Right Heart Function in FREEDOM-EV
My name is Paul Forfia. I'm a cardiologist and pulmonary hypertension specialist. I'm a professor of medicine at Temple University Hospital, and I serve as co-director of the Pulmonary Hypertension, Right Heart Failure, and CTEP Program at Temple University Hospital. Today, I'll be talking to you about right heart function and the FREEDOM-EV study.
When thinking about risk status and right heart function, we're often asked whether risk status correlates with right heart function, but we need to think about it another way.
When a person's parameters of risk, such as their functional class, their walk, and their BNP are all improving, it is not that these parameters are correlated with right heart function—it's that the improvements in risk status are directly caused by the improvement in right heart function.
First, it's important to note that the majority of our patients who are on therapy with PAH fall into an intermediate risk group. When we recognize that being in an intermediate risk group puts you at a five year survival, that can be as low as 50 percent.
Now, if you actually look at some recent data that was published, it actually shines even a brighter light on this issue. So, this was a, this was actually a retrospective study of 180 patients who were treatment-naive, who were then treated with dual upfront combination therapy. And then the patients had a repeat right heart catheterization six months after initiation of dual upfront combination therapy. And so we've got, in this study, a 35 percent reduction to PVR on average, but our target is probably something more like 50 to 60 percent.
FREEDOM-EV study was an interesting study that compared Orenitram versus placebo in a group of PAH patients who are already on established oral monotherapy.
Despite the relative stability of the PAH cohort at the time of enrollment, the patients who were treated with Orenitram and followed over time experienced a 61 percent reduction in relative disease progression as compared to placebo.
When we look at the hemodynamic substudy of FREEDOM-EV, we see that there was a 20 percent reduction in the pulmonary vascular resistance in the Orenitram group and in turn a 19 percent increase in the cardiac output. That relative increase in the cardiac output of course mirrors the relative fall in pulmonary vascular resistance and it speaks to the relative unloading of the right heart in response to Orenitram.
When we take a non-invasive look at the heart in the overall FREEDOM-EV study, we see that there was a 41 percent difference in the NT-proBNP level in the patients at 36 weeks. And this speaks to the relative offloading of the heart from the hemodynamic standpoint, and also from the biomarker standpoint.
Within the hemodynamic substudy, you had a 20 percent reduction in the pulmonary vascular resistance. You had a 19 percent increase in the cardiac output. You had a 41 percent difference in the NT-proBNP levels. So when you take a step back, you're seeing hemodynamic improvements, leading to biomarker improvements, leading to risk shift within the patient population.
When you study a patient population that are having all of these positive hemodynamic biomarker and risk shift effects occurring, it is internally consistent and makes sense that if you study the patient cohort long enough, you will actually see a relative reduction in the risk of death within the cohort.
INDICATION Orenitram is a prostacyclin mimetic indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%). IMPORTANT SAFETY INFORMATION FOR ORENITRAMContraindications
- Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.
- Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
- The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.
- In the 12-week, placebo-controlled, monotherapy study, and an event-driven, placebo-controlled, combination therapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, vomiting, flushing, pain in jaw, pain in extremity, hypokalemia, abdominal discomfort, and upper abdominal pain.
- Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.
- Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies with Orenitram in pregnant women.
- It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
- Safety and effectiveness of Orenitram in pediatric patients have not been established.
- Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and relative adverse event rates compared to younger patients. Caution should be used when selecting a dose for geriatric patients.
- There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients.