New Regimens May Optimize Outcomes, Reduce Toxicity

In the past decade the Food and Drug Administration (FDA) has approved a number of novel therapeutic agents for pulmonary arterial hypertension (PAH), and several more are in development or nearing approval. Nevertheless, currently available drugs for PAH produce heterogeneous responses, and significant morbidity and mortality persist. To overcome these limitations, physicians are investigating multidrug regimens. “Combination therapies are an important emerging clinical paradigm for pulmonary hypertension patients with suboptimally managed disease,” says cardiologist Raymond L. Benza, MD, director of the UAB Pulmonary Vascular Disease Program.

“Monotherapy with either an oral endothelin-1 receptor antagonist or a PDE5 inhibitor initially improves most patients’ symptoms, but their clinical improvement usually peaks or stalls after about 4 months, and some patients deteriorate,” Benza says. “Combining two drugs from different classes targets multiple pathophysiologic pathways, increasing efficacy and optimizing outcomes.” Using drugs with different mechanisms of action capitalizes on additive and synergistic actions on vascular remodeling and may have the most dramatic impact on clinical status. In addition, when drugs are used in combination, it may be possible to reduce individual drug dosages and decrease risks of adverse effects.

Clinical Trials
Researchers have studied the efficacy and safety of combination therapies in several small investigations. Studies of prostanoids plus an endothelin receptor antagonist (bosentan) have shown improved hemodynamics, exercise capacity, and functional class in children and adults (Eur Respir J. 2004;24:353-359) and (J Am Coll Cardiol. 2005;46:697-704).

Researchers also have combined prostacyclin analogues and the PDE5 inhibitor sildenafil with positive results. A German study showed sildenafil is a safe and effective rescue agent for waning clinical responses to inhaled iloprost (J Am Coll Cardiol. 2003;42:158-164). Studies of sildenafil plus treprostinil confirm the combination is well-tolerated, safe, and significantly improves 6-minute walk distance (Am J Cardiol. 2005;96:1334-1336).

Many of these trials, however, represent single center experiences or study the effects of adding a second drug in a patient with a known clinical response. To date there have been no investigations to address what factors should drive the addition of a second medication and the optimal time to add medications.

When to Add Additional Drugs
Based on information from large clinical trials on monotherapy for PAH, Benza feels the optimal time to make this decision is 4 months. “If you look at the response rates based on the 6-minute walk test, all current FDA-approved drugs, and even those pending approval, peak at 4 months.

“If, after a minimum of 4 months on monotherapy, patients cannot achieve normal daily function, walk more than 380 meters or demonstrate an improvement in right ventricular hemodynamics, we consider combination therapy,” he says. “Keeping in mind the rapidly progressive nature of this disease, an aggressive, tiered approach with additional drugs should be implemented at this time point.”

“The first multicenter event-driven PAH study to assess a tiered, step-wise approach of adding sildenafil to the regimen of patients who do not reach a critical walk distance after 4 months with bosentan is now under way at UAB. Novel imaging techniques combined with standardized risk factor assessments will help researchers make the first scientifically valid test of a tiered approach. Perhaps the most promising trial to date on drug combinations, this study should answer some important questions,” says Benza.

Researchers expect to enroll 150 participants at 15 centers across the nation, with UAB serving as the core facility for this protocol. “This landmark study for pulmonary hypertension will significantly impact the outcome of patients with this disease,” Benza says.

“We must be focused and answer questions with scientifically valid and well-structured studies. Combination therapy must be handled with due vigilance with heightened monitoring for adverse effects and drug-to-drug interactions,” he says. “We believe combination therapy will significantly alter the treatment of patients with pulmonary hypertension in the next 5 or 10 years.”

For more information:
Dr. Raymond Benza
1.800.UAB.MIST
mist@uabmc.edu