti P. New oral anticoagulants and oral pulmonary arterial hypertension therapies: potential pharmacological interactions Fundamental and Clinical Pharmacology 2013; 27:3-3.