How Do You Implement the Aggressive Monitoring with Sequential Combination Therapy?

Hello.I’m Dr. Richard Krasuski from Duke University. Today we’re gonna talk about implementing
aggressive monitoring and sequential combination therapy What is the rationale for this? On this slide, you can see an example of aggressive
monitoring and escalation of therapy. This is a patient who’s come in, who has functional
class II symptoms. You start them on initial monotherapy, and
then you wait for potential decline in their clinical status, or some other evidence that
they’re failing medical therapy. When that occurs, you add on a second agent,
and again, potentially a third agent. Again, sequential add-on, or switch strategies
may buy you time, but they don’t always push our patients to goal. Let’s talk about why we’re targeting therapies,
why we’re adding these agents on. Targeting multiple pathologic pathways improves
response. Again, combination agents are working on a
variety of pathways. On the left you can see, is the prostacyclin
pathway, which we know has derangements in it, in patients with pulmonary arterial hypertension. In the middle, you can see nitric oxide production,
which is clearly impacted in patients with pulmonary arterial hypertension. We now have different ways of approaching
this particular pathway with multiple agents. Again, these two agents should not be used
in combination, but we do have different ways of targeting them. And then, finally the endothelin pathway,
where we can also affect, and reduce the effects of endothelin on the vasculature. Let’s talk a little bit about the studies
with the data that supports this strategy. We’ll start with the PACES trial. The PACES trial, we looked at folks who are
on baseline epoprostenol, and looked at the addition of sildenafil. On the slide on the left, you can see six
minute walk change, over time. You can see when they were on placebo, there
was essentially no change compared to baseline where there was a statistically significant
improvement in the patients who got sildenafil. On the right you can see, looking at clinical
events, and clinical worsening. You see the patients who were started on sildenafil
versus placebo, had a statistically significant reduction in clinical events. Next is the PHIRST trial. In the PHIRST trial we looked at the addition
of tadalafil to baseline bosentan. This is again, looking at a change in six
minute walk distance. You can see over time, there’s a clear separation
between the curves, and those patients getting 40 milligrams of tadalafil, versus those patients,
who are treated with placebo. The next trial is the SERAPHIN trial. In the SERAPHIN trial, we’re looking here
at the patients, who were treated on baseline therapy, who got macitentan added onto baseline
PDE5 inhibitor. You can see clearly, an improvement in the
patients compared to those who remained on placebo. And finally, the GRIPHON study. The folks who are on baseline therapy. You can see the event rate, that’s the curve
on the bottom. Then you look at when selexipag was added
comparatively the statistically significant difference that was seen. You see about a 37% reduction in clinical
events by the addition of selexipag to those that were on baseline therapy. In what type of patients would you consider
a sequential combination type strategy? First of all, low to moderate risk patients. Again, those are unlikely to deteriorate rapidly. You should be very careful to assess these
patients early in their treatment course, ideally in the one to three month range. You really don’t want to stretch out that
follow up appointment too long. If the patients aren’t clearly moving towards
a low risk category, you should consider escalation of care, with a second or third agent. In summary, we’ve talked about the data behind
the aggressive observation in add on therapy strategy, which is reasonable. It is important to watch these patients very
carefully and add on drugs if necessary, and certainly the clinical outcomes appear to
be improved, compared to just keeping them on monotherapy. I thank you for your attention.