Is there any literature to support use of IV sildenafil in adults for pulmonary hypertension?

Comment by InpharmD Researcher

Data evaluating the use of IV sildenafil in adults with pulmonary hypertension is sparse. One trial in adult patients with chronic thromboembolic pulmonary hypertension (CTEPH) found IV sildenafil to significantly reduce mean pulmonary artery pressure and pulmonary vascular resistance, with greater hemodynamic changes compared to inhaled nitric oxide (see Table 1). Another study that evaluated IV sildenafil in both pediatric and adult patients similarly found significantly greater improvements in hemodynamic outcomes compared to inhaled nitric oxide. Finally, a phase 1 pharmacokinetic study in adults with pulmonary arterial hypertension found IV sildenafil to demonstrate comparable drug exposure levels to oral sildenafil, with only mild, self-limiting adverse events.

Background

A 2022 prospective, cross-sectional analytical investigation evaluated the comparative hemodynamic effects of intravenous sildenafil (ivS) and inhaled nitric oxide (iNO) during acute vasodilator testing (AVT) in treatment-naïve patients with pulmonary arterial hypertension (PAH). Conducted at a tertiary care center in South India between November 2015 and December 2020, the study enrolled 44 patients (mean age 20.5 ± 14.4 years; 61% female), including both pediatric and adult populations. Participants included those with idiopathic PAH, familial PAH, portopulmonary hypertension, residual PAH post-shunt closure, and patients undergoing operability assessment for congenital heart disease (CHD). Hemodynamic measurements were acquired at baseline, after administration of iNO (20 ppm), and again following a 15-minute iNO washout and a 10-minute slow infusion of ivS (0.25 mg/kg in pediatric patients, 10 mg in adults), with parameters assessed 20 minutes post-infusion. The investigators reported a strong intraclass correlation coefficient (ICC) between hemodynamic responses elicited by iNO and ivS across all major variables, including mean pulmonary artery pressure (mPAP, ICC = 0.903), pulmonary vascular resistance index (PVRI, ICC = 0.920), and systemic vascular resistance index (SVRI, ICC = 0.828), all with p-values <0.001. ivS demonstrated a significantly greater reduction in mPAP (−15.4% vs. −10.2%, p <0.001) and systolic pulmonary artery pressure (−15.3% vs. −9.9%, p = 0.002) compared to iNO. Both agents identified the same two acute responders, each with idiopathic PAH, satisfying Sitbon criteria. Among CHD patients, neither agent identified operability responders, although ivS resulted in a more pronounced decline in pressure metrics. Across the entire cohort, ivS exhibited hemodynamic changes comparable to iNO and was well tolerated, with no adverse events reported. These findings support the feasibility of ivS as a practical alternative to iNO for AVT, particularly in resource-limited settings where iNO access and infrastructure may be constrained. [1]

A 2011 single-center, open-label, Phase 1 trial evaluated the safety, tolerability, and pharmacokinetics of a 10 mg intravenous bolus dose of sildenafil in a cohort of ten patients with PAH who were stabilized on chronic oral sildenafil therapy. Eligible patients were adults (18 years old) with PAH who, while taking 20 mg oral sildenafil three times daily for 1 month, with or without additional PAH therapies, were haemodynamically stable. Participants, who were primarily in World Health Organization (WHO) Functional Class II–III, received a single intravenous 10 mg sildenafil dose in lieu of their usual morning oral dose while remaining recumbent in a monitored clinical setting for at least six hours. Blood pressure and heart rate were measured at predefined intervals, and plasma samples were collected up to six hours postdose for quantification of sildenafil and its active metabolite, desmethylsildenafil, using validated liquid chromatography–tandem mass spectrometry (LC-MS/MS). Plasma sildenafil concentrations demonstrated an initial rapid rise followed by stabilization within the pharmacokinetic range previously reported for patients receiving 20 mg oral sildenafil three times daily. At 30 minutes postdose, the mean change from baseline in sitting systolic and diastolic blood pressure was –8.4 ± 11.7 mmHg and –2.6 ± 7.3 mmHg, respectively, and heart rate decreased by –3.5 ± 10.4 beats per minute, with no reports of symptomatic hypotension or syncope. Pharmacokinetic analysis revealed a geometric mean Cmax of 213.3 ng/mL and AUC0–8 of 329.7 ng·h/mL for sildenafil, with a higher-than-anticipated desmethylsildenafil-to-sildenafil exposure ratio, attributed to baseline metabolite carryover. Only mild, self-limited adverse events (e.g., flushing and flatulence) were possibly treatment-related. Importantly, the intravenous formulation provided drug exposure levels comparable to oral dosing, supporting its utility as an alternative when oral administration is not feasible in PAH patients. [2]

References:

[1] Kumar S, Memon D, Raj M, et al. Comparison of intravenous sildenafil with inhaled nitric oxide for acute vasodilator testing in pulmonary arterial hypertension. Pulm Circ. 2022;12(4):e12180. Published 2022 Oct 1. doi:10.1002/pul2.12180
[2] Vachiery JL, Huez S, Gillies H, et al. Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension. Br J Clin Pharmacol. 2011;71(2):289-292. doi:10.1111/j.1365-2125.2010.03831.x
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Is there any literature to support use of IV sildenafil in adults for pulmonary hypertension?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH)
Design

Prospective study

N= 18
Objective To examine the acute haemodynamic responses to inhaled nitric oxide (iNO) and intravenous sildenafil in patients with distal chronic thromboembolic pulmonary hypertension (CTEPH)
Study Groups

De novo distal CTEPH (n= 9)

Residual CTEPH post-PEA (n= 9)
Inclusion Criteria

Patients with de novo distal CTEPH or persistent pulmonary hypertension post-pulmonary endarterectomy (PEA)
Exclusion Criteria Received any pulmonary hypertension-specific therapy or nitrate therapy in the 6 months prior to enrolment
Methods

Right heart catheterisation was performed to obtain baseline haemodynamic measurements. iNO was administered at 20 ppm for 10 min, followed by a washout period. Sildenafil was administered intravenously at two doses to achieve plasma levels equivalent to 25 mg and 50 mg orally. Haemodynamic measurements were taken after each intervention.
Duration Not specified
Outcome Measures

Reduction in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), correlation of individual mPAP and cardiac output (CO) responses to iNO and sildenafil
Baseline Characteristics Characteristic All patients (n= 18) De novo distal CTEPH (n= 9) Residual CTEPH post-PEA (n= 9) p-value
Age 55.1 (14.8) 55.5 (11.7) 54.7 (18.1) 0.92
Female, n 12 7 5 0.32
NYHA II:III 10:8 4:5 6:3 0.34
6MWT 337 (58) 335 (41) 338 (75) 0.92
FEV1 (% pred) 80.4 (18.5) 86.3 (17.8) 74.6 (18.3) 0.18
FVC (% pred) 91.8 (19.5) 90.9 (17.2) 92.3 (22.6) 0.85
TLCO (% pred) 67.4 (11.2) 71.4 (5.5) 63.9 (14.0) 0.18
RA (mm Hg) 7.4 (3.8) 8.4 (3.7) 6.3 (3.8) 0.249
mPAP (mm Hg) 44.2 (9.3) 50.2 (7.0) 38.1 (7.2) 0.002
CI (L/min/m2) 2.2 (0.5) 2.02 (0.5) 2.48 (0.4) 0.06
PAOP (mm Hg) 10.3 (3.4) 10.6 (3.1) 10.1 (4.0) 0.793
PVR (dyn/s/cm5) 725.8 (372.1) 946.4 (330.8) 505.2 (274.6) 0.007
SVR (dyn/s/cm5) 1824.9 (590.0) 2154.4 (622.6) 1495.5 (328.6) 0.013
MvO2 (%) 64.9 (6.7) 62.6 (7.5) 67.9 (4.5) 0.118

Data are presented as mean (standard deviation) except for gender and NYHA class.

NYHA = New York Heart Association; 6MWT= six minute walk test; FEV1= forced expiratory volume; FVC = forced vital capacity; TLCO = diffusing capacity for carbon monoxide; RA = right atrial pressure; mPAP =mean pulmonary arterial pressure; CI = cardiac index; PAOP= pulmonary arterial occlusion pressure; PVR = pulmonary vascular resistance; SVR = systemic vascular resistance; MvO2=mixed venous saturations.
Results Endpoint Baseline 1 iNO iv sildenafil 100 ng/l iv sildenafil 300 ng/l p-value
HR (beats/min) 85.2 (11.7) 81.1 (12.1) 77.8 (10.1) 77.8 (10.2) <0.01
mean SAP (mm Hg) 99.8 (16.5) 97.1 (15.0) 93.2 (15.3) 92.9 (15.2) 0.01
mPAP (mm Hg) 44.2 (9.3) 39.9 (10.4) 36.8 (9.2) 35.7 (8.1) <0.001
CI (L/min/m2) 2.24 (0.52) 2.25 (0.50) 2.36 (0.51) 2.37 (0.56) 0.18
PVR (dyn/s/cm5) 725.8 (372.1) 624.8 (338.2) 537.0 (273.4) 518.6 (272.9) <0.001
SVR (dyn/s/cm5) 1824.9 (590.0) 1780.3 (557.7) 1605.5 (438.6) 1603.8 (412.4) <0.01

Results are presented as mean (standard deviation).

HR = heart rate; SAP = systemic arterial pressure; AoO2
Adverse Events No adverse events were associated with the reductions in systemic arterial pressure (SAP) following sildenafil administration. Changes in SAP normalized within 1 hour of cessation of the study
Study Author Conclusions

Despite CTEPH being characterized by fixed thrombotic lesions, patients with distal disease display significant acute haemodynamic responses to vasoactive agents. Both iNO and iv sildenafil caused pulmonary vasodilatation, implying that elevated vascular tone forms a significant, and yet potentially reversible, component to this disease. Further long term trials of sildenafil in distal CTEPH are warranted.
Critique

The study's non-randomized and unblinded design, along with a small sample size, limits the generalizability of the findings. The lack of a sildenafil-only arm raises the possibility that iNO may have exaggerated the effects of sildenafil administration. Further studies with larger sample sizes and randomized controlled designs are needed to confirm these findings.

 

References:

Suntharalingam J, Hughes RJ, Goldsmith K, et al. Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH). Vascul Pharmacol. 2007;46(6):449-455. doi:10.1016/j.vph.2007.01.008