Are Direct Oral Anticoagulants Appropriate for PAH?

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Presentation transcript:

Are Direct Oral Anticoagulants Appropriate for PAH? Ioana Preston, MD Tufts University School of Medicine Boston, MA

Rationale for Anticoagulation in PAH Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-587. Huber K, Beckmann R, Frank H, et al. Fibrinogen, t-PA, and PAI-1 plasma levels in patients with pulmonary hypertension. Am J Respir Crit Care Med.1994;150:929-933.

Estimated Survival of the Whole Pulmonary Arterial Hypertension (PAH) Cohort. Non-matched and Matched EU cohort COMPERA: Kaplan-Meier estimates of survival at 36 months, IPAH Green=AC Non-Matched P=0.006 100% 80% 60% 40% 20% 0% 1 2 Survival of patients Disease duration since PAH diagnosis (years) Green=AC 100% 80% 60% 40% 20% 0% 1 2 3 Matched: sex, age, functional class, and PVR P=0.017 Survival of patients Disease duration since IPAH diagnosis (years) Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. 2014;129:57-65.

US Cohort REVEAL Kaplan-Meier Estimates of Survival at 36 Months IPAH SSc-PAH 6 12 18 24 30 36 Time from warfarin start/match (months) 100 90 80 70 60 50 40 Survival (%) 100 90 80 70 60 50 40 Survival (%) p=0.17 81.1 ± 3.6% 77.2 ± 3.7% p=0.03 62.0 ± 8.2% Started warfarin on study (n=43) Never on warfarin (n=43) 41.5 ± 8.2% Started warfarin on study (n=144) Never on warfarin (n=144) Hazard Ratio 95% Confidence Interval p-value Unadjusted 1.42 0.86, 2.32 0.17 PAH Risk Score adjusted* 1.37 0.84, 2.25 0.21 Hazard Ratio 95% Confidence Interval p-value Unadjusted 2.03 1.09, 3.79 0.03 PAH Risk Score adjusted* 1.60 0.84, 3.06 0.15 6 12 18 24 30 36 No. at risk No. at risk Warfarin Never warfarin 144 124 119 109 93 83 77 144 135 110 110 95 81 67 Time from warfarin start/match (months) Warfarin 144 124 119 109 93 83 77 Never warfarin 144 135 110 110 95 81 67 *PAH risk score at quarterly update corresponding to warfarin start. IPAH=idiopathic pulmonary arterial hypertension. *PAH risk score at quarterly update corresponding to warfarin start. PAH-SSc=pulmonary arterial hypertension associated with systemic sclerosis. Preston IR, Roberts KE, Miller DP, 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;132:2403-2411. Preston IR, Roberts KE, Miller DP, 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;132:2403-2411.

DOACs in PH: Rivaroxaban Attenuates Experimental PH Effects of chronic treatment with rivaroxaban, warfarin and enoxaparin on MCT-induced RV hemodynamics and RV hypertrophy 100 90 80 70 60 20 10 ** 30 40 50 * Control Placebo Rivaroxaban Warfarin Enoxaparin RVP (mmHg) MCT 2 1 ** Control Placebo Rivaroxaban Warfarin Enoxaparin RVEDP (mmHg) MCT 3 4 5 6 7 8 2 1 Control Placebo Rivaroxaban Warfarin Enoxaparin CO (mL/min) 20 80 100 120 40 60 MCT 140 2 1 0.0 ** Control Placebo Rivaroxaban Warfarin Enoxaparin RV/LV+S 0.1 0.4 0.5 0.6 0.2 0.3 MCT Delbeck M, Nickel KF, Perzborn E, et al. A role for coagulation factor Xa in experimental pulmonary arterial hypertension. Cardiovasc Res. 2011;92(1):159-168.

Rivaroxaban Attenuates Experimental PH Pulmonary remodeling RV remodeling Control Placebo Rivaroxaban MCT 3 10 2500 5000 7500 10000 12500 15000 17500 * BNP mRNA expression (arbitrary units) 25000 50000 75000 100000 Col1A2 150000 200000 250000 300000 350000 ANP 20000 30000 CTGF TIMP-1 2000 4000 6000 8000 12000 Fibronectin Delbeck M, Nickel KF, Perzborn E, et al. A role for coagulation factor Xa in experimental pulmonary arterial hypertension. Cardiovasc Res. 2011;92(1):159-168.

Apixaban in SSc-PAH Calderone A, Stevens W, Prior D, et al. Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol. BMJ Open. 2016;6(12):e011028.