Combination Therapy in Pulmonary Arterial Hypertension

Researchers have found that a combination of ambrisentan and tadalafil can lower the risk of clinical failure in patients with pulmonary arterial hypertension. The study, which appears in the Aug. 27 issue of the New England Journal of Medicine found that the combination of ambrisentan and tadalafil was more effective than either drug taken alone, although the combination had more side effects. Pulmonary arterial hypertension is a dangerous complication of connective tissue diseases such as systemic lupus erythematosus and particularly systemic sclerosis. Mortality is high without treatment and drug treatment only reduces mortality modestly. Several biological pathways have been identified, with drugs to target those pathways. Those drugs are often used in combination to increase their effectiveness by blocking different pathways and attacking different mechanisms of the disease. But good evidence is not always available for those combinations. Now a well-designed study shows the benefit of one combination. [[{"type":"media","view_mode":"media_crop","fid":"40875","attributes":{"alt":"©LungsSciencePics/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_1332102902233","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"4244","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.0080003738403px; line-height: 1.538em; float: right;","title":"©LungsSciencePicsShutterstock","typeof":"foaf:Image"}}]]The study, a randomized phase 3-4 trial, showed that the two drugs increase blood flow through the lungs by different mechanisms. Ambrisentan inhibits the endothelin receptor on the smooth muscle. Tadalafil inhibits phospodiesterase.  The primary analysis included 500 total patients, 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group.  The primary end point in the study was defined by a composite of death, hospitalization for pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. That end point was reached by 46 (18%) of the 253 who took combination of both drugs, but 77 (31%) of the 247 who took only one drug.  Led by Nazzareno Galiè of the University of Bologna in Italy, the treatment effect “was driven mainly by a lower rate of hospitalization for pulmonary arterial hypertension in the combination-therapy group.” Thirty (12%) of the patients who took only one drug were hospitalized. 

Combination (ambrisentan and tadalafil)

Pooled group (ambrisentan or tadalafil)

Ambrisentan

Tadalafil

N (500 total)

253

247

126

121

Primary end point

18%

31%

34%

28%

Hazard Ratio for primary end point

0.50

1.00

Satisfactory clinical response

39%

29%

6-minute walk distance

+49 m

+24 m

Clinical failure 50% lower with combination therapy

 The researchers, which consisted of a large international team, wrote:  “The risk of the primary end point of the first event of clinical failure was 50% lower among participants who received initial combination therapy with ambrisentan and tadalafil than among those who received monotherapy with either drug.”  Most previous studies of combination therapy “compared the addition of a therapy with placebo in participants already receiving background treatment with approved drugs (sequential combination therapy).” This study supports targeting multiple pathways and “showed that early combination therapy can be beneficial.”  A secondary end point was the distance patents could walk in 6 minutes. Before treatment, they could walk an average of about 350 meters. At the end, patients in the combination group could walk 49 meters farther. Patients who took only one drug could walk only 24 meters farther.  The study lasted 168 weeks, but patients were removed from the study if it was medically appropriate after they reached the primary end point, which includes no response, and only a small number made it to the end.  Of the 500 patients, 187 (37%) had pulmonary arterial hypertension associated with connective-tissue disease, which includes systemic sclerosis and systemic lupus erythematosus. For the largest group of patients, 265 (53%), the cause was unknown.  The adverse effects more common in the patients taking the combination drugs were peripheral edema, headache, nasal congestion and anemia. The most common serious adverse events were worsening of the pulmonary arterial hypertension and pneumonia.  A limitation of the study, they wrote, was the difficulty of distinguishing between pulmonary arterial hypertension and pulmonary hypertension due to left ventricular hypertension. Treatments for pulmonary arterial hypertension can be harmful to patients with left ventricular hypertension.  

Disclosures:

This study was supported by Gilead Sciences and GlaxoSmithKline.  

References:

Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. New England Journal of Medicine.  2015; 373(9):834-844. August 27, 2015. DOI: 10.1056/NEJMoa1413687