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Although statistically significant, the 16-meter improve-ment
in 6-minute walk distance was relatively modest and less
than the improvements demonstrated in the trials with
intravenous epoprostenol for both PPH and PAH related
to the scleroderma spectrum of diseases, which demonstra-ted
treatment effects of 47 meters and 99 meters, respectively.1,3
The reasons for the less impressive effects are multifactorial.
The entry criteria for the tre-prostinil trial were broader
than those for either of the epoprostenol trials. Key
sub-group analyses are listed in  Table
2. The epoprostenol trials included only patients who
were in NYHA Func-tional Class III or IV. Fifty-three
patients who were in NYHA Functional Class II were enrolled
in the treprostinil trial. Their treatment effect in the
6-minute walk distance was only two meters in the Functional
Class II patients compared with 17 meters for the 382
patients who were in Functional Class III and 54 meters
for the 34 patients who were in Functional Class IV. The
baseline 6-minute walk distance in the treprostinil study
was 326 ± 5 meters in the active treprostinil group and
327 ± 6 meters in the placebo group.
In comparison the baseline 6-minute walk distance in
the PPH epoprostenol trial was 315 meters in the epoprostenol
plus conventional therapy group versus 270 meters in the
conventional therapy group alone.1 In the scleroderma
epoprostenol trial the baseline 6-minute walk distance
was 272 meters in the epoprostenol plus conventional therapy
group and 240 meters in the group receiving conventional
therapy alone.3 This demonstrates that the patient population
was less ill in the treprostinil trial, which may have
contri-buted to the less impressive treatment effect.
The treatment effect was also related to the baseline
walk distance in the treprostinil trial (Table 2). Patients
who were able to walk between 351 and 450 meters did not
demon-strate a treatment effect at all, whereas those
patients who were able to walk in the lowest category
of 50 to 150 meters demonstrated a treatment effect of
51 meters. The etiology of PAH was also more broad in
the treprostinil trial. In addition to the inclusion of
PPH patients and PAH associated with collagen vascular
disease, PAH associated with congenital heart disease
was included. This group had been untested in the past
and in the treprostinil study did not demonstrate any
treatment effect at all. This may in part be related to
the patients’ long-standing disease and the difficulty
of making an impact on such a process over a short 12-week
period.
 The
nemesis of subcutaneous treprostinil has been pain and
erythema at the infusion site (Figure 2). A variety of
therapies have been used to control this adverse effect,
although none has emerged as uniformly successful. Local
remedies such as topical hot and cold packs, topical analgesics
and anti-inflammatory agents have been variably effective.
Some patients also responded to oral analgesics, such
as nons-teroidal anti-inflammatory drugs. More recently,
a pharmaceutical transdermal delivery vehicle, pluronic
lecithin organogel, has been compounded with a variety
of analgesic and anesthetic therapies for local application
in patients treated with treprostinil. Initial observations
appear promising, although the therapy has yet to be studied
in a controlled fashion.
A common observation has been that site pain and erythe-ma
improve after several months of therapy. Additionally,
the pain is not related to the dose of treprostinil. Given
the dose-response relationship, it is important to increase
the dose regularly, so that patients realize an improvement
in dyspnea. Under such circumstances, patients are more
likely to tolerate site discomfort. Some patients have
found that moving the infusion site every 3 days as opposed
to every day is useful. The infusion site most commonly
used was subcutaneous abdominal fat, although some patients
were able to use the outer hips and thighs and underside
of the upper arm with some success.
Because of the longer half-life of treprostinil, interruptions
of drug due to dislodgment of the catheter or pump malfunction
are less serious than with epoprostenol. In such instances,
either the catheter could be replaced or a backup pump,
which all patients had, could be exchanged without any
seri-ous consequences. The Mini-Med pump‚ used to administer
treprostinil, is smaller than the CADD pump used to administer
epoprostenol and is about the size of a pager. The drug
comes in a premixed-prefilled syringe and therefore patients
need only to place the syringe in the pump and do not
have to mix the medication in a sterile fashion on a daily
basis.
The Food and Drug Administration has approved subcutaneous
treprostinil for patients with Functional Class II, III,
and IV PAH. One should consider the use of subcutaneous
treprostinil in patients who are not candidates for or
decline therapy with intravenous epoprostenol, for example
someone with poor venous access or recurrent catheter
infections. In addition, patients who have contraindications
to or transami-nase elevations with the oral endothelin-receptor
antagonist bosentan might be candidates for subcutaneous
treprostinil. Treprostinil has not been studied in combination
with bosen-tan; however, there may be a theoretical benefit
to such a combination.
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