NT-proBNP levels predict outcomes in HF patients with or without atrial fibrillation
Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide Levels in Heart Failure Patients With and Without Atrial FibrillationLiterature - Kristensen SL, Jhund PS, Mogensen UM, et al. PARADIGM-HF and ATMOSPHERE Committees and Investigators - Circ Heart Fail. 2017 Oct;10(10). doi: 10.1161/CIRCHEARTFAILURE.117.004409
Higher levels of natriuretic peptides (NP) are associated with higher rates of CV death and heart failure (HF) hospitalization, and are influenced by many factors, including age, obesity, renal function, and atrial fibrillation (AF) [1-3]. NP levels peptides are generally higher in patients with AF, and the prognostic significance of a given NT-proBNP concentration in patients with AF, compared with those without AF, is uncertain.
This study compared the relationship between NT-proBNP concentrations and clinical outcomes in patients with and without AF, using data from 2 trials in patients with HFrEF, which had similar enrolment criteria. The main inclusion criteria for PARADIGM-HF and ATMOSPHERE were [4,5]: NYHA functional class II–IV, EF ≤35% and plasma BNP of ≥150 pg/mL or NT-proBNP of ≥600 pg/mL
In both PARADIGM-HF and ATMOSPHERE, patients first received enalapril (5 or) 10 mg BID (single-blind) and then sacubitril/valsartan (single-blind) for an additional 4 to 6 weeks in PARADIGM-HF and aliskiren plus enalapril in ATMOSPHERE. In PARADIGM-HF, patients tolerating both drugs at target doses were randomly assigned to enalapril 10 mg BID or sacubitril/valsartan 200 mg BID, and in ATMOSPHERE, patients who tolerated both drugs were randomized in a 1:1:1 ratio to receive either the combination of 5 or 10 mg enalapril BID and aliskiren 150 mg OD (combination group), or aliskiren 150 mg OD, or enalapril 5 or 10 mg BID.
Based on their NT-proBNP levels at baseline, patients were categorized as follows: NT-proBNP <400 pg/mL, NT-proBNP: 400-999 pg/mL (reference group), NT-proBNP: 1000-1999 pg/mL, NT-proBNP: 2000-2999 pg/mL or NT-proBNP ≥3000 pg/mL. The primary endpoint was the first occurrence of CV death or HF hospitalization. Other endpoints were CV death and HF hospitalization separately, as well as death from any cause.
- A total of 14 737 patients had a measurement of NT-proBNP at baseline, of whom 3575 (24%) had AF on their baseline ECG. Median NT-proBNP levels were 1817 pg/mL in those with AF and 1271 pg/mL in those without AF (P<0.0001).
- The rates of the composite outcome, each of its components, and all-cause death were significantly higher in patients with levels of NT-proBNP >1000 pg/mL compared with the reference group.
- There was a step-wise increase in the risk of the primary composite outcome across the 5 NT-proBNP groups in patients with and without AF, with the exception of AF patients in the 2 groups with the lowest NT-proBNP levels (<400 and 400–999 pg/mL).
- In patients with NT-proBNP >3000 pg/mL, the rate of the primary composite outcome was 23.0 per 100 patient-years (PY) in patients without AF and 22.7 per 100 PY in those with AF. The adjusted HRs, compared with individuals with 400-999 pg/mL, were 2.73 (95% CI: 2.46–3.03) and 2.91 (95% CI: 2.37–3.58), respectively (P value for interaction between the risk of the primary outcome and the presence or absence of AF: 0.125).
- No interaction between AF status and NT-proBNP levels was found for the other outcomes or when each trial was analyzed separately.
- Regarding age-adjusted event rates, there was a significant difference according to AF status for the primary outcome and all-cause death in patients with NT-proBNP <400 pg/mL (P=0.002 both), but not for CV death and HF hospitalization.
In a meta-analysis of the PARADIGM-HF and ATMOSPHERE trials, any given concentration of NT-proBNP above 400 pg/mL, had a similar predictive value for adverse outcomes in HFrEF patients with and without AF. These data suggest that although NT-proBNP levels are, on average, higher in patients with AF, this does not diminish their prognostic significance. Thus, this does not justify the now common policy to apply higher qualifying NT-proBNP levels for inclusion of AF patients in clinical trials.
In their editorial article, Voors and Lam  highlight the importance of the findings in two contexts:
- The clinical trial context, in which higher NT-proBNP levels are required to include AF patients. The authors note that this policy may lead to a selection bias of higher risk patients, and it caps the inclusion of AF patients in these trials.
- The clinical practice context, in which physicians thought that patients with HF and AF were ‘justified’ to have higher NT-proBNP levels, a myth that may influence the selection of therapeutic strategies.
The authors conclude: ‘Taken together, the data from the current study by Kristensen et al provide important lessons about the use of NT-proBNP in HF and AF. However, several key questions still need to be addressed, in particular the diagnostic thresholds of NPs in HF with versus without AF, the prognostic use of NPs in AF without HF, and the optimal NP cutoffs in HF with preserved ejection fraction, with and without AF.’