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Raymond L. Benza, MD - phaware® interview 447

Dec 19, 2023

Dr. Raymond Benza, a Professor of Medicine at the Icahn School of Medicine at Mount Sinai, discusses dual therapy in the treatment of pulmonary hypertension (PH) through the concept of risk stratification. 

Good day everyone. My name is Dr. Raymond Benza. I am a Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York. I am a Pulmonary Hypertension physician and researcher in risk stratification and genomics of the disease. Today, we're here to speak about the concept of dual therapy.

Now, the importance of dual therapy, I think, has been conceived in looking at the data and looking at the outcome of patients who have been treated with monotherapy versus dual therapy. This has evolved using the concepts of risk stratification. As we know, risk stratification is now one of the most important ways in which we judge the severity of disease and then try to match the aggressiveness of our medical therapy based on that level of risk.

Three main risk groups exist commonly, low, intermediate, and high risk. These are all based on mortality estimates. With a low-risk patient expected to experience a mortality rate of only 5% per year. An intermediate risk patient expected to experience a mortality of rate between five to 10%, and then a high-risk patient expected to have a mortality rate in excess of 10%. We use this risk stratification allocation, which are based on several multiparametric algorithms or formulas based on very common variables that we assess clinically; including functional class or natriuretic peptide levels, six-minute walk distance, and some imaging, and hemodynamic variables.

We use these to classify our patient's risk before we start therapy. What we have found is that patients even deemed low risk, seem to do better with two upfront drugs as opposed to one upfront drug. This is a very important concept, because as many of you remember about a decade ago, we would start medication serially.

We would try one drug and then if the expected functional improvements didn't match what we wanted, we would add a second drug and then wait a little bit and add a third drug. But we have really changed the way that we do that now based on these risk stratification schemes. So upfront patient treated initially would be with two drugs of different classes, most often an Endothelin Antagonist and a PDE5 inhibitor, irregardless of whether they were low or intermediate risk.

Patients who are higher risk would be treated with upfront triple therapy. So an Endothelin Antagonist, a PDE5 inhibitor, and prostacyclin analog. Using these upfront combination therapies, we have found that the outcome of patients have improved significantly within each one of those risk categories. That's not to say that patients who are low risk may not benefit from starting one therapy. In fact, there's been a recent study that was published a month or two ago in the CHEST Journal that demonstrated that people at ultra-low risk usually indicated by a REVEAL score of less than five can continue to benefit from monotherapy. This has not been translated into the guidelines yet.

So at this point, any low-risk patient according to the guidelines, to still get an upfront dual combination therapy in order to give them the maximum benefit to achieve low risk and to maintain low risk. That's our main concept now in our follow-up for patients with pulmonary hypertension. Usually at three-to-four-month markers, we will take a look at a patient in totality and calculate their risk scores. Again, either using the US system REVEAL or the European system, to see where they are in that risk continuum.

If patients continue to be at intermediate or higher risk is when we will add additional therapeutics to their regimens. Perhaps switching a PDE5 to riociguat or adding a prostacyclin analog, or titrating a prostacyclin analog. Even if they're on triple therapy, we may start considering whether they may be eligible for transplantation or not, or if any of our new experimental protocols that come out with some new compounds.

That's the good news for PH patients at this point, is that we have a lot of new drugs in the pipeline to treat this disease that really work on the disease in a different perspective than our older medications do. They really are now geared towards making the pulmonary vessels normal again, so not dilating them, but actually working on the meat of the vessel to make that vessel thinner and more compliant.

I think that's really captures the essence of the use of upfront combination therapy or dual therapy. Now, again, is to drive patients even at the lower ends of risk to the lowest risk possible, to give them the best mortality and morbidity expectations over the subsequent year with the caveat that frequent reassessments of patients is required and frequent adjustments of medications to keep them or to achieve low risk is indicated.

As always, thanks for listening. My name is Dr. Raymond Benza and I'm aware that my patients are rare.

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