Results of Long-term Use of Sildenafil in Inoperable Chronic Thromboembolic Pulmonary Hypertension

SubjectsSubjects

Of 21 subjects recruited, 19 subjects fulfilled inclusion criteria and were randomly assigned to receive either sildenafil at 40 mg tid (9 subjects) or placebo at two tablets tid (10 subjects). Baseline characteristics are shown in Table 1. Despite randomization, there were significant differences between the two groups with respect to baseline WHO functional status, CAMPHOR scores, and proportion of post-PEA subjects.

An extensive urticarial rash developed in one subject in the sildenafil arm, who was thus withdrawn from the study. No other code break took place before the 12-week assessment.

Acute Vasoreactivity Testing

The results of acute vasoreactivity testing with inhaled NO and IV sildenafil have been previously described elsewhere.

Outcome Measures: 12 Weeks

The changes from baseline in 6MWD (Fig 2) and Borg dyspnoea scale did not differ significantly between the sildenafil and placebo groups. Significant improvements were demonstrated however in WHO functional status and PVR (Table 2). The improvement in PVR remained significant even after results were adjusted for baseline differences. The difference in mPAP was not significant by intention-to-treat analysis (— 6.2 mm Hg; p = 0.052; 95% confidence interval [CI], — 12.4 to 0.1) but was significant when per-protocol analysis was applied (— 6.9 mm Hg; p = 0.04; 95% CI, — 13.4 to — 0.4). Furthermore, the change in mPAP within the sildenafil group was also significant when compared with baseline (— 6.5 mm Hg; p = 0.026; 95% CI, — 12.0 to — 1.1). Similarly, there was a significant improvement in the activity component of the CAMPHOR score within subjects receiving sildenafil (— 2.9; p = 0.008; 95% CI, — 4.7 to — 1.0).

Outcome Measures: 12 Months

As discussed, one subject was withdrawn due to a drug reaction, while another died at 16 weeks. As such, 17 subjects underwent reassessment at 12 months, of which 1 patient was started on combination therapy with bosentan at 9 months because of clinical deterioration. There were significant improvements at 12 months in 6MWD, symptom score, activity score, cardiac index, PVR, and NT-proBNP (Table 3). A moderate correlation was seen between the change in PVR after 12 months of sildenafil therapy and the change in PVR during vasoreactivity testing with inhaled NO (r = 0.493; p = 0.044), sildenafil infusion at 100 ng/L (r = 0.498; p = 0.042), and sildenafil infusion at 300 ng/L (r = 0.5; p = 0.041) [Fig 3].

Safety

An extensive urticarial rash developed in one subject after five doses of sildenafil. This resolved rapidly after medication was ceased, with no longterm sequelae. There were no other serious adverse events during the placebo-controlled phase of the study. The other most commonly reported symptoms were dyspepsia (sildenafil, 3 of 9 subjects; vs placebo, 1 of 10 subjects) and headache (sildenafil, 2 of 9 subjects; vs placebo, 1 of 10 subjects).

There was one death during the extension phase. This was attributed to right-heart failure secondary to decompensation of the underlying pulmonary hypertension. The subject had been allocated to sildenafil therapy during the initial phase of the trial and had shown improvements in both 6MWD and PVR at the end of 3 months. At the time of death, the subject had been receiving sildenafil for a total of 4 months, and the investigators were satisfied that this was not a contributory factor.

Table 1—Baseline Demographics

Variables Sildenafil(n = 9) Placebo (n = 10) pValue
Age, yr 49.9(13.1) 60.0 (14.4) 0.131
Female gender 78 30 0.405
Body mass index, kg/m2 27.7 (5.0) 29.8 (6.1) 0.454
PEA 22 70 0.037
WHO functional class, No. 0.04
II 3 8
III 6 2
6MWD, m 331.4 (50.3) 347.1 (66.2) 0.573
Borg dyspnea index 4.3 (3.0) 3.9 (2.6) 0.744
FEV1, % predicted 81.7(17.4) 78.0 (19.7) 0.674
FVC, % predicted 87.8(11.7) 95.8 (23.8) 0.360
Tlco, % predicted 66.0(11.1) 69.7(11.7) 0.505
CAMPHOR, symptoms 12.8 (4.6) 6.7 (4.9) 0.013
CAMPHOR, activity 13.4 (6.7) 8.0 (4.0) 0.044
CAMPHOR, QOL ‘ 11.1 (5.9) 4.3 (4.0) 0.009
NT-proBNP, pg/mL 1,301 (1,393) 788 (842) 0.338
Heart rate, beats/min 86 (16) 80 (10) 0.375
Mean systemic arterial pressure, mm Hg 103 (17) 97 (16) 0.454
Right atrial pressure, mm Hg 7.4 (3.4) 6.9 (4.3) 0.766
mPAP, mm Hg 45.8 (8.0) 42.7(10.1) 0.474
Cardiac index, L/min/m2 2.2 (0.6) 2.2 (0.4) 0.959
PAOP, mm Hg 9.8 (4.2) 10.6 (2.6) 0.610
PVR, dyne/s/cm 814(385) 654 (342) 0.350

Table 2—Outcome Measures at 12 Weeks

Variables Change From Baseline Difference Between Treatments
ISildenafil
(n = 9)
IPlacebo (n = 10) IDifference (95% CI) p Value
Change in WHO class 0.025
Improved more than one class 44 0
Deteriorated less than one class 0 20
6MWD, m 17.9 (33.9) 0.4 (49.1) 17.5 (- 23.9 to 58.8) 0.385
Borg dyspnea index – 0.7 (1.4) 0.2 (1.7) – 0.9 (- 2.4 to 0.6) 0.219
CAMPHOR, symptoms – 2.2 (4.6) – 0.1 (3.3) – 2.1 (- 5.9 to 1.7) 0.258
CAMPHOR, activity – 2.6 (2.3)t – 1.4 (3.4) – 1.2 (- 4.0 to 1.7) 0.407
CAMPHOR, QOL – 1.8 (6.7) – 0.2 (3.8) – 1.6 (- 6.8 to 1.7) 0.529
NT-proBNP, pg/mL – 355 (648) – 77 (130) – 278 (- 779 to – 223) 0.240
Right atrial pressure, mm Hg – 0.1 (5.1) – 0.8 (5.5) – 0.9 (- 6.1 to 4.2) 0.713
mPAP, mm Hg IDCO
CC
ID
0.4 (6.4) – 6.2 (- 12.4 to 0.1) 0.052
Cardiac index, L/min/m2 – 0.1 (0.5) – 0.1 (0.4) 0.0 (- 0.4 to 0.4) 0.994
PAOP, mm Hg 0.1 (3.4) – 0.4 (3.2) 0.5 (- 2.7 to 3.7) 0.742
PVR, dyne/s/cm – 179 (245) 18 (76) – 197 (- 389 to – 6) 0.044

Table 3—Outcome Measures at Baseline and at 12 Months (n = 17)

Variables Baseline 12 mo Difference (95% CI) p Value
WHO functional class, No.
II 9 14 0.13
III 8 3
6MWD, m 337 (60) 373 (94) 36 (8 to 64) 0.014
Borg dyspnea index 4.1 (2.7) 3.6 (2.2) – 0.5 (- 2.0 to 0.9) 0.449
CAMPHOR, symptoms 9.0 (5.4) 6.4 (5.7) – 2.6 (- 4.7 to – 0.5) 0.019
CAMPHOR, activity 10.6 (6.3) 7.3 (4.6) – 3.3 (- 6.0 to – 0.6) 0.02
CAMPHOR, QOL 6.7 (5.4) 5.5 (6.0) – 1.2 (- 3.4 to 1.0) 0.268
NT-proBNP, pg/mL 1,000 (1,168) 811 (1,095) – 189 (- 307 to – 72) 0.004
Right atrial pressure, mm Hg 7.3 (3.9) 8.9 (3.3) 1.6 (- 0.2 to 3.5) 0.078
mPAP, mm Hg 44.2 (9.6) 42 (10.2) – 2.2 (- 5.8 to 1.4) 0.224
Cardiac index, L/min/m2 2.2 (0.5) 2.4 (0.5) 0.2 (0.02 to 0.4) 0.03
PAOP, mm Hg 10.6 (3.4) 11.7 (3.8) 1.1 (- 0.4 to 2.6) 0.141
PVR, dyne/s/cm 722 (383) 573 (330) – 149 (- 228 to – 71) 0.001

Figure 2. Change in 6MWD from baseline to week 12. Bars denote SE.

Figure 2. Change in 6MWD from baseline to week 12. Bars denote SE.

Figure 3. Correlation for percentage change in PVR following acute vasoreactivity testing with IV sildenafil and following 12 months of sildenafil therapy.

Figure 3. Correlation for percentage change in PVR following acute vasoreactivity testing with IV sildenafil and following 12 months of sildenafil therapy.

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