From the Guidelines
Nitrates have a limited role in the management of heart failure, particularly in patients with heart failure with preserved ejection fraction (HFpEF), as they do not improve activity levels, quality of life, exercise tolerance, or NT-proBNP levels.
Key Points
- Nitrates in HFrEF: Nitrate therapy can reduce pulmonary congestion and improve exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) 1.
- Nitrates in HFpEF: The routine use of nitrates in patients with HFpEF is not recommended, as the NEAT-HFpEF trial found no beneficial effects on activity levels, QoL, exercise tolerance, or NT-proBNP levels 1.
- Exceptions: Nitrates may provide symptomatic relief in patients with HFpEF and symptomatic coronary artery disease (CAD) 1.
- Phosphodiesterase-5 Inhibition: Phosphodiesterase-5 inhibition, such as with sildenafil, does not improve oxygen consumption or exercise tolerance in patients with HFpEF 1.
Clinical Considerations
- Nitrates may be considered in patients with HFrEF to reduce pulmonary congestion and improve exercise tolerance.
- In patients with HFpEF, nitrates should only be used in those with symptomatic CAD, and their use should be individualized.
- Phosphodiesterase-5 inhibitors are not recommended for routine use in patients with HFpEF.
- The use of nitrates and phosphodiesterase-5 inhibitors should be guided by the patient's clinical response and tolerance, as well as their potential interactions with other medications.
- The 2022 AHA/ACC/HFSA guideline for the management of heart failure provides a comprehensive overview of the role of nitrates in heart failure management, and clinicians should consult this guideline for the most up-to-date recommendations 1.
From the Research
Role of Nitrates in Heart Failure Management
- Nitrates are commonly used in the therapy of congestive heart failure (CHF), exerting beneficial hemodynamic effects by decreasing left ventricular filling pressure and systemic vascular resistance while modestly improving cardiac output 2.
- Organic nitrates have been shown to have a beneficial effect on ischemia, hemodynamic profile, magnitude of mitral regurgitation, endothelial function, and cardiac remodeling 3, 4.
- Nitrates can improve exercise capacity and survival when used in combination with hydralazine, and may be used as an adjunctive therapy to angiotensin converting enzyme (ACE) inhibitors in patients with chronic heart failure 3.
Mechanisms and Limitations
- The major mechanism of nitrate tolerance is loss of vascular smooth muscle sensitivity to nitrates, which can be mitigated by intermittent dosing with a nitrate-free interval 2, 4.
- Nitrate resistance is due to reduced vascular response, requiring higher doses for treatment of patients with heart failure compared to those without 4.
- Recent information suggests that nitrate tolerance is caused by increased levels of superoxide at the vascular wall, leading to reduced nitric oxide levels and increased sensitivity to vasoconstrictive mechanisms 4.
Clinical Applications
- Intravenous or sublingual nitrates are first-line agents in the therapy of acute pulmonary edema, and may be used to break the vicious spiral of CHF in severe cases 2.
- Nitrates are available in various forms, including sublingual, oral, topical, transmucosal, intravenous, and spray preparations, with the choice depending on the clinical situation 5.
- However, a systematic review found a lack of robust evidence to support the use of nitrates in acute heart failure syndromes, highlighting the need for further studies to evaluate their safety and efficacy in modern heart failure therapy 6.