Effect of Sildenafil on Clinical Outcomes in Patients with Corrected - - PowerPoint PPT Presentation

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Effect of Sildenafil on Clinical Outcomes in Patients with Corrected - - PowerPoint PPT Presentation

Aug 30, 2022 163 likes •417 views

Effect of Sildenafil on Clinical Outcomes in Patients with Corrected Valvular Heart Disease and Residual Pulmonary Hypertension. The S ildenafil for I mproving O utcomes after Va lvular C orrection (SIOVAC) Trial. Javier Bermejo, on behalf of the

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Effect of Sildenafil on Clinical Outcomes in Patients with Corrected Valvular Heart Disease and Residual Pulmonary Hypertension.

The Sildenafil for Improving Outcomes after Valvular Correction (SIOVAC) Trial.

Javier Bermejo, on behalf of the SIOVAC investigators

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Background

  • Left heart disease is the most common cause of PH

worldwide.

  • Valvular heart disease is a very frequent source of

this type of PH, affecting virtually all pts. with severe mitral disease and almost 65% of pts. with symptomatic AS.

Galie et al EHJ 2016 Trends in causes of left-heart PH

Weitsman et al Am J Med 2017

  • After successful correction of the valvular

lesion, regression of PH is frequently incomplete.

PH after mitral valve annuloplasty Kainuma et al JTCS 2011

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  • Once established, residual

PH is an untreatable risk factor of mortality and disability in the long-term

  • PDE5 inhibitors have shown

discordant results in LHD-PH

Kainuma et al Circulation 2011; Ghoreishi et al JCTS 2011 Cam et al JCTS 2011; Chen et al JAHA 2016

Murashita et al ATCS 2015

PH & outcome after MVR

Background

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  • To determine whether chronic treatment with

sildenafil improves clinical outcomes in patients with VHD & residual PH. Objective Design

  • Academically-funded, multicenter, double-blind, placebo-controlled, parallel-

group, randomized clinical trial. 18 tertiary public hospitals in Spain.

clinicaltrials.gov #: NCT00862043

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The SIOVAC Design

Inclusion Criteria:

  • Full successful correction of primary VHD
  • 1 month clinical stability

Exclusion Criteria:

  • Prosthesis or valvular dysfunction
  • SBP < 90 mmHg
  • Previous MI or stroke
  • Significant liver or renal insufficiency
  • Established contraindications to sildenafil
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  • Primary endpoint:

The SIOVAC Trial

Worsened: death, hospital admission for heart failure (HF), worsening functional class, or significant worsening in global self- assessment. Improved: improvement in functional class, or significant improvement in global self- assessment.

  • Key secondary endpoints:
  • time to a major clinical event (death or HF admission)
  • number of HF admissions
  • ther functional (BNP, 6MWT) and imaging (ultrasound, MR)

COMPOSITE CLINICAL SCORE

Unchanged

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231 enrolled 200 randomized 104 assigned to SILDENAFIL 104 treated with sildenafil (Safety Set) 101 with data to adjudicate outcome (Full Analysis Set) 80 without major protocol deviations (Per Protocol Set) 96 assigned to PLACEBO 96 treated with placebo (Safety Set) 95 with data to adjudicate outcome (Full Analysis Set) 82 without major protocol deviations (Per Protocol Set) 11 discontinued treatment 4 Adverse events 3 Withdrew consent 2 Lost for follow-up 2 Died 85 completed study 85 completed study* 19 discontinued treatment 6 Adverse events 2 Lack of efficacy 1 Protocol deviation 3 Withdrew consent 2 Lost for follow-up 2 Died 3 Other 31 PH not confirmed

The SIOVAC Trial

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SILDENAFIL (N= 104) PLACEBO (N= 96) TOTAL (N= 200) Age (years) 70 (65, 77) 73 (67, 77) 72 (66, 77) Women, n (%) 76 (73) 78 (81) 154 (77) Weight, Kg 66 (59, 78) 72 (62, 80) 69 (60, 79) Systolic blood pressure (mm Hg) 131 (119, 144) 140 (127, 154) 136 (121, 150) Cardiovascular Risk Factors, n (%) Hypertension 59 (57) 69 (72) 128 (64) Diabetes 31 (30) 27 (28) 58 (29) Median (IQR)

Baseline Characteristics The SIOVAC Trial

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Aortic: N= 91 (45%) Tricuspid: N= 78 (39%)

  • Combined Surgery: N= 122 (61%)

Medical History

Sketch by: OpenStax College - Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6/ Jun 19, 2013

Repair: n= 22 (11%) Replacement: n= 160 (80%)

Mitral: N= 182 (91%)

N= 40 | N= 38 N= 96 | N= 86

The SIOVAC Trial

N= 51 | N= 40

  • Reinterventions: N= 63 (31%)
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SILDENAFIL (N= 104) PLACEBO (N= 96) TOTAL (N= 200) WHO functional class, n (%) I or II 59 (59) 52 (54) 111 (56) III 42 (42) 43 (45) 85 (43) Concomitant Medications Diuretics, n (%) 89 (86) 84 (88) 169 (87) Aldosterone receptor antagonist, n (%) 46 (44) 38 (40) 84 (42) ACE inhibitors/ARB, n (%) 67 (64) 53 (55) 120 (60) Median (IQR)

Baseline Functional Status & Medications The SIOVAC Trial

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Key Catheterization Data

SILDENAFIL (N= 104) PLACEBO (N= 96) TOTAL (N= 200) Mean Pulmonary Artery Pressure (mm Hg) 40 (34, 46) 37 (34, 44) 38 (34, 44) Mean Wedge Pulmonary Pressure (mm Hg) 23 (19, 26) 22 (19, 26) 22 (19, 26) Cardiac Index (L · min-1 · m-2) 2.8 (2.4, 3.2) 2.8 (2.3, 3.4) 2.8 (2.4, 3.3) Transpulmonary Pressure Gradient (mm Hg) 16.0 (13.0, 22.0) 15.0 (12.0, 20.0) 16.0 (12.0, 21.2) Diastolic Transpulmonary Pressure Gradient (mm Hg) 2.0 (0.0, 6.0) 3.0 (0.0, 7.0) 3.0 (0.0, 6.2) Pulmonary Vascular Resistance (Wood Units) 3.4 (2.4, 4.6) 3.1 (2.2, 4.9) 3.3 (2.3, 4.9) Median (IQR)

The SIOVAC Trial

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MAIN RESULTS

The SIOVAC Trial

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Primary Endpoint

The SIOVAC Trial

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Key Secondary Endpoints

The SIOVAC Trial

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The SIOVAC Trial

Key Secondary Endpoints

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Imaging Secondary Endpoints

The SIOVAC Trial Ultrasound MR

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Interaction Analysis

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Conclusions ü Treatment with oral sildenafil 40 mg thrice a day in patients with residual PH after successful correction of VHD is associated to unfavorable clinical outcomes as compared to placebo. ü Off-label indication of sildenafil in patients with LHD-PH due to valvular disease should be discouraged.

The SIOVAC Trial

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  • H. Puerta de Hierro
  • H. Gregorio Marañón
  • H. Alcorcón
  • H. A Coruña
  • H. Germán Triás i Pujol
  • H. Virgen de las Nieves
  • H. Infanta Leonor
  • H. Reina Sofía
  • H. U. de Valladolid
  • H. U. de Salamanca
  • H. 12 de Octubre
  • H. U. de León
  • H. Virgen de la Victoria
  • H. Araba
  • H. Galdakao
  • H. Santa Creu i Sant Pau
  • H. San Cecilio
  • H. Vall d’Hebron

The SIOVAC Trial

Steering Committee:

  • Javier Bermejo
  • Raquel Yotti
  • Francisco Fernández-Avilés

Adjudication and DSMB:

  • José A. García-Robles
  • Joaquín Alonso
  • Manuel Gómez-Bueno
  • Funded by the Spanish

Government

  • Coordinated by the

Spanish network Center for Cardiovascular Research (CIBERCV)

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Ipc-PH Cpc-PH

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43 % FC III 6MWD 352 (270, 402) m BNP 59 (26, 132) ng/L RA area 23 (19, 28) cm2 No effusion RAP 12 (9, 17) mmHg CI 2.8 (2.4, 3.3) L/min/m2 SVO2 64 (59, 70) % 5 % 1-year mortality

The SIOVAC POPULATION