By Van Selby, MD
Assistant Professor of Medicine, UCSF Cardiology Division, Advanced Heart Failure Section, San Francisco
Dr. Selby reports no financial relationships relevant to this field of study.
SOURCE: Galiè N, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373:834-844.
Pulmonary arterial hypertension (PAH) is often treated with a step-by-step approach, starting with a single drug and adding subsequent therapies only when a patient fails to respond. Upfront therapy with a combination of drugs targeting different pathways may be a superior strategy, but has not been evaluated in a large randomized trial.
The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial randomized 500 treatment-naïve subjects with PAH and functional class II or III symptoms to combination therapy with ambrisentan (an endothelin receptor antagonist) plus tadalafil (a phosphodiesterase type 5 inhibitor), ambrisentan-monotherapy, or tadalafil-monotherapy. The target doses of tadalafil and ambrisentan were 40 mg and 10 mg daily, respectively. The primary endpoint was time to clinical failure, defined as a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response. Combination therapy was compared to a pooled-monotherapy group (patients receiving either tadalafil or ambrisentan-monotherapy).
Upfront combination therapy reduced the risk of clinical failure by 50% compared to monotherapy (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72; P < 0.001). The difference was primarily driven by a lower risk of hospitalization in the combination therapy group. There was no difference in the risk of death between the two groups. Combination therapy was also associated with greater reduction in mean N-terminal pro b-type natriuretic peptide level and improvement in 6-minute walk distance (48.98 vs 23.80 meters; P < 0.001). There was no significant difference in change in functional class between the groups. Subjects randomized to combination therapy had higher rates of peripheral edema, headache, nasal congestion, and anemia. There were no significant differences in the discontinuation of the study drug or serious adverse events between the groups. The authors concluded that among subjects with PAH who are treatment naïve, initial combination therapy with tadalafil and ambrisentan is associated with significantly lower risk of clinical failure than initial monotherapy with either tadalafil or ambrisentan.
Currently approved therapies for PAH act on one of three pathways, and there are several reasons why combination therapy would be superior to monotherapy. First, no single drug has been shown to be effective in all PAH patients. Second, PAH is associated with progressive right ventricular failure and death. It makes sense that aggressive, upfront control of the disease would minimize the right ventricular remodeling that ultimately leads to morbidity and mortality in this population. Several studies have shown benefit to multi-drug therapy in PAH, and most patients with PAH will eventually end up on multiple drugs. AMBITION is the first large trial to show a clear benefit from upfront combination therapy. The findings from AMBITION and other recent PAH trials will likely cause a general shift toward more aggressive, upfront, multi-drug therapy for PAH. Similar to the approach used in conditions such as left heart failure or hypertension, there are advantages to initiating aggressive therapy as quickly as possible to get the disease under control rather than waiting to take action until a patient is deteriorating. One small, non-randomized study even looked at the benefits of upfront, three-drug therapy, and it would not be surprising to see this strategy evaluated in a larger trial.
The superiority of combination therapy was observed in all of the subgroups analyzed, including those with milder (WHO functional class II) symptoms. These patients may be more likely to receive single-drug therapy and less frequent follow-up. AMBITION reminds us that even class II patients are at risk for adverse outcomes, including hospitalizations, and the reduction in clinical failures associated with combination therapy was even greater in the class II patients than those with class III symptoms.
One important question is whether AMBITION demonstrates the benefit of the particular tadalafil/ambrisentan combination or the general strategy of upfront, two-drug therapy. There is no obvious reason why this particular combination would be particularly synergistic. That said, strict believers in evidence-based medicine will argue that available data only support this combination. Based on the findings of AMBITION, new guidelines published last month from the European Society of Cardiology give a class I recommendation for the use of tadalafil and ambrisentan as initial combination therapy for PAH, while other drug combinations receive class II recommendations.
In light of AMBITION and other recent trials, the era of starting PAH patients on a single drug and seeing them again for follow-up 6 months later is over. Outside of large PAH centers, those who are comfortable prescribing multiple classes of PAH therapies may choose to continue managing some PAH patients on their own. For many providers the increasingly complex PAH landscape and need to at least consider combination therapy in all patients will prompt more referrals to specialized centers. The results of AMBITION support initiating these referrals as soon as possible to begin an appropriate regimen in a timely manner.