NT-proBNP Response to Heart Failure Therapies: An Imperfect Surrogate

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The validation of natriuretic peptides (NPs)—B-type NP (BNP) and the more stable N-terminal proBNP (NT-proBNP)—as heart failure (HF) biomarkers over the past 3 decades has transformed clinical practice by providing a means to discriminate acute HF from other causes of dyspnea.  Subsequent proteomic analysis has shown that among the thousands of circulating proteins, NPs are the most specific for HF. NPs have become so central to HF diagnosis that they are now included in the definition of the disease. NPs also proved to be powerful prognostic markers, identifying patients at highest risk for events. Increasing levels precede HF worsening and hospitalization, while decreasing levels reflect clinical improvement.

 

The prognostic value of NPs has motivated their measurement in randomized trials of novel HF therapeutics. Elevated levels at baseline provide objective inclusion criteria to ensure the enrollment of patients who have HF and are likely to experience HF events. Postrandomization NP measurements serve as surrogate endpoints of study drug efficacy, particularly in phase 2 trials that lack power to show differences in clinical outcomes. NPs are appealing surrogates because they are easily measured, are strongly prognostic, and reflect the key pathophysiology of HF. However, as with any surrogate endpoint, the relationship between a drug’s effects on NPs and on clinical outcomes may be complex.

 

In this issue of the Journal, Januzzi et al  present an analysis of baseline and postrandomization NT-proBNP measurements from the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial of empagliflozin compared with placebo in chronic HF with reduced ejection fraction (HFrEF). This trial demonstrated large and highly significant reductions in HF events with empagliflozin. The current analysis represents the largest study of NT-proBNP in HF patients treated with sodium-glucose cotransporter-2 (SGLT2) inhibition and offers the first well-powered opportunity to assess how the magnitude of NT-proBNP reductions relate to clinical outcomes. The paper draws 3 key conclusions. First, baseline NT-proBNP and changes in NT-proBNP were strongly associated with subsequent rates of HF hospitalization and cardiovascular death, consistent with numerous prior studies. Primary endpoint event rates were 4-fold higher in the highest NT-proBNP quartile compared to the lowest. Second, the reduction in HF events with empagliflozin was similar regardless of baseline NT-proBNP. Third, and most interesting, empagliflozin reduced NT-proBNP by 5%-13% compared with placebo across multiple timepoints, ranging from 4 weeks to 2 years after randomization.

 

The consistent efficacy of empagliflozin regardless of baseline NT-proBNP is important given recent HFrEF trials demonstrating significant treatment interactions with NPs. In the GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure) trial, omecamtiv mecarbil reduced HF events to a greater extent in patients with greater than median NT-proBNP . Conversely, the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial of vericiguat enrolled a sicker cohort of patients, and the greatest treatment benefit was seen in those in the lower range of NT-proBNP (<4,000 pg/mL) . When the EMPEROR-Reduced and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trials are considered together, SGLT2 inhibition appears to be effective throughout a wide range of NT-proBNP, from 600-5,000 pg/mL.

 

The inclusion criteria of EMPEROR-Reduced complicate the interpretation of NT-proBNP and ejection fraction (EF) treatment interactions. To ensure the enrollment of patients at high risk, the minimum NT-proBNP required for inclusion was more stringent for patients with higher EF: 600 pg/mL for EF of <30%; 1,000 pg/mL for EF of 31% to 55%; and 2,500 pg/mL for EF of 36% to 40%. This design could have obscured an underlying interaction in which patients with lower EF and higher NT-proBNP benefitted more. However, a reassuring sensitivity analysis including only patients with an EF of <30% showed no treatment interaction by NT-proBNP (P = 0.96).

 

The 5%-13% reduction in NT-proBNP with empagliflozin observed in the present analysis is consistent with other studies of SGLT2 inhibitors. Dapagliflozin reduced NT-proBNP by 196 pg/mL (vs a 101-pg/mL increase from placebo) after 8 months in the DAPA-HF trial. Smaller studies of dapagliflozin and canagliflozin failed to show statistically significant changes in NT-proBNP. In DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction), there was a nonsignificant 5% reduction in NT-proBNP after 12 weeks from dapagliflozin compared to placebo, and in the CANDLE trial, NT-proBNP changes were small and comparable to patients randomized to glimepiride. In the CANVAS (Canagliflozin Cardiovascular Assessment Study) study of patients with type 2 diabetes, canagliflozin reduced NT-proBNP by 11% at 1 year, and a mediation analysis suggested that just 10% of the reduction in hospitalization for HF was reflected in NT-proBNP lowering. 

 

These early reductions in NT-proBNP with SGLT2 inhibition are smaller than for other HF therapies with a similar effect on HF events. Sacubitril/valsartan, compared with enalapril, reduced NT-proBNP by 28% after 8-10 weeks (vs a 6% reduction from enalapril) in the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) and by 30% after 2 weeks in the PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure). The reduction in HF hospitalizations with empagliflozin (30%) was similar or larger than that with sacubitril/valsartan (21%) (Figure 1). A meta-analysis of contemporary chronic HF trials found robust correlations between changes in NPs and therapeutic effects on HF hospitalizations (r = 0.63), but there was no significant correlation with all-cause mortality (r = 0.12). Recent trials of pharmacologic HFrEF therapies have shown a consistent relationship between reduction in NT-proBNP and reduction in HF events, in line with the findings from the meta-analysis. In GALACTIC-HF and VICTORIA, the HR for HF hospitalizations was 0.95 (95% CI: 0.87-1.03) and 0.90 (95% CI: 0.81-1.00), respectively. In GALACTIC-HF, NT-proBNP was reduced by 10% after 24 weeks of omecamtiv mecarbil compared to placebo, and in the phase 2 trial of vericiguat (SOCRATES-REDUCED), NT-proBNP was reduced by 11% after 12 weeks compared to placebo. In other words, vericiguat and omecamtiv mecarbil reduce NT-proBNP by the same amount as empagliflozin, despite inferior efficacy for clinical outcomes.

 

Changes in NT-proBNP and Clinical Outcomes in PARADIGM-HF and EMPEROR-Reduced

 

What mechanisms may explain the apparent disconnect between the modest reduction in NT-proBNP and more robust reduction in clinical events from SGLT2 inhibitors? First, improvements in HF outcomes with SGLT2 inhibitors may not be due to reductions in wall stress, filling pressures, and other hemodynamic determinants of NP expression. Interestingly, empagliflozin has been shown to significantly reduce left ventricular volumes, left ventricular mass, and systolic function in HFrEF. These results suggest that SGLT2 inhibitors are beneficial beyond their diuretic effect. Second, the early “dip” in estimated glomerular filtration rate after starting an SGLT2 inhibitor may cause a transient increase in NT-proBNP. Third, the metabolic benefits of SGLT2 inhibitors—increased fat oxidation, insulin sensitivity, and weight loss—may simultaneously increase NPs. Lower levels of NPs are consistently seen in patients with worse metabolic status, including both obesity and dysglycemia, also referred to as NP-deficient states. Furthermore, weight loss induced by bariatric surgery or lifestyle intervention and improved glycemic control have been shown to significantly increase levels of NPs. Collectively, these effects may result in lower adipocyte-derived NP clearance, offsetting declines in NP levels from improvement in HF status. Taken together, all of these effects may result in a modest net decline in NT-proBNP for most patients treated with SGLT2 inhibition. Large reductions in NT-proBNP with angiotensin receptor/neprilysin inhibitor may be explained by the direct effects of neprilysin inhibition on the NP system rather than only indirect effects as with SGLT2 inhibitors.

 

In conclusion, this important paper demonstrates that empagliflozin reduced HF events regardless of baseline NT-proBNP levels and that empagliflozin reduced NT-proBNP by 5%-13%. The dramatic clinical benefit of empagliflozin in chronic HFrEF is larger than might be expected given this more modest reduction in NT-proBNP. Smaller reductions in NT-proBNP should not dissuade clinicians from starting and continuing patients on this highly effective and safe new therapy for chronic HF.

 

 

 

 

This article is reproduced from JACC journals.

 

 

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