Inorganic Nitrates in Intermediate High-risk Pulmonary Embolism

Pulmonary embolism (PE) is a common and potentially life-threatening cardiovascular condition caused by obstruction of the pulmonary arteries by thromboembolic material. Acute PE may result in a sudden increase in pulmonary vascular resistance, leading to elevated pulmonary artery pressure, right ventricular (RV) dilatation, impaired RV function, and reduced cardiac output. Right ventricular failure is a major cause of morbidity and mortality in patients with acute PE.

Patients with intermediate high-risk pulmonary embolism are characterized by hemodynamic stability combined with evidence of RV dysfunction and myocardial injury, typically demonstrated by right ventricular dilatation on imaging and elevated cardiac biomarkers such as troponin. Although these patients are initially hemodynamically stable, they are at risk of clinical deterioration despite standard anticoagulation therapy.

The pathophysiology of hemodynamic compromise in acute PE is multifactorial and involves both mechanical obstruction of pulmonary blood flow and pulmonary vasoconstriction mediated by hypoxia, endothelial dysfunction, and release of vasoactive substances. This leads to increased pulmonary vascular resistance and elevated pulmonary artery pressures, resulting in increased RV afterload and impaired RV performance.

The present study aims to provide a detailed invasive hemodynamic characterization of patients with intermediate high-risk PE. Through right heart catheterization, the study will describe invasive hemodynamics and enable assessment of right ventricular afterload and right ventricular contractile performance using invasive pressure and flow-derived parameters. These measurements will improve understanding of the interaction between pulmonary vascular resistance, RV afterload, and RV function in the acute phase of PE.

Inorganic nitrates are dietary compounds that are converted in vivo to nitrite and nitric oxide, leading to nitric oxide-mediated vasodilation. Inorganic nitrate supplementation has been shown to lower systemic blood pressure and improve pulmonary hemodynamics in other cardiovascular conditions, and is generally considered safe. However, the physiological effects and safety of inorganic nitrate treatment in patients with intermediate high-risk pulmonary embolism have not previously been evaluated in a randomized controlled trial.

STUDY-OVERVIEW This study is a multicenter, double-blind, randomized, placebo-controlled trial conducted at Södersjukhuset and Karolinska Universitetssjukhuset Huddinge in Sweden. Adult patients (≥18 years) with confirmed acute pulmonary embolism diagnosed by computed tomography, symptom duration less than 14 days, evidence of right ventricular dilatation on CT or echocardiography, and elevated troponin T levels will be eligible for inclusion.

After admission to the coronary care unit, intensive care unit, or high dependency unit, eligible patients will receive standard-of-care treatment, including anticoagulation. After written informed consent is obtained, all patients will undergo right heart catheterization to obtain invasive hemodynamic measurements at baseline. These measurements include right atrial pressure, right ventricular pressure, pulmonary artery pressures (systolic, diastolic, and mean), pulmonary artery wedge pressure, cardiac output, cardiac index, pulmonary vascular resistance, systemic vascular resistance, and mixed venous oxygen saturation. These data will be used to describe invasive hemodynamics as well as right ventricular afterload and indices of right ventricular contractility.

Following completion of baseline invasive hemodynamic measurements, patients will be randomized in a 1:1 ratio to receive either oral inorganic nitrate or placebo. Randomization will be performed using predefined block randomization scheme to ensure balanced allocation between the two study groups. The randomization sequence will be concealed, and no member of the study team involved in patient inclusion, treatment, or outcome assessment will have knowledge of the randomization order. The study treatment will be double-blinded, with patients, treating clinicians, investigators, and outcome assessors unaware of treatment allocation.

Patients randomized to the intervention group will receive a single oral dose consisting of 14 cl of nitrate-rich beetroot juice, corresponding to a total inorganic nitrate dose of 12 mmol, administered immediately after randomization. Patients randomized to the control group will receive a visually and taste-matched placebo beetroot juice in the same volume. The study treatment will thereafter be continued once daily for a total of five days. The dosage and duration of treatment correspond to the previously published NITRATE-CIN protocol.

The primary outcome of the study is mean pulmonary artery pressure measured three hours after administration of the study treatment. A second set of other invasive hemodynamic measurements will be performed at this time point to assess the acute physiological effect of inorganic nitrate compared with placebo. Additional invasive hemodynamic measurements will be obtained at 24 hours after treatment initiation.

Secondary outcomes include detailed invasive hemodynamic parameters, biomarkers of myocardial injury, nitrate concentrations in blood and saliva, echocardiographic measurements of right ventricular size and function, respiratory and circulatory support requirements, and clinical outcomes. Safety outcomes include systemic hypotension, use of vasopressors, bleeding events, arrhythmias, complications related to right heart catheterization, allergic reactions to the study treatment, and death.

The results of this study will provide detailed invasive hemodynamic data describing pressures, flows, right ventricular afterload, and right ventricular function in patients with intermediate high-risk pulmonary embolism, and will clarify whether treatment with oral inorganic nitrate is safe, feasible, and associated with favorable physiological effects in this patient population.