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OPSUMIT - Pulmonary Hypertension After Left Ventricular Assist Device Implantation
Last Updated: 01/16/2025
SUMMARY
- SOPRANO was a prospective, multicenter, double-blind, randomized, placebo-controlled, parallel group, phase 2 study that assessed the efficacy and safety of OPSUMIT versus placebo in patients with pulmonary hypertension (PH)
after left ventricular assist device (LVAD) implantation.1 - The primary endpoint was change in pulmonary vascular resistance (PVR) at week 12 of therapy from baseline measured by thermodilution method.1
- The mean change in ratio of week 12 to baseline PVR was 0.59 in the OPSUMIT group and 0.76 in the placebo group. The placebo-adjusted geometric mean ratio (GMR) of OPSUMIT vs. placebo was 0.74 (95% CI, 0.58-0.94; P=0.0158), corresponding to a 26% reduction in PVR with OPSUMIT.1
- Secondary endpoints included change from baseline to week 12 in mean pulmonary arterial pressure (mPAP), mean right atrial pressure (mRAP), pulmonary arterial wedge pressure (PAWP), cardiac index, total pulmonary resistance (TPR), mixed venous oxygen saturation (SvO2), N-terminal pro b-type natriuretic peptide (NT-proBNP) and World Health Organization (WHO) functional class (FC).1
- There were no statistically significant differences in any predefined secondary endpoint between OPSUMIT and placebo.1
- The most frequent treatment emergent adverse events (TEAEs) in the OPSUMIT group were dizziness (14.3%), anticoagulation drug level below therapeutic (14.3%), NT-proBNP increased (14.3%), dyspnea (14.3%), fatigue (14.3%) and peripheral edema (14.3%).1
- Additional information for review is provided in the REFERENCES.2
CLINICAL DATA
Phase 2 Clinical Trial: SOPRANO
The SOPRANO study was a prospective, multicenter, double-blind, randomized, placebocontrolled, parallel group, phase 2 study that assessed the efficacy and safety of OPSUMIT versus placebo in patients with PH after LVAD implantation. Patients were ≥18 years with LVAD implanted within 90 days prior to randomization, had mPAP ≥25 mmHg at rest, PAWP ≤18 mmHg and PVR >3 Wood units (WU) (Figure: Study Design).1
Note:LVAD implant must have occurred within 90 days (inclusive) prior to the date of randomization, and randomization must have occurred within 14 days after qualifying RHC. Patients with documented advanced lung disease (severe obstructive lung disease, moderate-to-severe restrictive lung disease, or pulmonary venoocclusive disease) and background PAH therapies were excluded.
a
Abbreviations: CI, cardiac index; FC, functional class; LVAD, left ventricular assist device; mPAP, mean pulmonary arterial pressure; mRAP, mean right arterial pressure; NTproBNP, N-terminal pro B-type natriuretic peptide; PAH, pulmonary arterial pressure; PAWP, mean pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; SvO2, mixed venous oxygen saturation; RHC, right heart catheterization; TPR, total pulmonary resistance; WHO, World Health Organization.
The primary endpoint was change in PVR at week 12 of therapy from baseline measured by thermodilution method. Secondary endpoints included change from baseline to week 12 in mPAP, mRAP, PAWP, cardiac index, TPR, SvO2, NT-proBNP and WHO FC.1
Results
In SOPRANO, 57 of the planned 78 patients were randomized 1:1 to receive either OPSUMIT (n=28) or placebo (n=29) for 12 weeks. The study was stopped early due to slow enrollment. Baseline patient demographics and characteristics were well-balanced. (Table: Demographics and Baseline Characteristics).1
| OPSUMIT (n=28) | Placebo (n=29) | Total (N=57) | |
|---|---|---|---|
| Age, years (median [IQR]) | 57 (53-62) | 60 (55-63) | 58 (54-63) |
| Sex, female, n (%) | 6 (21.4) | 6 (20.7) | 12 (21.1) |
| Race, n (%) | |||
| White | 16 (57.1) | 18 (62.1) | 34 (59.6) |
| Black or African American | 8 (28.6) | 11 (37.9) | 19 (33.3) |
| Asian | 2 (7.1) | 0 | 2 (3.5) |
| Othera | 2 (7.1) | 0 | 2 (3.5) |
| Select laboratory values (median [IQR]) | |||
| NT-proBNP, pmol/L | 1943 (1257-3377)b | 2148 (1129-3041) | 2045.5 (1139.5-3098)b |
| Hemoglobin, g/dL | 9.7 (8.7-11) | 9.5 (8.8-11)c | 9.6 (8.7-11)c |
| WHO FC, n (%) | |||
| Class I | 2 (7.1) | 2 (6.9) | 4 (7) |
| Class II | 7 (25) | 10 (34.5) | 17 (29.8) |
| Class III | 17 (60.7) | 16 (55.2) | 33 (57.9) |
| Class IV | 1 (3.6) | 1 (3.4) | 2 (3.5) |
| Hemodynamics (median [IQR]) | |||
| mPAP, mmHg (end-expiratory mean line) | 30.5 (27.5-33.5) | 29 (27-33) | 30 (27-33) |
| PAWP, mmHg (end-expiratory mean line) | 12.5 (8-15.5) | 13 (10-14) | 13 (9-14) |
| PVR, WU (thermodilution)d | 4.1 (3.6-5) | 4.2 (3.4-4.8) | 4.2 (3.4-5) |
| CO, L/min (thermodilution)d | 4.5 (3.7-5.2) | 4.5 (3.8-4.9) | 4.5 (3.7-5) |
| mRAP, mmHg | 11 (7-15.5) | 11 (8-14) | 11 (7-15) |
| SvO2, % | 56.5 (47.5-62.6) | 54 (50-62) | 55 (49-62.1) |
| Note: Data presented for the full analysis set.aIncludes Latin American (n=1) and unknown (n=1). bOPSUMIT, n=27; total, n=56. cPlacebo, n=28; total, n=56. dOPSUMIT, n=27; placebo, n=28; total, n=55.Abbreviations: CO, cardiac output; FC, functional class; IQR, interquartile range; mPAP, mean pulmonary arterial pressure; mPAWP, mean pulmonary arterial wedge pressure; mRAP, mean right atrial pressure; PVR; | |||
Primary Endpoint
The mean change in ratio of week 12 to baseline PVR was 0.59 in the OPSUMIT group and 0.76 in the placebo group. The placebo-adjusted geometric mean ratio (GMR) of OPSUMIT vs. placebo was 0.74 (95% CI, 0.58-0.94 ; P=0.0158), corresponding to a 26% reduction in PVR with OPSUMIT.1
Secondary Endpoints
There were no statistically significant differences in any predefined secondary endpoint between OPSUMIT and placebo.1
Safety
The rate of patients experiencing at least 1 TEAE was 92.9% in the OPSUMIT group and 86.2% in the placebo group. The most frequent TEAEs in the OPSUMIT group were dizziness (14.3%), anticoagulation drug level below therapeutic (14.3%), NT-proBNP increased (14.3%), dyspnea (14.3%), fatigue (14.3%) and peripheral edema (14.3%). Three deaths occurred during the study due to TEAEs: 1 death in the OPSUMIT group due to cerebral hemorrhage and 2 deaths in the placebo group, 1 due to hemolysis and hemorrhagic stroke and 1 due to device-related complications.1
Post Hoc Analysis: Proportion of Patients Achieving a PVR <3 WU
A post hoc analysis of patients achieving a PVR <3 WU included 24 patients in the OPSUMIT group and 25 in the placebo group. More patients achieved a PVR <3 WU with OPSUMIT versus placebo (66.7% vs 40%; P=0.0383). Among patients with baseline PVR ≤4 WU, 90% (9/10) in the OPSUMIT group and 63.6% (7/11) in the placebo group had a post-baseline PVR <3 WU at week 12. Among patients with baseline PVR >4 WU, 50% (7/14) in the OPSUMIT group and 21.4% (3/14) in the placebo group had post-baseline PVR <3 WU at week 12.1
Literature Search
A literature search of MEDLINE®
References
| 1 | Frantz RP, Desai SS, Ewald G, et al. SOPRANO: Macitentan in patients with pulmonary hypertension following left ventricular assist device implantation. Pulm Circ. 2024;14(4):e12446. |
| 2 |