Initial Use of Letairis® (ambrisentan) plus Cialis® (tadalafil) in Pulmonary Arterial Hypertension

Julie Murphy, Mercer University College of Pharmacy

According to the American Lung Association, pulmonary arterial hypertension (PAH) is a rare condition, only affecting one patient out of 100,000 to one million people. It is described as elevated blood pressure in the arteries of the lungs which will progress overtime with no cure. The untreated survival rate is estimated to be approximately three years. PAH increases cardiac strain and can lead to cardiovascular disease and dramatic lifestyle changes.1

Title: Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension (PAH)2
Design Randomized, event-driven, double-blind study; N= 500
Objective To determine the effects of initial combination therapy on long-term clinical outcomes in patients who have not previously received treatment
Study Groups Combination therapy (ambrisentan+ tadalafil); n= 253

Ambrisentan Monotherapy (ambrisentan+ placebo); n= 126

Tadalafil Monotherapy (tadalafil+ placebo); n= 121

Methods Patients were enrolled from 120 center in 14 countries. Patients were stratified according to their cause and The World Health Organization (WHO) function classification of their pulmonary arterial hypertension. They were then randomized into either combination therapy, ambrisentan monotherapy, or tadalafil monotherapy at a 2:1:1 ratio. Efficacy and safety were assessed periodically throughout the study.
Duration October 18, 2010 to July 31, 2014
Primary Outcome Measure The first event of clinical failure, which include the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response
Baseline Characteristics no. (%) Combination Therapy

(n= 253)

Ambrisentan Monotherapy

(n= 126)

Tadalafil Monotherapy

(n= 121)

Age, years 54.5±14.3 53.9±14.7 54.5±15.2
Female 188 (74) 100 (79) 100 (83)
Body-mass index, (kg/m2) 27.7±6.3 27.6±6.5 28.6±7.2
Caucasian 233 (92) 107 (85) 106 (88)
North American 116 (46) 51 (40) 61 (50)
European 129 (51) 72 (57) 56 (46)
Hypertension 104 (41) 52 (41) 43 (36)
Diabetes 19 (8) 13 (10) 17 (14)
Coronary artery disease 16 (6) 2 (2) 2 (2)
Idiopathic PAH 127 (50) 72 (57) 66 (55)
PAH associated with connective-tissue disease 103 (41) 44 (35) 40 (33)
No history of PAH specific therapy 242 (96) 120 (95) 115 (95)
Prior Medication Use:
Oxygen 62 (25) 28 (22) 29 (24)
Anticoagulant 78 (31) 30 (24) 46 (38)
Calcium-channel blocker 70 (28) 32 (25) 37 (31)
Diuretic 142 (56) 72 (57) 67 (55)
Aldosterone antagonist 48 (19) 31 (25) 21 (17)
Median time between diagnosis to initiation of study drug (days) 20.0 20.5 29.0
Arterial Blood Pressure (mmHg) 90.1±12.9 89.5±12.1 88.8±11.3
Right arterial pressure (mmHg) 7.7±4.5 7.4±4.6 8.4±4.8
Pulmonary artery pressure (mmHg) 48.1±12.4 50.4±12.5 48.1±12.6
Pulmonary-capillary wedge pressure (mmHg) 8.4±3.1 8.6±3.3 9.3±3.5
Median N-terminal pro–B-type natriuretic peptide (NT-proBNP), (ng/L) 938.0 1171.0 869.0
Mean 6-minute walk distance (meters) 353.5±87.9 354.2±92.3 349.2±91.6
WHO functional class II 76 (30) 38 (30) 41 (34)
WHO functional class III 177 (70) 88 (70) 80 (66)
Results no. (%) Combination Therapy

(n= 253)

Ambrisentan Monotherapy

(n= 126)

Tadalafil Monotherapy

(n= 121)

First event of clinical failure 46 (18) 43 (34) 34 (28)
Death 9 (4) 2 (2) 6 (5)
Hospitalization for worsening PAH 10 (4) 18 (14) 12 (10)
Disease Progression 10 (4) 12 (10) 4 (3)
Unsatisfactory long-term clinical response 17 (7) 11 (9) 12 (10)
Hazard ratio (95% confidence interval) Reference 0.48

(0.31 to 0.72)

0.53

(0.34 to 0.83)

P Value <0.001 0.005
Adverse Events Common Adverse Events: Peripheral edema, headache, nasal congestion, diarrhea, dizziness, dyspnea, nausea, cough, flushing, anemia, nasopharyngitis, pain in extremity, upper respiratory tract infection, arthralgia, back pain, fatigue, dyspepsia, palpitations, vomiting, bronchitis, non-cardiac chest pain, myalgia, and urinary tract infection
Serious Adverse Events: Pneumonia
Percentage that Discontinued due to Adverse Events: Combination therapy (12%), Ambrisentan monotherapy (11%), Tadalafil monotherapy (12%)
Study Author Conclusions Combination therapy decreased the risk of first event of clinical failure significantly as compared to monotherapy with ambrisentan or tadalafil. This study demonstrated the importance of targeting multiple disease pathways with initial therapy for pulmonary arterial hypertension.

Patients with multiple risk factors for left ventricular dysfunction were excluded, in a protocol amendment, due to their elevated risk of negative outcomes caused by PAH therapy. The effects of the protocol amendment, on study outcomes, are unknown which could lead to difficulty applying this data to general practice. Retrospective rates of all-cause hospitalization were not significantly different between the three study groups. The primary outcome data suggested that long-term combination therapy may not provide additional benefit. There was no significant difference, between the study groups, in WHO functional class. This trial did not evaluate the possible benefit of switching monotherapies once a patient has failed to respond to their initial drug.2

References

  1. Understanding PAH. American Lung Association. http://www.lung.org/lung-disease/pulmonary-arterial-hypertension/understanding-pah.html. Accessed August 28, 2015.
  2. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015;373(9):834-844.
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