Between January 2014 and December 2017, 46 patients newly diagnosed with PAH were started on combination therapy with macitentan and tadalafil, receiving at least one dose of each medication. Demographic data and disease etiology are presented in Table 1. The median age was 56 years and 85% of patients were female. The etiology of PAH was relatively evenly divided between idiopathic PAH (50%) and PAH associated with connective tissue disease (43%), most commonly scleroderma (26%).
Table 1: Baseline Characteristics of Study Population
Cohort characteristics
|
Subjects, n
|
46
|
Age, median (Q1, Q3), years
|
56 (36, 68)
|
Sex, n (%)
|
|
Male
|
7 (15)
|
Female
|
39 (85)
|
BMI, mean (SD), m/kg2
|
27 (7)
|
Pulmonary Hypertension WHO Classification, n (%)
|
|
Idiopathic
|
23 (50)
|
Connective tissue disease
|
19 (41)
|
Scleroderma
|
12 (26)
|
Mixed connective tissue
|
3 (7)
|
Systemic lupus erythematosus
|
2 (4)
|
Myositis
|
1 (2)
|
Rheumatoid arthritis
|
1 (2)
|
Congenital heart disease
|
3 (7)
|
Human immunodeficiency virus
|
1 (2)
|
BMI=body mass index.
Effectiveness
Cohort composition by overall risk category at baseline and follow-up is shown in Figure 1. The median time from start of therapy to follow-up and reassessment via RHC was 161 days (IQR 72). Forty-three of 46 patients (93%) were at high or intermediate risk at baseline, of whom 18 patients (42%) met the primary endpoint and improved to low risk category on follow-up. Three patients died within 6 months of starting treatment: 2 were initially at moderate risk and did not tolerate macitentan, discontinuing the drug within one week of initiation, and 1 was initially high risk and remained so despite dual therapy. All 3 individuals who died were women with scleroderma aged >65 years.
Changes in PAH prognostic variables at baseline and follow-up are described in Table 2. Twenty-nine individuals (63%) improved in functional class while 2 (4%) worsened. Average 6MWD improved by 88m (95% CI 27, 148m) and BNP was reduced by 65% (geometric mean ratio 0.35, 95% CI 0.15, 0.82). With respect to hemodynamic variables, PVR decreased by 45% (geometric mean ratio 0.55, 95% CI 0.43, 0.71) and CI improved by 30% (geometric mean ratio 1.3, 95% CI 1.16, 1.46). Results remained similar when analysis was restricted to the subset of patients who tolerated and did not discontinue macitentan or tadalafil (Table S2). Change in risk category for individual PAH prognostic variables as per 2015 ESC/ERS guidelines are shown in Table S3.
Table 2: PAH Prognostic Variables at Baseline and Follow-up
|
Baseline
|
Follow-up
|
Change from baseline to follow-up
|
Mean (95% CI)
|
p
|
Subjects, n
|
46
|
46
|
|
|
Functional Class, (%)
|
|
|
|
|
I
|
0
|
6 (13)
|
Improved: 29 (63)
|
<0.0001
|
II
|
6 (13)
|
25 (54)
|
No change: 15 (33)
|
III
|
36 (78)
|
12 (26)
|
Worsened: 2 (4)
|
IV
|
4 (9)
|
3 (7)
|
|
Baseline 6MWDa
|
322 (139)
|
409 (151)
|
88 (27, 148)
|
<0.01
|
Baseline BNP, pg/mLb
|
421 (82, 840)
|
77 (24, 210)
|
0.35 (0.15, 0.82)d
|
0.02
|
Baseline RHC
|
|
|
|
PVR, WU
|
12.6 (9.4, 16.1)
|
7.0 (4.7, 10.3)
|
0.55 (0.43, 0.71)d
|
<0.0001
|
mPAP, mmHg
|
49.6 (12.0)
|
41.8 (17.2)
|
-7.8 (-13.9, -1.7)
|
0.01
|
RAP, mmHg
|
9.7 (5.5)
|
6.0 (5.0)
|
-3.7 (-5.9, -1.5)
|
<0.01
|
PCWP, mmHg
|
8.1 (3.5)
|
8.1 (3.5)
|
0 (-1.4, 1.4)
|
0.98
|
CI, L/min/m2
|
1.9 (1.6, 2.3)
|
2.5 (2.1, 2.9)
|
1.3 (1.16, 1.46)d
|
<0.0001
|
SvO2, % c
|
58.1 (9.8)
|
64.5 (10.1)
|
6.4 (2.0, 10.9)
|
<0.01
|
Median follow-up of 161 days (IQR 72 days). Variables expressed as mean (SD) with the exception of BNP, PVR and CI, which are lognormally distributed and expressed as median (IQR). Change from baseline expressed as arithmetic difference in means (95% confidence interval), with the exception of BNP, PVR and CI, which are expressed as a geometric mean ratio of follow-up and baseline values (95% confidence interval).
6MWD=6-minute walk distance, BNP=B-type natriuretic peptide, RHC=right heart catheterization, PVR=pulmonary vascular resistance, mPAP=mean pulmonary arterial pressure, PCWP=pulmonary capillary wedge pressure, CI=cardiac index, SvO2=mixed venous oxygen saturation.
a Based on 45 measurements
b Based on 32 measurements
c Based on 40 measurements
d Geometric mean ratio with CI
Tolerability and Safety
Adverse events and drug discontinuations are summarized in Table 3. In total, 8 of 46 patients (5 macitentan and 3 tadalafil; 17% total) discontinued therapy due to an adverse effect or intolerance. Baseline characteristics of individuals who discontinued either macitentan or tadalafil are shown in Table S4. Of these 8 patients, 2 expired within one year due to progressive disease, having only tolerated tadalafil monotherapy. Two other patients who discontinued macitentan or tadalafil went on with monotherapy; the remaining 4 had the ERA or PDE-5i substituted with a different drug of the same class.
The most common adverse events associated with combination therapy were headache and edema, occurring in 50% and 30% of individuals, respectively. Headache occurred within days of starting therapy, resulting in discontinuation of tadalafil in 2 individuals (4%). A further 4 cases required transient stopping and gradual re-introduction of tadalafil. Edema led to discontinuation of macitentan in 3 cases (7%), of which two patients required admission to hospital for intravenous diuresis.
Anemia occurred in 6 cases (13%) between 20 to 171 days of starting macitentan. Three of these cases were complicated by superimposed confounding factors felt to be the primary drivers of the anemia. One case required red blood cell transfusion, but anemia did not lead to discontinuation of macitentan in any of the 6 cases. Transaminitis greater than 3 times the upper limit of normal occurred in one patient 22 days after initiation of macitentan, reaching an ALT of 230 IU and AST of 456 IU from previously normal baseline values. Macitentan was discontinued and the patient was later started on ambrisentan without recurrence of transaminitis.
An additional 2 patients discontinued PAH therapy due to other adverse effects. One patient elected to stop tadalafil 18 days from initiation due to significant epistaxis, though this was also in the setting of a supratherapeutic INR of 5 and felt unlikely to be related to tadalafil. In another case, macitentan was discontinued within 8 days due to unremitting nausea and decreased appetite, possibly confounded by worsening PAH.
Table 3: Adverse Events and Discontinuation of Macitentan or Tadalafil
Adverse event
|
n (%)
|
Agent discontinued, n
|
Headache
|
23 (50)
|
2
|
Edema
|
14 (30)
|
3
|
Anemia
|
6 (13)
|
0
|
Hypotension
|
3 (7)
|
0
|
Transaminitis
|
1 (2)
|
1
|
Epistaxis
|
1 (2)
|
1
|
Muscle cramps
|
1 (2)
|
0
|
Nausea
|
1 (2)
|
1
|