RevatioBhatia et al.

In a retrospective analysis, Bhatia and colleagues reviewed the medical records of 13 patients with PAH who were receiving empirical adjunctive sildenafil therapy. The study was conducted at the Mayo Clinic’s intensive care unit (ICU) in Rochester, Minnesota between November 1, 2000, and August 31, 2001. The objective was to determine the immediate and long-term effects of adding to therapeutic regimens containing bosentan (Tracleer), a calcium-channel blocker, or intravenous epoprostenol (Flolan, GlaxoSmithKline) in patients with PAH.

The research team obtained baseline measurements of patients’ systemic arterial pressure, pulmonary arterial pressure, right atrial pressure, pulmonary capillary wedge pressure, thermodilu-tion cardiac output, and systemic arterial and mixed venous oxygen saturations. Each patient received a 25-mg oral dose of sildenafil. Every measurement was repeated at one to two, four, and eight hours. Oxygen saturation was measured only at the first interval.

Table 2 Long-Term Effects of Orally Administered Sildenafil

Parameter

Baseline

Follow-up

P Value

Right ventricular systolic pressure

89 ±24

83 ±27

.1

Right ventricular index of myocardial performance

0.6 ± 0.2

0.6 ± 0.2

.8

Six-minute walk (meters)

444.7 ± 111.5

451.3 ± 114.7

.8

* Right-sided heart function and functional status evaluations were performed for nine patients. All values are mean ± standard error of the mean.Data from Bhatia S, Frantz R,Severson C,et al.Mayo Clin Proc 2003;78:1207-1213.

After the last measurement interval, the investigators repeated the same procedure for all patients using 50-, 75-, and 100-mg doses of canadian sildenafil for 24 to 48 hours as long as the systemic systolic BP was below 90 mm Hg during hemo-dynamic monitoring. The long-term effects of this study were evaluated according to noninvasive right ventricular systolic pressures, the right ventricular index of myocardial performance, and a six-minute walking test (Table 2). Of the 13 participants, 10 were discharged from the hospital and resumed taking the highest tolerated dose of sildenafil every eight hours. All participants returned for follow-up. The researcher concluded that patients receiving empirical adjunctive sildenafil demonstrated an immediate pulmonary vasodilator effect (Table 3). However, the long-term effect on right-sided heart function and functional status was unclear. Further studies are needed.

Ghofrani et al.

A randomized, controlled, open-label trial, performed in an intensive care unit (ICU), included 30 patients (23 women and seven men) with severe PAH (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension caused by aplasia of the left pulmonary artery (n = 1). All of the patients had either Class III or IV PAH, according to the New York Heart Association guidelines. The goal was to evaluate the safety and efficacy of oral sildenafil medication alone and in combination with inhaled iloprost (Ventavis, CoTherix, Inc.), a prostacyclin analogue, for the treatment of PAH.

Table 3 Immediate Hemodynamic Effects of Orally Administered Sildenafil

Measurement

Baseline

Peak (P value) Trough (P value) Best
Cardiac output (L/minute) 6.2 ± 1.8

7.2 ± 2.8 (.4)

6.7 ± 3.4 (.4l)

8.2 ± 2.8

MAP (mm Hg) 90 ±11

80 ± 15 (.1)

80 ± l2 (.0l)

69 ± l0

MPAP (mm Hg) 48 ±11

43 ± 9 (.01)

44 ± l2 (.0l)

38 ± 8

MPAP/MAP 0.5 ± 0.1

.6 ± .2

.6 ± .l

0.6 ± 0.2

Pulmonary artery systolic pressure(mm Hg) 80 ± 19 71 ± 18 (<.00l)

73 ± 20

(.0l)

65 ± l7

PVR index (U) 8.6 ± 3.5

6.7 ± 2.4

(.00l)

8.3 ± 5.0 (.73)

5.7 ± 2.l

Right arterial pressure (mm Hg) (n = 12) 7.0 ± 4.0

5.8 ± 2.0 (.42)

5.3 ± 2.7 (.l6)

2.3 ±l.2

Patients were excluded from the trial if they had PAH secondary to chronic obstructive pulmonary disease, pulmonary venous congestion, congenital heart disease, or acute or chronic inflammatory lung disease. Patients were not eligible to enroll if they were pregnant, were documented to be using insufficient contraceptive measures, or had received previous PDE inhibitors, including theophylline preparations.

Each patient initially received inhaled short-term nitric oxide; a maximum vaso-dilatory response of 20 to 40 parts per million was required. After hemodynamic parameters returned to baseline values, aerosolized iloprost 2.8 mcg was given via variables and gas exchange were measured at 5, 15, 30, and 60 minutes after the iloprost inhalation.

After the hemodynamic variables returned to baseline, patients were randomly assigned to receive 12.5 mg of oral, 50 mg of sildenafil, 12.5 mg of sildenafil plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost. Baseline hemodynamic profiles and gas exchange variables were then assessed in all treatment groups following therapy (Table 4).

Table 4 Hemodynamic Baseline Profile with Sildenafil Alone and in Combination with Inhaled Iloprost

Treatment Group Heart Rate (beats/ minute) Mean Systemic Arterial Pressure
(mm Hg)
Mean Pulmonary Arterial Pressure
(mm Hg)
Pulmonary
Vascular Resistance (L/minute per m2)

Cardiac
Index (dyne/sec per cm)

Arterial Oxygen Saturation
(%%)
Mixed Venous Oxygen Saturation
(%)
Sildenafil 12.5 mg* 73 ± l0.l 89 ± l4.6

53 ± ll.9

l.86 ± 0.8

l,325 ± 728

95 ± 5.0

60 ± l2.4

Sildenafil 50 mgf 73 ± l6.7 l00 ± ll.9

57 ± l6.4

l.95 ± 0.3

1,262 ± 735

96 ± 2.0

59 ± l0.7

Sildenafil
l2.5 mg
plus iloprosti
67 ± 6.9 93 ± 7.4

53 ± ll.6

l.86 ± 0.5

1,230 ± 521

94 ± 3.7

60 ± l0.6

Sildenafil
50 mg
plus iloprost§
82 ± l2.4 98 ± l4.l

59 ± ll.6

l.63 ± 0.3

l,47l ± 577

94 ± 3.4

5l ± ll.6

Patients receiving aerosolized iloprost experienced a 27.1% decrease in pulmonary vascular resistance (PVR) and a 22.8% increase in the cardiac index. No significant differences were noted in either treatment group receiving iloprost.

The 12.5- and the 50-mg oral doses of sildenafil caused decreases of 8.5% and 13.5%, respectively, in mean pulmonary arterial pressure; increases of 5% and 13.2% in the cardiac index; and decreases of 14.7% and 24.3%, respectively, in PVR.

Patients receiving combination therapies showed dramatically increased pulmonary vasodilator responses compared with those receiving sildenafil alone.

Although this study used a small sample size and included only minimal long-term observations, it demonstrated that sildenafil plus iloprost achieved a syner-gistic effect when used as combination therapy. Caused significant pulmonary vasodilation in patients experiencing severe PAH and chronic throm-boembolic pulmonary hypertension.

In summary, sildenafil 12.5 mg and nitric oxide therapy were the least potent vasodilators, compared with the combination therapies. Patients taking sil-denafil 50 mg alone and iloprost alone had similar hemodynamic profiles, but these regimens demonstrated less potency than the combination therapies.