Sildenafil for the Prevention of Right Heart Failure Following LVAD Implantation

Study Description

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Brief Summary:

Continuous-flow left ventricular assist devices (LVAD) move blood from the left ventricle (the largest chamber of the heart) to the aorta (the body's main artery) to help the heart better meet the needs of the body and to improve survival for patients with advanced heart failure (HF). The ability of the right ventricle (the large chamber on the right side of the heart) to keep up with the improved blood flow following LVAD greatly effects how well a person does following surgery. It is understood that a high pulmonary artery pressure (pressure in the blood vessel that takes blood from the right side of the heart to the lungs) measured before surgery, indicates that a higher risk of right heart failure exists after LVAD implantation.

This is important because right heart failure after surgery is related to longer intensive care unit (ICU) and hospital stays, increased morbidity (other health problems) including organ failure and worse outcomes following heart transplant, and increased death rates.

Sildenafil (Revatio®) has been approved by Health Canada in the treatment of pulmonary arterial hypertension (high blood pressure in the lungs) in patients with connective tissue disease. Sildenafil has not yet been approved by Health Canada for the treatment of pulmonary hypertension in heart failure. Sildenafil lowers blood pressure in the lungs and lessens the workload of the right ventricle (the right side of the heart). The purpose of this study is to determine if lowering blood pressure in the lungs, in heart failure patients at risk for developing right heart failure after LVAD implant, lowers the incidence of right heart failure, shortens ICU and hospital stays and reduces morbidity (other health problems) and mortality (death rates).

This is an open label, single arm study. Everyone who participates in this study will receive sildenafil before and after LVAD surgery. It is expected that 24 patients who are scheduled to have LVAD implantation for advanced heart failure will be enrolled from 6 sites across Canada. Participants will be followed in the study for about 2 months.

Condition or disease	Intervention/treatment	Phase
End Stage Heart Failure	Drug: Sildenafil Citrate	Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	24 participants
Intervention Model:	Single Group Assignment
Intervention Model Description:	This is an open label single arm trial.
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	Sildenafil for the Prevention of Right Heart Failure Following Continuous-Flow Left Ventricular Assist Device Implantation (The REVAD Study)
Actual Study Start Date :	March 12, 2018
Estimated Primary Completion Date :	June 2019
Estimated Study Completion Date :	September 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: sildenafil citrate; Following enrolment, participants will be given an initial dose of sildenafil 20 mg. If tolerated, a schedule of 20 mg three times daily (tid) will be initiated. Dosage will be titrated over 3-4 days to the target dose of 40 mg tid. If the initial dose is not tolerated, the participant will be exited from the trial.	Drug: Sildenafil Citrate; 20 mg tablets; Other Name: Revatio

Outcome Measures

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Primary Outcome Measures :

1. Pulmonary vascular resistance (PVR) [ Time Frame: From baseline to postoperative day 14 ]
   Change in PVR reported in Wood Units as measured invasively via right heart catheterization (RHC)

Secondary Outcome Measures :

1. Right heart failure (RHF) [ Time Frame: From baseline to day 55 (end of study) ]
   Proportion of participants experiencing RHF defined as INTERMACS criteria: i) Requirement of continuous-flow right ventricular assist device (RVAD) implantation for hemodynamic support any time prior to study end
2. RHF [ Time Frame: Postoperative day 14 to postoperative day 55 (end of study) ]
   Proportion of participants experiencing RHF defined as INTERMACS criteria: ii) Prolonged inotropic support beyond postoperative day 14 directed for clinical RHF
3. RHF [ Time Frame: From baseline to postoperative day 55 (end of study) ]
   Proportion of participants experiencing RHF defined as INTERMACS criteria: iii) Discontinuation of study drug for the purpose of introduction of additional pulmonary vasodilator for the purpose of treatment of clinical RHF at any time during the study protocol
4. Inotrope requirement [ Time Frame: From baseline to day 55 (study end) ]
   Proportion of patients requiring any inotrope medication at study end
5. ICU [ Time Frame: From baseline to day 55 (end of study) ]
   Total number of hours in ICU by study end
6. Hospitalization [ Time Frame: From baseline to day 55 (end of study) ]
   Total hospital length of stay by study end

Other Outcome Measures:

1. Safety: Drug interruptions [ Time Frame: From baseline to day 55 (study end) ]
   Proportion of patients with temporary or permanent study drug interruptions
2. Safety: Renal [ Time Frame: From baseline to day 55 (study end) ]
   Proportion of patients requiring renal replacement therapy or doubling of serum creatinine
3. Safety: All-cause mortality [ Time Frame: From enrollment to day 85 (final SAE review) ]
   All-cause mortality at study end
4. Safety: Transfusion [ Time Frame: From baseline to hospital discharge ]
   Total number of units of packed red cells transfused during hospital stay
5. Safety: GFR [ Time Frame: From baseline fo day 55 (study end) ]
   Greatest percentage increase in glomerular filtration rate from baseline at any time during study
6. Safety: Mean arterial pressure [ Time Frame: At ICU discharge and at day 55 (study end) ]
   Mean arterial pressure
7. Safety: Symptomatic hypotension [ Time Frame: From baseline to day 55 (study end) ]
   Proportion of patients with > or = 1 episodes of symptomatic hypotension (syncope or orthostatic hypotension)
8. Safety: Liver enzymes [ Time Frame: From baseline to day 55 (study end) ]
   Increase in hepatic enzymes > or = 2x baseline (preoperative) levels
9. Safety: Pump time [ Time Frame: LVAD implantation day ]
   Total cardiac surgical bypass pump time
10. Safety: Adverse drug reactions [ Time Frame: From baseline to day 85 (final SAE review) ]
    Any and all adverse drug reactions

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients aged >18 years who are to receive durable (HeartMate II or III, or HeartWare HVAD) LVAD implantation for end-stage HF. Patients with all etiologies of HF will be included.
• Patients identified as having an increased risk for post-operative RHF using pre-operative hemodynamic assessment criteria, defined as the presence of ≥ 1 of the following: i) Central venous pressure (CVP):mean pulmonary capillary wedge pressure (PCWP) ratio ≥ 0.63 ii) RV stroke work index < 300 mmHg/mL/m2 iii) CVP ≥15 mmHg (CVP must be >8 mmHg if applying one of the other criteria) iv) Pre-operative PVR ≥ 3 Wood Units (240 dynes/cm5/sec)
• Systolic blood pressure ≥ 85 mmHg at study initiation
• Women of childbearing potential must have a negative pregnancy test. Women must not be breast feeding. Heterosexually active women of child bearing potential must use an effective method of contraception during the study.
• Ability to sign informed consent to participate

Exclusion Criteria:

• Preoperative INTERMACS level I or II
• Preoperative systemic hypotension with mean arterial pressure < 60 mmHg
• Planned insertion of RV support device (either temporary or permanent)
• Complex congenital heart disease where PVR measurement is not feasible or reliable (repaired or unrepaired)
• Right sided fixed or dynamic obstruction to blood flow (i.e., pulmonary stenosis) with resting gradient ≥ 10 mmHg.
• Previous organ transplantation
• Preoperative use of any oral pulmonary vasodilator therapy or oral/inhaled/nitrate therapy
• Patients requiring pre-operative hem - or peritoneal dialysis
• Pre-enrollment treatment with other pulmonary dilating agents such as other PDE5 inhibitors, endothelin antagonists, prostacyclin analogues. Use of postoperative nitric oxide will be permitted (although not concomitantly with the study medication) as clinically indicated in the postoperative setting
• Lack of ability to invasively measure right-sided pulmonary pressures
• Refusal or inability to sign informed consent
• Inability to accept preoperative study drug, or known sensitivity or allergy to sildenafil or any of its ingredients, or any other contra-indication to sildenafil as identified by product monograph
• Participation in any other current interventional (drug or device) study

Contacts and Locations

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Contacts

Contact: Nowell Fine, MD	403-956-3748	nowell.fine@albertahealthservices.ca
Contact: Jonathan Howlett, MD	403-944-3232	howlettjonathan@gmail.com

Locations

Canada, Alberta
University of Calgary	Recruiting
Calgary, Alberta, Canada, T2N 4Z6
University of Calgary	Recruiting
Calgary, Alberta, Canada
Contact: Jonathan G Howlett, MD

Sponsors and Collaborators

University of Calgary

Pfizer

Investigators

Principal Investigator:	Jonathan Howlett, MD	University of Calgary

More Information

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Responsible Party:	University of Calgary
ClinicalTrials.gov Identifier:	NCT03356353 History of Changes
Other Study ID Numbers:	RVD102017
First Posted:	November 29, 2017
Last Update Posted:	October 4, 2018
Last Verified:	October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Additional relevant MeSH terms:

Heart Failure; Heart Diseases; Cardiovascular Diseases; Citric Acid; Sildenafil Citrate; Anticoagulants; Calcium Chelating Agents; Chelating Agents	Sequestering Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Enzyme Inhibitors; Urological Agents