Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is described as a resting mean pulmonary arterial pressure (mPAP) of 25 mm Hg or higher, pulmonary capillary wedge pressure (PCWP) below 15 mm Hg, and pulmonary vascular resistance (PVR) above 3 Wood units in the absence of one of the common causes of pulmonary hypertension, such as left-sided heart disease, chronic lung disease, or venous thromboembolism.¹ PAH progresses over time and is fatal. Although targeted vasodilator therapy is the mainstay of treatment, thrombotic pulmonary vascular lesions are commonly found at postmortem examinations, and anticoagulant therapy with a vitamin K antagonist may be useful in some types of PAH.² Research suggests that thrombotic arteriopathy can contribute to the development of a prothrombotic condition in persons with idiopathic PAH, so that anticoagulant therapy (particularly warfarin) may be beneficial. Warfarin is the anticoagulant of choice in PAH inasmuch as experience with novel oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban, is limited.³

Current Concepts Regarding Anticoagulation Therapy (Mainly Warfarin) in PAH

Long-term treatment with warfarin has been shown to improve survival in patients with PAH in both retrospective and prospective trials. Anticoagulants are used for blood thinning and the prevention of clotting in patients who have PAH with thrombotic pulmonary vascular lesions.¹ In 2 major studies, COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) and REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management), the conclusions were conflicting, suggesting beneficial effects of warfarin in idiopathic PAH and detrimental effects in connective tissue disease-associated PAH (CTD-PAH). As a result, according to the most recent guidelines for the management of PAH, anticoagulant therapy should be considered for patients undergoing central catheter-based prostacyclin therapy but in most cases not for those with CTD-PAH.² Long-term warfarin therapy is recommended only for patients with idiopathic PAH, heritable PAH, or anorexigen-associated PAH, with the goal of achieving an international normalized ratio of 1.5 to 2.5.¹

Systemic anticoagulant therapy improves outcomes and quality of life and should be provided as disease-modifying therapy to all patients with idiopathic PAH; however, it decreases quality-adjusted survival and should not be given in most cases to patients with CTD-PAH. For a net gain in quality-adjusted life-years (QALYs), a PAH mortality hazard ratio (HR) of 0.95 or better must be demonstrated.²

Anticoagulant therapy may increase survival in patients with idiopathic PAH but decreases it in those with scleroderma-associated PAH, according to a meta-analysis. Currently, no randomized clinical studies are available; therefore, anticoagulant treatment should be based on the subtype of PAH until randomized data become available.⁴

Anticoagulant therapy appears to be ineffective in people with CTD-associated PAH, whereas the evidence is mixed in those with idiopathic PAH. Another crucial factor to be considered is that anticoagulants are constantly evolving. The efficacy of non-vitamin K oral anticoagulants has been shown to be similar to that of warfarin in the treatment of venous thromboembolism and atrial fibrillation; multiple studies have demonstrated reduced bleeding and death.⁵

Clinical Trials

Presently, 2 ongoing trials are evaluating anticoagulant drugs in patients with scleroderma-associated PAH. SPHYNX, a multicenter, double-blind, placebo-controlled randomised study, is examining the efficacy, safety, and cost-effectiveness of apixaban in scleroderma-associated PAH over a 3-year period. The SPHYNX trial will also include a cost-effectiveness analysis to confirm the findings of a prior medico-analytic investigation, which were that anticoagulant treatment is beneficial for patients with idiopathic PAH but not for those with scleroderma-associated PAH. One arm of the Pragmatic Clinical Trials in Scleroderma (PCTS) study, registered on Clinicaltrials.gov (NCT03610217), will assess the effectiveness of anticoagulant medication (warfarin, rivaroxaban, or apixaban) in PAH.⁶ 

References

1. Thenappan T, Ormiston ML, Ryan JJ, Archer SL. Pulmonary arterial hypertension: pathogenesis and clinical management. BMJ. 2018;360:j5492. doi:10.1136/bmj.j5492.
2. Jose A, Eckman MH, Elwing JM. Anticoagulation in pulmonary arterial hypertension: a decision analysis. Pulm Circ. 2019;9(4):2045894019895451. doi:10.1177/2045894019895451
3. Schwab KE. Pulmonary rterial hypertension treatment & management. Medscape. Updated May 27, 2022. Accessed May 31, 2022. 
4. Khan MS, Usman MS, Siddiqi TJ, et al. Is anticoagulation beneficial in pulmonary arterial hypertension? Circ Cardiovasc Qual Outcomes. 2018;11(9):e004757. doi:10.1161/CIRCOUTCOMES.118.004757
5. Bapat A. Anticoagulation in the management of pulmonary arterial hypertension.. American College of Cardiology. Published February 5, 2016. Accessed May 31, 2022. 
6. Bertoletti L, Mismetti V, Giannakoulas G. Use of anticoagulants in patients with pulmonary hypertension. Hamostaseologie. 2020;40(3):348-355. doi:10.1055/a-1171-3995

Reviewed by Hasan Avcu, MD, on 6/1/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.