Levels of natriuretic peptides related to therapeutic effect and CV outcomes in HFpEF patients
Interaction Between Spironolactone and Natriuretic Peptides in Patients With Heart Failure and Preserved Ejection Fraction
From the TOPCAT TrialAnand IS, Claggett B, Liu J, et al. - JACC, 2017;5(4):241-252
Levels of plasma natriuretic peptides (NPs) are increased in patients with heart failure and preserved ejection fraction (HFpEF) and are associated with adverse outcomes [1,2]. Whether the benefit of therapies for heart failure (HF) varies according to NP levels is unclear.
In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial), spironolactone had no benefit compared to placebo in HFpEF patients. However, a benefit was observed for the subgroup including people enrolled in America only [3,4].
This post hoc analyses of TOPCAT data explored the relationship between baseline NP levels and the primary composite endpoint of cardiovascular death, HF hospitalization and aborted cardiac arrest, as well as with the effects of spironolactone. For this, randomized patients were subcategorized into American or Russian/Georgian people and primary analysis was performed using data from 687 American people with elevated NP levels only (BNP ≥100 pg/ml or NT-proBNP ≥360 pg/ml) in the prior 60 days. Accordingly, 2 sensitivity analyses were performed using also 181 Russian/Georgian people with high NP levels and 555 patients with at least 1 hospitalization for HF in the prior 12 months. Follow-up was 35 months and patients were categorized into NT-BNP/BNP tertiles (1. Median BNP and NT-BNP were 132 and 480 pg/ml, 2. Medians were 234 and 900 and 3. Medians were 505 and 2339 pg/ml) or z-scores for NT-BNP/BNP continuous values were used.
- At baseline, American patients with higher NP levels were older and more likely to have atrial fibrillation, chronic kidney disease, microalbuminuria and lower albumin and less likely to be obese.
- Primary endpoint occurred in 21.5% of patients.
- The incidence rate for outcomes increased across NP tertiles: event rates were 5.9, 6.3 and 106/100 patients years, respectively.
- HRs primary endpoint for second and third tertile were 1.01 (95% CI 0.65-1.58, P=0.95) and 1.89 (95% CI 1.25-2.84, P=0.002) respectively, compared to first tertile. A similar trend was observed when all-cause mortality and HF hospitalization were analysed separately.
- When BNP and NT-proBNP values were analysed together using z-scores based on continuous values, HRs were 1.41 (95% CI 1.20-1.65, P<0.001), 1.48 (95% CI 1.25-1.76, P<0.001) and 1.49 (95% CI 1.24-1.78, P<0.001) for the primary endpoint, all-cause mortality and HF hospitalization.
- The effect of spironolactone corresponded to an HR of 0.64 (95% CI 0.46-0.90, P<0.01) for the primary endpoint. Most of this beneficial effect was restricted to the lowest NP tertile and the interaction between this effect and the tertile grouping of NT levels was significant (P=0.017). A similar effect was observed using z-scores and when also Russian/Georgian people were included.
- A higher NP tertile was associated with worse left ventricle diastolic function.
Using either continuous NP values or NP values grouped by tertiles, NP values were independently associated with an increased risk for the composite of cardiovascular death, HF hospitalization and aborted cardiac arrest in HFpEF patients. This confirms previous findings that NPs are important prognostic markers in patients with HFpEF. In addition, there was a significant interaction between the effect of spironolactone and NP levels, with most of the beneficial effects seen in lower-risk patients with low NP levels, in contrast to high NP levels. This suggests that patients at higher risk are not always more likely to benefit from treatment. Thus, the strategy of using elevated plasma concentrations of NPs as a patient selection criterion in trials of HFpEF needs to be re-examined in prospectively designed clinical trials.