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Study Summary

Impaired nitric oxide (NO) signaling has been postulated to play a key role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). The INDIE-HF trial sought to assess whether 4 weeks of inhaled inorganic nitrite (which functions as an in vivo reservoir for NO generation) would improve peak oxygen consumption (pVO2) during cardiopulmonary exercise testing in patients with HFpEF. Patients who tolerated a run-in dose of inorganic nitrite (80mg) were randomized to either placebo first (N = 52; with cross-over to inorganic nitrite) or inorganic nitrite first (N = 53; with cross-over to placebo) in this double-blinded cross-over study. Baseline characteristics were similar between the two treatment groups, except more females were included in the nitrite first group (68% vs 44%; p<0.05). No difference in the primary outcome — pVO2 difference — was observed after 4 weeks of inorganic nitrite, compared to placebo (p = 0.27). Similarly, no differences were found in the secondary outcomes of change in accelerometry, quality of life, NT-proBNP or New York Heart Association (NYHA) class (see accompanying Hurst’s Central Illustration).

Targeting Altered cGMP-NO Signaling in HFpEF

Commentary

Study Strengths: The pathophysiology of HFpEF is heterogeneous, thus therapies must target specific mechanistic pathways for an assessment of improvement in outcomes. While prior trials targeting the NO pathway, with such therapeutics as phosphodiesterase inhibitors and organic nitrates have been negative, INDIE-HF tested an alternative pathway for NO generation. The cross-over design minimized variability in treatment responses, and its 2 week drug-free period reduced any carryover effect from the prior inhaled nitrite phase. Additionally, by assessing tolerability of the study drug prior to randomization, drop-out rates were limited. The study utilized accelerometers to capture changes in daily activity levels, a contemporary method of assessing important patient information not otherwise captured during standard evaluations. Improvement in peak VO2 represents a valid primary endpoint as limitations in exercise tolerance remain central to the HFpEF syndrome.

Study Limitations: The study drug was administered at home, which may have increased variability in drug delivery and compliance. Additionally, adequate drug delivery was not measured and although the inhaled nitrite dose was uptitrated based on tolerability, a dose dependent response could not be assessed.

Next Steps/Clinical Perspective: The lack of efficacy of phosphodiesterase inhibitors, organic nitrates and now inorganic nitrites call into reconsideration the targeting of altered cGMP-NO signaling as a means to improve outcomes in HFpEF. Further refinement of therapies targeting the HFpEF phenotype studied may allow for relevant improvements in exercise capacity to be observed.

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