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INDIE-HFpEF: Inhaled nitrate fails to improve quality of life, activity levels
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ORLANDO, Fla. — Daily activity levels, peak exercise capacity, N-terminal pro-B-type natriuretic peptide and quality-of-life scores did not improve in patients with HF with preserved ejection fraction who were treated with inhaled, nebulized inorganic nitrite vs. placebo, according to a late-breaking clinical trial presented at the American College of Cardiology Scientific Session.
“These data do not support the use of inhaled, nebulized inorganic nitrite for symptom relief or to improve exercise capacity in the short duration in patients with HFpEF,” Barry A. Borlaug, MD, FACC, professor of medicine at Mayo Clinic in Rochester, Minnesota, said during the presentation.
Researchers of the INDIE-HFpEF trial analyzed data from 105 patients with NYHA class II to IV HF symptoms and an ejection fraction greater than 50%.
“Patients were asked a question to ensure that the heart failure symptoms were the dominant thing that limited them from being active rather than pain, orthopedic limitations or unsteadiness,” Borlaug said.
At baseline, cardiopulmonary exercise testing and evaluations were conducted along with a single-dose run-in dose of nitrite. If patients tolerated the run-in dose, they were assigned 46 mg nitrite three times per day then 80 mg three times per day (n = 53; mean age, 68 years; 68% women) or placebo (n = 52; mean age, 68 years; 44% women) first for 4 weeks after receiving no drugs for 2 weeks. After a 2-week washout period, patients crossed over to placebo or nitrite for 4 weeks.
The primary endpoint was peak oxygen consumption during cardiopulmonary exercise testing. Testing was conducted at baseline and after each 6-week period. Secondary endpoints included safety and tolerability, daily activity monitored by a patient-worn accelerometer and other standard HF endpoints such as HF-specific quality of life, NYHA functional class and other exercise endpoints. Secondary endpoints were assessed at every follow-up visit.
The baseline characteristics were similar to what is typically seen in patients with HFpEF, according to the presentation. The placebo-first and nitrite-first groups both had high BMI (35 kg/m2 vs. 35.6 kg/m2), a history of atrial fibrillation (45% in both groups) and a history of hypertension (81% in both groups). Both groups also had low mean peak VO2.
Compared with placebo, nitrite did not affect maximum exercise (P = .27) nor improve daily activity levels either by arbitrary units (5,503 vs. 5,497, respectively; P = .91) or relative to the baseline phase (97% vs. 100%, respectively; P = .6). Nitrite also did not improve quality of life (P = .32), natriuretic peptide levels (P = .74) or NYHA functional class (P = .43).
There was a trend toward a reduction in systolic BP with nitrite vs. placebo (121 mm Hg vs. 124 mm Hg), although this did not reach statistical significance (P = .1). There was no reduction in the estimation of filling pressures as seen with echocardiography measured at trough levels of the study drug, and exercise duration was not affected.
Nitrite was well-tolerated without an excess of serious adverse events vs. placebo.
“Further study is urgently needed to identify alternative, effective interventions to improve clinical status in this very large and growing population of patients suffering with HF,” Borlaug said during the presentation.
“The crossover effect is a very important study design for this type of patient,” Ileana L. Pina, MD, MPH, professor in the department of medicine and the department of epidemiology and population health at Montefiore Medical Center, and a member of the Cardiology Today Editorial Board, said during the presentation. “It’s very interesting to see the low peak VO2, which really confirms the inability of these patients to do much. It’s also interesting to see the [Kansas City Cardiomyopathy Questionnaire] values.” – by Darlene Dobkowski
Reference:
Borlaug BA, et al. Late-Breaking Clinical Trial III. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Disclosures: Borlaug reports he received consultant fees/honoraria from Actelion, Amgen, Arteriomedix, Merck and MyoKardia, and research support from AstraZeneca, Corvia, GlaxoSmithKline, Medtronic and Mesoblast. Pina reports she receives consultant fees/honoraria from Relypsa.
Disclosures: Borlaug reports he received consultant fees/honoraria from Actelion, Amgen, Arteriomedix, Merck and MyoKardia, and research support from AstraZeneca, Corvia, GlaxoSmithKline, Medtronic and Mesoblast. Pina reports she receives consultant fees/honoraria from Relypsa.
Perspective
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Gurusher Panjrath, MD, FACC
Regarding the INDIE trial, could change in mode of delivery or formulation have a more lasting effect than just a short-acting effect, which was tested in this trial? We will not know. Would a combination of this intervention with something else such as exercise training be more suitable or other sources of organic nitrites as being tested in some studies be beneficial? Unfortunately, the enthusiasm for anything targeting the nitric oxide pathway is going to be low, as we already know that oral nitrates don’t work.Given the results of this trial, this therapy shouldn’t be recommended right now, so this trial doesn’t change clinical practice. Recommendation against use of oral nitrates is already part of the recent HF guidelines.
One area I’d like to see more research in is tailoring therapy to phenotype, because from the results presented in this trial, we didn’t see much on what patient phenotypes were. We will have to look at further analysis from the trial to dissect the phenotypes. I have a strong conviction that if we start tailoring therapy based on those, we may see better results.We’re tailoring all HFpEF together now like we did in HFrEF in the past. We learned over time that we can’t pool all HFrEF together because there are so many presentations of HFrEF. However, it’s always more difficult to enroll patients and do large-scale clinicaltrials if you start separating out subgroups, but that might be essential. Another limitation is that exercise therapy in patients with HFpEF is not reimbursable at this time, as there is no large trial similar to HF ACTION for HFrEF. Cardiac rehab is only covered by CMS for HFrEF right now, even though we are all hoping that will change.
A lot of people are looking at that at various centers and trials. Then the question is exercise training and what kind of exercise training. Is aerobic training the way to go and whether resistance training is better? Patients with HFpEF are older and more likely to be women. There is the component of frailty aspect to them. Would resistance training be better in combination with this? Lastly, researchers are studying other modes of disease or symptom modification like virtual reality; it will be interesting to see if it makes a difference in quality of life.
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