NHLBI Heart Failure Clinical Research Network A Randomized Clinical Trial I norganic N itrite D elivery to I mprove E xercise Capacity in HFpEF INDIE HFpEF Heart Failure Clinical Research Network ID: 1043815
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1. Barry A. BorlaugOn behalf of the NHLBI Heart Failure Clinical Research NetworkA Randomized Clinical TrialInorganic Nitrite Delivery to Improve Exercise Capacity in HFpEFINDIE-HFpEF
2. Heart Failure Clinical Research NetworkMayo ClinicCleveland ClinicWashington UniversityTufts Medical CenterUniversity of Vermont Medical CenterUniversity of PennsylvaniaJefferson Medical CollegeEmory University School of MedicineDuke University School of MedicineRegional Clinical CentersCoordinating CenterDCRI Coordinating Centerwww.hfnetwork.orgBrigham and Women’s Hospital Massachusetts General Hospital
3. BackgroundExercise intolerance, manifest by dyspnea and fatigue, is a cardinal feature of HFpEF.Evidence suggests that impaired nitric oxide (NO) signalling plays key role in pathophysiology of HFpEFPrior efforts to improve NO with organic nitrates in HFpEF have failedPoorly tolerated (ISDN)Reduced activity levels (ISMN)
4. Inorganic Nitrite: Novel NO providing therapyLundberg et al. Nat Rev Drug Disc 2008Background
5. BackgroundNitrite can be delivered by inhaled, nebulized administrationPK similar to intravenous routeSmall, single center studies have shown improvements in hemodynamics and exercise capacity with inorganic nitrite/nitrate in HFpEFNo data available on longer term use in HFpEF
6. HypothesisAs compared to placebo, 4 weeks treatment with inhaled, nebulized inorganic nitrite will improve peak exercise capacity in HFpEF patients as assessed by cardiopulmonary exercise testing (CPET).
7. Study populationNYHA class II-IV HF symptoms + EF ≥ 50%Objective evidence of HF (at least one)HF hospitalization Elevated NT-proBNP or BNPElevated rest or exercise PAWP at RHC Echo Doppler DD + Loop diureticReduced exercise capacity (peak VO2≤75%)Identify HF symptoms as the primary factor limiting ability to be active on questionnaireVersus neurologic, orthopedic or life-style factors
8. Study Design: Randomized, double-blind, placebo-controlled crossover studyNitrite – 4 weeks4 weeksNo drug2 weeksPlacebo – 4 weeks4 weeksNo drug2 weeks80 mg if tolerated46mg80 mg if tolerated46mgPlacebo – 4 weeks 4 weeksNo drug2 weeksNitrite – 4 weeks4 weeksNo drug2 weeks80 mg if tolerated46mg80 mg if tolerated46mgVisit 2: CPET,Secondary EndpointsVisit 3: CPET Secondary EndpointsSingle-DoseRun InVisit 1: Baseline evaluations + Screening CPETYesNoRun In FailRandomizePatientToleratesRun In?
9. INDIE Primary End-pointPeak oxygen consumption (Peak VO2) during cardiopulmonary exercise testing
10. Secondary End-pointsDaily activity by patient-worn accelerometer Arbitrary activity Units (AAU)Other standard HF endpointsHF specific quality of life (KCCQ)NT-proBNP levelsNYHA functional classEchocardiographic indicators of congestionOther Exercise EndpointsSafety and tolerability
11. Crossover AnalysisIntention to treatMixed Model: Treatment Effect (Nitrite-Placebo)Sequence effectPeriod effectRandom effect of each patient105 patients powered to detect:0.6 ml/min*kg difference in peak VO2 (>80%)2.5% change relative to baseline in AAU (>90%)5 pts difference in KCCQ (>80%)
12. Baseline FeaturesCharacteristicPlacebo 1st (n=52)Nitrite 1st (N = 53)Age (years)6868Female44%68%White race87%89%BMI (kg/m2)35.035.6HF hsp in past year19%25%Hx hypertension81%81%Ischemic etiology71% 68%Diabetes33%38%Hx of atrial fibrillation45%45%All p > 0.05 except sexMean values or % shown
13. Baseline FeaturesCharacteristicPlacebo 1st (n=52)Nitrite 1st (N = 53)Systolic BP131130NYHA class II/III38% / 62%47% / 51%Peak VO2 (ml/kg/min) 13.813.9KCCQ (higher better)5259Ejection fraction (%)6161NT-proBNP (pg/ml)528471Mean values or % shown
14. p=0.27Peak VO2 (ml/min/kg)-505101520PlaceboInorganic NitriteTreatment DifferencePrimary Endpoint
15. Secondary EndpointsPlaceboNitriteP valueAccelerometry Arbitrary units550354970.91 Relative to BL (%)97%100%0.60KCCQ (Lower worse)60.861.80.32NT-proBNP (pg/ml)5335200.74NYHA class2.52.50.43Data are the model derived estimates of the mean treatment value
16. Secondary EndpointsPlaceboNitriteP valueSystolic BP (mmHg)1241210.10E/e’ ratio (trough)16.616.40.93LA volume index (ml/m2)39380.82PASP (mmHg)37380.47Ventilatory efficiency33.032.70.11Exercise Duration (min)11.010.80.30Data are the model derived estimates of the mean treatment value
17. Safety / Tolerability EndpointsCharacteristicPlacebo(n=105)Nitrite(n=105)Discontinued study drug58Any Event of Interest116 Arrhythmia21 Worsening HF83 Stroke00 Syncope10SAE - Death01SAE - Any45All p > 0.05
18. SummaryAs compared to placebo, inhaled, nebulized inorganic nitrite did not improve peak exercise capacity, daily activity levels, quality-of-life scores, NT-proBNP levels, or other indicators of clinical status in patients with HFpEF.
19. ConclusionsThese data do not support use of inhaled, nebulized inorganic nitrite for symptom relief in patients with HFpEF.Further study is urgently needed to identify effective, alternative interventions to restore NO-related signaling deficiencies and improve clinical status in HFpEF.
20. Mayo ClinicCleveland ClinicWashington UniversityTufts Medical CenterUniversity of Vermont Medical CenterUniversity of PennsylvaniaJefferson Medical CollegeEmory University School of MedicineDuke University School of MedicineRegional Clinical CentersCoordinating CenterDCRI Coordinating Centerwww.hfnetwork.orgBrigham and Women’s Hospital Massachusetts General Hospital Thank you for your attention