Author + information
- Adriaan A. Voors, MD, PhD∗ ()
- ↵∗Address for correspondence:
Dr. Adriaan A. Voors, Department of Cardiology, University Medical Center Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.
“If I could but know his heart, everything would become easy.”
—Jane Austen, Sense and Sensibility, 1811 (1)
Natriuretic peptides are used in almost all contemporary heart failure (HF) trials as one of the main inclusion criteria. There are several reasons for this, some of which will be outlined here. On the 1 hand, a higher threshold for inclusion is thought to be better for many reasons. On the other hand, higher thresholds lead to poorer feasibility and applicability when applied in clinical studies. The paper by Savarese et al. (2) in this issue of JACC: Heart Failure provides additional data to support or contradict the reasons to use higher thresholds of natriuretic peptides in clinical trials.
Reason 1: Higher N-Terminal pro–B-Type Natriuretic Peptide Makes Heart Failure More Likely
From the beginning of this millennium, B-type natriuretic peptide (BNP) and N-terminal pro–BNP (NT-proBNP) have become cornerstones of the diagnosis of HF. At the optimal mathematical cutoff levels, their sensitivity is much higher than their specificity. The odds of having HF in subjects with a low NTproBNP or BNP is very low, but higher levels of NTproBNP or BNP can be caused by many factors other than HF alone. This implies that the use of NTproBNP or BNP can be particularly useful in ruling out HF and less useful for establishing a diagnosis of HF. Nevertheless, at very high levels, specificities of >90% can be achieved. Therefore, this first argument makes sense, although elevated NTproBNP or BNP should never be the sole criterion to establish the diagnosis of HF and should always be accompanied by additional criteria.
Reason 2: Patients With Higher NT-ProBNP Levels Have Higher Clinical Event Rates
The second major reason to include NTproBNP or BNP as an eligibility criterion in HF trials is to “enrich” the study group with those patients who will have a greater likelihood of reaching 1 of the primary or secondary endpoints. This is particularly useful in phase III trials, where a positive outcome can be achieved with a lower number of included patients. This argument is strongly supported by a large number of studies that have consistently shown that a higher level of NTproBNP or BNP was associated with a higher risk of both (cardiovascular [CV]) death and (HF) hospital admission, which are the most frequently used primary endpoints in phase III clinical HF trials. Interestingly, this holds true, irrespective of associated conditions. For example, natriuretic peptide levels are generally lower in patients with HF with preserved ejection fraction (HFpEF) compared with patients with HF with reduced ejection fraction (HFrEF), but given a certain level of NTproBNP or BNP, the risk of (CV) death and (HF) hospital admission is the same in patients with HFrEF and HFpEF (3). Similarly, natriuretic peptide levels are generally higher in patients with atrial fibrillation compared with patients in sinus rhythm, but given a certain level of NTproBNP or BNP, the risk of events is the same in patients with or without atrial fibrillation (4).
Reason 3: Higher NT-ProBNP Levels Will Yield a Higher Percentage of Cardiovascular Versus Noncardiovascular Events
In the majority of phase III HF trials, CV events are chosen as the primary endpoints. Therefore, the occurrence of CV events is of particular relevance, and patients who die of non-CV conditions cannot have a CV event anymore. Although it is well established that higher NTproBNP or BNP levels are associated with higher CV event rates, less is known about the power of NTproBNP or BNP to predict non-CV events. In addition, whether higher NT-proBNP levels are related to a higher contribution of CV events compared with non-CV events is less well known. Therefore, data from the Swedish Heart Failure registry, presented by Savarese et al. (2) in this issue of JACC: Heart Failure, are of particular relevance. From 51,060 patients, the investigators selected 15,849 patients with both hospitalized and outpatient HF with data available on left ventricular ejection fraction and NT-proBNP (2). These investigators showed that overall, higher levels of NT-proBNP were associated with a higher rate of both CV and non-CV events, but the ratio of CV to non-CV events increased with higher levels of NT-proBNP. However, Savarese et al. (2) found important differences according to left ventricular ejection fraction. In patients with HFrEF, CV events were more frequent than non-CV events irrespective of the level of NT-proBNP, with a very modest increase in the ratio of CV to non CV events with increasing NT-proBNP levels. In patients with HF with midrange ejection fraction (HFmrEF), the percentages of CV and non-CV events were similar in the lower NT-proBNP regions, but at higher than a NT-proBNP level of approximately 3,000 pg/ml, the ratio of CV to non-CV events steadily increased. In HFpEF, the percentage of non-CV events was even slightly higher in the low NT-proBNP regions, and only at a level higher than approximately 5,000 pg/ml did the CV events prevail. Therefore, in particular in HFpEF, the percentage of CV events will increase with higher levels of NT-proBNP, but only at very high thresholds.
Reason 4: Patients With higher NT-ProBNP levels Will Respond Better to Therapy
The second main aim of the present study by Savarese et al. (2) was to study the response to angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), and beta-blockers according to the levels of NT-proBNP. The general assumption is that patients with higher levels of NT-proBNP are sicker, and sicker patients will respond better to therapies. The same assumption was the backbone of the natriuretic peptide–-guided trials. Data from the Swedish Heart Failure registry showed that treatment with ACE inhibitors or ARBs was associated with a significant reduction in risk of CV events in HFrEF, HFmrEF, and HFpEF, but the level of NT-proBNP did not influence the treatment benefit. Beta-blockers were associated with improved CV outcomes in only patients with HFrEF and HFmrEF, but not HFpEF. Nevertheless, the beneficial effects of beta-blockers in HFrEF and HFmrEF were not influenced by the level of NT-proBNP. However, an observational resource such as the Swedish Heart Failure registry is not the best source to study such an association. Nevertheless, these results are supported by subgroup analyses from several phase III randomized clinical trials with ACE-inhibitors, ARBs, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor neprilysin inhibitors. Interestingly, in TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) (5) and I-PRESERVE (Irbesartan in Heart Failure With Preserved Systolic Function) (6), the benefits of spironolactone and irbesartan were significant in low NTproBNP or BNP but not in high NTproBNP or BNP. This implies that if patients have advanced HF (reflected by very high NT-proBNP levels), they may become “beyond repair” and are less likely to benefit from treatment. On the other side, patients without disease will not respond to therapy, either. Therefore, the middle range is probably the “sweet spot” of patients who are preferably included in clinical trials. This may also explain the disappointing results of natriuretic peptide–guided trials where only patients with higher NP levels are treated more intensively.
In summary, there are several valid reasons for using NTproBNP or BNP as an eligibility criterion in later phase clinical HF trials. First, using NTproBNP or BNP as a diagnostic criterion makes sense. However, given the better sensitivity than specificity, and because of the disadvantage of slower enrollment and poorer clinical applicability with higher thresholds, a low (rule-out) threshold in combination with other criteria to support the diagnosis of HF would be preferred. Second, using higher thresholds to enrich the study group with patients with more events is absolutely reasonable, even in light of the previously mentioned disadvantages. Third, on the basis of data reported by Savarese et al. (2), it probably does not make sense to use higher cutoffs to increase the ratio of CV to non-CV events. In HFrEF, there is no real issue because the majority of events are CV events anyway. In HFmrEF and HFpEF, using higher thresholds would increase the percentage of CV events, but only at very high NTproBNP or BNP levels. Finding such patients would become very difficult. Finally, the concept that patients with higher plasma NTproBNP or BNP levels respond better to HF therapy has its basis in a feeling that is not supported by the facts.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Voors has received consultancy fees from Amgen, Bayer, Boehringer Ingelheim, Merck/Merck Sharp & Dohme, Novartis, Roche Diagnostics, Sanofi, Servier, Stealth Peptides, Singulex, Sphingotec, Trevena, and Vifor; research grants from Boehringer Ingelheim and Roche Diagnostics; and research support from Singulex, Sphingotec, and Vifor.
- 2018 American College of Cardiology Foundation
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- Corresponding Author
- Reason 1: Higher N-Terminal pro–B-Type Natriuretic Peptide Makes Heart Failure More Likely
- Reason 2: Patients With Higher NT-ProBNP Levels Have Higher Clinical Event Rates
- Reason 3: Higher NT-ProBNP Levels Will Yield a Higher Percentage of Cardiovascular Versus Noncardiovascular Events
- Reason 4: Patients With higher NT-ProBNP levels Will Respond Better to Therapy