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

2. 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:
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:

3. 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.

4. 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
Time from warfarin start/match (months)
Warfarin
Never warfarin
*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:
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:

5. 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):

6. 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):

7. 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):e