Inorganic Nitrates in Intermediate High-risk Pulmonary Embolism (NITRATE-PE)

Inorganic Nitrates in Pulmonary Embolism With Hemodynamic Instability

Pulmonary embolism (PE) is a serious condition caused by blood clots blocking the blood vessels in the lungs. In some patients, PE leads to increased pressure in the lung circulation and strain on the right side of the heart. Patients with intermediate high-risk PE have signs of right heart stress and heart muscle injury and are at risk of clinical deterioration despite standard treatment with anticoagulation.

In addition to the mechanical obstruction caused by blood clots, pulmonary embolism also causes narrowing of the lung blood vessels due to vasoconstriction. This increases pulmonary vascular resistance and contributes to elevated pressure in the pulmonary arteries, which can worsen right heart function. Treatments that reduce pulmonary artery pressure and vascular resistance could therefore potentially improve heart function and stabilize patients in the acute phase of PE. However, there is limited clinical evidence regarding the safety and effectiveness of pulmonary vasodilator therapy in this patient group.

Inorganic nitrates, found naturally in foods such as beetroot, are converted in the body to nitric oxide, a substance that relaxes blood vessels. Inorganic nitrates have been shown to lower blood pressure and improve pulmonary hemodynamics in other cardiovascular conditions, and are generally considered safe. Their effects in patients with intermediate high-risk pulmonary embolism have not previously been studied in a randomized controlled trial.

The aim of this study is twofold: first, to describe invasive hemodynamic measurements in patients with intermediate high-risk pulmonary embolism using right heart catheterization; and second, to investigate the safety, feasibility, and physiological effects of treatment with oral inorganic nitrate compared with placebo.

This is a multicenter, double-blind, randomized controlled trial conducted at two hospitals in Sweden. Adult patients with confirmed acute pulmonary embolism, right ventricular dilation, and elevated cardiac troponin levels will be included after providing informed consent. All patients will receive standard care, including anticoagulation therapy. In addition, all participants will undergo right heart catheterization to measure pressures and blood flow in the heart and lungs.

Participants will be randomly assigned to receive either nitrate-rich beetroot juice or a placebo beetroot juice for five days. Neither the patients nor the treating clinicians or investigators will know which treatment is given. The primary outcome is mean pulmonary artery pressure measured three hours after administration of the study treatment. Secondary outcomes include additional hemodynamic measurements, blood biomarkers, and safety outcomes such as low blood pressure or need for vasopressor treatment.

The results of this study will improve understanding of pulmonary hemodynamics in intermediate high-risk pulmonary embolism and help determine whether inorganic nitrate therapy is safe and has beneficial physiological effects in this patient population.

Study Overview

• Status: Recruiting
• Conditions: Pulmonary Embolism (Diagnosis)
• Intervention / Treatment: Dietary supplement: nitrate-rich beetroot juice/placebo beetroot juice

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jacob M Hollenberg, Professor; Phone Number: (+46) 070-4133442; Email: jacob.hollenberg@ki.se
• Study Contact Backup: Name: Olle M Andersson, PhD; Phone Number: (+46) 072-9174349; Email: olle.andersson@ki.se

Study Locations

• Sweden
  • Stockholm, Sweden
    • Recruiting
    • South hospital Stockholm
    • Contact: Olle M Andersson, MD; Phone Number: +46729174349; Email: olle.andersson@ki.se
    • Principal Investigator: Olle M Andersson, MD
  • Stockholm, Sweden
    • Not yet recruiting
    • Stockholm, Sweden
    • Contact: Eric Rullman, Ass. Professor; Phone Number: +46739708096; Email: eric.rullman@ki.se
    • Principal Investigator: Eric Rullman, Ass. Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Acute PE with symptoms < 14 days confirmed by computer tomography (CT) AND RV dilatation on CT or ECHO AND Troponin T > 45 pg/ml

Exclusion Criteria:

Cardiac arrest with cardiopulmonary resuscitation, Thrombolysis or endovascular thrombectomy, < 18 years of age, Pregnancy, INR > 2,5 or platelet count < 100, DAPT or OAK, Inability to give informed consent to the study, Contraindications for right heart catheterization: mechanical devices, endocarditis, GUCH-patients, Short expected lifespan < 120 days / withdrawal of care, Imdur or other medications with nitrates, Daily usage of mouth wash prescribed by dentist or doctor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inorganic nitrate; 14 cl of nitrate-rich beetroot juice	Dietary supplement: nitrate-rich beetroot juice/placebo beetroot juice; After written informed consent is obtained, all patients will undergo right heart catheterization to obtain invasive hemodynamic measurements at baseline. The experimental arm will drink 14 cl of nitrate-rich beetroot juice. The placebo comparator arm will drink 14 cl of visually and taste-matched placebo beetroot juice.; Other Names: right heart catheterization
Placebo Comparator: Placebo; 14 cl of visually and taste-matched placebo beetroot juice	Dietary supplement: nitrate-rich beetroot juice/placebo beetroot juice; After written informed consent is obtained, all patients will undergo right heart catheterization to obtain invasive hemodynamic measurements at baseline. The experimental arm will drink 14 cl of nitrate-rich beetroot juice. The placebo comparator arm will drink 14 cl of visually and taste-matched placebo beetroot juice.; Other Names: right heart catheterization

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean pulmonary artery pressure (mPAP)	Mean pulmonary artery pressure measured with right heart catheterization three hours after administration of beetroot juice or placebo-juice.	3 hours from administration of beetroot juice or placebo-juice.

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: South Hospital Stockholm
• Investigators: Principal Investigator: Jacob M Hollenberg, Professor, Karolinska Institutet

Publications and helpful links

General Publications

• Helms J, Carrier M, Klok FA. High-risk pulmonary embolism in the intensive care unit. Intensive Care Med. 2023;49(5):579-582. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing G-J, Harjola V-P, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2019;41(4):543-603. Andersen A, Waziri F, Schultz JG, Holmboe S, Becker SW, Jensen T, et al. Pulmonary vasodilation by sildenafil in acute intermediate-high risk pulmonary embolism: a randomized explorative trial. BMC Pulm Med. 2021;21(1):72. Jones DA, Beirne AM, Kelham M, Wynne L, Andiapen M, Rathod KS, et al. Inorganic nitrate benefits contrast-induced nephropathy after coronary angiography for acute coronary syndromes: the NITRATE-CIN trial. Eur Heart J. 2024;45(18):1647-1658. Henrohn D, Björkstrand K, Lundberg JO, Granstam SO, Baron T, Ingimarsdóttir IJ, et al. Effects of oral supplementation with nitrate-rich beetroot juice in patients with pulmonary arterial hypertension: results from BEET-PAH, an exploratory randomized, double-blind, placebo-controlled, crossover study. J Card Fail. 2018;24(10):640-653. Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, et al. Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived nitric oxide. Hypertension. 2010;56(2):274-281. Hoeper MM, Lee SH, Voswinckel R, Palazzini M, Jais X, Marinelli A, et al. Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers. J Am Coll Cardiol. 2006;48(12):2546-2552.

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2026
• Primary Completion (Estimated): February 25, 2028
• Study Completion (Estimated): February 25, 2028

Study Registration Dates

• First Submitted: February 18, 2026
• First Submitted That Met QC Criteria: February 18, 2026
• First Posted (Actual): February 24, 2026

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 18, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Pulmonary embolism; right heart catheterization; Invasive hemodynamics; Pulmonary vasodilation
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pathological Conditions, Signs and Symptoms; Pulmonary Embolism; Disease
• Other Study ID Numbers: NITRATE-PE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No