Natriuretic Peptides, 6-Min Walk Test, Quality-of-Life as Meaningful Endpoints in HF Trials

Ferreira JP, Duarte K, Graves TL, et al.
Natriuretic Peptides, 6-Min Walk Test, and Quality-of-Life Questionnaires as Clinically Meaningful Endpoints in HF Trials. J Am Coll Cardiol 2016;68:2690-2707.

The following are key points to remember about this review on the use of natriuretic peptides, such as N-terminal pro–B-type natriuretic peptide (NT-proBNP)/BNP, the 6-minute walk test distance (6MWD), and health-related quality of life (QoL) in heart failure (HF):

  1. An intermediate endpoint is a measure of clinical benefit or risk concerning a symptom or measure of function that is not the ultimate outcome of the disease (e.g., exercise tolerance and QoL in trials of device treatments for HF).
  2. A surrogate endpoint is not itself a measure of clinical benefit, but is used in trials as a substitute that is reasonably likely to predict clinical benefit, on the basis of epidemiological, therapeutic, pathophysiological, or other sources of scientific evidence; for example, laboratory or medical imaging measurements, or physical signs (e.g., natriuretic peptides [NPs] in HF trials, as a surrogate for HF hospitalization and cardiovascular [CV] death clinical endpoints).
  3. The use of clinically meaningful endpoints in clinical drug and device development may allow for pretesting the efficacy and safety of a treatment in phase 2 and proof-of-concept trials, as well as in premarket access trials of devices.
  4. Natriuretic peptides (NPs):
    • NPs are skewed variables with high dispersion of values (large interquartile ranges). Hence, the most robust test to compare the differences between groups is a nonparametric test, such as the Mann-Whitney U test, or NPs can be log-transformed to “normalize” the distribution, which allows the application of a parametric test, such as a Student t test.
    • HF with reduced ejection fraction (HFrEF): The association between changes in NP levels and treatment effect has been most extensively studied in patients with HFrEF. In general, when an HFrEF trial is clearly positive for a clinical benefit on morbidity and mortality, NP levels fall significantly, and either absolute or percent changes are likely to be appropriate for determining clinically significant differences between treatment groups in HFrEF. However, these methods need to be prespecified to avoid post hoc adaptations.
    • The enzyme neprilysin efficiently degrades circulating B-type natriuretic peptide (BNP) in vivo, whereas proBNP and N-terminal (NT)-proBNP are virtually resistant to enzymatic cleavage. It seems plausible that measuring BNP in patients on neprilysin inhibitors may not reliably reflect left ventricular dysfunction. BNP variability under neprilysin inhibition also depends on the assay used. Therefore, BNP levels are likely to increase under neprilysin inhibition, whereas NT-proBNP levels decrease in a sustained fashion. BNP, therefore, will reflect the action of the drug, whereas levels of NT-proBNP will reflect the effects of the drug on the heart. Hence, BNP can potentially be used for compliance monitoring, and NT-proBNP for treatment effect assessment. Consequently, in future trials, NT-proBNP will likely become the preferred NP for monitoring treatment response (e.g., device trials).
    • HF with preserved EF (HFpEF): The drop in NPs in these patients is also likely to be associated with lower event rates; however, it is not possible to determine the association between the drop in NPs and a favorable outcome due to the lack of evidence-based treatments that have been indisputably shown to reduce morbidity and mortality in this disease.
    • Acute HF: Discharge and change in NP values during hospitalization are strong predictors of subsequent outcomes in these patients. However, the association with treatment effect is challenging.
  5. Six-minute walk distance (6MWD) test:
    • There are limited data to define how much of a difference between treatment groups in 6MWD is enough to define a test as “positive” or “indicative of efficacy.” However, an increase in 6MWD is of much more value to severely symptomatic patients. In general, a 30-50 m increase in 6MWD is considered a clinically significant improvement, is associated with significant improvement in New York Heart Association functional class and health-related QoL, and has been used in the cardiac resynchronization therapy trials as relevant to premarket approval.
    • The 6MWD should be used when patients have severe disease and symptoms, and a statistically significant difference between mean distances or absolute delta distances should be considered as “pointing toward efficacy.”
    • 6MWD should be used in collaboration with other intermediate endpoints. For example, a positive effect on 6MWD is more valuable when it is congruent with positive changes in NP levels, or in another remodeling assessment, such as echocardiography or magnetic resonance imaging parameters.
  6. Quality of life (QoL):
    • Health-related QoL questionnaires: These questionnaires have been used extensively in cardiology research; however, data regarding external validation and association with prognosis are somewhat limited. Nonetheless, poor scores on QoL questionnaires have been associated with a dismal prognosis in HF.
    • HFrEF: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the Kansas City Cardiomyopathy Questionnaire (KCCQ) are quality instruments that are the most commonly used as a clinically relevant endpoint and an intermediate prognostic marker in several HFrEF trials. In HFrEF with severe symptoms, an improvement in health-related QoL also points toward a beneficial and clinically meaningful treatment effect if aligned with the other tests, particularly NPs and cardiac structural measures. In general, a 5- to 10-point decrease in MLHFQ QoL score is considered clinically and prognostically significant, and more so, if, as mentioned previously, this finding is congruent with decreased NP level and improved 6MWD.
    • HFpEF: The absence of an unequivocally positive trial has made it difficult for the authors of this article to evaluate the role of health-related QoL questionnaires as treatment effect surrogates in HFpEF.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Implantable Devices, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Exercise

Keywords: Biological Markers, Cardiac Resynchronization Therapy, Cardiomyopathies, Echocardiography, Endpoint Determination, Heart Failure, Magnetic Resonance Imaging, Natriuretic Peptide, Brain, Neprilysin, Prognosis, Quality of Life, Questionnaires, Stroke Volume, Treatment Outcome, Walking

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