Highlights on AMBITION Trial
1. What is your current practice when initiating oral therapy for pulmonary arterial hypertension (PAH)? Will this paper change your practice?
The treatment of PAH has experienced significant changes in the recent years due to the rapidly growing body of evidence and the approval for new therapies. The author of this article continues to use the proposed evidence-based treatment algorithm based on the 5th World Symposium on Pulmonary Hypertension (WSPH) in practice as a foundation for the initial treatment for PAH. Patients who have World Health Organization (WHO) functional class IV should receive parenteral epoprostanol, which is the only medication with a class I indication for this group. The current recommendations for patients who have WHO functional class II or III is to use sequential combination therapy if there is an inadequate clinical response to an initial drug.
In the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) Trial, patients who were treated upfront with a combination of tadalafil and ambrisertan had a 50% lower risk of developing a primary end point of first event of clinical failure than those who received monotherapy with either drug. It is important to mention that the primary end point in this study was mainly driven by a lower rate of hospitalization for PAH.
The author of this article believe that these results are convincing evidence that up front initial combination therapy is superior to an initial monotherapy strategy, and newly diagnosed PAH patients should be treated with this approach.
2. If patients have side effects after the initiation of dual therapy, how do you determine which agent is causing the side effects?
Distinguishing the side effects of medications that are started simultaneously represents a clinical challenge. In AMBITION, ambrisentan was given at a dose of 5 mg once daily for the first eight weeks and 10 mg once daily thereafter; tadalafil was administered at a dose of 20 mg once daily for the first four weeks and 40 mg once daily thereafter. Being that medications were titrated at different intervals, the culprit medication can be identified through correlation of side effects and time at which dose change occurred.
3. Do you feel these results are a class effect, and could be reproduced with macitentan? Or is it unique to ambrisentan?
Although it is likely that the clinical benefit corresponds to a class effect rather than to a specific synergistic effect of tadalafil and ambrisertan, the results of AMBITION cannot be extrapolated to other drugs in the same or other classes.
- Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015;373:834-44.
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