NEAT-HFpEF

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Redfield MM, et al. "Isosorbide mononitrate in heart failure with preserved ejection fraction". New England Journal of Medicine. 2015. 373(24):2314-2324.
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Clinical Question

In patients with heart failure with preserved ejection fraction (HFpEF, LVEF ≥ 50%) and mild-moderate (NYHA II-III) symptoms, does the long-acting nitrate isosorbide mononitrate improve activity tolerance versus placebo?

Bottom Line

In patients with HFpEF (LVEF ≥ 50%) and mild-moderate (NYHA II-III) symptoms, the addition of the long-acting nitrate isosorbide mononitrate appears to hinder rather than improve activity level. Patients on nitrate therapy had a borderline significant reduction in total activity units as well as about a 20-minute absolute reduction in activity time per day. There was no effect of nitrate therapy on 6-minute walk distance, quality of life, or clinical biomarkers.

Major Points

Although they have never been demonstrated to improve mortality in any cardiac condition, long-acting nitrates clearly provide symptomatic benefit in patients with angina. Furthermore, several small randomized trials have suggested that long-acting nitrates also improve exercise tolerance in patients with heart failure and reduced ejection fraction (HFrEF), presumably by improving cardiac filling pressures and hemodynamics.[1][2] As a result, these drugs are commonly used for symptom control in HFrEF.

The results of these findings are often extended to patients with heart failure with preserved ejection fraction (HFpEF), although there are no high quality data to support this approach. Moreover, given established differences in epidemiology, pathophysiology, and response to treatment in HFrEF versus HFpEF, it is certainly plausible that a benefit with nitrates in the former may not translate into the latter. As a result, the role of nitrates in HFpEF is unclear.

The 2015 Nitrate's Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) was designed to assess the effect of extended-release isosorbide mononitrate (a long-acting nitrate) on daily activity level in patients with HFpEF and predominantly mild to moderate symptoms (NYHA II-III). In NEAT-HFpEF, 110 patients with chronic HFpEF were randomized in a double crossover design to long-acting nitrate versus placebo. After a 6 week treatment period, nitrate use was associated with a borderline significant decrease in total activity as measured using continuous accelerometry. Furthermore, there was a progressive decrement in daily activity with increasing doses of nitrate therapy. Although accelerometer units are difficult to quantify, an analysis of total hours of activity per day suggested about a 20-minute absolute reduction in activity time with nitrate therapy. Despite the fact that accelerometer units are not a common measure of activity in patients with HFpEF, the accelerometer findings were corroborated by the failure of nitrates to improve 6-minute walk distance, subjective dyspnea on several validated patient questionnaires, and cardiac biomarkers. In addition, although adverse event rates were very low, there were numerically more patients with worsening heart failure symptoms on nitrate therapy when compared to placebo. Ultimately, the findings of NEAT-HFpEF demonstrate that not only is there currently no role for long-acting nitrates in patients with HFpEF, but that use of these agents may actually lead to worsening symptoms and functional capacity in this population in the absence of an alternative compelling indication for their use (e.g., anginal symptoms).

Guidelines

As of April 2016, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, placebo-controlled, double crossover study
  • N=110
    • Isosorbide Mononitrate first (n=51)
    • Placebo first (n=59)
  • Setting: 20 sites in the United States
  • Enrollment: April - October 2014
  • Duration of follow-up: 6 weeks
  • Analysis: Intention-to-treat
  • Primary Outcome: Average daily accelerometer units while receiving 120mg isosorbide mononitrate

Population

Inclusion Criteria

  • 50 years or older
  • LVEF ≥50% with any of the following within previous 12 months:
    • Hospitalization for heart failure with radiographic evidence of pulmonary congestion
    • Elevated LVEDP at rest (≥15mmHg)
    • Elevated PCWP at rest (≥20mmHg)
    • Elevated PCWP with exercise (≥25mmHg)
    • Elevated NTproBNP (>400pg/mL) or BNP (>200pg/mL)
    • Doppler evidence of diastolic dysfunction
  • Primary limitation to activity is dyspnea, fatigue, or chest pain

Exclusion Criteria

  • SBP < 110 mmHg or SBP > 180 mmHg
  • Previous adverse reaction to or current use of long-term nitrate or PDE5 inhibitor
  • Ischemia thought to contribute to dyspnea
  • ACS or revascularization within preceding 3 months

Baseline Characteristics

From the placebo group.

  • Demographics: Age 69 years, female 64%, white 92%
  • Comorbidities: BMI 35.1, hospitalization for heart failure 27%, HTN 92%, CAD 61%, AF 34%, DM 36%, COPD 17%, OSA 50%, anemia 31%, CKD stage 3 or greater 54%, depression 37%
  • Functional Measures: NYHA II 56%, NYHA III 41%, Kansas City Cardiomyopathy Questionnaire 58.0, Minnesota Living with Heart Failure Questionnaire 43.3, six-minute walk distance 321m, daily accelerometer units 9607, hours of activity per day 9.2
  • Physical Exam: Systolic BP 132mmHg, HR 70bpm, elevated JVP 29%, peripheral edema 59%
  • Medications: Loop diuretic 61%, thiazide 10%, ACE/ARB 61%, beta blocker 69%, aldosterone antagonist 22%, calcium channel blocker 41%, lipid-lowering agent 71%, antiplatelet/anticoagulant 80%
  • Laboratory Measures: Creatinine 1.2mg/dL, NTproBNP 248 pg/mL
  • Echocardiographic Characteristics: LVEF 65%, relative wall thickness >0.41 45%, left atrial volume 38.9mL/m2 BSA, E/E' ratio 15

Interventions

  • Patients underwent 6 weeks of therapy 1 followed by crossover to 6 weeks of therapy 2
    • Patients randomized 1:1 to active treatment first or active treatment second
    • During each 6-week period, patients underwent an initial 2 week washout followed by 30mg isosorbide for 1 week, 60mg isosorbide for 1 week, and 120mg isosorbide until end of 6 week period
  • After enrollment, patients underwent baseline echocardiography, quality-of-life scoring, 6-minute walk distance, and NTproBNP measurement
  • Patients were supplied with a belt outfitted with two kinetic activity monitors containing high-sensitivity accelerometers and were encouraged to wear them 24 hours per day except for bathing and swimming
  • Patients were called weekly to assess for side effects and encourage compliance
  • Patients with unacceptable side effects were dropped to the previous dose of study drug
  • Patients underwent repeat endpoint assessment at the end of each study period

Outcomes

Comparisons are long-acting nitrate vs. placebo

Primary Outcomes

Daily arbitrary accelerometer units during 120mg phase
8922 (8500-9345) vs. 9303 (8884-9723); treatment difference -381 (-780 to 17); p=0.06

Secondary Outcomes

Number of hours of activity per day
9.01 (8.75-9.27) vs. 9.31 (9.05-9.56); treatment difference -0.30 (-0.55 to -0.05); p=0.02
Daily arbitrary accelerometer units for all treatment doses
9185 (8822-9547) vs. 9623 (9271-9976); treatment difference -439 (-792 to -86); p=0.02
Six-minute walk test (meters)
322 (307-336) vs. 321 (307-336); treatment difference 0.57 (-9.63 to 10.78); p=0.91
Borg Dyspnea Score
3.89 (3.52-4.26) vs. 3.97 (3.59-4.34); treatment difference -0.07 (-0.50 to 0.36); p=0.74
Kansas City Cardiomyopathy Questionnaire
59.7 (57.0-62.5) vs. 61.6 (58.9-64.4); treatment difference -1.91 (-4.55 to 0.74); p=0.16
Minnesota Living with Heart Failure Questionnaire
37.0 (33.3-40.6) vs. 35.4 (31.6-39.2); treatment difference 1.62 (-1.98 to 5.23); p=0.37
NTproBNP (pg/mL)
550 (475-625) vs. 497 (422-572); treatment difference 53 (-33 to 138); p=0.22
Mean arterial blood pressure (mmHg)
88 (86-90) vs. 90 (88-92); treatment difference -2.3 (-4.4 to -0.2); p=0.03

Subgroup Analyses

There were no significant interactions between treatment effect and baseline characteristics

Adverse Events

Worsening heart failure (raw #)
5 vs. 1
Presyncope or syncope (raw #)
6 vs. 3
Death
0 vs. 0

Criticisms

  • Primary outcome of daily arbitrary accelerometer units has not been standardized or validated, making clinical significance of this endpoint unclear. However, these findings were corroborated by more commonly accepted secondary endpoints.
  • Weekly uptitration of isosorbide mononitrate may have been more aggressive than usual clinical practice. More gradual uptitration may have yielded more favorable results.
  • 6 week follow up is relatively limited. Thus, a longer-term beneficial effect with nitrate therapy cannot be ruled out.
  • Patients with symptoms thought to be referable to ischemia (i.e., angina) were excluded from the study. Thus, the possibility of salutary effects of nitrate therapy on activity level in patients with HFrEF and angina require further study.
  • 91 individuals had usable accelerometer data, their power calculation estimated that 94 participants were needed to detect the primary outcome.

Funding

  • NHLBI at the NIH
  • Several authors with multiple ties to industry

Further Reading

  1. Elkayam U et al. Double-blind, placebo-controlled study to evaluate the effect of organic nitrates in patients with chronic heart failure treated with angiotensin-converting enzyme inhibition. Circulation 1999. 99:2652-7.
  2. Leier CV et al. Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983. 67:817-22.