What Can be the Risks of Combination Therapy in PAH?

What Can be the Risks of Combination Therapy in PAH?


Hello, I’m Dr. Richard Krasuski from Duke
University. Today we’re going to talk about the risks,
or side effects, of combination therapy in pulmonary hypertension. First of all, the use of combination agents,
if you think about it, obviously brings forth the problems with one agent and combines it
with the problems of the other agent. When we talk about endothelin receptor antagonists,
bosentan especially, and macitentan less, can have a significant risk for transaminitis. Bosentan and sildenafil is especially problematic
in this regard. In fact, it’s a warning that you want to be
careful using those two in combination. Also, we have data that probably combining
those two agents may lessen the benefit of either agent. You’d think it would be an additive effect,
but it is not. Ambrisentan appears to have little to know
hepatotoxicity. And then the combination of an ERA and PDE5,
there is some nuisances. In particular nasal congestion appears worse
with ambrisentan, in particular, when used in combination with a PDE5. Headache and fluid retention are common, but
usually these are transient with combination therapy. And in AMBITION, interestingly enough, fluid
retention did not appear to be problematic. Riociguat – hemoptysis can occur, although
it’s fairly rare. But it should, obviously, be a concern if
it’s observed in a riociguat-treated patient. It’s important to recognize that this drug
is utilized in patients with thromboembolic disease. So it’s important to separate out an idiosyncratic
reaction of the drug to somebody who’s having pulmonary embolism and more complications. Hypotension appears more common than with
other PAH therapy. You should certainly, and importantly, never
use riociguat together with a PDE5 inhibitor. In general, the hypotension is usually not
problematic, and if you do have problems you typically will slow down escalation of the
dose. It’s not clearly amplified by background therapy
in the patent study. Prostacyclins and analogues are well-known
to have a number of side-effects, although there are very impressive data demonstrating
benefit to this group. It’s almost universal that patients will develop
problems related to prostaglandin, such as headaches, nausea, flushing, jaw pain, diarrhea,
leg and back pain. Adverse events, generally, are amplified in
intensity for those patients that are already on background therapy. It’s important to discuss the fact that these
are delivered in different ways and these delivery systems themselves have problems
associated with them. First, if you’re getting an IV prostanoid,
you are at increased risk with an indwelling line, for problems such as sepsis, thrombosis
and embolism-related to the line, and also endocarditis. If it’s administered subcutaneously, pain
is a major problem for these patients. As a matter of fact, the data suggests it’s
over 85% of patients that have significant pain when the drug is administered subcutaneously. And finally, in the inhaled form, it’s very,
very common that patients will have coughing. Particularly during administration of the
agent. Today, we discussed, in summary, the risks
and the side-effects that are associated with combination therapy. Again, when you’re combining agents of different
classes, you often amplify some of those side-effects. However, it’s important that you have to weigh
the benefits and the risks with each agent, and each of the patients that you take care
of, before prescribing them and leaving the patient on those medications. I thank you for your attention.

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