Sildenafil for the Prevention of Right Heart Failure Following Continuous-Flow Left Ventricular Assist Device Implantation (The REVAD Study)
试验速览
- 阶段
- 3 期
- 入组人数
- 24
- 试验地点
- 4
- 主要终点
- Pulmonary vascular resistance (PVR)
研究概览
简要总结
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.
详细描述
Initially implanted as a bridge to transplantation, LVADs are increasingly used for the purpose of destination therapy. About 250 patients/year will receive LVAD device therapy in 12 implanting Canadian centres. Outcomes after LVAD implantation are critically dependent on right ventricular (RV) function. Development of right heart failure (RHF) in LVAD patients has a direct effect on mortality and is associated with a prolonged length of intensive care unit (ICU) and hospital admission. RHF in LVAD patients leads to increased morbidity and is associated with worse outcomes after cardiac transplantation. Despite improvements in surgical and medical management the incidence of RHF after LVAD implantation has plateaued at approximately 20-30%. A critical concept in the prevention of post-operative complications involves appropriate patient selection and prophylactic measures directed toward risk factors for development of RHF. To mitigate the risk of RHF after LVAD implantation, many implanting centres are increasingly utilizing pulmonary vasodilating agents in the post-operative period. Despite little evidence to support this approach, the phosphodiesterase-5A (PDE5) inhibitor Sildenafil is now empirically administered for reduction of PVR in some centres after LVAD implantation. Duration of therapy varies but may extend beyond 3 months and in some cases may continue indefinitely or until the time of heart transplant. A small, single-centre, open label study demonstrated that Sildenafil effectively reduced PVR in LVAD patients with persistent pulmonary hypertension post-operatively, however only hemodynamic endpoints were examined. Importantly, the investigation of this strategy was limited to those with elevated PAP, irrespective of their clinical condition or pre-implantation hemodynamic profile. There is a clear need for further research to establish the safety and efficacy of pulmonary vasodilators to either treat or prevent RHF in the LVAD patient population.
The investigators hypothesize that the vasodilatory effects of sildenafil can prevent or reverse the effects of elevated RV afterload and consequent RHF following LVAD implantation, and that preoperative initiation of therapy in an at-risk population is feasible and will be well tolerated. As such, there is a large potential for sildenafil to meet an unmet therapeutic need for patients following LVAD implantation.
The primary objective of this pilot study is to evaluate the tolerability and efficacy of sildenafil therapy initiated prior to and continued after LVAD implantation for the purpose of reducing PVR in patients at increased risk for development of RHF by INTERMACS criteria. The feasibility of introducing sildenafil in this clinical setting along with the ability to reduce PVR will be assessed.
Secondary Objectives: a) To determine the efficacy of sildenafil to reduce the need for prolonged inotropic support and post-operative ICU admission duration b) To determine the tolerability and feasibility of the proposed dosing strategy c) To determine the impact of sildenafil therapy on renal function and systemic arterial blood pressure d) To assess the impact of sildenafil therapy on the likelihood of development of post-operative RHF by INTERMACS criteria
STUDY METHODS:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Sildenafil Citrate (Drug)
结局指标
主要结局
Pulmonary vascular resistance (PVR)
时间窗: From baseline to postoperative day 14
Change in PVR reported in Wood Units as measured invasively via right heart catheterization (RHC)
次要结局
- ICU(From baseline to day 55 (end of study))
- RHF(From baseline to postoperative day 55 (end of study))
- Inotrope requirement(From baseline to day 55 (study end))
- Hospitalization(From baseline to day 55 (end of study))
- Right heart failure (RHF)(From baseline to day 55 (end of study))